Clinical trial NCT03259308
Conditions: Ulcerative Colitis
Sponsor: Shire
Start date: 2017-12-05; Completion date: 2020-10-06
Enrollment: 279 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of SHP647 in inducing remission, based on composite score of patient-reported symptoms and centrally read endoscopy, in participants with moderate to severe ulcerative colitis (UC).

Detailed description:
27Mar2020: Enrollment of new patients into this study has been paused due to the COVID-19 situation. The duration of this pause is dependent on the leveling and control of the COVID-19 pandemic.

Arms: arm 1: Participants will receive 25 milligram (mg) of ontamalimab subcutaneous (SC) injection using a prefilled syringe (PFS) on Week 0, Week 4 and Week 8. arm 2: Participants will receive 75 mg of ontamalimab SC injection using PFS on Week 0, Week 4 and Week 8. arm 3: Participants will receive placebo matched to ontamalimab SC injection using PFS on Week 0, Week 4, and Week 8.
Interventions: intervention 1: Ontamalimab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 1 mL of ontamalimab sterile aqueous buffered solution at an appropriate concentration to provide the intended dose of drug (25 or 75 mg). intervention 2: Participants will receive 1 mL of sterile aqueous buffered solution.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT03259308 
 
Study Title:  
A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group 
Efficacy and Safety Study of SHP647 as Induction Therapy in Subjects with 
Moderate to Severe Ulcerative Colitis (FIGARO UC 302) 
 
Study Number:  
SHP647-302 
 
 
Protocol Version and Date:  
 
Original Protocol:  
06 Jul 2017 
Amendment 1:  
05 Sep 2018 
Amendment 2:  
11 Nov 2019 


PROTOCOL: SHP647-302
TITLE:
A Phase 3 Randomized, Double-blind, Placebo-controlled, 
Parallel-group Efficacy and Safety Study of SHP647 as Induction 
Therapy in Subjects with Moderate to Severe Ulcerative Colitis
(FIGARO UC 302)
DRUG:
SHP647
IND:
100,222
EUDRACT NO.:
2017-000572-28
SPONSOR:
Shire Human Genetic Therapies, Inc. ("Shire")
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
, MD, PhD
PROTOCOL 
HISTORY:
Original Protocol: 06 Jul 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.
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Protocol SHP647-302 
CONFIDENTIAL 
Page2 
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PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Date:
 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP647-302. 
Title: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and 
Safety Study of SHP64 7 as Induction Therapy in Subjects with Moderate to Severe Ulcerative 
Colitis (FIGARO UC 302). 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to pruticipate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with Intemational Council for Harmonisation guidelines on Good Clinical Practice 
and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
te1mination of my pruticipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely te1minate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: --------------------------------- Date: 
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or email the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to Shire Global Pharmacovigilance. Applicable fax numbers and 
email address can be found on the form (sent under separate cover). A copy of this form must
also be sent to the contract research organization (CRO)/Shire medical monitor by fax or email 
using the details below.
Fax
 (North America)
 (Global)
Email
For protocol- or safety-related issues, the investigator must contact the medical monitor via 
the appropriate regional safety hotline (24 hours):
North America:
PPD 24 Hour Safety Hotline: RTP 
; Wilmington 
PPD 24 Hour Safety Hotline Fax: RTP 
 or 
; 
Wilmington
 or 
Latin America:
PPD 24 Hour Safety Hotline: 
PPD 24 Hour Safety Hotline Fax: 
Europe, the Middle East, and Africa; and Asia-Pacific:
PPD 24 Hour Safety Hotline: 
PPD 24 Hour Safety Hotline Fax: 
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
Email Address
North and South America
European Union and Rest of World
Telephone number (provided for reference if needed):
Shire, Lexington, MA (USA)
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
TABLE OF CONTENTS.................................................................................................................5
LIST OF TABLES...........................................................................................................................9
LIST OF FIGURES .........................................................................................................................9
ABBREVIATIONS .......................................................................................................................10
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULE ....................................................................................................................21
1.
BACKGROUND INFORMATION.......................................................................................25
1.1
Indication and Current Treatment Options...............................................................25
1.2
Product Background and Clinical Information ........................................................25
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................26
2.1
Rationale for the Study.............................................................................................26
2.2
Study Objectives ......................................................................................................27
2.2.1
Primary Objective..................................................................................................27
2.2.2
Secondary Objectives.............................................................................................27
2.2.3
Exploratory Objectives ..........................................................................................28
3.
STUDY DESIGN ...................................................................................................................29
3.1
Study Design and Flow Chart ..................................................................................29
3.1.1
Rationale for Primary Endpoint.............................................................................31
3.1.2
Rationale for Key Secondary Endpoints................................................................31
3.2
Duration and Study Completion Definition .............................................................32
3.3
Sites and Regions .....................................................................................................32
4.
STUDY POPULATION.........................................................................................................33
4.1
Inclusion Criteria......................................................................................................33
4.2
Exclusion Criteria.....................................................................................................34
4.3
Restrictions...............................................................................................................38
4.4
Reproductive Potential .............................................................................................38
4.4.1
Contraceptive Methods for Female Study Subjects...............................................39
4.4.2
Contraceptive Methods for Male Study Subjects ..................................................39
4.5
Withdrawal of Subjects ............................................................................................40
4.5.1
Subject Withdrawal Criteria ..................................................................................40
4.5.2
Reasons for Withdrawal.........................................................................................41
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................41
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5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................42
5.1
Prior Treatment ........................................................................................................42
5.2
Concomitant Treatment............................................................................................42
5.2.1
Permitted Treatment...............................................................................................42
5.2.2
Prohibited Treatment .............................................................................................43
5.2.3
Rescue Therapy......................................................................................................43
6.
INVESTIGATIONAL PRODUCT ........................................................................................44
6.1
Identity of Investigational Product...........................................................................44
6.1.1
Blinding the Treatment Assignment......................................................................44
6.2
Administration of Investigational Product ...............................................................44
6.2.1
Interactive Response Technology for Investigational Product Management ........44
6.2.2
Allocation of Subjects to Treatment ......................................................................44
6.2.3
Dosing....................................................................................................................45
6.2.4
Unblinding the Treatment Assignment..................................................................45
6.3
Labeling, Packaging, Storage, and Handling ...........................................................46
6.3.1
Labeling .................................................................................................................46
6.3.2
Packaging...............................................................................................................46
6.3.3
Storage ...................................................................................................................46
6.3.4
Special Handling....................................................................................................47
6.4
Drug Accountability.................................................................................................47
6.5
Subject Compliance..................................................................................................48
7.
STUDY PROCEDURES........................................................................................................49
7.1
Study Schedule.........................................................................................................49
7.1.1
Screening Period....................................................................................................49
7.1.2
Treatment Period....................................................................................................50
7.1.3
Follow-up Period: Visits 7 and 8 (Weeks 20 and 28)............................................50
7.1.4
Additional Care of Subjects after the Study ..........................................................51
7.2
Study Evaluations and Procedures ...........................................................................51
7.2.1
Demographic and Other Baseline Characteristics .................................................51
7.2.2
Efficacy..................................................................................................................52
7.2.3
Safety .....................................................................................................................54
7.2.4
Others.....................................................................................................................59
7.2.5
Volume of Blood to Be Drawn from Each Subject ...............................................62
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................63
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................63
8.1.1
Severity Categorization..........................................................................................63
8.1.2
Relationship Categorization...................................................................................64
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8.1.3
Outcome Categorization ........................................................................................64
8.1.4
Symptoms of the Disease Under Study .................................................................64
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................65
8.1.6
Pregnancy...............................................................................................................65
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................66
8.2
Serious Adverse Event Procedures ..........................................................................66
8.2.1
Reference Safety Information................................................................................66
8.2.2
Reporting Procedures.............................................................................................66
8.2.3
Serious Adverse Event Definition .........................................................................67
8.2.4
Serious Adverse Event Collection Time Frame.....................................................67
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................68
8.2.6
Fatal Outcome........................................................................................................68
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................68
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................69
9.1
Data Collection.........................................................................................................69
9.2
Clinical Data Management.......................................................................................69
9.3
Data Handling Considerations..................................................................................69
9.4
Statistical Analysis Process......................................................................................69
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......70
9.6
Sample Size Calculation and Power Considerations................................................70
9.7
Study Population ......................................................................................................71
9.8
Efficacy Analyses.....................................................................................................72
9.8.1
Primary Efficacy Endpoint ....................................................................................72
9.8.2
Secondary Efficacy Endpoints...............................................................................75
9.8.3
Exploratory Efficacy Endpoints.............................................................................77
9.9
Safety Analyses........................................................................................................77
9.10
Other Analyses .........................................................................................................78
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................79
10.1
Sponsor’s Responsibilities .......................................................................................79
10.1.1 Good Clinical Practice Compliance.......................................................................79
10.1.2 Indemnity/Liability and Insurance.........................................................................79
10.1.3 Public Posting of Study Information......................................................................79
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................79
10.1.5 Study Suspension, Termination, and Completion..................................................80
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10.2
Investigator’s Responsibilities .................................................................................80
10.2.1 Good Clinical Practice Compliance.......................................................................80
10.2.2 Protocol Adherence and Investigator Agreement..................................................80
10.2.3 Documentation and Retention of Records.............................................................81
10.3
Ethical Considerations..............................................................................................82
10.3.1 Informed Consent...................................................................................................82
10.3.2 Institutional Review Board or Ethics Committee..................................................83
10.4
Privacy and Confidentiality......................................................................................83
10.5
Study Results/Publication Policy .............................................................................84
11. REFERENCES .......................................................................................................................86
12. APPENDICES ........................................................................................................................88
Appendix 1
Protocol History .....................................................................................88
Appendix 2
Scales and Assessments .........................................................................89
Appendix 3
Glucocorticoid Equivalent Doses.........................................................121
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LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................21
Table 2
Common Excluded Treatments .....................................................................43
Table 3
Quarterly Neurological Assessments ............................................................54
Table 4
Volume of Blood to Be Drawn from Each Subject.......................................62
Table 5
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints.....................................................................................71
LIST OF FIGURES
Figure 1
Overview of SHP647 Phase 3 Studies in Ulcerative Colitis.........................30
Figure 2
Study Design Flow Chart ..............................................................................31
Figure 3
Flow Diagram for Quarterly Neurological Assessments...............................55
Figure 4
Visualization of Alpha Propagation ..............................................................74
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ABBREVIATIONS
5-ASA
5-aminosalicylic acid
AE
adverse event
ADA
anti-drug antibodies
CI
confidence interval
CMH
Cochran-Mantel Haenszel
CNS
central nervous system
CRO
contract research organization
DMC
data monitoring committee
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic case report form
e-diary
electronic diary
EMA
European Medicines Agency
ET
Early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FWER
family-wise type I error rate
GCP
Good Clinical Practice
GI
gastrointestinal
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HEENT
head, eyes, ears, nose, and throat
HRQL
health-related quality of life
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Council for Harmonisation
IGRA
interferon gamma release assay
IRB
Institutional Review Board
IRT
interactive response technology
LTS
long-term safety extension
MAdCAM
mucosal addressin cell adhesion molecule
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PFS
prefilled syringe
PGA
physician global assessment
PML
progressive multifocal leukoencephalopathy
PRC
polymerase chain reaction
Q4W
once every 4 weeks
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SF-36
Short Form-36 
TB
tuberculosis
TEAE
treatment-emergent AE
TNF
tumor necrosis factor
UC
ulcerative colitis
US
United States
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STUDY SYNOPSIS
Protocol number: SHP647-302
Drug: SHP647
Title of the study: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety 
Study of SHP647 as Induction Therapy in Subjects with Moderate to Severe Ulcerative Colitis (FIGARO UC 302)
Number of subjects (total and for each treatment arm):
A total of 825 subjects (330 subjects at 25 mg SHP647, 330 subjects at 75 mg SHP647, and 165 placebo subjects) 
are planned for enrollment into the study.
Investigator(s): Multicenter study.
Site(s) and Region(s):
It is anticipated that the study will be conducted in at least 18 countries. Regions will include North America 
Europe, the Middle East, and Africa, Latin America, and Asia-Pacific. Approximately 175 sites will be utilized.
Study period (planned):
2017 to 2020
Clinical phase:
3
Objectives:
Primary: To evaluate the efficacy of SHP647 in inducing remission, based on composite score of patient-reported 
symptoms and centrally read endoscopy, in subjects with moderate to severe ulcerative colitis (UC).
Key Secondary:

To evaluate the efficacy of SHP647 in achieving endoscopic remission, based on centrally read 
endoscopy.

To evaluate the efficacy of SHP647 in achieving clinical remission, based on composite score of 
patient-reported symptoms.

To evaluate the efficacy of SHP647 in inducing clinical response, based on composite score of 
patient-reported symptoms and centrally read endoscopy.

To evaluate the efficacy of SHP647 in achieving mucosal healing, based on endoscopic and histological 
assessment.
Other Secondary:

To evaluate the safety and tolerability of SHP647.

To evaluate the effect of SHP647 induction treatment on other clinical outcomes.

To evaluate the effect of SHP647 on abdominal pain, urgency, diarrhea, and absolute stool frequency and 
bleeding scores.

To evaluate the effect of SHP647 on health-related quality of life.

To evaluate the effect of SHP647 on incidence of hospitalizations and total inpatient days.
Rationale:
This study is designed to evaluate the efficacy of SHP647 in inducing remission in subjects with moderate to 
severe UC.
SHP647 has been investigated in 2 completed dose-finding studies (A7281001 and A7281009) in subjects with 
moderate to severe UC; a third study (A7281010), an open-label long-term safety extension study, is ongoing. The 
Phase 1 study, A7281001, which investigated the safety, tolerance, pharmacokinetics, and pharmacodynamic 
properties of SHP647, supports further clinical development of SHP647 using subcutaneous (SC) administration. 
Therefore, SC doses of 25 mg or 75 mg of SHP647 or placebo on Day 1 (Week 0), Week 4, and Week 8 are 
recommended for the Phase 3 studies SHP647-301 and SHP647-302.
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Investigational product, dose, and mode of administration:
The test product is SHP647, which will be provided as a sterile aqueous buffered solution for SC administration in 
a glass prefilled syringe (PFS) with a fixed needle. Each PFS contains 1 mL of SHP647 solution at an appropriate 
concentration to provide the intended dose of drug (25 or 75 mg). Additional information is provided in the current 
SHP647 investigator’s brochure.
The reference product is placebo, which will be provided in a PFS with a fixed needle containing 1 mL of placebo 
solution for SC administration. The placebo solution will contain the same sterile aqueous buffered solution as the 
test product but will not contain SHP647.
Methodology:
A total of 825 subjects (330 subjects at 25 mg SHP647, 330 subjects at 75 mg SHP647, and 165 placebo subjects) 
are planned for enrollment into the study. Subjects must be at least 16 years of age and no more than 80 years of 
age at the time of signing the informed consent/assent form.
The study consists of a screening period up to 6 weeks and a 12-week treatment period. After the screening period, 
eligible subjects will be randomly assigned to receive 1 of 3 treatments (25 mg SHP647, 75 mg SHP647, or 
placebo) in a 2:2:1 ratio. Randomization will be stratified based upon the subject’s status of prior anti-TNF (tumor 
necrosis factor) treatment (naïve or experienced) and glucocorticoid use at baseline (on glucocorticoids at baseline 
versus not on glucocorticoids at baseline). Subjects will receive SC injections of SHP647 or placebo, using a PFS, 
on Week 0/Day 1 (Visit 2), Week 4 (Visit 4), and Week 8 (Visit 5). Subjects will undergo efficacy, 
 
 safety, and health outcome assessments at these visits.
Patient-reported UC signs and symptom data (including stool frequency, rectal bleeding severity and frequency, 
diarrhea frequency, urgency frequency, and abdominal pain worst severity) will be collected using a daily 
electronic diary (e-diary) during the treatment period. The Mayo score is a measure of UC disease activity
consisting of the following 4 subscores: stool frequency, rectal bleeding, findings of endoscopy, and physician 
global assessment (PGA). The partial Mayo score consists of the Mayo score without the endoscopic subscores.
The composite score is a recommended measure consisting of the Mayo score without the PGA subscore, and will 
be used for the primary efficacy endpoint. The Mayo scores and composite score will be based on subject daily e-
diary entries.
At the end of the 12-week treatment period, eligible subjects will be offered the opportunity to participate in a 
double-blind maintenance study (SHP647-303; for subjects who achieve clinical response) or a long-term safety 
extension (LTS) study (SHP647-304; for subjects who do not achieve a clinical response). Subjects who withdraw 
early from the 12-week treatment period or who do not wish to enter the maintenance study (SHP647-303) or LTS 
study (SHP647-304) will continue into a 16-week safety follow-up period. Only those subjects who complete the 
full course of investigational product treatment in the induction studies (SHP647-301 or SHP647-302) will be 
eligible to continue in the maintenance study or LTS study.
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Inclusion and exclusion criteria:
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study.
1.
Subjects and/or their parent or legally authorized representative must have an understanding, ability, and 
willingness to fully comply with study procedures and restrictions.
2.
Subjects must be able to voluntarily provide written, signed, and dated (personally or via a legally authorized 
representative) informed consent and/or assent, as applicable, to participate in the study.
3.
Subjects must be between ≥16 and ≤80 years of age at the time of the signing of the informed consent/assent 
form.
NOTE: Subjects <18 years of age must weigh ≥40 kg and must have body mass index (BMI) ≥16.5.
4.
Subjects must have a documented diagnosis (radiologic or endoscopic with histology) of UC for ≥3 months
before screening. The following must be available in each subject’s source documentation:

A biopsy report to confirm the histological diagnosis.

A report documenting disease duration based upon prior colonoscopy.
NOTE: If this documentation is not available at the time of screening, a colonoscopy with biopsy to 
confirm the diagnosis is required during the screening period.
5.
Subjects must be willing to undergo a flexible sigmoidoscopy or colonoscopy (if preferred), including biopsy 
sample collection, during screening after all other inclusion criteria have been met.
6.
Subjects must have moderate to severe active UC, defined as a total Mayo score of ≥6, including a 
centrally read endoscopic subscore ≥2, rectal bleeding subscore ≥1, and stool frequency subscore ≥1 at 
baseline (Visit 2).
7.
Subjects must have evidence of UC extending proximal to the rectum (ie, not limited to proctitis).
8.
Subjects must have had an inadequate response to, or lost response to, at least 1 conventional treatment such as 
mesalamine (5-aminosalicylic acid [5-ASA]), glucocorticoids, immunosuppressants (azathioprine [AZA], 
6-mercaptopurine [6-MP], or methotrexate [MTX]), or anti-TNF.
9.
Subjects receiving any treatment(s) for UC described in Section 5.2.1 of the protocol are eligible provided they
have been, and are anticipated to be, on a stable dose for the designated period of time.
10. Subjects are males or nonpregnant, nonlactating females who, if sexually active, agree to comply with the 
contraceptive requirements of the protocol, or females of nonchildbearing potential. Males and females of 
reproductive potential who are sexually active must agree to use acceptable contraception for the duration of 
the study.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Subjects with indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or 
clinical/histologic findings suggestive of Crohn’s disease.
2.
Subjects with colonic dysplasia or neoplasia. (Subjects with prior history of adenomatous polyps will be 
eligible if the polyps have been completely removed.)
3.
Subjects with past medical history or presence of toxic megacolon.
4.
Subjects with colonic stricture, past medical history of colonic resection, a history of bowel surgery within 
6 months before screening, or who are likely to require surgery for UC during the treatment period.
5.
Subjects at risk for colorectal cancer must have a colonoscopy performed during the screening period with 
results available within 10 days before the baseline visit (Visit 2), unless the subject has had a colonoscopy 
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within 1 year prior to screening, and any adenomatous polyps found at that examination have been excised. 
Colonoscopy report and pathology report (if biopsies are obtained) from the colonoscopy performed during 
screening or in the prior year must be available in the source documents.
Subjects at risk for colorectal cancer include, but are not limited to:

Subjects with extensive colitis for ≥8 years or disease limited to left side of colon (ie, distal to splenic 
flexure) for ≥10 years before screening, regardless of age.

Subjects ≥50 years of age at the time of signing of the informed consent form.
6.
Subjects have had prior treatment with SHP647 (formerly PF-00547659).
7.
Subjects with known or suspected intolerance or hypersensitivity to the investigational product(s), closely 
related compounds, or any of the stated ingredients.
8.
Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2).
9.
Subjects have received any biologic with immunomodulatory properties (other than anti-TNFs) within 
90 days before baseline (Visit 2).
10.
Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion molecule).
11.
Subjects have received parenteral or rectal glucocorticoids, or rectal 5-ASA, within 14 days before screening 
endoscopic procedure.
12.
Subjects have participated in other investigational studies within either 30 days or 5 half-lives of 
investigational product used in the study (whichever is longer) before baseline (Visit 2).
13.
Subjects have received a live (attenuated) vaccine within 30 days before the baseline visit (Visit 2).
14.
Subjects with active enteric infections (positive stool culture and sensitivity), Clostridium difficile infection or 
pseudomembranous colitis [subjects with C. difficile infection at screening may be allowed re-test after 
treatment], evidence of active cytomegalovirus infection or Listeria monocytogenes, known active invasive 
fungal infections such as histoplasmosis or parasitic infections, clinically significant underlying disease that 
could predispose the subjects to infections, or a history of serious infection (requiring parenteral antibiotic 
and/or hospitalization) within 4 weeks before the baseline visit (Visit 2).
15.
Subjects with abnormal chest x-ray findings at screening (Visit 1), such as presence of active tuberculosis 
(TB), general infections, heart failure, or malignancy. (A chest x-ray performed up to 12 weeks before study 
entry [screening, Visit 1] may be used if available; documentation of the official reading must be located and 
available in the source documentation.)
16.
Subjects with evidence of active or latent infection with Mycobacterium tuberculosis (TB) who have not 
completed a generally accepted full course of treatment before randomization are excluded. All other subjects 
must have either the Mantoux (purified protein derivative [PPD]) tuberculin skin test or interferon gamma 
release assay (IGRA) performed.
Subjects who have no history of previously diagnosed active or latent tuberculosis are excluded if they have a 
positive Mantoux (PPD) tuberculin skin test (ie ≥5 mm induration) or a positive IGRA (the latter to be tested 
at the site’s local laboratory) during screening or within 12 weeks before randomization. If IGRA test cannot 
be performed locally, a central laboratory may be used, with prior agreement from the sponsor.

An IGRA is strongly recommended for subjects with a prior Bacillus Calmette-Guérin (BCG) 
vaccination, but may be used for any subject. Documentation of IGRA product used and the test result 
must be in the subject's source documentation if performed locally. Acceptable IGRA products include 
Quantiferon TB Gold In-Tube Test.

If the results of the IGRA are indeterminate, the test may be repeated, and if a negative result is obtained, 
enrollment may proceed. In subjects with no history of treated active or latent tuberculosis, a positive test 
on repeat will exclude the subject. Subjects with a history of active or latent tuberculosis infection must 
follow instructions for “Subjects with a prior diagnosis of active or latent tuberculosis are excluded unless 
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both of the following criteria are met” in this criterion.

Subjects with repeat indeterminate IGRA results, with no prior TB history, may be enrolled after 
consultation with a pulmonary or infectious disease specialist who determines low risk of infection 
(ie, subject would be acceptable for immunosuppressant [eg, anti-TNF] treatment without additional 
action). This consultation must be included in source documentation.
Results from a chest x-ray, taken within the 3 months before or during screening (Visit 1) must show no 
abnormalities suggestive of active TB infection as determined by a qualified medical specialist.
Subjects with a prior diagnosis of active or latent tuberculosis are excluded unless both of the following 
criteria are met:

The subject has previously received an adequate course of treatment for either latent (eg, 9 months of 
isoniazid or an acceptable alternative regimen, in a locale where rates of primary multidrug TB resistance 
are <5%. Subjects from regions with higher rates of primary multidrug TB resistance are excluded) or 
active (acceptable multidrug regimen) TB infection. Evidence of diagnosis and treatment must be 
included in source documentation. Consultation with a pulmonary or infectious disease specialist to 
confirm adequate treatment (ie, subject would be acceptable for immunosuppressant [eg, anti-TNF] 
treatment without additional action) must be performed during the screening period. The consultation 
report must be included in source documentation prior to enrollment.

A chest x-ray performed within 3 months prior to screening (Visit 1) or during screening (Visit 1)
indicates no evidence of active or recurrent disease, and documentation of interpretation by a qualified 
medical specialist must be included in source documentation.
17.
Subjects with a pre-existing demyelinating disorder such as multiple sclerosis or new onset seizures, 
unexplained sensory motor, or cognitive behavioral, neurological deficits, or significant abnormalities noted 
during screening.
18.
Subjects with any unexplained symptoms suggestive of progressive multifocal leukoencephalopathy (PML) 
based on the targeted neurological assessment during the screening period.
19.
Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed.
20.
Subjects with a significant concurrent medical condition at the time of screening (Visit 1) or baseline 
(Visit 2), including, but not limited to, the following:

Any major illness/condition or evidence of an unstable clinical condition (eg, renal, hepatic, hematologic, 
gastrointestinal (except disease under study), endocrine, cardiovascular, pulmonary, immunologic [eg, 
Felty’s syndrome], or local active infection/infectious illness) that, in the investigator’s judgment will 
substantially increase the risk to the subject if he or she participates in the study.

Cancer or history of cancer or lymphoproliferative disease within the previous 5 years (other than resected 
cutaneous basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the uterine cervix that 
has been treated with no evidence of recurrence).

Presence of acute coronary syndrome (eg, acute myocardial infarction, unstable angina pectoris) within 
24 weeks before screening.

History of significant cerebrovascular disease within 24 weeks before screening.
21.
Subjects who have had significant trauma or major surgery within 4 weeks before the screening visit (Visit 1), 
or with any major elective surgery scheduled to occur during the study.
22.
Subjects with evidence of or suspected liver disease, liver injury due to methotrexate or primary sclerosing 
cholangitis.
23.
Subjects with evidence of positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). 
NOTE: if a subject tests negative for HBsAg, but positive for HBcAb, the subject would be considered 
eligible if the subject tests positive for antibody to Hepatitis B surface antigen (HBsAb also referred as 
anti-HBsAg) reflex testing.
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24.
Subjects with positive hepatitis C antibody (HCVAb) with confirmation by HCV-ribonucleic acid (RNA)
polymerase chain reaction (PCR) reflex testing.
25.
Subjects with any of the following abnormalities in hematology and/or serum chemistry profiles during 
screening. NOTE: Screening laboratory tests, if the results are considered by the investigator to be transient 
and inconsistent with the subject’s clinical condition, may be repeated once during the screening period for 
confirmation. Results must be reviewed for eligibility prior to the screening endoscopy procedure.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 2.0 times the upper limit 
of normal (ULN).

Total bilirubin level 1.5 times the ULN (except in subjects with documented diagnosis of Gilbert’s 
syndrome).

Hemoglobin level 80 g/L (8.0 g/dL).

Platelet count 100 × 109/L (100,000 cells/mm3) or 1000 × 109/L (1,000,000 cells/mm3).

White blood cell count 3.5 × 109/L (3500 cells/mm3).

Absolute neutrophil count (ANC) <2000 cells/mm3.

Serum creatinine level 177 mol/L (2 mg/dL) or estimated glomerular filtration rate (GFR) 
<40 ml/min/1.73m2 based on the abbreviated MDRD.
26.
Subjects with known infection with human immunodeficiency virus (HIV).
27.
Subjects who have, or who have a history of (within 2 years before screening [Visit 1]), serious psychiatric 
disease, alcohol dependency, or substance/drug abuse.
28.
Subjects using medicinal marijuana (cannabis) or related products for recreational purposes who have a 
known dependency per the criteria in the Diagnostic and Statistical Manual of Mental Disorders, Edition 5 
(including urine drug screen and medical history). Exceptions are those subjects who are prescribed 
marijuana (by a physician) for medicinal use and where the product is sourced from a licensed 
pharmacy/provider. Such subjects must be using the product, in a stable regimen, for at least 3 months before 
screening.
29.
Subjects with any other severe acute or chronic medical or psychiatric condition or laboratory or 
electrocardiogram (ECG) abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this study.
30.
Female subjects who are planning to become pregnant during the study period.
31.
Male subjects who are planning to donate sperm must agree not to do so for the duration of the study and 
through 16 weeks after last dose of investigational product.
32.
Subjects who are investigational site staff members or relatives of those site staff members or subjects who 
are Shire employees directly involved in the conduct of the study.
Maximum duration of subject involvement in the study:

Planned duration of screening period: Up to 6 weeks

Planned duration of treatment period: 12 weeks

Planned duration of follow-up period: 16 weeks
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Endpoints and statistical analysis:
Analysis Sets:
The screened set will consist of all subjects who have signed an informed consent document.
The randomized set will consist of all subjects in the screened set for whom a randomization number has been 
assigned.
The safety set will consist of all subjects who have received at least 1 dose of investigational product.
The full analysis set (FAS) will consist of all subjects in the randomized set who have received at least 1 dose of 
investigational product.
The per-protocol (PP) set will consist of all subjects in the FAS who complete the Week 12 visit and who do not 
have predefined protocol deviations that may affect the primary efficacy endpoint.
The completer set will consist of all subjects in the FAS who have completed the final scheduled primary 
assessment for this study.
 
 
Primary Efficacy Endpoint: The primary efficacy endpoint is the proportion of subjects in remission at the 
Week 12 visit. Remission is defined as a composite score of patient-reported symptoms using daily e-diary and 
centrally read endoscopy as follows:

stool frequency subscore of 0 or 1 with at least a 1-point change from baseline
AND

rectal bleeding subscore of 0
AND

endoscopic subscore of 0 or 1 (modified, excludes friability).
The primary efficacy endpoint will be compared for each active treatment group (25 mg or 75 mg SHP647) to the 
placebo group using a Cochran-Mantel Haenszel (CMH) chi-square test stratified by status of prior anti-TNF
treatment and glucocorticoid use at baseline (Visit 2). Subjects with missing remission data at the Week 12 visit 
will be considered failures and counted as nonresponders. The endoscopy score will be based on centrally read 
results.
The primary endpoint will be tested by the following hypothesis:
H0: δ = 0
H1: δ ≠ 0
Where δ is the common treatment difference across strata, j=1 to m. The common treatment difference is a 
weighted average of the stratum-specific treatment differences.
The global family-wise type I error rate (FWER) for the statistical tests of the primary and key secondary 
endpoints will be strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in Bretz, 
et al 2009 will be utilized to propagate α from primary to key secondary endpoints and between the two SHP647 
treatment group and placebo comparisons. Alpha is initially split equally at the .025 level (2-sided) for each of the 
pairwise treatment comparisons for the primary endpoint (P) and alpha is propagated in a hierarchical manner to 
each of the 4 key secondary endpoints (K1-K4) within a pairwise treatment comparison.
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Key Secondary Efficacy Endpoints:

Proportion of subjects with endoscopic remission, as defined by centrally read endoscopic subscore 0 or 1 
(modified, excludes friability), at the Week 12 visit.

Proportion of subjects with clinical remission, as defined by stool frequency subscore of 0 or 1 with at least a 
1-point change from baseline in stool frequency subscore, and rectal bleeding subscore of 0, at the Week 12 
visit.

Proportion of subjects with clinical response based on composite score at the Week 12 visit. Clinical response 
(composite) is defined as a decrease from baseline in the composite score of patient-reported symptoms using 
daily e-diary and centrally read endoscopy of at least 2 points and at least 30%, with an accompanying 
decrease in the subscore for rectal bleeding ≥1 point or a subscore for rectal bleeding ≤1.

Proportion of subjects with mucosal healing based on endoscopic and histological assessment at the Week 12 
visit. Mucosal healing is defined by centrally read endoscopic subscore 0 or 1 (modified, excludes friability) 
and centrally read Geboes score of ≤2.
The key secondary endpoints will be analyzed using the same approach as described for the primary efficacy 
endpoint. Subjects with missing key secondary endpoint data at the Week 12 visit will be considered failures and 
counted as nonresponders.
Other Secondary Efficacy Endpoints:

Proportion of subjects with remission, defined as a total Mayo score ≤2 with no individual subscore (stool 
frequency, rectal bleeding, endoscopy [modified, excludes friability], and physician’s global assessment) 
exceeding 1, at the Week 12 visit.

Proportion of subjects with clinical response based on total Mayo score at the Week 12 visit. Clinical response 
(Mayo) is defined as a decrease from baseline in the total Mayo score of at least 3 points and at least 30%, 
with an accompanying decrease in the subscore for rectal bleeding ≥1 point or an absolute subscore for rectal 
bleeding ≤1.

Proportion of subjects with partial Mayo score ≤2 with no individual subscore >1 at the Week 4, 8, and 12 
visits. The partial Mayo score does not include the endoscopy subscore.

Proportion of subjects with clinical remission as defined by stool frequency subscore of 0 or 1 with at least a 
1-point change from baseline in stool frequency subscore, and rectal bleeding subscore of 0, at Weeks 4 and 8.

Proportion of subjects with endoscopic remission at the Week 12 visit with endoscopic subscore of 0.

Proportion of subjects with clinical remission at the Week 4, 8, and 12 visits with both rectal bleeding and 
stool frequency subscores of 0.

Proportion of subjects with deep remission at the Week 12 visit. Deep remission is defined as both endoscopic 
and rectal bleeding subscores of 0, and stool frequency subscore ≤1 and a centrally read Geboes score of ≤2.

Change from baseline at the Week 12 visit in abdominal pain, diarrhea and urgency item scores, absolute stool 
frequency, absolute rectal bleeding and total sign/symptom score based on subject daily e-diary entries (sum of 
rectal bleeding, stool frequency, abdominal pain, diarrhea, and urgency).

Change from baseline in IBDQ domain and total (absolute) scores (time frame: Week 0, Week 8, up to 
Week 12, or early termination).

Change from baseline in Short Form-36 (SF-36), version 2, acute (physical and mental component summary 
scores and individual domain scores) to the Week 12/ET visit.

Incidence of all-cause hospitalizations and total inpatient days.
Other secondary/exploratory endpoints will be summarized by descriptive statistics and presented by treatment 
group. Where appropriate, other secondary efficacy endpoints will be analyzed with the following analysis 
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methods.

Binary endpoints will be analyzed using the same approach as described for the primary endpoint. Subjects 
with missing binary endpoint data at a visit will be considered failures and counted as nonresponders.

Continuous endpoints that are only measured at baseline and the Week 12 visit will be analyzed using an 
analysis of covariance (ANCOVA) model with fixed effects for treatment group (categorical), status of prior 
anti-TNF treatment (categorical), and glucocorticoid use at baseline (categorical), and the baseline value as a 
continuous covariate. From this model, estimates of the least squares means, treatment differences, standard 
errors, p-values, and 95% confidence intervals (CIs) for least squares mean treatment differences will be 
provided.

Continuous endpoints that are measured repeatedly over time will be analyzed using a linear repeated 
measures mixed model with restricted maximum likelihood estimation (REML). The model will include fixed 
effects for treatment group (categorical), visit (categorical), treatment group by visit interaction, status of prior 
anti-TNF treatment (categorical), and glucocorticoid use at baseline (categorical); baseline value as a 
continuous covariate; and repeated measures across visit for subject. From this model, estimates of least 
squares means, treatment differences, standard errors, p-values, and 95% CIs for least squares mean treatment 
differences for each visit will be provided.
Safety Analyses:
All safety analyses will be performed using the safety set. Subjects will be analyzed according to the treatment they 
actually received.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates at the time of or following the first exposure 
to investigational product. The number of events, incidence, and percentage of TEAEs will be calculated overall, 
by system organ class, by preferred term, and by treatment group. Treatment-emergent AEs will be further 
summarized by severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group and visit. 
Potentially clinically important findings will also be summarized or listed.
Antidrug antibody data will be summarized by treatment group and visit.
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STUDY SCHEDULE
Table 1
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
Informed consent/assent
X
Eligibility assessment
X
X
Xe
Demographics and medical historyf
X
Complete physical examinationg
X
X
X
Targeted physical examinationg
X
Targeted neurological assessmenth
X
X
X
Vital signsi
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
12-lead ECGi
X
X
X
Chest x-rayj
X
Contraception checkk
X
X
X
X
X
X
X
Laboratory Assessments
Hematology
Xl
X
X
X
X
X
Serum chemistry
Xl
X
X
X
X
X
Urinalysis
Xl
X
X
X
X
X
Stool microbiologym
Xl
HBsAg, HBcAb, HCV Abn
Xl
FSHo
Xl
Serum β–hCGp
Xl
Urine β–hCGp
X
X
X
X
X
TB test (PPD or QuantiFERON TB Gold)q
Xl
JCV antibody banked sampler
X
X
X
X
Xs
Xs
X
Xs
Xs
X
 
Xs
Xs
X
Xt
Xt
Xt
Xt
X
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Table 1
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
ADA and NAb sampling
Xs
X
Xs
Xs
X
X
Endoscopic Procedure
Endoscopy (including biopsy)u
Xu
X
UC Assessments
Total Mayo score
Xv
Xv
Partial Mayo score
X
X
Remission stool frequency and pre-UC stool 
frequencyw
X
PRO UC daily e-diary data instruction
X
PRO UC daily e-diary dataw
X
X
X
X
X
X
X
Health Assessmentx
IBDQ
X
X
X
X
X
X
Hospitalizations, inpatient days, 
(HRUA)
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36 v2, acute form
X
X
X
X
X
Treatment Procedures
Randomizationy
X
Administration of SHP647 or placeboy
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Concomitant medications and procedures
X
X
X
X
X
X
X
X
X
Dispense stool collection kit for stool samplez
X
X
X
Ab=antibody ADA=antidrug antibodies; β–hCG=beta-human chorionic gonadotropin; 
; ECG=electrocardiogram; ED=emergency department; 
; ET=early termination; FSH=follicle-stimulating hormone; GDH=glutamate dehydrogenase; 
HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; HRUA=Healthcare Resource Utilization Assessment; HCV=hepatitis C virus; HCV RNA=hepatitis C 
virus ribonucleic acid; HEENT=head, eyes, ears, nose, and throat; IBDQ=Inflammatory Bowel Disease Questionnaire; JCV=John Cunningham virus; LTS=long-term safety 
extension; 
; Nab=neutralizing antibody; PCR=polymerase chain reaction; PGA = physician’s global assessment;
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Table 1
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
 
 
; PML=progressive multifocal leukoencephalopathy; 
PPD=purified protein derivative; PRO=patient-reported outcomes; SF-36 v2= short form-36 health survey, version 2; TB=tuberculosis; 
 
; UC=ulcerative colitis; 
a
At least 2 visits will be necessary to complete the screening procedures, including endoscopy.
b
Subjects who withdraw early during the treatment period should return for the early termination (ET) visit and then enter into the safety follow-up period.
c
Participation in the safety follow-up period is not required if subject is entering the maintenance study (SHP647-303) or LTS (SHP647-304) at the completion of the Week 12 
visit. For subjects participating in the 16-week safety follow-up period (not entering the maintenance study or LTS study), the Week 20 (Visit 7) visit will routinely be 
conducted by telephone; however, as an exception the visit can be performed as a study site visit if preferred. The Week 28 (Visit 8) visit will be at the study site.
d
Part 1 of Visit 6 should be scheduled preferably within 5 to 7 days before Part 2 visit; this will allow sufficient time for data from the centrally read endoscopy to be available
at Part 2 of the visit.
e
The outcome of Visit 6, Part 2 is used to assess eligibility to enroll in the maintenance (SHP647-303) or LTS (SHP647-304) studies. Eligibility for SHP647-303 and 
SHP647-304 will be assessed under those respective protocols.
f
Medical history will include UC history, cardiac history, and smoking history.
g
Complete physical examination includes the review of the following body systems: general appearance, skin, HEENT, heart, lungs, confrontational visual fields (eyes), breast 
(optional), abdomen, external genitalia (optional), extremities, neurologic function, back, and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin, heart, lungs, confrontational visual fields (eyes), abdomen, and examination of body systems where there are symptom complaints by the 
subject.
h
Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, speech, 
verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of PML should be excluded. See Section 7.2.3.3 for 
further details.
i
Vital signs (including blood pressure, pulse, respiratory rate, and temperature) and 12-lead ECG should be performed before collection of blood samples for laboratory 
assessments and before endoscopic procedure.
j
A chest x-ray performed up to 12 weeks before screening (Visit 1) may be used if available; the official reading must be located in the subject’s source documentation.
k
Contraception check should be performed for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential. See Section 4.4 for 
further details.
l
Screening laboratory test results, if considered by the investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated once during the 
screening period for confirmation. Results of repeated tests must be reviewed for eligibility prior to the screening endoscopy procedure.
m
The detection of Clostridium difficile by toxigenic stool culture (stool culture followed by detection of toxin) is considered the gold standard for the diagnosis of the 
colonization or infection with pathogenic C. difficile. Comparable sensitivity may be achieved by direct testing of stool via point-of-use rapid membrane enzyme immunoassay 
card for both C. difficile toxin A and B and GDH antigen on a card. Use of the card for point-of-care screening is encouraged where permitted by local regulation; any samples 
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Table 1
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
showing a positive result with this method should be sent for toxigenic stool culture. Molecular techniques such as PCR for detection of toxin RNA are also acceptable 
alternatives. Refer to the laboratory manual for further guidance and instruction for C. difficile screening.
n
HCV RNA PCR if HCV Ab positive. If a subject tests negative for HBsAg, but positive for HBcAb, the subject would be considered eligible if the subject tests positive for 
antibody to Hepatitis B surface antigen (HBsAb also referred as anti-HBsAg) reflex testing.
o
For confirmation of postmenopausal status in females who have had 12 consecutive months of spontaneous amenorrhea and are 51 years of age.
p
For females of childbearing potential who are not surgically sterile, do not have confirmed ovarian failure, or do not meet the definition of postmenopausal as described in 
Section 4.4 and Section 7.2.3.7.
q
A documented negative PPD test within 12 weeks before baseline (Visit 2) is acceptable. Interferon gamma release assay official reading and method or test must be located in 
the source documentation.
r
A serum sample will be collected and banked. It may be analyzed if a subject shows neurologic symptoms suggestive of progressive multifocal leukoencephalopathy.
s
The sample must be collected before administration of investigational product.
t
The 
 sample must be collected before administration of investigational product. 
u
Flexible sigmoidoscopy or colonoscopy (if preferred) at screening must be performed on all subjects after the majority of other eligibility criteria (eg, laboratory values) are 
met. Endoscopy must be performed during the screening period within 10 days before baseline (Visit 2), preferably within 5 to 7 days before the baseline visit, to obtain the 
centrally read endoscopic subscore. Biopsy samples will be collected for histological evaluation using the Geboes Score classification. Subjects at risk of colorectal cancer, as 
defined in exclusion criterion 5 (see Section 4.2), must have a colonoscopy performed at screening.
v
Mayo score will be based on subject daily e-diary entries. The Mayo score at baseline will be calculated based on the stool frequency subscore and rectal bleeding subscore, 
reported by subjects in the PRO UC daily e-diary and PGA obtained at baseline and the centrally read endoscopic subscore for the endoscopy performed during the screening 
period. The Mayo score at the Week 12 visit will be calculated based on the stool frequency subscore and rectal bleeding subscore reported by subjects in the PRO UC daily 
e-diary and PGA and the centrally read endoscopic subscore for the endoscopy performed at Week 12, Visit 6 (Part 1). See Section 7.2.2.2 for further details.
w
PRO UC daily e-diary will be collected using a daily e-diary during the treatment period. Collection of the daily e-diary data must begin at least 10 days before the baseline 
visit (Visit 2). The subject should be provided with the handheld device to take home on their first visit. See Section 7.2.2.3 for further details. Compliance is assessed by site 
staff at each visit. The site staff will instruct the subject on the appropriate use of the e-diary, particularly when compliance is below 80% (eg, <23 out of 28 e-diary entries) 
when compared with the previous visit.
x
All health outcome or patient-reported questionnaires should be completed before completing any other visit assessments.
y
Interactive response technology will be used for randomization and dispensation of study treatment.
z
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the visit at which testing will be done.
Note: See Section 7.2 for the order in which assessments should be performed. Timing of visits is relative to baseline (Visit 2).
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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Ulcerative colitis (UC) is a chronic, relapsing disease marked by ulceration and inflammation of 
the colonic mucosa and submucosa. Initially it usually involves the rectum but may extend 
proximally to involve a portion of, or the entirety of, the colon. In the early stages, hemorrhagic 
and erythematous tissue is observed, progressing to mucosal ulceration with purulent exudates in 
severe cases. The ulceration pattern is continuous and may extend the entire length of the colon. 
Perforation of the bowel wall causing ileus and peritonitis can occur with transmural extension of 
the ulceration. Bloody diarrhea with or without mucus and lower abdominal pain with periods of 
remission and exacerbation are the most common symptoms.
The incidence of UC is estimated to be up to 24.3 cases per 100,000 persons per year in Europe 
and up to 19.2 cases per 100,000 persons per year in North America. No clear difference in 
incidence has been observed between men and women. Although UC can occur at any age, peak 
incidence has been observed in the second to fourth decades of life (Molodecky et al., 2012).
Ulcerative colitis is a lifelong condition with a serious effect on the quality of life. Current 
treatment primarily consists of symptomatic management with dietary modifications and opiates 
(loperamide), as well as disease modifying agents such as 5-aminosalicylic acid (5-ASA), 
systemic glucocorticoids, immunosuppressive agents (azathioprine/6-mercaptopurine, 
cyclosporine), and biologic therapy with anti-tumor necrosis factor (TNF) or anti-integrin agents. 
Despite recent advances, there is still an unmet need for an effective pharmacological treatment 
that will induce and maintain remission.
1.2
Product Background and Clinical Information
The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal sites of the 
gastrointestinal (GI) tract is influenced by the endothelial expression of mucosal addressin cell 
adhesion molecule (MAdCAM). MAdCAM is a member of the immunoglobulin super family of 
cell adhesion molecules and is mostly expressed on the cell surface of high endothelial venules 
of organized intestinal lymphoid tissue such as Peyer’s patches and mesenteric lymph nodes 
(Briskin et al., 1997; Liaskou et al., 2011; Shyjan et al., 1996). MAdCAM plays a role in gut 
immune surveillance, and also appears to facilitate excessive lymphocyte infiltration under 
conditions of chronic GI inflammation. The α4β7 integrin is the recognized ligand for MAdCAM,
and expression of this ligand on populations of CD4+ and CD8+ T cells, as well as on subsets of 
B cells, distinguishes them as unique gut homing lymphocytes.
SHP647 (previously known as PF-00547659) is a fully human immunoglobulin G2 kappa 
(IgG2k) monoclonal antibody that binds to human MAdCAM to reduce lymphocyte homing to 
the gut and GI inflammation. SHP647 binds MAdCAM-1 with high affinity and selectivity that 
prevents the binding of α4β7
+ lymphocytes to MAdCAM expressing sites in the high endothelial 
venules of the GI tract.
Always refer to the latest version of the SHP647 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the 
pharmacokinetics, efficacy, and safety of SHP647.
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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
SHP647, a fully human IgG2k antihuman MAdCAM monoclonal antibody, is under development 
for the treatment of UC. SHP647 prevents the binding of α4β7
+ lymphocytes to 
MAdCAM-expressing sites with high affinity and selectivity. Principal sites of MAdCAM 
expression on normal tissue include intestine, pancreas, stomach, esophagus, spleen, and to a 
lesser extent lung, liver, and bladder but not the central nervous system (CNS) (Steffen et al., 
1996).
Although selective targeting of the MAdCAM receptors is a novel approach, the basic 
interference of lymphocyte homing by preventing the binding of these α4β7
+ lymphocytes to the 
MAdCAM receptor and the resultant efficacy in UC is well established (Feagan et al., 2013). 
SHP647 is differentiated from other molecules used for the treatment of UC in that it blocks the 
interaction of α4β7
+ lymphocytes to the MAdCAM receptor by selectively binding to MAdCAM 
in the gut (and related tissues) whereas other molecules only target the integrins on the 
infiltrating lymphocytes. Additionally, SHP647 does not bind to the vascular cell adhesion 
molecule; therefore, SHP647 is not expected to be an effective treatment for multiple sclerosis,
or affect lymphocyte homing or surveillance in the CNS.
This study is designed to evaluate the efficacy of SHP647 in inducing remission in subjects with 
moderate to severe UC.
SHP647 has been investigated in 2 completed dose-finding studies (A7281001 and A7281009) in 
subjects with moderate to severe UC; a third study (A7281010), an open-label long-term safety 
extension study, is ongoing. Phase 1 study A7281001 evaluated both single (0.03-10.0 mg/kg 
intravenous [IV]; 3.0 mg/kg subcutaneous [SC]) and multiple doses (0.1-3.0 mg/kg IV; 0.3 and 
1.0 mg/kg SC) of SHP647 in subjects with UC. Safety evaluation revealed a safety profile for 
SHP647 similar to that of placebo, with no pattern of adverse events (AEs) suggestive of 
increased risk of opportunistic infections or CNS effects, and no evidence of adverse effects on 
laboratory parameters, electrocardiograms (ECGs), vital signs, or neurological function. Events 
leading to withdrawal were due to exacerbations of the underlying UC.
Study A7281009 was a Phase 2b proof-of-concept (randomized, double-blind, 
placebo-controlled, parallel, dose-ranging) study designed to evaluate the efficacy, safety, and 
pharmacokinetics of SHP647 in subjects with moderate to severe UC. Treatment was assigned in 
a 1:1:1:1:1 ratio to dose levels of 7.5, 22.5, 75, or 225 mg SHP647 or placebo administered SC 
once every 4 weeks (Q4W at Weeks 0, 4, and 8). The primary endpoint of the study was the 
proportion of subjects in clinical remission at Week 12, with remission defined as a total Mayo 
score of ≤2 with no individual subscore >1 (see Appendix 2 for details of the Mayo score). More 
subjects were in clinical remission at Week 12 in SHP647-treated groups than in the placebo 
group, with statistical significance achieved for the 7.5, 22.5, and 75-mg doses (Vermeire et al., 
2017). Based upon the total Mayo score with a centrally read endoscopic severity component, 
the increase in clinical remission rates over placebo at Week 12 for the 7.5, 22.5, and 75-mg 
doses were 8.0% (p=.043), 12.8% (p=.010), and 11.8% (p=.012). When the clinical remission 
rate at Week 12 was analyzed by stratum of previous anti-TNF exposure (experienced or naïve), 
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a similar trend was observed across dose levels in both the anti-TNF experienced and anti-TNF 
naïve subjects. There was no evidence of an adverse safety signal, and there was no increase in 
the frequency of infections in MAdCAM-bearing tissues as evidenced by similar rates of 
nasopharyngitis among treatment arms.
Based on the efficacy and safety data in Study A7281009 and the systemic population 
pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation, clinical remission, 
clinical response and mucosal healing rates were higher in subjects with UC receiving doses of 
22.5 and 75 mg Q4W than in those receiving doses of 7.5 mg and 225 mg Q4W. The induction 
responses were not demonstrated either at Week 4 or Week 8, but were observed at Week 12 
regardless of dose level. No difference in the clinical responses between a 22.5-mg dose and a 
25-mg dose is expected based on the current understanding of the mode of action of SHP647 and 
clinical observations to date. To better understand the exposure (dose)-response relationship in 
this population and understand individual patient exposure needs, the 25-mg and 75-mg doses 
(Q4W) will be tested in the Phase 3 program. Therefore, SC doses of 25 mg or 75 mg of SHP647 
or placebo on Day 1 (Week 0), Week 4, and Week 8 are recommended for the 2 planned Phase 3 
studies SHP647-301 and SHP647-302. The Phase 1 study, A7281001, which investigated the 
safety, tolerance, pharmacokinetics, and pharmacodynamic properties of SHP647, supports 
further clinical development of SHP647 using SC administration.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of the study is to evaluate the efficacy of SHP647 in inducing remission,
based on composite score of patient-reported symptoms and centrally read endoscopy, in 
subjects with moderate to severe UC.
2.2.2
Secondary Objectives
2.2.2.1
Key Secondary Objective
The key secondary objectives are as follows:

To evaluate the efficacy of SHP647 in achieving endoscopic remission, based on 
centrally read endoscopy.

To evaluate the efficacy of SHP647 in achieving clinical remission, based on composite 
score of patient-reported symptoms.

To evaluate the efficacy of SHP647 in inducing clinical response, based on composite score 
of patient-reported symptoms and centrally read endoscopy.

To evaluate the efficacy of SHP647 in achieving mucosal healing, based on a centrally read 
endoscopic and histological assessment.
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2.2.2.2
Other Secondary Objectives
The other secondary objectives are as follows:

To evaluate the safety and tolerability of SHP647.

To evaluate the effect of SHP647 induction treatment on other clinical outcomes.

To evaluate the effect of SHP647 on abdominal pain, urgency, diarrhea, and absolute stool 
frequency and bleeding scores.

To evaluate the effect of SHP647 on health-related quality of life (HRQL).

To evaluate the effect of SHP647 on incidence of hospitalizations and total inpatient days.
2.2.3
Exploratory Objectives
The exploratory objectives of the study are as follows:
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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study designed to 
evaluate the efficacy and safety of SHP647 in inducing remission in subjects with moderate to 
severe UC.
A total of 825 subjects (330 subjects at 25 mg SHP647, 330 subjects at 75 mg SHP647, and 
165 placebo subjects) are planned for enrollment into the study (Figure 1). Subjects must be at 
least 16 years of age and no more than 80 years of age at the time of signing the informed 
consent/assent form.
The study consists of a screening period up to 6 weeks and a 12-week treatment period. After the 
screening period, eligible subjects will be randomly assigned to receive 1 of 3 treatments (25 mg 
SHP647, 75 mg SHP647, or placebo) in a 2:2:1 ratio. Randomization will be stratified based 
upon the subject’s status of prior anti-tumor necrosis factor (TNF) treatment (naïve or 
experienced) and glucocorticoid use at baseline (on glucocorticoids at baseline versus not on 
glucocorticoids at baseline). Subjects will receive SC injections of SHP647 or placebo, using a 
prefilled syringe (PFS), on Week 0/Day 1 (Visit 2), Week 4 (Visit 4), and Week 8 (Visit 5).
Subjects will undergo efficacy, 
, 
, safety, and health outcome assessments at these 
visits as detailed in Table 1.
At the end of the 12-week treatment period, eligible subjects will be offered the opportunity to 
participate in a double-blind maintenance study (SHP647-303; for subjects who achieve clinical 
response) or a long-term safety extension (LTS) study (SHP647-304; for subjects who do not 
achieve a clinical response) as shown in Figure 1. Subjects who withdraw early from the 
12-week treatment period or who do not wish to enter the maintenance study (SHP647-303) or 
LTS study (SHP647-304) will continue into a 16-week safety follow-up period. Only those 
subjects who complete the full course of investigational product treatment in the induction 
studies (SHP647-301 or SHP647-302) will be eligible to continue in the maintenance study or 
LTS study.
The overall study design is shown in Figure 2.
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Figure 1
Overview of SHP647 Phase 3 Studies in Ulcerative Colitis
Placebo 
25 mg
75 mg
Non-Respondersa
Induction
(SHP647-301, SHP647-302) 
Maintenance
(SHP647-303) 
Long-term Safety 
Extension
(SHP647-304) 
25 mg
Placebo
75 mg
Placebo
Placebo
Respondersa
Respondersa
Respondersa
75 mg
25 mg
a
Clinical response is defined as:
1. A decrease from the induction study (SHP647-301 or SHP647-302) baseline in the composite score of patient-reported 
symptoms using daily e-diary and centrally read endoscopy of at least 2 points and at least 30%, with an accompanying 
decrease in the subscore for rectal bleeding ≥1 point or a subscore for rectal bleeding ≤1
OR 
2. A decrease from the induction study (SHP647-301 or SHP647-302) baseline total Mayo score of at least 3 points and at 
least 30%, with an accompanying decrease in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore 
of ≤1.
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Figure 2
Study Design Flow Chart
LTS=long-term safety extension; W=week
a Subjects who withdraw early from the 12-week treatment period or who do not wish to enter the maintenance study 
(SHP647-303) or LTS study (SHP647-304) will continue into a 16-week safety follow-up period.
3.1.1
Rationale for Primary Endpoint
The Mayo score has historically been used as the primary endpoint for pivotal studies of agents 
intended to treat UC. Over the past decade, health authority thinking regarding efficacy 
endpoints for UC has evolved such that the traditional Mayo score is no longer recommended. 
Current regulatory guidance (FDA Ulcerative Colitis: Clinical Trial Endpoints Guidance for 
Industry [Draft], 2016; EMA Guideline on the Development of New Medicinal Products for the 
Treatment of Ulcerative Colitis [Draft], 2016) includes a dual measurement of patient-reported 
signs and symptoms outcomes (stool frequency and rectal bleeding), and clinician-reported 
endoscopic outcomes (scoring any endoscopy with evidence of friability as a 2), including 
histology. Per agreement with health authorities, these 3 outcomes will be reported as a 
composite score.
Data will be collected to calculate the total Mayo score using both the traditional and modified 
endoscopy subscore as a sensitivity analysis and to estimate the impact of the modification on 
the primary endpoint. The clinical relevance of the traditional Mayo score is supported by its 
correlation with significant improvement in disease-specific HRQL as measured by the 
Inflammatory Bowel Disease Questionnaire (IBDQ) and in generic HRQL as measured by the 
Short Form-36 (SF-36) questionnaire.
3.1.2
Rationale for Key Secondary Endpoints
The first 2 key secondary endpoints are included to comply with EMA advice. European 
Medicines Agency would agree to the composite primary endpoint only if supported by a key 
secondary analysis, where the patient-reported symptoms and clinician-reported endoscopy are 
analyzed as “co-primary”.
Placebo
25 mg SHP647
75 mg SHP647
Screening: Up to 
6 weeks
Randomization
Maintenance study 
(SHP647-303)
or
LTS study 
(SHP647-304)
W0
W4
W8
Dosing:
Treatment period: 12 weeks
16-week safety 
follow-up perioda
Week 12/End of 
Treatment
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The clinical response endpoint is based on the new composite score, and also represents 1 of the 
entry criteria for the maintenance study. This endpoint has not been previously tested.
Mucosal healing as a key secondary endpoint comprises both endoscopic and histologic 
components as recommended in the draft FDA and EMA guidance on UC (FDA Ulcerative 
Colitis: Clinical Trial Endpoints Guidance for Industry [Draft], 2016; EMA Guideline on the 
Development of New Medicinal Products for the Treatment of Ulcerative Colitis [Draft], 2016).
The Geboes Score (see Appendix 2) will be used to evaluate histologic remission and to 
complement the endoscopic subscore in the assessment of mucosal healing.
3.2
Duration and Study Completion Definition
Each subject’s final visit in this study may be at the end of the treatment period (Week 12) if 
continuing to Study SHP647-303 or SHP647-304, or at the end of the safety follow-up period 
(Week 28) if not continuing to either of these studies. In either case, the final visit will be in 
person at the site. A subject’s maximum duration of participation is expected to be 
approximately 34 weeks: a screening period of up to 6 weeks, a treatment period of 12 weeks, 
and a safety follow-up period of 16 weeks (if applicable). It is expected that the study will be 
completed in approximately 3 years.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
It is anticipated that the study will be conducted in at least 18 countries. Regions will include 
North America, Europe, the Middle East, and Africa, Latin America, and Asia-Pacific. 
Approximately 175 sites will be utilized.
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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed. Subject eligibility 
should be reviewed and documented by an appropriately qualified member of the investigator’s 
study team before subjects are included in the study.
4.1
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study.
1. Subjects and/or their parent or legally authorized representative must have an understanding, 
ability, and willingness to fully comply with study procedures and restrictions.
2. Subjects must be able to voluntarily provide written, signed, and dated (personally or via a 
legally authorized representative) informed consent and/or assent, as applicable, to 
participate in the study.
3. Subjects must be between ≥16 and ≤80 years of age at the time of the signing of the informed 
consent/assent form.
NOTE: Subjects <18 years of age must weigh ≥40 kg and must have body mass index (BMI) 
≥16.5.
4. Subjects must have a documented diagnosis (radiologic or endoscopic with histology) of UC 
for 3 months before screening. The following must be available in each subject’s source 
documentation:

A biopsy report to confirm the histological diagnosis.

A report documenting disease duration based upon prior colonoscopy.
NOTE: If this documentation is not available at the time of screening, a colonoscopy 
with biopsy to confirm the diagnosis is required during the screening period.
5. Subjects must be willing to undergo a flexible sigmoidoscopy or colonoscopy (if preferred), 
including biopsy sample collection, during screening after all other inclusion criteria have 
been met.
6. Subjects must have moderate to severe active UC, defined as a total Mayo score of 6,
including a centrally read endoscopic subscore 2, rectal bleeding subscore 1, and stool 
frequency subscore 1 at baseline (Visit 2).
7. Subjects must have evidence of UC extending proximal to the rectum (ie, not limited to 
proctitis).
8. Subjects must have had an inadequate response to, or lost response to, at least 1 conventional 
treatment such as mesalamine (5-ASA), glucocorticoids, immunosuppressants (azathioprine
[AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]), or anti-TNF.
9. Subjects receiving any treatment(s) for UC described in Section 5.2.1 are eligible provided 
they have been, and are anticipated to be, on a stable dose for the designated period of time.
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10. Subjects are males or nonpregnant, nonlactating females who, if sexually active, agree to 
comply with the contraceptive requirements of the protocol, or females of nonchildbearing 
potential. Males and females of reproductive potential who are sexually active must agree to 
use acceptable contraception (as described in Section 4.4) for the duration of the study.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met.
1.
Subjects with indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or 
clinical/histologic findings suggestive of Crohn’s disease.
2.
Subjects with colonic dysplasia or neoplasia. (Subjects with prior history of adenomatous 
polyps will be eligible if the polyps have been completely removed.)
3.
Subjects with past medical history or presence of toxic megacolon.
4.
Subjects with colonic stricture, past medical history of colonic resection, a history of bowel 
surgery within 6 months before screening, or who are likely to require surgery for UC during 
the treatment period.
5.
Subjects at risk for colorectal cancer must have a colonoscopy (Eaden and Mayberry, 2002)
performed during the screening period with results available within 10 days before the 
baseline visit (Visit 2), unless the subject has had a colonoscopy within 1 year prior to 
screening, and any adenomatous polyps found at that examination have been excised. 
Colonoscopy report and pathology report (if biopsies are obtained) from the colonoscopy 
performed during screening or in the prior year must be available in the source documents.
Subjects at risk for colorectal cancer include, but are not limited to:

Subjects with extensive colitis for ≥8 years or disease limited to left side of colon 
(ie, distal to splenic flexure) for ≥10 years before screening, regardless of age.

Subjects ≥50 years of age at the time of signing of the informed consent form.
6.
Subjects have had prior treatment with SHP647 (formerly PF-00547659).
7.
Subjects with known or suspected intolerance or hypersensitivity to the investigational 
product(s), closely related compounds, or any of the stated ingredients.
8.
Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2).
9.
Subjects have received any biologic with immunomodulatory properties (other than 
anti-TNFs) within 90 days before baseline (Visit 2).
10. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, 
vedolizumab, efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion 
molecule).
11. Subjects have received parenteral or rectal glucocorticoids, or rectal 5-ASA, within 14 days 
before screening endoscopic procedure.
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12. Subjects have participated in other investigational studies within either 30 days or 
5 half-lives of investigational product used in the study (whichever is longer) before baseline 
(Visit 2).
13. Subjects have received a live (attenuated) vaccine within 30 days before the baseline visit 
(Visit 2).
14. Subjects with active enteric infections (positive stool culture and sensitivity), Clostridium 
difficile infection or pseudomembranous colitis [subjects with C. difficile infection at 
screening may be allowed re-test after treatment], evidence of active cytomegalovirus 
infection or Listeria monocytogenes, known active invasive fungal infections such as 
histoplasmosis or parasitic infections, clinically significant underlying disease that could 
predispose the subjects to infections, or a history of serious infection (requiring parenteral 
antibiotic and/or hospitalization) within 4 weeks before the baseline visit (Visit 2).
15. Subjects with abnormal chest x-ray findings at screening (Visit 1), such as presence of active 
tuberculosis (TB), general infections, heart failure, or malignancy. (A chest x-ray performed 
up to 12 weeks before study entry [screening, Visit 1] may be used if available; 
documentation of the official reading must be located and available in the source 
documentation.)
16. Subjects with evidence of active or latent infection with Mycobacterium tuberculosis (TB) 
who have not completed a generally accepted full course of treatment before randomization 
are excluded. All other subjects must have either the Mantoux (purified protein derivative 
[PPD]) tuberculin skin test or interferon gamma release assay (IGRA) performed.
Subjects who have no history of previously diagnosed active or latent tuberculosis are 
excluded if they have a positive Mantoux (PPD) tuberculin skin test (ie ≥5 mm induration) 
or a positive IGRA (the latter to be tested at the site’s local laboratory) during screening or 
within 12 weeks before randomization. If IGRA test cannot be performed locally, a central 
laboratory may be used, with prior agreement from the sponsor.

An IGRA is strongly recommended for subjects with a prior Bacillus Calmette-Guérin 
(BCG) vaccination, but may be used for any subject. Documentation of IGRA product 
used and the test result must be in the subject's source documentation if performed 
locally. Acceptable IGRA products include Quantiferon TB Gold In-Tube Test.

If the results of the IGRA are indeterminate, the test may be repeated, and if a negative 
result is obtained, enrollment may proceed. In subjects with no history of treated active or 
latent tuberculosis, a positive test on repeat will exclude the subject. Subjects with a 
history of active or latent tuberculosis infection must follow instructions for “Subjects 
with a prior diagnosis of active or latent tuberculosis are excluded unless both of the 
following criteria are met” in this criterion.

Subjects with repeat indeterminate IGRA results, with no prior TB history, may be 
enrolled after consultation with a pulmonary or infectious disease specialist who 
determines low risk of infection (ie, subject would be acceptable for immunosuppressant 
[eg, anti-TNF] treatment without additional action). This consultation must be included in 
source documentation.
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Results from a chest x-ray, taken within the 3 months before or during screening (Visit 1) 
must show no abnormalities suggestive of active TB infection as determined by a qualified 
medical specialist.
Subjects with a prior diagnosis of active or latent tuberculosis are excluded unless both of 
the following criteria are met:

The subject has previously received an adequate course of treatment for either latent
(eg, 9 months of isoniazid or an acceptable alternative regimen, in a locale where rates of 
primary multidrug TB resistance are <5%. Subjects from regions with higher rates of 
primary multidrug TB resistance are excluded) or active (acceptable multidrug regimen) 
TB infection. Evidence of diagnosis and treatment must be included in source 
documentation. Consultation with a pulmonary or infectious disease specialist to confirm 
adequate treatment (ie, subject would be acceptable for immunosuppressant [eg, 
anti-TNF] treatment without additional action) must be performed during the screening 
period. The consultation report must be included in source documentation prior to 
enrollment.

A chest x-ray performed within 3 months prior to screening (Visit 1) or during screening 
(Visit 1) indicates no evidence of active or recurrent disease, and documentation of 
interpretation by a qualified medical specialist must be included in source documentation.
17. Subjects with a pre-existing demyelinating disorder such as multiple sclerosis or new onset 
seizures, unexplained sensory motor, or cognitive behavioral, neurological deficits, or 
significant abnormalities noted during screening.
18. Subjects with any unexplained symptoms suggestive of progressive multifocal 
leukoencephalopathy (PML) based on the targeted neurological assessment during the 
screening period (see Section 7.2.3.3).
19. Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed.
20. Subjects with a significant concurrent medical condition at the time of screening (Visit 1) or 
baseline (Visit 2), including, but not limited to, the following:

Any major illness/condition or evidence of an unstable clinical condition (eg, renal, 
hepatic, hematologic, GI (except disease under study), endocrine, cardiovascular, 
pulmonary, immunologic [eg, Felty’s syndrome], or local active infection/infectious 
illness) that, in the investigator’s judgment will substantially increase the risk to the 
subject if he or she participates in the study.

Cancer or history of cancer or lymphoproliferative disease within the previous 5 years 
(other than resected cutaneous basal cell carcinoma, squamous cell carcinoma, or 
carcinoma in situ of the uterine cervix that has been treated with no evidence of 
recurrence).

Presence of acute coronary syndrome (eg, acute myocardial infarction, unstable angina 
pectoris) within 24 weeks before screening (Visit 1).

History of significant cerebrovascular disease within 24 weeks before screening (Visit 1).
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21. Subjects who have had significant trauma or major surgery within 4 weeks before the 
screening visit (Visit 1), or with any major elective surgery scheduled to occur during the 
study.
22. Subjects with evidence of or suspected liver disease, liver injury due to methotrexate or 
primary sclerosing cholangitis.
23. Subjects with evidence of positive hepatitis B surface antigen (HBsAg) or hepatitis B core 
antibody (HBcAb). NOTE: if a subject tests negative for HBsAg, but positive for HBcAb, 
the subject would be considered eligible if the subject tests positive for antibody to 
Hepatitis B surface antigen (HBsAb also referred as anti-HBsAg) reflex testing.
24. Subjects with positive hepatitis C antibody (HCVAb) with confirmation by 
HCV-ribonucleic acid (RNA) polymerase chain reaction (PCR) reflex testing.
25. Subjects with any of the following abnormalities in hematology and/or serum chemistry 
profiles during screening. NOTE: Screening laboratory tests, if the results are considered by 
the investigator to be transient and inconsistent with the subject’s clinical condition, may be 
repeated once during the screening period for confirmation. Results must be reviewed for 
eligibility prior to the screening endoscopy procedure.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 2.0 times 
the upper limit of normal (ULN).

Total bilirubin level 1.5 times the ULN (except in subjects with documented diagnosis 
of Gilbert’s syndrome).

Hemoglobin level 80 g/L (8.0 g/dL).

Platelet count 100 × 109/L (100,000 cells/mm3) or 1000 × 109/L 
(1,000,000 cells/mm3).

White blood cell count 3.5 × 109/L (3500 cells/mm3).

Absolute neutrophil count (ANC) <2000 cells/mm3.

Serum creatinine level 177 mol/L (2 mg/dL) or estimated glomerular filtration rate 
(GFR) <40 ml/min/1.73m2 based on the abbreviated MDRD.
26. Subjects with known infection with human immunodeficiency virus (HIV).
27. Subjects who have, or who have a history of (within 2 years before screening [Visit 1]), 
serious psychiatric disease, alcohol dependency, or substance/drug abuse.
28. Subjects using medicinal marijuana (cannabis) or related products for recreational purposes,
who have a known dependency per the criteria in the Diagnostic and Statistical Manual of 
Mental Disorders, Edition 5 (including urine drug screen and medical history). Exceptions 
are those subjects who are prescribed marijuana (by a physician) for medicinal use and 
where the product is sourced from a licensed pharmacy/provider. Such subjects must be 
using the product, in a stable regimen, for at least 3 months before screening.
29. Subjects with any other severe acute or chronic medical or psychiatric condition or 
laboratory or ECG abnormality that may increase the risk associated with study participation 
or investigational product administration or may interfere with the interpretation of study 
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results and, in the judgment of the investigator, would make the subject inappropriate for 
entry into this study.
30. Female subjects who are planning to become pregnant during the study period.
31. Male subjects who are planning to donate sperm must agree not to do so for the duration of 
the study and through 16 weeks after last dose of investigational product.
32. Subjects who are investigational site staff members or relatives of those site staff members 
or subjects who are Shire employees directly involved in the conduct of the study.
4.3
Restrictions
Smoking can have an influence on the severity of UC disease symptoms. Subjects should inform 
the investigator of any changes to their smoking habits during the study; however, these data will 
not be captured in the electronic case report form (eCRF). Use of nicotine patches should be 
recorded as concomitant medication (see Section 5.2).
For the purposes of this protocol, dietary supplements (such as vitamins, minerals, purified food 
substances, and herbals with pharmaceutical properties) are considered to be concomitant 
medications (see Section 5.2).
4.4
Reproductive Potential
The potential effects of SHP647 on embryofetal or postnatal development have not yet been 
assessed in animals or humans; these will be assessed in future studies. To minimize the risk of 
unintentional exposure of the embryo or fetus in the clinical study, all sexually active male and 
female subjects who, in the opinion of the investigator, are biologically capable of having 
children and with their partners are at risk of pregnancy, must agree to use an acceptable form of 
contraception, in accordance with the package instructions/leaflet, for the duration of the active 
treatment period and for at least 16 weeks after the last dose of investigational product.
True abstinence is considered to be a highly effective contraception (ie, a method that results in a 
failure rate of <1% per year) when it is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
declaration of abstinence for the duration of exposure to investigational product, and withdrawal 
are not acceptable methods of contraception.
During the screening visit, the investigator or designee in consultation with the subject will 
confirm the subject’s childbearing potential status. For subjects of childbearing potential, it must 
be confirmed and documented that the subject has selected the most appropriate method of 
contraception from the permitted list of contraception methods. Subjects must affirm the 
consistent and correct use of at least 1 of the selected methods. Regular contraception check 
discussions will take place at the time points specified in Table 1 (ie, at each site visit) and will 
be documented. In addition, the subject must be instructed to call the site immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected.
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4.4.1
Contraceptive Methods for Female Study Subjects
Sexually active females of childbearing potential must be using an acceptable form of 
contraception, and must be advised to use acceptable contraceptives throughout the study period 
and for 16 weeks following the last dose of investigational product. If hormonal contraceptives 
are used they should be administered according to the package insert.
Female subjects should be in one of the following categories:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and 51 years of age); 
postmenopausal status should be confirmed by follicle-stimulating hormone (FSH) testing.

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks poststerilization or has medically confirmed ovarian failure.

Females of childbearing potential with a negative serum pregnancy test result at screening 
and a negative urine pregnancy test result at baseline. Females of childbearing potential must 
agree to abstain from sexual activity that could result in pregnancy or agree to use acceptable 
methods of highly effective contraception.
Acceptable methods of highly effective contraception (ie, methods that result in a failure rate of 
<1% per year) are:

Combined (estrogen- and progestogen-containing) hormonal contraceptives associated with 
inhibition of ovulation (oral, intravaginal, transdermal) stabilized for at least 30 days before 
the screening visit (Visit 1)

Progestogen-only hormonal contraception associated with inhibition of ovulation plus a 
barrier method

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Male sterilization/vasectomized partner with absence of sperm in the postvasectomy
ejaculate

True abstinence (see Section 4.4).
4.4.2
Contraceptive Methods for Male Study Subjects
Contraception is required for all sexually active male subjects, who with their partners, must 
agree to use 1 of the following acceptable methods of contraception throughout the study period 
and for 16 weeks following the last dose of investigational product:

Male condom with spermicide; however if spermicide is not available in the country, 
additional contraception (ie, one of those listed below) must be used in addition to a condom
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
Female condom with spermicide (use by female sexual partner); however, if spermicide is 
not available in the country, additional contraception (ie, one of those listed below) must be 
used in addition to a condom

Sterile sexual partner

Intrauterine device with spermicide (use by female sexual partner)

Contraceptive sponge with spermicide (use by female sexual partner)

Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with spermicide, or a
cervical cap with spermicide) (use by female sexual partner)

Oral, implantable, transdermal, or injectable hormonal contraceptive (use by female sexual 
partner) plus a barrier method.

Male sterilization with absence of sperm in the postvasectomy ejaculate.
4.5
Withdrawal of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 12/ET (Visit 6) are to be performed. All subjects who discontinue treatment with 
investigational product should also undergo the protocol-specified 16-week safety follow-up
period. In the event that subjects are unable to attend in person for the follow-up visits, all efforts 
should be made to collect information on AEs and concomitant medications. Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded. The reason for 
termination, date of stopping investigational product, and the total amount of investigational 
product taken must be recorded.
Subjects who discontinue will not be replaced.
4.5.1
Subject Withdrawal Criteria
Additional reasons a subject may be withdrawn from active treatment include but are not limited 
to:

AEs

Serious adverse events (SAEs)

Protocol violations

Failure to return for visits
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A subject should be withdrawn from study treatment:

If a new therapy is initiated for UC, or

If a subject undergoes surgery for UC
Subjects who withdraw from active treatment due to an increase in disease symptoms may see 
nonstudy-related physicians for treatment, which may include treatments prohibited during the 
treatment periods of this study.
If a subject withdraws their consent, no further evaluation should be performed, and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
4.5.2
Reasons for Withdrawal
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol deviation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Other (if “Other” is selected, the investigator must specify the reason)

Death

Physician decision

Pregnancy

Screen failure

Site terminated by sponsor.
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point before the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and that they return their electronic diary.
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5.
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal remedies and vitamins)
received within 30 days (or PK equivalent of 5 half-lives, whichever is longer) of the first dose 
of investigational product. Use of biologics for indications other than UC during the 90 days 
before screening must also be recorded.
Prior and concomitant UC-specific treatments from the previous 10 years will be recorded. The 
subject’s entire history of biologic UC-specific treatments will be recorded.
5.2
Concomitant Treatment
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the safety follow-up period, inclusive.
5.2.1
Permitted Treatment
Subjects must remain on stable doses of permitted UC treatments until completion of the 
Week 12 visit, unless decreases are required because of AEs. Stable doses of the following 
treatments for UC are permitted as concomitant medication:

Oral 5-ASA or sulfasalazine, providing that the dose is stable for at least 2 weeks before 
baseline (Visit 2)

Immunosuppressants (AZA, 6-MP, or MTX), providing that the dose is stable for at least 
8 weeks before baseline (Visit 2).

Oral glucocorticoids (prednisone or equivalent (see Appendix 3) up to a maximum of 
20 mg/day or budesonide up to a maximum of 9 mg/day), providing that the dose is stable for 
at least 2 weeks before screening endoscopic procedure.
NOTE: Rectal 5-ASA and parenteral or rectal glucocorticoids are prohibited.
Subjects using medicinal marijuana (cannabis) under a physician’s prescription, and who obtain 
the product from a licensed pharmacy or provider, should continue to use it under the same 
regimen for the duration of the study, unless otherwise instructed by the investigator or treating 
physician. Such subjects must be using the product, in a stable regimen, for at least 3 months 
before screening.
Routine nonlive vaccinations are allowed during the study.
Dietary and herbal supplements and probiotics are allowed in the study, provided they are being 
taken at stable doses at the time of the baseline visit (Visit 2) and for the duration of the study.
They should be recorded as concomitant medications.
Use of nicotine patches should be recorded as concomitant medication.
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5.2.2
Prohibited Treatment
Table 2 details the minimum required number of days before baseline (Visit 2) for common prior 
treatments that are excluded medications for this study.
Table 2
Common Excluded Treatments
Permanently 
Excluded
Minimum Required Number of Days Before 
Baseline (Visit 2)
Treatment
14
30
60
90
SHP647 (PF-00547659) in a previous study
X
Anti-integrin or antiadhesion molecule 
treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab)
X
Parenteral and rectal glucocorticoids
Xa
Rectal 5-ASA
Xa
Investigational products
Xb
Live (attenuated) vaccine
X
Anti-TNF treatment
X
Biologics with immunomodulatory properties 
(other than anti-TNFs)
X
5-ASA=5-aminosalicylate; TNF=tumor necrosis factor.
a The minimum required number of days before baseline (Visit 2) for rectal 5-ASA and parenteral or rectal glucocorticoids is 
defined as 14 days before screening endoscopic procedure (see Section 4.2, exclusion criterion 11).
b Or 5 half-lives if longer.
Treatments not listed in Table 2 may be considered allowable; see Section 5.2.1 for further 
details.
No new nonpharmacological therapies that might affect bowel habit or GI function should be 
started during the study.
5.2.3
Rescue Therapy
Subjects must maintain their stable dose of background UC treatment, unless dose reduction or 
discontinuation are required due to associated AEs. If a subject requires initiation of a new 
therapy or increase in glucocorticoids for UC above the SHP647-301 or SHP647-302 baseline, 
the subject should be withdrawn from study treatment and enter the safety follow-up period, and
appropriate treatment should be given at the discretion of the investigator.
Subjects who enter the safety follow-up period will no longer need to abstain from the 
medications that were prohibited during the baseline and treatment periods. High-dose 
glucocorticoids and other UC treatments will be allowed. Biologics or nonbiologic 
immunosuppressants should not be initiated during the safety follow-up period without prior 
discussion with the sponsor study physician or designee due to the long half-life of SHP647.
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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is SHP647, which will be provided as a sterile aqueous buffered solution for SC 
administration in a glass PFS with a fixed needle. Each PFS contains 1 mL of SHP647 solution
at an appropriate concentration to provide the intended dose of drug (25 or 75 mg). Additional 
information is provided in the current SHP647 investigator’s brochure.
The reference product is placebo, which will be provided in a PFS with a fixed needle containing 
1 mL of placebo solution for SC administration. The placebo solution will contain the same 
sterile aqueous buffered solution as the test product but will not contain SHP647.
6.1.1
Blinding the Treatment Assignment
The placebo syringes and solution will match the SHP647 syringes in appearance. The fill 
volume for all syringes will be the same.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive response technology (IRT) system will be used for screening and enrolling 
subjects, recording subject visits, randomization, investigational product supply dispensation and 
management, inventory management and supply ordering, investigational product expiration 
tracking and management, and emergency unblinding. Please refer to the Study Manual for 
additional details regarding the IRT system.
6.2.2
Allocation of Subjects to Treatment
This is a double-blind, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.
The total Mayo score will be calculated at baseline (Visit 2) before randomization. Endoscopic 
subscore based on the central reader’s assessment will be used to determine eligibility. Subjects 
with a total Mayo score of ≥6, including a centrally read endoscopic subscore ≥2, rectal bleeding 
subscore ≥1, and stool frequency subscore ≥1, and who fulfill all other eligibility criteria, will be 
randomized in a ratio of 2:2:1 via a computer-generated randomization schedule to receive SC 
injections of 25 mg SHP647, 75 mg SHP647, or placebo, respectively. The randomization will 
be performed centrally and stratified by status of prior anti-TNF therapy (2 strata: naïve versus
experienced) and glucocorticoid use at baseline (2 strata: on glucocorticoids at baseline versus
not on glucocorticoids at baseline).
To ensure that the allocation of subjects with prior anti-TNF therapy exposure is similar to that 
observed in Study A7281009, the percentage of subjects with prior anti-TNF therapy exposure 
will be capped at 60% of the sample population. There will be no cap on the number of anti-TNF
naïve subjects randomized.
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Subject numbers are assigned to all eligible subjects as they consent to take part in the study. 
Within each site (numbered uniquely within a protocol), the subject number will be assigned to 
subjects according to the sequence of presentation for study participation.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment will be 
automatically assigned by the IRT system.
Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment assignment as 
dictated by the study. In these cases, the same investigational product packing identification 
number may not be assigned to more than 1 subject.
6.2.3
Dosing
Investigational product (SHP647 or placebo) will be administered subcutaneously by qualified 
site personnel Q4W (Weeks 0, 4, and 8). See Section 7.2 for the timing of dosing relative to 
other procedures.
Investigational product should be administered in the anterolateral right or left thighs. If there are 
clinical reasons why the drug cannot be administered in the leg, the drug may be administered in 
the deltoid area or abdomen with appropriate documentation. The location of the investigational 
product administration will be recorded.
After the first administration of investigational product, the subject must be observed by a 
member of the study staff for at least 30 minutes (the total duration should be determined at the 
discretion of the investigator). For subsequent administrations, observation of the subject is at the 
discretion of the investigator. Injection site and allergic reaction monitoring should be completed 
by a member of the study staff.
Investigator-directed delays in dosing due to abnormal laboratory findings or AEs should be 
discussed with the medical monitor to determine whether the subject should continue with the 
treatment. Only those subjects who complete the full course of investigational product treatment 
in the induction studies (SHP647-301 or SHP647-302) will be eligible to continue in the 
maintenance study or LTS study.
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational product is dispensed by qualified staff members.
6.2.4
Unblinding the Treatment Assignment
Whenever possible, the investigator or subinvestigator should contact the Shire physician and/or 
assigned medical monitor before breaking the blind. It is understood that in an emergency 
situation it may not be possible to communicate with the study team before breaking the blind. 
The safety of the subject should be of primary concern. When the blinding code is broken the 
reasons must be fully documented.
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In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded on the IRT and the source 
documents. Upon breaking the blind, the subject is withdrawn from the study, but should be 
followed up for safety purposes. The IRT will notify the relevant personnel in the event of any 
code break. Code-break information is held by the pharmacist/designated person at the site.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
The sponsor will provide the investigator with packaged investigational product labeled in 
accordance with specific country regulatory requirements. All investigational product is labeled 
with a minimum of the following: protocol number, medication identification number, dosage 
form (including product name and quantity in pack), directions for use, storage conditions, 
expiry date (if applicable), batch number and/or packaging reference, the statements “For clinical 
trial use only” and/or “CAUTION: New Drug – Limited by Federal (or US) Law to 
Investigational Use”, and the sponsor’s name and address.
Additional labels may be applied in order to meet local or institutional requirements, but must 
not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name
Additional labels may not be added without the sponsor’s prior written agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers: PFS with nominal fill 
volume of 1 mL. The PFS will be packaged in a labeled carton.
Changes to sponsor-supplied packaging before dosing may not occur without prior written 
agreement by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or delegated member of the study team. The pharmacist or delegated 
team member will enter the unique subject identifier on the investigational product labels as they 
are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
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records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
The investigational product should be protected from light and should not be frozen. Do not 
shake.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying his/her treatment assignment. All administered
investigational product will be documented in the subject’s source document and/or other 
investigational product record.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
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With the written agreement of the sponsor, at the end of the study all unused stock may be 
destroyed at the site or a local facility. In this case, destruction records identifying what was 
destroyed, when and how, must be obtained with copies provided to the sponsor. Destruction of 
investigational products must be in accordance with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, cartons) or at 
the individual count level for opened containers/packaging. The pharmacist or delegated team 
member will record details on the drug accountability form.
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7.
STUDY PROCEDURES
7.1
Study Schedule
The investigator may schedule visits (unscheduled visits) in addition to those listed on the 
schedule of activities (Table 1) in order to conduct evaluations or assessments required to protect 
the wellbeing of the subject.
7.1.1
Screening Period
7.1.1.1
Screening Visit (Visit 1)
Subjects will be screened within 6 weeks before the baseline visit (Visit 2) to determine 
eligibility to participate in the study and to perform the other assessments and procedures 
specified in Table 1. Each subject or subject’s parent or legally authorized representative must 
participate in the informed consent process and provide written informed consent/assent before 
any assessments or procedures specified in the protocol are performed. Screening assessments 
may take place over more than 1 day (at least 2 visits will be necessary to complete the screening 
procedures, including endoscopy).
A screen failure is a subject who has given informed consent or assent, as applicable (and whose
parents or legally authorized representatives have given informed consent, as applicable), failed 
to meet the inclusion criteria and/or met at least 1 of the exclusion criteria, and has not been 
randomized or administered investigational product.
A subject may be rescreened if their condition has changed and they may potentially be eligible. 
Subjects may be rescreened 1 time. NOTE: Screening laboratory tests, if considered by the 
investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated 
once during the screening period for confirmation. Results of repeated tests must be reviewed for 
eligibility prior to the screening endoscopy procedure.
Flexible sigmoidoscopy or colonoscopy (if preferred) must be performed on all subjects after the 
majority of other eligibility criteria (eg, laboratory values) are met. Endoscopy must be 
performed during the screening period within 10 days before baseline (Visit 2), preferably within 
5 to 7 days before the baseline visit, to obtain the centrally read endoscopic subscore (see 
Section 7.2.2.1). Biopsy samples will be collected for histological evaluation using the Geboes 
Score classification. Subjects at risk of colorectal cancer, as defined in exclusion criterion 5 (see 
Section 4.2), must have a colonoscopy performed at screening.
If a subject has had the following procedures performed as a part of standard medical care within 
12 weeks before screening (Visit 1), these procedures do not need to be repeated as a part of 
screening:

Chest x-ray 

Documented negative PPD test or IGRA for TB
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7.1.1.2
Baseline Visit (Visit 2; Week 0)
The baseline visit will take place on Day 1 (Week 0). The assessments and procedures specified 
in Table 1 will be performed.
After eligibility has been reconfirmed and all baseline procedures and assessments have been 
completed, each subject will be randomized to 1 of the 3 treatment groups as described in 
Section 6.2.2 and the first dose of investigational product will be administered.
Results of the baseline laboratory tests are not required for investigational product administration 
but must be reviewed as soon as possible thereafter.
7.1.2
Treatment Period
7.1.2.1
Visit 3 (Week 2)
Visit 3 is scheduled to take place on Day 14 ±3 days (Week 2). The assessments and procedures 
specified in Table 1 will be performed.
7.1.2.2
Visits 4 and 5 (Weeks 4 and 8)
Visits 4 and 5 are scheduled to take place on Day 28 ±3 days (Week 4) and Day 56 ±3 days
(Week 8), respectively. The assessments and procedures specified in Table 1 will be performed.
7.1.2.3
Final On-treatment Visits: Visit 6, Parts 1 and 2 
(Week 12/Early Termination)
The Week 12/ET visit (Visit 6) consists of 2 parts.
Part 1 of Visit 6 should be scheduled preferably within 5 to 7 days before Part 2; this will allow 
sufficient time for data from the centrally read endoscopy to be available at Part 2 of the visit.
The Week 12/ET assessments and procedures that will take place during Part 1 are specified in 
Table 1.
Part 2 of Visit 6 will take place on Day 84 ±3 days. The Week 12/ET assessments and 
procedures that will take place during Part 2 are specified in Table 1.
At Part 2 of Visit 6, after review of the Mayo score, health outcome assessments, and safety 
assessments, it will be determined whether the subject should enter the safety follow-up period 
of this study or enroll in the maintenance (SHP647-303) or LTS (SHP647-304) studies. Entry
into the maintenance or LTS studies is dependent upon the subject’s response and whether the 
subject agrees to participate.
The Week 12 assessments and procedures will also form the ET assessments for any subjects 
who are withdrawn early or discontinued from the study.
7.1.3
Follow-up Period: Visits 7 and 8 (Weeks 20 and 28)
Subjects who are withdrawn early from the study, or who do not enter either the maintenance or 
LTS studies, should enter the safety follow-up phase for safety monitoring. The safety follow-up 
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period for this protocol is 16 weeks from the last dose of investigational product administered to 
each subject.
During the safety follow-up period, the Week 20 visit (Visit 7) will take place on Day 140 
±7 days. This visit will routinely be conducted by telephone; however, as an exception the visit 
can be performed as a study site visit if preferred.
At the end of the safety follow-up period, there will be a visit at the site on Day 196 ±7 days, 
which will form the Week 28 visit (Visit 8). The assessments and procedures specified in Table 1
will be performed, including querying for SAEs, AEs, and concomitant medications and 
procedures. All AEs and SAEs that are not resolved at the time of this visit will be followed to 
closure (see Section 8.1).
Subjects who are proceeding to the maintenance or LTS studies will not enter the safety 
follow-up period.
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside the control of the investigator, which may make it unfeasible to perform 
the tests and procedures. In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the subject.
When timing of procedures and assessments coincide, the following order should be followed:

Health outcome and patient-reported questionnaires

Vital signs and ECG

Blood sample collection

Investigational product administration

Endoscopy (generally performed at a separate visit; see Section 7.2.2.1).
7.2.1
Demographic and Other Baseline Characteristics
Demographic characteristics will be recorded at the screening visit (Visit 1).
Each subject’s stool frequency before symptoms of UC started or during remission will be 
recorded at the screening visit. The reference/normal stool frequency questions in Appendix 2
will be asked and the responses documented.
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7.2.2
Efficacy
The primary efficacy endpoint is the proportion of subjects in remission at the Week 12 visit. 
Remission is defined as a composite score of patient-reported symptoms using daily electronic 
diary (e-diary) and centrally read endoscopy as described in Section 9.8.1.
7.2.2.1
Endoscopy and Histology
Endoscopy will be performed at the time points specified in Table 1 and will consist of either 
flexible sigmoidoscopy or colonoscopy (if preferred).
If it is necessary, bowel preparation should be conducted as per local routine. The position of the 
endoscope will be based on the length of the instrument at various levels of insertion as well as 
the morphological features of the intestine as seen during endoscopy at baseline. The endoscopy 
report and any photographs and/or video recordings taken during the procedure per local custom 
should be filed in the subject’s medical record.
During endoscopy, 2 biopsy samples will be collected from the most inflamed area of the 
sigmoid colon at Week 12/ET. Endoscopy and biopsy procedures will be defined in an 
endoscopy instructions manual and/or reference card(s), on which all sites will be trained. 
Endoscopy results will be reviewed by a central reader.
Biopsy samples will be centrally reviewed using the Geboes Score classification system (see 
Appendix 2) for the evaluation of histological disease severity in UC with higher numbers 
corresponding to more inflammation.
7.2.2.2
Mayo Score
The Mayo score is a measure of UC disease activity. Mayo scores (total or partial) will be 
recorded at the time points specified in Table 1.
The total Mayo score ranges from 0 to 12 points and consists of the following 4 subscores, each 
graded from 0 to 3 with higher scores indicating more severe disease (see Appendix 2):

Stool frequency (0-3)

Rectal bleeding (0-3)

Findings of endoscopy (0-3)

Physician global assessment (PGA, 0-3).
The partial Mayo score consists of the Mayo score without the endoscopic subscores and ranges 
from 0 to 9 points.
The composite score is a recommended measure consisting of the Mayo score without the PGA 
subscore and ranges from 0 to 9 points. The composite score will be used for the primary 
efficacy endpoint.
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Calculation of the total and partial Mayo scores and composite score requires a self-assessment 
by the subject for stool frequency and the amount of blood in the stool. These data on stool 
frequency and rectal bleeding will be captured in the PRO-UC daily e-diary (see Section 7.2.2.3).
The Mayo stool frequency and rectal bleeding subscores will be calculated based on each
subject’s daily e-diary data recorded over the most recent 3 days (consecutive or nonconsecutive) 
prior to the visit excluding the following days: day of any bowel preparation, day of endoscopy, 
any days between day of bowel preparation and day of endoscopy, and the 2 days after the day of 
endoscopy.
The mucosal appearance during the sigmoidoscopic portion of the endoscopic examination will 
be assessed for the Mayo endoscopic subscore based on the scoring system provided in the 
protocol (see Appendix 2). The endoscopic appearance will be read by both the study site 
investigator and a central reader through video recorded during the procedure. Centrally read 
endoscopic subscores will be used for both eligibility and efficacy analyses.
The PGA acknowledges the 3 other criteria: the subject’s recollection of abdominal discomfort 
and general sense of wellbeing and other observations (such as physical findings and the 
subject’s performance status). The endoscopic subscore and the PGA must be performed by a 
physician qualified to perform endoscopy, and it is recommended that the same physician 
performs all such assessments for a particular subject throughout the study.
7.2.2.3
Patient-reported Outcome – Ulcerative Colitis E-Diary
Patient-reported UC signs and symptom data will be collected using a daily e-diary during the 
treatment period. Collection of the daily e-diary data must begin at least 10 days before the 
baseline visit (Visit 2). Subjects will enter data on UC signs and symptoms items using an
electronic handheld device that will be provided to subjects at the start of the study. Compliance 
is assessed by site staff at each visit. The site staff will instruct the subject on the appropriate use 
of the e-diary, particularly when compliance is below 80% (eg, <23 out of 28 e-diary entries) 
when compared with the previous visit.
Subjects will be asked to record the following signs and symptom data, as experienced over the 
previous 24 hours, in the e-diary:

Stool frequency

Rectal bleeding severity and frequency

Diarrhea frequency

Urgency frequency

Abdominal pain worst severity
The full PRO-UC e-diary consists of 6 items. The first 2 items (stool frequency and rectal 
bleeding severity) will be used to determine the Mayo stool frequency and rectal bleeding 
subscores, which will be used to calculate the total and partial Mayo scores and the composite 
score. The PRO-UC e-diary is presented in Appendix 2.
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7.2.3
Safety
7.2.3.1
Medical and Medication History
Medical history will be documented at screening (Visit 1), including UC history, cardiac history, 
and smoking history. Prior and concomitant medications and procedures will also be 
documented.
7.2.3.2
Physical Examination (Including Height and Weight)
Complete and targeted physical examinations will be performed at the time points specified in 
Table 1. Complete physical examination includes the review of the following body systems: 
general appearance, skin, HEENT, heart, lungs, confrontational visual fields (eyes), breast 
(optional), abdomen, external genitalia (optional), extremities, neurologic function, back, and 
lymph nodes. Targeted physical examination includes the review of the following body systems: 
skin, heart, lungs, confrontational visual fields (eyes), abdomen, and examination of body 
systems where there are symptom complaints by the subject.
Weight will be measured at the time points specified in Table 1. Height will be measured at 
screening (Visit 1) only.
Changes after the screening visit that are deemed clinically significant in the opinion of the 
investigator will be recorded as an AE.
7.2.3.3
Targeted Neurological Assessment
Targeted neurological assessments to monitor for the development of signs and/or symptoms of 
PML will be performed at the time points specified in Table 1. Subjects will be evaluated to 
reveal any potential abnormalities in the following neurological domains: vision, motor, tactile 
sensation, coordination/cerebellar function, speech, verbal comprehension, and 
cognition/behavior.
If any abnormalities are indicated, subjects will be further evaluated to help clarify any potential 
abnormal responses. Focus will be placed on possible alternative etiology (eg, fracture or stroke). 
If additional evaluation reveals an unexplained new abnormality, neurologic examination(s), 
targeted to the abnormal domain, will be performed by an investigator or qualified personnel.
Subjects with any unexplained positive neurological assessment item at screening should be 
excluded from enrollment in the study (exclusion criterion 18, Section 4.2).
A step-wise approach for the proposed neurological assessment plan is provided in Table 3.
Table 3
Quarterly Neurological Assessments
Domain
Step 1: Targeted Neurologic 
History
Step 2: If Abnormal Response
Vision
Diplopia or visual/visual field loss
Perform visual field assessment
Motor
Major motor weakness (eg, legs, arms)
Test leg strength (hopping, foot tapping), 
finger tapping, pronator drift and bilateral 
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Table 3
Quarterly Neurological Assessments
Domain
Step 1: Targeted Neurologic 
History
Step 2: If Abnormal Response
muscle strength
Tactile sensation
Paresthesia, anesthesia in any domain 
(peripheral, central)
Pinprick test
Coordination/Cerebellar
Clumsiness, difficulty with walking, 
writing, or fine motor skills, etc.
Finger-nose, heel-shin, heel-toe walk, 
writing sample, draw a clock
Speech
Dysarthria, expressive aphasia
Naming objects, repeat multipart phrase, 
observe for dysarthria or aphasia
Verbal comprehension
Agnosia, receptive aphasia
Test to follow routine commands, 
eg, close eyes, touch finger to ear.
Cognition/Behavior
New onset of difficulties with memory or 
thinking, important changes in behavior
Recall 3 objects over 1 minute, serial 7 s, 
proverbs. Changes in activities of daily 
living over prior 6 months
Additionally, should there be any unexplained abnormal neurological findings, the subject is to 
be urgently referred to a neurologist. The sites will immediately inform the sponsor of any such 
occurrences. If the neurologist confirms the presence of PML, appropriate actions, including 
discontinuation of investigational product, will be taken. Suspected PML cases will be reviewed 
promptly by Data Monitoring Committee (DMC) members with PML expertise and presented at 
the next scheduled DMC meeting(s). If PML is diagnosed, the treatment code will be unblinded 
and there will be an urgent meeting of the DMC. A flow diagram of the quarterly assessments 
and actions is presented in Figure 3. Any concerns from the DMC will be promptly 
communicated to the sponsor, investigator, and treating neurologist.
Figure 3
Flow Diagram for Quarterly Neurological Assessments
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DMC=Data Monitoring Committee; IND=investigational new drug; neuro=neurological; PML=progressive multifocal 
leukoencephalopathy.
It is important to note that assessments based on neurological evaluations are collected and 
evaluated in a different manner than observed or volunteered AEs. Given these differences, no 
attempt will be made to reconcile any apparent discrepancies between observed or volunteered 
AEs and data from neurological assessment collected from subjects. Investigators may determine 
if any finding on neurological testing constitutes an AE. Adverse event incidence rates will not 
be calculated from these neurological evaluation data but rather from the AE information 
recorded by the investigator.
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent and/or assent is signed until the end 
of the defined follow-up period stated in Section 7.1.3. (See Section 8, Adverse and Serious 
Adverse Events Assessment.)
7.2.3.5
Vital Signs
Vital signs will be measured at the time points specified in Table 1. Additional collection times 
or changes to collection times will be permitted, as necessary to ensure appropriate collection of 
safety data. Vital signs include blood pressure, pulse, respiratory rate, and temperature. Vital 
signs should be recorded before laboratory blood collection and endoscopic procedures are 
performed.
Single measurements of sitting blood pressure will be recorded at each time point. Blood 
pressure should be determined by cuff with the subject’s arm supported at the level of the heart 
and recorded to the nearest mm Hg using the same method, the same arm (preferably the 
dominant arm), and the same position throughout the study.
Respiratory rate will be measured with the subject in a comfortable position. The observer 
should hold the extremity of the subject as a distraction for the subject (ie, pretending he/she is 
taking the subject’s radial pulse) and count the respiration for 1 minute.
Oral temperature should be taken by placing a digital thermometer under the tongue for at least 
30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be 
used.
Any deviations from baseline (Visit 2) vital signs that are deemed clinically significant in the 
opinion of the investigator are to be recorded as an AE, unless documented in the subject’s
medical history as a pre-existing medical condition.
7.2.3.6
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the central laboratory’s normal 
procedures. Reference ranges are to be supplied by the central laboratory and will be used to 
assess the clinical laboratory data for clinical significance and out-of-range pathological changes. 
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The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
Screening laboratory tests, if considered by the investigator to be transient and inconsistent with 
the subject’s clinical condition, may be repeated once during the screening period for 
confirmation. The following clinical laboratory assessments will be performed at the time points 
specified in Table 1:
Serum chemistry

alkaline phosphatase 

aspartate aminotransferase

alanine aminotransferase

total bilirubin

total protein

albumin

glucose

blood urea nitrogen

creatinine

sodium 

potassium 

chloride 

calcium

carbon dioxide
Hematology

hemoglobin 

hematocrit 

mean corpuscular hemoglobin

mean corpuscular hemoglobin concentration

mean corpuscular volume

erythrocyte (red blood cell) count

leukocyte (white blood cell) count

neutrophils

lymphocytes

monocytes

eosinophils

basophils

platelet count
Virology

hepatitis B surface antigen (HBsAg)

hepatitis B core antibody (HBcAb)

hepatitis B surface antibody (HBsAb also 
referred as anti-HBsAg) if HBsAg is 
negative and HBcAb is positive

hepatitis C virus antibody (HCV Ab)

HCV ribonucleic acid (RNA) polymerase 
chain reaction (PCR) if HCV Ab is positive
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Urinalysis

glucose

protein

specific gravity

pH

nitrite

bilirubin

ketones

hemoglobin

urobilinogen

leukocyte esterase
Virology test results must be confirmed as negative before enrollment in the study; if a virology 
test result is positive, the subject will be excluded from entering the study. Results of the 
virology screen will be reviewed and verified by the study monitor, but will not be collected in 
the CRF database.
Stool microbiology will be performed at the screening visit (Visit 1). The detection of 
Clostridium difficile by toxigenic stool culture (stool culture followed by detection of toxin) is 
considered the gold standard for the diagnosis of the colonization or infection with pathogenic 
C. difficile. Comparable sensitivity may be achieved by direct testing of stool via point-of-use 
rapid membrane enzyme immunoassay card for both C. difficile toxin A and B and glutamate 
dehydrogenase antigen on a card. Use of the card for point-of-care screening is encouraged 
where permitted by local regulation; any samples showing a positive result with this method 
should be sent for toxigenic stool culture. Molecular techniques such as PCR for detection of 
toxin RNA are also acceptable alternatives. Refer to the laboratory manual for further guidance 
and instruction for C. difficile screening.
A tuberculosis (TB) test (purified protein derivative [PPD] or QuantiFERON TB Gold) will be 
performed at the screening visit (Visit 1). A documented negative PPD test within 12 weeks 
before baseline (Visit 2) is acceptable. The IGRA official reading and method or test must be 
located in the source documentation.
A serum sample will be collected and banked for John Cunningham virus antibody testing. It 
may be analyzed if a subject shows neurologic symptoms suggestive of PML.
All laboratory assessments should be performed at central laboratories, with the exception of the 
following assessments: stool microbiology (local or central laboratory) and TB test (PPD or 
QuantiFERON TB GOLD) (refer to laboratory manual for details).
7.2.3.7
Pregnancy Test and Follicle-stimulating Hormone Test
A beta–human chorionic gonadotropin (β–HCG) pregnancy test will be performed on all females
of childbearing potential at the time points specified in Table 1; if pregnancy is suspected; or on 
withdrawal of the subject from the study. A serum pregnancy test will be performed at the 
screening visit (Visit 1); all other pregnancy tests will be urine tests.
Pregnancy tests are not required for females of nonchildbearing potential who have undergone 
hysterectomy or bilateral oophorectomy, have medically confirmed ovarian failure, or are 
medically confirmed postmenopausal (cessation of regular menses for at least 12 consecutive 
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months with no alternative pathological or physiological cause; postmenopausal status should be 
confirmed by FSH testing in females who have had 12 consecutive months of spontaneous 
amenorrhea and are 51 years of age or older).
7.2.3.8
Electrocardiogram
A 12-lead ECG will be recorded at the time points specified in Table 1. When timing of 
measurements coincide, ECGs should be performed before laboratory blood collection and 
endoscopic procedure.
A central ECG reader will be used in this study. The eligibility of the subject is based on the 
assessment of the ECG by the investigator. If abnormal results are observed following 
assessment by the central reader, the investigator, in consultation with the appointed sponsor or 
contract research organization (CRO) medical monitor, reconfirms subject eligibility to continue.
7.2.3.9
Chest X-ray
A chest x-ray will be performed during screening (Visit 1). If a subject has had a chest x-ray 
performed as a part of standard medical care within 12 weeks before screening (Visit 1), it does 
not need to be repeated as a part of screening. The official reading must be located in the 
subject’s source documentation.
7.2.3.10 Antidrug Antibodies
A blood sample for measurement of antidrug antibodies (ADA) and Nab will be collected at the 
time points specified in Table 1. Blood samples must be collected before administration of 
investigational product.
7.2.4
Others
 
 
 
 
 
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7.2.4.3
Health-related Quality of Life Assessments
Each subject will complete the HRQL assessments at the site during the visits specified in 
Table 1, using an electronic device. All health outcome and patient-reported questionnaires 
should be completed before any other assessments. The study site staff should check for 
completion of all PRO questionnaires.
It is important to note that patient-reported outcome (PRO) assessments are collected and 
evaluated in a different manner than observed or volunteered AEs. Given these differences, no 
attempt will be made to reconcile any apparent discrepancies between observed or volunteered 
AEs and PRO data collected from subjects. Adverse event incidence rates will not be calculated 
from these solicited data but rather from the information recorded by the investigator.
Inflammatory Bowel Disease Questionnaire
The IBDQ is a psychometrically validated PRO instrument for measuring the disease-specific 
HRQL in subjects with inflammatory bowel disease, including UC. The IBDQ consists of 32
items, which are grouped into 4 dimensions: bowel function, emotional status, systemic 
symptoms, and social function (Irvine et al., 1994). The 4 domains are scored as follows: 

Bowel symptoms: 10 to 70

Systemic symptoms: 5 to 35

Emotional function: 12 to 84

Social function: 5 to 35.
The total IBDQ score ranges from 32 to 224. For the total score and each domain, a higher score
indicates better HRQL. A score of at least 170 corresponds to clinical remission and an increase 
of at least 16 points is considered to indicate a clinically meaningful improvement.
The IBDQ is presented in Appendix 2.
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Short Form-36 Health Survey, Acute Form
The SF-36 is a generic quality-of-life instrument that has been widely used to assess HRQL of 
subjects. Generic instruments are used in general populations to assess a wide range of domains 
applicable to a variety of health states, conditions, and diseases. The SF-36 consists of 36 items 
that are aggregated into 8 multi-item scales (physical functioning, role – physical, bodily pain, 
general health, vitality, social functioning, role – emotional, and mental health), with scores 
ranging from 0 to 100 (Ware and Sherbourne, 1992). Higher scores indicate better HRQL.
7.2.4.4
Healthcare Resource Utilization Assessments
Hospitalizations, inpatient days, and 
 will be recorded at the time points specified in 
Table 1. Ulcerative colitis-related and other surgeries will be collected from subjects during the 
treatment period.
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7.2.5
Volume of Blood to Be Drawn from Each Subject
Table 4
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of Samples
Total Volume (mL)
Hematology
1
6
6
Serum chemistry
6
6
36
HBsAg
2
1
2
HBcAb
2
1
2
HCV Ab
2
1
2
FSH
2
1
2
Serum -hCGa
2
1
2
TB test (QuantiFERON TB Gold or 
PPD)
3
1
3
JCV antibody banked sample
3.5
1
3.5
2.5
3
7.5
5
3
15
4
3
12
 
3
5
15
ADA and NAb sampling
3
6
18
Total mL
126
Ab=antibody; ADA=antidrug antibodies; -hCG=beta-human chorionic gonadotropin; 
; FSH=follicle-
stimulating hormone; HBsAg=hepatitis B surface antigen; HBcAb=hepatitis B core antibody; HCV=hepatitis C virus; 
JCV=John Cunningham virus; 
; Nab=neutralizing antibody; 
PPD=purified protein derivative; TB=tuberculosis
a -hCG testing for female subjects only.
b If a catheter is used, the first mL is to be discarded; then take 4 mL into appropriate tube for 
. A total 
of 5 mL of blood drawn has been used in determination of sample volume.
The amount of blood to be drawn for each assessment is an estimate. The amount of blood to be 
drawn may vary according to the instructions provided by the manufacturer or laboratory for an 
individual assessment; however, the total volume drawn over the course of the study should be 
approximately 126 mL. When more than 1 blood assessment is to be done at the time
point/period, if they require the same type of tube, the assessments may be combined.
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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).
All AEs are collected from the time the informed consent and/or assent is signed until the end of 
the defined follow-up period stated in Section 7.1.3. This includes events occurring during the 
screening phase of the study, regardless of whether or not investigational product is 
administered. Where possible, a diagnosis rather than a list of symptoms should be recorded. If a 
diagnosis has not been made, then each symptom should be listed individually. All AEs should 
be captured in the subject’s source document. In addition to untoward AEs, unexpected benefits 
outside the investigational product indication should also be captured in the subject’s source 
document.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia before
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded in the subject’s source document).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
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Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study in the eCRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown.
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
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8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to Shire Global Pharmacovigilance using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine beta 
human chorionic gonadotropin (-hCG) test or ultrasound result will determine the pregnancy 
onset date.
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8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Intentional or unintentional administration of investigational product at a dose 
interval that is less than 2 weeks between doses

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
There is no specific antidote for overdose with SHP647. Treatment should be symptomatic and 
supportive.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is Section 6.8 of the SHP647 investigator’s 
brochure, which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to Shire Global 
Pharmacovigilance and the CRO/Shire medical monitor within 24 hours of the first awareness of 
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the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse,
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or email the form to Shire Global Pharmacovigilance. A 
copy of the Shire Clinical Study Serious Adverse Event and Non-serious AEs Required by the 
Protocol Form (and any applicable follow-up reports) must also be sent to the CRO/Shire 
medical monitor using the details specified in the emergency contact information section of the 
protocol.
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death.

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an ED or at 
home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; or the 
development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be reported 
to Shire Global Pharmacovigilance and the CRO/Shire medical monitor within 24 hours of the 
first awareness of the event.
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In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to Shire Global 
Pharmacovigilance within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor or the CRO is responsible for notifying the relevant regulatory authorities, US 
central Institutional Review Boards (IRBs), and European Union (EU) central Ethics Committees 
(ECs) of related, unexpected SAEs.
In addition the CRO is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP647 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered in the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process. These data will be handled in such a way that, before unblinding, 
any data that may unblind study team personnel will be presented as blinded information or 
otherwise will not be made available. If applicable, unblinded data may be made available to 
quality assurance representatives for the purposes of conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
The SAP will be finalized before unblinding to preserve the integrity of the statistical analysis 
and study conclusions.
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All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, Cary, 
NC, USA).
Unless otherwise specified, summary tabulations will be presented by treatment group. All data 
listings will be sorted by treatment group, site, and subject number, and will include the subject’s 
age, sex, and race.
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented.
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis or adaptive design in this study.
An external DMC will be established to review the overall safety of the study subjects on an 
ongoing basis.
The DMC will be responsible for the ongoing monitoring of safety of subjects enrolled in the 
study according to the DMC charter. Recommendations made by the DMC to alter the conduct 
of the study or to amend the protocol will be forwarded to Shire for review and for a final 
decision. Shire or its designee will notify investigative sites and regulatory authorities as 
appropriate, of DMC recommendations (which may include summaries of aggregate analyses of 
endpoint events and of safety data that are not endpoints).
Further details regarding the DMC can be found in the DMC charter, which will be available 
before the administration of investigational product to any subject. Analyses of the data for DMC 
review will be conducted according to the DMC charter and DMC SAP. Because no formal 
hypothesis testing for safety assessments is planned, multiplicity concerns regarding repeated 
analyses are not applicable.
9.6
Sample Size Calculation and Power Considerations
Graphical methods are used to control the global family-wise type I error rate (FWER) at the 
.05 level (2-sided) for the comparisons of the 2 SHP647 treatment groups with the placebo 
group. Alpha is initially split equally at the .025 level (2-sided) for each of the pairwise treatment 
comparisons for the primary endpoint. Therefore, the power analysis and sample size estimation 
was calculated based on the chi-square test of proportions using nQuery Advisor Version 7.0 for 
an individual SHP647 dose compared with placebo.
Assuming a .025 (2-sided) significance level for each pairwise treatment comparison, 
approximately 1375 subjects will be screened to randomize 825 subjects (2:2:1 allocation ratio: 
330 subjects in the 25 mg SHP647 treatment group, 330 subjects in the 75 mg SHP647 treatment 
group, and 165 subjects in the placebo group) which would yield an approximately 93% power 
to detect individual pairwise treatment difference in the primary efficacy endpoint, remission at 
Week 12, of 11% (5% placebo versus 16% SHP647). Expected remission rates at Week 12 are 
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based on observed rates from the A7281009 study and placebo remission rates from literature 
(Feagan et al., 2013; Sandborn et al., 2017). No adjustment for missing data is required in these 
sample size calculations as subjects with missing data for clinical remission at Week 12 are 
imputed as failures and the above rates account for these subjects.
With the sample size of 825, Table 5 provides the power for detecting a treatment difference 
between a SHP647 treatment group and the placebo group for the key secondary endpoints.
Table 5
Power to Detect the Corresponding Treatment Effect for Key Secondary 
Endpoints
Key Secondary Endpoint at Week 12
SHP647 Assumption
Placebo Assumption
Power
Endoscopic remission
24%
8%
0.99
Clinical remission
30%
16%
0.89
Clinical response by composite score
50%
35%
0.82
Mucosal healing
15%
5%
0.88
9.7
Study Population
The screened set will consist of all subjects who have signed an informed consent document.
The randomized set will consist of all subjects in the screened set for whom a randomization 
number has been assigned.
The safety set will consist of all subjects who have received at least 1 dose of investigational 
product.
The full analysis set (FAS) will consist of all subjects in the randomized set who have received at 
least 1 dose of investigational product.
The per-protocol (PP) set will consist of all subjects in the FAS who complete the Week 12 visit 
and who do not have predefined protocol deviations that may affect the primary efficacy 
endpoint. 
The completer set will consist of all subjects in the FAS who have completed the final scheduled 
primary assessment for this study.
 
 
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9.8
Efficacy Analyses
Unless otherwise specified, all efficacy analyses will be based on the FAS and subjects will be 
analyzed according to their randomized treatment, regardless of the treatment they actually 
received.
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects in remission at the Week 12 visit. 
Remission is defined as a composite score of patient-reported symptoms using daily e-diary and 
centrally read endoscopy as follows:

stool frequency subscore of 0 or 1 with at least a 1-point change from baseline
AND

rectal bleeding subscore of 0
AND

endoscopic subscore of 0 or 1 (modified, excludes friability)
The primary efficacy endpoint will be compared for each active treatment group (25 mg or 
75 mg SHP647) to the placebo group using a Cochran-Mantel Haenszel (CMH) chi-square test
stratified by status of prior anti-TNF treatment and glucocorticoid use at baseline (Visit 2). 
Subjects with missing remission data at the Week 12 visit will be considered failures and 
counted as nonresponders. The endoscopy score will be based on centrally read results.
The primary endpoint will be tested by the following hypothesis:
H0: δ = 0
H1: δ ≠ 0
Where δ is the common treatment difference across strata, j=1 to m. The common treatment 
difference is a weighted average of the stratum-specific treatment differences.
The estimate of the common treatment difference along with the corresponding stratified 
Newcombe 95% confidence interval (CI) using the method of Yan and Su (2010) and CMH 
p-value will be presented for each active treatment group to placebo comparison.
Sensitivity analyses which explore the impact of missing data on the primary efficacy endpoint 
will be conducted. These analyses may compare imputations of the missing values which favor 
placebo (eg, worst case) and/or imputations which favor active treatment (eg, best case). In 
addition, imputation methods based on informative missingness and other missing data 
mechanisms may be performed. Additional sensitivity analyses will also be conducted using the 
per-protocol set and the completer set. Additional analyses may be developed in the SAP. All 
sensitivity analyses will be described in the SAP.
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Prespecified subgroup analyses are planned for the primary endpoint including, but not limited to 
gender, prior anti-TNF treatment, glucocorticoid use at baseline, randomization stratum, and 
other important subjects. A full list of important subgroups will be described within the SAP. 
Within subgroups, efficacy endpoints will be compared for each active treatment group (25 mg 
SHP647 and 75 mg SHP647) with the placebo group using a Chi-square test. Subjects with 
missing remission data at the Week 12 visit will be considered failures and counted as 
nonresponders. The endoscopy subscore will be based on centrally read results. The estimate of 
the treatment difference, along with the corresponding Newcombe (hybrid-score) 95% CI and 
Chi-square test p-value, will be presented.
Adjustments for Multiplicity
The global FWER for the statistical tests of the primary and key secondary endpoints will be 
strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in Bretz 
et al (2009) will be utilized to propagate α from primary to key secondary endpoints and between 
the two SHP647 treatment group and placebo comparisons. Alpha is initially split equally at the 
.025 level (2-sided) for each of the pairwise treatment comparisons for the primary endpoint (P) 
and alpha is propagated in a hierarchical manner to each of the 4 key secondary endpoints 
(K1-K4) within a pairwise treatment comparison. A graphical visualization of the α propagation
is presented in Figure 4.
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Figure 4
Visualization of Alpha Propagation
Only p-values that are significant according to this graphical approach are inferential and 
statistically significant. All other p-values are descriptive.
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9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoints are as follows:

Proportion of subjects with endoscopic remission, as defined by centrally read endoscopic 
subscore 0 or 1 (modified, excludes friability), at the Week 12 visit.

Proportion of subjects with clinical remission, as defined by stool frequency subscore of 0 or 
1 with at least a 1-point change from baseline in stool frequency subscore, and rectal 
bleeding subscore of 0, at the Week 12 visit.

Proportion of subjects with clinical response based on composite score at the Week 12 visit. 
Clinical response (composite) is defined as a decrease from baseline in the composite score 
of patient-reported symptoms using daily e-diary and centrally read endoscopy of at least 
2 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding 
≥1 point or a subscore for rectal bleeding ≤1.

Proportion of subjects with mucosal healing based on endoscopic and histological assessment 
at the Week 12 visit. Mucosal healing is defined by centrally read endoscopic subscore 0 or 1 
(modified, excludes friability) and centrally read Geboes score of ≤2.
Similar to the primary endpoint, the 4 key secondary endpoints will all be tested by the following 
hypothesis:
H0: δ = 0
H1: δ ≠ 0
The key secondary endpoints will be analyzed using the same approach as described for the 
primary efficacy endpoint. Subjects with missing key secondary endpoint data at the Week 12 
visit will be considered failures and counted as nonresponders.
In addition, the sensitivity analyses and prespecified subgroup analyses described for the primary 
endpoint will be repeated for the key secondary endpoints.
9.8.2.2
Other Secondary Efficacy Endpoints
The other secondary endpoints are as follows:

Proportion of subjects with remission, defined as a total Mayo score ≤2 with no individual 
subscore (stool frequency, rectal bleeding, endoscopy [modified, excludes friability], and 
physician’s global assessment) exceeding 1, at the Week 12 visit.

Proportion of subjects with clinical response based on total Mayo score at the Week 12 visit. 
Clinical response (Mayo) is defined as a decrease from baseline in the total Mayo score of at 
least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal 
bleeding ≥1 point or a subscore for rectal bleeding ≤1.
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
Proportion of subjects with partial Mayo score ≤2 with no individual subscore >1 at the 
Week 4, 8, and 12 visits. The partial Mayo score does not include the endoscopy subscore.

Proportion of subjects with clinical remission as defined by stool frequency subscore of 0 or 
1 with at least a 1-point change from baseline in stool frequency subscore, and rectal 
bleeding subscore of 0, at Weeks 4 and 8.

Proportion of subjects with endoscopic remission at the Week 12 visit with endoscopic 
subscore of 0.

Proportion of subjects with clinical remission at the Week 4, 8, and 12 visits with both rectal 
bleeding and stool frequency subscores of 0.

Proportion of subjects with deep remission at the Week 12 visit. Deep remission is defined as 
both endoscopic and rectal bleeding subscores of 0, and stool frequency subscore ≤1 and a 
centrally read Geboes score of ≤2.

Change from baseline at the Week 12 visit in abdominal pain, urgency and diarrhea item 
scores, absolute stool frequency, absolute rectal bleeding and total sign/symptom score based 
on subject daily e-diary entries (sum of rectal bleeding, stool frequency, abdominal pain, 
diarrhea, and urgency).

Change from baseline in IBDQ domain and total (absolute) scores (time frame: Week 0, 
Week 8, up to Week 12, or early termination).

Change from baseline in SF-36, version 2, acute (physical and mental component summary 
scores and individual domain scores) to the Week 12/ET visit.

Incidence of all-cause hospitalizations and total inpatient days.
Other secondary/exploratory endpoints will be summarized by descriptive statistics and 
presented by treatment group. Where appropriate, other secondary efficacy endpoints will be 
analyzed with the following analysis methods.

Binary endpoints will be analyzed using the same approach as described for the primary 
endpoint. Subjects with missing binary endpoint data at a visit will be considered failures and 
counted as nonresponders.

Continuous endpoints that are only measured at baseline and the Week 12 visit will be 
analyzed using an analysis of covariance (ANCOVA) model with fixed effects for treatment 
group (categorical), status of prior anti-TNF treatment (categorical), and glucocorticoid use 
at baseline (categorical), and the baseline value as a continuous covariate. From this model, 
estimates of the least squares means, treatment differences, standard errors, p-values, and 
95% CIs for least squares mean treatment differences will be provided.

Continuous endpoints that are measured repeatedly over time will be analyzed using a linear 
repeated measures mixed model with restricted maximum likelihood estimation (REML). 
The model will include fixed effects for treatment group (categorical), visit (categorical), 
treatment group by visit interaction, status of prior anti-TNF treatment (categorical), and 
glucocorticoid use at baseline (categorical); baseline value as a continuous covariate; and 
repeated measures across visit for subject. From this model, estimates of least squares means, 
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treatment differences, standard errors, p-values, and 95% CIs for least squares mean 
treatment differences for each visit will be provided.
Full details of the analysis of other secondary efficacy endpoints will be included in the SAP.
9.8.3
Exploratory Efficacy Endpoints
The exploratory endpoints are as follows:
Exploratory efficacy endpoints will be summarized with descriptive statistics and presented by 
treatment group. Exploratory efficacy endpoints will be analyzed using the same approach 
described as for the other secondary endpoints. See Section 9.8.2.2 for an overview of the 
planned analyses. Full details for the analysis of exploratory efficacy endpoints will be included 
in the SAP.
9.9
Safety Analyses
All safety analyses will be performed using the safety set. Subjects will be analyzed according to 
the treatment they actually received.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. 
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Treatment-emergent AEs (TEAEs) are defined as AEs with start dates at the time of or following 
the first exposure to investigational product. The number of events, incidence, and percentage of 
TEAEs will be calculated overall, by SOC, by preferred term, and by treatment group. 
Treatment-emergent AEs will be further summarized by severity and relationship to 
investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized/listed.
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group 
and visit. Potentially clinically important findings will also be summarized or listed.
Antidrug antibody data will be summarized by treatment group and visit.
Further details of safety analyses will be described in the SAP.
9.10 Other Analyses
 
 
 
 
 
 
 
 
 
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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1 Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996) and E6 R2 (2017), EU Directive 
2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required before release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place before the start of 
the study. An insurance certificate is supplied to the CRO and investigator as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will upload the clinical study report to the EudraCT database and will also provide a 
summary of the clinical study report to the CRO for submission to the competent authority of the 
countries concerned as required by local regulatory requirement(s). This requirement will be 
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fulfilled within 1 year for nonpediatric studies as per guidance. The ECs will be provided with a 
copy of the same summary as locally required.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2 Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements 
and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site before commitment to participate in this study. The investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s or subject’s legally authorized representative’s consent and/or assent, as applicable,
inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any coinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor or designee. Upon study completion, the investigator will provide the sponsor, 
IRB/EC, and regulatory agency with final reports and summaries as required by (inter)national 
regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded in eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic CRFs must be 
completed by the investigator or designee as stated in the site delegation log.
All data in the eCRF will have a separate source (eg, paper or ePRO); no data will be recorded 
directly in the eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate/study monitor will verify the contents against the source data per 
the monitoring plan. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject e-diary, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The clinical research associate/study monitor (and auditors, IRB/EC or regulatory inspectors) 
may check the CRF entries against the source documents. The consent form includes a statement 
by which the subject agrees to the monitor/auditor from the sponsor or its representatives, 
national or local regulatory authorities, or the IRB/EC, having access to source data 
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(eg, subject’s medical file, appointment books, original laboratory reports, x-rays etc). Nonstudy 
site personnel will not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3 Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and/or assent from 
all study subjects before any study-related procedures including screening assessments. All 
consent documentation must be in accordance with applicable regulations and GCP. Each subject 
or the subject’s legally authorized representative, as applicable, is requested to sign and date the 
subject informed consent form or a certified translation if applicable, after the subject has 
received and read (or been read) the written subject information and received an explanation of 
what the study involves, including but not limited to: the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities. A copy of the informed consent 
documentation (ie, a complete set of subject information sheets and fully executed signature 
pages) must be given to the subject or the subject’s legally authorized representative, as 
applicable. This document may require translation into the local language. Signed consent forms 
must remain in each subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor before
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the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) before study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved before site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Before implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4 Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the sponsor or designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP647; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
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and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5 Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg,
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish before release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days before
submission for publication. If requested in writing by Shire, the institution and principal 
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investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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11.
REFERENCES
 
 
Bretz, F., Maurer, W., Brannath, W. & Posch, M. 2009. A graphical approach to sequentially 
rejective multiple test procedures. Stat Med, 28, 586-604.
Briskin, M., Winsor-Hines, D., Shyjan, A., Cochran, N., Bloom, S., Wilson, J., McEvoy, L. M., 
Butcher, E. C., Kassam, N., Mackay, C. R., Newman, W. & Ringler, D. J. 1997. Human 
mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract 
and associated lymphoid tissue. Am J Pathol, 151, 97-110.
 
 
Eaden, J. A. & Mayberry, J. F. 2002. Guidelines for screening and surveillance of asymptomatic 
colorectal cancer in patients with inflammatory bowel disease. Gut, 51, V10-2.
Feagan, B. G., Rutgeerts, P., Sands, B. E., Hanauer, S., Colombel, J. F., Sandborn, W. J., Van 
Assche, G., Axler, J., Kim, H. J., Danese, S., Fox, I., Milch, C., Sankoh, S., Wyant, T., 
Xu, J. & Parikh, A. 2013. Vedolizumab as induction and maintenance therapy for 
ulcerative colitis. N Engl J Med, 369, 699-710.
Geboes, K., Riddell, R., Ost, A., Jensfelt, B., Persson, T. & Lofberg, R. 2000. A reproducible 
grading scale for histological assessment of inflammation in ulcerative colitis. Gut, 47, 
404-9.
Irvine, E., Feagan, B. G., Rochon, J., Archambault, A., Fedorak, R. N. & Groll, A. 1994. Quality 
of life: a valid and reliable measure of therapeutic efficacy in the treatment of IBD. 
Canadian Crohn’s Relapse Prevention Trial Study Group. Gastroenterology, 106, 287-
296.
 
.
Lacy, C., Armstrong, L., Goldman, M. & Lance, L. 2001-2002. Drug Information Handbook, 
Cleveland, OH, LexiComp, Inc.
Liaskou, E., Karikoski, M., Reynolds, G. M., Lalor, P. F., Weston, C. J., Pullen, N., Salmi, M., 
Jalkanen, S. & Adams, D. H. 2011. Regulation of mucosal addressin cell adhesion 
molecule 1 expression in human and mice by vascular adhesion protein 1 amine oxidase 
activity. Hepatology, 53, 661-72.
Molodecky, N. A., Soon, I. S., Rabi, D. M., Ghali, W. A., Ferris, M., Chernoff, G., Benchimol, 
E. I., Panaccione, R., Ghosh, S., Barkema, H. W. & Kaplan, G. G. 2012. Increasing 
incidence and prevalence of the inflammatory bowel diseases with time, based on 
systematic review. Gastroenterology, 142, 46-54.e42; quiz e30.
Sandborn, W. J., Su, C., Sands, B. E., D'Haens, G. R., Vermeire, S., Schreiber, S., Danese, S., 
Feagan, B. G., Reinisch, W., Niezychowski, W., Friedman, G., Lawendy, N., Yu, D., 
Woodworth, D., Mukherjee, A., Zhang, H., Healey, P. & Panes, J. 2017. Tofacitinib as 
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Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med, 376, 1723-
1736.
Schroeder, K. W., Tremaine, W. J. & Ilstrup, D. M. 1987. Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J 
Med, 317, 1625-9.
Shyjan, A. M., Bertagnolli, M., Kenney, C. J. & Briskin, M. J. 1996. Human mucosal addressin 
cell adhesion molecule-1 (MAdCAM-1) demonstrates structural and functional 
similarities to the alpha 4 beta 7-integrin binding domains of murine MAdCAM-1, but 
extreme divergence of mucin-like sequences. J Immunol, 156, 2851-7.
Steffen, B. J., Breier, G., Butcher, E. C., Schulz, M. & Engelhardt, B. 1996. ICAM-1, VCAM-1, 
and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and 
mediate binding of lymphocytes in vitro. Am J Pathol, 148, 1819-38.
Vermeire, S., Sandborn, W. J., Danese, S., Hebuterne, X., Salzberg, B. A., Klopocka, M., 
Tarabar, D., Vanasek, T., Gregus, M., Hellstern, P. A., Kim, J. S., Sparrow, M. P., 
Gorelick, K. J., Hinz, M., Ahmad, A., Pradhan, V., Hassan-Zahraee, M., Clare, R., 
Cataldi, F. & Reinisch, W. 2017. Anti-MAdCAM antibody (PF-00547659) for ulcerative 
colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. 
Lancet.
Ware, J. E., Jr. & Sherbourne, C. D. 1992. The MOS 36-item short-form health survey (SF-36). 
I. Conceptual framework and item selection. Med Care, 30, 473-83.
Yan, X. & Su, X. 2010. Stratified Wilson and Newcombe Confidence Intervals for Multiple 
Binomial Proportions. Stat Biopharm Res, 2, 329-35.
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12.
APPENDICES
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
06 Jul 2017
Global
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Appendix 2
Scales and Assessments
The following scales/assessments will be used in the study and are provided in this appendix:

Stool frequency screening questions

Mayo scoring system

Geboes score grading system

PRO-UC diary

IBDQ

SF-36
For questionnaires, language-specific validated versions will be used only.
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Stool Frequency Screening Questions
1. Think back to before you ever had symptoms of UC. How many bowel movements did you 
typically have in a 24-hour period before ever having symptoms of UC? 
Number of bowel movements in a 24-hour period before ever having symptoms of UC:
____________
2. Remission of ulcerative colitis (UC) is defined as a time when your symptoms have gone 
away, you’re feeling well, and/or your UC is no longer impacting your regular daily 
activities. Have you ever experienced a remission of UC? 
Yes
No
If YES,
When you are in remission how many bowel movements do you typically have in a 24-hour 
period? Remember that remission is a time when your symptoms have gone away, you’re 
feeling well, and/or your UC is no longer impacting you regular daily activities.
Number of bowel movements in a 24-hour period when in remission:
____________
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Mayo Scoring System for Assessment of Ulcerative Colitis Activity
Stool frequencya
0 = Normal number of stools for this subject
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
Subscore, 0 to 3
Rectal bleedingb
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood (more than just streaks) or streaks of blood with stool most of the time
3 = Blood alone passes
Subscore, 0 to 3
Findings on endoscopy
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern)
2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Subscore, 0 to 3
Physician’s global assessmentc:
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Subscore, 0 to 3
The total Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.
a
Each subject serves as his or her own control to establish the degree of abnormality of the stool frequency.
b
The daily bleeding score represents the most severe bleeding of the day.
c
The physician’s global assessment acknowledges the three other criteria, the subject’s daily recollection of abdominal 
discomfort and general sense of wellbeing, and other observations, such as physical findings and the subject’s performance 
status.
Source: Schroeder et al., 1987.
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Geboes Score Grading System
Grade 0 – Structural (architectural change) 
Subgrades
0.0
No abnormality 
0.1
Mild abnormality 
0.2
Mild or moderate diffuse or multifocal abnormalities
0.3
Severe diffuse or multifocal abnormalities 
Grade 1 – Chronic inflammatory infiltrate 
Subgrades
1.0
No increase
1.1
Mild but unequivocal increase
1.2
Moderate increase
1.3
Marked increase
Grade 2A – Lamina propria eosinophils 
Subgrades
2A.0
No increase
2A.1
Mild but unequivocal increase
2A.2
Moderate increase
2A.3
Marked increase
Grade 2B – Lamina propria neutrophils
Subgrades
2B.0
None 
2B.1
Mild but unequivocal increase
2B.2
Moderate increase
2B.3
Marked increase
Grade 3 – Neutrophils in epithelium 
Subgrades
3.0
None 
3.1
< 5% crypts involved 
3.2
< 50% crypts involved 
3.3
> 50% crypts involved 
Grade 4 – Crypt destruction 
Subgrades
4.0
None 
4.1
Probable – local excess of neutrophils in part of crypt 
4.2
Probable – marked attenuation 
4.3
Unequivocal crypt destruction 
Grade 5 – Erosion or ulceration 
Subgrades
5.0
No erosion, ulceration, or granulation tissue
5.1
Recovering epithelium + adjacent inflammation 
5.2
Probable erosion - focally stripped 
5.3
Unequivocal erosion 
5.4
Ulcer or granulation tissue
Source: Geboes et al., 2000
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Patient-reported Outcomes – Ulcerative Colitis (PRO-UC) Diary Version 1
Item #
Item
1.
Please indicate how often you had a bowel movement over the past 24 hours. A bowel movement is 
defined as a trip to the toilet and passing stool (liquid, soft, or solid), passing blood only, passing 
blood and mucus, or passing mucus only.
Enter number of bowel movements passed: 
2.
Please rate your worst experience of rectal bleeding over the past 24 hours.
No blood seen
Streaks of blood with stool less than half of the time
Obvious blood (more than just streaks) or streaks of blood with stool most of the time
Blood alone passes
3.
You indicated you had X bowel movements in the past 24 hours. Of these, how many had blood, 
either in the stool, in the toilet bowl, or on the toilet paper?
Enter the number of bowel movements with blood: 
4.
You indicated you had X bowel movements in the past 24 hours. Of these, how many were loose or 
watery?
Enter number of loose or watery bowel movements: 
5.
You indicated you had X bowel movements in the past 24 hours. How many of those involved 
urgency (having to suddenly rush to the toilet to make it on time)?
Enter number of bowel movements with urgency: 
6.
Please rate your worst abdominal pain over the past 24 hours.
0-10 numeric rating scale, with 0 anchor at “No pain” and 10 at “Worst Imaginable Pain”
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Inflammatory Bowel Disease Questionnaire (IBDQ)
This questionnaire is designed to find out how you have been feeling during the last 2 weeks.
You will be asked about symptoms you have been having as a result of your inflammatory bowel 
disease, the way you have been feeling in general, and how your mood has been.
1. How frequent have your bowel movements been during the last two weeks? Please indicate 
how frequent your bowel movements have been during the last two weeks by picking one of 
the options from:
1. BOWEL MOVEMENTS AS OR MORE FREQUENT THAN THEY HAVE EVER 
BEEN
2. EXTREMELY FREQUENT
3. VERY FREQUENT
4. MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
5. SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
6. SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
7. NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
2. How often has the feeling of fatigue or of being tired and worn out been a problem for you 
during the last 2 weeks? Please indicate how often the feeling of fatigue or tiredness has been 
a problem for you during the last 2 weeks by picking one of the options from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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3. How often during the last 2 weeks have you felt frustrated, impatient, or restless? Please 
choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
4. How often during the last 2 weeks have you been unable to attend school or do your work 
because of your bowel problem? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
5. How much of the time during the last 2 weeks have your bowel movements been loose?
Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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6. How much energy have you had during the last 2 weeks? Please choose an option from:
1. NO ENERGY AT ALL
2. VERY LITTLE ENERGY
3. A LITTLE ENERGY
4. SOME ENERGY
5. A MODERATE AMOUNT OF ENERGY
6. A LOT OF ENERGY
7. FULL OF ENERGY
7. How often during the last 2 weeks did you feel worried about the possibility of needing to 
have surgery because of your bowel problem. Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
8. How often during the last 2 weeks have you had to delay or cancel a social engagement 
because of your bowel problem? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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9. How often during the last 2 weeks have you been troubled by cramps in your abdomen?
Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
10. How often during the last 2 weeks have you felt generally unwell? Please choose an option 
from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
11. How often during the last 2 weeks have you been troubled because of fear of not finding a 
washroom? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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12. How much difficulty have you had, as a result of your bowel problems, doing leisure or 
sports activities you would have liked to have done during the last 2 weeks? Please choose an 
option from:
1. A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE
2. A LOT OF DIFFICULTY
3. A FAIR BIT OF DIFFICULTY
4. SOME DIFFICULTY
5. A LITTLE DIFFICULTY
6. HARDLY ANY DIFFICULTY
7. NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS OR 
LEISURE ACTIVITIES
13. How often during the last 2 weeks have you been troubled by pain in the abdomen? Please 
choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
14. How often during the last 2 weeks have you had problems getting a good night’s sleep, or 
been troubled by waking up during the night? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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15. How often during the last 2 weeks have you felt depressed or discouraged? Please choose an 
option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
16. How often during the last 2 weeks have you had to avoid attending events where there was 
no washroom close at hand? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
17. Overall, in the last 2 weeks, how much of a problem have you had with passing large 
amounts of gas? Please choose an option from:
1. A MAJOR PROBLEM
2. A BIG PROBLEM
3. A SIGNIFICANT PROBLEM
4. SOME TROUBLE
5. A LITTLE TROUBLE
6. HARDLY ANY TROUBLE
7. NO TROUBLE
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18. Overall, in the last 2 weeks, how much a problem have you had maintaining or getting to, the 
weight you would like to be at. Please choose an option from:
1. A MAJOR PROBLEM
2. A BIG PROBLEM
3. A SIGNIFICANT PROBLEM
4. SOME TROUBLE
5. A LITTLE TROUBLE
6. HARDLY ANY TROUBLE
7. NO TROUBLE
19. Many patients with bowel problems often have worries and anxieties related to their illness.
These include worries about getting cancer, worries about never feeling any better, and 
worries about having a relapse. In general, how often during the last 2 weeks have you felt 
worried or anxious? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
20. How much of the time during the last 2 weeks have you been troubled by a feeling of 
abdominal bloating? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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21. How often during the last 2 weeks have you felt relaxed and free of tension? Please choose 
an option from:
1. NONE OF THE TIME
2. A LITTLE OF THE TIME
3. SOME OF THE TIME
4. A GOOD BIT OF THE TIME
5. MOST OF THE TIME
6. ALMOST ALL OF THE TIME
7. ALL OF THE TIME
22. How much of the time during the last 2 weeks have you had a problem with rectal bleeding 
with your bowel movements? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
23. How much of the time during the last 2 weeks have you felt embarrassed as a result of your 
bowel problem? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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24. How much of the time during the last 2 weeks have you been troubled by a feeling of having 
to go to the bathroom even though your bowels were empty? Please choose an option from
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
25. How much of the time during the last 2 weeks have you felt tearful or upset? Please choose 
an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
26. How much of the time during the last 2 weeks have you been troubled by accidental soiling 
of your underpants? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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27. How much of the time during the last 2 weeks have you felt angry as a result of your bowel 
problem? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
28. To what extent has your bowel problem limited sexual activity during the last 2 weeks?
Please choose an option from:
1. NO SEX AS A RESULT OF BOWEL DISEASE
2. MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE
3. MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE
4. SOME LIMITATION AS A RESULT OF BOWEL DISEASE
5. A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE
6. HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE
7. NO LIMITATION AS A RESULT OF BOWEL DISEASE
29. How much of the time during the last 2 weeks have you been troubled by nausea or feeling 
sick to your stomach? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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06 Jul 2017
30. How much of the time during the last 2 weeks have you felt irritable? Please choose an 
option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
31. How often during the past 2 weeks have you felt a lack of understanding from others? Please 
choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
32. How satisfied, happy, or pleased have you been with your personal life during the past 
2 weeks? Please choose one of the following options from:
1. VERY DISSATISFIED, UNHAPPY MOST OF THE TIME
2. GENERALLY DISSATISFIED, UNHAPPY
3. SOMEWHAT DISSATISFIED, UNHAPPY
4. GENERALLY SATISFIED, PLEASED
5. SATISFIED MOST OF THE TIME, HAPPY
6. VERY SATISFIED MOST OF THE TIME, HAPPY
7. EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY OR 
PLEASED
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Short Form-36 Health Survey, Acute Form
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Appendix 3
Glucocorticoid Equivalent Doses
Glucocorticoid
Equivalent Dose (mg)
Short Acting:
Cortisone
25
Hydrocortisone
20
Intermediate Acting:
Methlyprednisolone
4
Prednisolone
5
Prednisone
5
Triamcinolone
4
Long Acting:
Betamethasone
0.6
Dexamethasone
0.75
Reference: Lacy et al., 2001-2002
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PROTOCOL: SHP647-302
TITLE:
A Phase 3 Randomized, Double-blind, Placebo-controlled, 
Parallel-group Efficacy and Safety Study of SHP647 as Induction 
Therapy in Subjects with Moderate to Severe Ulcerative Colitis
(FIGARO UC 302)
DRUG:
SHP647
IND:
100,222
EUDRACT NO.:
2017-000572-28
SPONSOR:
Shire Human Genetic Therapies, Inc. ("Shire")
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
, MD, PhD
PROTOCOL 
HISTORY:
Protocol Amendment 1: 05 Sep 2018
Original Protocol: 06 Jul 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.
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Shire 
CONFIDENTIAL 
Page 2 
SHP647-302 Protocol Amendment 1 
SHP647 
 
05 Sep 2018 
 
PROTOCOL SIGNATURE PAGE 
Sponsor’s (Shire) Approval 
Signature: 
Date: 
 MD,
 
 
Investigator’s Acknowledgement 
I have read this protocol for Shire Study SHP647-302. 
Title: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and 
Safety Study of SHP647 as Induction Therapy in Subjects with Moderate to Severe Ulcerative 
Colitis (FIGARO UC 302). 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation guidelines on Good Clinical Practice 
and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
 
 
 
 
Signature: 
 
Date: 
 
11-SEP-2018
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Page 3
SHP647-302 Protocol Amendment 1
SHP647
05 Sep 2018
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1
Amendment Date
05 Sep 2018
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Emergency Contact Information
Section 8.2.2, Reporting Procedures
Section 8.2.4, Serious Adverse 
Event Collection Time Frame
Replaced “Shire Global 
Pharmacovigilance” with “the Shire 
Global Drug Safety Department.”
Updated the global fax number and 
email address for serious adverse 
event reporting.
To provide updated emergency 
contact information.
The email address was updated in 
accordance with SHP647-302
Protocol Administrative Change 
Memo #4, dated 03 May 2018.
Product Quality Complaints
Updated the email address for 
reporting of product complaints that 
originate in the European Union and 
Rest of World.  The email address 
now is the same for all regions.
To provide updated information for 
reporting of product complaints.
Study Synopsis, Site(s) and 
Region(s)
Section 3.3, Sites and Regions
Revised the anticipated number of 
study sites from 175 to 210.
To provide a revised projection for 
the number of study sites expected to 
participate.
Study Synopsis, Objectives, Other 
Secondary
Section 2.2.2.2, Other Secondary 
Objectives
Section 2.2.3, Exploratory 
Objectives
Added text to clarify the endpoints 
associated with the other secondary 
objectives based on “other clinical 
outcomes” and
 
 
To clarify the measures that support 
those objectives.
Study Synopsis, Inclusion and
exclusion criteria
Section 4.2, Exclusion Criteria
Updated exclusion criterion #1 to 
indicate that subjects with non-
steroidal anti-inflammatory drug-
induced colitis will be excluded.
To further define the exclusion of 
subjects with colitis.
Study Synopsis, Inclusion and 
exclusion criteria
Section 4.2, Exclusion Criteria
Added exclusion criterion #10: 
“Subjects have received any 
nonbiologic treatment with 
immunomodulatory properties 
(other than their current background 
UC treatment) within 30 days 
before baseline (Visit 2).”
To indicate exclusion of subjects with 
prior nonbiologic treatment with 
immunomodulatory properties within 
the specified timeframe.
Study Synopsis, Inclusion and 
exclusion criteria
Section 4.2, Exclusion Criteria
Section 5.2.2, Prohibited 
Treatments
Added exclusion criterion #13: 
“Subjects have received leukocyte 
apheresis or selective lymphocyte, 
monocyte, or granulocyte apheresis 
or plasma exchange within 30 days 
before baseline (Visit 2).”
To indicated exclusion of subjects 
with prior apheresis or plasma 
exchange within the specified 
timeframe.
Study Synopsis, Inclusion and
exclusion criteria
Section 4.2, Exclusion Criteria
Updated exclusion criterion #16 
(now #18) to clarify that subjects 
with a history of Mycobacterium 
tuberculosis (TB) infection will be 
excluded.
To further define the exclusion of 
subjects with any history of positive 
TB.
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CONFIDENTIAL
Page 4
SHP647-302 Protocol Amendment 1
SHP647
05 Sep 2018
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1
Amendment Date
05 Sep 2018
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Study Synopsis, Inclusion and 
exclusion criteria
Section 4.2, Exclusion Criteria
Section 7.2.3.6, Clinical Laboratory 
Evaluations
Revised the name of interferon 
gamma release assay (IGRA) from 
“QuantiFERON TB Gold In-Tube 
Test” to “QuantiFERON TB Gold 
Plus In-Tube Test.”
To reflect a change in assay for 
detection of TB.
Study Synopsis, Inclusion and
exclusion criteria
Section 4.2, Exclusion Criteria
Updated exclusion criterion #22 
(now #24) to indicate that subjects 
with cirrhosis with or without 
decompensation will be excluded.
To further define the exclusion of 
subjects with compromised liver 
function.
Study Synopsis, Inclusion and
exclusion criteria
Section 4.2, Exclusion Criteria
Moved exclusion of subjects with 
primary sclerosing cholangitis from 
exclusion criterion #22 to new 
criterion #25. 
To further define the exclusion of 
subjects with compromised liver 
function.
Study Synopsis, Inclusion and
exclusion criteria
Section 4.2, Exclusion Criteria
Updated exclusion criterion #24
(now #26) to indicate that subjects 
with negative HBsAg but positive 
HBcAb may be eligible if no 
presence of HBV DNA is 
confirmed.
To clarify that subjects with positive 
HBcAb, without HBV DNA, may be 
eligible for the study.
Study Synopsis, Inclusion and
exclusion criteria
Section 4.2, Exclusion Criteria
Updated exclusion criterion #25 
(now #27) to indicate that subjects 
with chronic hepatitis C (HCV) 
without evidence of HCVRNA 
within 12 weeks of baseline may be 
considered eligible.
To clarify that subjects with chronic 
HCV, without HCVRNA, may be 
eligible for the study.
Study Synopsis, Inclusion and
exclusion criteria
Section 4.2, Exclusion Criteria
Updated exclusion criterion #26 
(now #28) to indicate that subjects 
meeting the following lab criteria 
would be excluded:
•
ALT or AST ≥3×ULN 
•
Total bilirubin level 1.5 
times the ULN (>2 times the 
ULN if subject has a known 
documented history of 
Gilbert’s syndrome)
Added a note to exclusion criterion 
#26 (now #28) to specify that, if 
platelet count is <150,000 
cells/mm3, a further evaluation 
should be performed to rule out 
cirrhosis, unless another etiology 
has already been identified.
To align criteria with FDA 
guidelines.
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Page 5
SHP647-302 Protocol Amendment 1
SHP647
05 Sep 2018
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1
Amendment Date
05 Sep 2018
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Study Synopsis, Inclusion and 
exclusion criteria
Section 4.2, Exclusion Criteria
Updated exclusion criterion #28 
(now #30) to include exclusion of 
subjects with abuse of medicinal 
marijuana. Deleted former exclusion 
criterion #28 related to medicinal 
marijuana dependency. 
To indicate that subjects with 
medicinal marijuana abuse would be 
excluded. 
Study Synopsis, Inclusion and 
exclusion criteria
Section 4.2, Exclusion Criteria
Updated exclusion criterion #31 
(now #33) to indicate the exclusion 
of subjects who do not agree to 
postpone donation of any organ or 
tissue, including male subjects are 
planning to bank or donate sperm 
and female subjects who are 
planning to harvest or donate eggs, 
for the duration of the study and for 
16 weeks after last dose of 
investigational product.
To specify the exclusion of subjects 
who do not agree to postpone 
donation of any organ or tissue, 
including sperm banking or donation 
for male subjects and egg donation or 
harvest for female subjects.
Study Synopsis, Endpoints and 
statistical analysis, Analysis Sets
Section 9.7, Study Population
 
 
.
For clarity and consistency of how 
these are defined across the Phase 3 
protocols.
Study Synopsis, Endpoints and 
statistical analysis, Analysis Sets
Section 9.8.1, Primary Efficacy 
Endpoint
Section 9.8.2, Secondary Efficacy 
Endpoints
Section 9.8.3, Exploratory Efficacy 
Endpoints
Removed “subjects with” and 
“proportion of subjects with” from 
the efficacy endpoints where 
applicable.
To describe the endpoints correctly.
Study Synopsis, Safety Analyses
Section 9.9, Safety Analyses
Added further details on planned 
summary presentations for the 
safety analyses.  Clarified definition 
of TEAE.
For clarity.
Section 1.3, Benefit and Risk 
Assessment
Added new section describing risk 
and benefits of SHP647 treatment.
To provide updated risk and benefit 
information for SHP647.
Schedule of Assessments, footnote 
“m”
Section 7.2.3.6, Clinical Laboratory 
Evaluations
Updated SOA footnote “m” and 
added text in Section 7.2.3.6 to 
clarify that diagnosis of C. difficile 
infection should be made using the 
central laboratory. 
Added diagnostic algorithms and 
relevant related to C. difficile testing 
and diagnosis.
To provide appropriate guidance 
regarding laboratory testing for C. 
difficile infection.
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CONFIDENTIAL
Page 6
SHP647-302 Protocol Amendment 1
SHP647
05 Sep 2018
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1
Amendment Date
05 Sep 2018
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Schedule of Assessments, footnote 
“o”
Added new row to SOA and 
footnote ‘o’ to indicate HIV tests 
may be performed at local 
laboratories (per local requirements) 
if documentation of a negative HIV 
test within 6 months of screening is 
unavailable.
To clarify the timing of acceptable 
documentation of HIV status.
Schedule of Assessments, footnote 
“v”
Section 2.2.3, Exploratory 
Objectives
Section 7.1.1.1, Screening Visit 
(Visit 1)
Section 7.2.2.1, Endoscopy and 
Histology
Section 9.8.3, Exploratory Efficacy 
Endpoints
Appendix 2, Scales and 
Assessments
Section 3.1, Study Design and Flow 
Chart
Updated Figure 2 to show more 
clearly the possible paths for 
subjects following completion of the 
12-week treatment period, ie either 
entering the maintenance study 
SHP647-303, entering the LTS 
study SHP647-304, or entering the 
16-week safety follow-up period in 
this induction study.
To provide clarity regarding the flow 
of subjects following completion of 
the 12-week treatment period in this 
study.
Section 4.4, Reproductive Potential
Made edits to clarify the appropriate 
methods of contraception for female 
and male subjects of reproductive 
potential.
To clarify language regarding 
appropriate contraceptive methods for 
subjects of reproductive potential.
Section 4.5.1, Subject Withdrawal 
Criteria
Added pregnancy to the list of 
reasons a subject may be withdrawn 
from study treatment.
For clarity and consistency with 
language in Section 8.1.6.
Section 5.2.2, Prohibited 
Treatments
Updated Table 2 to add 
nonbiologics with 
immunomodulatory properties as 
prohibited medications.
To include nonbiologics with 
immunomodulatory properties as 
prohibited medications.
Section 6.2.2, Allocation of 
Subjects to Treatment
Added language to place a cap on 
the Japan-specific sample 
population with prior anti-TNF 
exposure at 60%.
To ensure comparability to the rest of 
the global population, which has the 
same cap on prior anti-TNF therapy 
exposure.
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Page 7
SHP647-302 Protocol Amendment 1
SHP647
05 Sep 2018
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1
Amendment Date
05 Sep 2018
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Section 7.1.3, Follow-up Period:  
Visits 7 and 8 (Weeks 20 and 28)
Revised text to clarify that the 16-
week safety follow-up period is 
timed relative to the End of 
Treatment visit, not to the subject’s 
last dose of investigational product.
To accurately reflect the timing for 
the start of the safety follow-up 
period and align with the Schedule of 
Assessments. 
This change was made with SHP647-
302 Protocol Administrative Change 
Memo #1 (dated 08 Aug 2017).
Section 7.2, Study Evaluations and 
Procedures
Added statement that blood and 
tissue samples may be stored for up 
to the duration allowed by local 
regulations, but for no longer than 
25 years.
Revised from “blood sample 
collection” to “laboratory sample 
collection” to clarify that this 
includes other sample collection, eg 
urine.
Moved investigational product 
administration to the last bullet 
point in the ordering of procedures.
To provide clarity regarding the 
length of time that blood and tissue 
samples may be stored.  This change 
was made with SHP647-302 Protocol 
Administrative Change Memo #2 
(dated 07 Sep 2017).
To improve clarity.
To improve clarity.
Section 7.2.2.2, Mayo score
Removed language stating that 
endoscopic appearance would be 
read locally; it is to be centrally read 
only.
To clarify that endoscopic appearance 
will be read centrally, not locally.
Section 7.2.3.5, Vital Signs
Removed language that specified 
measuring body temperature orally 
with a digital thermometer or by 
using tympanic temperature.
To clarify how body temperature 
should be obtained.
Section 7.2.3.6, Clinical Laboratory 
Evaluations
Added information on laboratory 
testing for C. difficile infection, 
including diagnostic algorithms.
To provide appropriate guidance 
regarding laboratory testing for C. 
difficile infection.
Section 7.2.5, Volume of Blood to 
be Drawn for Each Subject
Made corrections to the blood 
sample volumes for hematology, 
serum chemistry, and serum CRP, 
and the approximate total blood 
volume in Table 4 (Volume of 
Blood to be Drawn for Each 
Subject) and in the paragraph 
thereafter.
Added sample collections/blood 
volumes for HIV and HBV DNA.
Updated the blood sample volumes 
and approximate total blood volume 
to reflect these changes.
To reflect accurately the blood 
sample volumes for hematology, 
serum chemistry, and serum CRP, 
and reflect addition of HIV and HBV
DNA testing.
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Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1
Amendment Date
05 Sep 2018
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Section 8.1.8, Unexpected Adverse 
Event
Section 8.1.9, Suspected 
Unexpected Serious Adverse 
Reaction
Added definitions of unexpected 
adverse event and suspected 
unexpected serious adverse reaction.
To define unexpected adverse event 
and suspected unexpected serious 
adverse reaction.
Section 8.2.7, Regulatory Agency, 
Institutional Review Board, Ethics 
Committee, and Site Reporting
Added text to clarify that “related, 
unexpected SAEs” refers to 
“SUSARs.”
To clarify that “related, unexpected 
SAEs” refers to “SUSARs.”
Section 8.2.8, Safety Monitoring 
Rules
Added new section describing 
safety monitoring and stopping 
algorithms for elevated hepatic 
blood tests. 
To provide appropriate guidance on 
patients who have been enrolled with 
elevated liver function test values or 
who experience and increase in liver 
function test(s) during the study.
Section 10, Sponsor’s and 
Investigator’s Responsibilities
Added a statement that compliance 
with the noted regulations and 
guidelines also constitutes 
compliance with the ethical 
principles described in the 
Declaration of Helsinki.
To clarify that the study is conducted 
in accordance with the ethical 
principles in the Declaration of 
Helsinki.
Section 10.1.1, Good Clinical 
Practice Compliance
Added language to clarify that the 
sponsor will ensure that local 
regulatory requirements are met 
during the study, including annual 
safety reporting, ie, Development 
Safety Update Reports.
To clarify language regarding 
regulatory reporting requirements.
Appendix 2, Mayo Scoring System 
for Assessment of Ulcerative Colitis 
Activity
Added a footnote (“c”) to the Mayo 
Scoring System for Assessment of 
Ulcerative Colitis Activity to clarify 
that the “findings on endoscopy” 
scoring represents the modified 
endoscopy subscore and that data 
will be collected to calculate the 
total Mayo score using both the 
modified endoscopy subscore and 
traditional endoscopy subscore, 
which will be used as a sensitivity 
analysis and to estimate the impact 
of the modification on the primary 
endpoint.  
To provide clarity regarding Mayo 
Scoring System and use of the 
modified and traditional endoscopy 
scores. This change was described in 
SHP647-302 Protocol Administrative 
Change Memo #2 (dated 07 Sep 
2017).
Appendix 2, Scales and 
Assessments
 
 
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Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1
Amendment Date
05 Sep 2018
Global/Country/Site Specific
Global
Section(s) Affected by Change
Description of Change
Rationale
Appendix 4, Determination of
Failure or Intolerance to Prior 
Treatment for Ulcerative Colitis
Added new appendix section, 
“Determination of Failure or 
intolerance to Prior Treatment for 
Ulcerative Colitis” to provide 
guidance as related to inclusion 
criterion #8 in which subjects 
meeting these criteria on prior 
conventional treatments (eg, 
sulfasalazine, mesalamine, 
glucocorticoids, 
immunosuppressants, or anti-TNF) 
may be eligible for this study. 
To provide additional granularity 
regarding the eligibility of subjects 
who demonstrated inadequate 
response, loss of response, or 
intolerance on conventional 
treatment.
Appendix 5, Guidance for 
Treatment of Increased 
Gastrointestinal Symptoms
Added new Appendix 5, “Guidance 
for Treatment of Increased 
Gastrointestinal Symptoms related 
to diagnosis and treatment of C. 
difficile infection.”
To provide updated treatment 
guidance for subjects diagnosed with 
C. difficile infection.
Throughout protocol
Minor changes to wording. 
To improve clarity, consistency, and 
remove redundancy of text. 
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or email the Shire 
“Clinical Study Serious Adverse Event and Non-serious AE as Required by the Protocol Form”
within 24 hours to the Shire Global Drug Safety Department. The fax number and email address 
are provided on the form (sent under separate cover). A copy of this form must also be sent to the 
contract research organization (CRO)/Shire medical monitor using the details below.
Fax
(Global)
Email
For protocol- or safety-related issues, the investigator must contact the medical monitor via 
the appropriate regional safety hotline (24 hours):
North America:
PPD 24 Hour Safety Hotline: RTP 
; Wilmington 
PPD 24 Hour Safety Hotline Fax: RTP 
 or 
; 
Wilmington
 or 
Latin America:
PPD 24 Hour Safety Hotline: 
PPD 24 Hour Safety Hotline Fax: 
Europe, the Middle East, and Africa; and Asia-Pacific:
PPD 24 Hour Safety Hotline: 
PPD 24 Hour Safety Hotline Fax: 
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
Email Address
North and South America, the European 
Union, and Rest of World
Telephone number (provided for reference if needed):
Shire, Lexington, MA (USA)
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION..............................................................................10
PRODUCT QUALITY COMPLAINTS........................................................................................11
LIST OF TABLES.........................................................................................................................17
LIST OF FIGURES .......................................................................................................................17
ABBREVIATIONS .......................................................................................................................18
STUDY SYNOPSIS ......................................................................................................................20
STUDY SCHEDULE ....................................................................................................................29
1
BACKGROUND INFORMATION.......................................................................................34
1.1
Indication and Current Treatment Options...............................................................34
1.2
Product Background and Clinical Information ........................................................34
1.3
Benefit/Risk Assessment..........................................................................................35
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................37
2.1
Rationale for the Study.............................................................................................37
2.2
Study Objectives ......................................................................................................38
2.2.1
Primary Objective..................................................................................................38
2.2.2
Secondary Objectives.............................................................................................38
2.2.2.1
Key Secondary Objectives .....................................................................38
2.2.2.2
Other Secondary Objectives...................................................................39
2.2.3
Exploratory Objectives ..........................................................................................39
3
STUDY DESIGN ...................................................................................................................40
3.1
Study Design and Flow Chart ..................................................................................40
3.1.1
Rationale for Primary Endpoint.............................................................................42
3.1.2
Rationale for Key Secondary Endpoints:...............................................................43
3.2
Duration and Study Completion Definition .............................................................43
3.3
Sites and Regions .....................................................................................................43
4
STUDY POPULATION.........................................................................................................44
4.1
Inclusion Criteria......................................................................................................44
4.2
Exclusion Criteria.....................................................................................................45
4.3
Restrictions...............................................................................................................49
4.4
Reproductive Potential .............................................................................................49
4.4.1
Contraceptive Methods for Female Study Subjects...............................................50
4.4.2
Contraceptive Methods for Male Study Subjects ..................................................51
4.5
Withdrawal of Subjects ............................................................................................51
4.5.1
Subject Withdrawal Criteria ..................................................................................52
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4.5.2
Reasons for Withdrawal.........................................................................................52
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................53
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................54
5.1
Prior Treatment ........................................................................................................54
5.2
Concomitant Treatment............................................................................................54
5.2.1
Permitted Treatment...............................................................................................54
5.2.2
Prohibited Treatment .............................................................................................55
5.2.3
Rescue Therapy......................................................................................................56
6
INVESTIGATIONAL PRODUCT ........................................................................................57
6.1
Identity of Investigational Product...........................................................................57
6.1.1
Blinding the Treatment Assignment......................................................................57
6.2
Administration of Investigational Product ...............................................................57
6.2.1
Interactive Response Technology for Investigational Product Management ........57
6.2.2
Allocation of Subjects to Treatment ......................................................................57
6.2.3
Dosing....................................................................................................................58
6.2.4
Unblinding the Treatment Assignment..................................................................58
6.3
Labeling, Packaging, Storage, and Handling ...........................................................59
6.3.1
Labeling .................................................................................................................59
6.3.2
Packaging...............................................................................................................59
6.3.3
Storage ...................................................................................................................59
6.3.4
Special Handling....................................................................................................60
6.4
Drug Accountability.................................................................................................60
6.5
Subject Compliance..................................................................................................61
7
STUDY PROCEDURES........................................................................................................62
7.1
Study Schedule.........................................................................................................62
7.1.1
Screening Period....................................................................................................62
7.1.1.1
Screening Visit (Visit 1).........................................................................62
7.1.1.2
Baseline Visit (Visit 2; Week 0).............................................................63
7.1.2
Treatment Period....................................................................................................63
7.1.2.1
Visit 3 (Week 2) .....................................................................................63
7.1.2.2
Visits 4 and 5 (Weeks 4 and 8) ..............................................................63
7.1.2.3
Final On-treatment Visits: Visit 6, Parts 1 and 2 
(Week 12/Early Termination) ................................................................63
7.1.3
Follow-up Period: Visits 7 and 8 (Weeks 20 and 28)............................................63
7.1.4
Additional Care of Subjects after the Study ..........................................................64
7.2
Study Evaluations and Procedures ...........................................................................64
7.2.1
Demographic and Other Baseline Characteristics .................................................64
7.2.2
Efficacy..................................................................................................................65
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7.2.2.1
Endoscopy and Histology.......................................................................65
7.2.2.2
Mayo Score ............................................................................................65
7.2.2.3
Patient-reported Outcome – Ulcerative Colitis E-Diary ........................66
7.2.3
Safety .....................................................................................................................67
7.2.3.1
Medical and Medication History............................................................67
7.2.3.2
Physical Examination (Including Height and Weight) ..........................67
7.2.3.3
Targeted Neurological Assessment........................................................67
7.2.3.4
Adverse Event Collection.......................................................................69
7.2.3.5
Vital Signs..............................................................................................69
7.2.3.6
Clinical Laboratory Evaluations.............................................................69
7.2.3.7
Pregnancy Test and Follicle-stimulating Hormone Test........................71
7.2.3.8
Electrocardiogram ..................................................................................71
7.2.3.9
Chest X-ray ............................................................................................72
7.2.3.10
Antidrug Antibodies...............................................................................72
7.2.4
Others.....................................................................................................................72
7.2.4.3
Health-related Quality of Life Assessments...........................................72
7.2.4.4
Healthcare Resource Utilization Assessments .......................................74
7.2.5
Volume of Blood to Be Drawn from Each Subject ...............................................74
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................76
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................76
8.1.1
Severity Categorization..........................................................................................76
8.1.2
Relationship Categorization...................................................................................77
8.1.3
Outcome Categorization ........................................................................................77
8.1.4
Symptoms of the Disease Under Study .................................................................77
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................77
8.1.6
Pregnancy...............................................................................................................78
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................78
8.1.8
Unexpected Adverse Event....................................................................................79
8.1.9
Suspected Unexpected Serious Adverse Reaction.................................................79
8.2
Serious Adverse Event Procedures ..........................................................................80
8.2.1
Reference Safety Information................................................................................80
8.2.2
Reporting Procedures.............................................................................................80
8.2.3
Serious Adverse Event Definition .........................................................................80
8.2.4
Serious Adverse Event Collection Time Frame.....................................................81
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................81
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8.2.6
Fatal Outcome........................................................................................................81
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................82
8.2.8
Safety Monitoring for Potential Cases of Drug-induced Liver Injury...................82
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................85
9.1
Data Collection.........................................................................................................85
9.2
Clinical Data Management.......................................................................................85
9.3
Data Handling Considerations..................................................................................85
9.4
Statistical Analysis Process......................................................................................85
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......86
9.6
Sample Size Calculation and Power Considerations................................................86
9.7
Study Population ......................................................................................................87
9.8
Efficacy Analyses.....................................................................................................87
9.8.1
Primary Efficacy Endpoint ....................................................................................88
9.8.2
Secondary Efficacy Endpoints...............................................................................90
9.8.2.1
Key Secondary Efficacy Endpoint .........................................................90
9.8.2.2
Other Secondary Efficacy Endpoints .....................................................90
9.8.3
Exploratory Efficacy Endpoints.............................................................................92
9.9
Safety Analyses........................................................................................................92
9.10
Other Analyses .........................................................................................................93
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................94
10.1
Sponsor’s Responsibilities .......................................................................................94
10.1.1 Good Clinical Practice Compliance.......................................................................94
10.1.2 Indemnity/Liability and Insurance.........................................................................94
10.1.3 Public Posting of Study Information......................................................................94
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................95
10.1.5 Study Suspension, Termination, and Completion..................................................95
10.2
Investigator’s Responsibilities .................................................................................95
10.2.1 Good Clinical Practice Compliance.......................................................................95
10.2.2 Protocol Adherence and Investigator Agreement..................................................96
10.2.3 Documentation and Retention of Records.............................................................96
10.2.3.1
Case Report Forms.................................................................................96
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................96
10.2.3.3
Audit/Inspection.....................................................................................97
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10.2.3.4
Financial Disclosure...............................................................................97
10.3
Ethical Considerations..............................................................................................97
10.3.1 Informed Consent...................................................................................................97
10.3.2 Institutional Review Board or Ethics Committee..................................................98
10.4
Privacy and Confidentiality......................................................................................98
10.5
Study Results/Publication Policy .............................................................................99
11 REFERENCES .....................................................................................................................101
12 APPENDICES ......................................................................................................................103
Appendix 1
Protocol History ...................................................................................104
Appendix 2
Scales and Assessments .......................................................................105
Appendix 3
Glucocorticoid Equivalent Doses.........................................................138
Appendix 4
Determination of Failure or Intolerance to Prior Treatment for 
Ulcerative Colitis.................................................................................139
Appendix 5
Guidance for Diagnosis and Treatment of Increased 
Gastrointestinal Symptoms..................................................................146
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LIST OF TABLES
Table 1:
Schedule of Assessments...............................................................................29
Table 2:
Common Excluded Treatments .....................................................................55
Table 3:
Quarterly Neurological Assessments ............................................................68
Table 4:
Volume of Blood to Be Drawn from Each Subject.......................................74
Table 5:
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin.........................................................................................................83
Table 6:
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints.....................................................................................87
LIST OF FIGURES
Figure 1:
Overview of SHP647 Phase 3 Studies in Ulcerative Colitis.........................41
Figure 2:
Study Design Flow Chart ..............................................................................42
Figure 3:
Flow Diagram for Quarterly Neurological Assessments...............................68
Figure 4:
Visualization of Alpha Propagation ..............................................................89
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ABBREVIATIONS
5-ASA
5-aminosalicylic acid
ADA
anti-drug antibodies
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
CI
confidence interval
CMH
Cochran-Mantel Haenszel
CNS
central nervous system
CRO
contract research organization
DMC
data monitoring committee
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic case report form
e-diary
electronic diary
EMA
European Medicines Agency
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FWER
family-wise type I error rate
GCP
Good Clinical Practice
GI
gastrointestinal
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HEENT
head, eyes, ears, nose, and throat
HIV
human immunodeficiency virus
HRQL
health-related quality of life
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Council for Harmonisation
IGRA
interferon gamma release assay
IRB
Institutional Review Board
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IRT
interactive response technology
LTS
long-term safety extension
PFS
prefilled syringe
PGA
physician global assessment
PML
progressive multifocal leukoencephalopathy
PPD
purified protein derivative
PRC
polymerase chain reaction
PRO
patient-reported outcome
Q4W
once every 4 weeks
REML
restricted maximum likelihood estimation
RNA
ribonucleic acid
RSI
reference safety information
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SF-36
Short Form-36 
SOC
system organ class
SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
tuberculosis
TEAE
treatment-emergent AE
TNF
tumor necrosis factor
UC
ulcerative colitis
ULN
upper limit of normal 
US
United States
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STUDY SYNOPSIS
Protocol number: SHP647-302
Drug: SHP647
Title of the study: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety 
Study of SHP647 as Induction Therapy in Subjects with Moderate to Severe Ulcerative Colitis (FIGARO UC 302)
Number of subjects (total and for each treatment arm):
A total of 825 subjects (330 subjects at 25 mg SHP647, 330 subjects at 75 mg SHP647, and 165 placebo subjects) 
are planned for enrollment into the study.
Investigator(s): Multicenter study.
Site(s) and Region(s):
It is anticipated that the study will be conducted in at least 18 countries. Regions will include North America 
Europe, the Middle East, and Africa, Latin America, and Asia-Pacific. Approximately 210 sites will be utilized.
Study period (planned):
2017 to 2020
Clinical phase:
3
Objectives:
Primary: To evaluate the efficacy of SHP647 in inducing remission, based on composite score of patient-reported 
symptoms and centrally read endoscopy, in subjects with moderate to severe ulcerative colitis (UC).
Key Secondary:

To evaluate the efficacy of SHP647 in achieving endoscopic remission, based on centrally read endoscopy.

To evaluate the efficacy of SHP647 in achieving clinical remission, based on composite score of 
patient-reported symptoms.

To evaluate the efficacy of SHP647 in inducing clinical response, based on composite score of 
patient-reported symptoms and centrally read endoscopy.

To evaluate the efficacy of SHP647 in achieving mucosal healing, based on endoscopic and histological 
assessment using the Geboes Score grading system.
Other Secondary:

To evaluate the safety and tolerability of SHP647.

To evaluate the effect of SHP647 induction treatment on other clinical and endoscopic outcomes (including 
Mayo-based remission and clinical response, partial Mayo score over time, clinical remission over time, 
endoscopic remission, and deep remission).

To evaluate the effect of SHP647 on abdominal pain, urgency, diarrhea, and absolute stool frequency and 
bleeding scores.

To evaluate the effect of SHP647 on health-related quality of life (as measured by the Inflammatory Bowel 
Disease Questionnaire [IBDQ] and the Short Form-36 Health Survey [SF-36]).

To evaluate the effect of SHP647 on incidence of hospitalizations and total inpatient days.
Rationale:
This study is designed to evaluate the efficacy and safety of SHP647 in inducing remission in subjects with 
moderate to severe UC.
SHP647 has been investigated in 2 completed dose-finding studies (A7281001 and A7281009) in subjects with 
moderate to severe UC; a third study (A7281010), an open-label long-term safety extension study, is ongoing. The 
Phase 1 study, A7281001, which investigated the safety, tolerance, pharmacokinetics, and pharmacodynamic 
properties of SHP647, supports further clinical development of SHP647 using subcutaneous (SC) administration. SC
doses of 25 mg or 75 mg of SHP647 or placebo on Day 1 (Week 0), Week 4, and Week 8 are recommended for the 
Phase 3 studies SHP647-301 and SHP647-302.
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Investigational product, dose, and mode of administration:
The test product is SHP647, which will be provided as a sterile aqueous buffered solution for SC administration in a 
glass prefilled syringe (PFS) with a fixed needle. Each PFS contains 1 mL of SHP647 solution for injection at an 
appropriate concentration to provide the intended dose of drug (25 or 75 mg). Additional information is provided in 
the current SHP647 investigator’s brochure.
The reference product is placebo, which will be provided in a PFS with a fixed needle containing 1 mL of placebo 
solution for SC administration. The placebo solution will contain the same sterile aqueous buffered solution as the 
test product but will not contain SHP647.
Methodology:
A total of 825 subjects (330 subjects at 25 mg SHP647, 330 subjects at 75 mg SHP647, and 165 placebo subjects) 
are planned for enrollment into the study. Subjects must be at least 16 years of age and no more than 80 years of age 
at the time of signing the informed consent/assent form.
The study consists of a screening period up to 6 weeks and a 12-week treatment period. After the screening period, 
eligible subjects will be randomly assigned to receive 1 of 3 treatments (25 mg SHP647, 75 mg SHP647, or placebo) 
in a 2:2:1 ratio. Randomization will be stratified based upon the subject’s status of prior anti-TNF (tumor necrosis 
factor) treatment (naïve or experienced) and glucocorticoid use at baseline (on glucocorticoids at baseline versus not 
on glucocorticoids at baseline). Subjects will receive SC injections of SHP647 or placebo, using a PFS, on 
Week 0/Day 1 (Visit 2), Week 4 (Visit 4), and Week 8 (Visit 5). Subjects will undergo efficacy, 
, 
 safety, and health outcome assessments at these visits.
Patient-reported UC signs and symptom data (including stool frequency, rectal bleeding severity and frequency, 
diarrhea frequency, urgency frequency, and abdominal pain worst severity) will be collected using a daily electronic 
diary (e-diary) during the treatment period. The Mayo score is a measure of UC disease activity consisting of the 
following 4 subscores: stool frequency, rectal bleeding, findings of endoscopy, and physician global assessment 
(PGA). The partial Mayo score consists of the Mayo score without the endoscopic subscores. The composite score is 
a recommended measure consisting of the Mayo score without the PGA subscore, and will be used for the primary 
efficacy endpoint. The Mayo scores and composite score will be based on subject daily e-diary entries.
At the end of the 12-week treatment period, eligible subjects will be offered the opportunity to participate in a 
double-blind maintenance study (SHP647-303; for subjects who achieve clinical response) or a long-term safety 
extension (LTS) study (SHP647-304; for subjects who do not achieve a clinical response). Subjects who withdraw 
early from the 12-week treatment period or who do not wish to enter the maintenance study (SHP647-303) or LTS 
study (SHP647-304) will continue into a 16-week safety follow-up period. Only those subjects who complete the 
full course of investigational product treatment in the induction studies (SHP647-301 or SHP647-302) will be 
eligible to continue in the maintenance study or LTS study.
Inclusion and exclusion criteria:
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study.
1.
Subjects and/or their parent or legally authorized representative must have an understanding, ability, and 
willingness to fully comply with study procedures and restrictions.
2.
Subjects must be able to voluntarily provide written, signed, and dated (personally or via a legally authorized 
representative) informed consent and/or assent, as applicable, to participate in the study.
3.
Subjects must be between ≥16 and ≤80 years of age at the time of the signing of the informed consent/assent 
form.
NOTE: Subjects <18 years of age must weigh ≥40 kg and must have body mass index (BMI) ≥16.5.
4.
Subjects must have a documented diagnosis (radiologic or endoscopic with histology) of UC for ≥3 months 
before screening. The following must be available in each subject’s source documentation:

A biopsy report to confirm the histological diagnosis.
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
A report documenting disease duration based upon prior colonoscopy.
NOTE: If this documentation is not available at the time of screening, a colonoscopy with biopsy to 
confirm the diagnosis is required during the screening period.
5.
Subjects must be willing to undergo a flexible sigmoidoscopy or colonoscopy (if preferred), including biopsy 
sample collection, during screening after all other inclusion criteria have been met.
6.
Subjects must have moderate to severe active UC, defined as a total Mayo score of ≥6, including a 
centrally read endoscopic subscore ≥2, rectal bleeding subscore ≥1, and stool frequency subscore ≥1 at baseline 
(Visit 2).
7.
Subjects must have evidence of UC extending proximal to the rectum (ie, not limited to proctitis).
8.
Subjects must have had an inadequate response to, or lost response to, or had an intolerance to at least 1 
conventional treatment such as mesalamine (5-aminosalicylic acid [5-ASA]), glucocorticoids, 
immunosuppressants (azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]), or anti-TNF
(refer to Appendix 4 for guidance).
9.
Subjects receiving any treatment(s) for UC described in Section 5.2.1 of the protocol are eligible provided they 
have been, and are anticipated to be, on a stable dose for the designated period of time.
10. Subjects are males or nonpregnant, nonlactating females who, if sexually active, agree to comply with the 
contraceptive requirements of the protocol, or females of nonchildbearing potential. Males and females of 
reproductive potential who are sexually active must agree to use appropriate contraception for the duration of 
the study.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Subjects with indeterminate colitis, microscopic colitis, non-steroidal anti-inflammatory drug-induced colitis, 
ischemic colitis, infectious colitis, or clinical/histologic findings suggestive of Crohn’s disease.
2.
Subjects with colonic dysplasia or neoplasia. (Subjects with prior history of adenomatous polyps will be 
eligible if the polyps have been completely removed.)
3.
Subjects with past medical history or presence of toxic megacolon.
4.
Subjects with colonic stricture, past medical history of colonic resection, a history of bowel surgery within 
6 months before screening, or who are likely to require surgery for UC during the treatment period.
5.
Subjects at risk for colorectal cancer must have a colonoscopy performed during the screening period with 
results available within 10 days before the baseline visit (Visit 2), unless the subject has had a surveillance 
colonoscopy performed within 1 year prior to screening, and any adenomatous polyps found at that 
examination have been excised. Colonoscopy report and pathology report (if biopsies are obtained) from the 
colonoscopy performed during screening or in the prior year confirming no evidence of dysplasia and colon 
cancer must be available in the source documents.
Subjects at risk for colorectal cancer include, but are not limited to:

Subjects with extensive colitis for ≥8 years or disease limited to left side of colon (ie, distal to splenic 
flexure) for ≥10 years before screening, regardless of age.

Subjects ≥50 years of age at the time of signing of the informed consent form.
6.
Subjects have had prior treatment with SHP647 (formerly PF-00547659).
7.
Subjects with known or suspected intolerance or hypersensitivity to the investigational product(s), closely 
related compounds, or any of the stated ingredients.
8.
Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2).
9.
Subjects have received any biologic with immunomodulatory properties (other than anti-TNFs) within 90 days 
before baseline (Visit 2).
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10.
Subjects have received any nonbiologic treatment with immunomodulatory properties (other than their current 
background UC treatment) within 30 days before baseline (Visit 2).
11.
Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion molecule).
12.
Subjects have received parenteral or rectal glucocorticoids, or rectal 5-ASA, within 14 days before screening 
endoscopic procedure.
13.
Subjects have received leukocyte apheresis or selective lymphocyte, monocyte, or granulocyte apheresis or 
plasma exchange within 30 days before baseline (Visit 2).
14.
Subjects have participated in other investigational studies within either 30 days or 5 half-lives of 
investigational product used in the study (whichever is longer) before baseline (Visit 2).
15.
Subjects have received a live (attenuated) vaccine within 30 days before the baseline visit (Visit 2).
16.
Subjects with active enteric infections (positive stool culture and sensitivity), Clostridium difficile infection or 
pseudomembranous colitis [subjects with C. difficile infection at screening may be allowed re-test after 
treatment], evidence of active cytomegalovirus infection or Listeria monocytogenes, known active invasive 
fungal infections such as histoplasmosis or parasitic infections, clinically significant underlying disease that 
could predispose the subjects to infections, or a history of serious infection (requiring parenteral antibiotic 
and/or hospitalization) within 4 weeks before the baseline visit (Visit 2).
17.
Subjects with abnormal chest x-ray findings at screening (Visit 1), such as presence of active tuberculosis 
(TB), general infections, heart failure, or malignancy. (A chest x-ray performed up to 12 weeks before study 
entry [screening, Visit 1] may be used if available; documentation of the official reading must be located and 
available in the source documentation.)
18.
Subjects with evidence of active or latent infection with Mycobacterium tuberculosis (TB) or subjects with this 
history who have not completed a generally accepted full course of treatment before randomization are 
excluded. All other subjects must have either the Mantoux (purified protein derivative [PPD]) tuberculin skin 
test or interferon gamma release assay (IGRA) performed.
Subjects who have no history of previously diagnosed active or latent tuberculosis are excluded if they have a 
positive Mantoux (PPD) tuberculin skin test (ie ≥5 mm induration) or a positive IGRA (the latter to be tested at 
the site’s local laboratory) during screening or within 12 weeks before randomization. If IGRA test cannot be 
performed locally, a central laboratory may be used, with prior agreement from the sponsor.

An IGRA is strongly recommended for subjects with a prior Bacillus Calmette-Guérin (BCG) vaccination, 
but may be used for any subject. Documentation of IGRA product used and the test result must be in the 
subject's source documentation if performed locally. Acceptable IGRA products include QuantiFERON TB 
Gold Plus In-Tube Test.

If the results of the IGRA are indeterminate, the test may be repeated, and if a negative result is obtained, 
enrollment may proceed. In subjects with no history of treated active or latent tuberculosis, a positive test 
on repeat will exclude the subject. Subjects with a history of active or latent tuberculosis infection must 
follow instructions for “Subjects with a prior diagnosis of active or latent tuberculosis are excluded unless 
both of the following criteria are met” in this criterion.

Subjects with repeat indeterminate IGRA results, with no prior TB history, may be enrolled after 
consultation with a pulmonary or infectious disease specialist who determines low risk of infection 
(ie, subject would be acceptable for immunosuppressant [eg, anti-TNF] treatment without additional 
action). This consultation must be included in source documentation.
Results from a chest x-ray, taken within the 3 months before or during screening (Visit 1) must show no 
abnormalities suggestive of active TB infection as determined by a qualified medical specialist.
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Subjects with a prior diagnosis of active or latent tuberculosis are excluded unless both of the following criteria 
are met:

The subject has previously received an adequate course of treatment for either latent (eg, 9 months of 
isoniazid or an acceptable alternative regimen, in a locale where rates of primary multidrug TB resistance 
are <5%. Subjects from regions with higher rates of primary multidrug TB resistance are excluded) or 
active (acceptable multidrug regimen) TB infection. Evidence of diagnosis and treatment must be included 
in source documentation. Consultation with a pulmonary or infectious disease specialist to confirm 
adequate treatment (ie, subject would be acceptable for immunosuppressant [eg, anti-TNF] treatment 
without additional action) must be performed during the screening period. The consultation report must be 
included in source documentation prior to enrollment.

A chest x-ray performed within 3 months prior to screening (Visit 1) or during screening (Visit 1) indicates 
no evidence of active or recurrent disease, and documentation of interpretation by a qualified medical 
specialist must be included in source documentation.
19.
Subjects with a pre-existing demyelinating disorder such as multiple sclerosis or new onset seizures, 
unexplained sensory motor, or cognitive behavioral, neurological deficits, or significant abnormalities noted 
during screening.
20.
Subjects with any unexplained symptoms suggestive of progressive multifocal leukoencephalopathy (PML) 
based on the targeted neurological assessment during the screening period.
21.
Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed.
22.
Subjects with a significant concurrent medical condition at the time of screening (Visit 1) or baseline (Visit 2), 
including, but not limited to, the following:

Any major illness/condition or evidence of an unstable clinical condition (eg, renal, hepatic, hematologic, 
gastrointestinal (except disease under study), endocrine, cardiovascular, pulmonary, immunologic [eg, 
Felty’s syndrome], or local active infection/infectious illness) that, in the investigator’s judgment will 
substantially increase the risk to the subject if he or she participates in the study.

Cancer or history of cancer or lymphoproliferative disease within the previous 5 years (other than resected 
cutaneous basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the uterine cervix that has 
been treated with no evidence of recurrence).

Presence of acute coronary syndrome (eg, acute myocardial infarction, unstable angina pectoris) within 
24 weeks before screening.

History of significant cerebrovascular disease within 24 weeks before screening.
23.
Subjects who have had significant trauma or major surgery within 4 weeks before the screening visit (Visit 1), 
or with any major elective surgery scheduled to occur during the study.
24.
Subjects with evidence of cirrhosis with or without decompensation.
25.
Subjects with primary sclerosing cholangitis.
26.
Subjects with evidence of positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). 
NOTE: if a subject tests negative for HBsAg, but positive for HBcAb, the subject would be considered eligible 
if no presence of HBV DNA is confirmed by HBV DNA PCR reflex testing performed in the central 
laboratory.
27.
Subjects with chronic hepatitis C (HCV) (positive HCVAb and HCVRNA). Note: Subjects who are HCVAb 
positive without evidence of HCVRNA may be considered eligible (spontaneous viral clearance or previously 
treated and cured [defined as no evidence of HCVRNA at least 12 weeks prior to baseline]).
28.
Subjects with any of the following abnormalities in hematology and/or serum chemistry profiles during 
screening. NOTE: Screening laboratory tests, if the results are considered by the investigator to be transient 
and inconsistent with the subject’s clinical condition, may be repeated once during the screening period for 
confirmation. Results must be reviewed for eligibility prior to the screening endoscopy procedure.
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
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 3.0 × the upper limit of 
normal (ULN).

Total bilirubin level 1.5 × ULN or >2.0 × ULN if the subject has a known documented history of Gilbert’s 
syndrome).

Hemoglobin level 80 g/L (8.0 g/dL).

Platelet count 100 × 109/L (100,000 cells/mm3) or 1000 × 109/L (1,000,000 cells/mm3).*

White blood cell count 3.5 × 109/L (3500 cells/mm3).

Absolute neutrophil count (ANC) <2 × 109/L (2000 cells/mm3).

Serum creatinine level >1.5× ULN or estimated glomerular filtration rate <30 mL/min/1.73 m2 based on 
the abbreviated Modification of Diet in Renal Disease Study Equation.
*Note: If platelet count is <150,000 cells/mm3, a further evaluation should be performed to rule out 
cirrhosis, unless another etiology has already been identified.
29.
Subjects with known HIV infection based on documented history, with positive serological test, or positive 
HIV serologic test at screening, tested at the site’s local laboratory in accordance with country requirements, or 
tested at the central laboratory. Note: A documented negative HIV test within 6 months of screening is 
acceptable and does not need to be repeated.
30.
Subjects who have, or who have a history of (within 2 years before screening [Visit 1]), serious psychiatric 
disease, alcohol dependency, or substance/drug abuse or dependency of any kind, including abuse of medicinal 
marijuana (cannabis).
31.
Subjects with any other severe acute or chronic medical or psychiatric condition or laboratory or 
electrocardiogram (ECG) abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this study.
32.
Female subjects who are planning to become pregnant during the study period.
33.
Subjects who do not agree to postpone donation of any organ or tissue, including male subjects who are 
planning to bank or donate sperm, and female subjects who are planning to harvest or donate eggs, for the 
duration of the study and through 16 weeks after last dose of investigational product.
34.
Subjects who are investigational site staff members or relatives of those site staff members or subjects who are 
Shire employees directly involved in the conduct of the study.
Maximum duration of subject involvement in the study:

Planned duration of screening period: Up to 6 weeks

Planned duration of treatment period: 12 weeks

Planned duration of follow-up period: 16 weeks
Endpoints and statistical analysis:
Analysis Sets:
The screened set will consist of all subjects who have signed an informed consent document.
The randomized set will consist of all subjects in the screened set for whom a randomization number has been 
assigned.
The safety set will consist of all subjects who have received at least 1 dose of investigational product.
The full analysis set (FAS) will consist of all subjects in the randomized set who have received at least 1 dose of 
investigational product.
The per-protocol (PP) set will consist of all subjects in the FAS who do not have predefined protocol deviations that 
may affect the primary efficacy endpoint.
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The completer set will consist of all subjects in the FAS who have completed the final scheduled primary 
assessment for this study.
 
Primary Efficacy Endpoint: The primary efficacy endpoint is remission at the Week 12 visit. Remission is defined 
as a composite score of patient-reported symptoms using daily e-diary and centrally read endoscopy as follows:

stool frequency subscore of 0 or 1 with at least a 1-point change from baseline
AND

rectal bleeding subscore of 0
AND

endoscopic subscore of 0 or 1 (modified, excludes friability).
The primary efficacy endpoint will be compared for each active treatment group (25 mg or 75 mg SHP647) to the 
placebo group using a Cochran-Mantel Haenszel (CMH) chi-square test stratified by status of prior anti-TNF
treatment and glucocorticoid use at baseline (Visit 2). Subjects with missing remission data at the Week 12 visit will 
be considered failures and counted as nonresponders. The endoscopy score will be based on centrally read results.
The primary endpoint will be tested by the following hypothesis:
H0: δ = 0
H1: δ ≠ 0
Where δ is the common treatment difference across strata, j=1 to m. The common treatment difference is a weighted 
average of the stratum-specific treatment differences.
The global family-wise type I error rate (FWER) for the statistical tests of the primary and key secondary endpoints 
will be strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in Bretz, et al 2009
will be utilized to propagate α from primary to key secondary endpoints and between the two SHP647 treatment 
group and placebo comparisons. Alpha is initially split equally at the .025 level (2-sided) for each of the pairwise 
treatment comparisons for the primary endpoint (P) and alpha is propagated in a hierarchical manner to each of the 
4 key secondary endpoints (K1-K4) within a pairwise treatment comparison.
Key Secondary Efficacy Endpoints:

Endoscopic remission, as defined by centrally read endoscopic subscore 0 or 1 (modified, excludes friability), at 
the Week 12 visit.

Clinical remission, as defined by stool frequency subscore of 0 or 1 with at least a 1-point change from baseline 
in stool frequency subscore, and rectal bleeding subscore of 0, at the Week 12 visit.

Clinical response based on composite score at the Week 12 visit. Clinical response (composite) is defined as a 
decrease from baseline in the composite score of patient-reported symptoms using daily e-diary and 
centrally read endoscopy of at least 2 points and at least 30%, with an accompanying decrease in the subscore 
for rectal bleeding ≥1 point or a subscore for rectal bleeding ≤1.

Mucosal healing based on endoscopic and histological assessment at the Week 12 visit. Mucosal healing is 
defined by centrally read endoscopic subscore 0 or 1 (modified, excludes friability) and centrally read Geboes 
score of ≤2.
The key secondary endpoints will be analyzed using the same approach as described for the primary efficacy 
endpoint. Subjects with missing key secondary endpoint data at the Week 12 visit will be considered failures and 
counted as nonresponders.
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Other Secondary Efficacy Endpoints:

Remission, defined as a total Mayo score ≤2 with no individual subscore (stool frequency, rectal bleeding, 
endoscopy [modified, excludes friability], and physician’s global assessment) exceeding 1, at the Week 12 visit.

Clinical response based on total Mayo score at the Week 12 visit. Clinical response (Mayo) is defined as a 
decrease from baseline in the total Mayo score of at least 3 points and at least 30%, with an accompanying 
decrease in the subscore for rectal bleeding ≥1 point or an absolute subscore for rectal bleeding ≤1.

Partial Mayo score ≤2 with no individual subscore >1 at the Week 4, 8, and 12 visits. The partial Mayo score 
does not include the endoscopy subscore.

Clinical remission as defined by stool frequency subscore of 0 or 1 with at least a 1-point change from baseline 
in stool frequency subscore, and rectal bleeding subscore of 0, at Weeks 4 and 8.

Endoscopic remission at the Week 12 visit with endoscopic subscore of 0.

Clinical remission at the Week 4, 8, and 12 visits with both rectal bleeding and stool frequency subscores of 0.

Deep remission at the Week 12 visit. Deep remission is defined as both endoscopic and rectal bleeding 
subscores of 0, and stool frequency subscore ≤1 and a centrally read Geboes score of ≤2.

Change from baseline at the Week 12 visit in abdominal pain, diarrhea and urgency item scores, absolute stool 
frequency, absolute rectal bleeding and total sign/symptom score based on subject daily e-diary entries (sum of 
rectal bleeding, stool frequency, abdominal pain, diarrhea, and urgency).

Change from baseline in IBDQ domain and total (absolute) scores (time frame: Week 0, Week 8, up to 
Week 12, or early termination).

Change from baseline in Short Form-36 (SF-36), version 2, acute (physical and mental component summary 
scores and individual domain scores) to the Week 12/ET visit.

Incidence of all-cause hospitalizations and total inpatient days.
Other secondary endpoints will be summarized by descriptive statistics and presented by treatment group. Where 
appropriate, other secondary efficacy endpoints will be analyzed with the following analysis methods.

Binary endpoints will be analyzed using the same approach as described for the primary endpoint. Subjects with 
missing binary endpoint data at a visit will be considered failures and counted as nonresponders.

Continuous endpoints that are only measured at baseline and the Week 12 visit will be analyzed using an 
analysis of covariance (ANCOVA) model with fixed effects for treatment group (categorical), status of prior 
anti-TNF treatment (categorical), and glucocorticoid use at baseline (categorical), and the baseline value as a 
continuous covariate. From this model, estimates of the least squares means, treatment differences, standard 
errors, p-values, and 95% confidence intervals (CIs) for least squares mean treatment differences will be 
provided.

Continuous endpoints that are measured repeatedly over time will be analyzed using a linear repeated measures 
mixed model with restricted maximum likelihood estimation (REML). The model will include fixed effects for 
treatment group (categorical), visit (categorical), treatment group by visit interaction, status of prior anti-TNF
treatment (categorical), and glucocorticoid use at baseline (categorical); baseline value as a continuous 
covariate; and repeated measures across visit for subject. From this model, estimates of least squares means, 
treatment differences, standard errors, p-values, and 95% CIs for least squares mean treatment differences for 
each visit will be provided.
Safety Analyses:
All safety analyses will be performed using the safety set. Subjects will be analyzed according to the treatment they 
actually received.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.
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Treatment-emergent AEs (TEAEs) are defined as AEs with start dates at the time of or following the first exposure 
to investigational product. The number of events, incidence, and percentage of TEAEs will be calculated overall, by 
system organ class, by preferred term, and by treatment group. Treatment-emergent AEs will be further summarized 
by severity and relationship to investigational product. Adverse events leading to withdrawal, serious AEs, and 
deaths will be similarly summarized or listed.
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group and visit. Potentially 
clinically important findings will also be summarized or listed.
Antidrug antibody data will be summarized by treatment group and visit.
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STUDY SCHEDULE
Table 1:
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
Informed consent/assent
X
Eligibility assessment
X
X
Xe
Demographics and medical historyf
X
Complete physical examinationg
X
X
X
Targeted physical examinationg
X
Targeted neurological assessmenth
X
X
X
Vital signsi
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
12-lead ECGi
X
X
X
Chest x-rayj
X
Contraception checkk
X
X
X
X
X
X
X
Laboratory Assessments
Hematology
Xl
X
X
X
X
X
Serum chemistry
Xl
X
X
X
X
X
Urinalysis
Xl
X
X
X
X
X
Stool microbiologym
Xl
HBsAg, HBcAb, HCV Abn
Xl
HIV testing per local regulationo
X
FSHp
Xl
Serum β–hCGq
Xl
Urine β–hCGq
X
X
X
X
X
TB test (PPD or QuantiFERON TB Gold
Plus)r
Xl
JCV antibody banked samples
X
X
X
X
Xt
Xt
X
Xt
Xt
X
 
Xt
Xt
X
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Table 1:
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
Xu
Xu
Xu
Xu
X
ADA and NAb sampling
Xt
X
Xt
Xt
X
X
Endoscopic Procedure
Endoscopy (including biopsy)v
Xv
X
UC Assessments
Total Mayo score
Xw
Xw
Partial Mayo score
X
X
Remission stool frequency and pre-UC stool 
frequency
X
PRO UC daily e-diary data instruction
X
PRO UC daily e-diary datax
X
X
X
X
X
X
X
Health Assessmenty
IBDQ
X
X
X
X
X
X
Hospitalizations, inpatient days, 
 
(HRUA)
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36 v2, acute form
X
X
X
X
X
Treatment Procedures
Randomizationz
X
Administration of SHP647 or placeboz
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Concomitant medications and procedures
X
X
X
X
X
X
X
X
X
Dispense stool collection kit for stool sampleaa
X
X
X
Ab=antibody ADA=antidrug antibodies; β–hCG=beta-human chorionic gonadotropin; 
; ECG=electrocardiogram; ED=emergency department; 
; ET=early termination; FSH=follicle-stimulating hormone; GDH=glutamate dehydrogenase; 
HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; HRUA=Healthcare Resource Utilization Assessment; HCV=hepatitis C virus; HCV RNA=hepatitis C 
virus ribonucleic acid; HEENT=head, eyes, ears, nose, and throat; IBDQ=Inflammatory Bowel Disease Questionnaire; JCV=John Cunningham virus; 
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Table 1:
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
LTS=long-term safety extension; 
; Nab=neutralizing antibody; PCR=polymerase chain reaction; PGA=physician’s global 
assessment;
; 
; 
; PML=progressive multifocal leukoencephalopathy; 
PPD=purified protein derivative; PRO=patient-reported outcomes; SF-36 v2=short form-36 health survey, version 2; TB=tuberculosis; 
 
; UC=ulcerative colitis; 
.
a
At least 2 visits will be necessary to complete the screening procedures, including endoscopy.
b
Subjects who withdraw early during the treatment period should return for the early termination (ET) visit and then enter into the safety follow-up period.
c
Participation in the safety follow-up period is not required if subject is entering the maintenance study (SHP647-303) or LTS (SHP647-304) at the completion of the Week 12 
visit. For subjects participating in the 16-week safety follow-up period (not entering the maintenance study or LTS study), the Week 20 (Visit 7) visit will routinely be 
conducted by telephone; however, as an exception the visit can be performed as a study site visit if preferred. The Week 28 (Visit 8) visit will be at the study site.
d
Part 1 of Visit 6 should be scheduled preferably within 5 to 7 days before Part 2 visit; this will allow sufficient time for data from the centrally read endoscopy to be available 
at Part 2 of the visit.
e
The outcome of Visit 6, Part 2 is used to assess eligibility to enroll in the maintenance (SHP647-303) or LTS (SHP647-304) studies. Eligibility for SHP647-303 and 
SHP647-304 will be assessed under those respective protocols.
f
Medical history will include UC history, cardiac history, and smoking history.
g
Complete physical examination includes the review of the following body systems: general appearance, skin, HEENT, heart, lungs, confrontational visual fields (eyes), breast
(optional), abdomen, external genitalia (optional), extremities, neurologic function, back, and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin, heart, lungs, confrontational visual fields (eyes), abdomen, and examination of body systems where there are symptom complaints by the 
subject.
h
Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, speech, 
verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of PML should be excluded. See Section 7.2.3.3 for 
further details.
i
Vital signs (including blood pressure, pulse, respiratory rate, and temperature) and 12-lead ECG should be performed before collection of blood samples for laboratory 
assessments and before endoscopic procedure.
j
A chest x-ray performed up to 12 weeks before screening (Visit 1) may be used if available; the official reading must be located in the subject’s source documentation.
k
Contraception check should be performed for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential. See Section 4.4 for 
further details.
l
Screening laboratory test results, if considered by the investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated once during the 
screening period for confirmation. Results of repeated tests must be reviewed for eligibility prior to the screening endoscopy procedure.
m
Diagnosis of C. difficile infection should be made using the central laboratory. If for any reason the central laboratory is not available, refer to Appendix 5 for guidance 
regarding alternate diagnostic algorithms. 
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Table 1:
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
n
Subjects who test negative for HBsAg but positive for HBcAb without HBV DNA may be considered eligible. For subjects who test positive for HBcAb and negative for 
HBsAg, a blood sample should be taken for HBV DNA. Blood for HBV DNA reflex testing is collected for required subjects only. If HBV DNA is positive, these subjects 
will not be eligible.
o
Documentation of a negative HIV test result within 6 months prior to screening will be accepted.
p
For confirmation of postmenopausal status in females who have had 12 consecutive months of spontaneous amenorrhea and are 51 years of age.
q
For females of childbearing potential who are not surgically sterile, do not have confirmed ovarian failure, or do not meet the definition of postmenopausal as described in 
Section 4.4 and Section 7.2.3.7.
r
A documented negative PPD test within 12 weeks before baseline (Visit 2) is acceptable. Interferon gamma release assay official reading and method or test must be located in 
the source documentation.
s
A serum sample will be collected and banked. It may be analyzed if a subject shows neurologic symptoms suggestive of progressive multifocal leukoencephalopathy.
t
The sample must be collected before administration of investigational product.
u
The 
 sample must be collected before administration of investigational product. 
v
Flexible sigmoidoscopy or colonoscopy (if preferred) at screening must be performed on all subjects after the majority of other eligibility criteria (eg, laboratory values) are 
met. Endoscopy must be performed during the screening period within 10 days before baseline (Visit 2), preferably within 5 to 7 days before the baseline visit, to obtain the 
centrally read endoscopic subscore. Biopsy samples will be collected for histological evaluation using the Geboes Score classification for the key secondary efficacy endpoint 
and 
. Subjects at risk of colorectal cancer, as defined in exclusion criterion 5 (see Section 4.2), 
must have a colonoscopy performed at screening, unless the subject has had a surveillance colonoscopy performed within 1 year prior to screening, and any adenomatous 
polyps found at that examination have been excised. Colonoscopy report and pathology report (if biopsies are obtained) from the colonoscopy performed during screening or 
in the prior year confirming no evidence of dysplasia and colon cancer must be available in the source documents.
w
Mayo score will be based on subject daily e-diary entries. The Mayo score at baseline will be calculated based on the stool frequency subscore and rectal bleeding subscore, 
reported by subjects in the PRO UC daily e-diary and PGA obtained at baseline and the centrally read endoscopic subscore for the endoscopy performed during the screening 
period. The Mayo score at the Week 12 visit will be calculated based on the stool frequency subscore and rectal bleeding subscore reported by subjects in the PRO UC daily
e-diary and PGA and the centrally read endoscopic subscore for the endoscopy performed at Week 12, Visit 6 (Part 1). See Section 7.2.2.2 for further details.
x
PRO UC daily e-diary will be collected using a daily e-diary during the treatment period. Collection of the daily e-diary data must begin at least 10 days before the baseline 
visit (Visit 2). The subject should be provided with the handheld device to take home on their first visit. See Section 7.2.2.3 for further details. Compliance is assessed by site 
staff at each visit. The site staff will instruct the subject on the appropriate use of the e-diary, particularly when compliance is below 80% (eg, <23 out of 28 e-diary entries) 
when compared with the previous visit.
y
All health outcome or patient-reported questionnaires should be completed before completing any other visit assessments.
z
Interactive response technology will be used for randomization and dispensation of study treatment.
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Table 1:
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
aa
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the visit at which testing will be done.
Note: See Section 7.2 for the order in which assessments should be performed. Timing of visits is relative to baseline (Visit 2).
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1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
Ulcerative colitis (UC) is a chronic, relapsing disease marked by ulceration and inflammation of 
the colonic mucosa and submucosa. Initially it usually involves the rectum but may extend 
proximally to involve a portion of, or the entirety of, the colon. In the early stages, hemorrhagic 
and erythematous tissue is observed, progressing to mucosal ulceration with purulent exudates in 
severe cases. The ulceration pattern is continuous and may extend the entire length of the colon. 
Perforation of the bowel wall causing ileus and peritonitis can occur with transmural extension of 
the ulceration. Bloody diarrhea with or without mucus and lower abdominal pain with periods of 
remission and exacerbation are the most common symptoms.
The incidence of UC is estimated to be up to 24.3 cases per 100,000 persons per year in Europe 
and up to 19.2 cases per 100,000 persons per year in North America. No clear difference in 
incidence has been observed between men and women. Although UC can occur at any age, peak
incidence has been observed in the second to fourth decades of life (Molodecky et al. 2012).
Ulcerative colitis is a lifelong condition with a serious effect on the quality of life. Current 
treatment primarily consists of symptomatic management with dietary modifications and opiate
antidiarrheal drugs (loperamide), as well as disease modifying agents such as 5-aminosalicylic 
acid (5-ASA), systemic glucocorticoids, immunosuppressive agents 
(azathioprine/6-mercaptopurine, cyclosporine), and biologic therapy with anti-tumor necrosis 
factor (TNF) or anti-integrin agents. Despite recent advances, there is still an unmet need for an 
effective pharmacological treatment that will induce and maintain remission.
1.2
Product Background and Clinical Information
The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal sites of the 
gastrointestinal (GI) tract is influenced by the endothelial expression of mucosal addressin cell 
adhesion molecule (MAdCAM). MAdCAM is a member of the immunoglobulin super family of 
cell adhesion molecules and is mostly expressed on the cell surface of high endothelial venules 
of organized intestinal lymphoid tissue such as Peyer’s patches and mesenteric lymph nodes 
(Briskin et al. 1997; Shyjan et al. 1996; Liaskou et al. 2011). MAdCAM plays a role in gut 
immune surveillance, and also appears to facilitate excessive lymphocyte infiltration under 
conditions of chronic GI inflammation. The α4β7 integrin is the recognized ligand for MAdCAM,
and expression of this ligand on populations of CD4+ and CD8+ T cells, as well as on subsets of 
B cells, distinguishes them as unique gut homing lymphocytes.
SHP647 (previously known as PF-00547659) is a fully human immunoglobulin G2 kappa 
(IgG2k) monoclonal antibody that binds to human MAdCAM to reduce lymphocyte homing to 
the gut and GI inflammation. SHP647 binds MAdCAM-1 with high affinity and selectivity that 
prevents the binding of α4β7
+ lymphocytes to MAdCAM expressing sites in the high endothelial 
venules of the GI tract.
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1.3
Benefit/Risk Assessment
SHP647 has been evaluated in Phase 1 and 2 clinical studies in subjects with UC and CD. In UC 
study A7281009, induction with SHP647 at doses of 7.5 mg, 22.5 mg, or 75 mg every 4 weeks 
resulted in statistically significantly higher proportions of subjects in remission at Week 12 based 
on total Mayo score (both local and central read) when compared with placebo treatment.  In CD 
study A7281006, induction with SHP647 did not meet the primary endpoint; no statistically 
significant differences were observed between the active treatment arms and the placebo arm in 
CDAI-70 response rate at Week 8 or Week 12. Post hoc analyses suggested evidence of drug 
effect in subjects with more inflammation at baseline, as indicated by higher serum 
concentrations of CRP or Simple Endoscopic Score for CD (SES-CD).
In UC induction study A7281009, decreases in fecal calprotectin were observed in all groups, 
including placebo; however, there were no statistically significant differences in the decrease in 
fecal calprotectin between any dose level of SHP647 and placebo. Decreases in hsCRP were also 
observed in all 4 treatment groups; however, other than the 75 mg dose group at Week 12, no 
statistically significant differences were observed in active treatment vs placebo. In the induction 
Study A7281006 in subjects with CD, compared to placebo, nominally statistically significant 
decreases in fecal calprotectin were observed in the 75 mg group at Week 8 and in the 22.5 mg 
and 75 mg groups at Week 12. Generally, decreases from baseline in hsCRP were observed in all 
4 treatment groups over the 12-week induction period. Compared to placebo, nominally 
statistically significant decreases in hsCRP were observed in all 3 active treatment groups 
(22.5 mg, 75 mg, and 225 mg) at Week 12. There was no evidence of a dose response for either 
of these parameters. A nominally statistically significant increase was observed in circulating β7+
central memory T lymphocytes at Weeks 8 and 12, consistent with the predicted mechanism of 
action.
The most common SAEs across all studies were CD and UC. In Study A7281006, the 
randomized, placebo-controlled induction study in CD, TEAEs were most commonly reported 
within the GI disorders system organ class (SOC) followed by the infections and infestations 
SOC.  The most common all-causality TEAEs were CD (worsening and progression of 
underlying disease), followed by pyrexia, headache, and arthralgia, all of which had similar 
incidences in the placebo treatment group compared with the active treatment groups. In Study 
A7281009, the randomized, placebo-controlled induction study in UC, TEAEs were most 
commonly reported within the GI disorders SOC followed by the infections and infestations 
SOC.  The most common all-causality TEAE was headache, followed by abdominal pain, 
nasopharyngitis, UC (worsening and progression of underlying disease), and nausea, all with 
similar incidence between placebo- and drug-treated subjects.
The long-term, open-label safety studies (Studies A7281007 and A7281010) were not 
placebo-controlled, but permitted exposure to the investigational product at doses of 75 mg or 
225 mg every 4 weeks for 18 and 36 months, respectively. In Study A7281007, the most 
common all-causality TEAE was CD (worsening or progression), arthralgia, nasopharyngitis, 
and abdominal pain. In Study A7281010, the most common all-causality TEAEs have been UC 
(worsening or progression), arthralgia, and nasopharyngitis.
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SHP647 appears to be generally well tolerated, with the majority of TEAEs distributed at similar 
frequencies among treatment arms with only peripheral edema, gastroenteritis, and arthralgia 
more frequently reported in SHP647- than placebo-treated subjects in the pooled induction 
studies. In the placebo-controlled induction studies, nasopharyngitis was not reported more 
frequently in SHP647- than placebo-treated subjects, but occurred at relatively high frequency 
during long-term safety studies. SHP647 does not appear to be associated with impaired CNS 
immune surveillance. No case of PML or myocarditis has been reported. SHP647, in doses of 
7.5 mg, 22.5 mg, and 75 mg, appears to increase the rate of remission in subjects with UC, and 
may have an effect in patients with CD who have greater evidence of inflammation based on 
biomarker or endoscopic data.
Always refer to the latest version of the SHP647 investigator’s brochure for the overall 
benefit/risk assessment and the most accurate and current information regarding the 
pharmacokinetics, efficacy, and safety of SHP647.
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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
SHP647, a fully human IgG2k antihuman MAdCAM monoclonal antibody, is under development 
for the treatment of UC. SHP647 prevents the binding of α4β7
+ lymphocytes to 
MAdCAM-expressing sites with high affinity and selectivity. Principal sites of MAdCAM 
expression on normal tissue include intestine, pancreas, stomach, esophagus, spleen, and to a 
lesser extent lung, liver, and bladder but not the central nervous system (CNS) (Steffen et al. 
1996).
Although selective targeting of the MAdCAM receptors is a novel approach, the basic 
interference of lymphocyte homing by preventing the binding of these α4β7
+ lymphocytes to the 
MAdCAM receptor and the resultant efficacy in UC is well established (Feagan et al. 2013). 
SHP647 is differentiated from other molecules used for the treatment of UC in that it blocks the 
interaction of α4β7
+ lymphocytes to the MAdCAM receptor by selectively binding to MAdCAM 
in the gut (and related tissues) whereas other molecules only target the integrins on the 
infiltrating lymphocytes. Additionally, SHP647 does not bind to the vascular cell adhesion 
molecule; therefore, SHP647 is not expected to be an effective treatment for multiple sclerosis, 
or affect lymphocyte homing or surveillance in the CNS.
This study is designed to evaluate the efficacy of SHP647 in inducing remission in subjects with 
moderate to severe UC.
SHP647 has been investigated in 2 completed dose-finding studies (A7281001 and A7281009) in 
subjects with moderate to severe UC; a third study (A7281010), an open-label long-term safety 
extension study, is ongoing. Phase 1 study A7281001 evaluated both single (0.03-10.0 mg/kg 
intravenous [IV]; 3.0 mg/kg subcutaneous [SC]) and multiple doses (0.1-3.0 mg/kg IV; 0.3 and 
1.0 mg/kg SC) of SHP647 in subjects with UC. Safety evaluation revealed a safety profile for 
SHP647 similar to that of placebo, with no pattern of adverse events (AEs) suggestive of 
increased risk of opportunistic infections or CNS effects, and no evidence of adverse effects on 
laboratory parameters, electrocardiograms (ECGs), vital signs, or neurological function. Events 
leading to withdrawal were due to exacerbations of the underlying UC.
Study A7281009 was a Phase 2b proof-of-concept (randomized, double-blind, 
placebo-controlled, parallel, dose-ranging) study designed to evaluate the efficacy, safety, and 
pharmacokinetics of SHP647 in subjects with moderate to severe UC. Treatment was assigned in 
a 1:1:1:1:1 ratio to dose levels of 7.5, 22.5, 75, or 225 mg SHP647 or placebo administered SC 
once every 4 weeks (Q4W at Weeks 0, 4, and 8). The primary endpoint of the study was the 
proportion of subjects in clinical remission at Week 12, with remission defined as a total Mayo 
score of ≤2 with no individual subscore >1 (see Appendix 2 for details of the Mayo score). 
More subjects were in clinical remission at Week 12 in SHP647-treated groups than in the 
placebo group, with statistical significance achieved for the 7.5, 22.5, and 75-mg doses
(Vermeire et al. 2017). Based upon the total Mayo score with a centrally read endoscopic 
severity component, the increase in clinical remission rates over placebo at Week 12 for the 7.5, 
22.5, and 75-mg doses were 8.0% (p=.043), 12.8% (p=.010), and 11.8% (p=.012). 
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When the clinical remission rate at Week 12 was analyzed by stratum of previous anti-TNF 
exposure (experienced or naïve), a similar trend was observed across dose levels in both the 
anti-TNF experienced and anti-TNF naïve subjects. There was no evidence of an adverse safety 
signal, and there was no increase in the frequency of infections in MAdCAM-bearing tissues as 
evidenced by similar rates of nasopharyngitis among treatment arms.
Based on the efficacy and safety data in Study A7281009 and the systemic population 
pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation, clinical remission, 
clinical response and mucosal healing rates were higher in subjects with UC receiving doses of 
22.5 and 75 mg Q4W than in those receiving doses of 7.5 mg and 225 mg Q4W. The induction 
responses were not demonstrated either at Week 4 or Week 8, but were observed at Week 12 
regardless of dose level. No difference in the clinical responses between a 22.5-mg dose and a 
25-mg dose is expected based on the current understanding of the mode of action of SHP647 and 
clinical observations to date. To better understand the exposure (dose)-response relationship in 
this population and understand individual patient exposure needs, the 25-mg and 75-mg doses 
(Q4W) will be tested in the Phase 3 program. Therefore, SC doses of 25 mg or 75 mg of SHP647 
or placebo on Day 1 (Week 0), Week 4, and Week 8 are recommended for the 2 planned Phase 3 
studies SHP647-301 and SHP647-302. The Phase 1 study, A7281001, which investigated the 
safety, tolerance, pharmacokinetics, and pharmacodynamic properties of SHP647, supports 
further clinical development of SHP647 using SC administration.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of the study is to evaluate the efficacy of SHP647 in inducing remission,
based on composite score of patient-reported symptoms and centrally read endoscopy, in 
subjects with moderate to severe UC.
2.2.2
Secondary Objectives
2.2.2.1
Key Secondary Objectives
The key secondary objectives are as follows:

To evaluate the efficacy of SHP647 in achieving endoscopic remission, based on 
centrally read endoscopy.

To evaluate the efficacy of SHP647 in achieving clinical remission, based on composite 
score of patient-reported symptoms.

To evaluate the efficacy of SHP647 in inducing clinical response, based on composite 
score of patient-reported symptoms and centrally read endoscopy.

To evaluate the efficacy of SHP647 in achieving mucosal healing, based on a 
centrally read endoscopic and histological assessment using the Geboes Score grading 
system.
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2.2.2.2
Other Secondary Objectives
The other secondary objectives are as follows:

To evaluate the safety and tolerability of SHP647.

To evaluate the effect of SHP647 induction treatment on other clinical and endoscopic 
outcomes (including Mayo-based remission and clinical response, partial Mayo score 
over time, clinical remission over time, endoscopic remission, and deep remission)

To evaluate the effect of SHP647 on abdominal pain, urgency, diarrhea, and absolute 
stool frequency and bleeding scores.

To evaluate the effect of SHP647 on health-related quality of life (HRQL) (as measured 
by the Inflammatory Bowel Disease Questionnaire [IBDQ] and the Short Form-36 Health 
Survey [SF-36]).

To evaluate the effect of SHP647 on incidence of hospitalizations and total inpatient 
days.
2.2.3
Exploratory Objectives
The exploratory objectives of the study are as follows:
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3
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study designed to 
evaluate the efficacy and safety of SHP647 in inducing remission in subjects with moderate to 
severe UC.
A total of 825 subjects (330 subjects at 25 mg SHP647, 330 subjects at 75 mg SHP647, and 
165 placebo subjects) are planned for enrollment into the study (Figure 1). Subjects must be at 
least 16 years of age and no more than 80 years of age at the time of signing the informed 
consent/assent form.
The study consists of a screening period up to 6 weeks and a 12-week treatment period. After the 
screening period, eligible subjects will be randomly assigned to receive 1 of 3 treatments (25 mg 
SHP647, 75 mg SHP647, or placebo) in a 2:2:1 ratio. Randomization will be stratified based 
upon the subject’s status of prior anti-tumor necrosis factor (TNF) treatment (naïve or 
experienced) and glucocorticoid use at baseline (on glucocorticoids at baseline versus not on 
glucocorticoids at baseline). Subjects will receive SC injections of SHP647 or placebo, using a 
prefilled syringe (PFS), on Week 0/Day 1 (Visit 2), Week 4 (Visit 4), and Week 8 (Visit 5). 
Subjects will undergo efficacy, 
, 
, safety, and health outcome assessments at these 
visits as detailed in Table 1.
At the end of the 12-week treatment period, eligible subjects will be offered the opportunity to 
participate in a double-blind maintenance study (SHP647-303; for subjects who achieve clinical 
response) or a long-term safety extension (LTS) study (SHP647-304; for subjects who do not 
achieve a clinical response) as shown in Figure 1. Subjects who withdraw early from the 
12-week treatment period or who do not wish to enter the maintenance study (SHP647-303) or 
LTS study (SHP647-304) will continue into a 16-week safety follow-up period. Only those 
subjects who complete the full course of investigational product treatment in the induction 
studies (SHP647-301 or SHP647-302) will be eligible to continue in the maintenance study or 
LTS study.
The overall study design is shown in Figure 2.
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Figure 1:
Overview of SHP647 Phase 3 Studies in Ulcerative Colitis
Placebo 
25 mg
75 mg
Non-Respondersa
Induction
(SHP647-301, SHP647-302) 
Maintenance
(SHP647-303) 
Long-term Safety 
Extension
(SHP647-304) 
25 mg
Placebo
75 mg
Placebo
Placebo
Respondersa
Respondersa
Respondersa
75 mg
25 mg
a
Clinical response is defined as:
1. A decrease from the induction study (SHP647-301 or SHP647-302) baseline in the composite score of 
patient-reported symptoms using daily e-diary and centrally read endoscopy of at least 2 points and at least 30%, 
with an accompanying decrease in the subscore for rectal bleeding ≥1 point or a subscore for rectal bleeding ≤1
OR 
2. A decrease from the induction study (SHP647-301 or SHP647-302) baseline total Mayo score of at least 
3 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of ≥1 point or an 
absolute rectal bleeding subscore of ≤1.
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Figure 2:
Study Design Flow Chart
LTS=long-term safety extension; W=week.
a Subjects who withdraw early from the 12-week treatment period or who do not wish to enter the maintenance study 
(SHP647-303) or LTS study (SHP647-304) will continue into a 16-week safety follow-up period.
3.1.1
Rationale for Primary Endpoint
The Mayo score has historically been used as the primary endpoint for pivotal studies of agents 
intended to treat UC. Over the past decade, health authority thinking regarding efficacy 
endpoints for UC has evolved such that the traditional Mayo score is no longer recommended. 
Current regulatory guidance (FDA Ulcerative Colitis: Clinical Trial Endpoints Guidance for 
Industry [Draft], 2016; EMA Guideline on the Development of New Medicinal Products for the 
Treatment of Ulcerative Colitis [Draft], 2016) includes a dual measurement of patient-reported 
signs and symptoms outcomes (stool frequency and rectal bleeding), and clinician-reported 
endoscopic outcomes (scoring any endoscopy with evidence of friability as a 2), including 
histology. Per agreement with health authorities, these 3 outcomes will be reported as a 
composite score.
Data will be collected to calculate the total Mayo score using both the traditional and modified 
endoscopy subscore as a sensitivity analysis and to estimate the impact of the modification on 
the primary endpoint. The clinical relevance of the traditional Mayo score is supported by its 
correlation with significant improvement in disease-specific HRQL as measured by the 
Inflammatory Bowel Disease Questionnaire (IBDQ) and in generic HRQL as measured by the 
Short Form-36 (SF-36) questionnaire.
Placebo
25 mg SHP647
75 mg SHP647
Screening: Up to 
6 weeks
Randomization
Maintenance study 
(SHP647-303)
or
LTS study 
(SHP647-304)
or
W0
W4
W8
Dosing:
Treatment period: 12 weeks
Week 12/End of 
Treatment
16-week safety 
follow-up perioda
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3.1.2
Rationale for Key Secondary Endpoints:
The first 2 key secondary endpoints are included to comply with EMA advice. European 
Medicines Agency would agree to the composite primary endpoint only if supported by a key 
secondary analysis, where the patient-reported symptoms and clinician-reported endoscopy are 
analyzed as “co-primary”.
The clinical response endpoint is based on the new composite score, and also represents 1 of the 
entry criteria for the maintenance study. This endpoint has not been previously tested.
Mucosal healing as a key secondary endpoint comprises both endoscopic and histologic 
components as recommended in the draft FDA and EMA guidance on UC (FDA Ulcerative 
Colitis: Clinical Trial Endpoints Guidance for Industry [Draft], 2016; EMA Guideline on the 
Development of New Medicinal Products for the Treatment of Ulcerative Colitis [Draft], 2016).
The Geboes Score (see Appendix 2) will be used to evaluate histologic remission and to 
complement the endoscopic subscore in the assessment of mucosal healing for the key secondary 
endpoint.
3.2
Duration and Study Completion Definition
Each subject’s final visit in this study may be at the end of the treatment period (Week 12) if 
continuing to Study SHP647-303 or SHP647-304, or at the end of the safety follow-up period 
(Week 28) if not continuing to either of these studies. In either case, the final visit will be in 
person at the site. A subject’s maximum duration of participation is expected to be 
approximately 34 weeks: a screening period of up to 6 weeks, a treatment period of 12 weeks, 
and a safety follow-up period of 16 weeks (if applicable). It is expected that the study will be 
completed in approximately 3 years.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
It is anticipated that the study will be conducted in at least 18 countries. Regions will include 
North America, Europe, the Middle East, and Africa, Latin America, and Asia-Pacific. 
Approximately 210 sites will be utilized.
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4
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed. Subject eligibility 
should be reviewed and documented by an appropriately qualified member of the investigator’s 
study team before subjects are included in the study.
4.1
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study.
1. Subjects and/or their parent or legally authorized representative must have an understanding, 
ability, and willingness to fully comply with study procedures and restrictions.
2. Subjects must be able to voluntarily provide written, signed, and dated (personally or via a 
legally authorized representative) informed consent and/or assent, as applicable, to 
participate in the study.
3. Subjects must be between ≥16 and ≤80 years of age at the time of the signing of the informed 
consent/assent form.
NOTE: Subjects <18 years of age must weigh ≥40 kg and must have body mass index (BMI) 
≥16.5.
4. Subjects must have a documented diagnosis (radiologic or endoscopic with histology) of UC 
for 3 months before screening. The following must be available in each subject’s source 
documentation:

A biopsy report to confirm the histological diagnosis.

A report documenting disease duration based upon prior colonoscopy.
NOTE: If this documentation is not available at the time of screening, a colonoscopy 
with biopsy to confirm the diagnosis is required during the screening period.
5. Subjects must be willing to undergo a flexible sigmoidoscopy or colonoscopy (if preferred), 
including biopsy sample collection, during screening after all other inclusion criteria have 
been met.
6. Subjects must have moderate to severe active UC, defined as a total Mayo score of 6,
including a centrally read endoscopic subscore 2, rectal bleeding subscore 1, and stool 
frequency subscore 1 at baseline (Visit 2).
7. Subjects must have evidence of UC extending proximal to the rectum (ie, not limited to 
proctitis).
8. Subjects must have had an inadequate response to, or lost response to, or had an intolerance 
to at least 1 conventional treatment such as mesalamine (5-ASA), glucocorticoids, 
immunosuppressants (azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate 
[MTX]), or anti-TNF (refer to Appendix 4 for guidance).
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9. Subjects receiving any treatment(s) for UC described in Section 5.2.1 are eligible provided 
they have been, and are anticipated to be, on a stable dose for the designated period of time.
10. Subjects are males or nonpregnant, nonlactating females who, if sexually active, agree to 
comply with the contraceptive requirements of the protocol, or females of nonchildbearing 
potential. Males and females of reproductive potential who are sexually active must agree to 
use appropriate contraception (as described in Section 4.4) for the duration of the study.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met.
1.
Subjects with indeterminate colitis, microscopic colitis, non-steroidal anti-inflammatory 
drug-induced colitis, ischemic colitis, infectious colitis, or clinical/histologic findings 
suggestive of Crohn’s disease.
2.
Subjects with colonic dysplasia or neoplasia. (Subjects with prior history of adenomatous 
polyps will be eligible if the polyps have been completely removed.)
3.
Subjects with past medical history or presence of toxic megacolon.
4.
Subjects with colonic stricture, past medical history of colonic resection, a history of bowel 
surgery within 6 months before screening, or who are likely to require surgery for UC during 
the treatment period.
5.
Subjects at risk for colorectal cancer must have a colonoscopy (Eaden and Mayberry 2002)
performed during the screening period with results available within 10 days before the 
baseline visit (Visit 2), unless the subject has had a surveillance colonoscopy performed 
within 1 year prior to screening, and any adenomatous polyps found at that examination 
have been excised. Colonoscopy report and pathology report (if biopsies are obtained) from 
the colonoscopy performed during screening or in the prior year confirming no evidence of 
dysplasia and colon cancer must be available in the source documents.
Subjects at risk for colorectal cancer include, but are not limited to:

Subjects with extensive colitis for ≥8 years or disease limited to left side of colon 
(ie, distal to splenic flexure) for ≥10 years before screening, regardless of age.

Subjects ≥50 years of age at the time of signing of the informed consent form.
6.
Subjects have had prior treatment with SHP647 (formerly PF-00547659).
7.
Subjects with known or suspected intolerance or hypersensitivity to the investigational 
product(s), closely related compounds, or any of the stated ingredients.
8.
Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2).
9.
Subjects have received any biologic with immunomodulatory properties (other than 
anti-TNFs) within 90 days before baseline (Visit 2).
10. Subjects have received any nonbiologic treatment with immunomodulatory properties (other 
than their current background UC treatment) within 30 days before baseline (Visit 2).
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11. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, 
vedolizumab, efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion 
molecule).
12. Subjects have received parenteral or rectal glucocorticoids, or rectal 5-ASA, within 14 days 
before screening endoscopic procedure.
13. Subjects have received leukocyte apheresis or selective lymphocyte, monocyte, or 
granulocyte apheresis or plasma exchange within 30 days before baseline (Visit 2).
14. Subjects have participated in other investigational studies within either 30 days or 
5 half-lives of investigational product used in the study (whichever is longer) before baseline 
(Visit 2).
15. Subjects have received a live (attenuated) vaccine within 30 days before the baseline visit 
(Visit 2).
16. Subjects with active enteric infections (positive stool culture and sensitivity), Clostridium 
difficile infection or pseudomembranous colitis [subjects with C. difficile infection at 
screening may be allowed re-test after treatment], evidence of active cytomegalovirus 
infection or Listeria monocytogenes, known active invasive fungal infections such as 
histoplasmosis or parasitic infections, clinically significant underlying disease that could 
predispose the subjects to infections, or a history of serious infection (requiring parenteral 
antibiotic and/or hospitalization) within 4 weeks before the baseline visit (Visit 2).
17. Subjects with abnormal chest x-ray findings at screening (Visit 1), such as presence of active 
tuberculosis (TB), general infections, heart failure, or malignancy. (A chest x-ray performed 
up to 12 weeks before study entry [screening, Visit 1] may be used if available; 
documentation of the official reading must be located and available in the source 
documentation.)
18. Subjects with evidence of active or latent infection with Mycobacterium tuberculosis (TB) 
or subjects with this history who have not completed a generally accepted full course of 
treatment before randomization are excluded. All other subjects must have either the 
Mantoux (purified protein derivative [PPD]) tuberculin skin test or interferon gamma release 
assay (IGRA) performed.
Subjects who have no history of previously diagnosed active or latent tuberculosis are 
excluded if they have a positive Mantoux (PPD) tuberculin skin test (ie ≥5 mm induration) 
or a positive IGRA (the latter to be tested at the site’s local laboratory) during screening or 
within 12 weeks before randomization. If IGRA test cannot be performed locally, a central 
laboratory may be used, with prior agreement from the sponsor.

An IGRA is strongly recommended for subjects with a prior Bacillus Calmette-Guérin 
(BCG) vaccination, but may be used for any subject. Documentation of IGRA product 
used and the test result must be in the subject's source documentation if performed 
locally. Acceptable IGRA products include QuantiFERON TB Gold Plus In-Tube Test.

If the results of the IGRA are indeterminate, the test may be repeated, and if a negative 
result is obtained, enrollment may proceed. In subjects with no history of treated active or 
latent tuberculosis, a positive test on repeat will exclude the subject. 
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Subjects with a history of active or latent tuberculosis infection must follow instructions 
for “Subjects with a prior diagnosis of active or latent tuberculosis are excluded unless 
both of the following criteria are met” in this criterion.

Subjects with repeat indeterminate IGRA results, with no prior TB history, may be 
enrolled after consultation with a pulmonary or infectious disease specialist who 
determines low risk of infection (ie, subject would be acceptable for immunosuppressant 
[eg, anti-TNF] treatment without additional action). This consultation must be included in 
source documentation.
Results from a chest x-ray, taken within the 3 months before or during screening (Visit 1) 
must show no abnormalities suggestive of active TB infection as determined by a qualified 
medical specialist.
Subjects with a prior diagnosis of active or latent tuberculosis are excluded unless both of 
the following criteria are met:

The subject has previously received an adequate course of treatment for either latent
(eg, 9 months of isoniazid or an acceptable alternative regimen, in a locale where rates of 
primary multidrug TB resistance are <5%. Subjects from regions with higher rates of 
primary multidrug TB resistance are excluded) or active (acceptable multidrug regimen) 
TB infection. Evidence of diagnosis and treatment must be included in source 
documentation. Consultation with a pulmonary or infectious disease specialist to confirm 
adequate treatment (ie, subject would be acceptable for immunosuppressant [eg, 
anti-TNF] treatment without additional action) must be performed during the screening 
period. The consultation report must be included in source documentation prior to 
enrollment.

A chest x-ray performed within 3 months prior to screening (Visit 1) or during screening 
(Visit 1) indicates no evidence of active or recurrent disease, and documentation of 
interpretation by a qualified medical specialist must be included in source documentation.
19. Subjects with a pre-existing demyelinating disorder such as multiple sclerosis or new onset 
seizures, unexplained sensory motor, or cognitive behavioral, neurological deficits, or 
significant abnormalities noted during screening.
20. Subjects with any unexplained symptoms suggestive of progressive multifocal 
leukoencephalopathy (PML) based on the targeted neurological assessment during the 
screening period (see Section 7.2.3.3).
21. Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed.
22. Subjects with a significant concurrent medical condition at the time of screening (Visit 1) or 
baseline (Visit 2), including, but not limited to, the following:

Any major illness/condition or evidence of an unstable clinical condition (eg, renal, 
hepatic, hematologic, GI (except disease under study), endocrine, cardiovascular, 
pulmonary, immunologic [eg, Felty’s syndrome], or local active infection/infectious 
illness) that, in the investigator’s judgment will substantially increase the risk to the 
subject if he or she participates in the study.
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
Cancer or history of cancer or lymphoproliferative disease within the previous 5 years 
(other than resected cutaneous basal cell carcinoma, squamous cell carcinoma, or 
carcinoma in situ of the uterine cervix that has been treated with no evidence of 
recurrence).

Presence of acute coronary syndrome (eg, acute myocardial infarction, unstable angina 
pectoris) within 24 weeks before screening (Visit 1).

History of significant cerebrovascular disease within 24 weeks before screening (Visit 1).
23. Subjects who have had significant trauma or major surgery within 4 weeks before the 
screening visit (Visit 1), or with any major elective surgery scheduled to occur during the 
study.
24. Subjects with evidence of cirrhosis with or without decompensation. 
25. Subjects with primary sclerosing cholangitis.
26. Subjects with evidence of positive hepatitis B surface antigen (HBsAg) or hepatitis B core 
antibody (HBcAb). NOTE: if a subject tests negative for HBsAg, but positive for HBcAb, 
the subject would be considered eligible if no presence of HBV DNA is confirmed by HBV 
DNA PCR reflex testing performed in the central laboratory.
27. Subjects with chronic hepatitis C (HCV) (positive HCVAb and HCVRNA). Note: Subjects 
who are HCVAb positive without evidence of HCVRNA may be considered eligible 
(spontaneous viral clearance or previously treated and cured [defined as no evidence of 
HCVRNA at least 12 weeks prior to baseline]).
28. Subjects with any of the following abnormalities in hematology and/or serum chemistry 
profiles during screening. NOTE: Screening laboratory tests, if the results are considered by 
the investigator to be transient and inconsistent with the subject’s clinical condition, may be 
repeated once during the screening period for confirmation. Results must be reviewed for 
eligibility prior to the screening endoscopy procedure.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels 3.0 × the 
upper limit of normal (ULN).

Total bilirubin level 1.5 ×ULN or >2.0×ULN if the subject has a known documented 
history of Gilbert’s syndrome.

Hemoglobin level 80 g/L (8.0 g/dL).

Platelet count 100 × 109/L (100,000 cells/mm3) or 1000 × 109/L 
(1,000,000 cells/mm3).*

White blood cell count 3.5 × 109/L (3500 cells/mm3).

Absolute neutrophil count (ANC) <2 × 109/L (2000 cells/mm3).

Serum creatinine level >1.5 × ULN or estimated glomerular filtration rate 
<30 mL/min/1.73m2 based on the abbreviated Modification of Diet in Renal Disease 
Study Equation.
*Note:  If platelet count is <150,000 cells/mm3, a further evaluation should be performed
to rule out cirrhosis, unless another etiology has already been identified.
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29. Subjects with known human immunodeficiency (HIV) infection based on documented 
history, with positive serological test, or positive HIV serologic test at screening, tested at 
the site's local laboratory in accordance with country requirements or tested at the central 
laboratory. Note: A documented negative HIV test within 6 months of screening is 
acceptable and does not need to be repeated.
30. Subjects who have, or who have a history of (within 2 years before screening [Visit 1]), 
serious psychiatric disease, alcohol dependency, or substance/drug abuse or dependency of 
any kind, including abuse of medical marijuana (cannabis).
31. Subjects with any other severe acute or chronic medical or psychiatric condition or 
laboratory or electrocardiogram (ECG) abnormality that may increase the risk associated 
with study participation or investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the investigator, would make the 
subject inappropriate for entry into this study.
32. Female subjects who are planning to become pregnant during the study period.
33. Subjects who do not agree to postpone donation of any organ or tissue, including male 
subjects who are planning to bank or donate sperm and female subjects who are planning to 
harvest or donate eggs, for the duration of the study and through 16 weeks after last dose of 
investigational product.
34. Subjects who are investigational site staff members or relatives of those site staff members 
or subjects who are Shire employees directly involved in the conduct of the study.
4.3
Restrictions

Smoking can have an influence on the severity of UC disease symptoms. Subjects should 
inform the investigator of any changes to their smoking habits during the study; however, 
these data will not be captured in the electronic case report form (eCRF). Use of nicotine 
patches should be recorded as concomitant medication (see Section 5.2).

For the purposes of this protocol, dietary supplements (such as vitamins, minerals, 
purified food substances, and herbals with pharmaceutical properties) are considered to 
be concomitant medications (see Section 5.2).
4.4
Reproductive Potential
The potential effects of SHP647 on embryofetal or postnatal development have not yet 
been assessed in animals or humans; these will be assessed in future studies. To minimize 
the risk of unintentional exposure of the embryo or fetus in the clinical study, all sexually 
active male and female subjects who, in the opinion of the investigator, are biologically capable 
of having children and with their partners are at risk of pregnancy, must agree to use an 
appropriate form of contraception, in accordance with the package instructions/leaflet, for the 
duration of the active treatment period and for at least 16 weeks after the last dose of 
investigational product.
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True abstinence is considered to be a highly effective contraception (ie, a method that results in a 
failure rate of <1% per year) when it is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
declaration of abstinence for the duration of exposure to investigational product, and withdrawal 
are not appropriate methods of contraception.
During the screening visit, the investigator or designee in consultation with the subject will 
confirm the subject’s childbearing potential status. For subjects of childbearing potential, it must 
be confirmed and documented that the subject has selected the most appropriate method of 
contraception from the permitted list of contraception methods. Subjects must affirm the 
consistent and correct use of at least 1 of these selected methods. Regular contraception check 
discussions will take place at the time points specified in Table 1 (ie, at each site visit) and will 
be documented. In addition, the subject must be instructed to call the site immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected.
4.4.1
Contraceptive Methods for Female Study Subjects
Sexually active females of childbearing potential must already be using an established highly 
effective form of contraception, and must be advised to use appropriate contraceptives 
throughout the study period and for 16 weeks following the last dose of investigational product. 
If hormonal contraceptives are used they should be administered according to the package insert.
Female subjects should be in one of the following categories:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and 51 years of 
age); postmenopausal status should be confirmed by follicle-stimulating hormone (FSH)
testing.

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks poststerilization or has medically confirmed ovarian failure.

Females of childbearing potential with a negative serum pregnancy test result at 
screening and a negative urine pregnancy test result at baseline (Visit 2). Females of 
childbearing potential must agree to practice true abstinence (refrain from sexual activity 
that could result in pregnancy) or agree to use appropriate methods of highly effective 
contraception.
Highly effective contraception (ie, methods that result in a failure rate of <1% per year when 
used consistently and correctly) are:

Combined (estrogen- and progestogen-containing) hormonal contraceptives associated 
with inhibition of ovulation (oral, intravaginal, transdermal) stabilized for at least 30 days 
before the screening visit (Visit 1)

Progestogen-only hormonal contraception associated with inhibition of ovulation plus a 
barrier method

Intrauterine device
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
Intrauterine hormone-releasing system

Bilateral tubal occlusion

Male sterilization/vasectomized partner with documented absence of sperm in the 
postvasectomy ejaculate

True abstinence (see Section 4.4).
4.4.2
Contraceptive Methods for Male Study Subjects
Contraception is required for all sexually active male subjects, who with their female sexual 
partners, must agree to use 1 of the following appropriate methods of contraception throughout 
the study period and for 16 weeks following the last dose of investigational product.
Appropriate methods of contraception for male subjects are:

Male condom with spermicide; however, if spermicide is not available in the country, 
additional contraception (ie, one of those listed below) must be used in addition to a male 
condom

Male sterilization with documented absence of sperm in the postvasectomy ejaculate.
Appropriate methods for female sexual partners of male subjects are (unless the female sexual 
partner is sterile [surgically or documented nonsurgical sterility]):

Use of a highly effective method of contraception listed in Section 4.4.1 OR an 
acceptable method of contraception (failure rate of >1% per year):
o
Female condom with spermicide (use by female sexual partner); however, if 
spermicide is not available in the country, additional contraception (ie, one of 
those listed below) must be used in addition to a female condom
o
Intrauterine device with spermicide
o
Contraceptive sponge with spermicide
o
Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with 
spermicide, or a cervical cap with spermicide). 
4.5
Withdrawal of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 12/ET (Visit 6) are to be performed. All subjects who discontinue treatment with 
investigational product should also undergo the protocol-specified 16-week safety follow-up
period. In the event that subjects are unable to attend in person for the follow-up visits, all efforts 
should be made to collect information on AEs and concomitant medications. 
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Comments (spontaneous or elicited) or complaints made by the subject must be recorded. The 
reason for termination and date of stopping investigational product must be recorded.
Subjects who discontinue will not be replaced.
4.5.1
Subject Withdrawal Criteria
Additional reasons a subject may be withdrawn from study treatment include but are not limited 
to:

AEs

Serious adverse events (SAEs)

Pregnancy

Protocol violations

Failure to return for visits.
A subject should be withdrawn from study treatment:

If a new therapy is initiated for UC, or

If a subject undergoes surgery for UC.
Subjects who withdraw from study treatment due to an increase in disease symptoms may see 
nonstudy-related physicians for treatment, which may include treatments prohibited during the 
treatment periods of this study.
If a subject withdraws their consent, no further evaluation should be performed, and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
4.5.2
Reasons for Withdrawal
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol deviation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Other (if “Other” is selected, the investigator must specify the reason)

Death
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
Physician decision

Pregnancy

Screen failure

Site terminated by sponsor.
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point before the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and that they return their electronic diary.
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5
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal remedies and vitamins)
received within 30 days (or PK equivalent of 5 half-lives, whichever is longer) of the first dose 
of investigational product. Use of biologics for indications other than UC during the 90 days 
before screening must also be recorded.
Prior and concomitant UC-specific treatments from the previous 10 years will be recorded. The 
subject’s entire history of biologic UC-specific treatments will be recorded.
Subjects must have had an inadequate response to, or lost response to, or had an intolerance to at 
least 1 conventional treatment such as sulfasalazine or 5-ASA, glucocorticoids, 
immunosuppressants (AZA, 6-MP, or MTX), or anti-TNF agents.  Please refer to Appendix 4 for 
guidance on defining prior treatment failure and intolerance to prior treatment for UC.
5.2
Concomitant Treatment
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the safety follow-up period, inclusive.
5.2.1
Permitted Treatment
Subjects must remain on stable doses of permitted UC treatments until completion of the 
Week 12 visit, unless decreases are required because of AEs. Stable doses of the following 
treatments for UC are permitted as concomitant medication:

Oral 5-ASA or sulfasalazine, providing that the dose is stable for at least 2 weeks before 
baseline (Visit 2)

Immunosuppressants (AZA, 6-MP, or MTX), providing that the dose is stable for at least 
8 weeks before baseline (Visit 2).

Oral glucocorticoids (prednisone or equivalent [see Appendix 3] up to a maximum of 
20 mg/day or budesonide up to a maximum of 9 mg/day), providing that the dose is 
stable for at least 2 weeks before screening endoscopic procedure.
NOTE: Rectal 5-ASA and parenteral or rectal glucocorticoids are prohibited from within 14 days 
before screening endoscopic procedure.
Subjects using medicinal marijuana (cannabis) under a physician’s prescription, and who obtain 
the product from a licensed pharmacy or provider, should continue to use it under the same 
regimen for the duration of the study, unless otherwise instructed by the investigator or treating 
physician. Such subjects must be using the product, in a stable regimen, for at least 3 months 
before screening.
Routine nonlive vaccinations are allowed during the study.
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Dietary and herbal supplements and probiotics are allowed in the study, provided they are being 
taken at stable doses at the time of the baseline visit (Visit 2) and for the duration of the study.
They should be recorded as concomitant medications.
Use of nicotine patches should be recorded as concomitant medication.
5.2.2
Prohibited Treatment
Table 2 details the minimum required number of days before baseline (Visit 2) for common prior 
treatments that are excluded medications for this study.
Table 2:
Common Excluded Treatments
Permanently 
Excluded
Minimum Required Number of Days Before 
Baseline (Visit 2)
Treatment
14
30
60
90
SHP647 (PF-00547659) in a previous study
X
Anti-integrin or antiadhesion molecule 
treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab)
X
Parenteral and rectal glucocorticoids
Xa
Rectal 5-ASA
Xa
Investigational products
Xb
Live (attenuated) vaccine
X
Nonbiologics with immunomodulatory 
properties (other than their current 
background UC treatment)
X
Anti-TNF treatment
X
Leukocyte apheresis or selective lymphocyte, 
monocyte, or granulocyte apheresis or plasma 
exchange
X
Biologics with immunomodulatory properties 
(other than anti-TNFs) including biosimilars
X
5-ASA=5-aminosalicylate; TNF=tumor necrosis factor.
a The minimum required number of days before baseline (Visit 2) for rectal 5-ASA and parenteral or rectal glucocorticoids is 
defined as 14 days before screening endoscopic procedure (see Section 4.2, exclusion criterion 11).
b Or 5 half-lives if longer.
Treatments not listed in Table 2 may be considered allowable; see Section 5.2.1 for further 
details.
No new nonpharmacological therapies that might affect bowel habit or GI function should be
started during the study.
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5.2.3
Rescue Therapy
Subjects must maintain their stable dose of background UC treatment, unless dose reduction or 
discontinuation is required due to associated AEs. If a subject requires initiation of a new therapy 
or increase in glucocorticoids for UC above the SHP647-301 or SHP647-302 baseline, the 
subject should be withdrawn from study treatment and enter the safety follow-up period, and
appropriate treatment should be given at the discretion of the investigator.
Subjects who enter the safety follow-up period will no longer need to abstain from the 
medications that were prohibited during the baseline and treatment periods. High-dose 
glucocorticoids and other UC treatments will be allowed. Biologics or nonbiologic 
immunosuppressants should not be initiated during the safety follow-up period without prior 
discussion with the sponsor study physician or designee due to the long half-life of SHP647.
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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is SHP647, which will be provided as a sterile aqueous buffered solution for SC 
administration in a glass PFS with a fixed needle. Each PFS contains 1 mL of SHP647 solution
for injection at an appropriate concentration to provide the intended dose of drug (25 or 75 mg).
Additional information is provided in the current SHP647 investigator’s brochure.
The reference product is placebo, which will be provided in a PFS with a fixed needle containing 
1 mL of placebo solution for SC administration. The placebo solution will contain the same 
sterile aqueous buffered solution as the test product but will not contain SHP647.
6.1.1
Blinding the Treatment Assignment
The placebo syringes and solution will match the SHP647 syringes in appearance. The fill 
volume for all syringes will be the same.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive response technology (IRT) system will be used for screening and enrolling 
subjects, recording subject visits, randomization, investigational product supply dispensation and 
management, inventory management and supply ordering, investigational product expiration 
tracking and management, and emergency unblinding. Please refer to the Study Manual for 
additional details regarding the IRT system.
6.2.2
Allocation of Subjects to Treatment
This is a double-blind, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.
The total Mayo score will be calculated at baseline (Visit 2) before randomization. Endoscopic 
subscore based on the central reader’s assessment will be used to determine eligibility. Subjects 
with a total Mayo score of ≥6, including a centrally read endoscopic subscore ≥2, rectal bleeding 
subscore ≥1, and stool frequency subscore ≥1, and who fulfill all other eligibility criteria, will be 
randomized in a ratio of 2:2:1 via a computer-generated randomization schedule to receive SC 
injections of 25 mg SHP647, 75 mg SHP647, or placebo, respectively. The randomization will 
be performed centrally and stratified by status of prior anti-TNF therapy (2 strata: naïve versus
experienced) and glucocorticoid use at baseline (2 strata: on glucocorticoids at baseline versus
not on glucocorticoids at baseline).
To ensure that the allocation of subjects with prior anti-TNF therapy exposure is similar to that 
observed in Study A7281009, the percentage of subjects with prior anti-TNF therapy exposure 
will be capped at 60% of the sample population. Additionally, in Japan only, enrollment of 
Japanese subjects with prior anti-TNF therapy exposure will be capped at 60%, to ensure 
comparability to the rest of the global study population.  There will be no cap on the number of 
anti-TNF naïve subjects randomized.
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Subject numbers are assigned to all eligible subjects as they consent to take part in the study. 
Within each site (numbered uniquely within a protocol), the subject number will be assigned to 
subjects according to the sequence of presentation for study participation.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment will be 
automatically assigned by the IRT system.
Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment assignment as
dictated by the study. In these cases, the same investigational product packing identification 
number may not be assigned to more than 1 subject.
6.2.3
Dosing
Investigational product (SHP647 or placebo) will be administered subcutaneously by qualified 
site personnel Q4W (Weeks 0, 4, and 8). See Section 7.2 for the timing of dosing relative to 
other procedures.
Investigational product should be administered in the anterolateral right or left thigh. If there are 
clinical reasons why the investigational product cannot be administered in the thigh, the 
investigational product may be administered in the deltoid area or abdomen with appropriate 
documentation. The location of the investigational product administration will be recorded.
After the first administration of investigational product, the subject must be observed by a 
member of the study staff for at least 30 minutes (the total duration should be determined at the 
discretion of the investigator). For subsequent administrations, observation of the subject is at the 
discretion of the investigator. Injection site and allergic reaction monitoring should be completed 
by a member of the study staff.
Investigator-directed delays in dosing due to abnormal laboratory findings or AEs should be 
discussed with the medical monitor to determine whether the subject should continue with the 
treatment. Only those subjects who complete the full course of investigational product treatment 
in the induction studies (SHP647-301 or SHP647-302) will be eligible to continue in the 
maintenance study or LTS study.
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational product is dispensed by qualified staff members.
6.2.4
Unblinding the Treatment Assignment
Whenever possible, the investigator or subinvestigator should contact the Shire physician and/or 
assigned medical monitor before breaking the blind. It is understood that in an emergency 
situation it may not be possible to communicate with the study team before breaking the blind. 
The safety of the subject should be of primary concern. When the blinding code is broken the 
reasons must be fully documented.
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In the event that the treatment assignment is broken, the date, the signature of the person 
who broke the code, and the reason for breaking the code are recorded on the IRT and the 
source documents. Upon breaking the blind, the subject is withdrawn from the study, but 
should be followed up for safety purposes. The IRT will notify the relevant personnel in the 
event of any code break. Code-break information is held by the pharmacist/designated person at 
the site.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
The sponsor will provide the investigator with packaged investigational product labeled in 
accordance with specific country regulatory requirements. All investigational product is labeled 
with a minimum of the following: protocol number, medication identification number, dosage 
form (including product name and quantity in pack), directions for use, storage conditions, 
expiry date (if applicable), batch number and/or packaging reference, the statements “For clinical 
trial use only” and/or “CAUTION: New Drug – Limited by Federal (or US) Law to 
Investigational Use”, and the sponsor’s name and address.
Additional labels may be applied in order to meet local or institutional requirements, but must 
not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior written agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers: PFS with nominal fill 
volume of 1 mL. The PFS will be packaged in a labeled carton.
Changes to sponsor-supplied packaging before dosing may not occur without prior written 
agreement by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or delegated member of the study team. The pharmacist or delegated 
team member will enter the unique subject identifier on the investigational product labels as they 
are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. 
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The investigator is responsible for ensuring that the temperature is monitored throughout the 
duration of the study and that records are maintained; the temperature should be monitored 
continuously by using either an in-house system, a mechanical recording device such as a 
calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording. The sponsor must be notified immediately upon discovery of any excursion from the 
established range. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the investigational 
product and will provide supportive documentation as necessary. Under no circumstances should 
the product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
The investigational product should be protected from light and should not be frozen. Do not 
shake.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying his/her treatment assignment. All administered
investigational product will be documented in the subject’s source document and/or other 
investigational product record.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
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The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
With the written agreement of the sponsor, at the end of the study all unused stock may be 
destroyed at the site or a local facility. In this case, destruction records identifying what was 
destroyed, when and how, must be obtained with copies provided to the sponsor. Destruction of 
investigational products must be in accordance with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, cartons) or at 
the individual count level for opened containers/packaging. The pharmacist or delegated team 
member will record details on the drug accountability form.
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7
STUDY PROCEDURES
7.1
Study Schedule
The investigator may schedule visits (unscheduled visits) in addition to those listed on the 
schedule of activities (Table 1) in order to conduct evaluations or assessments required to protect 
the wellbeing of the subject.
7.1.1
Screening Period
7.1.1.1
Screening Visit (Visit 1)
Subjects will be screened within 6 weeks before the baseline visit (Visit 2) to determine 
eligibility to participate in the study and to perform the other assessments and procedures 
specified in Table 1. Each subject or subject’s parent or legally authorized representative must 
participate in the informed consent process and provide written informed consent/assent before 
any assessments or procedures specified in the protocol are performed. Screening assessments 
may take place over more than 1 day (at least 2 visits will be necessary to complete the screening 
procedures, including endoscopy).
A screen failure is a subject who has given informed consent or assent, as applicable (and whose
parents or legally authorized representatives have given informed consent, as applicable), failed 
to meet the inclusion criteria and/or met at least 1 of the exclusion criteria, and has not been 
randomized or administered investigational product.
A subject may be rescreened if their condition has changed and they may potentially be eligible. 
Subjects may be rescreened 1 time. NOTE: Screening laboratory tests, if considered by the 
investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated 
once during the screening period for confirmation. Results of repeated tests must be reviewed for 
eligibility prior to the screening endoscopy procedure.
Flexible sigmoidoscopy or colonoscopy (if preferred) must be performed on all subjects after the 
majority of other eligibility criteria (eg, laboratory values) are met. Endoscopy must be 
performed during the screening period within 10 days before baseline (Visit 2), preferably within 
5 to 7 days before the baseline visit, to obtain the centrally read endoscopic subscore (see 
Section 7.2.2.1). Biopsy samples will be collected for histological evaluation using the Geboes 
Score classification and
. Subjects at risk of colorectal cancer, 
as defined in exclusion criterion 5 (see Section 4.2), must have a colonoscopy performed at 
screening, unless the subject has had a surveillance colonoscopy performed within 1 year prior to 
screening, and any adenomatous polyps found at that examination have been excised. 
Colonoscopy report and pathology report (if biopsies are obtained) from the colonoscopy 
performed during screening or in the prior year confirming no presence of dysplasia and colon 
cancer must be available in the source documents.
If a subject has had the following procedures performed as a part of standard medical care within 
12 weeks before screening (Visit 1), these procedures do not need to be repeated as a part of 
screening:

Chest x-ray 

Documented negative PPD test or IGRA for TB.
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7.1.1.2
Baseline Visit (Visit 2; Week 0)
The baseline visit will take place on Day 1 (Week 0). The assessments and procedures specified 
in Table 1 will be performed.
After eligibility has been reconfirmed and all baseline procedures and assessments have been 
completed, each subject will be randomized to 1 of the 3 treatment groups as described in 
Section 6.2.2 and the first dose of investigational product will be administered.
Results of the baseline laboratory tests are not required for investigational product administration 
but must be reviewed as soon as possible thereafter.
7.1.2
Treatment Period
7.1.2.1
Visit 3 (Week 2)
Visit 3 is scheduled to take place on Day 14 ±3 days (Week 2). The assessments and procedures 
specified in Table 1 will be performed.
7.1.2.2
Visits 4 and 5 (Weeks 4 and 8)
Visits 4 and 5 are scheduled to take place on Day 28 ±3 days (Week 4) and Day 56 ±3 days
(Week 8), respectively. The assessments and procedures specified in Table 1 will be performed.
7.1.2.3
Final On-treatment Visits: Visit 6, Parts 1 and 2 
(Week 12/Early Termination)
The Week 12/ET visit (Visit 6) consists of 2 parts.
Part 1 of Visit 6 should be scheduled preferably within 5 to 7 days before Part 2; this will allow 
sufficient time for data from the centrally read endoscopy to be available at Part 2 of the visit.
The Week 12/ET assessments and procedures that will take place during Part 1 are specified in 
Table 1.
Part 2 of Visit 6 will take place on Day 84 ±3 days. The Week 12/ET assessments and 
procedures that will take place during Part 2 are specified in Table 1.
At Part 2 of Visit 6, after review of the Mayo score, health outcome assessments, and safety 
assessments, it will be determined whether the subject should enter the safety follow-up period 
of this study or enroll in the maintenance (SHP647-303) or LTS (SHP647-304) studies. Entry 
into the maintenance or LTS studies is dependent upon the subject’s response and whether the 
subject agrees to participate.
The Week 12 assessments and procedures will also form the ET assessments for any subjects 
who are withdrawn early or discontinued from the study.
7.1.3
Follow-up Period: Visits 7 and 8 (Weeks 20 and 28)
Subjects who are withdrawn early from the study, or who do not enter either the maintenance or 
LTS studies, should enter the 16-week safety follow-up phase for safety monitoring. 
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During the safety follow-up period, the Week 20 visit (Visit 7) will take place on Day 140 
±7 days or 8 weeks ±7 days after the subject’s last visit in the treatment period for subjects who 
are withdrawn early from the study. This visit will routinely be conducted by telephone; 
however, as an exception the visit can be performed as a study site visit if preferred.
At the end of the safety follow-up period, there will be a visit at the site on Day 196 ±7 days, or 
16 weeks ±7 days after the subject’s last visit in the treatment period for subjects who are 
withdrawn early from the study, which will form the Week 28 visit (Visit 8). The assessments 
and procedures specified in Table 1 will be performed, including querying for SAEs, AEs, and 
concomitant medications and procedures. All AEs and SAEs that are not resolved at the time of 
this visit will be followed to closure (see Section 8.1).
Subjects who are proceeding to the maintenance or LTS studies will not enter the safety 
follow-up period.
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside the control of the investigator, which may make it unfeasible to perform 
the tests and procedures. In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the subject.
When timing of procedures and assessments coincide, the following order should be followed:

Health outcome and patient-reported questionnaires

Vital signs and ECG

Laboratory sample collection

Endoscopy (generally performed at a separate visit; see Section 7.2.2.1).

Investigational product administration
Note: Blood and tissue samples may be stored for up to the duration allowed by local 
regulations, but for no longer than 25 years.
7.2.1
Demographic and Other Baseline Characteristics
Demographic characteristics will be recorded at the screening visit (Visit 1).
Each subject’s stool frequency before symptoms of UC started or during remission will be 
recorded at the screening visit. The reference/normal stool frequency questions in Appendix 2
will be asked and the responses documented.
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7.2.2
Efficacy
The primary efficacy endpoint is remission at the Week 12 visit. Remission is defined as a 
composite score of patient-reported symptoms using daily electronic diary (e-diary) and 
centrally read endoscopy as described in Section 9.8.1.
7.2.2.1
Endoscopy and Histology
Endoscopy will be performed at the time points specified in Table 1 and will consist of either 
flexible sigmoidoscopy or colonoscopy (if preferred).
If it is necessary, bowel preparation should be conducted as per local routine. The position of the 
endoscope will be based on the length of the instrument at various levels of insertion as well as 
the morphological features of the intestine as seen during endoscopy at baseline. The endoscopy 
report and any photographs and/or video recordings taken during the procedure per local custom 
should be filed in the subject’s medical record.
During endoscopy, 2 biopsy samples will be collected from the most inflamed area of the 
sigmoid colon at screening and Week 12/ET. Endoscopy and biopsy procedures will be defined 
in an endoscopy instructions manual and/or reference card(s), on which all sites will be trained. 
Endoscopy results will be reviewed by a central reader.
Biopsy samples will be centrally reviewed using the Geboes Score classification system and 
 (see Appendix 2) for the evaluation of histological disease 
severity in UC with higher numbers corresponding to more inflammation.  The Geboes score 
will be used for the key secondary efficacy evaluation and 
 
.
Subjects at risk for colorectal cancer (see exclusion criterion number 5) must have a colonoscopy 
performed during the screening period with results available within 10 days before the baseline 
visit (Visit 2), unless the subject has had a surveillance colonoscopy performed within 1 year 
prior to screening, and any adenomatous polyps found at that examination have been excised. 
Colonoscopy report and pathology report (if biopsies are obtained) from the colonoscopy 
performed during screening or in the prior year confirming no evidence of dysplasia and colon 
cancer must be available in the source documents.
7.2.2.2
Mayo Score
The Mayo score is a measure of UC disease activity. Mayo scores (total or partial) will be 
recorded at the time points specified in Table 1.
The total Mayo score ranges from 0 to 12 points and consists of the following 4 subscores, each 
graded from 0 to 3 with higher scores indicating more severe disease (see Appendix 2):

Stool frequency (0-3)

Rectal bleeding (0-3)

Findings of endoscopy (0-3)

Physician global assessment (PGA, 0-3).
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The partial Mayo score consists of the Mayo score without the endoscopic subscores and ranges 
from 0 to 9 points.
The composite score is a recommended measure consisting of the Mayo score without the PGA 
subscore and ranges from 0 to 9 points. The composite score will be used for the primary 
efficacy endpoint.
Calculation of the total and partial Mayo scores and composite score requires a self-assessment 
by the subject for stool frequency and the amount of blood in the stool. These data on stool 
frequency and rectal bleeding will be captured in the PRO-UC daily e-diary (see Section 7.2.2.3).
The Mayo stool frequency and rectal bleeding subscores will be calculated based on each
subject’s daily e-diary data recorded over the most recent 3 days (consecutive or nonconsecutive) 
of the last 10 days prior to the visit excluding the following days: day of any bowel preparation, 
day of endoscopy, any days between day of bowel preparation and day of endoscopy, and the 
2 days after the day of endoscopy.
The mucosal appearance during the sigmoidoscopic portion of the endoscopic examination will 
be assessed for the Mayo endoscopic subscore based on the scoring system provided in the 
protocol (see Appendix 2). The endoscopic appearance will be read by a central reader through 
video recorded during the procedure. Centrally read endoscopic subscores will be used for both 
eligibility and efficacy analyses.
The PGA acknowledges the 3 other criteria: the subject’s recollection of abdominal discomfort 
and general sense of wellbeing and other observations (such as physical findings and the 
subject’s performance status). The endoscopic subscore and the PGA must be performed by a 
physician qualified to perform endoscopy, and it is recommended that the same physician 
performs all such assessments for a particular subject throughout the study.
7.2.2.3
Patient-reported Outcome – Ulcerative Colitis E-Diary
Patient-reported UC signs and symptom data will be collected using a daily e-diary starting 
during the screening period. Collection of the daily e-diary data must begin at least 10 days 
before the baseline visit (Visit 2). Subjects will enter data on UC signs and symptoms items 
using an electronic handheld device that will be provided to subjects at the start of the study.
Compliance is assessed by site staff at each visit. The site staff will instruct the subject on the 
appropriate use of the e-diary, particularly when compliance is below 80% (eg, <23 out of 
28 e-diary entries) when compared with the previous visit.
Subjects will be asked to record the following signs and symptom data, as experienced over the 
previous 24 hours, in the e-diary:

Stool frequency

Rectal bleeding severity and frequency

Diarrhea frequency

Urgency frequency

Abdominal pain worst severity.
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The full PRO-UC e-diary consists of 6 items. The first 2 items (stool frequency and rectal 
bleeding severity) will be used to determine the Mayo stool frequency and rectal bleeding 
subscores, which will be used to calculate the total and partial Mayo scores and the composite 
score. The PRO-UC e-diary is presented in Appendix 2.
7.2.3
Safety
7.2.3.1
Medical and Medication History
Medical history will be documented at screening (Visit 1), including UC history, cardiac history, 
and smoking history. Prior and concomitant medications and procedures will also be 
documented.
7.2.3.2
Physical Examination (Including Height and Weight)
Complete and targeted physical examinations will be performed at the time points specified in 
Table 1. Complete physical examination includes the review of the following body systems: 
general appearance, skin, HEENT, heart, lungs, confrontational visual fields (eyes), breast 
(optional), abdomen, external genitalia (optional), extremities, neurologic function, back, and 
lymph nodes. Targeted physical examination includes the review of the following body systems: 
skin, heart, lungs, confrontational visual fields (eyes), abdomen, and examination of body 
systems where there are symptom complaints by the subject.
Weight will be measured at the time points specified in Table 1. Height will be measured at 
screening (Visit 1) only.
Changes after the screening visit that are deemed clinically significant in the opinion of the 
investigator will be recorded as an AE.
7.2.3.3
Targeted Neurological Assessment
Targeted neurological assessments to monitor the development of signs and/or symptoms of 
PML will be performed at the time points specified in Table 1. Subjects will be evaluated to 
reveal any potential abnormalities in the following neurological domains: vision, motor, tactile 
sensation, coordination/cerebellar function, speech, verbal comprehension, and 
cognition/behavior.
If any abnormalities are indicated, subjects will be further evaluated to help clarify any potential 
abnormal responses. Focus will be placed on possible alternative etiology (eg, fracture or stroke). 
If additional evaluation reveals an unexplained new abnormality, neurologic examination(s), 
targeted to the abnormal domain, will be performed by an investigator or qualified personnel.
Subjects with any unexplained positive neurological assessment item at screening should be 
excluded from enrollment in the study (exclusion criterion 18, Section 4.2).
A step-wise approach for the proposed neurological assessment plan is provided in Table 3.
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Table 3:
Quarterly Neurological Assessments
Domain
Step 1: Targeted Neurologic 
History
Step 2: If Abnormal Response
Vision
Diplopia or visual/visual field loss
Perform visual field assessment
Motor
Major motor weakness (eg, legs, arms)
Test leg strength (hopping, foot tapping), 
finger tapping, pronator drift and bilateral 
muscle strength
Tactile sensation
Paresthesia, anesthesia in any domain 
(peripheral, central)
Pinprick test
Coordination/Cerebellar
Clumsiness, difficulty with walking, 
writing, or fine motor skills, etc.
Finger-nose, heel-shin, heel-toe walk, 
writing sample, draw a clock
Speech
Dysarthria, expressive aphasia
Naming objects, repeat multipart phrase, 
observe for dysarthria or aphasia
Verbal comprehension
Agnosia, receptive aphasia
Test to follow routine commands, 
eg, close eyes, touch finger to ear.
Cognition/Behavior
New onset of difficulties with memory or 
thinking, important changes in behavior
Recall 3 objects over 1 minute, serial 7 s, 
proverbs. Changes in activities of daily 
living over prior 6 months
Additionally, should there be any unexplained abnormal neurological findings, the subject is to 
be urgently referred to a neurologist. The sites will immediately inform the sponsor of any such 
occurrences. If the neurologist confirms the presence of PML, appropriate actions, including 
discontinuation of investigational product, will be taken. Suspected PML cases will be reviewed 
promptly by Data Monitoring Committee (DMC) members with PML expertise and presented at 
the next scheduled DMC meeting(s). If PML is diagnosed, the treatment code will be unblinded 
and there will be an urgent meeting of the DMC. A flow diagram of the quarterly assessments 
and actions is presented in Figure 3. Any concerns from the DMC will be promptly 
communicated to the sponsor, investigator, and treating neurologist.
Figure 3:
Flow Diagram for Quarterly Neurological Assessments
DMC=Data Monitoring Committee; IND=investigational new drug; neuro=neurological; PML=progressive 
multifocal leukoencephalopathy.
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It is important to note that assessments based on neurological evaluations are collected and 
evaluated in a different manner than observed or volunteered AEs. Given these differences, no 
attempt will be made to reconcile any apparent discrepancies between observed or volunteered 
AEs and data from neurological assessment collected from subjects. Investigators may determine 
if any finding on neurological testing constitutes an AE. Adverse event incidence rates will not 
be calculated from these neurological evaluation data but rather from the AE information 
recorded by the investigator.
7.2.3.4
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent and/or assent is signed until the end 
of the defined follow-up period stated in Section 7.1.3. (See Section 8, Adverse and Serious 
Adverse Events Assessment.)
7.2.3.5
Vital Signs
Vital signs will be measured at the time points specified in Table 1. Additional collection times 
or changes to collection times will be permitted, as necessary to ensure appropriate collection of 
safety data. Vital signs include blood pressure, pulse, respiratory rate, and temperature. Vital 
signs should be recorded before laboratory blood collection and endoscopic procedures are 
performed.
Single measurements of sitting blood pressure will be recorded at each time point. Blood 
pressure should be determined by cuff with the subject’s arm supported at the level of the heart 
and recorded to the nearest mm Hg using the same method, the same arm (preferably the 
dominant arm), and the same position throughout the study.
Respiratory rate will be measured with the subject in a comfortable position. The observer 
should hold the extremity of the subject as a distraction for the subject (ie, pretending he/she is 
taking the subject’s radial pulse) and count the respiration for 1 minute.
Body temperature should be taken using a thermometer and reported in degrees Celsius or 
Fahrenheit. 
Any deviations from baseline (Visit 2) vital signs that are deemed clinically significant in the 
opinion of the investigator are to be recorded as an AE, unless documented in the subject’s
medical history as a pre-existing medical condition.
7.2.3.6
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the central laboratory’s 
normal procedures. Reference ranges are to be supplied by the central laboratory and will 
be used to assess the clinical laboratory data for clinical significance and out-of-range 
pathological changes. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or 
clinically significant. 
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Abnormal clinical laboratory values, which are unexpected or not explained by the subject’s 
clinical condition, may, at the discretion of the investigator or sponsor, be repeated as soon as 
possible until confirmed, explained, or resolved.
Screening laboratory tests, if considered by the investigator to be transient and inconsistent with 
the subject’s clinical condition, may be repeated once during the screening period for 
confirmation. The following clinical laboratory assessments will be performed at the time points 
specified in Table 1:
Serum chemistry
alkaline phosphatase 
aspartate aminotransferase
alanine aminotransferase
total bilirubin
total protein
albumin
glucose 
blood urea nitrogen 
creatinine
sodium 
potassium 
chloride 
calcium
carbon dioxide
Hematology
hemoglobin 
hematocrit 
mean corpuscular hemoglobin
mean corpuscular hemoglobin concentration
mean corpuscular volume
erythrocyte (red blood cell) count
leukocyte (white blood cell) count
neutrophils
lymphocytes
monocytes
eosinophils
basophils
platelet count
Virology
hepatitis B surface antigen (HBsAg)
hepatitis B core antibody (HBcAb)
hepatitis B DNA if HBsAg is negative and 
HBcAb is positive
hepatitis C virus antibody (HCV Ab)
HCV ribonucleic acid (RNA) polymerase 
chain reaction (PCR) if HCV Ab is positive
HIV
Urinalysis
glucose
protein
specific gravity
pH
nitrite
bilirubin
ketones
hemoglobin
urobilinogen
leukocyte esterase
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Virology test results must be confirmed as negative before enrollment in the study; if a virology 
test result is positive, the subject will be excluded from entering the study. Results of the 
virology screen will be reviewed and verified by the study monitor, but will not be collected in 
the CRF database.
Stool microbiology will be performed at the screening visit (Visit 1). Diagnosis of C. difficile
infection should be made using the central laboratory. If, for any reason, the central laboratory is 
not available, please refer to Appendix 5 for guidance regarding diagnostic algorithms. 
A tuberculosis (TB) test (purified protein derivative [PPD] or QuantiFERON TB Gold Plus) will 
be performed at the screening visit (Visit 1). A documented negative PPD test within 12 weeks 
before baseline (Visit 2) is acceptable. The IGRA official reading and method or test must be 
located in the source documentation.
A serum sample will be collected and banked for John Cunningham virus antibody testing. It 
may be analyzed if a subject shows neurologic symptoms suggestive of PML.
All laboratory assessments should be performed at central laboratories, with the exception of the 
following assessments: stool microbiology (local or central laboratory) and TB test (PPD or 
QuantiFERON TB Gold Plus) (refer to laboratory manual for details).
7.2.3.7
Pregnancy Test and Follicle-stimulating Hormone Test
A beta–human chorionic gonadotropin (β–HCG) pregnancy test will be performed on all females
of childbearing potential at the time points specified in Table 1; if pregnancy is suspected; or on 
withdrawal of the subject from the study. A serum pregnancy test will be performed at the 
screening visit (Visit 1); all other pregnancy tests will be urine tests.
Pregnancy tests are not required for females of nonchildbearing potential who have undergone 
hysterectomy or bilateral oophorectomy, have medically confirmed ovarian failure, or are 
medically confirmed postmenopausal (cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause; postmenopausal status should be 
confirmed by FSH testing in females who have had 12 consecutive months of spontaneous 
amenorrhea and are 51 years of age or older).
7.2.3.8
Electrocardiogram
A 12-lead ECG will be recorded at the time points specified in Table 1. When timing of 
measurements coincide, ECGs should be performed before laboratory blood collection and 
endoscopic procedure.
A central ECG reader will be used in this study. The eligibility of the subject is based on the 
assessment of the ECG by the investigator. If abnormal results are observed following 
assessment by the central reader, the investigator, in consultation with the appointed sponsor or 
contract research organization (CRO) medical monitor, reconfirms subject eligibility to continue.
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7.2.3.9
Chest X-ray
A chest x-ray will be performed during screening (Visit 1). If a subject has had a chest x-ray 
performed as a part of standard medical care within 12 weeks before screening (Visit 1), it does 
not need to be repeated as a part of screening. The official reading must be located in the 
subject’s source documentation.
7.2.3.10
Antidrug Antibodies
A blood sample for measurement of antidrug antibodies (ADA) and Nab will be collected at the 
time points specified in Table 1. Blood samples must be collected before administration of 
investigational product.
7.2.4
Others
 
 
 
 
7.2.4.3
Health-related Quality of Life Assessments
Each subject will complete the HRQL assessments at the site during the visits specified in 
Table 1, using an electronic device. All health outcome and patient-reported questionnaires 
should be completed before any other assessments. The study site staff should check for 
completion of all PRO questionnaires.
It is important to note that patient-reported outcome (PRO) assessments are collected and 
evaluated in a different manner than observed or volunteered AEs. Given these differences, no 
attempt will be made to reconcile any apparent discrepancies between observed or volunteered 
AEs and PRO data collected from subjects. Adverse event incidence rates will not be calculated 
from these solicited data but rather from the information recorded by the investigator.
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Inflammatory Bowel Disease Questionnaire
The IBDQ is a psychometrically validated PRO instrument for measuring the disease-specific 
HRQL in subjects with inflammatory bowel disease, including UC. The IBDQ consists of 32 
items, which are grouped into 4 dimensions: bowel function, emotional status, systemic 
symptoms, and social function (Irvine et al. 1994). The 4 domains are scored as follows: 

Bowel symptoms: 10 to 70

Systemic symptoms: 5 to 35

Emotional function: 12 to 84

Social function: 5 to 35.
The total IBDQ score ranges from 32 to 224. For the total score and each domain, a higher score
indicates better HRQL. A score of at least 170 corresponds to clinical remission and an increase 
of at least 16 points is considered to indicate a clinically meaningful improvement.
The IBDQ is presented in Appendix 2.
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Short Form-36 Health Survey, Acute Form
The SF-36 is a generic quality-of-life instrument that has been widely used to assess HRQL of 
subjects. Generic instruments are used in general populations to assess a wide range of domains 
applicable to a variety of health states, conditions, and diseases. The SF-36 consists of 36 items 
that are aggregated into 8 multi-item scales (physical functioning, role – physical, bodily pain, 
general health, vitality, social functioning, role – emotional, and mental health), with scores 
ranging from 0 to 100 (Ware and Sherbourne 1992). Higher scores indicate better HRQL.
7.2.4.4
Healthcare Resource Utilization Assessments
Hospitalizations, inpatient days, and 
will be recorded at the time points specified in 
Table 1. Ulcerative colitis-related and other surgeries will be collected from subjects during the 
treatment period.
7.2.5
Volume of Blood to Be Drawn from Each Subject
Table 4:
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of Samples
Total Volume (mL)
Hematology
2
6
12
Serum chemistry
4
6
24
HBsAg
2
1
2
HBcAb
2
1
2
HCV Ab
2
1
2
HBV DNA
6
1
6
HIV
2
1
2
FSH
2
1
2
Serum -hCGa
2
1
2
TB test (QuantiFERON TB Gold Plus 
or PPD)
4
1
4
JCV antibody banked sample
3.5
1
3.5
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Table 4:
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of Samples
Total Volume (mL)
2
3
6
5
3
15
 
4
3
12
3
5
15
ADA and NAb sampling
3
6
18
Total mL
127.5
Ab=antibody; ADA=antidrug antibodies; -hCG=beta-human chorionic gonadotropin; 
; 
FSH=follicle-stimulating hormone; HBsAg=hepatitis B surface antigen; HBcAb=hepatitis B core antibody; HBV DNA=hepatitis 
B virus deoxyribonucleic acid; HCV=hepatitis C virus; HIV=human immunodeficiency virus; JCV=John Cunningham virus; 
; Nab=neutralizing antibody; PPD=purified protein derivative; 
TB=tuberculosis.
a -hCG testing for female subjects only.
b If a catheter is used, the first mL is to be discarded; then take 4 mL into appropriate tube for 
. A total of 
5 mL of blood drawn has been used in determination of sample volume.
The amount of blood to be drawn for each assessment is an estimate. The amount of blood to be 
drawn may vary according to the instructions provided by the manufacturer or laboratory for an 
individual assessment; however, the total volume drawn over the course of the study should be 
approximately 127.5 mL. When more than 1 blood assessment is to be done at the time
point/period, if they require the same type of tube, the assessments may be combined.
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8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).
All AEs are collected from the time the informed consent and/or assent is signed until the end of 
the defined follow-up period stated in Section 7.1.3. This includes events occurring during the 
screening phase of the study, regardless of whether or not investigational product is 
administered. Where possible, a diagnosis rather than a list of symptoms should be recorded. If a 
diagnosis has not been made, then each symptom should be listed individually. All AEs should 
be captured in the subject’s source document. In addition to untoward AEs, unexpected benefits 
outside the investigational product indication should also be captured in the subject’s source 
document.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia before
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded in the subject’s source document).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study in the eCRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown.
8.1.4
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. 
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When evaluating such changes, the extent of deviation from the reference range, the duration 
until return to the reference range, either while continuing treatment or after the end of treatment 
with the investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Global Drug Safety Department using 
the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire “Clinical Study Serious Adverse 
Event and Non-serious AE as Required by the Protocol Form.” Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire “Clinical Study Serious Adverse Event and 
Non-serious AE as Required by the Protocol Form” as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine beta 
human chorionic gonadotropin (-hCG) test or ultrasound result will determine the pregnancy 
onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
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The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)

Overdose – Intentional or unintentional administration of investigational product at a 
dose interval that is less than 2 weeks between doses

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
There is no specific antidote for overdose with SHP647. Treatment should be symptomatic and 
supportive.
8.1.8
Unexpected Adverse Event
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not consistent with 
the term, representation, or description used in the reference safety information (RSI). 
“Unexpected” also refers to the AEs that are mentioned in the IB as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation.
The expectedness of AEs will be determined by the sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed, but 
not on the basis of what might be anticipated from the pharmacological properties of a product.
8.1.9
Suspected Unexpected Serious Adverse Reaction
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active comparators) that is both serious and 
unexpected.
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The event(s) must meet all of the following: 
•
Suspected adverse reaction
•
Serious
•
Unexpected
•
Assessed as related to study treatment
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is Section 6.8 of the SHP647 investigator’s 
brochure, which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the CRO/Shire medical monitor within 24 hours of the first 
awareness of the event. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors (see Section 8.1.7) unless they result in 
an SAE. 
The investigator must complete, sign, and date the Shire “Clinical Study Serious Adverse Event 
and Non-serious AE as Required by the Protocol Form” and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested) and fax or email the form to the Shire Global 
Drug Safety Department. A copy of the Shire “Clinical Study Serious Adverse Event and 
Non-serious AE as Required by the Protocol Form” (and any applicable follow-up reports) must
also be sent to the CRO/Shire medical monitor using the details specified in the emergency 
contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s).
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
Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an ED or at home; blood dyscrasias or convulsions that do not 
result in inpatient hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be reported 
to the Shire Global Drug Safety Department and the CRO/Shire medical monitor within 24 hours 
of the first awareness of the event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
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8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor or the CRO is responsible for notifying the relevant regulatory authorities, US 
central Institutional Review Boards (IRBs), and European Union (EU) central Ethics Committees 
(ECs) of related, unexpected SAEs (ie, SUSARs).
In addition the CRO is responsible for notifying active sites of all related, unexpected SAEs (ie, 
SUSARs) occurring during all interventional studies across the SHP647 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.2.8
Safety Monitoring for Potential Cases of Drug-induced Liver Injury
The following safety monitoring and stopping criteria are provided for elevated hepatic blood 
tests based on normal and elevated baseline ALT and total bilirubin levels.
Abnormal values in ALT concurrent with abnormal elevations in total bilirubin that meet the 
criteria outlined below in the absence of other causes of liver injury are considered potential 
cases of drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities per Table 5 should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values. The measurement(s) 
should be reconfirmed with another blood draw preferably within 48 to 72 hours of the initial 
finding of potential concern. Please refer to lab manual for further instructions. 
Guidance for Dosing Interruption: Investigator-directed delays in dosing due to abnormal 
laboratory findings or AEs should be discussed with the medical monitor to determine whether 
the subject should continue with the treatment. Only those subjects who complete the full course 
of investigational product treatment in the induction studies (SHP647-301 or SHP647-302) will 
be eligible to continue in the maintenance study or LTS study.
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Table 5:
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin
Treatment emergent ALT 
Treatment-
emergent total 
bilirubin 
Treatment-
emergent 
symptoms
Action
Normal baseline
ALT≥5x ULN
Elevated baselinea:
ALT ≥ 3x baseline 
or
≥300 U/L (whichever occurs first)
Normal
Patients with Gilbert’s 
syndrome or 
hemolysis: No change 
in baseline TBL
None
Repeat ALT, AST, ALP, TBL, in 2-5 days.
Follow-up for symptoms.
Initiate evaluation for other etiologies of 
abnormal liver tests. 
Testing for hepatitis A, B, and/or C 
infection may be warranted. Subjects who 
entered the study with HBcAb with or 
without HBsAb would need evaluation 
with HBV DNA to rule out HBV 
reactivation.c
Normal baseline
ALT ≥ 8x ULN
Elevated baselinea:
ALT ≥ 5x baseline or 
≥500 U/L (whichever occurs first)
Normal
Patients with Gilbert’s 
syndrome or 
hemolysis: No change 
in baseline TBL
None
Interrupt study drug.b
Initiate close monitoring and workup for 
competing etiologies.
Study drug can be restarted only if another 
etiology is identified and liver enzymes 
return to baseline.
Testing for hepatitis A, B, and/or C 
infection may be warranted. Subjects who 
entered the study with HBcAb with or 
without HBsAb would need evaluation 
with HBV DNA to rule out HBV 
reactivation.c
Normal baseline 
ALT ≥3x ULN 
Elevated baselinea: 
ALT ≥ 2x baseline or 
≥300 U/L (whichever occurs first)
TBL≥2mg/dL
increased  over 
baseline
or
Patients with Gilbert’s 
syndrome of 
hemolysis: Doubling 
of baseline direct 
bilirubin 
None
Interrupt study drug.b
Initiate close monitoring and workup for 
competing etiologies.
Study drug can be restarted only if another 
etiology is identified and liver enzymes 
return to baseline.
Testing for hepatitis A, B, and/or C 
infection may be warranted. Subjects who 
entered the study with HBcAb with or 
without HBsAb would need evaluation 
with HBV DNA to rule out HBV 
reactivation.c
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Table 5:
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin
Treatment emergent ALT 
Treatment-
emergent total 
bilirubin 
Treatment-
emergent 
symptoms
Action
Normal baseline
ALT ≥ 5x ULN 
Elevated baselinea: 
ALT≥ 2x baseline or 
≥300 U/L (whichever occurs first)
Normal or elevated
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain
or
Immunologic 
symptoms Rash 
Eosinophilia > 
5%
Interrupt study drug.b
Initiate close monitoring and workup for 
competing etiologies.
Study drug can be restarted only if another 
etiology is identified and liver enzymes 
return to baseline.
Testing for hepatitis A, B, and/or C 
infection may be warranted. Subjects who 
entered the study with HBcAb with or 
without HBsAb would need evaluation 
with HBV DNA to rule out HBV 
reactivation.c
ALT=alanine aminotransferase; AST=aspartate aminotransferase; TBL=total bilirubin, ALP=alkaline phosphatase; ULN=upper 
limit of normal.
a Elevated baseline ALT defined as ALT≥ 1.5× ULN
b Confirmatory repeat liver-related blood tests should be performed within 2-3 days before the investigational product (IP) is 
interrupted.
c If HBV DNA positive, antivirals would need to be started ASAP.
Source: Adapted from Chalasani and Regev 2016.
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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered in the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational 
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process. These data will be handled in such a way that, before unblinding, 
any data that may unblind study team personnel will be presented as blinded information or 
otherwise will not be made available. If applicable, unblinded data may be made available to 
quality assurance representatives for the purposes of conducting independent drug audits.
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
The SAP will be finalized before unblinding to preserve the integrity of the statistical analysis 
and study conclusions.
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All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, Cary, 
NC, USA).
Unless otherwise specified, summary tabulations will be presented by treatment group. All data 
listings will be sorted by treatment group, site, and subject number, and will include the subject’s 
age, sex, and race.
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented.
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis or adaptive design in this study.
An external DMC will be established to review the overall safety of the study subjects on an 
ongoing basis.
The DMC will be responsible for the ongoing monitoring of safety of subjects enrolled in the 
study according to the DMC charter. Recommendations made by the DMC to alter the conduct 
of the study or to amend the protocol will be forwarded to Shire for review and for a final 
decision. Shire or its designee will notify investigative sites and regulatory authorities as 
appropriate, of DMC recommendations (which may include summaries of aggregate analyses of 
endpoint events and of safety data that are not endpoints).
Further details regarding the DMC can be found in the DMC charter, which will be available 
before the administration of investigational product to any subject. Analyses of the data for DMC 
review will be conducted according to the DMC charter and DMC SAP. Because no formal 
hypothesis testing for safety assessments is planned, multiplicity concerns regarding repeated 
analyses are not applicable.
9.6
Sample Size Calculation and Power Considerations
Graphical methods are used to control the global family-wise type I error rate (FWER) at the 
.05 level (2-sided) for the comparisons of the 2 SHP647 treatment groups with the placebo 
group. Alpha is initially split equally at the .025 level (2-sided) for each of the pairwise treatment 
comparisons for the primary endpoint. Therefore, the power analysis and sample size estimation 
was calculated based on the chi-square test of proportions using nQuery Advisor Version 7.0 
(Statistical Solutions Ltd, Cork, Ireland) for an individual SHP647 dose compared with placebo.
Power calculations are made based on assuming a .025 (2-sided) significance level for each 
pairwise treatment comparison. Approximately 1375 subjects will be screened to randomize 
825 subjects (2:2:1 allocation ratio: 330 subjects in the 25 mg SHP647 treatment group, 
330 subjects in the 75 mg SHP647 treatment group, and 165 subjects in the placebo group) 
which would yield an approximately 93% power to detect individual pairwise treatment 
difference in the primary efficacy endpoint, remission at Week 12, of 11% (5% placebo 
versus 16% SHP647). Expected remission rates at Week 12 are based on observed rates from 
the A7281009 study and placebo remission rates from literature (Feagan et al. 2013;Sandborn et 
al. 2017).
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No adjustment for missing data is required in these sample size calculations as subjects with 
missing data for remission at Week 12 are imputed as failures and the above rates account for 
these subjects.
With the sample size of 825, Table 6 provides the power for detecting a treatment difference 
between a SHP647 treatment group and the placebo group for the key secondary endpoints.
Table 6:
Power to Detect the Corresponding Treatment Effect for Key Secondary 
Endpoints
Key Secondary Endpoint at Week 12
SHP647 Premise
Placebo Premise
Power
Endoscopic remission
24%
8%
0.99
Clinical remission
30%
16%
0.89
Clinical response by composite score
50%
35%
0.82
Mucosal healing
15%
5%
0.88
9.7
Study Population
The screened set will consist of all subjects who have signed an informed consent document.
The randomized set will consist of all subjects in the screened set for whom a randomization 
number has been assigned.
The safety set will consist of all subjects who have received at least 1 dose of investigational 
product.
The full analysis set (FAS) will consist of all subjects in the randomized set who have received at 
least 1 dose of investigational product.
The per-protocol (PP) set will consist of all subjects in the FAS who do not have predefined 
protocol deviations that may affect the primary efficacy endpoint. 
The completer set will consist of all subjects in the FAS who have completed the final scheduled 
primary assessment for this study.
 
 
9.8
Efficacy Analyses
Unless otherwise specified, all efficacy analyses will be based on the FAS and subjects will be 
analyzed according to their randomized treatment, regardless of the treatment they actually 
received.
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9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is remission at the Week 12 visit. Remission is defined as a 
composite score of patient-reported symptoms using daily e-diary and centrally read endoscopy 
as follows:

stool frequency subscore of 0 or 1 with at least a 1-point change from baseline
AND

rectal bleeding subscore of 0
AND

endoscopic subscore of 0 or 1 (modified, excludes friability).
The primary efficacy endpoint will be compared for each active treatment group (25 mg or 
75 mg SHP647) to the placebo group using a Cochran-Mantel Haenszel (CMH) chi-square test
stratified by status of prior anti-TNF treatment and glucocorticoid use at baseline (Visit 2). 
Subjects with missing remission data at the Week 12 visit will be considered failures and 
counted as nonresponders. The endoscopy score will be based on centrally read results.
The primary endpoint will be tested by the following hypothesis:
H0: δ = 0
H1: δ ≠ 0
Where δ is the common treatment difference across strata, j=1 to m. The common treatment 
difference is a weighted average of the stratum-specific treatment differences.
The estimate of the common treatment difference along with the corresponding stratified 
Newcombe 95% confidence interval (CI) using the method of Yan and Su (2010) and CMH 
p-value will be presented for each active treatment group to placebo comparison.
Sensitivity analyses which explore the impact of missing data on the primary efficacy endpoint 
will be conducted. These analyses may compare imputations of the missing values which favor 
placebo (eg, worst case) and/or imputations which favor active treatment (eg, best case). In 
addition, imputation methods based on informative missingness and other missing data 
mechanisms may be performed. Additional sensitivity analyses will also be conducted using the 
per-protocol set and the completer set. Additional analyses may be developed in the SAP. All 
sensitivity analyses will be described in the SAP.
Prespecified subgroup analyses are planned for the primary endpoint including, but not limited to 
gender, prior anti-TNF treatment, glucocorticoid use at baseline, region, age group, 
randomization stratum, and other important subgroups. A full list of important subgroups will be 
described within the SAP. Within subgroups, efficacy endpoints will be compared for each 
active treatment group (25 mg SHP647 and 75 mg SHP647) with the placebo group using a 
Chi-square test. 
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Subjects with missing remission data at the Week 12 visit will be considered failures and 
counted as nonresponders. The endoscopy subscore will be based on centrally read results. The 
estimate of the treatment difference, along with the corresponding Newcombe (hybrid-score) 
95% CI and Chi-square test p-value, will be presented.
Adjustments for Multiplicity
The global FWER for the statistical tests of the primary and key secondary endpoints will be 
strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in Bretz 
et al (2009) will be utilized to propagate α from primary to key secondary endpoints and between 
the two SHP647 treatment group and placebo comparisons. Alpha is initially split equally at the 
.025 level (2-sided) for each of the pairwise treatment comparisons for the primary endpoint (P) 
and alpha is propagated in a hierarchical manner to each of the 4 key secondary endpoints 
(K1-K4) within a pairwise treatment comparison. A graphical visualization of the α propagation 
is presented in Figure 4.
Figure 4:
Visualization of Alpha Propagation
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Only p-values that are significant according to this graphical approach are inferential and 
statistically significant. All other p-values are descriptive.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoints are as follows:

Endoscopic remission, as defined by centrally read endoscopic subscore 0 or 1 (modified, 
excludes friability), at the Week 12 visit.

Clinical remission, as defined by stool frequency subscore of 0 or 1 with at least a 1-point 
change from baseline in stool frequency subscore, and rectal bleeding subscore of 0, at 
the Week 12 visit.

Clinical response based on composite score at the Week 12 visit. Clinical response
(composite) is defined as a decrease from baseline in the composite score of 
patient-reported symptoms using daily e-diary and centrally read endoscopy of at least 
2 points and at least 30%, with an accompanying decrease in the subscore for rectal 
bleeding ≥1 point or a subscore for rectal bleeding ≤1.

Mucosal healing based on endoscopic and histological assessment at the Week 12 visit. 
Mucosal healing is defined by centrally read endoscopic subscore 0 or 1 (modified, 
excludes friability) and centrally read Geboes score of ≤2.
Similar to the primary endpoint, the 4 key secondary endpoints will all be tested by the following 
hypothesis:
H0: δ = 0
H1: δ ≠ 0
The key secondary endpoints will be analyzed using the same approach as described for the 
primary efficacy endpoint. Subjects with missing key secondary endpoint data at the Week 12 
visit will be considered failures and counted as nonresponders.
In addition, the sensitivity analyses and prespecified subgroup analyses described for the primary 
endpoint will be repeated for the key secondary endpoints.
9.8.2.2
Other Secondary Efficacy Endpoints
The other secondary endpoints are as follows:

Remission, defined as a total Mayo score ≤2 with no individual subscore (stool 
frequency, rectal bleeding, endoscopy [modified, excludes friability], and physician’s 
global assessment) exceeding 1, at the Week 12 visit.

Clinical response based on total Mayo score at the Week 12 visit. Clinical response
(Mayo) is defined as a decrease from baseline in the total Mayo score of at least 3 points 
and at least 30%, with an accompanying decrease in the subscore for rectal bleeding ≥1 
point or a subscore for rectal bleeding ≤1.
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
Partial Mayo score ≤2 with no individual subscore >1 at the Week 4, 8, and 12 visits. The 
partial Mayo score does not include the endoscopy subscore.

Clinical remission as defined by stool frequency subscore of 0 or 1 with at least a 1-point 
change from baseline in stool frequency subscore, and rectal bleeding subscore of 0, at 
Weeks 4 and 8.

Endoscopic remission at the Week 12 visit with endoscopic subscore of 0.

Clinical remission at the Week 4, 8, and 12 visits with both rectal bleeding and stool 
frequency subscores of 0.

Deep remission at the Week 12 visit. Deep remission is defined as both endoscopic and 
rectal bleeding subscores of 0, and stool frequency subscore ≤1 and a centrally read 
Geboes score of ≤2.

Change from baseline at the Week 12 visit in abdominal pain, urgency and diarrhea item 
scores, absolute stool frequency, absolute rectal bleeding and total sign/symptom score 
based on subject daily e-diary entries (sum of rectal bleeding, stool frequency, abdominal 
pain, diarrhea, and urgency).

Change from baseline in IBDQ domain and total (absolute) scores (time frame: Week 0, 
Week 8, up to Week 12, or early termination).

Change from baseline in SF-36, version 2, acute (physical and mental component 
summary scores and individual domain scores) to the Week 12/ET visit.

Incidence of all-cause hospitalizations and total inpatient days.
Other secondary endpoints will be summarized by descriptive statistics and presented by 
treatment group. Where appropriate, other secondary efficacy endpoints will be analyzed with 
the following analysis methods.
Binary endpoints will be analyzed using the same approach as described for the primary 
endpoint. Subjects with missing binary endpoint data at a visit will be considered failures and 
counted as nonresponders.
Continuous endpoints that are only measured at baseline and the Week 12 visit will be analyzed 
using an analysis of covariance (ANCOVA) model with fixed effects for treatment group 
(categorical), status of prior anti-TNF treatment (categorical), and glucocorticoid use at baseline 
(categorical), and the baseline value as a continuous covariate. From this model, estimates of the 
least squares means, treatment differences, standard errors, p-values, and 95% CIs for least 
squares mean treatment differences will be provided.
Continuous endpoints that are measured repeatedly over time will be analyzed using a linear 
repeated measures mixed model with restricted maximum likelihood estimation (REML). The 
model will include fixed effects for treatment group (categorical), visit (categorical), treatment 
group by visit interaction, status of prior anti-TNF treatment (categorical), and glucocorticoid use 
at baseline (categorical); baseline value as a continuous covariate; and repeated measures across 
visit for subject. From this model, estimates of least squares means, treatment differences, 
standard errors, p-values, and 95% CIs for least squares mean treatment differences for each visit 
will be provided.
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Full details of the analysis of other secondary efficacy endpoints will be included in the SAP.
9.8.3
Exploratory Efficacy Endpoints
The exploratory endpoints are as follows:
Exploratory efficacy endpoints will be summarized with descriptive statistics and presented by 
treatment group. Exploratory efficacy endpoints will be analyzed using the same approach 
described as for the other secondary endpoints. See Section 9.8.2.2 for an overview of the 
planned analyses. Full details for the analysis of exploratory efficacy endpoints will be included 
in the SAP.
9.9
Safety Analyses
All safety analyses will be performed using the safety set. Subjects will be analyzed according to 
the treatment they actually received.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. 
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Treatment-emergent AEs (TEAEs) are defined as AEs with start dates at the time of or following 
the first exposure to investigational product. The number of events, incidence, and percentage of 
TEAEs will be calculated overall, by SOC, by preferred term, and by treatment group. 
Treatment-emergent AEs will be further summarized by severity and relationship to 
investigational product. Adverse events leading to withdrawal, serious AEs, and deaths will be 
similarly summarized or listed.
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group 
and visit. Potentially clinically important findings will also be summarized or listed.
Antidrug antibody data will be summarized by treatment group and visit.
Further details of safety analyses will be described in the SAP.
9.10 Other Analyses
 
 
 
 
 
 
 
 
 
 
 
 
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10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1 Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996) and E6 R2 (2017), EU Directive 
2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before and during the 
study (including annual safety reporting, ie, Development Safety Update Reports). The sponsor 
(or a nominated designee) is responsible for the preparation, submission, and confirmation of 
receipt of any regulatory authority approvals required before release of investigational product 
for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place before the start of 
the study. An insurance certificate is supplied to the CRO and investigator as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
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10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will upload the clinical study report to the EudraCT database and will also provide a 
summary of the clinical study report to the CRO for submission to the competent authority of the 
countries concerned as required by local regulatory requirement(s). This requirement will be 
fulfilled within 1 year for nonpediatric studies as per guidance. The ECs will be provided with a 
copy of the same summary as locally required.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2 Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements 
and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site before commitment to participate in this study. The investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s or subject’s legally authorized representative’s consent and/or assent, as applicable, 
inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
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10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any coinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor or designee. Upon study completion, the investigator will provide the sponsor, 
IRB/EC, and regulatory agency with final reports and summaries as required by (inter)national 
regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded in eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic CRFs must be 
completed by the investigator or designee as stated in the site delegation log.
All data in the eCRF will have a separate source (eg, paper or ePRO); no data will be recorded 
directly in the eCRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate/study monitor will verify the contents against the source data per 
the monitoring plan. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject e-diary, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
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The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The clinical research associate/study monitor (and auditors, IRB/EC or regulatory inspectors) 
may check the CRF entries against the source documents. The consent form includes a statement 
by which the subject agrees to the monitor/auditor from the sponsor or its representatives, 
national or local regulatory authorities, or the IRB/EC, having access to source data 
(eg, subject’s medical file, appointment books, original laboratory reports, x-rays etc). Nonstudy 
site personnel will not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3 Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and/or assent from 
all study subjects before any study-related procedures including screening assessments. All 
consent documentation must be in accordance with applicable regulations and GCP. Each subject 
or the subject’s legally authorized representative, as applicable, is requested to sign and date the 
subject informed consent form or a certified translation if applicable, after the subject has 
received and read (or been read) the written subject information and received an explanation of 
what the study involves, including but not limited to: the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities. 
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A copy of the informed consent documentation (ie, a complete set of subject information sheets 
and fully executed signature pages) must be given to the subject or the subject’s legally
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor before
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) before study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved before site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Before implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4 Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the sponsor or designee.
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The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP647; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5 Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg,
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish before release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days before
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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11
REFERENCES
 
Azulfidine 2016. US Prescribing Information.
Bretz, F., Maurer, W., Brannath, W. & Posch, M. 2009. A graphical approach to sequentially 
rejective multiple test procedures. Stat Med, 28, 586-604.
Briskin, M., Winsor-Hines, D., Shyjan, A., Cochran, N., Bloom, S., Wilson, J., McEvoy, L. M., 
Butcher, E. C., Kassam, N., Mackay, C. R., Newman, W. & Ringler, D. J. 1997. Human 
mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and 
associated lymphoid tissue. Am J Pathol, 151, 97-110.
 
.
 
Chalasani, N. & Regev, A. 2016. Drug-Induced Liver Injury in Patients With Preexisting 
Chronic Liver Disease in Drug Development: How to Identify and Manage? 
Gastroenterology, 151, 1046-1051.
Eaden, J. A. & Mayberry, J. F. 2002. Guidelines for screening and surveillance of asymptomatic 
colorectal cancer in patients with inflammatory bowel disease. Gut, 51, V10-2.
Feagan, B. G., Rutgeerts, P., Sands, B. E., Hanauer, S., Colombel, J. F., Sandborn, W. J., Van 
Assche, G., Axler, J., Kim, H. J., Danese, S., Fox, I., Milch, C., Sankoh, S., Wyant, T., Xu, 
J. & Parikh, A. 2013. Vedolizumab as induction and maintenance therapy for ulcerative 
colitis. N Engl J Med, 369, 699-710.
Geboes, K., Riddell, R., Ost, A., Jensfelt, B., Persson, T. & Lofberg, R. 2000. A reproducible 
grading scale for histological assessment of inflammation in ulcerative colitis. Gut, 47, 404-
9.
Humira® 2017. US Prescribing Information.
Imuran® 2014. US Prescribing Information.
Irvine, E., Feagan, B. G., Rochon, J., Archambault, A., Fedorak, R. N. & Groll, A. 1994. Quality 
of life: a valid and reliable measure of therapeutic efficacy in the treatment of IBD. 
Canadian Crohn’s Relapse Prevention Trial Study Group. Gastroenterology, 106, 287-296.
Khanna, S., Shin, A. & Kelly, C. 2017. Management of Clostridium difficile Infection in 
Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates Committee 
of the AGA Institute. Clin Gastroenterol Hepatol, 15, 166-74.
 
Lacy, C., Armstrong, L., Goldman, M. & Lance, L. 2001-2002. Drug Information Handbook, 
Cleveland, OH, LexiComp, Inc.
Lialda® 2018. US Prescribing Information.
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Liaskou, E., Karikoski, M., Reynolds, G. M., Lalor, P. F., Weston, C. J., Pullen, N., Salmi, M., 
Jalkanen, S. & Adams, D. H. 2011. Regulation of mucosal addressin cell adhesion molecule 
1 expression in human and mice by vascular adhesion protein 1 amine oxidase activity. 
Hepatology, 53, 661-72.
McDonald, L. C., Gerding, D. N., Johnson, S., Bakken, J. S., Carroll, K. C., Coffin, S. E., 
Dubberke, E. R., Garey, K. W., Gould, C. V., Kelly, C., Loo, V., Shaklee Sammons, J., 
Sandora, T. J. & Wilcox, M. H. 2018. Clinical Practice Guidelines for Clostridium difficile 
Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of 
America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clinical 
Infectious Diseases, 66, e1-e48.
Medrol® 2018. US Prescribing Information.
Methotrexate® 2018. US Prescribing Information.
Molodecky, N. A., Soon, I. S., Rabi, D. M., Ghali, W. A., Ferris, M., Chernoff, G., Benchimol, 
E. I., Panaccione, R., Ghosh, S., Barkema, H. W. & Kaplan, G. G. 2012. Increasing 
incidence and prevalence of the inflammatory bowel diseases with time, based on 
systematic review. Gastroenterology, 142, 46-54.e42; quiz e30.
Mosli, M. H., Feagan, B. G. & Zou, G. 2015. Development and Validation of a histological 
index for UC. Gut, Prepub.
Purinethol® 2011. US Prescribing Information.
Sandborn, W. J., Su, C., Sands, B. E., D'Haens, G. R., Vermeire, S., Schreiber, S., Danese, S., 
Feagan, B. G., Reinisch, W., Niezychowski, W., Friedman, G., Lawendy, N., Yu, D., 
Woodworth, D., Mukherjee, A., Zhang, H., Healey, P. & Panes, J. 2017. Tofacitinib as 
Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med, 376, 1723-1736.
Schroeder, K. W., Tremaine, W. J. & Ilstrup, D. M. 1987. Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J 
Med, 317, 1625-9.
Shane, A. L., Mody, R. K., Crump, J. A., Tarr, P. I., Steiner, T. S., Kotloff, K., Langley, J. M., 
Wanke, C., Warren, C. A., Cheng, A. C., Cantey, J. & Pickering, L. K. 2017. 2017 
Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and 
Management of Infectious Diarrhea. Clinical Infectious Diseases, 65, 1963-1973.
Shyjan, A. M., Bertagnolli, M., Kenney, C. J. & Briskin, M. J. 1996. Human mucosal addressin 
cell adhesion molecule-1 (MAdCAM-1) demonstrates structural and functional similarities 
to the alpha 4 beta 7-integrin binding domains of murine MAdCAM-1, but extreme 
divergence of mucin-like sequences. J Immunol, 156, 2851-7.
Steffen, B. J., Breier, G., Butcher, E. C., Schulz, M. & Engelhardt, B. 1996. ICAM-1, VCAM-1, 
and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and
mediate binding of lymphocytes in vitro. Am J Pathol, 148, 1819-38.
Vermeire, S., Sandborn, W. J., Danese, S., Hebuterne, X., Salzberg, B. A., Klopocka, M., 
Tarabar, D., Vanasek, T., Gregus, M., Hellstern, P. A., Kim, J. S., Sparrow, M. P., Gorelick, 
K. J., Hinz, M., Ahmad, A., Pradhan, V., Hassan-Zahraee, M., Clare, R., Cataldi, F. & 
Reinisch, W. 2017. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis 
(TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet.
Ware, J. E., Jr. & Sherbourne, C. D. 1992. The MOS 36-item short-form health survey (SF-36). 
I. Conceptual framework and item selection. Med Care, 30, 473-83.
Yan, X. & Su, X. 2010. Stratified Wilson and Newcombe Confidence Intervals for Multiple 
Binomial Proportions. Stat Biopharm Res, 2, 329-35.
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APPENDICES
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APPENDIX 1 PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Protocol Amendment 1
05 Sep 2018
Global
Original Protocol
06 Jul 2017
Global
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APPENDIX 2 SCALES AND ASSESSMENTS
The following scales/assessments will be used in the study and are provided in this appendix:

Stool frequency screening questions

Mayo scoring system

Geboes score grading system

PRO-UC diary

IBDQ

SF-36
For questionnaires, language-specific validated versions will be used only.
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Stool Frequency Screening Questions
1. Think back to before you ever had symptoms of UC. How many bowel movements did you 
typically have in a 24-hour period before ever having symptoms of UC? 
Number of bowel movements in a 24-hour period before ever having symptoms of UC:
____________
2. Remission of ulcerative colitis (UC) is defined as a time when your symptoms have gone 
away, you’re feeling well, and/or your UC is no longer impacting your regular daily 
activities. Have you ever experienced a remission of UC? 

Yes

No
If YES,
When you are in remission how many bowel movements do you typically have in a 24-hour 
period? Remember that remission is a time when your symptoms have gone away, you’re 
feeling well, and/or your UC is no longer impacting you regular daily activities.
Number of bowel movements in a 24-hour period when in remission:
____________
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Mayo Scoring System for Assessment of Ulcerative Colitis Activity
Stool frequencya
0 = Normal number of stools for this subject
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
Subscore, 0 to 3
Rectal bleedingb
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood (more than just streaks) or streaks of blood with stool most of the time
3 = Blood alone passes
Subscore, 0 to 3
Findings on endoscopyc
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern)
2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Subscore, 0 to 3
Physician’s global assessmentd:
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Subscore, 0 to 3
The total Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.
a
Each subject serves as his or her own control to establish the degree of abnormality of the stool frequency.
b
The daily bleeding score represents the most severe bleeding of the day.
c
Findings on endoscopy scoring represents the modified endoscopy subscore (value of 1 does not include friability).
NOTE:  Data will be collected to calculate the total Mayo score using both the modified endoscopy subscore and traditional 
endoscopy subscore (value of 1 including mild friability) as a sensitivity analysis and to estimate the impact of the 
modification on the primary endpoint.
d
The physician’s global assessment acknowledges the three other criteria, the subject’s daily recollection of abdominal 
discomfort and general sense of wellbeing, and other observations, such as physical findings and the subject’s performance 
status.
Source: Schroeder et al. 1987
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Geboes Score Grading System
Grade 0 – Structural (architectural change) 
Subgrades
0.0
No abnormality 
0.1
Mild abnormality 
0.2
Mild or moderate diffuse or multifocal abnormalities
0.3
Severe diffuse or multifocal abnormalities 
Grade 1 – Chronic inflammatory infiltrate 
Subgrades
1.0
No increase
1.1
Mild but unequivocal increase
1.2
Moderate increase
1.3
Marked increase
Grade 2A – Lamina propria eosinophils 
Subgrades
2A.0
No increase
2A.1
Mild but unequivocal increase
2A.2
Moderate increase
2A.3
Marked increase
Grade 2B – Lamina propria neutrophils
Subgrades
2B.0
None 
2B.1
Mild but unequivocal increase
2B.2
Moderate increase
2B.3
Marked increase
Grade 3 – Neutrophils in epithelium 
Subgrades
3.0
None 
3.1
< 5% crypts involved 
3.2
< 50% crypts involved 
3.3
> 50% crypts involved 
Grade 4 – Crypt destruction 
Subgrades
4.0
None 
4.1
Probable – local excess of neutrophils in part of crypt 
4.2
Probable – marked attenuation 
4.3
Unequivocal crypt destruction 
Grade 5 – Erosion or ulceration 
Subgrades
5.0
No erosion, ulceration, or granulation tissue
5.1
Recovering epithelium + adjacent inflammation 
5.2
Probable erosion - focally stripped 
5.3
Unequivocal erosion 
5.4
Ulcer or granulation tissue
Source: Geboes et al. 2000
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Patient-reported Outcomes – Ulcerative Colitis (PRO-UC) Diary Version 1
Item #
Item
1.
Please indicate how often you had a bowel movement over the past 24 hours. A bowel movement is 
defined as a trip to the toilet and passing stool (liquid, soft, or solid), passing blood only, passing 
blood and mucus, or passing mucus only.
Enter number of bowel movements passed: 
2.
Please rate your worst experience of rectal bleeding over the past 24 hours.

No blood seen

Streaks of blood with stool less than half of the time

Obvious blood (more than just streaks) or streaks of blood with stool most of the time

Blood alone passes
3.
You indicated you had X bowel movements in the past 24 hours. Of these, how many had blood, 
either in the stool, in the toilet bowl, or on the toilet paper?
Enter the number of bowel movements with blood: 
4.
You indicated you had X bowel movements in the past 24 hours. Of these, how many were loose or 
watery?
Enter number of loose or watery bowel movements: 
5.
You indicated you had X bowel movements in the past 24 hours. How many of those involved 
urgency (having to suddenly rush to the toilet to make it on time)?
Enter number of bowel movements with urgency: 
6.
Please rate your worst abdominal pain over the past 24 hours.

0-10 numeric rating scale, with 0 anchor at “No pain” and 10 at “Worst Imaginable Pain”
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Inflammatory Bowel Disease Questionnaire (IBDQ)
This questionnaire is designed to find out how you have been feeling during the last 2 weeks.
You will be asked about symptoms you have been having as a result of your inflammatory bowel 
disease, the way you have been feeling in general, and how your mood has been.
1. How frequent have your bowel movements been during the last two weeks? Please indicate 
how frequent your bowel movements have been during the last two weeks by picking one of 
the options from:
1. BOWEL MOVEMENTS AS OR MORE FREQUENT THAN THEY HAVE EVER 
BEEN
2. EXTREMELY FREQUENT
3. VERY FREQUENT
4. MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
5. SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
6. SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
7. NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
2. How often has the feeling of fatigue or of being tired and worn out been a problem for you 
during the last 2 weeks? Please indicate how often the feeling of fatigue or tiredness has been 
a problem for you during the last 2 weeks by picking one of the options from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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3. How often during the last 2 weeks have you felt frustrated, impatient, or restless? Please 
choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
4. How often during the last 2 weeks have you been unable to attend school or do your work 
because of your bowel problem? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
5. How much of the time during the last 2 weeks have your bowel movements been loose?
Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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6. How much energy have you had during the last 2 weeks? Please choose an option from:
1. NO ENERGY AT ALL
2. VERY LITTLE ENERGY
3. A LITTLE ENERGY
4. SOME ENERGY
5. A MODERATE AMOUNT OF ENERGY
6. A LOT OF ENERGY
7. FULL OF ENERGY
7. How often during the last 2 weeks did you feel worried about the possibility of needing to 
have surgery because of your bowel problem? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
8. How often during the last 2 weeks have you had to delay or cancel a social engagement 
because of your bowel problem? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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9. How often during the last 2 weeks have you been troubled by cramps in your abdomen?
Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
10. How often during the last 2 weeks have you felt generally unwell? Please choose an option 
from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
11. How often during the last 2 weeks have you been troubled because of fear of not finding a 
washroom? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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12. How much difficulty have you had, as a result of your bowel problems, doing leisure or 
sports activities you would have liked to have done during the last 2 weeks? Please choose an 
option from:
1. A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE
2. A LOT OF DIFFICULTY
3. A FAIR BIT OF DIFFICULTY
4. SOME DIFFICULTY
5. A LITTLE DIFFICULTY
6. HARDLY ANY DIFFICULTY
7. NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS OR 
LEISURE ACTIVITIES
13. How often during the last 2 weeks have you been troubled by pain in the abdomen? Please 
choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
14. How often during the last 2 weeks have you had problems getting a good night’s sleep, or 
been troubled by waking up during the night? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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15. How often during the last 2 weeks have you felt depressed or discouraged? Please choose an 
option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
16. How often during the last 2 weeks have you had to avoid attending events where there was 
no washroom close at hand? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
17. Overall, in the last 2 weeks, how much of a problem have you had with passing large 
amounts of gas? Please choose an option from:
1. A MAJOR PROBLEM
2. A BIG PROBLEM
3. A SIGNIFICANT PROBLEM
4. SOME TROUBLE
5. A LITTLE TROUBLE
6. HARDLY ANY TROUBLE
7. NO TROUBLE
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18. Overall, in the last 2 weeks, how much a problem have you had maintaining or getting to, the 
weight you would like to be at? Please choose an option from:
1. A MAJOR PROBLEM
2. A BIG PROBLEM
3. A SIGNIFICANT PROBLEM
4. SOME TROUBLE
5. A LITTLE TROUBLE
6. HARDLY ANY TROUBLE
7. NO TROUBLE
19. Many patients with bowel problems often have worries and anxieties related to their illness.
These include worries about getting cancer, worries about never feeling any better, and 
worries about having a relapse. In general, how often during the last 2 weeks have you felt 
worried or anxious? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
20. How much of the time during the last 2 weeks have you been troubled by a feeling of 
abdominal bloating? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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21. How often during the last 2 weeks have you felt relaxed and free of tension? Please choose 
an option from:
1. NONE OF THE TIME
2. A LITTLE OF THE TIME
3. SOME OF THE TIME
4. A GOOD BIT OF THE TIME
5. MOST OF THE TIME
6. ALMOST ALL OF THE TIME
7. ALL OF THE TIME
22. How much of the time during the last 2 weeks have you had a problem with rectal bleeding 
with your bowel movements? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
23. How much of the time during the last 2 weeks have you felt embarrassed as a result of your 
bowel problem? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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24. How much of the time during the last 2 weeks have you been troubled by a feeling of having 
to go to the bathroom even though your bowels were empty? Please choose an option from
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
25. How much of the time during the last 2 weeks have you felt tearful or upset? Please choose 
an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
26. How much of the time during the last 2 weeks have you been troubled by accidental soiling 
of your underpants? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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27. How much of the time during the last 2 weeks have you felt angry as a result of your bowel 
problem? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
28. To what extent has your bowel problem limited sexual activity during the last 2 weeks?
Please choose an option from:
1. NO SEX AS A RESULT OF BOWEL DISEASE
2. MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE
3. MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE
4. SOME LIMITATION AS A RESULT OF BOWEL DISEASE
5. A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE
6. HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE
7. NO LIMITATION AS A RESULT OF BOWEL DISEASE
29. How much of the time during the last 2 weeks have you been troubled by nausea or feeling 
sick to your stomach? Please choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
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30. How much of the time during the last 2 weeks have you felt irritable? Please choose an 
option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
31. How often during the past 2 weeks have you felt a lack of understanding from others? Please 
choose an option from:
1. ALL OF THE TIME
2. MOST OF THE TIME
3. A GOOD BIT OF THE TIME
4. SOME OF THE TIME
5. A LITTLE OF THE TIME
6. HARDLY ANY OF THE TIME
7. NONE OF THE TIME
32. How satisfied, happy, or pleased have you been with your personal life during the past 
2 weeks? Please choose one of the following options from:
1. VERY DISSATISFIED, UNHAPPY MOST OF THE TIME
2. GENERALLY DISSATISFIED, UNHAPPY
3. SOMEWHAT DISSATISFIED, UNHAPPY
4. GENERALLY SATISFIED, PLEASED
5. SATISFIED MOST OF THE TIME, HAPPY
6. VERY SATISFIED MOST OF THE TIME, HAPPY
7. EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY OR 
PLEASED
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Short Form-36 Health Survey, Acute Form
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Your Health and Well-Being 
This survey asks for your views about your health. This information will help 
keep track of how you feel and how well you are able to do your usual activities. 
Thank you for completing this survey! 
For each of the following questions, please mark an IZJ in the one box that best 
describes your answer. 
1. In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 
T 
T 
T 
T 
T 
01 
Oz 
03 
04 
Os 
2. 
Compared to one week ago, how would you rate your health in general 
now? 
Much better 
Somewhat 
About the 
Somewhat 
Much worse 
now than one 
better 
same as one 
worse 
now than one 
week ago 
now than one 
week ago 
now than one 
week ago 
week ago 
week ago 
T 
T 
T 
T 
T 
01 
Oz 
03 
04 
Os 
SF -36v2® Health Survey© 1992, 2000 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. 
SF -36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, Cnited States (English)) 
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3. The following questions are about activities you might do during a typical 
day. Does your health now limit you in these activities? If so, how much? 
Yes, 
Yes, 
No, not 
limited 
limited 
limited 
a lot 
a little 
at all 
... 
... 
... 
Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous sports ...................... D 1 ............. D 2 ............. D 3 
Moderate activities, such as moving a table, pushing 
a vacuum cleaner, bowling, or playing golf ............................ D 1 ............. D 2 ............. D 3 
Lifting or carrying groceries .................................................... D 1 ............. D 2 ............. D 3 
Climbing several flights of stairs ............................................. D 1 ............. D 2 ............. D 3 
Climbing one flight of stairs .................................................... D 1 ............. D 2 ............. D 3 
r Bending, kneeling, or stooping ................................................ D 1 ............. D 2 ............. D 3 
Walking more than a mile ........................................................ D 1 ............. D 2 ............. D 3 
Walking several hundred yards ............................................... D 1 ............. D 2 ............. D 3 
Walking one hundred yards ..................................................... D 1 ............. D 2 ............. D 3 
Bathing or dressing yourself.. .................................................. D 1 ............. D 2 ............. D 3 
SF -36v2® Health Survey© 1992, 2000 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. 
SF -36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
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40 
During the past week, how much of the time have you had any of the 
following problems with your work or other regular daily activities.!!.!..!!. 
result of your physical health? 
Cut down on the amount of 
time you spent on work or 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
None of 
the time 
the time 
T 
T 
other activities 0000000000000000000000000000000000 l.oooooooooooooO 2oooooooooooooo0 3oooooooooooooo0 4ooooooooooooo 0 5 
t 
Accomplished less than you 
would like 00000000000000000000000000000000000000000 l.oooooooooooooO 2oooooooooooooo0 3oooooooooooooo0 4ooooooooooooo 0 5 
Were limited in the kind of 
work or other activities 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 
1. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 
4o 0 0 0 0 0 0 0 0 0 0 0 0 0 5 
ct 
Had difficulty performing the 
work or other activities (for 
example, it took extra effort) .......... 00 1. ............ 00 2 .............. 0 3 .............. 0 4 ............ 0 0 5 
5o 
During the past week, how much of the time have you had any of the 
following problems with your work or other regular daily activities.!!.!..!!. 
result of any emotional problems (such as feeling depressed or anxious)? 
Cut down on the amount of 
time you spent on work or 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
None of 
the time 
the time 
T 
T 
other activities ................................ 00 1. ............ 00 2 .............. 0 3 .............. 0 4 ............ 0 0 5 
t 
Accomplished less than you 
would like ........................................ 0 
1. ............ 00 2 .............. 0 3 .............. 0 4 ............ 0 0 5 
Did work or other activities 
less carefully than usual... ................ O 
1. ............ 00 2 .............. 0 3 .............. 0 4 ............ 0 0 5 
SF -36v2® Health Survey© 1992, 2000 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. 
SF -36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
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6. During the past week, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, 
neighbors, or groups? 
Not at all 
Slightly 
T 
Dz 
Moderately 
Quite a bit 
Extremely 
7. How much bodily pain have you had during the past week? 
None 
Very mild 
T 
Dz 
Mild 
Moderate 
Severe 
Very severe 
8. During the past week, how much did pain interfere with your normal work 
(including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
T 
03 
SF -36v2® Health Survey© 1992, 2000 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. 
SF -36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
T 
Ds 
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9. 
These questions are about how you feel and how things have been with you 
during the past week. For each question, please give the one answer that 
comes closest to the way you have been feeling. How much of the time 
during the past week ... 
All of 
the time 
Most of 
the time 
Some of 
A little of 
None of 
the time 
the time 
the time 
T 
T 
T 
Did you feel full of life? .................. 0 1. ............. 0 2 •••••••••••••• 0 3 •••••••••••••• 0 4 •••••••••••••• 0 5 
1 Have you been very nervous? .......... O 1. ............. 0 2 •••••••••••••• 0 3 •••••••••••••• 0 4 •••••••••••••• 0 5 
Have you felt so down in the 
dumps that nothing could 
cheer you up? ................................... O 1. ............. 0 2 •••••••••••••• 0 3 •••••••••••••• 0 4 •••••••••••••• 0 5 
ct Have you felt calm and 
peaceful? .......................................... O 1 •••••••••••••• 0 2 •••••••••••••• 0 3 •••••••••••••• 0 4 •••••••••••••• 0 5 
Did you have a lot of energy? .......... O 1. ............. 0 2 •••••••••••••• 0 3 •••••••••••••• 0 4 •••••••••••••• 0 5 
r Have you felt downhearted 
and depressed? ................................. O 1 •••••••••••••• 0 2 •••••••••••••• 0 3 •••••••••••••• 0 4 •••••••••••••• 0 5 
g Did you feel worn out? .................... 0 1. ............. 0 2 •••••••••••••• 0 3 •••••••••••••• 0 4 •••••••••••••• 0 5 
h Have you been happy? ..................... O 1. ............. 0 2 •••••••••••••• 0 3 •••••••••••••• 0 4 •••••••••••••• 0 5 
Did you feel tired? ........................... 0 1. ............. 0 2 •••••••••••••• 0 3 •••••••••••••• 0 4 •••••••••••••• 0 5 
10. 
During the past week, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)? 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
SF -36v2® Health Survey© 1992, 2000 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. 
SF -36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
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11. 
How TRUE or FALSE is each of the following statements for you? 
I seem to get sick a little 
Definitely 
true 
Mostly 
true 
Don't 
know 
Mostly 
false 
Definitely 
false 
easier than other people .................. 0 1 •••••••••••••• 0 2 ••••••••••••• 0 3 •••••••••••••• 0 4 .............. 0 5 
t 
I am as healthy as 
anybody I know .............................. 0 1 •••••••••••••• 0 2 ••••••••••••• 0 3 •••••••••••••• 04 .............. 0 5 
I expect my health to 
get worse ......................................... 0 1 •••••••••••••• 0 2 ••••••••••••• 0 3 •••••••••••••• 04 .............. 0 5 
ct 
My health is excellent ..................... 0 1 •••••••••••••• 0 2 ••••••••••••• 0 3 •••••••••••••• 0 4 .............. 0 5 
Thank you for completing these questions! 
SF -36v2® Health Survey© 1992, 2000 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved. 
SF -36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
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APPENDIX 3 GLUCOCORTICOID EQUIVALENT DOSES
Glucocorticoid
Equivalent Dose (mg)
Short Acting:
Cortisone
25
Hydrocortisone
20
Intermediate Acting:
Methylprednisolone
4
Prednisolone
5
Prednisone
5
Triamcinolone
4
Long Acting:
Betamethasone
0.6
Dexamethasone
0.75
Reference: Lacy et al. 2001-2002
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APPENDIX 4 DETERMINATION OF FAILURE OR INTOLERANCE TO PRIOR 
TREATMENT FOR ULCERATIVE COLITIS
The information below should serve as guidance. Local therapeutic standards and investigator 
judgment should be considered. 
AMINOSALICYLATES
Mesalamine (5-ASA)
Inadequate response to or loss of response:  defined as persistent signs and symptoms of active 
disease despite treatment with mesalamine for at least 8 weeks at daily doses of 4.8 g/day.
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to 
mesalamine treatment. 
As guidance, the US package insert of mesalamine lists the following AEs. Please check the 
respective latest label of your country as well (Lialda® 2018): 
Renal Impairment including minimal change nephropathy, acute and chronic interstitial 
nephritis, and renal failure. 
Acute intolerance syndrome includes cramping, acute abdominal pain and bloody 
diarrhea, and sometimes fever, headache, and rash. 
Hypersensitivity Reactions including cardiac hypersensitivity reactions (myocarditis and 
pericarditis)
Hepatic Impairment: hepatic failure in patients with pre-existing liver disease
Photosensitivity in patients with pre-existing skin conditions such as atopic dermatitis 
and atopic eczema
Other treatment related adverse events: headache, flatulence, abnormal liver function 
test, alopecia, pruritus, tachycardia, hypertension, hypotension, acne, prurigo, rash, 
urticaria, abdominal distention, colitis, diarrhea, pancreatitis, rectal polyp, vomiting, 
decreased platelet count, arthralgia, back pain, somnolence, tremor, pharyngolaryngeal 
pain, asthenia, face edema, fatigue, pyrexia, ear pain. Based on postmarketing 
experience when it is not always possible to reliably establish a causal relationship to 
drug exposure: lupus-like syndrome, drug fever,  pericarditis, pericardial effusion, 
myocarditis, pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal 
bleeding, perforated peptic ulcer,  jaundice, cholestatic jaundice, hepatitis, liver necrosis, 
liver failure, Kawasaki-like syndrome including changes in liver enzymes, 
agranulocytosis, aplastic anemia, anaphylactic reaction, angioedema, Stevens-Johnson 
syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), 
myalgia, lupus-like syndrome, peripheral neuropathy, Guillain-Barre syndrome, 
transverse myelitis, intracranial hypertension, interstitial nephritis, nephrogenic diabetes 
insipidus, interstitial lung disease, hypersensitivity pneumonitis (including interstitial 
pneumonitis, allergic alveolitis, eosinophilic pneumonitis), psoriasis, pyoderma 
gangrenosum, erythema nodosum, photosensitivity, oligospermia. 
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Sulfasalazine (SSZ)
Inadequate response or loss of response: defined as persistent signs and symptoms of active 
disease despite treatment with at least one 8-week induction regimen at daily dose at 4g/day. 
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to
sulfasalazine treatment.
As guidance, the US package insert of sulfasalazine lists the following AEs. Please check the 
respective latest label of your country as well (Azulfidine® 2016):  
Hypersensitivity reactions: erythema multiforme (Stevens-Johnson syndrome), exfoliative 
dermatitis, epidermal necrolysis (Lyell´s syndrome) with corneal damage, drug rash with 
eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness syndrome, 
interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing 
alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, 
polyarteritis nodosa, lupus erythematosus-like syndrome, hepatitis and hepatic necrosis 
with or without immune complexes, fulminant hepatitis, sometimes leading to liver 
transplantation, parapsoriasis varioliformis acuta (Mucha-Haberman syndrome), 
rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival and 
scleral injection, and alopecia. 
Blood dyscrasias: agranulocytosis, leukopenia, myelodysplastic syndrome, aplastic 
anemia, megaloblastic (macrocytic) anemia, hemolytic anemia, cyanosis, 
methemoglobinemia, Heinz body anemia, hypoprothrombinemia, and thrombocytopenia. 
Gastrointestinal reactions: hepatitis, hepatic failure, pancreatitis, bloody diarrhea, 
impaired folic acid absorption, impaired digoxin absorption, stomatitis, diarrhea, 
abdominal pains, and neutropenic enterocolitis.
Central nervous system reactions: transverse myelitis, convulsions, meningitis, transient 
lesions of the posterior spinal column, cauda equina syndrome, Guillain-Barre 
syndrome, peripheral neuropathy, mental depression, vertigo, hearing loss, insomnia, 
ataxia, hallucinations, tinnitus, and drowsiness.
Renal reactions: toxic nephrosis with oliguria and anuria, nephritis, nephrotic 
syndrome, urinary tract infections, hematuria, crystalluria, proteinuria, and hemolytic-
uremic syndrome.
Other reactions: urine discoloration and skin discoloration, Goiter production, diuresis 
and hypoglycemia, oligospermia. Based on postmarketing experience when it is not 
always possible to reliably establish a causal relationship to drug exposure: elevated 
liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), 
jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including 
liver necrosis and liver failure, folate deficiency, nephrolithiasis, oropharyngeal pain, 
angioedema. 
In addition anorexia, headache, nausea, vomiting, gastric distress, pruritus, urticaria, 
rash, fever, sore throat, fever, pallor, purpura.
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GLUCOCORTICOIDS
Inadequate response or loss of response: defined as persistent signs and symptoms of active 
disease despite a history of at least one 4-week induction regimen that included a dose equivalent 
to prednisone 30 mg daily orally for 2 weeks or intravenously for 1 week OR two failed attempts 
to taper corticosteroids to below a dose equivalent to 10 mg prednisone (oral) daily.
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to 
glucocorticoid treatment. 
As guidance, the US package insert of Medrol® lists the followings AEs. Please check the 
respective latest label of your country as well (Medrol® 2018):  
Fluid and Electrolyte Disturbances: sodium retention, congestive heart failure, 
hypertension, fluid retention, potassium loss, and hypokalemic alkalosis
Musculoskeletal: muscle weakness, loss of muscle mass, steroid myopathy, osteoporosis, 
tendon rupture, vertebral compression fractures, aseptic necrosis of femoral and humeral 
heads, and pathologic fracture of long bones.
Gastrointestinal: peptic ulcer with or without perforation and hemorrhage, pancreatitis, 
abdominal distention, and ulcerative esophagitis, 
Dermatologic: impaired wound healing, petechiae and ecchymoses, thin fragile skin, 
facial erythema, and increased sweating
Neurological: increased intracranial pressure with papilledema (pseudo-tumor cerebri), 
convulsions, vertigo, and headache
Psychic derangements: euphoria, insomnia, mood swings, personality changes, severe 
depression, psychotic manifestations, aggravated existing emotional instability or 
psychotic tendencies. 
Endocrine: Cushingoid state, secondary adrenocortical and pituitary unresponsiveness,  
menstrual irregularities, decreased carbohydrate tolerance, manifestations of latent 
diabetes mellitus, increased requirements of insulin or oral hypoglycemic agents in 
diabetics
Ophthalmic: Posterior subcapsular cataracts, increased intraocular pressure, glaucoma, 
exophthalmos, and secondary ocular infections.
Metabolic: negative nitrogen balance due to protein catabolism
Other: urticaria and other allergic, anaphylactic or hypersensitivity reactions.
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IMMUNOSUPPRESSANTS
Azathioprine (AZA)
Inadequate response or loss of response: defined as persistent signs and symptoms of active 
disease despite a history of AZA use for at least 12 weeks at daily doses ≥1.5 mg/kg, including 
its use as adjunctive therapy or steroid-sparing therapy.
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related 
AZA treatment. 
As guidance, the US package insert of an AZA product lists the following AEs. Please check the 
respective latest label of your country as well (Imuran® 2014):
Gastrointestinal hypersensitivity reaction characterized by severe nausea, vomiting and 
potentially with diarrhea, rash, fever, malaise, myalgia, elevations in liver enzymes, and 
occasionally, hypotension. 
Hypersensitivity pancreatitis.
Hepatotoxicity that may be associated with anorexia, diarrhea, jaundice and ascites.
Cytopenias: leukopenia, thrombocytopenia, anemias including macrocytic anemia, 
and/or pancytopenia, bone marrow suppression, and myelotoxicity.
Serious infections (bacterial, viral, fungal, protozoal, and opportunistic infections, 
including reactivation of latent infections) secondary to treatment
Other: skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen 
balance, reversible interstitial pneumonitis, hepatosplenic T-cell lymphoma and Sweet’s 
Syndrome (acute febrile neutrophilic dermatosis).
Mercaptopurine (6-MP)
Inadequate response or loss of response defined as persistent signs and symptoms of active 
disease despite a history of 6-MP use for at least 12 weeks at daily doses ≥0.75 mg/kg, including 
its use as adjunctive therapy or steroid-sparing therapy.
Intolerance defined as documented treatment discontinuation for AEs suspected to be related to 
6-MP treatment. 
As guidance, the US package insert of a 6-MP product lists the following AEs. Please check the 
respective latest label of your country as well (Purinethol® 2011):
Myelosuppression: anemia, leukopenia, and thrombocytopenia
Embryo-Fetal Toxicity
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Treatment Related Malignancies
Renal: hyperuricemia and/or hyperuricosuria
Gastrointestinal: including hepatotoxicity: elevated transaminases, elevated bilirubin, 
ascites potentially intestinal ulceration, oral lesions, nausea, vomiting, anorexia, 
diarrhea and sprue-like symptoms, pancreatitis
Miscellaneous: skin rashes, hyperpigmentation, alopecia, drug fever, oligospermia
Methotrexate (MTX)
Inadequate response or loss of response: defined as failure to respond to at least one 8-week 
regimen of or maintain remission at doses of at least 15 mg/week, given by the intramuscular or 
subcutaneous route. 
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to 
MTX treatment. 
As guidance, the US package insert of a MTX product lists the following AEs. Please check the 
respective latest label of your country as well (Methotrexate® 2018):
Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, 
diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, 
pancreatitis.
Blood and Lymphatic System Disorders: anemia, aplastic anemia, pancytopenia, 
leukopenia, neutropenia and/or thrombocytopenia, lymphadenopathy and 
lymphoproliferative disorders, hypogammaglobulinemia
Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic 
events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal 
vein thrombosis, thrombophlebitis, and pulmonary embolus)
Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, 
speech impairment including dysarthria and aphasia, hemiparesis, paresis and 
convulsions, cognitive dysfunction, mood alteration, unusual cranial sensations, 
leukoencephalopathy, or encephalopathy
Hepatobiliary: acute (elevated transaminases) and chronic (fibrosis and cirrhosis) 
hepatotoxicity decrease in serum albumin, and liver enzyme elevations
Infection: opportunistic infections e.g. Pneumocystis carinii pneumonia, pneumonia, 
sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, H. simplex hepatitis, 
and disseminated H. simplex
Musculoskeletal System: stress fracture
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Ophthalmic: conjunctivitis, serious visual changes of unknown etiology
Pulmonary System: respiratory fibrosis, respiratory failure, interstitial pneumonitis, 
chronic interstitial obstructive pulmonary disease
Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, 
alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic 
epidermal necrolysis, Stevens-Johnson Syndrome, skin necrosis, skin ulceration, and 
exfoliative dermatitis.
Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria; 
defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, 
vaginal discharge, and gynecomastia; infertility, abortion, fetal defects
Other: nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, 
osteoporosis, sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue 
necrosis and osteonecrosis, anaphylactoid reactions
ANTI-TNF AGENTS
Inadequate response or loss of response: defined as persistent signs and symptoms of active 
disease despite at least one 4 week induction regimen with the following minimum doses of: 

infliximab (5 mg/kg IV, 2 doses at least 2 weeks apart) or 

adalimumab (one 80 mg SC dose followed by one 40 mg dose at least 2 weeks apart) or

golimumab (one 200 mg SC dose followed by 100 mg dose at least 2 weeks apart)
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to 
Anti-TNF agents. 
As guidance, the US package insert of a Humira lists the following AEs. Please check the 
respective latest labels for the other Anti-TNF agents and the labels of your country as well 
(Humira® 2017):
Anaphylaxis or serious allergic reactions: generalized rash and flushing, 
hypersensitivity reactions including angioneurotic edema 
Development of neutralizing autoantibodies
Body As A Whole: Pain in extremity, pelvic pain, surgery, thorax pain
Cardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery 
disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, 
pericardial effusion, pericarditis, syncope, tachycardia, heart failure 
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Gastrointestinal: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, 
gastrointestinal hemorrhage, vomiting, nausea, abdominal pain, hepatic reactions 
including acute liver failure, hepatic necrosis 
Lupus-like syndrome
Endocrine System: Parathyroid disorder 
Hemic and Lymphatic System: Cytopenias, pancytopenia, Agranulocytosis, 
polycythemia
Infections: tuberculosis (new and reactivation of latent tuberculosis) and opportunistic 
infections pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, 
cellulitis, diverticulitis, and pyelonephritis
Metabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, 
paraproteinemia, peripheral edema 
Musculo-Skeletal System: Arthritis, bone disorder, bone fracture (not spontaneous), 
bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, 
tendon disorder
Neoplasia: Adenoma
Nervous System: Confusion, paresthesia, subdural hematoma, tremor 
Respiratory System: upper respiratory infection, sinusitis, flu syndrome, asthma, 
bronchospasm, dyspnea, lung function decreased, pleural effusion 
Special Senses: Cataract 
Thrombosis: Thrombosis leg 
Urogenital System: Cystitis, kidney calculus, menstrual disorder
Other: headache, rash, injection site reaction, infusion-related reactions such as fever or 
chills, cardiopulmonary reactions such as chest pain, hypotension, hypertension, or 
dyspnea and/or pruritus or urticaria, back pain, urinary tract infection, hypertension
For non-commercial use only


Shire
CONFIDENTIAL
Page 146
SHP647-302 Protocol Amendment 1
SHP647
05 Sep 2018
APPENDIX 5 GUIDANCE FOR DIAGNOSIS AND TREATMENT OF INCREASED 
GASTROINTESTINAL SYMPTOMS 
If, for any reason, the central laboratory is not available, the preferred diagnostic algorithm is to 
use the Alere Quik Chek card test (Figure A1).
Figure A1
Algorithm for C. difficile Diagnosis Using the Quick Check Card Test
If the Alere Quik Chek card test is not available, then a diagnosis may be established by 
following either of the algorithms shown in Figure A2 (using PCR for toxin), Figure A3 using 
toxigenic culture) or Figure A4 (using toxigenic culture, followed by PCR). The rationale for the 
method in Figure A3 is that the majority of PCR tests are expected to be negative for toxin, thus 
obviating the need for the test at the central laboratory. The expected turnaround time at the 
central laboratory for a GDH card test is expected to be shorter than that for stool culture for 
C. difficile at the local laboratory. The details of the sensitivity and specificity of these tests were 
reported by Khanna (Khanna et al. 2017).
When medically reasonable, treatment decisions should be deferred until an etiology has been 
determined. When this is not feasible, management of symptoms should be dictated by the 
clinical situation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 147
SHP647-302 Protocol Amendment 1
SHP647
05 Sep 2018
Figure A2
Alternative 1 for C. difficile Testing Using Local Laboratory When No Alere 
Quick Chek Card Test is Available
Figure A3
Alternative 2 for C. difficile Testing Using Local Laboratory When No Card 
Test is Available
For non-commercial use only


Shire
CONFIDENTIAL
Page 148
SHP647-302 Protocol Amendment 1
SHP647
05 Sep 2018
Figure A4
Alternative 3 for C. difficile Testing Using Local Laboratory When No Alere 
Quick Chek Card Test is Available
Treatment
When medically reasonable, treatment decisions should be deferred until an etiology has been 
determined. When this is not feasible, management of symptoms should be dictated by the 
clinical situation. If management requires a prohibited treatment (eg, intravenous 
glucocorticoids for induction or maintenance studies) the subject should be withdrawn 
from treatment.
If treatment has been deferred, once an etiology is determined (eg, C. difficile, disease 
exacerbation, Campylobacter), appropriate treatment should be promptly implemented without 
waiting for a scheduled visit. If the etiology is determined to be C. difficile, treatment guidelines 
conforming to the current IDSA recommendations for C. difficile infection (McDonald et al. 
2018) or the recent expert review on C. difficile infection in IBD (Khanna et al. 2017) should be 
consulted.
If C. difficile infection was identified, clinical improvement should be noted within about 5 days 
after the start of treatment. If improvement does not occur, the etiology is most likely an IBD 
flare secondary to C. difficile and treatment failure assessment should proceed per the protocol. 
Another possible explanation is primary failure of C. difficile therapy which is unlikely.
If an infectious etiology other than C. difficile is identified, it should be managed as appropriate, 
with reference to current clinical guidelines (Shane et al. 2017).
If any infectious etiology is determined, the site should contact the medical monitor to make him 
or her aware of the diagnosis and to discuss treatment and ongoing study participation.
For non-commercial use only


 
PROTOCOL: SHP647-302 
TITLE: 
A Phase 3 Randomized, Double-blind, Placebo-controlled, 
Parallel-group Efficacy and Safety Study of SHP647 as Induction 
Therapy in Subjects with Moderate to Severe Ulcerative Colitis 
(FIGARO UC 302) 
DRUG: 
Ontamalimab (SHP647) 
IND: 
100,222 
EUDRACT NO.: 
2017-000572-28 
SPONSOR: 
Shire Human Genetic Therapies, Inc. (“Shire”) 
300 Shire Way, Lexington, MA 02421 USA 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
, MD, PhD 
PROTOCOL 
HISTORY: 
Protocol Amendment 2: 11 Nov 2019 
Protocol Amendment 1: 05 Sep 2018 
Original Protocol: 06 Jul 2017 
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 2 
SHP647-302 Protocol Amendment 2
Ontamalimab
11 Nov 2019
PROTOCOL SIGNATURE PAGE
Sponsor’s (Shire) Approval
Signature:
Date:
MD,
Investigator’s Acknowledgement 
I have read this protocol for Shire Study SHP647-302. 
Title: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and 
Safety Study of SHP647 as Induction Therapy in Subjects with Moderate to Severe Ulcerative 
Colitis (FIGARO UC 302). 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation guidelines on Good Clinical Practice 
and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study.
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor.
Investigator Name and Address:
(please hand print or type)
Signature:
Date:
MD, 
11 NOV 2019 
For non-commercial use only
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Shire 
CONFIDENTIAL 
Page 3 
SHP647-302 Protocol Amendment 2 
Ontamalimab 
 
11 Nov 2019 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
11 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Product Quality Complaints 
Updated language regarding 
reporting of product quality 
complaints. 
To align product quality complaints 
language with current Shire template. 
Study Synopsis, Number of 
Subjects (total and for each 
treatment arm), Methodology 
Section 3.1, Study Design and Flow 
Chart 
Section 9.6, Sample Size 
Calculation and Power 
Considerations 
Updated sample size projections. 
 
 
 
 
 
Updated sample size projections 
and power considerations. 
To reflect a decrease in the sample size 
in this study due to a reduced number 
of subjects required to rollover to the 
SHP647-303 study to meet targeted 
power levels. 
Study Synopsis, Rationale 
Section 2.1, Rationale for the Study 
Revised to describe 
Study A7281010 as a completed 
study. 
To reflect that Study A7281010 has 
been completed. 
Study Synopsis, Inclusion Criteria 
Section 4.1, Inclusion Criteria 
Section 4.4, Reproductive Potential 
Added the term ‘highly effective 
methods for female and medically 
appropriate methods for male 
study subjects’ to inclusion 
criterion #10 in parentheses after 
the term ‘appropriate 
contraception’. Also added after 
the terms ‘appropriate form of 
contraception’ and ‘appropriate 
method of contraception’ in 
Section 4.4. 
To clarify what is meant by 
appropriate contraception methods. 
Study Synopsis, Exclusion Criteria 
Table 1, Schedule of Assessments 
footnote ‘r’ 
Section 4.2, Exclusion Criteria 
Section 7.2.3.6, Clinical Laboratory 
Evaluations 
Language in exclusion 
criterion #18, changed from 
‘12 weeks before randomization’ 
to ‘12 weeks before screening’. 
Language in the footnote and 
section 7.2.3.6 revised to 
‘12 weeks before baseline’ to 
‘12 weeks before screening’. 
For consistency with other sections. 
Study Synopsis, Exclusion Criteria 
Section 4.2, Exclusion Criteria 
Language in exclusion 
criterion #18, changed from 
‘3 months before and during 
screening visit’ and ‘3 months 
prior to screening visit’ to 
‘12 weeks before and during 
screening visit’. 
For consistency with other sections. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 4 
SHP647-302 Protocol Amendment 2 
Ontamalimab 
 
11 Nov 2019 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
11 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Analysis Sets 
Section 9.7, Study Population 
 
 
 
 
Study Synopsis, Other Secondary 
Efficacy Endpoints 
Section 9.8.2.2, Other Secondary 
Efficacy Endpoints 
For the endpoint “change from 
baseline at the Week 12 visit in 
abdominal pain, diarrhea, and 
urgency item scores, absolute stool 
frequency, absolute rectal bleeding 
and total sign/symptom score 
based on subject daily e-diary 
entries (sum of rectal bleeding, 
stool frequency, abdominal pain, 
diarrhea, and urgency)”, revised 
the text in parentheses to read 
“(average of rectal bleeding, stool 
frequency, abdominal pain, 
diarrhea, and urgency)”. 
To correctly describe the scoring of 
patient-reported ulcerative colitis (UC) 
sign and symptom data. 
Study Synopsis, Safety Analyses 
Section 9.9, Safety Analyses 
Added that adverse events of 
special interest will be summarized 
by treatment group. 
To include analysis of adverse events 
of special interest. 
Table 1, Schedule of Assessments 
footnote ‘d’ 
Section 7.1.2.3, Final On-treatment 
Visits: Visit 6, Parts 1 and 2 
(Week 12/Early Termination) 
Revised to extend the window 
between the colonoscopy 
procedure at Visit 6 (Part 1) and 
Visit 6 (Part 2) to 10 days, 
although 5 to 7 days is preferable. 
To allow sufficient time for data from 
the centrally read endoscopy to be 
available at Part 2 of Visit 6. 
Table 1, Schedule of Assessments 
footnote ‘r’ 
Added interferon-gamma release 
assay along with purified protein 
derivative test. 
For consistency with other sections. 
Table 1, Schedule of Assessments 
footnote ‘m’ 
Section 7.2.3.6, Clinical Laboratory 
Evaluations 
Section 7.2.3.12, Evaluation of 
Increased Gastrointestinal 
Symptoms 
Added new subsection to 
Section 7.2.3 and language to 
describe the evaluation of 
increased gastrointestinal 
symptoms. 
To clarify that infectious etiology must 
be evaluated when a subject 
experiences an increase in 
gastrointestinal symptoms. 
Table 1, Schedule of Assessments 
footnote ‘aa’ 
Section 7.2.3.11, Monitoring for 
Type I and Type III Immune 
Reactions 
Added new row to Table 1, new 
subsection to Section 7.2.3, and 
language to describe the 
monitoring for hypersensitivity. 
To address Food and Drug 
Administration (FDA) 
recommendation to evaluate the risk of 
hypersensitivity reactions in the 
Phase 3 studies and aid in the 
collection of relevant safety data. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 5 
SHP647-302 Protocol Amendment 2 
Ontamalimab 
 
11 Nov 2019 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
11 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 4.4, Reproductive Potential 
Updated text to reflect results of an 
enhanced pre- and postnatal 
development (ePPND) toxicity 
study in nonhuman primates. 
Updated information to reflect 
preliminary results from an ePPND 
toxicity study of ontamalimab in 
nonhuman primates, which indicated 
that, at the dose levels tested (30 and 
60 mg/kg), infant losses were 
increased in ontamalimab-exposed 
animals when compared both to 
control animals in the study and to the 
historical control animal data from the 
testing facility. 
The relevance of this finding to 
humans is unknown but cannot be 
excluded. 
Results of the ePPND study were 
reported in the ontamalimab 
Investigator’s Brochure Edition 8.0. 
Section 4.4.1, Contraceptive 
Methods for Female Study Subjects 
Added text to specify that 
contraception methods with low 
user dependency should preferably 
be used, in particular when 
contraception is introduced as a 
result of participation in the 
clinical study. 
To align with guidance document 
“Recommendations related to 
contraception and pregnancy testing in 
clinical trials” of Clinical Trial 
Facilitation Group. 
Section 4.5.1, Subject Withdrawal 
Criteria 
The term ‘protocol violations’ has 
been changed to ‘protocol 
deviations’. 
For consistency with Section 4.5.2 
(Reasons for Withdrawal). 
Section 5.2.1, Permitted Treatment 
Added that oral beclomethasone up 
to a maximum of 5 mg/day is 
permitted (providing that the dose 
is stable for at least 2 weeks before 
screening endoscopic procedure). 
To reflect that beclomethasone is a 
topically active oral glucocorticoid 
used in certain regions as standard of 
care for UC. 
Section 7.2.3.3, Targeted 
Neurological Assessment 
Revised wording from ‘exclusion 
criterion 18’ to ‘exclusion 
criterion 20’ to reflect the correct 
criterion. 
For clarity regarding exclusion criteria. 
Table 3, Quarterly Neurological 
Assessments 
Column heading changed from 
‘targeted neurological history’ to 
‘interim neurologic history and 
targeted neurologic examination’. 
To align with language of newly 
proposed electronic case report form. 
Section 7.2.4.3, Health-related 
Quality of Life Assessments 
Changed the term ‘dimensions’ to 
‘domains’. 
For consistency. 
Section 7.2.5, Volume of Blood to 
Be Drawn from Each Subject 
Increased 
 sample 
volume from 3 mL to 5 mL. 
To correct the sample volume needed 
for the 
. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 6 
SHP647-302 Protocol Amendment 2 
Ontamalimab 
 
11 Nov 2019 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
11 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 8.1.3, Adverse Events of 
Special Interest 
Added new subsection to describe 
classification of hypersensitivity as 
an adverse event of special 
interest. 
To address FDA recommendation to 
evaluate the risk of hypersensitivity 
reactions in the Phase 3 studies and aid 
in the collection of relevant safety 
data. 
Section 8.1.7, Pregnancy 
Added text to specify that in cases 
of pregnancy, where the outcome 
is a live birth, the vital status and 
clinical condition of the infant 
should be obtained and 
documented at 1 year postpartum. 
To extend the timeframe for follow-up 
of pregnancy outcomes for female 
study participants or partners of male 
study participants in response to 
preliminary findings of the ePPND 
study.  
Section 9.5, Planned Interim 
Analysis, Adaptive Design, Data 
Monitoring Committee, and 
Hypersensitivity Adjudication 
Committee 
Added text to specify that external 
hypersensitivity adjudication 
committee will be established to 
review data from subjects who 
experience a suspected Type I or 
Type III hypersensitivity reaction. 
To address FDA recommendation to 
evaluate the risk of hypersensitivity 
reactions in the Phase 3 studies and aid 
in the collection of relevant safety 
data. 
Section 9.8.3, Exploratory Efficacy 
Endpoints 
 
 
 
 
 
 
 
. 
Section 10.1.5, Study Suspension, 
Termination, and Completion 
To clarify that the end-of-study 
declaration may be made by the 
sponsor or alternatively its 
representatives. 
Added for clarity. 
Appendix 2, Scales and 
Assessments 
Added instructions before the start 
of questions for Treatment 
Satisfaction Questionnaire for 
Medication. 
For consistency with other 
ontamalimab Phase 3 protocols. 
Appendix 4, Determination of 
Failure or Intolerance to Prior 
Treatment for Ulcerative Colitis  
Added guidance for the 
determination of failure or 
intolerance to prior tofacitinib 
treatment. 
To include tofacitinib, as it is a 
common prior treatment for UC. 
Throughout protocol 
‘SHP647’ was updated to 
‘ontamalimab’ throughout the 
protocol. 
To reflect that ontamalimab is the 
international nonproprietary name for 
SHP647. 
Throughout protocol 
Minor changes to wording and 
editorial changes. 
To improve clarity, consistency, and 
remove redundancy of text. 
See Appendix 1 for protocol history, including all amendments. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 7 
SHP647-302 Protocol Amendment 2 
Ontamalimab 
 
11 Nov 2019 
 
EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must fax or email the Shire 
“Clinical Study Serious Adverse Event and Nonserious AE as Required by the Protocol Form” 
within 24 hours to the Shire Global Drug Safety Department. The fax number and email address 
are provided on the form (sent under separate cover). A copy of this form must also be sent to the 
contract research organization (CRO)/Shire medical monitor using the details below. 
Fax 
 (Global) 
Email 
 
For protocol- or safety-related issues, the investigator must contact the medical monitor via 
the appropriate regional safety hotline (24 hours): 
North America: 
PPD 24 Hour Safety Hotline: RTP 
; Wilmington 
 
PPD 24 Hour Safety Hotline Fax: RTP 
 or 
; 
Wilmington 
 or 
 
Latin America: 
PPD 24 Hour Safety Hotline: 
 
PPD 24 Hour Safety Hotline Fax: 
 
Europe, the Middle East, and Africa; and Asia-Pacific: 
PPD 24 Hour Safety Hotline: 
 
PPD 24 Hour Safety Hotline Fax: 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 8 
SHP647-302 Protocol Amendment 2 
Ontamalimab 
 
11 Nov 2019 
 
PRODUCT QUALITY COMPLAINTS 
Investigators are required to report investigational product quality complaints or nonmedical 
complaints to Shire within 24 hours. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis. 
A product quality complaint includes any instances where there is an allegation or report relating 
to Shire licensed or investigational products, received in writing, electronically, or orally, which 
indicates an impact to a product’s strength, identity, safety, purity, or quality, or which suggests 
that a product did not meet the criteria defined in the regulatory applications, licenses, or 
marketing authorizations for the product. Examples of investigational product quality complaints 
include, but are not limited to, the following: 
Unit issues 
• Capsule fill empty or overage 
• Bottle/vial fill shortage or overage 
• Capsule/tablet damaged/broken 
• Syringe/vial cracked/broken 
• Syringe leakage 
• Missing components 
• Product discoloration 
• Device malfunction 
Labeling 
• Label missing 
• Leaflet or Instructions For Use 
(IFU) missing  
• Label illegible 
• Incomplete, inaccurate, or 
misleading labeling 
• Lot number or serial number missing 
Packaging 
• Damaged packaging (eg, secondary, 
primary, bag/pouch) 
• Tampered seals 
• Inadequate or faulty closure 
• Missing components within package 
Foreign 
material 
• Contaminated product 
• Particulate in bottle/vial 
• Particulate in packaging 
 
Please report the product quality complaint using the “Product Complaint Data Collection Form” 
via the email address: 
 
 
Telephone number (provided for reference if needed): 
Shire, Lexington, MA (USA) 
 
For instructions on reporting adverse events related to product complaints, see Section 8.2.2. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 9 
SHP647-302 Protocol Amendment 2 
Ontamalimab 
 
11 Nov 2019 
 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ........................................................3 
EMERGENCY CONTACT INFORMATION ................................................................................7 
PRODUCT QUALITY COMPLAINTS..........................................................................................8 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF TABLES .........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................14 
LIST OF APPENDICES ................................................................................................................14 
ABBREVIATIONS .......................................................................................................................15 
STUDY SYNOPSIS ......................................................................................................................18 
STUDY SCHEDULE ....................................................................................................................27 
1 
BACKGROUND INFORMATION .......................................................................................32 
1.1 
Indication and Current Treatment Options ...............................................................32 
1.2 
Product Background and Clinical Information ........................................................32 
1.3 
Benefit/Risk Assessment ..........................................................................................33 
2 
STUDY OBJECTIVES AND PURPOSE ..............................................................................35 
2.1 
Rationale for the Study .............................................................................................35 
2.2 
Study Objectives .......................................................................................................36 
2.2.1 Primary Objective ..................................................................................................36 
2.2.2 Secondary Objectives .............................................................................................36 
2.2.2.1 
Key Secondary Objectives .....................................................................36 
2.2.2.2 
Other Secondary Objectives ...................................................................37 
2.2.3 Exploratory Objectives ..........................................................................................37 
3 
STUDY DESIGN ...................................................................................................................38 
3.1 
Study Design and Flow Chart ..................................................................................38 
3.1.1 Rationale for Primary Endpoint .............................................................................40 
3.1.2 Rationale for Key Secondary Endpoints: ...............................................................41 
3.2 
Duration and Study Completion Definition .............................................................41 
3.3 
Sites and Regions .....................................................................................................41 
4 
STUDY POPULATION .........................................................................................................42 
4.1 
Inclusion Criteria ......................................................................................................42 
4.2 
Exclusion Criteria .....................................................................................................43 
4.3 
Restrictions ...............................................................................................................47 
4.4 
Reproductive Potential .............................................................................................47 
4.4.1 Contraceptive Methods for Female Study Subjects ...............................................48 
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Shire 
CONFIDENTIAL 
Page 10 
SHP647-302 Protocol Amendment 2 
Ontamalimab 
 
11 Nov 2019 
 
4.4.2 Contraceptive Methods for Male Study Subjects ..................................................49 
4.5 
Withdrawal of Subjects ............................................................................................50 
4.5.1 Subject Withdrawal Criteria ..................................................................................50 
4.5.2 Reasons for Withdrawal .........................................................................................51 
4.5.3 Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................51 
5 
PRIOR AND CONCOMITANT TREATMENT ...................................................................52 
5.1 
Prior Treatment .........................................................................................................52 
5.2 
Concomitant Treatment ............................................................................................52 
5.2.1 Permitted Treatment ...............................................................................................52 
5.2.2 Prohibited Treatment .............................................................................................53 
5.2.3 Rescue Therapy ......................................................................................................54 
6 
INVESTIGATIONAL PRODUCT ........................................................................................55 
6.1 
Identity of Investigational Product ...........................................................................55 
6.1.1 Blinding the Treatment Assignment ......................................................................55 
6.2 
Administration of Investigational Product ...............................................................55 
6.2.1 Interactive Response Technology for Investigational Product Management ........55 
6.2.2 Allocation of Subjects to Treatment ......................................................................55 
6.2.3 Dosing ....................................................................................................................56 
6.2.4 Unblinding the Treatment Assignment ..................................................................56 
6.3 
Labeling, Packaging, Storage, and Handling ...........................................................57 
6.3.1 Labeling .................................................................................................................57 
6.3.2 Packaging ...............................................................................................................57 
6.3.3 Storage ...................................................................................................................57 
6.3.4 Special Handling ....................................................................................................58 
6.4 
Drug Accountability .................................................................................................58 
6.5 
Subject Compliance ..................................................................................................59 
7 
STUDY PROCEDURES ........................................................................................................60 
7.1 
Study Schedule .........................................................................................................60 
7.1.1 Screening Period ....................................................................................................60 
7.1.1.1 
Screening Visit (Visit 1) .........................................................................60 
7.1.1.2 
Baseline Visit (Visit 2; Week 0).............................................................61 
7.1.2 Treatment Period ....................................................................................................61 
7.1.2.1 
Visit 3 (Week 2) .....................................................................................61 
7.1.2.2 
Visits 4 and 5 (Weeks 4 and 8) ..............................................................61 
7.1.2.3 
Final On-treatment Visits: Visit 6, Parts 1 and 2 
(Week 12/Early Termination) ................................................................61 
7.1.3 Follow-up Period: Visits 7 and 8 (Weeks 20 and 28) ............................................62 
7.1.4 Additional Care of Subjects After the Study .........................................................62 
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Shire 
CONFIDENTIAL 
Page 11 
SHP647-302 Protocol Amendment 2 
Ontamalimab 
 
11 Nov 2019 
 
7.2 
Study Evaluations and Procedures ...........................................................................62 
7.2.1 Demographic and Other Baseline Characteristics .................................................63 
7.2.2 Efficacy ..................................................................................................................63 
7.2.2.1 
Endoscopy and Histology .......................................................................63 
7.2.2.2 
Mayo Score ............................................................................................64 
7.2.2.3 
Patient-reported Outcome – Ulcerative Colitis Daily E-diary ...............65 
7.2.3 Safety .....................................................................................................................65 
7.2.3.1 
Medical and Medication History ............................................................65 
7.2.3.2 
Physical Examination (Including Height and Weight)...........................65 
7.2.3.3 
Targeted Neurological Assessment ........................................................66 
7.2.3.4 
Adverse Event Collection .......................................................................67 
7.2.3.5 
Vital Signs ..............................................................................................67 
7.2.3.6 
Clinical Laboratory Evaluations .............................................................68 
7.2.3.7 
Pregnancy Test and Follicle-stimulating Hormone Test ........................70 
7.2.3.8 
Electrocardiogram ..................................................................................70 
7.2.3.9 
Chest X-ray ............................................................................................70 
7.2.3.10 
Antidrug Antibodies ...............................................................................70 
7.2.3.11 
Monitoring for Type I and Type III Immune Reactions ........................70 
7.2.3.12 
Evaluation of Increased Gastrointestinal Symptoms..............................71 
7.2.4 Others .....................................................................................................................71 
 
 
 
 
7.2.4.3 
Health-related Quality-of-Life Assessments ..........................................72 
7.2.4.4 
Healthcare Resource Utilization Assessments .......................................73 
7.2.5 Volume of Blood to Be Drawn from Each Subject ...............................................74 
8 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................75 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events .......................................................................................................................75 
8.1.1 Severity Categorization ..........................................................................................75 
8.1.2 Relationship Categorization ...................................................................................76 
8.1.3 Adverse Events of Special Interest ........................................................................76 
8.1.3.1 
Hypersensitivity .....................................................................................76 
8.1.4 Outcome Categorization ........................................................................................79 
8.1.5 Symptoms of the Disease Under Study .................................................................79 
8.1.6 Clinical Laboratory and Other Safety Evaluations ................................................79 
8.1.7 Pregnancy ...............................................................................................................79 
8.1.8 Abuse, Misuse, Overdose, and Medication Error ..................................................80 
8.1.9 Unexpected Adverse Event ....................................................................................81 
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8.1.10 Suspected Unexpected Serious Adverse Reaction .................................................81 
8.2 
Serious Adverse Event Procedures ...........................................................................81 
8.2.1 Reference Safety Information ................................................................................81 
8.2.2 Reporting Procedures .............................................................................................81 
8.2.3 Serious Adverse Event Definition .........................................................................82 
8.2.4 Serious Adverse Event Collection Time Frame .....................................................82 
8.2.5 Serious Adverse Event Onset and Resolution Dates .............................................83 
8.2.6 Fatal Outcome ........................................................................................................83 
8.2.7 Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................83 
8.2.8 Safety Monitoring for Potential Cases of Drug-induced Liver Injury ...................83 
9 
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................86 
9.1 
Data Collection .........................................................................................................86 
9.2 
Clinical Data Management .......................................................................................86 
9.3 
Data Handling Considerations ..................................................................................86 
9.4 
Statistical Analysis Process ......................................................................................86 
9.5 
Planned Interim Analysis, Adaptive Design, Data Monitoring Committee, and 
Hypersensitivity Adjudication Committee ...............................................................87 
9.6 
Sample Size Calculation and Power Considerations ................................................87 
9.7 
Study Population ......................................................................................................88 
9.8 
Efficacy Analyses .....................................................................................................89 
9.8.1 Primary Efficacy Endpoint ....................................................................................89 
9.8.2 Secondary Efficacy Endpoints ...............................................................................92 
9.8.2.1 
Key Secondary Efficacy Endpoint .........................................................92 
9.8.2.2 
Other Secondary Efficacy Endpoints .....................................................92 
9.8.3 Exploratory Efficacy Endpoints .............................................................................94 
9.9 
Safety Analyses ........................................................................................................94 
9.10 
Other Analyses .........................................................................................................95 
 
 
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...........................................96 
10.1 
Sponsor’s Responsibilities .......................................................................................96 
10.1.1 Good Clinical Practice Compliance .......................................................................96 
10.1.2 Indemnity/Liability and Insurance .........................................................................96 
10.1.3 Public Posting of Study Information ......................................................................96 
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees ...........................................97 
10.1.5 Study Suspension, Termination, and Completion..................................................97 
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10.2 
Investigator’s Responsibilities .................................................................................97 
10.2.1 Good Clinical Practice Compliance .......................................................................97 
10.2.2 Protocol Adherence and Investigator Agreement ..................................................98 
10.2.3 Documentation and Retention of Records .............................................................98 
10.2.3.1 
Case Report Forms .................................................................................98 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study 
Documents ..............................................................................................98 
10.2.3.3 
Audit/Inspection .....................................................................................99 
10.2.3.4 
Financial Disclosure ...............................................................................99 
10.3 
Ethical Considerations ..............................................................................................99 
10.3.1 Informed Consent...................................................................................................99 
10.3.2 Institutional Review Board or Ethics Committee ................................................100 
10.4 
Privacy and Confidentiality ....................................................................................101 
10.5 
Study Results/Publication Policy ...........................................................................101 
11 REFERENCES .....................................................................................................................103 
 
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LIST OF TABLES 
Table 1 
Schedule of Assessments ...............................................................................27 
Table 2 
Common Excluded Treatments .....................................................................53 
Table 3 
Quarterly Neurological Assessments ............................................................66 
Table 4 
Volume of Blood to Be Drawn from Each Subject .......................................74 
Table 5 
Clinical Criteria for Diagnosing Anaphylaxis (Type 1 
Hypersensitivity) ...........................................................................................78 
Table 6 
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin .........................................................................................................84 
Table 7 
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints .....................................................................................88 
 
LIST OF FIGURES 
Figure 1 
Overview of Ontamalimab Phase 3 Studies in Ulcerative Colitis .................39 
Figure 2 
Study Design Flow Chart ..............................................................................40 
Figure 3 
Flow Diagram for Quarterly Neurological Assessments ...............................67 
Figure 4 
Potential Immunogenicity of Therapeutic Monoclonal Antibodies ..............77 
Figure 5 
Visualization of Alpha Propagation ..............................................................91 
 
LIST OF APPENDICES 
Appendix 1 
Protocol History ...........................................................................................106 
Appendix 2 
Scales and Assessments ...............................................................................113 
Appendix 3 
Glucocorticoid Equivalent Doses ................................................................145 
Appendix 4 
Determination of Failure or Intolerance to Prior Treatment for 
Ulcerative Colitis .........................................................................................146 
Appendix 5 
Guidance for Diagnosis and Treatment of Increased Gastrointestinal 
Symptoms ....................................................................................................154 
 
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ABBREVIATIONS 
5-ASA 
5-aminosalicylic acid 
6-MP 
6-mercaptopurine 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AZA 
azathioprine 
β–hCG 
beta–human chorionic gonadotropin 
CD 
Crohn’s disease 
CI 
confidence interval 
CMH 
Cochran-Mantel Haenszel 
CNS 
central nervous system 
CRO 
contract research organization 
CRP 
C-reactive protein 
DMC 
data monitoring committee 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED 
emergency department 
e-diary 
electronic diary 
EMA 
European Medicines Agency 
 
 
 
 
ET 
early termination 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FWER 
family-wise Type I error rate 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
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HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCVAb 
hepatitis C virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRQL 
health-related quality of life 
hsCRP 
high-sensitivity C-reactive protein 
IB 
investigator’s brochure 
IBD 
inflammatory bowel disease 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICH 
International Council for Harmonisation 
IgG2κ 
immunoglobulin G2 kappa 
IGRA 
interferon gamma release assay 
IRB 
institutional review board 
IRT 
interactive response technology 
IV 
intravenous 
LTS 
long-term safety extension 
 
 
MTX 
methotrexate 
NAb 
neutralizing antibody 
PCR 
polymerase chain reaction 
 
PFS 
prefilled syringe 
PGA 
physician global assessment 
 
 
 
 
 
PML 
progressive multifocal leukoencephalopathy 
PP 
per-protocol 
PPD 
purified protein derivative 
PRO 
patient-reported outcome 
Q4W 
once every 4 weeks 
RSI 
reference safety information 
SAE 
serious adverse event 
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SAP 
statistical analysis plan 
SC 
subcutaneous 
SF-36 
Short Form-36 Health Survey 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
 
UC 
ulcerative colitis 
ULN 
upper limit of normal  
VAS 
visual analog scale 
 
 
 
 
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STUDY SYNOPSIS 
Protocol number: SHP647-302 
Drug: Ontamalimab (SHP647) 
Title of the study: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety 
Study of SHP647 as Induction Therapy in Subjects with Moderate to Severe Ulcerative Colitis (FIGARO UC 302) 
Number of subjects (total and for each treatment arm): 
A total of 740 subjects (296 subjects at 25 mg ontamalimab, 296 subjects at 75 mg ontamalimab, and 148 subjects on 
placebo) are planned for enrollment into the study. 
Investigator(s): Multicenter study. 
Site(s) and Region(s): 
It is anticipated that the study will be conducted in at least 18 countries. Regions will include North America Europe, 
the Middle East, and Africa, Latin America, and Asia-Pacific. Approximately 210 sites will be utilized.  
Study period (planned): 
2017 to 2020 
Clinical phase: 
3 
Objectives: 
Primary: To evaluate the efficacy of ontamalimab in inducing remission, based on composite score of 
patient-reported symptoms and centrally read endoscopy, in subjects with moderate to severe ulcerative colitis (UC). 
Key Secondary: 
• 
To evaluate the efficacy of ontamalimab in achieving endoscopic remission, based on centrally read 
endoscopy 
• 
To evaluate the efficacy of ontamalimab in achieving clinical remission, based on composite score of 
patient-reported symptoms 
• 
To evaluate the efficacy of ontamalimab in inducing clinical response, based on composite score of 
patient-reported symptoms and centrally read endoscopy 
• 
To evaluate the efficacy of ontamalimab in achieving mucosal healing, based on endoscopic and 
histological assessment using the Geboes Score grading system. 
Other Secondary: 
• 
To evaluate the safety and tolerability of ontamalimab 
• 
To evaluate the effect of ontamalimab induction treatment on other clinical and endoscopic outcomes 
(including Mayo-based remission and clinical response, partial Mayo score over time, clinical remission 
over time, endoscopic remission, and deep remission) 
• 
To evaluate the effect of ontamalimab on abdominal pain, urgency, diarrhea, and absolute stool frequency 
and bleeding scores 
• 
To evaluate the effect of ontamalimab on health-related quality of life (as measured by the Inflammatory 
Bowel Disease Questionnaire [IBDQ] and the Short Form-36 Health Survey [SF-36]) 
• 
To evaluate the effect of ontamalimab on incidence of hospitalizations and total inpatient days. 
Rationale: 
This study is designed to evaluate the efficacy and safety of ontamalimab in inducing remission in subjects with 
moderate to severe UC. 
Ontamalimab has been investigated in subjects with moderate to severe UC in 3 completed studies: 2 dose-finding 
studies (A7281001 and A7281009) and an open-label, long-term safety extension (LTS) study (A7281010), which 
was ongoing at the time of the original protocol and has since completed. The Phase 1 study, A7281001, which 
investigated the safety, tolerance, pharmacokinetics (PK), and pharmacodynamic (PD) properties of ontamalimab, 
supports further clinical development of ontamalimab using subcutaneous (SC) administration. Subcutaneous doses 
of 25 mg or 75 mg of ontamalimab or placebo on Day 1 (Week 0), Week 4, and Week 8 are recommended for the 
Phase 3 studies SHP647-301 and SHP647-302. 
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Investigational product, dose, and mode of administration: 
The test product is ontamalimab, which will be provided as a sterile aqueous buffered solution for SC administration 
in a glass prefilled syringe (PFS) with a fixed needle. Each PFS contains 1 mL of ontamalimab solution for injection 
at an appropriate concentration to provide the intended dose of drug (25 or 75 mg). Additional information is 
provided in the current ontamalimab investigator’s brochure. 
The reference product is placebo, which will be provided in a PFS with a fixed needle containing 1 mL of placebo 
solution for SC administration. The placebo solution will contain the same sterile aqueous buffered solution as the 
test product but will not contain ontamalimab. 
Methodology: 
A total of 740 subjects (296 subjects at 25 mg ontamalimab, 296 subjects at 75 mg ontamalimab, and 148 subjects on 
placebo) are planned for enrollment into the study. Subjects must be at least 16 years of age and no more than 
80 years of age at the time of signing the informed consent/assent form. 
The study consists of a screening period up to 6 weeks and a 12-week treatment period. After the screening period, 
eligible subjects will be randomly assigned to receive 1 of 3 treatments (25 mg ontamalimab, 75 mg ontamalimab, or 
placebo) in a 2:2:1 ratio. Randomization will be stratified based upon the subject’s status of prior anti-tumor necrosis 
factor (TNF) treatment (naïve or experienced) and glucocorticoid use at baseline (on glucocorticoids at baseline 
versus not on glucocorticoids at baseline). Subjects will receive SC injections of ontamalimab or placebo, using a 
PFS, on Week 0/Day 1 (Visit 2), Week 4 (Visit 4), and Week 8 (Visit 5). Subjects will undergo efficacy, 
 
 safety, and health outcome assessments at these visits. 
Patient-reported UC signs and symptom data (including stool frequency, rectal bleeding severity and frequency, 
diarrhea frequency, urgency frequency, and abdominal pain worst severity) will be collected using a daily electronic 
diary (e-diary) during the treatment period. The Mayo score is a measure of UC disease activity consisting of the 
following 4 subscores: stool frequency, rectal bleeding, findings of endoscopy, and physician global assessment 
(PGA). The partial Mayo score consists of the Mayo score without the endoscopic subscores. The composite score is 
a recommended measure consisting of the Mayo score without the PGA subscore, and will be used for the primary 
efficacy endpoint. The Mayo scores and composite score will be based on subject daily e-diary entries. 
At the end of the 12-week treatment period, eligible subjects will be offered the opportunity to participate in a 
double-blind maintenance study (SHP647-303; for subjects who achieve clinical response) or an LTS study 
(SHP647-304; for subjects who do not achieve a clinical response). Subjects who withdraw early from the 12-week 
treatment period or who do not wish to enter the maintenance study (SHP647-303) or LTS study (SHP647-304) will 
continue into a 16-week safety follow-up period. Only those subjects who complete the full course of investigational 
product treatment in the induction studies (SHP647-301 or SHP647-302) will be eligible to continue in the 
maintenance study or LTS study. 
Inclusion and exclusion criteria: 
Inclusion Criteria: 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study. 
1. Subjects and/or their parent or legally authorized representative must have an understanding, ability, and 
willingness to fully comply with study procedures and restrictions. 
2. Subjects must be able to voluntarily provide written, signed, and dated (personally or via a legally authorized 
representative) informed consent and/or assent, as applicable, to participate in the study. 
3. Subjects must be between ≥16 and ≤80 years of age at the time of the signing of the informed consent/assent 
form. 
Note: Subjects <18 years of age must weigh ≥40 kg and must have body mass index ≥16.5 kg/m2. 
4. Subjects must have a documented diagnosis (radiologic or endoscopic with histology) of UC for ≥3 months 
before screening. The following must be available in each subject’s source documentation: 
• 
A biopsy report to confirm the histological diagnosis 
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• 
A report documenting disease duration based upon prior colonoscopy. 
Note: If this documentation is not available at the time of screening, a colonoscopy with biopsy to confirm 
the diagnosis is required during the screening period. 
5. Subjects must be willing to undergo a flexible sigmoidoscopy or colonoscopy (if preferred), including biopsy 
sample collection, during screening after all other inclusion criteria have been met. 
6. Subjects must have moderate to severe active UC, defined as a total Mayo score of ≥6, including a centrally read 
endoscopic subscore ≥2, rectal bleeding subscore ≥1, and stool frequency subscore ≥1 at baseline (Visit 2). 
7. Subjects must have evidence of UC extending proximal to the rectum (ie, not limited to proctitis). 
8. Subjects must have had an inadequate response to, or lost response to, or had an intolerance to at least 1 
conventional treatment such as mesalamine (5-aminosalicylic acid [5-ASA]), glucocorticoids, 
immunosuppressants (azathioprine, 6-mercaptopurine, or methotrexate), or anti-TNF (see Appendix 4 of the 
protocol for guidance). 
9. Subjects receiving any treatment(s) for UC described in Section 5.2.1 of the protocol are eligible provided they 
have been, and are anticipated to be, on a stable dose for the designated period of time. 
10. Subjects are males or nonpregnant, nonlactating females who, if sexually active, agree to comply with the 
contraceptive requirements of the protocol, or females of nonchildbearing potential. Males and females of 
reproductive potential who are sexually active must agree to use appropriate contraception (ie, highly effective 
methods for female and medically appropriate methods for male study subjects) (as described in Section 4.4 of 
the protocol) for the duration of the study. 
Exclusion Criteria: 
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. 
Subjects with indeterminate colitis, microscopic colitis, nonsteroidal anti-inflammatory drug-induced colitis, 
ischemic colitis, infectious colitis, or clinical/histologic findings suggestive of Crohn’s disease. 
2. 
Subjects with colonic dysplasia or neoplasia. (Subjects with prior history of adenomatous polyps will be 
eligible if the polyps have been completely removed.) 
3. 
Subjects with past medical history or presence of toxic megacolon. 
4. 
Subjects with colonic stricture, past medical history of colonic resection, a history of bowel surgery within 
6 months before screening, or who are likely to require surgery for UC during the treatment period. 
5. 
Subjects at risk for colorectal cancer must have a colonoscopy (Eaden and Mayberry, 2002) performed during 
the screening period with results available within 10 days before the baseline visit (Visit 2), unless the subject 
has had a surveillance colonoscopy performed within 1 year prior to screening, and any adenomatous polyps 
found at that examination have been excised. Colonoscopy report and pathology report (if biopsies are 
obtained) from the colonoscopy performed during screening or in the prior year confirming no evidence of 
dysplasia and colon cancer must be available in the source documents. 
Subjects at risk for colorectal cancer include, but are not limited to: 
• 
Subjects with extensive colitis for ≥8 years or disease limited to left side of colon (ie, distal to splenic 
flexure) for ≥10 years before screening, regardless of age 
• 
Subjects ≥50 years of age at the time of signing of the informed consent form. 
6. 
Subjects have had prior treatment with ontamalimab (formerly PF-00547659; SHP647). 
7. 
Subjects with known or suspected intolerance or hypersensitivity to the investigational product(s), closely 
related compounds, or any of the stated ingredients. 
8. 
Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2). 
9. 
Subjects have received any biologic with immunomodulatory properties (other than anti-TNFs) within 90 days 
before baseline (Visit 2). 
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10. Subjects have received any nonbiologic treatment with immunomodulatory properties (other than their current 
background UC treatment) within 30 days before baseline (Visit 2). 
11. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion molecule). 
12. Subjects have received parenteral or rectal glucocorticoids, or rectal 5-ASA, within 14 days before screening 
endoscopic procedure. 
13. Subjects have received leukocyte apheresis or selective lymphocyte, monocyte, or granulocyte apheresis or 
plasma exchange within 30 days before baseline (Visit 2). 
14. Subjects have participated in other investigational studies within either 30 days or 5 half-lives of investigational 
product used in the study (whichever is longer) before baseline (Visit 2). 
15. Subjects have received a live (attenuated) vaccine within 30 days before the baseline visit (Visit 2). 
16. Subjects with active enteric infections (positive stool culture and sensitivity), Clostridium difficile infection or 
pseudomembranous colitis (subjects with C. difficile infection at screening may be allowed re-test after 
treatment), evidence of active cytomegalovirus infection or Listeria monocytogenes, known active invasive 
fungal infections such as histoplasmosis or parasitic infections, clinically significant underlying disease that 
could predispose the subjects to infections, or a history of serious infection (requiring parenteral antibiotic 
and/or hospitalization) within 4 weeks before the baseline visit (Visit 2). 
17. Subjects with abnormal chest x-ray findings at screening (Visit 1), such as presence of active tuberculosis (TB), 
general infections, heart failure, or malignancy. (A chest x-ray performed up to 12 weeks before study entry 
[screening, Visit 1] may be used if available; documentation of the official reading must be located and 
available in the source documentation.) 
18. Subjects with evidence of active or latent infection with Mycobacterium tuberculosis (TB) or subjects with this 
history who have not completed a generally accepted full course of treatment before randomization are 
excluded. All other subjects must have either the Mantoux (purified protein derivative [PPD]) tuberculin skin 
test or interferon gamma release assay (IGRA) performed. 
Subjects who have no history of previously diagnosed active or latent TB are excluded if they have a positive 
Mantoux (PPD) tuberculin skin test (ie ≥5 mm induration) or a positive IGRA (the latter to be tested at the 
site’s local laboratory) during screening or within 12 weeks before screening. If IGRA test cannot be performed 
locally, a central laboratory may be used, with prior agreement from the sponsor. 
• 
An IGRA is strongly recommended for subjects with a prior Bacillus Calmette-Guérin vaccination, but may 
be used for any subject. Documentation of IGRA product used and the test result must be in the subject's 
source documentation if performed locally. Acceptable IGRA products include QuantiFERON TB Gold 
Plus In-Tube Test. 
• 
If the results of the IGRA are indeterminate, the test may be repeated, and if a negative result is obtained, 
enrollment may proceed. In subjects with no history of treated active or latent TB, a positive test on repeat 
will exclude the subject. Subjects with a history of active or latent TB infection must follow instructions for 
“Subjects with a prior diagnosis of active or latent TB are excluded unless both of the following criteria are 
met” in this criterion. 
• 
Subjects with repeat indeterminate IGRA results, with no prior TB history, may be enrolled after 
consultation with a pulmonary or infectious disease specialist who determines low risk of infection 
(ie, subject would be acceptable for immunosuppressant [eg, anti-TNF] treatment without additional 
action). This consultation must be included in source documentation. 
Results from a chest x-ray, taken within the 12 weeks before or during screening (Visit 1) must show no 
abnormalities suggestive of active TB infection as determined by a qualified medical specialist. 
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Subjects with a prior diagnosis of active or latent TB are excluded unless both of the following criteria are met: 
• 
The subject has previously received an adequate course of treatment for either latent (eg, 9 months of 
isoniazid or an acceptable alternative regimen, in a locale where rates of primary multidrug TB resistance 
are <5%. Subjects from regions with higher rates of primary multidrug TB resistance are excluded) or 
active (acceptable multidrug regimen) TB infection. Evidence of diagnosis and treatment must be included 
in source documentation. Consultation with a pulmonary or infectious disease specialist to confirm adequate 
treatment (ie, subject would be acceptable for immunosuppressant [eg, anti-TNF] treatment without 
additional action) must be performed during the screening period. The consultation report must be included 
in source documentation prior to enrollment. 
• 
A chest x-ray performed within 12 weeks before or during screening (Visit 1) indicates no evidence of 
active or recurrent disease, and documentation of interpretation by a qualified medical specialist must be 
included in source documentation. 
19. Subjects with a pre-existing demyelinating disorder such as multiple sclerosis or new onset seizures, 
unexplained sensory motor, or cognitive behavioral, neurological deficits, or significant abnormalities noted 
during screening. 
20. Subjects with any unexplained symptoms suggestive of progressive multifocal leukoencephalopathy based on 
the targeted neurological assessment during the screening period (see Section 7.2.3.3 of the protocol). 
21. Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed. 
22. Subjects with a significant concurrent medical condition at the time of screening (Visit 1) or baseline (Visit 2), 
including, but not limited to, the following: 
• 
Any major illness/condition or evidence of an unstable clinical condition (eg, renal, hepatic, hematologic, 
gastrointestinal (except disease under study), endocrine, cardiovascular, pulmonary, immunologic [eg, 
Felty’s syndrome], or local active infection/infectious illness) that, in the investigator’s judgment will 
substantially increase the risk to the subject if he or she participates in the study 
• 
Cancer or history of cancer or lymphoproliferative disease within the previous 5 years (other than resected 
cutaneous basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of the uterine cervix that has 
been treated with no evidence of recurrence) 
• 
Presence of acute coronary syndrome (eg, acute myocardial infarction, unstable angina pectoris) within 
24 weeks before screening 
• 
History of significant cerebrovascular disease within 24 weeks before screening. 
23. Subjects who have had significant trauma or major surgery within 4 weeks before the screening visit (Visit 1), 
or with any major elective surgery scheduled to occur during the study. 
24. Subjects with evidence of cirrhosis with or without decompensation. 
25. Subjects with primary sclerosing cholangitis. 
26. Subjects with evidence of positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). 
Note: if a subject tests negative for HBsAg, but positive for HBcAb, the subject would be considered eligible if 
no presence of hepatitis B virus (HBV) DNA is confirmed by HBV DNA polymerase chain reaction reflex 
testing performed in the central laboratory. 
27. Subjects with chronic hepatitis C virus (HCV) (positive HCV antibody [HCVAb] and HCV RNA). 
Note: Subjects who are HCVAb positive without evidence of HCV RNA may be considered eligible 
(spontaneous viral clearance or previously treated and cured [defined as no evidence of HCV RNA at least 
12 weeks prior to baseline]). 
28. Subjects with any of the following abnormalities in hematology and/or serum chemistry profiles during 
screening. Note: Screening laboratory tests, if the results are considered by the investigator to be transient and 
inconsistent with the subject’s clinical condition, may be repeated once during the screening period for 
confirmation. Results must be reviewed for eligibility prior to the screening endoscopy procedure. 
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• 
Alanine aminotransferase and aspartate aminotransferase levels ≥3.0 × the upper limit of normal (ULN) 
• 
Total bilirubin level ≥1.5 × ULN or >2.0 × ULN if the subject has a known documented history of Gilbert’s 
syndrome) 
• 
Hemoglobin level ≤80 g/L (8.0 g/dL) 
• 
Platelet count ≤100 × 109/L (100,000 cells/mm3) or ≥1000 × 109/L (1,000,000 cells/mm3)* 
• 
White blood cell count ≤3.5 × 109/L (3500 cells/mm3) 
• 
Absolute neutrophil count <2 × 109/L (2000 cells/mm3) 
• 
 Serum creatinine level >1.5× ULN or estimated glomerular filtration rate <30 mL/min/1.73 m2 based on the 
abbreviated Modification of Diet in Renal Disease Study Equation. 
*Note: If platelet count is <150,000 cells/mm3, a further evaluation should be performed to rule out 
cirrhosis, unless another etiology has already been identified. 
29. Subjects with known human immunodeficiency virus (HIV) infection based on documented history, with 
positive serological test, or positive HIV serologic test at screening, tested at the site’s local laboratory in 
accordance with country requirements, or tested at the central laboratory. Note: A documented negative HIV 
test within 6 months of screening is acceptable and does not need to be repeated. 
30. Subjects who have, or who have a history of (within 2 years before screening [Visit 1]), serious psychiatric 
disease, alcohol dependency, or substance/drug abuse or dependency of any kind, including abuse of medicinal 
marijuana (cannabis). 
31. Subjects with any other severe acute or chronic medical or psychiatric condition or laboratory or 
electrocardiogram (ECG) abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this study. 
32. Female subjects who are planning to become pregnant during the study period. 
33. Subjects who do not agree to postpone donation of any organ or tissue, including male subjects who are 
planning to bank or donate sperm, and female subjects who are planning to harvest or donate eggs, for the 
duration of the study and through 16 weeks after last dose of investigational product. 
34. Subjects who are investigational site staff members or relatives of those site staff members or subjects who are 
Shire employees directly involved in the conduct of the study. 
Maximum duration of subject involvement in the study: 
• 
Planned duration of screening period: Up to 6 weeks 
• 
Planned duration of treatment period: 12 weeks 
• 
Planned duration of follow-up period: 16 weeks 
Endpoints and statistical analysis: 
Analysis Sets: 
The screened set will consist of all subjects who have signed an informed consent document. 
The randomized set will consist of all subjects in the screened set for whom a randomization number has been 
assigned. 
The safety set will consist of all subjects who have received at least 1 dose of investigational product. 
The full analysis set (FAS) will consist of all subjects in the randomized set who have received at least 1 dose of 
investigational product. 
The per-protocol set will consist of all subjects in the FAS who do not have predefined protocol deviations that may 
affect the primary efficacy endpoint. 
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The completer set will consist of all subjects in the FAS who have completed the final scheduled primary assessment 
for this study. 
 
 
Primary Efficacy Endpoint:  
Unless otherwise specified, all efficacy analyses will be based on the FAS and subjects will be analyzed according to 
their randomized treatment, regardless of the treatment they actually received. 
The primary efficacy endpoint is remission at the Week 12 visit. Remission is defined as a composite score of 
patient-reported symptoms using daily e-diary and centrally read endoscopy as follows: 
• 
stool frequency subscore of 0 or 1 with at least a 1-point change from baseline 
AND 
• 
rectal bleeding subscore of 0 
AND 
• 
endoscopic subscore of 0 or 1 (modified, excludes friability). 
The primary efficacy endpoint will be compared for each active treatment group (25 mg or 75 mg ontamalimab) to 
the placebo group using a Cochran-Mantel Haenszel chi-square test stratified by status of prior anti-TNF treatment 
and glucocorticoid use at baseline (Visit 2). Subjects with missing remission data at the Week 12 visit will be 
considered failures and counted as nonresponders. The endoscopy score will be based on centrally read results. 
The primary endpoint will be tested by the following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
Where δ is the common treatment difference across strata, j=1 to m. The common treatment difference is a weighted 
average of the stratum-specific treatment differences. 
The global family-wise Type I error rate (FWER) for the statistical tests of the primary and key secondary endpoints 
will be strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in Bretz et al. (2009) 
will be utilized to propagate α from primary to key secondary endpoints and between the 2 ontamalimab treatment 
group and placebo comparisons. Alpha is initially split equally at the .025 level (2-sided) for each of the pairwise 
treatment comparisons for the primary endpoint (P) and alpha is propagated in a hierarchical manner to each of the 
4 key secondary endpoints (K1-K4) within a pairwise treatment comparison. 
Key Secondary Efficacy Endpoints: 
• 
Endoscopic remission, as defined by centrally read endoscopic subscore 0 or 1 (modified, excludes friability), at 
the Week 12 visit. 
• 
Clinical remission, as defined by stool frequency subscore of 0 or 1 with at least a 1-point change from baseline 
in stool frequency subscore, and rectal bleeding subscore of 0, at the Week 12 visit. 
• 
Clinical response based on composite score at the Week 12 visit. Clinical response (composite) is defined as a 
decrease from baseline in the composite score of patient-reported symptoms using daily e-diary and 
centrally read endoscopy of at least 2 points and at least 30%, with an accompanying decrease in the subscore 
for rectal bleeding ≥1 point or a subscore for rectal bleeding ≤1. 
• 
Mucosal healing based on endoscopic and histological assessment at the Week 12 visit. Mucosal healing is 
defined by centrally read endoscopic subscore 0 or 1 (modified, excludes friability) and centrally read Geboes 
score of ≤2. 
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The key secondary endpoints will be analyzed using the same approach as described for the primary efficacy 
endpoint. Subjects with missing key secondary endpoint data at the Week 12 visit will be considered failures and 
counted as nonresponders. 
Other Secondary Efficacy Endpoints: 
• 
Remission, defined as a total Mayo score ≤2 with no individual subscore (stool frequency, rectal bleeding, 
endoscopy [modified, excludes friability], and physician’s global assessment) exceeding 1, at the Week 12 visit. 
• 
Clinical response based on total Mayo score at the Week 12 visit. Clinical response (Mayo) is defined as a 
decrease from baseline in the total Mayo score of at least 3 points and at least 30%, with an accompanying 
decrease in the subscore for rectal bleeding ≥1 point or an absolute subscore for rectal bleeding ≤1. 
• 
Partial Mayo score ≤2 with no individual subscore >1 at the Week 4, 8, and 12 visits. The partial Mayo score 
does not include the endoscopy subscore. 
• 
Clinical remission as defined by stool frequency subscore of 0 or 1 with at least a 1-point change from baseline 
in stool frequency subscore, and rectal bleeding subscore of 0, at Weeks 4 and 8. 
• 
Endoscopic remission at the Week 12 visit with endoscopic subscore of 0. 
• 
Clinical remission at the Week 4, 8, and 12 visits with both rectal bleeding and stool frequency subscores of 0. 
• 
Deep remission at the Week 12 visit. Deep remission is defined as both endoscopic and rectal bleeding 
subscores of 0, and stool frequency subscore ≤1 and a centrally read Geboes score of ≤2. 
• 
Change from baseline at the Week 12 visit in abdominal pain, diarrhea, and urgency item scores, absolute stool 
frequency, absolute rectal bleeding and total sign/symptom score based on subject daily e-diary entries (average 
of rectal bleeding, stool frequency, abdominal pain, diarrhea, and urgency). 
• 
Change from baseline in IBDQ domain and total (absolute) scores (time frame: Week 0, Week 8, up to 
Week 12, or early termination [ET]). 
• 
Change from baseline in SF-36, version 2, acute (physical and mental component summary scores and 
individual domain scores) to the Week 12/ET visit. 
• 
Incidence of all-cause hospitalizations and total inpatient days. 
Other secondary endpoints will be summarized by descriptive statistics and presented by treatment group. Where 
appropriate, other secondary efficacy endpoints will be analyzed with the following analysis methods. 
Binary endpoints will be analyzed using the same approach as described for the primary endpoint. Subjects with 
missing binary endpoint data at a visit will be considered failures and counted as nonresponders. 
Continuous endpoints that are only measured at baseline and the Week 12 visit will be analyzed using an analysis of 
covariance model with fixed effects for treatment group (categorical), status of prior anti-TNF treatment 
(categorical), and glucocorticoid use at baseline (categorical), and the baseline value as a continuous covariate. From 
this model, estimates of the least squares means, treatment differences, standard errors, p-values, and 
95% confidence intervals (CIs) for least squares mean treatment differences will be provided. 
Continuous endpoints that are measured repeatedly over time will be analyzed using a linear repeated measures 
mixed model with restricted maximum likelihood estimation. The model will include fixed effects for treatment 
group (categorical), visit (categorical), treatment group by visit interaction, status of prior anti-TNF treatment 
(categorical), and glucocorticoid use at baseline (categorical); baseline value as a continuous covariate; and repeated 
measures across visit for subject. From this model, estimates of least squares means, treatment differences, standard 
errors, p-values, and 95% CIs for least squares mean treatment differences for each visit will be provided. 
Safety Analyses: 
All safety analyses will be performed using the safety set. Subjects will be analyzed according to the treatment they 
actually received. 
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Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities. 
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates at the time of or following the first exposure 
to investigational product. The number of events, incidence, and percentage of TEAEs will be calculated overall, by 
system organ class, by preferred term, and by treatment group. Treatment-emergent AEs will be further summarized 
by severity and relationship to investigational product. Adverse events leading to withdrawal, serious AEs, and 
deaths will be similarly summarized or listed. Adverse events of special interest will be summarized by treatment 
group. 
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group and visit. Potentially 
clinically important findings will also be summarized or listed. 
Antidrug antibody data will be summarized by treatment group and visit. 
 
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STUDY SCHEDULE 
Table 1 
Schedule of Assessments 
Study Procedure 
Screeninga 
Baseline 
Treatment 
Follow-up 
Weeks -6 to -1 
Week 0/ 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12/ETb 
Week 20c 
Week 28c 
Visit Number 
1 
2 
3 
4 
5 
6  
(Part 1)d 
6  
(Part 2) 
7 
8 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
 
84 ±3 
140 ±7 
196 ±7 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
Xe 
 
 
Demographics and medical historyf 
X 
 
 
 
 
 
 
 
 
Complete physical examinationg 
X 
 
 
 
 
 
X 
 
X 
Targeted physical examinationg 
 
X 
 
 
 
 
 
 
 
Targeted neurological assessmenth 
X 
 
 
 
 
 
X 
 
X 
Vital signsi 
X 
X 
 
X 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
X 
 
X 
 
X 
12-lead ECGi 
X 
X 
 
 
 
 
X 
 
 
Chest x-rayj 
X 
 
 
 
 
 
 
 
 
Contraception checkk 
X 
X 
X 
X 
X 
 
X 
 
X 
Laboratory Assessments 
Hematology 
Xl 
X 
 
X 
X 
 
X 
 
X 
Serum chemistry 
Xl 
X 
 
X 
X 
 
X 
 
X 
Urinalysis 
Xl 
X 
 
X 
X 
 
X 
 
X 
Stool microbiologym 
Xl 
 
 
 
 
 
 
 
 
HBsAg, HBcAb, HCVAbn 
Xl 
 
 
 
 
 
 
 
 
HIV testing per local regulationo 
X 
 
 
 
 
 
 
 
 
FSHp 
Xl 
 
 
 
 
 
 
 
 
Serum β–hCGq 
Xl 
 
 
 
 
 
 
 
 
Urine β–hCGq 
 
X 
 
X 
X 
 
X 
 
X 
TB test (PPD or QuantiFERON TB Gold 
Plus)r 
Xl 
 
 
 
 
 
 
 
 
JCV antibody banked samples 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Xt 
 
 
Xt 
 
X 
 
 
 
 
Xt 
 
 
Xt 
 
X 
 
 
 
 
Xt 
 
 
Xt 
 
X 
 
 
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Table 1 
Schedule of Assessments 
Study Procedure 
Screeninga 
Baseline 
Treatment 
Follow-up 
Weeks -6 to -1 
Week 0/ 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12/ETb 
Week 20c 
Week 28c 
Visit Number 
1 
2 
3 
4 
5 
6  
(Part 1)d 
6  
(Part 2) 
7 
8 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
 
84 ±3 
140 ±7 
196 ±7 
 
 
Xu 
Xu 
Xu 
Xu 
 
X 
 
 
ADA and NAb sampling 
 
Xt 
X 
Xt 
Xt 
 
X 
 
X 
Endoscopic Procedure 
Endoscopy (including biopsy)v 
Xv 
 
 
 
 
X 
 
 
 
UC Assessments 
Total Mayo score 
 
Xw 
 
 
 
 
Xw 
 
 
Partial Mayo score 
 
 
 
X 
X 
 
 
 
 
Remission stool frequency and pre-UC stool 
frequency 
X 
 
 
 
 
 
 
 
 
PRO-UC daily e-diary data instruction 
X 
 
 
 
 
 
 
 
 
PRO-UC daily e-diary datax 
X 
X 
X 
X 
X 
X 
X 
 
 
Health Assessmenty 
 
IBDQ 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Hospitalizations, inpatient days, 
 
(HRUA) 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
SF-36, v2, acute form 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
Treatment Procedures 
 
Randomizationz 
 
X 
 
 
 
 
 
 
 
Administration of ontamalimab or placeboz 
 
X 
 
X 
X 
 
 
 
 
Hypersensitivity monitoringaa 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications and procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense stool collection kit for stool sampleab 
X 
 
 
X 
X 
 
 
 
 
ADA=antidrug antibody; β–hCG=beta-human chorionic gonadotropin; 
; ECG=electrocardiogram; ED=emergency department; e-diary=electronic diary; 
; ET=early termination; FSH=follicle-stimulating hormone; HBcAb=hepatitis B core antibody; 
HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCVAb=hepatitis C virus antibody; HEENT=head, eyes, ears, nose, and throat; 
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Table 1 
Schedule of Assessments 
Study Procedure 
Screeninga 
Baseline 
Treatment 
Follow-up 
Weeks -6 to -1 
Week 0/ 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12/ETb 
Week 20c 
Week 28c 
Visit Number 
1 
2 
3 
4 
5 
6  
(Part 1)d 
6  
(Part 2) 
7 
8 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
 
84 ±3 
140 ±7 
196 ±7 
HIV=human immunodeficiency virus; HRUA=Healthcare Resource Utilization Assessment; IBDQ=Inflammatory Bowel Disease Questionnaire; IGRA= interferon-gamma 
release assay; JCV=John Cunningham virus; LTS=long-term safety extension; 
; NAb=neutralizing antibody; 
PGA=physician global assessment; 
; 
; 
; PML=progressive multifocal 
leukoencephalopathy; PPD=purified protein derivative; PRO=patient-reported outcome; SF-36 v2=Short Form-36 Health Survey, version 2; TB=tuberculosis; 
 
; UC=ulcerative colitis; 
 
a 
At least 2 visits will be necessary to complete the screening procedures, including endoscopy. 
b 
Subjects who withdraw early during the treatment period should return for the ET visit and then enter into the safety follow-up period. 
c 
Participation in the safety follow-up period is not required if subject is entering the maintenance study (SHP647-303) or LTS (SHP647-304) at the completion of the Week 12 
visit. For subjects participating in the 16-week safety follow-up period (not entering the maintenance study or LTS study), the Week 20 (Visit 7) visit will routinely be 
conducted by telephone; however, as an exception the visit can be performed as a study site visit if preferred. The Week 28 (Visit 8) visit will be at the study site. 
d 
Part 1 of Visit 6 must be completed within 10 days (preferably, within 5 to 7 days) before Part 2; this will allow sufficient time for data from the centrally read endoscopy to be 
available at Part 2 of the visit. 
e 
The outcome of Visit 6, Part 2 is used to assess eligibility to enroll in the maintenance (SHP647-303) or LTS (SHP647-304) studies. Eligibility for SHP647-303 and 
SHP647-304 will be assessed under those respective protocols. 
f 
Medical history will include UC history, cardiac history, and smoking history. 
g 
Complete physical examination includes the review of the following body systems: general appearance, skin, HEENT, heart, lungs, confrontational visual fields (eyes), breast 
(optional), abdomen, external genitalia (optional), extremities, neurologic function, back, and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin, heart, lungs, confrontational visual fields (eyes), abdomen, and examination of body systems where there are symptom complaints by the 
subject. 
h 
Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, speech, 
verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of PML should be excluded. See Section 7.2.3.3 for 
further details. 
i 
Vital signs (including blood pressure, pulse, respiratory rate, and temperature) and 12-lead ECG should be performed before collection of blood samples for laboratory 
assessments and before endoscopic procedure. 
j 
A chest x-ray performed up to 12 weeks before screening (Visit 1) may be used if available; the official reading must be located in the subject’s source documentation. 
k 
Contraception check should be performed for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential. See Section 4.4 for 
further details. 
l 
Screening laboratory test results, if considered by the investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated once during the 
screening period for confirmation. Results of repeated tests must be reviewed for eligibility prior to the screening endoscopy procedure. 
m 
Diagnosis of Clostridium difficile infection should be made using the central laboratory. If for any reason the central laboratory is not available, see Appendix 5 for guidance 
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Table 1 
Schedule of Assessments 
Study Procedure 
Screeninga 
Baseline 
Treatment 
Follow-up 
Weeks -6 to -1 
Week 0/ 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12/ETb 
Week 20c 
Week 28c 
Visit Number 
1 
2 
3 
4 
5 
6  
(Part 1)d 
6  
(Part 2) 
7 
8 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
 
84 ±3 
140 ±7 
196 ±7 
regarding alternate diagnostic algorithms. When a subject experiences an increase in gastrointestinal symptoms, which could be an exacerbation of disease, an infectious 
etiology must be evaluated including testing for C. difficile as described in Appendix 5. 
n 
Subjects who test negative for HBsAg but positive for HBcAb without HBV DNA may be considered eligible. For subjects who test positive for HBcAb and negative for 
HBsAg, a blood sample should be taken for HBV DNA. Blood for HBV DNA reflex testing is collected for required subjects only. If HBV DNA is positive, these subjects 
will not be eligible. 
o 
Documentation of a negative HIV test result within 6 months prior to screening will be accepted. 
p 
For confirmation of postmenopausal status in females who have had 12 consecutive months of spontaneous amenorrhea and are ≥51 years of age. 
q 
For females of childbearing potential who are not surgically sterile, do not have confirmed ovarian failure, or do not meet the definition of postmenopausal as described in 
Section 4.4.1 and Section 7.2.3.7. 
r 
A documented negative IGRA or PPD test within 12 weeks before screening (Visit 1) is acceptable provided that an IGRA result or PPD official reading and method is located 
in the source documentation. 
s 
A serum sample will be collected and banked. It may be analyzed if a subject shows neurologic symptoms suggestive of PML. 
t 
The sample must be collected before administration of investigational product. 
u 
The 
 sample must be collected before administration of investigational product.  
v 
Flexible sigmoidoscopy or colonoscopy (if preferred) at screening must be performed on all subjects after the majority of other eligibility criteria (eg, laboratory values) are 
met. Endoscopy must be performed during the screening period within 10 days before baseline (Visit 2), preferably within 5 to 7 days before the baseline visit, to obtain the 
centrally read endoscopic subscore. Biopsy samples will be collected for histological evaluation using the Geboes Score classification for the key secondary efficacy endpoint 
and 
 Subjects at risk of colorectal cancer, as defined in exclusion criterion 5 (see Section 4.2), 
must have a colonoscopy performed at screening, unless the subject has had a surveillance colonoscopy performed within 1 year prior to screening, and any adenomatous 
polyps found at that examination have been excised. Colonoscopy report and pathology report (if biopsies are obtained) from the colonoscopy performed during screening or 
in the prior year confirming no evidence of dysplasia and colon cancer must be available in the source documents. 
w 
Mayo score will be based on subject daily e-diary entries. The Mayo score at baseline will be calculated based on the stool frequency subscore and rectal bleeding subscore, 
reported by subjects in the PRO-UC daily e-diary and PGA obtained at baseline and the centrally read endoscopic subscore for the endoscopy performed during the screening 
period. The Mayo score at the Week 12 visit will be calculated based on the stool frequency subscore and rectal bleeding subscore reported by subjects in the PRO-UC daily 
e-diary and PGA and the centrally read endoscopic subscore for the endoscopy performed at Week 12, Visit 6 (Part 1). See Section 7.2.2.2 for further details. 
x 
PRO-UC daily e-diary will be collected using a daily e-diary during the treatment period. Collection of the daily e-diary data must begin at least 10 days before the baseline 
visit (Visit 2). The subject should be provided with the handheld device to take home on their first visit. See Section 7.2.2.3 for further details. Compliance is assessed by site 
staff at each visit. The site staff will instruct the subject on the appropriate use of the e-diary, particularly when compliance is below 80% (eg, <23 out of 28 e-diary entries) 
when compared with the previous visit. 
y 
All health outcome or patient-reported questionnaires should be completed before completing any other visit assessments. 
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Table 1 
Schedule of Assessments 
Study Procedure 
Screeninga 
Baseline 
Treatment 
Follow-up 
Weeks -6 to -1 
Week 0/ 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12/ETb 
Week 20c 
Week 28c 
Visit Number 
1 
2 
3 
4 
5 
6  
(Part 1)d 
6  
(Part 2) 
7 
8 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
 
84 ±3 
140 ±7 
196 ±7 
z 
Interactive response technology will be used for randomization and dispensation of study treatment. 
aa Beginning at Visit 2, at each visit the subject will be assessed for the presence of Type I and Type III hypersensitivity reactions since the prior visit. If a suspected 
hypersensitivity reaction has occurred, the next dose of investigational product should be withheld if necessary until the precise etiology (investigational product related or not) 
has been determined. If a Type III reaction is suspected, appropriate samples for testing will be collected and stored until the adjudication committee determines whether 
testing is appropriate. 
ab Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the visit at which testing will be done. 
Note: See Section 7.2 for the order in which assessments should be performed. Timing of visits is relative to baseline (Visit 2). 
 
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1 
BACKGROUND INFORMATION 
1.1 
Indication and Current Treatment Options 
Ulcerative colitis (UC) is a chronic, relapsing disease marked by ulceration and inflammation of 
the colonic mucosa and submucosa. Initially it usually involves the rectum but may extend 
proximally to involve a portion of, or the entirety of, the colon. In the early stages, hemorrhagic 
and erythematous tissue is observed, progressing to mucosal ulceration with purulent exudates in 
severe cases. The ulceration pattern is continuous and may extend the entire length of the colon. 
Perforation of the bowel wall causing ileus and peritonitis can occur with transmural extension of 
the ulceration. Bloody diarrhea with or without mucus and lower abdominal pain with periods of 
remission and exacerbation are the most common symptoms. 
The incidence of UC is estimated to be up to 24.3 cases per 100,000 persons per year in Europe 
and up to 19.2 cases per 100,000 persons per year in North America. No clear difference in 
incidence has been observed between men and women. Although UC can occur at any age, peak 
incidence has been observed in the second to fourth decades of life (Molodecky et al., 2012). 
Ulcerative colitis is a lifelong condition with a serious effect on the quality of life. Current 
treatment primarily consists of symptomatic management with dietary modifications and opiate 
antidiarrheal drugs (loperamide), as well as disease modifying agents such as 5-aminosalicylic 
acid (5-ASA), systemic glucocorticoids, immunosuppressive agents (azathioprine 
[AZA]/6-mercaptopurine [6-MP], cyclosporine), and biologic therapy with anti-tumor necrosis 
factor (TNF) or anti-integrin agents. Despite recent advances, there is still an unmet need for an 
effective pharmacological treatment that will induce and maintain remission. 
1.2 
Product Background and Clinical Information 
The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal sites of the 
gastrointestinal (GI) tract is influenced by the endothelial expression of mucosal addressin cell 
adhesion molecule (MAdCAM). MAdCAM is a member of the immunoglobulin super family of 
cell adhesion molecules and is mostly expressed on the cell surface of high endothelial venules 
of organized intestinal lymphoid tissue such as Peyer’s patches and mesenteric lymph nodes 
(Briskin et al., 1997; Shyjan et al., 1996; Liaskou et al., 2011). MAdCAM plays a role in gut 
immune surveillance, and also appears to facilitate excessive lymphocyte infiltration under 
conditions of chronic GI inflammation. The α4β7 integrin is the recognized ligand for MAdCAM, 
and expression of this ligand on populations of CD4+ and CD8+ T cells, as well as on subsets of 
B cells, distinguishes them as unique gut homing lymphocytes. 
Ontamalimab (previously known as PF-00547659 and SHP647) is a fully human 
immunoglobulin G2 kappa (IgG2κ) monoclonal antibody that binds to human MAdCAM to 
reduce lymphocyte homing to the gut and GI inflammation. Ontamalimab binds MAdCAM-1 
with high affinity and selectivity that prevents the binding of α4β7+ lymphocytes to MAdCAM 
expressing sites in the high endothelial venules of the GI tract. 
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1.3 
Benefit/Risk Assessment 
Ontamalimab has been evaluated in Phase 1 and Phase 2 clinical studies in subjects with UC and 
Crohn’s disease (CD). In UC Study A7281009, induction with ontamalimab at doses of 7.5 mg, 
22.5 mg, or 75 mg once every 4 weeks (Q4W) resulted in statistically significantly higher 
proportions of subjects in remission at Week 12 based on total Mayo score (both local and 
central read) when compared with placebo treatment. In CD Study A7281006, induction with 
ontamalimab did not meet the primary endpoint; no statistically significant differences were 
observed between the active treatment arms and the placebo arm in CD Activity Index-70 
response rate at Week 8 or Week 12. Post hoc analyses suggested evidence of drug effect in 
subjects with more inflammation at baseline, as indicated by higher serum concentrations of 
C-reactive protein (CRP) or Simple Endoscopic Score for CD. 
In UC induction Study A7281009, decreases in fecal calprotectin were observed in all groups, 
including placebo; however, there were no statistically significant differences in the decrease in 
fecal calprotectin between any dose level of ontamalimab and placebo. Decreases in 
high-sensitivity (hs)CRP were also observed in all 4 treatment groups; however, other than the 
75 mg dose group at Week 12, no statistically significant differences were observed in active 
treatment versus placebo. In the induction Study A7281006 in subjects with CD, compared to 
placebo, nominally statistically significant decreases in fecal calprotectin were observed in the 
75 mg group at Week 8 and in the 22.5 mg and 75 mg groups at Week 12. Generally, decreases 
from baseline in hsCRP were observed in all 4 treatment groups over the 12-week induction 
period. Compared to placebo, nominally statistically significant decreases in hsCRP were 
observed in all 3 active treatment groups (22.5 mg, 75 mg, and 225 mg) at Week 12. There was 
no evidence of a dose response for either of these parameters. A nominally statistically 
significant increase was observed in circulating β7+ central memory T lymphocytes at Weeks 8 
and 12, consistent with the predicted mechanism of action. 
The most common serious adverse events (SAEs) across all studies were CD and UC. In 
Study A7281006, the randomized, placebo-controlled induction study in CD, treatment-emergent 
adverse events (TEAEs) were most commonly reported within the GI disorders system organ 
class (SOC) followed by the infections and infestations SOC. The most common all-causality 
TEAEs were CD (worsening and progression of underlying disease), followed by pyrexia, 
headache, and arthralgia, all of which had similar incidences in the placebo treatment group 
compared with the active treatment groups. In Study A7281009, the randomized, 
placebo-controlled induction study in UC, TEAEs were most commonly reported within the GI 
disorders SOC followed by the infections and infestations SOC. The most common all-causality 
TEAE was headache, followed by abdominal pain, nasopharyngitis, UC (worsening and 
progression of underlying disease), and nausea, all with similar incidence between placebo- and 
drug-treated subjects. 
The long-term, open-label safety studies (Studies A7281007 and A7281010) were not 
placebo-controlled, but permitted exposure to the investigational product at doses of 75 mg or 
225 mg Q4W for 18 and 36 months, respectively. In Study A7281007, the most common all-
causality TEAE was CD (worsening or progression), arthralgia, nasopharyngitis, and abdominal 
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pain. In Study A7281010, the most common all-causality TEAEs were UC (worsening or 
progression), arthralgia, and nasopharyngitis. 
Ontamalimab appears to be generally well tolerated, with the majority of TEAEs distributed at 
similar frequencies among treatment arms with only peripheral edema, gastroenteritis, and 
arthralgia more frequently reported in ontamalimab- than placebo-treated subjects in the pooled 
induction studies. In the placebo-controlled induction studies, nasopharyngitis was not reported 
more frequently in ontamalimab- than placebo-treated subjects, but occurred at relatively high 
frequency during long-term safety studies. Ontamalimab does not appear to be associated with 
impaired central nervous system (CNS) immune surveillance. No case of progressive multifocal 
leukoencephalopathy (PML) or myocarditis has been reported. Ontamalimab, in doses of 7.5 mg, 
22.5 mg, and 75 mg, appears to increase the rate of remission in subjects with UC, and may have 
an effect in patients with CD who have greater evidence of inflammation based on biomarker or 
endoscopic data. 
Always refer to the latest version of the ontamalimab investigator’s brochure (IB) for the overall 
benefit/risk assessment and the most accurate and current information regarding the 
pharmacokinetics (PK), efficacy, and safety of ontamalimab. 
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2 
STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the Study 
Ontamalimab, a fully human IgG2κ antihuman MAdCAM monoclonal antibody, is under 
development for the treatment of UC. Ontamalimab prevents the binding of α4β7+ lymphocytes to 
MAdCAM-expressing sites with high affinity and selectivity. Principal sites of MAdCAM 
expression on normal tissue include intestine, pancreas, stomach, esophagus, spleen, and to a 
lesser extent lung, liver, and bladder but not the CNS (Steffen et al., 1996). 
Although selective targeting of the MAdCAM receptors is a novel approach, the basic 
interference of lymphocyte homing by preventing the binding of these α4β7+ lymphocytes to the 
MAdCAM receptor and the resultant efficacy in UC is well established (Feagan et al., 2013). 
Ontamalimab is differentiated from other molecules used for the treatment of UC in that it blocks 
the interaction of α4β7+ lymphocytes to the MAdCAM receptor by selectively binding to 
MAdCAM in the gut (and related tissues) whereas other molecules only target the integrins on 
the infiltrating lymphocytes. Additionally, ontamalimab does not bind to the vascular cell 
adhesion molecule; therefore, ontamalimab is not expected to be an effective treatment for 
multiple sclerosis, or affect lymphocyte homing or surveillance in the CNS. 
This study is designed to evaluate the efficacy of ontamalimab in inducing remission in subjects 
with moderate to severe UC. 
Ontamalimab has been investigated in subjects with moderate to severe UC in 3 completed 
studies: 2 dose-finding studies (A7281001 and A7281009) and an open-label, long-term safety 
extension (LTS) study (A7281010), which was ongoing at the time of the original protocol and 
has since completed. Phase 1 Study A7281001 evaluated both single (0.03–10.0 mg/kg 
intravenous [IV]; 3.0 mg/kg subcutaneous [SC]) and multiple doses (0.1–3.0 mg/kg IV; 0.3 and 
1.0 mg/kg SC) of ontamalimab in subjects with UC. Safety evaluation revealed a safety profile 
for ontamalimab similar to that of placebo, with no pattern of adverse events (AEs) suggestive of 
increased risk of opportunistic infections or CNS effects, and no evidence of adverse effects on 
laboratory parameters, electrocardiograms (ECGs), vital signs, or neurological function. Events 
leading to withdrawal were due to exacerbations of the underlying UC. 
Study A7281009 was a Phase 2b proof-of-concept (randomized, double-blind, 
placebo-controlled, parallel, dose-ranging) study designed to evaluate the efficacy, safety, and 
PK of ontamalimab in subjects with moderate to severe UC. Treatment was assigned in a 
1:1:1:1:1 ratio to dose levels of 7.5, 22.5, 75, or 225 mg ontamalimab or placebo administered 
SC Q4W at Weeks 0, 4, and 8. The primary endpoint of the study was the proportion of subjects 
in clinical remission at Week 12, with remission defined as a total Mayo score of ≤2 with no 
individual subscore >1 (see Appendix 2 for details of the Mayo score). More subjects were in 
clinical remission at Week 12 in the ontamalimab-treated groups than in the placebo group, with 
statistical significance achieved for the 7.5, 22.5, and 75 mg doses (Vermeire et al., 2017). Based 
upon the total Mayo score with a centrally read endoscopic severity component, the increase in 
clinical remission rates over placebo at Week 12 for the 7.5, 22.5, and 75 mg doses were 8.0% 
(p=.043), 12.8% (p=.010), and 11.8% (p=.012), respectively. When the clinical remission rate at 
Week 12 was analyzed by stratum of previous anti-TNF exposure (experienced or naïve), a 
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similar trend was observed across dose levels in both the anti-TNF experienced and anti-TNF 
naïve subjects. There was no evidence of an adverse safety signal, and there was no increase in 
the frequency of infections in MAdCAM-bearing tissues as evidenced by similar rates of 
nasopharyngitis among treatment arms. 
Based on the efficacy and safety data in Study A7281009 and the systemic population PK and 
pharmacodynamic (PD) modeling and simulation, clinical remission, clinical response and 
mucosal healing rates were higher in subjects with UC receiving doses of 22.5 and 75 mg Q4W 
than in those receiving doses of 7.5 mg and 225 mg Q4W. The induction responses were not 
demonstrated either at Week 4 or Week 8, but were observed at Week 12 regardless of dose 
level. No difference in the clinical responses between a 22.5 mg dose and a 25 mg dose is 
expected based on the current understanding of the mode of action of ontamalimab and clinical 
observations to date. To better understand the exposure (dose)-response relationship in this 
population and understand individual patient exposure needs, the 25 and 75 mg doses (Q4W) 
will be tested in the Phase 3 program. Therefore, SC doses of 25 mg or 75 mg of ontamalimab or 
placebo on Day 1 (Week 0), Week 4, and Week 8 are recommended for the 2 planned Phase 3 
studies SHP647-301 and SHP647-302. The Phase 1 study, A7281001, which investigated the 
safety, tolerance, PK, and PD properties of ontamalimab, supports further clinical development 
of ontamalimab using SC administration. 
2.2 
Study Objectives 
2.2.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of ontamalimab in inducing 
remission, based on composite score of patient-reported symptoms and centrally read endoscopy, 
in subjects with moderate to severe UC. 
2.2.2 
Secondary Objectives 
2.2.2.1 
Key Secondary Objectives 
The key secondary objectives are as follows: 
• To evaluate the efficacy of ontamalimab in achieving endoscopic remission, based on 
centrally read endoscopy 
• To evaluate the efficacy of ontamalimab in achieving clinical remission, based on 
composite score of patient-reported symptoms 
• To evaluate the efficacy of ontamalimab in inducing clinical response, based on 
composite score of patient-reported symptoms and centrally read endoscopy 
• To evaluate the efficacy of ontamalimab in achieving mucosal healing, based on a 
centrally read endoscopic and histological assessment using the Geboes Score grading 
system. 
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2.2.2.2 
Other Secondary Objectives 
The other secondary objectives are as follows: 
• To evaluate the safety and tolerability of ontamalimab 
• To evaluate the effect of ontamalimab induction treatment on other clinical and 
endoscopic outcomes (including Mayo-based remission and clinical response, partial 
Mayo score over time, clinical remission over time, endoscopic remission, and deep 
remission) 
• To evaluate the effect of ontamalimab on abdominal pain, urgency, diarrhea, and absolute 
stool frequency and bleeding scores 
• To evaluate the effect of ontamalimab on health-related quality of life (HRQL) (as 
measured by the Inflammatory Bowel Disease Questionnaire [IBDQ] and the Short 
Form-36 Health Survey [SF-36]) 
• To evaluate the effect of ontamalimab on incidence of hospitalizations and total inpatient 
days. 
2.2.3 
Exploratory Objectives 
The exploratory objectives of the study are as follows: 
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3 
STUDY DESIGN 
3.1 
Study Design and Flow Chart 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study designed to 
evaluate the efficacy and safety of ontamalimab in inducing remission in subjects with moderate 
to severe UC. 
A total of 740 subjects (296 subjects at 25 mg ontamalimab, 296 subjects at 75 mg ontamalimab, 
and 148 subjects on placebo) are planned for enrollment into the study (Figure 1). Subjects must 
be at least 16 years of age and no more than 80 years of age at the time of signing the informed 
consent/assent form. 
The study consists of a screening period up to 6 weeks and a 12-week treatment period. After the 
screening period, eligible subjects will be randomly assigned to receive 1 of 3 treatments (25 mg 
ontamalimab, 75 mg ontamalimab, or placebo) in a 2:2:1 ratio. Randomization will be stratified 
based upon the subject’s status of prior anti- TNF treatment (naïve or experienced) and 
glucocorticoid use at baseline (on glucocorticoids at baseline versus not on glucocorticoids at 
baseline). Subjects will receive SC injections of ontamalimab or placebo, using a prefilled 
syringe (PFS), on Week 0/Day 1 (Visit 2), Week 4 (Visit 4), and Week 8 (Visit 5). Subjects will 
undergo efficacy, 
 
 safety, and health outcome assessments at these visits as 
detailed in Table 1. 
At the end of the 12-week treatment period, eligible subjects will be offered the opportunity to 
participate in a double-blind maintenance study (SHP647-303; for subjects who achieve clinical 
response) or an LTS study (SHP647-304; for subjects who do not achieve a clinical response) as 
shown in Figure 1. Subjects who withdraw early from the 12-week treatment period or who do 
not wish to enter the maintenance study (SHP647-303) or LTS study (SHP647-304) will 
continue into a 16-week safety follow-up period. Only those subjects who complete the full 
course of investigational product treatment in the induction studies (SHP647-301 or 
SHP647-302) will be eligible to continue in the maintenance study or LTS study. 
The overall study design is shown in Figure 2. 
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Figure 1 
Overview of Ontamalimab Phase 3 Studies in Ulcerative Colitis 
Placebo 
25 mg
75 mg
Non-Respondersa
Induction
(SHP647-301, SHP647-302) 
Maintenance
(SHP647-303) 
Long-term Safety 
Extension
(SHP647-304) 
25 mg
Placebo
75 mg
Placebo
Placebo
Respondersa
Respondersa
Respondersa
75 mg
25 mg
 
a 
Clinical response is defined as: 
1. A decrease from the induction study (SHP647-301 or SHP647-302) baseline in the composite score of 
patient-reported symptoms using daily electronic-diary and centrally read endoscopy of at least 2 points and at 
least 30%, with an accompanying decrease in the subscore for rectal bleeding ≥1 point or a subscore for rectal 
bleeding ≤1 
OR  
2. A decrease from the induction study (SHP647-301 or SHP647-302) baseline total Mayo score of at least 
3 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of ≥1 point or an 
absolute rectal bleeding subscore of ≤1. 
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Figure 2 
Study Design Flow Chart 
 
LTS=long-term safety extension; W=week 
a Subjects who withdraw early from the 12-week treatment period or who do not wish to enter the maintenance study 
(SHP647-303) or LTS study (SHP647-304) will continue into a 16-week safety follow-up period. 
3.1.1 
Rationale for Primary Endpoint 
The Mayo score has historically been used as the primary endpoint for pivotal studies of agents 
intended to treat UC. Over the past decade, health authority thinking regarding efficacy 
endpoints for UC has evolved such that the traditional Mayo score is no longer recommended. 
Current regulatory guidance (Food and Drug Administration [FDA] Ulcerative Colitis: Clinical 
Trial Endpoints Guidance for Industry [Draft], 2016; European Medicines Agency [EMA] 
Guideline on the Development of New Medicinal Products for the Treatment of Ulcerative 
Colitis [Draft], 2016) includes a dual measurement of patient-reported signs and symptoms 
outcomes (stool frequency and rectal bleeding), and clinician-reported endoscopic outcomes 
(scoring any endoscopy with evidence of friability as a 2), including histology. Per agreement 
with health authorities, these 3 outcomes will be reported as a composite score. 
Data will be collected to calculate the total Mayo score using both the traditional and modified 
endoscopy subscore as a sensitivity analysis and to estimate the impact of the modification on 
the primary endpoint. The clinical relevance of the traditional Mayo score is supported by its 
correlation with significant improvement in disease-specific HRQL as measured by the IBDQ 
and in generic HRQL as measured by the SF-36 questionnaire. 
Placebo 
25 mg ontamalimab 
75 mg ontamalimab 
Screening: Up to 
6 weeks 
Randomization 
Maintenance study 
(SHP647-303) 
or 
LTS study 
(SHP647-304) 
or 
W0 
W4 
W8 
Dosing:
Treatment period: 12 weeks 
Week 12/End of 
Treatment 
16-week safety 
follow-up perioda 
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3.1.2 
Rationale for Key Secondary Endpoints: 
The first 2 key secondary endpoints are included to comply with EMA advice. The EMA would 
agree to the composite primary endpoint only if supported by a key secondary analysis, where 
the patient-reported symptoms and clinician-reported endoscopy are analyzed as “co-primary”. 
The clinical response endpoint is based on the new composite score, and also represents 1 of the 
entry criteria for the maintenance study. This endpoint has not been previously tested. 
Mucosal healing as a key secondary endpoint comprises both endoscopic and histologic 
components as recommended in the draft FDA and EMA guidance on UC (FDA Ulcerative 
Colitis: Clinical Trial Endpoints Guidance for Industry [Draft], 2016; EMA Guideline on the 
Development of New Medicinal Products for the Treatment of Ulcerative Colitis [Draft], 2016). 
The Geboes Score (see Appendix 2) will be used to evaluate histologic remission and to 
complement the endoscopic subscore in the assessment of mucosal healing for the key secondary 
endpoint. 
3.2 
Duration and Study Completion Definition 
Each subject’s final visit in this study may be at the end of the treatment period (Week 12) if 
continuing to Study SHP647-303 or SHP647-304, or at the end of the safety follow-up period 
(Week 28) if not continuing to either of these studies. In either case, the final visit will be in 
person at the site. A subject’s maximum duration of participation is expected to be 
approximately 34 weeks: a screening period of up to 6 weeks, a treatment period of 12 weeks, 
and a safety follow-up period of 16 weeks (if applicable). It is expected that the study will be 
completed in approximately 3 years. 
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting. 
3.3 
Sites and Regions 
It is anticipated that the study will be conducted in at least 18 countries. Regions will include 
North America, Europe, the Middle East, and Africa, Latin America, and Asia-Pacific. 
Approximately 210 sites will be utilized. 
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4 
STUDY POPULATION 
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed. Subject eligibility 
should be reviewed and documented by an appropriately qualified member of the investigator’s 
study team before subjects are included in the study. 
4.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study. 
1. Subjects and/or their parent or legally authorized representative must have an understanding, 
ability, and willingness to fully comply with study procedures and restrictions. 
2. Subjects must be able to voluntarily provide written, signed, and dated (personally or via a 
legally authorized representative) informed consent and/or assent, as applicable, to 
participate in the study. 
3. Subjects must be between ≥16 and ≤80 years of age at the time of the signing of the informed 
consent/assent form. 
Note: Subjects <18 years of age must weigh ≥40 kg and must have body mass 
index ≥16.5 kg/m2. 
4. Subjects must have a documented diagnosis (radiologic or endoscopic with histology) of UC 
for ≥3 months before screening. The following must be available in each subject’s source 
documentation: 
• A biopsy report to confirm the histological diagnosis 
• A report documenting disease duration based upon prior colonoscopy. 
Note: If this documentation is not available at the time of screening, a colonoscopy with 
biopsy to confirm the diagnosis is required during the screening period. 
5. Subjects must be willing to undergo a flexible sigmoidoscopy or colonoscopy (if preferred), 
including biopsy sample collection, during screening after all other inclusion criteria have 
been met. 
6. Subjects must have moderate to severe active UC, defined as a total Mayo score of ≥6, 
including a centrally read endoscopic subscore ≥2, rectal bleeding subscore ≥1, and stool 
frequency subscore ≥1 at baseline (Visit 2). 
7. Subjects must have evidence of UC extending proximal to the rectum (ie, not limited to 
proctitis). 
8. Subjects must have had an inadequate response to, or lost response to, or had an intolerance 
to at least 1 conventional treatment such as mesalamine (5-ASA), glucocorticoids, 
immunosuppressants (AZA, 6-MP, or methotrexate [MTX]), or anti-TNF (see Appendix 4 
for guidance). 
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9. Subjects receiving any treatment(s) for UC described in Section 5.2.1 are eligible provided 
they have been, and are anticipated to be, on a stable dose for the designated period of time. 
10. Subjects are males or nonpregnant, nonlactating females who, if sexually active, agree to 
comply with the contraceptive requirements of the protocol, or females of nonchildbearing 
potential. Males and females of reproductive potential who are sexually active must agree to 
use appropriate contraception (ie, highly effective methods for female and medically 
appropriate methods for male study subjects) (as described in Section 4.4) for the duration of 
the study. 
4.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Subjects with indeterminate colitis, microscopic colitis, nonsteroidal anti-inflammatory 
drug-induced colitis, ischemic colitis, infectious colitis, or clinical/histologic findings 
suggestive of CD. 
2. Subjects with colonic dysplasia or neoplasia. (Subjects with prior history of adenomatous 
polyps will be eligible if the polyps have been completely removed.) 
3. Subjects with past medical history or presence of toxic megacolon. 
4. Subjects with colonic stricture, past medical history of colonic resection, a history of bowel 
surgery within 6 months before screening, or who are likely to require surgery for UC during 
the treatment period. 
5. Subjects at risk for colorectal cancer must have a colonoscopy (Eaden and Mayberry, 2002) 
performed during the screening period with results available within 10 days before the 
baseline visit (Visit 2), unless the subject has had a surveillance colonoscopy performed 
within 1 year prior to screening, and any adenomatous polyps found at that examination 
have been excised. Colonoscopy report and pathology report (if biopsies are obtained) from 
the colonoscopy performed during screening or in the prior year confirming no evidence of 
dysplasia and colon cancer must be available in the source documents. 
Subjects at risk for colorectal cancer include, but are not limited to: 
• Subjects with extensive colitis for ≥8 years or disease limited to left side of colon 
(ie, distal to splenic flexure) for ≥10 years before screening, regardless of age 
• Subjects ≥50 years of age at the time of signing of the informed consent form. 
6. Subjects have had prior treatment with ontamalimab (formerly PF-00547659; SHP647). 
7. Subjects with known or suspected intolerance or hypersensitivity to the investigational 
product(s), closely related compounds, or any of the stated ingredients. 
8. Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2). 
9. Subjects have received any biologic with immunomodulatory properties (other than 
anti-TNFs) within 90 days before baseline (Visit 2). 
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10. Subjects have received any nonbiologic treatment with immunomodulatory properties (other 
than their current background UC treatment) within 30 days before baseline (Visit 2). 
11. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, 
vedolizumab, efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion 
molecule). 
12. Subjects have received parenteral or rectal glucocorticoids, or rectal 5-ASA, within 14 days 
before screening endoscopic procedure. 
13. Subjects have received leukocyte apheresis or selective lymphocyte, monocyte, or 
granulocyte apheresis or plasma exchange within 30 days before baseline (Visit 2). 
14. Subjects have participated in other investigational studies within either 30 days or 
5 half-lives of investigational product used in the study (whichever is longer) before baseline 
(Visit 2). 
15. Subjects have received a live (attenuated) vaccine within 30 days before the baseline visit 
(Visit 2). 
16. Subjects with active enteric infections (positive stool culture and sensitivity), Clostridium 
difficile infection or pseudomembranous colitis (subjects with C. difficile infection at 
screening may be allowed re-test after treatment), evidence of active cytomegalovirus 
infection or Listeria monocytogenes, known active invasive fungal infections such as 
histoplasmosis or parasitic infections, clinically significant underlying disease that could 
predispose the subjects to infections, or a history of serious infection (requiring parenteral 
antibiotic and/or hospitalization) within 4 weeks before the baseline visit (Visit 2). 
17. Subjects with abnormal chest x-ray findings at screening (Visit 1), such as presence of active 
tuberculosis (TB), general infections, heart failure, or malignancy. (A chest x-ray performed 
up to 12 weeks before study entry [screening, Visit 1] may be used if available; 
documentation of the official reading must be located and available in the source 
documentation.) 
18. Subjects with evidence of active or latent infection with Mycobacterium tuberculosis (TB) 
or subjects with this history who have not completed a generally accepted full course of 
treatment before randomization are excluded. All other subjects must have either the 
Mantoux (purified protein derivative [PPD]) tuberculin skin test or interferon gamma release 
assay (IGRA) performed. 
Subjects who have no history of previously diagnosed active or latent TB are excluded if 
they have a positive Mantoux (PPD) tuberculin skin test (ie ≥5 mm induration) or a positive 
IGRA (the latter to be tested at the site’s local laboratory) during screening or within 
12 weeks before screening. If IGRA test cannot be performed locally, a central laboratory 
may be used, with prior agreement from the sponsor. 
• An IGRA is strongly recommended for subjects with a prior Bacillus Calmette-Guérin 
vaccination, but may be used for any subject. Documentation of IGRA product used and 
the test result must be in the subject's source documentation if performed locally. 
Acceptable IGRA products include QuantiFERON TB Gold Plus In-Tube Test. 
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• If the results of the IGRA are indeterminate, the test may be repeated, and if a negative 
result is obtained, enrollment may proceed. In subjects with no history of treated active or 
latent TB, a positive test on repeat will exclude the subject. Subjects with a history of 
active or latent TB infection must follow instructions for “Subjects with a prior diagnosis 
of active or latent TB are excluded unless both of the following criteria are met” in this 
criterion. 
• Subjects with repeat indeterminate IGRA results, with no prior TB history, may be 
enrolled after consultation with a pulmonary or infectious disease specialist who 
determines low risk of infection (ie, subject would be acceptable for immunosuppressant 
[eg, anti-TNF] treatment without additional action). This consultation must be included in 
source documentation. 
Results from a chest x-ray, taken within the 12 weeks before or during screening (Visit 1) 
must show no abnormalities suggestive of active TB infection as determined by a qualified 
medical specialist. 
Subjects with a prior diagnosis of active or latent TB are excluded unless both of the 
following criteria are met: 
• The subject has previously received an adequate course of treatment for either latent 
(eg, 9 months of isoniazid or an acceptable alternative regimen, in a locale where rates of 
primary multidrug TB resistance are <5%. Subjects from regions with higher rates of 
primary multidrug TB resistance are excluded) or active (acceptable multidrug regimen) 
TB infection. Evidence of diagnosis and treatment must be included in source 
documentation. Consultation with a pulmonary or infectious disease specialist to confirm 
adequate treatment (ie, subject would be acceptable for immunosuppressant [eg, 
anti-TNF] treatment without additional action) must be performed during the screening 
period. The consultation report must be included in source documentation prior to 
enrollment. 
• A chest x-ray performed within 12 weeks before or during screening (Visit 1) indicates 
no evidence of active or recurrent disease, and documentation of interpretation by a 
qualified medical specialist must be included in source documentation. 
19. Subjects with a pre-existing demyelinating disorder such as multiple sclerosis or new onset 
seizures, unexplained sensory motor, or cognitive behavioral, neurological deficits, or 
significant abnormalities noted during screening. 
20. Subjects with any unexplained symptoms suggestive of PML based on the targeted 
neurological assessment during the screening period (see Section 7.2.3.3). 
21. Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed. 
22. Subjects with a significant concurrent medical condition at the time of screening (Visit 1) or 
baseline (Visit 2), including, but not limited to, the following: 
• Any major illness/condition or evidence of an unstable clinical condition (eg, renal, 
hepatic, hematologic, GI [except disease under study], endocrine, cardiovascular, 
pulmonary, immunologic [eg, Felty’s syndrome], or local active infection/infectious 
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illness) that, in the investigator’s judgment will substantially increase the risk to the 
subject if he or she participates in the study 
• Cancer or history of cancer or lymphoproliferative disease within the previous 5 years 
(other than resected cutaneous basal cell carcinoma, squamous cell carcinoma, or 
carcinoma in situ of the uterine cervix that has been treated with no evidence of 
recurrence) 
• Presence of acute coronary syndrome (eg, acute myocardial infarction, unstable angina 
pectoris) within 24 weeks before screening (Visit 1) 
• History of significant cerebrovascular disease within 24 weeks before screening (Visit 1). 
23. Subjects who have had significant trauma or major surgery within 4 weeks before the 
screening visit (Visit 1), or with any major elective surgery scheduled to occur during the 
study. 
24. Subjects with evidence of cirrhosis with or without decompensation.  
25. Subjects with primary sclerosing cholangitis. 
26. Subjects with evidence of positive hepatitis B surface antigen (HBsAg) or hepatitis B core 
antibody (HBcAb). Note: if a subject tests negative for HBsAg, but positive for HBcAb, the 
subject would be considered eligible if no presence of hepatitis B virus (HBV) DNA is 
confirmed by HBV DNA polymerase chain reaction (PCR) reflex testing performed in the 
central laboratory. 
27. Subjects with chronic hepatitis C virus (HCV) (positive HCV antibody [HCVAb] and 
HCV RNA). Note: Subjects who are HCVAb positive without evidence of HCV RNA may 
be considered eligible (spontaneous viral clearance or previously treated and cured [defined 
as no evidence of HCV RNA at least 12 weeks prior to baseline]). 
28. Subjects with any of the following abnormalities in hematology and/or serum chemistry 
profiles during screening. Note: Screening laboratory tests, if the results are considered by 
the investigator to be transient and inconsistent with the subject’s clinical condition, may be 
repeated once during the screening period for confirmation. Results must be reviewed for 
eligibility prior to the screening endoscopy procedure. 
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≥3.0 × the 
upper limit of normal (ULN) 
• Total bilirubin level ≥1.5 × ULN or >2.0 × ULN if the subject has a known documented 
history of Gilbert’s syndrome 
• Hemoglobin level ≤80 g/L (8.0 g/dL) 
• Platelet count ≤100 × 109/L (100,000 cells/mm3) or ≥1000 × 109/L 
(1,000,000 cells/mm3)* 
• White blood cell count ≤3.5 × 109/L (3500 cells/mm3) 
• Absolute neutrophil count <2 × 109/L (2000 cells/mm3) 
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• Serum creatinine level >1.5 × ULN or estimated glomerular filtration rate 
<30 mL/min/1.73m2 based on the abbreviated Modification of Diet in Renal Disease 
Study Equation. 
*Note: If platelet count is <150,000 cells/mm3, a further evaluation should be performed 
to rule out cirrhosis, unless another etiology has already been identified. 
29. Subjects with known human immunodeficiency virus (HIV) infection based on documented 
history, with positive serological test, or positive HIV serologic test at screening, tested at 
the site's local laboratory in accordance with country requirements or tested at the central 
laboratory. Note: A documented negative HIV test within 6 months of screening is 
acceptable and does not need to be repeated. 
30. Subjects who have, or who have a history of (within 2 years before screening [Visit 1]), 
serious psychiatric disease, alcohol dependency, or substance/drug abuse or dependency of 
any kind, including abuse of medical marijuana (cannabis). 
31. Subjects with any other severe acute or chronic medical or psychiatric condition or 
laboratory or ECG abnormality that may increase the risk associated with study participation 
or investigational product administration or may interfere with the interpretation of study 
results and, in the judgment of the investigator, would make the subject inappropriate for 
entry into this study. 
32. Female subjects who are planning to become pregnant during the study period. 
33. Subjects who do not agree to postpone donation of any organ or tissue, including male 
subjects who are planning to bank or donate sperm, and female subjects who are planning to 
harvest or donate eggs, for the duration of the study and through 16 weeks after last dose of 
investigational product. 
34. Subjects who are investigational site staff members or relatives of those site staff members 
or subjects who are Shire employees directly involved in the conduct of the study. 
4.3 
Restrictions 
Smoking can have an influence on the severity of UC disease symptoms. Subjects should inform 
the investigator of any changes to their smoking habits during the study; however, these data will 
not be captured in the electronic case report form (eCRF). Use of nicotine patches should be 
recorded as concomitant medication (see Section 5.2). 
For the purposes of this protocol, dietary supplements (such as vitamins, minerals, purified food 
substances, and herbals with pharmaceutical properties) are considered to be concomitant 
medications (see Section 5.2). 
4.4 
Reproductive Potential 
The potential effects of ontamalimab on embryofetal or postnatal development have not been 
assessed in humans. Preliminary results from an enhanced pre- and postnatal development 
toxicity study of ontamalimab in nonhuman primates indicated that, at the dose levels tested 
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(30 and 60 mg/kg), infant losses were increased in ontamalimab-exposed animals when 
compared both to control animals in the study and to the historical control animal data from the 
testing facility. The relevance of this finding to humans is unknown but cannot be excluded. 
Based on the exposure in the Phase 2 clinical study A7281009 (area under the concentration-time 
curve [AUC] from 0 to 672 hours [AUC0-672h] at 6140 µg∙h/mL following repeated SC 
administration of 75 mg SHP647 Q4W), maternal exposure (AUC) in cynomolgus monkeys 
within a similar duration at 30 and 60 mg/kg once every 10 days is approximately 77 times and 
172 times the clinical exposure, respectively. 
To minimize the risk of unintentional exposure of the embryo or fetus in the clinical study, all 
sexually active male and female subjects who, in the opinion of the investigator, are biologically 
capable of having children and with their partners are at risk of pregnancy, must agree to use an 
appropriate form of contraception (ie, highly effective methods for female and medically 
appropriate methods for male study subjects), in accordance with the package 
instructions/leaflet, for the duration of the active treatment period and for at least 16 weeks after 
the last dose of investigational product. 
True abstinence is considered to be a highly effective contraception (ie, a method that results in a 
failure rate of <1% per year) when it is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
declaration of abstinence for the duration of exposure to investigational product, and withdrawal 
are not appropriate methods of contraception. 
During the screening visit, the investigator or designee in consultation with the subject will 
confirm the subject’s childbearing potential status. For subjects of childbearing potential, it must 
be confirmed and documented that the subject has selected the most appropriate method of 
contraception (ie, highly effective methods for female and medically appropriate methods for 
male study subjects) from the permitted list of contraception methods. Subjects must affirm the 
consistent and correct use of at least 1 of these selected methods. Regular contraception check 
discussions will take place at the time points specified in Table 1 (ie, at each site visit) and will 
be documented. In addition, the subject must be instructed to call the site immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected. 
4.4.1 
Contraceptive Methods for Female Study Subjects 
Sexually active females of childbearing potential must already be using an established highly 
effective form of contraception, and must be advised to use appropriate contraceptives 
throughout the study period and for 16 weeks following the last dose of investigational product. 
If hormonal contraceptives are used they should be administered according to the package insert. 
Contraception methods with low user dependency should preferably be used, in particular when 
contraception is introduced as a result of participation in the clinical study. The following highly 
effective contraceptive methods are considered to be methods with low user dependency: 
• Intrauterine device  
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
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• Male sterilization/vasectomized partner 
• Implantable progesterone-only hormonal contraception associated with inhibition of 
ovulation. 
Female subjects should be in one of the following categories: 
• Postmenopausal (12 consecutive months of spontaneous amenorrhea and ≥51 years of 
age); postmenopausal status should be confirmed by follicle-stimulating hormone (FSH) 
testing. 
• Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks poststerilization or has medically confirmed ovarian failure. 
• Females of childbearing potential with a negative serum pregnancy test result at 
screening and a negative urine pregnancy test result at baseline (Visit 2). Females of 
childbearing potential must agree to practice true abstinence (refrain from sexual activity 
that could result in pregnancy) or agree to use appropriate methods of highly effective 
contraception. 
Highly effective contraception (ie, methods that result in a failure rate of <1% per year when 
used consistently and correctly) are: 
• 
Combined (estrogen- and progestogen-containing) hormonal contraceptives associated 
with inhibition of ovulation (oral, intravaginal, transdermal) stabilized for at least 30 days 
before the screening visit (Visit 1) 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation plus a 
barrier method 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Male sterilization/vasectomized partner with documented absence of sperm in the 
postvasectomy ejaculate 
• 
True abstinence (see Section 4.4). 
4.4.2 
Contraceptive Methods for Male Study Subjects 
Contraception is required for all sexually active male subjects, who with their female sexual 
partners, must agree to use one of the following appropriate methods of contraception throughout 
the study period and for 16 weeks following the last dose of investigational product. 
Appropriate methods of contraception for male subjects are: 
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• 
Male condom with spermicide; however, if spermicide is not available in the country, 
additional contraception (ie, one of those listed below) must be used in addition to a male 
condom 
• 
Male sterilization with documented absence of sperm in the postvasectomy ejaculate. 
Appropriate methods for female sexual partners of male subjects are (unless the female sexual 
partner is sterile [surgically or documented nonsurgical sterility]): 
• 
Use of a highly effective method of contraception listed in Section 4.4.1 OR an 
acceptable method of contraception (failure rate of >1% per year)  
o Female condom with spermicide (use by female sexual partner); however, if 
spermicide is not available in the country, additional contraception (ie, one of 
those listed below) must be used in addition to a female condom 
o Intrauterine device with spermicide 
o Contraceptive sponge with spermicide 
o Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with 
spermicide, or a cervical cap with spermicide).  
4.5 
Withdrawal of Subjects 
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 12/early termination (ET; Visit 6) are to be performed. All subjects who discontinue 
treatment with investigational product should also undergo the protocol-specified 16-week safety 
follow-up period. In the event that subjects are unable to attend in person for the follow-up visits, 
all efforts should be made to collect information on AEs and concomitant medications. 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded. The 
reason for termination and date of stopping investigational product must be recorded. 
Subjects who discontinue will not be replaced. 
4.5.1 
Subject Withdrawal Criteria 
Additional reasons a subject may be withdrawn from study treatment include but are not limited 
to: 
• Adverse events 
• Serious AEs 
• Pregnancy 
• Protocol deviations 
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• Failure to return for visits. 
A subject should be withdrawn from study treatment: 
• If a new therapy is initiated for UC, or 
• If a subject undergoes surgery for UC. 
Subjects who withdraw from study treatment due to an increase in disease symptoms may see 
nonstudy-related physicians for treatment, and may receive treatments prohibited during the 
treatment periods of this study. 
If a subject withdraws their consent, no further evaluation should be performed, and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
4.5.2 
Reasons for Withdrawal 
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record. 
Reasons for discontinuation include but are not limited to: 
• Adverse event 
• Protocol deviation 
• Withdrawal by subject 
• Lost to follow-up 
• Lack of efficacy 
• Other (if “other” is selected, the investigator must specify the reason) 
• Death 
• Physician decision 
• Pregnancy 
• Screen failure 
• Site terminated by sponsor. 
4.5.3 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point before the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and that they return their electronic diary (e-diary). 
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5 
PRIOR AND CONCOMITANT TREATMENT 
5.1 
Prior Treatment 
Prior treatment includes all treatment (including but not limited to herbal remedies and vitamins) 
received within 30 days (or PK equivalent of 5 half-lives, whichever is longer) of the first dose 
of investigational product. Use of biologics for indications other than UC during the 90 days 
before screening must also be recorded. 
Prior and concomitant UC-specific treatments from the previous 10 years will be recorded. The 
subject’s entire history of biologic UC-specific treatments will be recorded. 
Subjects must have had an inadequate response to, or lost response to, or had an intolerance to at 
least 1 conventional treatment such as sulfasalazine or 5-ASA, glucocorticoids, 
immunosuppressants (AZA, 6-MP, or MTX), or anti-TNF agents. Please see Appendix 4 for 
guidance on defining prior treatment failure and intolerance to prior treatment for UC. 
5.2 
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the safety follow-up period, inclusive. 
5.2.1 
Permitted Treatment 
Subjects must remain on stable doses of permitted UC treatments until completion of the 
Week 12 visit, unless decreases are required because of AEs. Stable doses of the following 
treatments for UC are permitted as concomitant medication: 
• Oral 5-ASA or sulfasalazine, providing that the dose is stable for at least 2 weeks before 
baseline (Visit 2) 
• Immunosuppressants (AZA, 6-MP, or MTX), providing that the dose is stable for at least 
8 weeks before baseline (Visit 2) 
• Oral glucocorticoids (prednisone or equivalent [see Appendix 3] up to a maximum of 
20 mg/day or oral budesonide up to a maximum of 9 mg/day or oral beclomethasone up 
to a maximum of 5 mg/day), providing that the dose is stable for at least 2 weeks before 
screening endoscopic procedure. 
Note: Rectal 5-ASA and parenteral or rectal glucocorticoids are prohibited from within 14 days 
before screening endoscopic procedure. 
Subjects using medicinal marijuana (cannabis) under a physician’s prescription, and who obtain 
the product from a licensed pharmacy or provider, should continue to use it under the same 
regimen for the duration of the study, unless otherwise instructed by the investigator or treating 
physician. Such subjects must be using the product, in a stable regimen, for at least 3 months 
before screening. 
Routine nonlive vaccinations are allowed during the study. 
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Dietary and herbal supplements and probiotics are allowed in the study, provided they are being 
taken at stable doses at the time of the baseline visit (Visit 2) and for the duration of the study. 
They should be recorded as concomitant medications. 
Use of nicotine patches should be recorded as concomitant medication. 
5.2.2 
Prohibited Treatment 
Table 2 details the minimum required number of days before baseline (Visit 2) for common prior 
treatments that are excluded medications for this study. 
Table 2 
Common Excluded Treatments 
 
Permanently 
Excluded 
Minimum Required Number of Days Before 
Baseline (Visit 2) 
Treatment 
 
14 
30 
60 
90 
Ontamalimab (PF-00547659; SHP647) in a 
previous study 
X 
 
 
 
 
Anti-integrin or antiadhesion molecule 
treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab) 
X 
 
 
 
 
Parenteral and rectal glucocorticoids 
 
Xa 
 
 
 
Rectal 5-ASA 
 
Xa 
 
 
 
Investigational products 
 
 
Xb 
 
 
Live (attenuated) vaccine 
 
 
X 
 
 
Nonbiologics with immunomodulatory 
properties (other than their current 
background UC treatment) 
 
 
X 
 
 
Anti-TNF treatment 
 
 
 
X 
 
Leukocyte apheresis or selective lymphocyte, 
monocyte, or granulocyte apheresis or plasma 
exchange 
 
 
X 
 
 
Biologics with immunomodulatory properties 
(other than anti-TNFs) including biosimilars 
 
 
 
 
X 
5-ASA=5-aminosalicylate; TNF=tumor necrosis factor; UC=ulcerative colitis 
a The minimum required number of days before baseline (Visit 2) for rectal 5-ASA and parenteral or rectal glucocorticoids is 
defined as 14 days before screening endoscopic procedure (see Section 4.2, exclusion criterion 12). 
b Or 5 half-lives if longer. 
Treatments not listed in Table 2 may be considered allowable; see Section 5.2.1 for further 
details. 
No new nonpharmacological therapies that might affect bowel habit or GI function should be 
started during the study. 
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5.2.3 
Rescue Therapy 
Subjects must maintain their stable dose of background UC treatment, unless dose reduction or 
discontinuation is required due to associated AEs. If a subject requires initiation of a new therapy 
or increase in glucocorticoids for UC above the SHP647-301 or SHP647-302 baseline, the 
subject should be withdrawn from study treatment and enter the safety follow-up period, and 
appropriate treatment should be given at the discretion of the investigator. 
Subjects who enter the safety follow-up period will no longer need to abstain from the 
medications that were prohibited during the baseline and treatment periods. High-dose 
glucocorticoids and other UC treatments will be allowed. Biologics or nonbiologic 
immunosuppressants should not be initiated during the safety follow-up period without prior 
discussion with the sponsor study physician or designee due to the long half-life of ontamalimab. 
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6 
INVESTIGATIONAL PRODUCT 
6.1 
Identity of Investigational Product 
The test product is ontamalimab, which will be provided as a sterile aqueous buffered solution 
for SC administration in a glass PFS with a fixed needle. Each PFS contains 1 mL of 
ontamalimab solution for injection at an appropriate concentration to provide the intended dose 
of drug (25 or 75 mg). Additional information is provided in the current ontamalimab IB. 
The reference product is placebo, which will be provided in a PFS with a fixed needle containing 
1 mL of placebo solution for SC administration. The placebo solution will contain the same 
sterile aqueous buffered solution as the test product but will not contain ontamalimab. 
6.1.1 
Blinding the Treatment Assignment 
The placebo syringes and solution will match the ontamalimab syringes in appearance. The fill 
volume for all syringes will be the same. 
6.2 
Administration of Investigational Product 
6.2.1 
Interactive Response Technology for Investigational Product Management 
An interactive response technology (IRT) system will be used for screening and enrolling 
subjects, recording subject visits, randomization, investigational product supply dispensation and 
management, inventory management and supply ordering, investigational product expiration 
tracking and management, and emergency unblinding. Please refer to the Study Manual for 
additional details regarding the IRT system. 
6.2.2 
Allocation of Subjects to Treatment 
This is a double-blind, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule. 
The total Mayo score will be calculated at baseline (Visit 2) before randomization. Endoscopic 
subscore based on the central reader’s assessment will be used to determine eligibility. Subjects 
with a total Mayo score of ≥6, including a centrally read endoscopic subscore ≥2, rectal bleeding 
subscore ≥1, and stool frequency subscore ≥1, and who fulfill all other eligibility criteria, will be 
randomized in a ratio of 2:2:1 via a computer-generated randomization schedule to receive SC 
injections of 25 mg ontamalimab, 75 mg ontamalimab, or placebo, respectively. The 
randomization will be performed centrally and stratified by status of prior anti-TNF therapy 
(2 strata: naïve versus experienced) and glucocorticoid use at baseline (2 strata: on 
glucocorticoids at baseline versus not on glucocorticoids at baseline). 
To ensure that the allocation of subjects with prior anti-TNF therapy exposure is similar to that 
observed in Study A7281009, the percentage of subjects with prior anti-TNF therapy exposure 
will be capped at 60% of the sample population. Additionally, in Japan only, enrollment of 
Japanese subjects with prior anti-TNF therapy exposure will be capped at 60%, to ensure 
comparability to the rest of the global study population. There will be no cap on the number of 
anti-TNF naïve subjects randomized. 
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Subject numbers are assigned to all eligible subjects as they consent to take part in the study. 
Within each site (numbered uniquely within a protocol), the subject number will be assigned to 
subjects according to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment will be 
automatically assigned by the IRT system. 
Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment assignment as 
dictated by the study. In these cases, the same investigational product packing identification 
number may not be assigned to more than 1 subject. 
6.2.3 
Dosing 
Investigational product (ontamalimab or placebo) will be administered subcutaneously by 
qualified site personnel Q4W (Weeks 0, 4, and 8). See Section 7.2 for the timing of dosing 
relative to other procedures. 
Investigational product should be administered in the anterolateral right or left thigh. If there are 
clinical reasons why the investigational product cannot be administered in the thigh, the 
investigational product may be administered in the deltoid area or abdomen with appropriate 
documentation. The location of the investigational product administration will be recorded. 
After the first administration of investigational product, the subject must be observed by a 
member of the study staff for at least 30 minutes (the total duration should be determined at the 
discretion of the investigator). For subsequent administrations, observation of the subject is at the 
discretion of the investigator. Injection site and allergic reaction monitoring should be completed 
by a member of the study staff. 
Investigator-directed delays in dosing due to abnormal laboratory findings or AEs should be 
discussed with the medical monitor to determine whether the subject should continue with the 
treatment. Only those subjects who complete the full course of investigational product treatment 
in the induction studies (SHP647-301 or SHP647-302) will be eligible to continue in the 
maintenance study or LTS study. 
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational product is dispensed by qualified staff members. 
6.2.4 
Unblinding the Treatment Assignment 
Whenever possible, the investigator or subinvestigator should contact the Shire physician and/or 
assigned medical monitor before breaking the blind. It is understood that in an emergency 
situation it may not be possible to communicate with the study team before breaking the blind. 
The safety of the subject should be of primary concern. When the blinding code is broken the 
reasons must be fully documented. 
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In the event that the treatment assignment is broken, the date, the signature of the person 
who broke the code, and the reason for breaking the code are recorded on the IRT and the 
source documents. Upon breaking the blind, the subject is withdrawn from the study, but 
should be followed up for safety purposes. The IRT will notify the relevant personnel in the 
event of any code break. Code-break information is held by the pharmacist/designated person at 
the site. 
6.3 
Labeling, Packaging, Storage, and Handling 
6.3.1 
Labeling 
The sponsor will provide the investigator with packaged investigational product labeled in 
accordance with specific country regulatory requirements. All investigational product is labeled 
with a minimum of the following: protocol number, medication identification number, dosage 
form (including product name and quantity in pack), directions for use, storage conditions, 
expiry date (if applicable), batch number and/or packaging reference, the statements “For clinical 
trial use only” and/or “CAUTION: New Drug – Limited by Federal (or US) Law to 
Investigational Use”, and the sponsor’s name and address. 
Additional labels may be applied in order to meet local or institutional requirements, but must 
not: 
• Contradict the clinical study label 
• Obscure the clinical study label 
• Identify the study subject by name. 
Additional labels may not be added without the sponsor’s prior written agreement. 
6.3.2 
Packaging 
Investigational product is packaged in the following labeled containers: PFS with nominal fill 
volume of 1 mL. The PFS will be packaged in a labeled carton. 
Changes to sponsor-supplied packaging before dosing may not occur without prior written 
agreement by the sponsor. 
6.3.3 
Storage 
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or delegated member of the study team. The pharmacist or delegated 
team member will enter the unique subject identifier on the investigational product labels as they 
are distributed. 
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
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for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified minimum/maximum 
thermometer) would require manual resetting upon each recording. The sponsor must be notified 
immediately upon discovery of any excursion from the established range. Temperature 
excursions will require site investigation as to cause and remediation. The sponsor will determine 
the ultimate impact of excursions on the investigational product and will provide supportive 
documentation as necessary. Under no circumstances should the product be dispensed to subjects 
until the impact has been determined and the product is deemed appropriate for use by the 
sponsor. 
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room. 
6.3.4 
Special Handling 
The investigational product should be protected from light and should not be frozen. Do not 
shake. 
6.4 
Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section. 
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form. 
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying his/her treatment assignment. All administered 
investigational product will be documented in the subject’s source document and/or other 
investigational product record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer. 
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The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised. 
With the written agreement of the sponsor, at the end of the study all unused stock may be 
destroyed at the site or a local facility. In this case, destruction records identifying what was 
destroyed, when and how, must be obtained with copies provided to the sponsor. Destruction of 
investigational products must be in accordance with local, state, and national laws. 
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction. 
6.5 
Subject Compliance 
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, cartons) or at 
the individual count level for opened containers/packaging. The pharmacist or delegated team 
member will record details on the drug accountability form. 
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7 
STUDY PROCEDURES 
7.1 
Study Schedule 
The investigator may schedule visits (unscheduled visits) in addition to those listed on the 
schedule of activities (Table 1) in order to conduct evaluations or assessments required to protect 
the well-being of the subject. 
7.1.1 
Screening Period 
7.1.1.1 
Screening Visit (Visit 1) 
Subjects will be screened within 6 weeks before the baseline visit (Visit 2) to determine 
eligibility to participate in the study and to perform the other assessments and procedures 
specified in Table 1. Each subject or subject’s parent or legally authorized representative must 
participate in the informed consent process and provide written informed consent/assent before 
any assessments or procedures specified in the protocol are performed. Screening assessments 
may take place over more than 1 day (at least 2 visits will be necessary to complete the screening 
procedures, including endoscopy). 
A screen failure is a subject who has given informed consent or assent, as applicable (and whose 
parents or legally authorized representatives have given informed consent, as applicable), failed 
to meet the inclusion criteria and/or met at least 1 of the exclusion criteria, and has not been 
randomized or administered investigational product. 
A subject may be rescreened if their condition has changed and they may potentially be eligible. 
Subjects may be rescreened 1 time. Note: Screening laboratory tests, if considered by the 
investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated 
once during the screening period for confirmation. Results of repeated tests must be reviewed for 
eligibility prior to the screening endoscopy procedure. 
Flexible sigmoidoscopy or colonoscopy (if preferred) must be performed on all subjects after the 
majority of other eligibility criteria (eg, laboratory values) are met. Endoscopy must be 
performed during the screening period within 10 days before baseline (Visit 2), preferably within 
5 to 7 days before the baseline visit, to obtain the centrally read endoscopic subscore 
(see Section 7.2.2.1). Biopsy samples will be collected for histological evaluation using the 
Geboes Score classification and 
. Subjects at risk of colorectal 
cancer, as defined in exclusion criterion 5 (see Section 4.2), must have a colonoscopy performed 
at screening, unless the subject has had a surveillance colonoscopy performed within 1 year prior 
to screening, and any adenomatous polyps found at that examination have been excised. 
Colonoscopy report and pathology report (if biopsies are obtained) from the colonoscopy 
performed during screening or in the prior year confirming no presence of dysplasia and colon 
cancer must be available in the source documents. 
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If a subject has had the following procedures performed as a part of standard medical care within 
12 weeks before screening visit (Visit 1), these procedures do not need to be repeated as a part of 
screening: 
• Chest x-ray 
• Documented negative PPD test or IGRA for TB. 
7.1.1.2 
Baseline Visit (Visit 2; Week 0) 
The baseline visit will take place on Day 1 (Week 0). The assessments and procedures specified 
in Table 1 will be performed. 
After eligibility has been reconfirmed and all baseline procedures and assessments have been 
completed, each subject will be randomized to 1 of the 3 treatment groups as described in 
Section 6.2.2 and the first dose of investigational product will be administered. 
Results of the baseline laboratory tests are not required for investigational product administration 
but must be reviewed as soon as possible thereafter. 
7.1.2 
Treatment Period 
7.1.2.1 
Visit 3 (Week 2) 
Visit 3 is scheduled to take place on Day 14 ±3 days (Week 2). The assessments and procedures 
specified in Table 1 will be performed. 
7.1.2.2 
Visits 4 and 5 (Weeks 4 and 8) 
Visits 4 and 5 are scheduled to take place on Day 28 ±3 days (Week 4) and Day 56 ±3 days 
(Week 8), respectively. The assessments and procedures specified in Table 1 will be performed. 
7.1.2.3 
Final On-treatment Visits: Visit 6, Parts 1 and 2 
(Week 12/Early Termination) 
The Week 12/ET visit (Visit 6) consists of 2 parts. 
Part 1 of Visit 6 must be completed within 10 days (preferably, within 5 to 7 days) before Part 2; 
this will allow sufficient time for data from the centrally read endoscopy to be available at Part 2 
of the visit. The Week 12/ET assessments and procedures that will take place during Part 1 are 
specified in Table 1. 
Part 2 of Visit 6 will take place on Day 84 ±3 days. The Week 12/ET assessments and 
procedures that will take place during Part 2 are specified in Table 1. 
At Part 2 of Visit 6, after review of the Mayo score, health outcome assessments, and safety 
assessments, it will be determined whether the subject should enter the safety follow-up period 
of this study or enroll in the maintenance (SHP647-303) or LTS (SHP647-304) studies. Entry 
into the maintenance or LTS studies is dependent upon the subject’s response and whether the 
subject agrees to participate. 
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The Week 12 assessments and procedures will also form the ET assessments for any subjects 
who are withdrawn early or discontinued from the study. 
7.1.3 
Follow-up Period: Visits 7 and 8 (Weeks 20 and 28) 
Subjects who are withdrawn early from the study, or who do not enter either the maintenance or 
LTS studies, should enter the 16-week safety follow-up phase for safety monitoring.  
During the safety follow-up period, the Week 20 visit (Visit 7) will take place on 
Day 140 ±7 days or 8 weeks ±7 days after the subject’s last visit in the treatment period for 
subjects who are withdrawn early from the study. This visit will routinely be conducted by 
telephone; however, as an exception the visit can be performed as a study site visit if preferred. 
At the end of the safety follow-up period, there will be a visit at the site on Day 196 ±7 days, or 
16 weeks ±7 days after the subject’s last visit in the treatment period for subjects who are 
withdrawn early from the study, which will form the Week 28 visit (Visit 8). The assessments 
and procedures specified in Table 1 will be performed, including querying for SAEs, AEs, and 
concomitant medications and procedures. All AEs and SAEs that are not resolved at the time of 
this visit will be followed to closure (see Section 8.1). 
Subjects who are proceeding to the maintenance or LTS studies will not enter the safety 
follow-up period. 
7.1.4 
Additional Care of Subjects After the Study 
No aftercare is planned for this study. 
7.2 
Study Evaluations and Procedures 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside the control of the investigator, which may make it unfeasible to perform 
the tests and procedures. In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. 
When timing of procedures and assessments coincide, the following order should be followed: 
• Health outcome and patient-reported questionnaires 
• Vital signs and ECG 
• Laboratory sample collection 
• Endoscopy (generally performed at a separate visit; see Section 7.2.2.1). 
• Investigational product administration. 
Note: Blood and tissue samples may be stored for up to the duration allowed by local 
regulations, but for no longer than 25 years. 
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7.2.1 
Demographic and Other Baseline Characteristics 
Demographic characteristics will be recorded at the screening visit (Visit 1). 
Each subject’s stool frequency before symptoms of UC started or during remission will be 
recorded at the screening visit. The reference/normal stool frequency questions in Appendix 2 
will be asked and the responses documented. 
7.2.2 
Efficacy 
The primary efficacy endpoint is remission at the Week 12 visit. Remission is defined as a 
composite score of patient-reported symptoms using a daily e-diary and centrally read endoscopy 
as described in Section 9.8.1. 
7.2.2.1 
Endoscopy and Histology 
Endoscopy will be performed at the time points specified in Table 1 and will consist of either 
flexible sigmoidoscopy or colonoscopy (if preferred). 
If it is necessary, bowel preparation should be conducted as per local routine. The position of the 
endoscope will be based on the length of the instrument at various levels of insertion as well as 
the morphological features of the intestine as seen during endoscopy at baseline. The endoscopy 
report and any photographs and/or video recordings taken during the procedure per local custom 
should be filed in the subject’s medical record. 
During endoscopy, 2 biopsy samples will be collected from the most inflamed area of the 
sigmoid colon at screening and Week 12/ET. Endoscopy and biopsy procedures will be defined 
in an endoscopy instructions manual and/or reference card(s), on which all sites will be trained. 
Endoscopy results will be reviewed by a central reader. 
Biopsy samples will be centrally reviewed using the Geboes Score classification system and 
 (see Appendix 2) for the evaluation of histological disease 
severity in UC with higher numbers corresponding to more inflammation. The Geboes score will 
be used for the key secondary efficacy evaluation and 
 
. 
Subjects at risk for colorectal cancer (see exclusion criterion number 5) must have a colonoscopy 
performed during the screening period with results available within 10 days before the baseline 
visit (Visit 2), unless the subject has had a surveillance colonoscopy performed within 1 year 
prior to screening, and any adenomatous polyps found at that examination have been excised. 
Colonoscopy report and pathology report (if biopsies are obtained) from the colonoscopy 
performed during screening or in the prior year confirming no evidence of dysplasia and colon 
cancer must be available in the source documents. 
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7.2.2.2 
Mayo Score 
The Mayo score is a measure of UC disease activity. Mayo scores (total or partial) will be 
recorded at the time points specified in Table 1. 
The total Mayo score ranges from 0 to 12 points and consists of the following 4 subscores, each 
graded from 0 to 3 with higher scores indicating more severe disease (see Appendix 2): 
• Stool frequency (0-3) 
• Rectal bleeding (0-3) 
• Findings of endoscopy (0-3) 
• Physician global assessment (PGA; 0-3). 
The partial Mayo score consists of the Mayo score without the endoscopic subscores and ranges 
from 0 to 9 points. 
The composite score is a recommended measure consisting of the Mayo score without the PGA 
subscore and ranges from 0 to 9 points. The composite score will be used for the primary 
efficacy endpoint. 
Calculation of the total and partial Mayo scores and composite score requires a self-assessment 
by the subject for stool frequency and the amount of blood in the stool. These data on stool 
frequency and rectal bleeding will be captured in the patient-reported outcome (PRO)-UC daily 
e-diary (see Section 7.2.2.3). 
The Mayo stool frequency and rectal bleeding subscores will be calculated based on each 
subject’s daily e-diary data recorded over the most recent 3 days (consecutive or nonconsecutive) 
of the last 10 days prior to the visit excluding the following days: day of any bowel preparation, 
day of endoscopy, any days between day of bowel preparation and day of endoscopy, and the 
2 days after the day of endoscopy. 
The mucosal appearance during the sigmoidoscopic portion of the endoscopic examination will 
be assessed for the Mayo endoscopic subscore based on the scoring system provided in the 
protocol (see Appendix 2). The endoscopic appearance will be read by a central reader through 
video recorded during the procedure. Centrally read endoscopic subscores will be used for both 
eligibility and efficacy analyses. 
The PGA acknowledges the 3 other criteria: the subject’s recollection of abdominal discomfort 
and general sense of well-being and other observations (such as physical findings and the 
subject’s performance status). The endoscopic subscore and the PGA must be performed by a 
physician qualified to perform endoscopy, and it is recommended that the same physician 
performs all such assessments for a particular subject throughout the study. 
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7.2.2.3 
Patient-reported Outcome – Ulcerative Colitis Daily E-diary 
Patient-reported UC signs and symptom data will be collected using a daily e-diary starting 
during the screening period. Collection of the daily e-diary data must begin at least 10 days 
before the baseline visit (Visit 2). Subjects will enter data on UC signs and symptoms items 
using an electronic handheld device that will be provided to subjects at the start of the study. 
Compliance is assessed by site staff at each visit. The site staff will instruct the subject on the 
appropriate use of the e-diary, particularly when compliance is below 80% (eg, <23 out of 
28 e-diary entries) when compared with the previous visit. 
Subjects will be asked to record the following signs and symptom data, as experienced over the 
previous 24 hours, in the e-diary: 
• Stool frequency 
• Rectal bleeding severity and frequency 
• Diarrhea frequency 
• Urgency frequency 
• Abdominal pain worst severity. 
The full PRO-UC e-diary consists of 6 items. The first 2 items (stool frequency and rectal 
bleeding severity) will be used to determine the Mayo stool frequency and rectal bleeding 
subscores, which will be used to calculate the total and partial Mayo scores and the composite 
score. The PRO-UC e-diary is presented in Appendix 2. 
7.2.3 
Safety 
7.2.3.1 
Medical and Medication History 
Medical history will be documented at screening (Visit 1), including UC history, cardiac history, 
and smoking history. Prior and concomitant medications and procedures will also be 
documented. 
7.2.3.2 
Physical Examination (Including Height and Weight) 
Complete and targeted physical examinations will be performed at the time points specified in 
Table 1. Complete physical examination includes the review of the following body systems: 
general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; confrontational visual 
fields (eyes); breast (optional); abdomen; external genitalia (optional); extremities; neurologic 
function; back; and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin, heart, lungs, confrontational visual fields (eyes), abdomen, and 
examination of body systems where there are symptom complaints by the subject. 
Weight will be measured at the time points specified in Table 1. Height will be measured at 
screening (Visit 1) only. 
Changes after the screening visit that are deemed clinically significant in the opinion of the 
investigator will be recorded as an AE. 
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7.2.3.3 
Targeted Neurological Assessment 
Targeted neurological assessments to monitor the development of signs and/or symptoms of 
PML will be performed at the time points specified in Table 1. Subjects will be evaluated to 
reveal any potential abnormalities in the following neurological domains: vision, motor, tactile 
sensation, coordination/cerebellar function, speech, verbal comprehension, and 
cognition/behavior. 
If any abnormalities are indicated, subjects will be further evaluated to help clarify any potential 
abnormal responses. Focus will be placed on possible alternative etiology (eg, fracture or stroke). 
If additional evaluation reveals an unexplained new abnormality, neurologic examination(s), 
targeted to the abnormal domain, will be performed by an investigator or qualified personnel. 
Subjects with any unexplained positive neurological assessment item at screening should be 
excluded from enrollment in the study (exclusion criterion 20, Section 4.2). 
A step-wise approach for the proposed neurological assessment plan is provided in Table 3. 
Table 3 
Quarterly Neurological Assessments 
Domain 
Step 1: Interim Neurologic History 
and Targeted Neurological 
Examination 
Step 2: If Abnormal Response 
Vision 
Diplopia or visual/visual field loss 
Perform visual field assessment 
Motor 
Major motor weakness (eg, legs, arms) 
Test leg strength (hopping, foot tapping), 
finger tapping, pronator drift and bilateral 
muscle strength 
Tactile sensation 
Paresthesia, anesthesia in any domain 
(peripheral, central) 
Pinprick test 
Coordination/Cerebellar 
Clumsiness, difficulty with walking, 
writing, or fine motor skills, etc. 
Finger-nose, heel-shin, heel-toe walk, 
writing sample, draw a clock 
Speech 
Dysarthria, expressive aphasia 
Naming objects, repeat multipart phrase, 
observe for dysarthria or aphasia 
Verbal comprehension 
Agnosia, receptive aphasia 
Test to follow routine commands, 
eg, close eyes, touch finger to ear. 
Cognition/Behavior 
New onset of difficulties with memory or 
thinking, important changes in behavior 
Recall 3 objects over 1 minute, serial 7 s, 
proverbs. Changes in activities of daily 
living over prior 6 months 
 
Additionally, should there be any unexplained abnormal neurological findings, the subject is to 
be urgently referred to a neurologist. The sites will immediately inform the sponsor of any such 
occurrences. If the neurologist confirms the presence of PML, appropriate actions, including 
discontinuation of investigational product, will be taken. Suspected PML cases will be reviewed 
promptly by data monitoring committee (DMC) members with PML expertise and presented at 
the next scheduled DMC meeting(s). If PML is diagnosed, the treatment code will be unblinded 
and there will be an urgent meeting of the DMC. A flow diagram of the quarterly assessments 
and actions is presented in Figure 3. Any concerns from the DMC will be promptly 
communicated to the sponsor, investigator, and treating neurologist. 
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Figure 3 
Flow Diagram for Quarterly Neurological Assessments 
 
DMC=data monitoring committee; IND=investigational new drug; neuro=neurological; PML=progressive 
multifocal leukoencephalopathy 
It is important to note that assessments based on neurological evaluations are collected and 
evaluated in a different manner than observed or volunteered AEs. Given these differences, no 
attempt will be made to reconcile any apparent discrepancies between observed or volunteered 
AEs and data from neurological assessment collected from subjects. Investigators may determine 
if any finding on neurological testing constitutes an AE. Adverse event incidence rates will not 
be calculated from these neurological evaluation data but rather from the AE information 
recorded by the investigator. 
7.2.3.4 
Adverse Event Collection 
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent and/or assent is signed until the end 
of the defined follow-up period stated in Section 7.1.3. (See Section 8, Adverse and Serious 
Adverse Events Assessment.) 
7.2.3.5 
Vital Signs 
Vital signs will be measured at the time points specified in Table 1. Additional collection times 
or changes to collection times will be permitted, as necessary to ensure appropriate collection of 
safety data. Vital signs include blood pressure, pulse, respiratory rate, and temperature. Vital 
signs should be recorded before laboratory blood collection and endoscopic procedures are 
performed. 
Single measurements of sitting blood pressure will be recorded at each time point. Blood 
pressure should be determined by cuff with the subject’s arm supported at the level of the heart 
and recorded to the nearest mmHg using the same method, the same arm (preferably the 
dominant arm), and the same position throughout the study. 
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Respiratory rate will be measured with the subject in a comfortable position. The observer 
should hold the extremity of the subject as a distraction for the subject (ie, pretending he/she is 
taking the subject’s radial pulse) and count the respiration for 1 minute. 
Body temperature should be taken using a thermometer and reported in degrees Celsius or 
Fahrenheit.  
Any deviations from baseline (Visit 2) vital signs that are deemed clinically significant in the 
opinion of the investigator are to be recorded as an AE, unless documented in the subject’s 
medical history as a pre-existing medical condition. 
7.2.3.6 
Clinical Laboratory Evaluations 
All clinical laboratory assays will be performed according to the central laboratory’s 
normal procedures. Reference ranges are to be supplied by the central laboratory and will 
be used to assess the clinical laboratory data for clinical significance and out-of-range 
pathological changes. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or 
clinically significant. Abnormal clinical laboratory values that are unexpected or not explained 
by the subject’s clinical condition may, at the discretion of the investigator or sponsor, be 
repeated as soon as possible until confirmed, explained, or resolved. 
Screening laboratory tests, if considered by the investigator to be transient and inconsistent with 
the subject’s clinical condition, may be repeated once during the screening period for 
confirmation. The following clinical laboratory assessments will be performed at the time points 
specified in Table 1: 
Serum chemistry 
 
alkaline phosphatase  
AST 
ALT 
total bilirubin 
total protein 
albumin 
glucose  
blood urea nitrogen  
creatinine 
sodium  
potassium  
chloride  
calcium 
carbon dioxide 
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Hematology 
 
hemoglobin  
hematocrit  
mean corpuscular hemoglobin 
mean corpuscular hemoglobin concentration 
mean corpuscular volume 
erythrocyte (red blood cell) count 
leukocyte (white blood cell) count 
neutrophils 
lymphocytes 
monocytes 
eosinophils 
basophils 
platelet count 
Virology 
 
HBsAg 
HBcAb 
hepatitis B DNA if HBsAg is negative and 
HBcAb is positive 
HCVAb 
HCV RNA PCR if HCVAb is positive 
HIV 
Urinalysis 
 
glucose 
protein 
specific gravity 
pH 
nitrite 
bilirubin 
ketones 
hemoglobin 
urobilinogen 
leukocyte esterase 
Virology test results must be confirmed as negative before enrollment in the study; if a virology 
test result is positive, the subject will be excluded from entering the study. Results of the 
virology screen will be reviewed and verified by the study monitor, but will not be collected in 
the eCRF. 
Stool microbiology will be performed at the screening visit (Visit 1) or at any time a subject 
experiences an increase in GI symptoms (see Section 7.2.3.12). Diagnosis of C. difficile infection 
should be made using the central laboratory. If, for any reason, the central laboratory is not 
available, see Appendix 5 for guidance regarding diagnostic algorithms. 
A TB test (PPD or QuantiFERON TB Gold Plus) will be performed at the screening visit 
(Visit 1). A documented negative PPD test within 12 weeks before screening (Visit 1) is 
acceptable. The IGRA official reading and method or test must be located in the source 
documentation. 
A serum sample will be collected and banked for John Cunningham virus antibody testing. It 
may be analyzed if a subject shows neurologic symptoms suggestive of PML. 
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All laboratory assessments should be performed at central laboratories, with the exception of the 
following assessments: stool microbiology (local or central laboratory) and TB test (PPD or 
QuantiFERON TB Gold Plus) (refer to laboratory manual for details). 
7.2.3.7 
Pregnancy Test and Follicle-stimulating Hormone Test 
A beta–human chorionic gonadotropin (β–hCG) pregnancy test will be performed on all females 
of childbearing potential at the time points specified in Table 1 if pregnancy is suspected or on 
withdrawal of the subject from the study. A serum pregnancy test will be performed at the 
screening visit (Visit 1); all other pregnancy tests will be urine tests. 
Pregnancy tests are not required for females of nonchildbearing potential who have undergone 
hysterectomy or bilateral oophorectomy, have medically confirmed ovarian failure, or are 
medically confirmed postmenopausal (cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause; postmenopausal status should be 
confirmed by FSH testing in females who have had 12 consecutive months of spontaneous 
amenorrhea and are 51 years of age or older). 
7.2.3.8 
Electrocardiogram 
A 12-lead ECG will be recorded at the time points specified in Table 1. When timing of 
measurements coincide, ECGs should be performed before laboratory blood collection and 
endoscopic procedure. 
A central ECG reader will be used in this study. The eligibility of the subject is based on the 
assessment of the ECG by the investigator. If abnormal results are observed following 
assessment by the central reader, the investigator, in consultation with the appointed sponsor or 
contract research organization (CRO) medical monitor, reconfirms subject eligibility to continue. 
7.2.3.9 
Chest X-ray 
A chest x-ray will be performed during screening (Visit 1). If a subject has had a chest x-ray 
performed as a part of standard medical care within 12 weeks before screening (Visit 1), it does 
not need to be repeated as a part of screening. The official reading must be located in the 
subject’s source documentation. 
7.2.3.10 
Antidrug Antibodies 
Blood samples for measurement of antidrug antibodies (ADAs) and neutralizing antibodies 
(NAbs) will be collected at the time points specified in Table 1. Blood samples must be collected 
before the administration of investigational product at that visit. 
7.2.3.11 
Monitoring for Type I and Type III Immune Reactions 
Subjects will be educated on the signs and symptoms of hypersensitivity reactions and how to 
respond to them. In addition, subjects will be instructed to report hypersensitivity AEs to the 
investigator at the time of occurrence, and to seek immediate medical care if hypersensitivity 
develops. At each visit, the subject will be queried for adverse events of special interest (AESIs) 
related to hypersensitivity.  
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Subjects will be also instructed to report AEs such as serum-sickness, vasculitis, Arthus reaction, 
and severe injection-related reactions to the investigator, and to seek immediate medical care if 
these events are severe in intensity. 
Subjects who experience a hypersensitivity reaction or severe or serious injection-related 
reaction (eg, shortness of breath, wheezing, stridor, angioedema, life-threatening change in vital 
signs) should discontinue investigational product until the adjudication committee assesses the 
case and finalizes recommendation of permanent discontinuation or rechallenge with 
investigational product. 
Subjects who experience an AE suggestive of the presence of circulating immune complexes 
formation (eg, fever, rash [including hives], arthralgia, myalgia, vasculitis, Arthus reaction, 
general ill feeling, itching, and swollen lymph nodes) will have the related AEs reviewed by the 
adjudication committee and if the AEs are assessed as related to formation of circulating of 
immune complexes and not related to underlying disease, blood samples will be collected and 
stored at the central laboratory. Tests will be performed as confirmatory of presence of 
circulating immune complexes at the request of the adjudication committee. 
Further details of hypersensitivity reactions as AESIs are provided in Section 8.1.3.1. 
7.2.3.12 
Evaluation of Increased Gastrointestinal Symptoms 
When a subject experiences an increase in GI symptoms, which could be an exacerbation of 
disease, an infectious etiology must be evaluated including testing for C. difficile as described in 
Appendix 5. 
In each case, the appropriate AE (eg, infection, exacerbation) should be recorded in the subject’s 
source document. 
7.2.4 
Others 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.2.4.3 
Health-related Quality-of-Life Assessments 
Each subject will complete the HRQL assessments at the site during the visits specified in 
Table 1, using an electronic device. All health outcome and patient-reported questionnaires 
should be completed before any other assessments. The study site staff should check for 
completion of all PRO questionnaires. 
It is important to note that PRO assessments are collected and evaluated in a different manner 
than observed or volunteered AEs. Given these differences, no attempt will be made to reconcile 
any apparent discrepancies between observed or volunteered AEs and PRO data collected from 
subjects. Adverse event incidence rates will not be calculated from these solicited data but rather 
from the information recorded by the investigator. 
Inflammatory Bowel Disease Questionnaire 
The IBDQ is a psychometrically validated PRO instrument for measuring the disease-specific 
HRQL in subjects with inflammatory bowel disease (IBD), including UC. The IBDQ consists of 
32 items, which are grouped into 4 domains: bowel function, emotional status, systemic 
symptoms, and social function (Irvine et al., 1994). The 4 domains are scored as follows:  
• Bowel symptoms: 10 to 70 
• Systemic symptoms: 5 to 35 
• Emotional function: 12 to 84 
• Social function: 5 to 35. 
The total IBDQ score ranges from 32 to 224. For the total score and each domain, a higher score 
indicates better HRQL. A score of at least 170 corresponds to clinical remission and an increase 
of at least 16 points is considered to indicate a clinically meaningful improvement. 
The IBDQ is presented in Appendix 2. 
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Short Form-36 Health Survey, Acute Form 
The SF-36 is a generic quality-of-life instrument that has been widely used to assess HRQL of 
subjects. Generic instruments are used in general populations to assess a wide range of domains 
applicable to a variety of health states, conditions, and diseases. The SF-36 consists of 36 items 
that are aggregated into 8 multi-item scales (physical functioning, role – physical, bodily pain, 
general health, vitality, social functioning, role – emotional, and mental health), with scores 
ranging from 0 to 100 (Ware and Sherbourne, 1992). Higher scores indicate better HRQL. 
7.2.4.4 
Healthcare Resource Utilization Assessments 
Hospitalizations, inpatient days, and ED visits will be recorded at the time points specified in 
Table 1. Ulcerative colitis-related and other surgeries will be collected from subjects during the 
treatment period. 
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7.2.5 
Volume of Blood to Be Drawn from Each Subject 
Table 4 
Volume of Blood to Be Drawn from Each Subject 
Assessment 
Sample Volume (mL) 
Number of Samples 
Total Volume (mL) 
Hematology 
2 
6 
12 
Serum chemistry 
4 
6 
24 
HBsAg 
2 
1 
2 
HBcAb 
2 
1 
2 
HCVAb 
2 
1 
2 
HBV DNA 
6 
1 
6 
HIV 
2 
1 
2 
FSH 
2 
1 
2 
Serum β-hCGa 
2 
1 
2 
TB test (QuantiFERON TB Gold Plus 
or PPD) 
4 
1 
4 
JCV antibody banked sample 
3.5 
1 
3.5 
 
 
 
2 
3 
6 
 
5 
3 
15 
 
4 
3 
12 
 
5 
5 
25 
ADA and NAb sampling 
3 
6 
18 
Total mL 
137.5 
ADA=antidrug antibody; β-hCG=beta-human chorionic gonadotropin; 
; FSH=follicle-stimulating 
hormone; HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCVAb=hepatitis C 
virus antibody; HIV=human immunodeficiency virus; JCV=John Cunningham virus; 
 
; NAb=neutralizing antibody; PPD=purified protein derivative; TB=tuberculosis 
a β-hCG testing for female subjects only. 
b If a catheter is used, the first mL is to be discarded; then take 4 mL into appropriate tube for 
. A total of 
5 mL of blood drawn has been used in determination of sample volume. 
The amount of blood to be drawn for each assessment is an estimate. The amount of blood to be 
drawn may vary according to the instructions provided by the manufacturer or laboratory for an 
individual assessment; however, the total volume drawn over the course of the study should be 
approximately 137.5 mL. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments may be combined. 
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8 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Council for Harmonisation [ICH] Guidance E2A 1995). 
All AEs are collected from the time the informed consent and/or assent is signed until the end of 
the defined follow-up period stated in Section 7.1.3. This includes events occurring during the 
screening phase of the study, regardless of whether or not investigational product is 
administered. Where possible, a diagnosis rather than a list of symptoms should be recorded. If a 
diagnosis has not been made, then each symptom should be listed individually. All AEs should 
be captured in the subject’s source document. In addition to untoward AEs, unexpected benefits 
outside the investigational product indication should also be captured in the subject’s source 
document. 
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented. 
8.1.1 
Severity Categorization 
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia before 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded in the subject’s source document). 
The medical assessment of severity is determined by using the following definitions: 
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living. 
Moderate: 
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject. 
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Severe: 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
8.1.2 
Relationship Categorization 
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document. 
The following additional guidance may be helpful: 
Term 
Relationship Definition 
Related 
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident. 
Not Related 
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event. 
8.1.3 
Adverse Events of Special Interest 
Adverse events of special interest will be captured and monitored during this study. Investigators 
will report all AESIs to the sponsor, regardless of causality, using the same timelines as 
described for SAE reporting (see Section 8.2.2). The following describe the AESIs and the 
criteria for reporting AESIs. 
8.1.3.1 
Hypersensitivity 
Potential hypersensitivity, serum sickness, vasculitis, and Arthus reactions to ontamalimab will 
be regarded as AESIs. These events must be reported on Shire “Clinical Study SAE and 
Nonserious AE as Required by the Protocol Form” and within the time frame mandated for 
SAEs (see Section 8.2.2). 
It is well known that the administration of foreign proteins can cause immune responses 
including hypersensitivity reactions such as anaphylaxis and serum sickness. Other immune 
responses to foreign proteins include the development of ADAs and NAbs. 
Monoclonal antibodies have been used in human therapeutics since the 1980s. The first 
monoclonal antibody approved for human use (ORTHOCLONE OKT3®), was a murine protein 
which caused rapid production of NAbs. Since then, much effort has been expended to reduce 
the immunogenicity of these useful therapeutic proteins by reducing the extent of “foreignness” 
from chimeric antibodies such as infliximab, to humanized antibodies such as vedolizumab, and 
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finally to fully human antibodies such as adalimumab and ontamalimab (Isabwe et al., 2018) 
(see Figure 4). 
Figure 4 
Potential Immunogenicity of Therapeutic Monoclonal Antibodies 
 
Ontamalimab is a fully human antibody of the immunoglobulin G2 subclass. In Phase 1 and 
Phase 2 clinical trials of ontamalimab, in which over 700 subjects were treated for up to 3 years, 
there has been no case of anaphylaxis. There have been 2 reported cases of drug hypersensitivity: 
serum sickness attributed to concomitant administration of penicillin; and a reaction 
characterized by dyspnea, facial erythema, and chest pain with onset 2 days after administration 
of the fifth dose of ontamalimab. The latter event mimicked a reaction that the subject had 
previously experienced after 4 doses of infliximab. In addition, low titer activity has been 
observed in ADA assays, including pretreatment samples and placebo-treated subjects, and no 
subject has had a 2-fold or greater increase in ADA titer. Analysis of PK and clinical parameters 
has shown no difference between subjects whose ADA assays results are positive as compared 
with those whose are negative. 
Nonetheless, the possibility of a hypersensitivity reaction occurring after drug exposure cannot 
be fully ruled out. The reactions of concern are Type I (anaphylaxis) and Type III (immune 
complex) reactions. The clinical presentation of anaphylactic reactions is described in Table 5. 
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Table 5 
Clinical Criteria for Diagnosing Anaphylaxis (Type 1 Hypersensitivity) 
Anaphylaxis is highly likely when below criterion and at least any one of the following criteria a and b are 
fulfilled: 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, 
generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST 1 OF THE FOLLOWING: 
a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
b) Reduced BPa or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, 
incontinence) 
BP=blood pressure; PEF=peak expiratory flow 
a Low systolic BP for children is defined as less than 90 mmHg from 11 to 17 years. 
Source: Adapted from Sampson et al., 2006. 
Type III hypersensitivity responses, including those mediated by immune complexes and T-cells 
(delayed hypersensitivity responses in the older literature), are relatively rare with respect to 
therapeutic protein products and a high degree of clinical suspicion is necessary for the diagnosis 
(Center for Drug Evaluation and Research - Guidance for industry: Immunogenicity assessment 
for therapeutic protein products, 2014). Type III hypersensitivity reactions involve the formation 
of biologic/ADA immune complexes in the circulation which, when present in the correct 
stoichiometric ratio, become deposited in tissues. Once immune complexes are deposited, they 
can elicit complement activation and inflammation, leading to tissue damage. When immune 
complexes are deposited in tissues, they tend to localize in small postcapillary venules where 
there is loss of laminar blood flow, in sites of ultrafiltration where there is high pressure and 
fenestrated endothelium (eg, choroid plexus, ciliary body, synovium, and glomeruli), in sites of 
turbulent blood flow (eg, coronary artery branches off aorta, aortic bifurcations, and cardiac 
valve leaflets), and in renal glomerular endothelium. 
Signs and symptoms of immune complex deposition typically have onset 1 to 3 weeks after 
exposure (Warrington et al., 2018) usually improving in 7 to 10 days, with full recovery in 
2 to 4 weeks and may include fever, rash (including hives), arthralgia, myalgia, vasculitis, Arthus 
reaction, general ill feeling, itching, and swollen lymph nodes. Some of these findings, such as 
fever, rash, arthralgia, and myalgia are consistent with findings associated with IBD and may 
therefore be very difficult to assign to a particular etiology. When such a reaction is suspected, 
samples for laboratory assessment will be obtained and stored. Tests will be performed if the 
diagnosis is confirmed and requested by the adjudication committee. 
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8.1.4 
Outcome Categorization 
The outcome of AEs must be recorded during the course of the study in the eCRF. Outcomes are 
as follows: 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved With Sequelae  
• Recovering/Resolving 
• Unknown. 
8.1.5 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. 
8.1.6 
Clinical Laboratory and Other Safety Evaluations 
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration. 
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values. 
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE. 
8.1.7 
Pregnancy 
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3. 
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Global Drug Safety Department using 
the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
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Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. If 
the pregnancy outcome is a live birth, the vital status and clinical condition of the infant should 
be obtained and documented at 1 year postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire “Clinical Study Serious Adverse 
Event and Nonserious AE as Required by the Protocol Form”. Note: An elective abortion is not 
considered an SAE. 
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire “Clinical Study Serious Adverse Event and 
Nonserious AE as Required by the Protocol Form” as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine β-hCG 
test or ultrasound result will determine the pregnancy onset date. 
8.1.8 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE.  
The categories below are not mutually exclusive; the event can meet more than 1 category. 
• Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society 
• Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol) 
• Overdose – Intentional or unintentional administration of investigational product at a 
dose interval that is less than 2 weeks between doses 
• Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below. 
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
Medication errors should be collected/reported for all products under investigation. 
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The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error. 
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
There is no specific antidote for overdose with ontamalimab. Treatment should be symptomatic 
and supportive. 
8.1.9 
Unexpected Adverse Event 
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not consistent with 
the term, representation, or description used in the reference safety information (RSI). 
“Unexpected” also refers to the AEs that are mentioned in the IB as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation. 
The expectedness of AEs will be determined by the sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed, but 
not on the basis of what might be anticipated from the pharmacological properties of a product. 
8.1.10 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is defined as any suspected adverse 
reaction to study treatment (ie, including active comparators) that is both serious and unexpected. 
The event(s) must meet all of the following:  
• Suspected adverse reaction 
• Serious 
• Unexpected 
• Assessed as related to study treatment. 
8.2 
Serious Adverse Event Procedures 
8.2.1 
Reference Safety Information 
The reference for safety information for this study is Section 6.8 of the ontamalimab IB, which 
the sponsor has provided under separate cover to all investigators. 
8.2.2 
Reporting Procedures 
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the CRO/Shire medical monitor within 24 hours of the first 
awareness of the event. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors (see Section 8.1.8) unless they result in 
an SAE.  
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The investigator must complete, sign, and date the Shire “Clinical Study Serious Adverse Event 
and Nonserious AE as Required by the Protocol Form” and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested) and fax or email the form to the Shire Global 
Drug Safety Department. A copy of the Shire “Clinical Study Serious Adverse Event and 
Nonserious AE as Required by the Protocol Form” (and any applicable follow-up reports) must 
also be sent to the CRO/Shire medical monitor using the details specified in the emergency 
contact information section of the protocol. 
8.2.3 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 
• Results in death. 
• Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAE(s). 
• Results in persistent or significant disability/incapacity. 
• Is a congenital abnormality/birth defect. 
• Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an ED or at home; blood dyscrasias or convulsions that do not 
result in inpatient hospitalization; or the development of drug dependency or drug abuse. 
8.2.4 
Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be reported 
to the Shire Global Drug Safety Department and the CRO/Shire medical monitor within 24 hours 
of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event. 
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8.2.5 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate. 
8.2.6 
Fatal Outcome 
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The sponsor or the CRO is responsible for notifying the relevant regulatory authorities, 
US central institutional review boards (IRBs), and European Union (EU) central ethics 
committees (ECs) of related, unexpected SAEs (ie, SUSARs). 
In addition, the CRO is responsible for notifying active sites of all related, unexpected SAEs (ie, 
SUSARs) occurring during all interventional studies across the ontamalimab program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required. 
8.2.8 
Safety Monitoring for Potential Cases of Drug-induced Liver Injury 
The following safety monitoring and stopping criteria are provided for elevated hepatic blood 
tests based on normal and elevated baseline ALT and total bilirubin levels. 
Abnormal values in ALT concurrent with abnormal elevations in total bilirubin that meet the 
criteria outlined below in the absence of other causes of liver injury are considered potential 
cases of drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events. 
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The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities per Table 6 should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values. The measurement(s) 
should be reconfirmed with another blood draw preferably within 48 to 72 hours of the initial 
finding of potential concern. Please refer to laboratory manual for further instructions.  
Guidance for Dosing Interruption: Investigator-directed delays in dosing due to abnormal 
laboratory findings or AEs should be discussed with the medical monitor to determine whether 
the subject should continue with the treatment. Only those subjects who complete the full course 
of investigational product treatment in the induction studies (SHP647-301 or SHP647-302) will 
be eligible to continue in the maintenance study or LTS study. 
Table 6 
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin 
Treatment-emergent ALT  
Treatment-emergent 
total bilirubin  
Treatment-emergent 
symptoms 
Action 
Normal baseline  
ALT ≥5× ULN 
Elevated baselinea: 
ALT ≥3 × baseline  
or 
≥300 U/L (whichever occurs 
first) 
Normal 
 
Patients with Gilbert’s 
syndrome or hemolysis: 
No change in baseline 
TBL 
None 
Repeat ALT, AST, ALP, TBL, in 
2-5 days. 
Follow-up for symptoms. 
Initiate evaluation for other 
etiologies of abnormal liver tests.  
Testing for hepatitis A, B, and/or C 
infection may be warranted. Subjects 
who entered the study with HBcAb 
with or without HBsAb would need 
evaluation with HBV DNA to rule 
out HBV reactivation.c 
Normal baseline  
ALT ≥8× ULN 
Elevated baselinea: 
ALT ≥5 × baseline or  
≥500 U/L (whichever occurs 
first) 
 
Normal 
 
 
Patients with Gilbert’s 
syndrome or hemolysis: 
No change in baseline 
TBL 
None 
Interrupt investigational product.b 
Initiate close monitoring and workup 
for competing etiologies. 
Investigational product can be 
restarted only if another etiology is 
identified and liver enzymes return to 
baseline. 
Testing for hepatitis A, B, and/or C 
infection may be warranted. Subjects 
who entered the study with HBcAb 
with or without HBsAb would need 
evaluation with HBV DNA to rule 
out HBV reactivation.c 
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Table 6 
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin 
Treatment-emergent ALT  
Treatment-emergent 
total bilirubin  
Treatment-emergent 
symptoms 
Action 
Normal baseline  
ALT ≥3× ULN  
Elevated baselinea:  
ALT ≥2 × baseline or  
≥300 U/L (whichever occurs 
first) 
 
TBL≥2mg/dL increased 
over baseline 
or 
Patients with Gilbert’s 
syndrome of hemolysis: 
Doubling of baseline 
direct bilirubin  
None 
Interrupt investigational product.b 
Initiate close monitoring and workup 
for competing etiologies. 
Investigational product can be 
restarted only if another etiology is 
identified and liver enzymes return to 
baseline. 
Testing for hepatitis A, B, and/or C 
infection may be warranted. Subjects 
who entered the study with HBcAb 
with or without HBsAb would need 
evaluation with HBV DNA to rule 
out HBV reactivation.c 
Normal baseline 
ALT ≥5× ULN  
Elevated baselinea:  
ALT ≥2× baseline or  
≥300 U/L (whichever occurs 
first) 
  
Normal or elevated 
Severe fatigue, nausea, 
vomiting, right upper 
quadrant pain 
or 
Immunologic symptoms 
Rash Eosinophilia > 5% 
Interrupt investigational product.b 
Initiate close monitoring and workup 
for competing etiologies. 
Investigational product can be 
restarted only if another etiology is 
identified and liver enzymes return to 
baseline. 
Testing for hepatitis A, B, and/or C 
infection may be warranted. Subjects 
who entered the study with HBcAb 
with or without HBsAb would need 
evaluation with HBV DNA to rule 
out HBV reactivation.c 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; HBcAb=hepatitis B core antibody; 
HBsAb=hepatitis B surface antibody; HBV=hepatitis B virus; TBL=total bilirubin; ULN=upper limit of normal 
a Elevated baseline ALT defined as ALT ≥ 1.5 × ULN. 
b Confirmatory repeat liver-related blood tests should be performed within 2 to 3 days before the investigational product is 
interrupted. 
c If HBV DNA positive, antivirals would need to be started as soon as possible. 
Source: Adapted from Chalasani and Regev, 2016. 
 
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9 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1 
Data Collection 
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered in the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. It is expected that site personnel will complete the eCRF 
entry within approximately 3 business days of the subject’s visit. 
9.2 
Clinical Data Management 
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 
9.3 
Data Handling Considerations 
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational 
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process. These data will be handled in such a way that, before unblinding, 
any data that may unblind study team personnel will be presented as blinded information or 
otherwise will not be made available. If applicable, unblinded data may be made available to 
quality assurance representatives for the purposes of conducting independent drug audits. 
9.4 
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed. 
The SAP will be finalized before unblinding to preserve the integrity of the statistical analysis 
and study conclusions. 
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All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, 
Cary, NC, USA). 
Unless otherwise specified, summary tabulations will be presented by treatment group. All data 
listings will be sorted by treatment group, site, and subject number, and will include the subject’s 
age, sex, and race. 
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation, minimum, and maximum 
values will be presented. 
9.5 
Planned Interim Analysis, Adaptive Design, Data Monitoring Committee, and 
Hypersensitivity Adjudication Committee 
There is no planned interim analysis or adaptive design in this study. 
An external DMC will be established to review the overall safety of the study subjects on an 
ongoing basis. 
The DMC will be responsible for the ongoing monitoring of safety of subjects enrolled in the 
study according to the DMC charter. Recommendations made by the DMC to alter the conduct 
of the study or to amend the protocol will be forwarded to Shire for review and for a final 
decision. Shire or its designee will notify investigative sites and regulatory authorities as 
appropriate, of DMC recommendations (which may include summaries of aggregate analyses of 
endpoint events and of safety data that are not endpoints). 
Further details regarding the DMC can be found in the DMC charter, which will be available 
before the administration of investigational product to any subject. Analyses of the data for DMC 
review will be conducted according to the DMC charter and the DMC SAP. Because no formal 
hypothesis testing for safety assessments is planned, multiplicity concerns regarding repeated 
analyses are not applicable. 
An external hypersensitivity adjudication committee will be established to review data from 
subjects who experience a suspected Type I or Type III hypersensitivity reaction in order to 
confirm the nature and etiology of the reaction, to determine whether testing should be 
performed on stored blood samples, and to finalize recommendations of permanent 
discontinuation or rechallenge with investigational product. Further details regarding the 
adjudication committee can be found in the adjudication charter. 
9.6 
Sample Size Calculation and Power Considerations 
Graphical methods are used to control the global family-wise Type I error rate (FWER) at the 
.05 level (2-sided) for the comparisons of the 2 ontamalimab treatment groups with the placebo 
group. Alpha is initially split equally at the .025 level (2-sided) for each of the pairwise treatment 
comparisons for the primary endpoint. Therefore, the power analysis and sample size estimation 
were calculated based on the chi-square test of proportions using nQuery Advisor Version 7.0 
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(Statistical Solutions Ltd, Cork, Ireland) for an individual ontamalimab dose compared with 
placebo. 
Power calculations are made based on assuming a .025 (2-sided) significance level for each 
pairwise treatment comparison. Approximately 1346 subjects will be screened to randomize 
740 subjects (2:2:1 allocation ratio: 296 subjects in the 25 mg ontamalimab treatment group, 
296 subjects in the 75 mg ontamalimab treatment group, and 148 subjects in the placebo group) 
which would yield an approximately 90% power to detect individual pairwise treatment 
difference in the primary efficacy endpoint, remission at Week 12, of 11% (5% placebo 
versus 16% ontamalimab). Expected remission rates at Week 12 are based on observed rates 
from the A7281009 study and placebo remission rates from literature (Feagan et al., 2013; 
Sandborn et al., 2017). No adjustment for missing data is required in these sample size 
calculations as subjects with missing data for remission at Week 12 are imputed as failures and 
the above rates account for these subjects. 
With the sample size of 740 subjects, Table 7 provides the power for detecting a treatment 
difference between a ontamalimab treatment group and the placebo group for the key secondary 
endpoints. 
Table 7 
Power to Detect the Corresponding Treatment Effect for Key Secondary 
Endpoints 
Key Secondary Endpoint at Week 12 
SHP647 Premise 
Placebo Premise 
Power 
Endoscopic remission 
24% 
8% 
0.98 
Clinical remission 
30% 
16% 
0.85 
Clinical response by composite score 
50% 
35% 
0.78 
Mucosal healing 
15% 
5% 
0.84 
 
9.7 
Study Population 
The screened set will consist of all subjects who have signed an informed consent document. 
The randomized set will consist of all subjects in the screened set for whom a randomization 
number has been assigned. 
The safety set will consist of all subjects who have received at least 1 dose of investigational 
product. 
The full analysis set (FAS) will consist of all subjects in the randomized set who have received at 
least 1 dose of investigational product. 
The per-protocol (PP) set will consist of all subjects in the FAS who do not have predefined 
protocol deviations that may affect the primary efficacy endpoint.  
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The completer set will consist of all subjects in the FAS who have completed the final scheduled 
primary assessment for this study. 
 
 
 
9.8 
Efficacy Analyses 
Unless otherwise specified, all efficacy analyses will be based on the FAS and subjects will be 
analyzed according to their randomized treatment, regardless of the treatment they actually 
received. 
9.8.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is remission at the Week 12 visit. Remission is defined as a 
composite score of patient-reported symptoms using daily e-diary and centrally read endoscopy 
as follows: 
• stool frequency subscore of 0 or 1 with at least a 1-point change from baseline 
AND 
• rectal bleeding subscore of 0 
AND 
• endoscopic subscore of 0 or 1 (modified, excludes friability). 
The primary efficacy endpoint will be compared for each active treatment group (25 mg or 
75 mg ontamalimab) to the placebo group using a Cochran-Mantel Haenszel (CMH) chi-square 
test stratified by status of prior anti-TNF treatment and glucocorticoid use at baseline (Visit 2). 
Subjects with missing remission data at the Week 12 visit will be considered failures and 
counted as nonresponders. The endoscopy score will be based on centrally read results. 
The primary endpoint will be tested by the following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
Where δ is the common treatment difference across strata, j=1 to m. The common treatment 
difference is a weighted average of the stratum-specific treatment differences. 
The estimate of the common treatment difference along with the corresponding stratified 
Newcombe 95% confidence interval (CI) using the method of Yan and Su (2010) and CMH 
p-value will be presented for each active treatment group to placebo comparison. 
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Sensitivity/supplementary analyses which explore the impact of missing data on the primary 
efficacy endpoint will be conducted. These analyses may compare imputations of the missing 
values which favor placebo (eg, worst case) and/or imputations which favor active treatment (eg, 
best case). In addition, imputation methods based on informative missingness and other missing 
data mechanisms may be performed. Additional sensitivity/supplementary analyses will also be 
conducted using the PP analysis set and the completer set. Additional analyses may be developed 
in the SAP. All sensitivity/supplementary analyses will be described in the SAP. 
Prespecified subgroup analyses are planned for the primary endpoint including, but not limited to 
gender, prior anti-TNF treatment, glucocorticoid use at baseline, region, age group, 
randomization stratum, and other important subgroups. A full list of important subgroups will be 
described within the SAP. Within subgroups, efficacy endpoints will be compared for each 
active treatment group (25 mg ontamalimab and 75 mg ontamalimab) with the placebo group 
using a Chi-square test. Subjects with missing remission data at the Week 12 visit will be 
considered failures and counted as nonresponders. The endoscopy subscore will be based on 
centrally read results. The estimate of the treatment difference, along with the corresponding 
Newcombe (hybrid-score) 95% CI and Chi-square test p-value, will be presented. 
Adjustments for Multiplicity 
The global FWER for the statistical tests of the primary and key secondary endpoints will be 
strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in Bretz 
et al. (2009) will be utilized to propagate α from primary to key secondary endpoints and 
between the 2 ontamalimab treatment group and placebo comparisons. Alpha is initially split 
equally at the .025 level (2-sided) for each of the pairwise treatment comparisons for the primary 
endpoint (P) and alpha is propagated in a hierarchical manner to each of the 4 key secondary 
endpoints (K1-K4) within a pairwise treatment comparison. A graphical visualization of the α 
propagation is presented in Figure 5. 
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Figure 5 
Visualization of Alpha Propagation 
 
Only p-values that are significant according to this graphical approach are inferential and 
statistically significant. All other p-values are descriptive. 
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9.8.2 
Secondary Efficacy Endpoints 
9.8.2.1 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoints are as follows: 
• Endoscopic remission, as defined by centrally read endoscopic subscore 0 or 1 (modified, 
excludes friability), at the Week 12 visit. 
• Clinical remission, as defined by stool frequency subscore of 0 or 1 with at least a 1-point 
change from baseline in stool frequency subscore, and rectal bleeding subscore of 0, at 
the Week 12 visit. 
• Clinical response based on composite score at the Week 12 visit. Clinical response 
(composite) is defined as a decrease from baseline in the composite score of 
patient-reported symptoms using daily e-diary and centrally read endoscopy of at least 
2 points and at least 30%, with an accompanying decrease in the subscore for rectal 
bleeding ≥1 point or a subscore for rectal bleeding ≤1. 
• Mucosal healing based on endoscopic and histological assessment at the Week 12 visit. 
Mucosal healing is defined by centrally read endoscopic subscore 0 or 1 (modified, 
excludes friability) and centrally read Geboes score of ≤2. 
Similar to the primary endpoint, the 4 key secondary endpoints will all be tested by the following 
hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
The key secondary endpoints will be analyzed using the same approach as described for the 
primary efficacy endpoint. Subjects with missing key secondary endpoint data at the Week 12 
visit will be considered failures and counted as nonresponders. 
In addition, the sensitivity/supplementary analyses and prespecified subgroup analyses described 
for the primary endpoint will be repeated for the key secondary endpoints. 
9.8.2.2 
Other Secondary Efficacy Endpoints 
The other secondary endpoints are as follows: 
• Remission, defined as a total Mayo score ≤2 with no individual subscore (stool 
frequency, rectal bleeding, endoscopy [modified, excludes friability], and physician’s 
global assessment) exceeding 1, at the Week 12 visit. 
• Clinical response based on total Mayo score at the Week 12 visit. Clinical response 
(Mayo) is defined as a decrease from baseline in the total Mayo score of at least 3 points 
and at least 30%, with an accompanying decrease in the subscore for rectal bleeding 
≥1 point or a subscore for rectal bleeding ≤1. 
• Partial Mayo score ≤2 with no individual subscore >1 at the Week 4, 8, and 12 visits. The 
partial Mayo score does not include the endoscopy subscore. 
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• Clinical remission as defined by stool frequency subscore of 0 or 1 with at least a 1-point 
change from baseline in stool frequency subscore, and rectal bleeding subscore of 0, at 
Weeks 4 and 8. 
• Endoscopic remission at the Week 12 visit with endoscopic subscore of 0. 
• Clinical remission at the Week 4, 8, and 12 visits with both rectal bleeding and stool 
frequency subscores of 0. 
• Deep remission at the Week 12 visit. Deep remission is defined as both endoscopic and 
rectal bleeding subscores of 0, and stool frequency subscore ≤1 and a centrally read 
Geboes score of ≤2. 
• Change from baseline at the Week 12 visit in abdominal pain, diarrhea, and urgency item 
scores, absolute stool frequency, absolute rectal bleeding and total sign/symptom score 
based on subject daily e-diary entries (average of rectal bleeding, stool frequency, 
abdominal pain, diarrhea, and urgency). 
• Change from baseline in IBDQ domain and total (absolute) scores (time frame: Week 0, 
Week 8, up to Week 12, or ET). 
• Change from baseline in SF-36, version 2, acute (physical and mental component 
summary scores and individual domain scores) to the Week 12/ET visit. 
• Incidence of all-cause hospitalizations and total inpatient days. 
Other secondary endpoints will be summarized by descriptive statistics and presented by 
treatment group. Where appropriate, other secondary efficacy endpoints will be analyzed with 
the following analysis methods. 
Binary endpoints will be analyzed using the same approach as described for the primary 
endpoint. Subjects with missing binary endpoint data at a visit will be considered failures and 
counted as nonresponders. 
Continuous endpoints that are only measured at baseline and the Week 12 visit will be analyzed 
using an analysis of covariance model with fixed effects for treatment group (categorical), status 
of prior anti-TNF treatment (categorical), and glucocorticoid use at baseline (categorical), and 
the baseline value as a continuous covariate. From this model, estimates of the least squares 
means, treatment differences, standard errors, p-values, and 95% CIs for least squares mean 
treatment differences will be provided. 
Continuous endpoints that are measured repeatedly over time will be analyzed using a linear 
repeated measures mixed model with restricted maximum likelihood estimation. The model will 
include fixed effects for treatment group (categorical), visit (categorical), treatment group by 
visit interaction, status of prior anti-TNF treatment (categorical), and glucocorticoid use at 
baseline (categorical); baseline value as a continuous covariate; and repeated measures across 
visit for subject. From this model, estimates of least squares means, treatment differences, 
standard errors, p-values, and 95% CIs for least squares mean treatment differences for each visit 
will be provided. 
Full details of the analysis of other secondary efficacy endpoints will be included in the SAP. 
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9.8.3 
Exploratory Efficacy Endpoints 
The exploratory endpoints are as follows: 
Exploratory efficacy endpoints will be summarized with descriptive statistics and presented by 
treatment group. Exploratory efficacy endpoints will be analyzed using the same approach 
described as for the other secondary endpoints. See Section 9.8.2.2 for an overview of the 
planned analyses. Full details for the analysis of exploratory efficacy endpoints will be included 
in the SAP. 
9.9 
Safety Analyses 
All safety analyses will be performed using the safety set. Subjects will be analyzed according to 
the treatment they actually received. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  
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Treatment-emergent AEs are defined as AEs with start dates at the time of or following the first 
exposure to investigational product. The number of events, incidence, and percentage of TEAEs 
will be calculated overall, by SOC, by preferred term, and by treatment group. 
Treatment-emergent AEs will be further summarized by severity and relationship to 
investigational product. Adverse events leading to withdrawal, SAEs, and deaths will be 
similarly summarized or listed. Adverse events of special interest will be summarized by 
treatment group. 
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group 
and visit. Potentially clinically important findings will also be summarized or listed. 
Antidrug antibody data will be summarized by treatment group and visit. 
Further details of safety analyses will be described in the SAP. 
9.10 Other Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate. 
10.1 Sponsor’s Responsibilities 
10.1.1 
Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996) and E6 
R2 (2017), EU Directive 2001/20/EC, as well as all applicable national and local laws and 
regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The sponsor ensures that local regulatory authority requirements are met before and during the 
study (including annual safety reporting, ie, Development Safety Update Reports). The sponsor 
(or a nominated designee) is responsible for the preparation, submission, and confirmation of 
receipt of any regulatory authority approvals required before release of investigational product 
for shipment to the site. 
10.1.2 
Indemnity/Liability and Insurance 
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines. 
The sponsor ensures that suitable clinical study insurance coverage is in place before the start of 
the study. An insurance certificate is supplied to the CRO and investigator as necessary. 
10.1.3 
Public Posting of Study Information 
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information. 
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10.1.4 
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees 
The sponsor will upload the clinical study report to the EudraCT database and will also provide a 
summary of the clinical study report to the CRO for submission to the competent authority of the 
countries concerned as required by local regulatory requirement(s). This requirement will be 
fulfilled within 1 year for nonpediatric studies as per guidance. The ECs will be provided with a 
copy of the same summary as locally required. 
10.1.5 
Study Suspension, Termination, and Completion 
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. 
The sponsor and/or its representatives will make an end-of-study declaration to the relevant 
competent authority as required by Article 10 (c) of Directive 2001/20/EC. 
10.2 Investigator’s Responsibilities 
10.2.1 
Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements 
and guidelines. 
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site before commitment to participate in this study. The investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s or subject’s legally authorized representative’s consent and/or assent, as applicable, 
inform them of the subject’s participation in the study. 
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995).  
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10.2.2 
Protocol Adherence and Investigator Agreement 
The investigator and any coinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor or designee. Upon study completion, the investigator will provide the sponsor, 
IRB/EC, and regulatory agency with final reports and summaries as required by (inter)national 
regulations. 
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement. 
10.2.3 
Documentation and Retention of Records 
10.2.3.1 
Case Report Forms 
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded in eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. The eCRFs must be completed 
by the investigator or designee as stated in the site delegation log. 
All data in the eCRF will have a separate source (eg, paper or electronic PRO); no data will be 
recorded directly in the eCRF. 
All data sent to the sponsor must be endorsed by the investigator. 
The clinical research associate/study monitor will verify the contents against the source data per 
the monitoring plan. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data. 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject e-diary, original clinical laboratory reports, and histology and 
pathology reports. 
All key data must be recorded in the subject’s medical records. 
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The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media. 
The clinical research associate/study monitor (and auditors, IRB/EC or regulatory inspectors) 
may check the eCRF entries against the source documents. The consent form includes a 
statement by which the subject agrees to the monitor/auditor from the sponsor or its 
representatives, national or local regulatory authorities, or the IRB/EC, having access to source 
data (eg, subject’s medical file, appointment books, original laboratory reports, x-rays, etc.). 
Nonstudy site personnel will not disclose any personal information or personal medical 
information. 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
10.2.3.3 
Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site. 
10.2.3.4 
Financial Disclosure 
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 Code of Federal 
Regulations 54 2(b) (1998). 
10.3 Ethical Considerations 
10.3.1 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent and/or assent from 
all study subjects before any study-related procedures including screening assessments. All 
consent documentation must be in accordance with applicable regulations and GCP. Each subject 
or the subject’s legally authorized representative, as applicable, is requested to sign and date the 
subject informed consent form or a certified translation if applicable, after the subject has 
received and read (or been read) the written subject information and received an explanation of 
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what the study involves, including but not limited to: the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities. A copy of the informed consent 
documentation (ie, a complete set of subject information sheets and fully executed signature 
pages) must be given to the subject or the subject’s legally authorized representative, as 
applicable. This document may require translation into the local language. Signed consent forms 
must remain in each subject’s study file and must be available for verification at any time. 
The principal investigator provides the sponsor with a copy of the consent form that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor before 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) before study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor. 
10.3.2 
Institutional Review Board or Ethics Committee 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved before site initiation. 
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions. 
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Before implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. 
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents. 
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs. 
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10.4 Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor or designee. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market ontamalimab; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities. 
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).  
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities. 
10.5 Study Results/Publication Policy 
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy. 
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish before release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
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or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications. 
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form. 
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days before 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application. 
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented. 
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications. 
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11 
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Briskin, M., Winsor-Hines, D., Shyjan, A., Cochran, N., Bloom, S., Wilson, J., McEvoy, L. M., 
Butcher, E. C., Kassam, N., Mackay, C. R., Newman, W. and Ringler, D. J. 1997. Human 
mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract 
and associated lymphoid tissue. Am J Pathol, 151, 97-110. 
 
 
 
 
 
Chalasani, N. and Regev, A. 2016. Drug-Induced Liver Injury in Patients With Preexisting 
Chronic Liver Disease in Drug Development: How to Identify and Manage? 
Gastroenterology, 151, 1046-1051. 
Eaden, J. A. and Mayberry, J. F. 2002. Guidelines for screening and surveillance of 
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Feagan, B. G., Rutgeerts, P., Sands, B. E., Hanauer, S., Colombel, J. F., Sandborn, W. J., Van 
Assche, G., Axler, J., Kim, H. J., Danese, S., Fox, I., Milch, C., Sankoh, S., Wyant, T., 
Xu, J. and Parikh, A. 2013. Vedolizumab as induction and maintenance therapy for 
ulcerative colitis. N Engl J Med, 369, 699-710. 
Geboes, K., Riddell, R., Ost, A., Jensfelt, B., Persson, T. and Lofberg, R. 2000. A reproducible 
grading scale for histological assessment of inflammation in ulcerative colitis. Gut, 47, 
404-9. 
Humira® 2017. US Prescribing Information. 
Imuran® 2014. US Prescribing Information. 
Irvine, E., Feagan, B. G., Rochon, J., Archambault, A., Fedorak, R. N. and Groll, A. 1994. 
Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of 
IBD. Canadian Crohn’s Relapse Prevention Trial Study Group. Gastroenterology, 106, 
287-296. 
Isabwe, G. A. C., Garcia Neuer, M., de Las Vecillas Sanchez, L., Lynch, D. M., Marquis, K. and 
Castells, M. 2018. Hypersensitivity reactions to therapeutic monoclonal antibodies: 
Phenotypes and endotypes. J Allergy Clin Immunol, 142, 159-170 e2. 
Khanna, S., Shin, A. and Kelly, C. 2017. Management of Clostridium difficile Infection in 
Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates 
Committee of the AGA Institute. Clin Gastroenterol Hepatol, 15, 166-74. 
 
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Lacy, C., Armstrong, L., Goldman, M. and Lance, L. 2001-2002. Drug Information Handbook, 
Cleveland, OH, LexiComp, Inc. 
Lialda® 2018. US Prescribing Information. 
Liaskou, E., Karikoski, M., Reynolds, G. M., Lalor, P. F., Weston, C. J., Pullen, N., Salmi, M., 
Jalkanen, S. and Adams, D. H. 2011. Regulation of mucosal addressin cell adhesion 
molecule 1 expression in human and mice by vascular adhesion protein 1 amine oxidase 
activity. Hepatology, 53, 661-72. 
McDonald, L. C., Gerding, D. N., Johnson, S., Bakken, J. S., Carroll, K. C., Coffin, S. E., 
Dubberke, E. R., Garey, K. W., Gould, C. V., Kelly, C., Loo, V., Shaklee Sammons, J., 
Sandora, T. J. and Wilcox, M. H. 2018. Clinical Practice Guidelines for Clostridium 
difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases 
Society of America (IDSA) and Society for Healthcare Epidemiology of America 
(SHEA). Clinical Infectious Diseases, 66, e1-e48. 
Medrol® 2018. US Prescribing Information. 
Methotrexate® 2018. US Prescribing Information. 
Molodecky, N. A., Soon, I. S., Rabi, D. M., Ghali, W. A., Ferris, M., Chernoff, G., Benchimol, 
E. I., Panaccione, R., Ghosh, S., Barkema, H. W. and Kaplan, G. G. 2012. Increasing 
incidence and prevalence of the inflammatory bowel diseases with time, based on 
systematic review. Gastroenterology, 142, 46-54.e42; quiz e30. 
Mosli, M. H., Feagan, B. G. and Zou, G. 2015. Development and Validation of a histological 
index for UC. Gut, Prepub. 
Purinethol® 2011. US Prescribing Information. 
Sampson, H. A., Munoz-Furlong, A., Campbell, R. L., Adkinson, N. F., Jr., Bock, S. A., 
Branum, A., Brown, S. G., Camargo, C. A., Jr., Cydulka, R., Galli, S. J., Gidudu, J., 
Gruchalla, R. S., Harlor, A. D., Jr., Hepner, D. L., Lewis, L. M., Lieberman, P. L., 
Metcalfe, D. D., O'Connor, R., Muraro, A., Rudman, A., Schmitt, C., Scherrer, D., 
Simons, F. E., Thomas, S., Wood, J. P. and Decker, W. W. 2006. Second symposium on 
the definition and management of anaphylaxis: summary report--Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. The Journal of allergy and clinical immunology, 117, 391-7. 
Sandborn, W. J., Su, C., Sands, B. E., D'Haens, G. R., Vermeire, S., Schreiber, S., Danese, S., 
Feagan, B. G., Reinisch, W., Niezychowski, W., Friedman, G., Lawendy, N., Yu, D., 
Woodworth, D., Mukherjee, A., Zhang, H., Healey, P. and Panes, J. 2017. Tofacitinib as 
Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med, 376, 1723-
1736. 
Schroeder, K. W., Tremaine, W. J. and Ilstrup, D. M. 1987. Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J 
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Shane, A. L., Mody, R. K., Crump, J. A., Tarr, P. I., Steiner, T. S., Kotloff, K., Langley, J. M., 
Wanke, C., Warren, C. A., Cheng, A. C., Cantey, J. and Pickering, L. K. 2017. 2017 
Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis 
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Shyjan, A. M., Bertagnolli, M., Kenney, C. J. and Briskin, M. J. 1996. Human mucosal addressin 
cell adhesion molecule-1 (MAdCAM-1) demonstrates structural and functional 
similarities to the alpha 4 beta 7-integrin binding domains of murine MAdCAM-1, but 
extreme divergence of mucin-like sequences. J Immunol, 156, 2851-7. 
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Steffen, B. J., Breier, G., Butcher, E. C., Schulz, M. and Engelhardt, B. 1996. ICAM-1, 
VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not 
endothelium and mediate binding of lymphocytes in vitro. Am J Pathol, 148, 1819-38. 
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Tarabar, D., Vanasek, T., Gregus, M., Hellstern, P. A., Kim, J. S., Sparrow, M. P., 
Gorelick, K. J., Hinz, M., Ahmad, A., Pradhan, V., Hassan-Zahraee, M., Clare, R., 
Cataldi, F. and Reinisch, W. 2017. Anti-MAdCAM antibody (PF-00547659) for 
ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-
controlled trial. Lancet. 
Ware, J. E., Jr. and Sherbourne, C. D. 1992. The MOS 36-item short-form health survey (SF-36). 
I. Conceptual framework and item selection. Med Care, 30, 473-83. 
Warrington, R., Silviu-Dan, F. and Wong, T. 2018. Drug allergy. Allergy, Asthma & Clinical 
Immunology, 14, 1-11. 
XELJANZ® 2019. US Prescribing Information. 
Yan, X. and Su, X. 2010. Stratified Wilson and Newcombe Confidence Intervals for Multiple 
Binomial Proportions. Stat Biopharm Res, 2, 329-35. 
 
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APPENDIX 1 PROTOCOL HISTORY 
Document 
Date 
Global/Country/Site Specific 
Protocol Amendment 2 
11 Nov 2019 
Global 
Protocol Amendment 1 
05 Sep 2018 
Global 
Original Protocol 
06 Jul 2017 
Global 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
05 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Emergency Contact Information  
Section 8.2.2, Reporting Procedures 
Section 8.2.4, Serious Adverse 
Event Collection Time Frame 
Replaced “Shire Global 
Pharmacovigilance” with “the Shire 
Global Drug Safety Department.” 
Updated the global fax number and 
email address for serious adverse 
event reporting. 
To provide updated emergency 
contact information. 
The email address was updated in 
accordance with SHP647-302 
Protocol Administrative Change 
Memo #4, dated 03 May 2018. 
Product Quality Complaints 
Updated the email address for 
reporting of product complaints that 
originate in the European Union and 
Rest of World. The email address 
now is the same for all regions. 
To provide updated information for 
reporting of product complaints. 
Study Synopsis, Site(s) and 
Region(s) 
Section 3.3, Sites and Regions 
Revised the anticipated number of 
study sites from 175 to 210. 
To provide a revised projection for 
the number of study sites expected to 
participate. 
Study Synopsis, Objectives, Other 
Secondary 
Section 2.2.2.2, Other Secondary 
Objectives 
Section 2.2.3, Exploratory 
Objectives 
Added text to clarify the endpoints 
associated with the other secondary 
objectives based on “other clinical 
outcomes” and
 
 
 
 
To clarify the measures that support 
those objectives. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Updated exclusion criterion #1 to 
indicate that subjects with 
non-steroidal anti-inflammatory 
drug-induced colitis will be 
excluded. 
To further define the exclusion of 
subjects with colitis. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Added exclusion criterion #10: 
“Subjects have received any 
nonbiologic treatment with 
immunomodulatory properties 
(other than their current background 
UC treatment) within 30 days 
before baseline (Visit 2).” 
To indicate exclusion of subjects with 
prior nonbiologic treatment with 
immunomodulatory properties within 
the specified timeframe. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
05 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Section 5.2.2, Prohibited 
Treatments 
Added exclusion criterion #13:  
“Subjects have received leukocyte 
apheresis or selective lymphocyte, 
monocyte, or granulocyte apheresis 
or plasma exchange within 30 days 
before baseline (Visit 2).” 
To indicated exclusion of subjects 
with prior apheresis or plasma 
exchange within the specified 
timeframe. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
 
Updated exclusion criterion #16 
(now #18) to clarify that subjects 
with a history of Mycobacterium 
tuberculosis (TB) infection will be 
excluded. 
To further define the exclusion of 
subjects with any history of positive 
TB. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Section 7.2.3.6, Clinical Laboratory 
Evaluations 
Revised the name of interferon 
gamma release assay (IGRA) from 
“QuantiFERON TB Gold In-Tube 
Test” to “QuantiFERON TB Gold 
Plus In-Tube Test.” 
To reflect a change in assay for 
detection of TB. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Updated exclusion criterion #22 
(now #24) to indicate that subjects 
with cirrhosis with or without 
decompensation will be excluded. 
To further define the exclusion of 
subjects with compromised liver 
function. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Moved exclusion of subjects with 
primary sclerosing cholangitis from 
exclusion criterion #22 to new 
criterion #25.  
To further define the exclusion of 
subjects with compromised liver 
function. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
 
Updated exclusion criterion #24 
(now #26) to indicate that subjects 
with negative HBsAg but positive 
HBcAb may be eligible if no 
presence of HBV DNA is 
confirmed. 
To clarify that subjects with positive 
HBcAb, without HBV DNA, may be 
eligible for the study. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
 
Updated exclusion criterion #25 
(now #27) to indicate that subjects 
with chronic hepatitis C (HCV) 
without evidence of HCVRNA 
within 12 weeks of baseline may be 
considered eligible. 
To clarify that subjects with chronic 
HCV, without HCVRNA, may be 
eligible for the study. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
05 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Updated exclusion criterion #26 
(now #28) to indicate that subjects 
meeting the following lab criteria 
would be excluded: 
• 
ALT or AST ≥3×ULN  
• 
Total bilirubin level ≥1.5 
times the ULN (>2 times the 
ULN if subject has a known 
documented history of 
Gilbert’s syndrome) 
Added a note to exclusion criterion 
#26 (now #28) to specify that, if 
platelet count is <150,000 
cells/mm3, a further evaluation 
should be performed to rule out 
cirrhosis, unless another etiology 
has already been identified. 
To align criteria with FDA 
guidelines. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Updated exclusion criterion #28 
(now #30) to include exclusion of 
subjects with abuse of medicinal 
marijuana. Deleted former exclusion 
criterion #28 related to medicinal 
marijuana dependency.  
To indicate that subjects with 
medicinal marijuana abuse would be 
excluded.  
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Updated exclusion criterion #31 
(now #33) to indicate the exclusion 
of subjects who do not agree to 
postpone donation of any organ or 
tissue, including male subjects are 
planning to bank or donate sperm 
and female subjects who are 
planning to harvest or donate eggs, 
for the duration of the study and for 
16 weeks after last dose of 
investigational product. 
To specify the exclusion of subjects 
who do not agree to postpone 
donation of any organ or tissue, 
including sperm banking or donation 
for male subjects and egg donation or 
harvest for female subjects. 
Study Synopsis, Endpoints and 
statistical analysis, Analysis Sets 
Section 9.7, Study Population 
 
. 
For clarity and consistency of how 
these are defined across the Phase 3 
protocols. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
05 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Endpoints and 
statistical analysis, Analysis Sets 
Section 9.8.1, Primary Efficacy 
Endpoint 
Section 9.8.2, Secondary Efficacy 
Endpoints 
Section 9.8.3, Exploratory Efficacy 
Endpoints 
Removed “subjects with” and 
“proportion of subjects with” from 
the efficacy endpoints where 
applicable. 
 
To describe the endpoints correctly. 
Study Synopsis, Safety Analyses 
Section 9.9, Safety Analyses 
Added further details on planned 
summary presentations for the 
safety analyses. Clarified definition 
of TEAE. 
For clarity. 
Section 1.3, Benefit and Risk 
Assessment 
Added new section describing risk 
and benefits of SHP647 treatment. 
To provide updated risk and benefit 
information for SHP647. 
Schedule of Assessments, footnote 
“m” 
Section 7.2.3.6, Clinical Laboratory 
Evaluations 
Updated SOA footnote “m” and 
added text in Section 7.2.3.6 to 
clarify that diagnosis of C. difficile 
infection should be made using the 
central laboratory.  
Added diagnostic algorithms and 
relevant related to C. difficile testing 
and diagnosis. 
To provide appropriate guidance 
regarding laboratory testing for 
C. difficile infection. 
Schedule of Assessments, footnote 
“o” 
Added new row to SOA and 
footnote ‘o’ to indicate HIV tests 
may be performed at local 
laboratories (per local requirements) 
if documentation of a negative HIV 
test within 6 months of screening is 
unavailable. 
To clarify the timing of acceptable 
documentation of HIV status. 
Schedule of Assessments, footnote 
“v” 
Section 2.2.3, Exploratory 
Objectives 
Section 7.1.1.1, Screening Visit 
(Visit 1) 
Section 7.2.2.1, Endoscopy and 
Histology 
Section 9.8.3, Exploratory Efficacy 
Endpoints 
Appendix 2, Scales and 
Assessments 
 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
05 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 3.1, Study Design and Flow 
Chart 
Updated Figure 2 to show more 
clearly the possible paths for 
subjects following completion of the 
12-week treatment period, ie either 
entering the maintenance study 
SHP647-303, entering the LTS 
study SHP647-304, or entering the 
16-week safety follow-up period in 
this induction study. 
To provide clarity regarding the flow 
of subjects following completion of 
the 12-week treatment period in this 
study. 
Section 4.4, Reproductive Potential 
 
Made edits to clarify the appropriate 
methods of contraception for female 
and male subjects of reproductive 
potential. 
To clarify language regarding 
appropriate contraceptive methods for 
subjects of reproductive potential. 
Section 4.5.1, Subject Withdrawal 
Criteria 
Added pregnancy to the list of 
reasons a subject may be withdrawn 
from study treatment. 
For clarity and consistency with 
language in Section 8.1.6. 
Section 5.2.2, Prohibited 
Treatments 
Updated Table 2 to add 
nonbiologics with 
immunomodulatory properties as 
prohibited medications. 
To include nonbiologics with 
immunomodulatory properties as 
prohibited medications. 
Section 6.2.2, Allocation of 
Subjects to Treatment 
Added language to place a cap on 
the Japan-specific sample 
population with prior anti-TNF 
exposure at 60%. 
To ensure comparability to the rest of 
the global population, which has the 
same cap on prior anti-TNF therapy 
exposure. 
Section 7.1.3, Follow-up Period: 
Visits 7 and 8 (Weeks 20 and 28) 
Revised text to clarify that the 16-
week safety follow-up period is 
timed relative to the End of 
Treatment visit, not to the subject’s 
last dose of investigational product. 
To accurately reflect the timing for 
the start of the safety follow-up 
period and align with the Schedule of 
Assessments. 
This change was made with 
SHP647-302 Protocol Administrative 
Change Memo #1 (dated 
08 Aug 2017). 
Section 7.2, Study Evaluations and 
Procedures 
Added statement that blood and 
tissue samples may be stored for up 
to the duration allowed by local 
regulations, but for no longer than 
25 years. 
Revised from “blood sample 
collection” to “laboratory sample 
collection” to clarify that this 
includes other sample collection, eg 
urine. 
Moved investigational product 
administration to the last bullet 
point in the ordering of procedures. 
To provide clarity regarding the 
length of time that blood and tissue 
samples may be stored. This change 
was made with SHP647-302 Protocol 
Administrative Change Memo #2 
(dated 07 Sep 2017). 
 
To improve clarity. 
 
 
To improve clarity. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
05 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 7.2.2.2, Mayo score 
Removed language stating that 
endoscopic appearance would be 
read locally; it is to be centrally read 
only. 
To clarify that endoscopic appearance 
will be read centrally, not locally. 
Section 7.2.3.5, Vital Signs 
Removed language that specified 
measuring body temperature orally 
with a digital thermometer or by 
using tympanic temperature. 
To clarify how body temperature 
should be obtained. 
Section 7.2.3.6, Clinical Laboratory 
Evaluations 
Added information on laboratory 
testing for C. difficile infection, 
including diagnostic algorithms. 
To provide appropriate guidance 
regarding laboratory testing for 
C. difficile infection. 
Section 7.2.5, Volume of Blood to 
be Drawn for Each Subject 
Made corrections to the blood 
sample volumes for hematology, 
serum chemistry, and serum CRP, 
and the approximate total blood 
volume in Table 4 (Volume of 
Blood to be Drawn for Each 
Subject) and in the paragraph 
thereafter. 
Added sample collections/blood 
volumes for HIV and HBV DNA. 
Updated the blood sample volumes 
and approximate total blood volume 
to reflect these changes. 
To reflect accurately the blood 
sample volumes for hematology, 
serum chemistry, and serum CRP, 
and reflect addition of HIV and 
HBV DNA testing. 
Section 8.1.8, Unexpected Adverse 
Event 
Section 8.1.9, Suspected 
Unexpected Serious Adverse 
Reaction 
Added definitions of unexpected 
adverse event and suspected 
unexpected serious adverse reaction. 
 
To define unexpected adverse event 
and suspected unexpected serious 
adverse reaction. 
Section 8.2.7, Regulatory Agency, 
Institutional Review Board, Ethics 
Committee, and Site Reporting 
Added text to clarify that “related, 
unexpected SAEs” refers to 
“SUSARs.” 
To clarify that “related, unexpected 
SAEs” refers to “SUSARs.” 
Section 8.2.8, Safety Monitoring 
Rules 
Added new section describing 
safety monitoring and stopping 
algorithms for elevated hepatic 
blood tests.  
To provide appropriate guidance on 
patients who have been enrolled with 
elevated liver function test values or 
who experience and increase in liver 
function test(s) during the study. 
Section 10, Sponsor’s and 
Investigator’s Responsibilities 
Added a statement that compliance 
with the noted regulations and 
guidelines also constitutes 
compliance with the ethical 
principles described in the 
Declaration of Helsinki. 
To clarify that the study is conducted 
in accordance with the ethical 
principles in the Declaration of 
Helsinki. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
05 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 10.1.1, Good Clinical 
Practice Compliance 
Added language to clarify that the 
sponsor will ensure that local 
regulatory requirements are met 
during the study, including annual 
safety reporting, ie, Development 
Safety Update Reports. 
To clarify language regarding 
regulatory reporting requirements. 
Appendix 2, Mayo Scoring System 
for Assessment of Ulcerative Colitis 
Activity 
Added a footnote (“c”) to the Mayo 
Scoring System for Assessment of 
Ulcerative Colitis Activity to clarify 
that the “findings on endoscopy” 
scoring represents the modified 
endoscopy subscore and that data 
will be collected to calculate the 
total Mayo score using both the 
modified endoscopy subscore and 
traditional endoscopy subscore, 
which will be used as a sensitivity 
analysis and to estimate the impact 
of the modification on the primary 
endpoint.  
To provide clarity regarding Mayo 
Scoring System and use of the 
modified and traditional endoscopy 
scores. This change was described in 
SHP647-302 Protocol Administrative 
Change Memo #2 (dated 
07 Sep 2017). 
Appendix 2, Scales and 
Assessments 
 
 
 
 
Appendix 4, Determination of 
Failure or Intolerance to Prior 
Treatment for Ulcerative Colitis 
Added new appendix section, 
“Determination of Failure or 
intolerance to Prior Treatment for 
Ulcerative Colitis” to provide 
guidance as related to inclusion 
criterion #8 in which subjects 
meeting these criteria on prior 
conventional treatments (eg, 
sulfasalazine, mesalamine, 
glucocorticoids, 
immunosuppressants, or anti-TNF) 
may be eligible for this study.  
To provide additional granularity 
regarding the eligibility of subjects 
who demonstrated inadequate 
response, loss of response, or 
intolerance on conventional 
treatment. 
Appendix 5, Guidance for 
Treatment of Increased 
Gastrointestinal Symptoms 
Added new Appendix 5, “Guidance 
for Treatment of Increased 
Gastrointestinal Symptoms related 
to diagnosis and treatment of C. 
difficile infection.” 
To provide updated treatment 
guidance for subjects diagnosed with 
C. difficile infection. 
Throughout protocol 
Minor changes to wording.  
To improve clarity, consistency, and 
remove redundancy of text.  
 
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APPENDIX 2 SCALES AND ASSESSMENTS 
The following scales/assessments will be used in the study and are provided in this appendix: 
• Stool frequency screening questions 
• Mayo scoring system 
• Geboes score grading system 
 
 
• PRO-UC diary 
• IBDQ 
 
 
 
 
 
 
 
 
• SF-36 
 
 
For questionnaires, language-specific validated versions will be used only. 
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Stool Frequency Screening Questions 
1. Think back to before you ever had symptoms of UC. How many bowel movements did you 
typically have in a 24-hour period before ever having symptoms of UC?  
Number of bowel movements in a 24-hour period before ever having symptoms of UC: 
____________ 
 
2. Remission of ulcerative colitis (UC) is defined as a time when your symptoms have gone 
away, you’re feeling well, and/or your UC is no longer impacting your regular daily 
activities. Have you ever experienced a remission of UC?  
• Yes 
• No 
If YES, 
When you are in remission how many bowel movements do you typically have in a 24-hour 
period? Remember that remission is a time when your symptoms have gone away, you’re 
feeling well, and/or your UC is no longer impacting your regular daily activities. 
Number of bowel movements in a 24-hour period when in remission: 
____________ 
 
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Mayo Scoring System for Assessment of Ulcerative Colitis Activity 
Stool frequencya 
0 = Normal number of stools for this subject 
1 = 1 to 2 stools more than normal 
2 = 3 to 4 stools more than normal 
3 = 5 or more stools more than normal 
Subscore, 0 to 3 
Rectal bleedingb 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood (more than just streaks) or streaks of blood with stool most of the time 
3 = Blood alone passes 
Subscore, 0 to 3 
Findings on endoscopyc 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) 
2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration) 
Subscore, 0 to 3 
Physician’s global assessmentd 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
Subscore, 0 to 3 
The total Mayo score ranges from 0 to 12, with higher scores indicating more severe disease. 
a 
Each subject serves as his or her own control to establish the degree of abnormality of the stool frequency. 
b 
The daily bleeding score represents the most severe bleeding of the day. 
c 
Findings on endoscopy scoring represents the modified endoscopy subscore (value of 1 does not include friability). 
Note: Data will be collected to calculate the total Mayo score using both the modified endoscopy subscore and traditional 
endoscopy subscore (value of 1 including mild friability) as a sensitivity analysis and to estimate the impact of the 
modification on the primary endpoint. 
d 
The physician’s global assessment acknowledges the three other criteria, the subject’s daily recollection of abdominal 
discomfort and general sense of well-being, and other observations, such as physical findings and the subject’s performance 
status. 
Source: Schroeder et al., 1987. 
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Geboes Score Grading System 
Grade 0 – Structural (architectural change)  
Subgrades 
 
0.0 
No abnormality  
0.1 
Mild abnormality  
0.2 
Mild or moderate diffuse or multifocal abnormalities 
0.3 
Severe diffuse or multifocal abnormalities  
Grade 1 – Chronic inflammatory infiltrate  
Subgrades 
 
1.0 
No increase 
1.1 
Mild but unequivocal increase 
1.2 
Moderate increase 
1.3 
Marked increase 
Grade 2A – Lamina propria eosinophils  
Subgrades 
 
2A.0 
No increase 
2A.1 
Mild but unequivocal increase 
2A.2 
Moderate increase 
2A.3 
Marked increase 
Grade 2B – Lamina propria neutrophils 
Subgrades 
 
2B.0 
None  
2B.1 
Mild but unequivocal increase 
2B.2 
Moderate increase 
2B.3 
Marked increase 
Grade 3 – Neutrophils in epithelium  
Subgrades 
 
3.0 
None  
3.1 
< 5% crypts involved  
3.2 
< 50% crypts involved  
3.3 
> 50% crypts involved  
Grade 4 – Crypt destruction  
Subgrades 
 
4.0 
None  
4.1 
Probable – local excess of neutrophils in part of crypt  
4.2 
Probable – marked attenuation  
4.3 
Unequivocal crypt destruction  
Grade 5 – Erosion or ulceration  
Subgrades 
 
5.0 
No erosion, ulceration, or granulation tissue 
5.1 
Recovering epithelium + adjacent inflammation  
5.2 
Probable erosion - focally stripped  
5.3 
Unequivocal erosion  
5.4 
Ulcer or granulation tissue 
Source: Geboes et al., 2000. 
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Patient-reported Outcomes – Ulcerative Colitis (PRO-UC) Diary Version 1 
Item # 
Item 
1. 
Please indicate how often you had a bowel movement over the past 24 hours. A bowel movement is 
defined as a trip to the toilet and passing stool (liquid, soft, or solid), passing blood only, passing 
blood and mucus, or passing mucus only. 
 
Enter number of bowel movements passed:  
2. 
Please rate your worst experience of rectal bleeding over the past 24 hours. 
• 
No blood seen 
• 
Streaks of blood with stool less than half of the time 
• 
Obvious blood (more than just streaks) or streaks of blood with stool most of the time 
• 
Blood alone passes 
3. 
You indicated you had X bowel movements in the past 24 hours. Of these, how many had blood, 
either in the stool, in the toilet bowl, or on the toilet paper? 
 
Enter the number of bowel movements with blood:  
4. 
You indicated you had X bowel movements in the past 24 hours. Of these, how many were loose or 
watery? 
 
Enter number of loose or watery bowel movements:  
5. 
You indicated you had X bowel movements in the past 24 hours. How many of those involved 
urgency (having to suddenly rush to the toilet to make it on time)? 
 
Enter number of bowel movements with urgency:  
6. 
Please rate your worst abdominal pain over the past 24 hours. 
• 
0-10 numeric rating scale, with 0 anchor at “No pain” and 10 at “Worst Imaginable Pain” 
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Inflammatory Bowel Disease Questionnaire (IBDQ) 
This questionnaire is designed to find out how you have been feeling during the last 2 weeks. 
You will be asked about symptoms you have been having as a result of your inflammatory bowel 
disease, the way you have been feeling in general, and how your mood has been. 
1. How frequent have your bowel movements been during the last two weeks? Please indicate 
how frequent your bowel movements have been during the last two weeks by picking one of 
the options from: 
1. BOWEL MOVEMENTS AS OR MORE FREQUENT THAN THEY HAVE EVER 
BEEN 
2. EXTREMELY FREQUENT 
3. VERY FREQUENT 
4. MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS 
5. SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS 
6. SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS 
7. NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS 
2. How often has the feeling of fatigue or of being tired and worn out been a problem for you 
during the last 2 weeks? Please indicate how often the feeling of fatigue or tiredness has been 
a problem for you during the last 2 weeks by picking one of the options from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
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3. How often during the last 2 weeks have you felt frustrated, impatient, or restless? Please 
choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
4. How often during the last 2 weeks have you been unable to attend school or do your work 
because of your bowel problem? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
5. How much of the time during the last 2 weeks have your bowel movements been loose? 
Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
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6. How much energy have you had during the last 2 weeks? Please choose an option from: 
1. NO ENERGY AT ALL 
2. VERY LITTLE ENERGY 
3. A LITTLE ENERGY 
4. SOME ENERGY 
5. A MODERATE AMOUNT OF ENERGY 
6. A LOT OF ENERGY 
7. FULL OF ENERGY 
7. How often during the last 2 weeks did you feel worried about the possibility of needing to 
have surgery because of your bowel problem? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
8. How often during the last 2 weeks have you had to delay or cancel a social engagement 
because of your bowel problem? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
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9. How often during the last 2 weeks have you been troubled by cramps in your abdomen? 
Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
10. How often during the last 2 weeks have you felt generally unwell? Please choose an option 
from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
11. How often during the last 2 weeks have you been troubled because of fear of not finding a 
washroom? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
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12. How much difficulty have you had, as a result of your bowel problems, doing leisure or 
sports activities you would have liked to have done during the last 2 weeks? Please choose an 
option from: 
1. A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE 
2. A LOT OF DIFFICULTY 
3. A FAIR BIT OF DIFFICULTY 
4. SOME DIFFICULTY 
5. A LITTLE DIFFICULTY 
6. HARDLY ANY DIFFICULTY 
7. NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS OR 
LEISURE ACTIVITIES 
13. How often during the last 2 weeks have you been troubled by pain in the abdomen? Please 
choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
14. How often during the last 2 weeks have you had problems getting a good night’s sleep, or 
been troubled by waking up during the night? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
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15. How often during the last 2 weeks have you felt depressed or discouraged? Please choose an 
option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
16. How often during the last 2 weeks have you had to avoid attending events where there was 
no washroom close at hand? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
17. Overall, in the last 2 weeks, how much of a problem have you had with passing large 
amounts of gas? Please choose an option from: 
1. A MAJOR PROBLEM 
2. A BIG PROBLEM 
3. A SIGNIFICANT PROBLEM 
4. SOME TROUBLE 
5. A LITTLE TROUBLE 
6. HARDLY ANY TROUBLE 
7. NO TROUBLE 
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18. Overall, in the last 2 weeks, how much a problem have you had maintaining or getting to, the 
weight you would like to be at? Please choose an option from: 
1. A MAJOR PROBLEM 
2. A BIG PROBLEM 
3. A SIGNIFICANT PROBLEM 
4. SOME TROUBLE 
5. A LITTLE TROUBLE 
6. HARDLY ANY TROUBLE 
7. NO TROUBLE 
19. Many patients with bowel problems often have worries and anxieties related to their illness. 
These include worries about getting cancer, worries about never feeling any better, and 
worries about having a relapse. In general, how often during the last 2 weeks have you felt 
worried or anxious? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
20. How much of the time during the last 2 weeks have you been troubled by a feeling of 
abdominal bloating? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
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21. How often during the last 2 weeks have you felt relaxed and free of tension? Please choose 
an option from: 
1. NONE OF THE TIME 
2. A LITTLE OF THE TIME 
3. SOME OF THE TIME 
4. A GOOD BIT OF THE TIME 
5. MOST OF THE TIME 
6. ALMOST ALL OF THE TIME 
7. ALL OF THE TIME 
22. How much of the time during the last 2 weeks have you had a problem with rectal bleeding 
with your bowel movements? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
23. How much of the time during the last 2 weeks have you felt embarrassed as a result of your 
bowel problem? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
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24. How much of the time during the last 2 weeks have you been troubled by a feeling of having 
to go to the bathroom even though your bowels were empty? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
25. How much of the time during the last 2 weeks have you felt tearful or upset? Please choose 
an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
26. How much of the time during the last 2 weeks have you been troubled by accidental soiling 
of your underpants? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
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27. How much of the time during the last 2 weeks have you felt angry as a result of your bowel 
problem? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
28. To what extent has your bowel problem limited sexual activity during the last 2 weeks? 
Please choose an option from: 
1. NO SEX AS A RESULT OF BOWEL DISEASE 
2. MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE 
3. MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE 
4. SOME LIMITATION AS A RESULT OF BOWEL DISEASE 
5. A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE 
6. HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE 
7. NO LIMITATION AS A RESULT OF BOWEL DISEASE 
29. How much of the time during the last 2 weeks have you been troubled by nausea or feeling 
sick to your stomach? Please choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
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30. How much of the time during the last 2 weeks have you felt irritable? Please choose an 
option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
31. How often during the past 2 weeks have you felt a lack of understanding from others? Please 
choose an option from: 
1. ALL OF THE TIME 
2. MOST OF THE TIME 
3. A GOOD BIT OF THE TIME 
4. SOME OF THE TIME 
5. A LITTLE OF THE TIME 
6. HARDLY ANY OF THE TIME 
7. NONE OF THE TIME 
32. How satisfied, happy, or pleased have you been with your personal life during the past 
2 weeks? Please choose one of the following options from: 
1. VERY DISSATISFIED, UNHAPPY MOST OF THE TIME 
2. GENERALLY DISSATISFIED, UNHAPPY 
3. SOMEWHAT DISSATISFIED, UNHAPPY 
4. GENERALLY SATISFIED, PLEASED 
5. SATISFIED MOST OF THE TIME, HAPPY 
6. VERY SATISFIED MOST OF THE TIME, HAPPY 
7. EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY OR 
PLEASED 
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Short Form-36 Health Survey, Acute Form 
 
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APPENDIX 3 GLUCOCORTICOID EQUIVALENT DOSES 
Glucocorticoid 
Equivalent Dose (mg) 
Short Acting: 
 
Cortisone 
25 
Hydrocortisone 
20 
Intermediate Acting: 
 
Methylprednisolone 
4 
Prednisolone 
5 
Prednisone 
5 
Triamcinolone 
4 
Long Acting: 
 
Betamethasone 
0.6 
Dexamethasone 
0.75 
Reference: Lacy et al., 2001-2002. 
 
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APPENDIX 4 DETERMINATION OF FAILURE OR INTOLERANCE TO PRIOR 
TREATMENT FOR ULCERATIVE COLITIS 
The information below should serve as guidance. Local therapeutic standards and investigator 
judgment should be considered.  
AMINOSALICYLATES 
Mesalamine (5-ASA) 
Inadequate response to or loss of response: defined as persistent signs and symptoms of active 
disease despite treatment with mesalamine for at least 8 weeks at daily doses of 4.8 g/day. 
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to 
mesalamine treatment.  
As guidance, the US package insert of mesalamine lists the following AEs. Please check the 
respective latest label of your country as well (Lialda®, 2018):  
Renal impairment including minimal change nephropathy, acute and chronic interstitial 
nephritis, and renal failure 
Acute intolerance syndrome includes cramping, acute abdominal pain and bloody 
diarrhea, and sometimes fever, headache, and rash 
Hypersensitivity reactions including cardiac hypersensitivity reactions (myocarditis and 
pericarditis) 
Hepatic impairment: hepatic failure in patients with pre-existing liver disease 
Photosensitivity in patients with pre-existing skin conditions such as atopic dermatitis 
and atopic eczema 
Other treatment-related AEs: headache, flatulence, abnormal liver function test, 
alopecia, pruritus, tachycardia, hypertension, hypotension, acne, prurigo, rash, urticaria, 
abdominal distention, colitis, diarrhea, pancreatitis, rectal polyp, vomiting, decreased 
platelet count, arthralgia, back pain, somnolence, tremor, pharyngolaryngeal pain, 
asthenia, face edema, fatigue, pyrexia, ear pain. Based on postmarketing experience 
when it is not always possible to reliably establish a causal relationship to drug 
exposure: lupus-like syndrome, drug fever, pericarditis, pericardial effusion, myocarditis, 
pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated 
peptic ulcer, jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, 
Kawasaki-like syndrome including changes in liver enzymes, agranulocytosis, aplastic 
anemia, anaphylactic reaction, angioedema, Stevens-Johnson syndrome (SJS), drug 
reaction with eosinophilia and systemic symptoms (DRESS), myalgia, lupus-like 
syndrome, peripheral neuropathy, Guillain-Barre syndrome, transverse myelitis, 
intracranial hypertension, interstitial nephritis, nephrogenic diabetes insipidus, 
interstitial lung disease, hypersensitivity pneumonitis (including interstitial pneumonitis, 
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allergic alveolitis, eosinophilic pneumonitis), psoriasis, pyoderma gangrenosum, 
erythema nodosum, photosensitivity, oligospermia 
Sulfasalazine (SSZ) 
Inadequate response or loss of response: defined as persistent signs and symptoms of active 
disease despite treatment with at least one 8-week induction regimen at daily dose at 4g/day.  
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to 
sulfasalazine treatment.  
As guidance, the US package insert of sulfasalazine lists the following AEs. Please check the 
respective latest label of your country as well (Azulfidine®, 2016): 
Hypersensitivity reactions: erythema multiforme (Stevens-Johnson syndrome), exfoliative 
dermatitis, epidermal necrolysis (Lyell´s syndrome) with corneal damage, drug rash with 
eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness syndrome, 
interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing 
alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, 
polyarteritis nodosa, lupus erythematosus-like syndrome, hepatitis and hepatic necrosis 
with or without immune complexes, fulminant hepatitis, sometimes leading to liver 
transplantation, parapsoriasis varioliformis acuta (Mucha-Haberman syndrome), 
rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival and 
scleral injection, and alopecia 
Blood dyscrasias: agranulocytosis, leukopenia, myelodysplastic syndrome, aplastic 
anemia, megaloblastic (macrocytic) anemia, hemolytic anemia, cyanosis, 
methemoglobinemia, Heinz body anemia, hypoprothrombinemia, and thrombocytopenia 
Gastrointestinal reactions: hepatitis, hepatic failure, pancreatitis, bloody diarrhea, 
impaired folic acid absorption, impaired digoxin absorption, stomatitis, diarrhea, 
abdominal pains, and neutropenic enterocolitis 
Central nervous system reactions: transverse myelitis, convulsions, meningitis, transient 
lesions of the posterior spinal column, cauda equina syndrome, Guillain-Barre 
syndrome, peripheral neuropathy, mental depression, vertigo, hearing loss, insomnia, 
ataxia, hallucinations, tinnitus, and drowsiness 
Renal reactions: toxic nephrosis with oliguria and anuria, nephritis, nephrotic 
syndrome, urinary tract infections, hematuria, crystalluria, proteinuria, and hemolytic-
uremic syndrome 
Other reactions: urine discoloration and skin discoloration, Goiter production, diuresis 
and hypoglycemia, oligospermia. Based on postmarketing experience when it is not 
always possible to reliably establish a causal relationship to drug exposure: elevated 
liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), 
jaundice, cholestatic jaundice, cirrhosis, and possible hepatocellular damage including 
liver necrosis and liver failure, folate deficiency, nephrolithiasis, oropharyngeal pain, 
angioedema 
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In addition, anorexia, headache, nausea, vomiting, gastric distress, pruritus, urticaria, 
rash, fever, sore throat, fever, pallor, purpura 
GLUCOCORTICOIDS 
Inadequate response or loss of response: defined as persistent signs and symptoms of active 
disease despite a history of at least one 4-week induction regimen that included a dose equivalent 
to prednisone 30 mg daily orally for 2 weeks or intravenously for 1 week OR 2 failed attempts to 
taper corticosteroids to below a dose equivalent to 10 mg prednisone (oral) daily. 
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to 
glucocorticoid treatment.  
As guidance, the US package insert of Medrol® lists the following AEs. Please check the 
respective latest label of your country as well (Medrol®, 2018): 
Fluid and electrolyte disturbances: sodium retention, congestive heart failure, 
hypertension, fluid retention, potassium loss, and hypokalemic alkalosis 
Musculoskeletal: muscle weakness, loss of muscle mass, steroid myopathy, osteoporosis, 
tendon rupture, vertebral compression fractures, aseptic necrosis of femoral and humeral 
heads, and pathologic fracture of long bones 
Gastrointestinal: peptic ulcer with or without perforation and hemorrhage, pancreatitis, 
abdominal distention, and ulcerative esophagitis 
Dermatologic: impaired wound healing, petechiae and ecchymoses, thin fragile skin, 
facial erythema, and increased sweating 
Neurological: increased intracranial pressure with papilledema (pseudo-tumor cerebri), 
convulsions, vertigo, and headache 
Psychic derangements: euphoria, insomnia, mood swings, personality changes, severe 
depression, psychotic manifestations, aggravated existing emotional instability or 
psychotic tendencies 
Endocrine: Cushingoid state, secondary adrenocortical and pituitary unresponsiveness, 
menstrual irregularities, decreased carbohydrate tolerance, manifestations of latent 
diabetes mellitus, increased requirements of insulin or oral hypoglycemic agents in 
diabetics 
Ophthalmic: posterior subcapsular cataracts, increased intraocular pressure, glaucoma, 
exophthalmos, and secondary ocular infections 
Metabolic: negative nitrogen balance due to protein catabolism 
Other: urticaria and other allergic, anaphylactic or hypersensitivity reactions 
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IMMUNOSUPPRESSANTS 
Azathioprine (AZA) 
Inadequate response or loss of response: defined as persistent signs and symptoms of active 
disease despite a history of AZA use for at least 12 weeks at daily doses ≥1.5 mg/kg, including 
its use as adjunctive therapy or steroid-sparing therapy. 
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related 
AZA treatment.  
As guidance, the US package insert of an AZA product lists the following AEs. Please check the 
respective latest label of your country as well (Imuran®, 2014): 
Gastrointestinal hypersensitivity reaction characterized by severe nausea, vomiting and 
potentially with diarrhea, rash, fever, malaise, myalgia, elevations in liver enzymes, and 
occasionally, hypotension 
Hypersensitivity pancreatitis 
Hepatotoxicity that may be associated with anorexia, diarrhea, jaundice and ascites 
Cytopenias: leukopenia, thrombocytopenia, anemias including macrocytic anemia, 
and/or pancytopenia, bone marrow suppression, and myelotoxicity 
Serious infections (bacterial, viral, fungal, protozoal, and opportunistic infections, 
including reactivation of latent infections) secondary to treatment 
Other: skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen 
balance, reversible interstitial pneumonitis, hepatosplenic T-cell lymphoma and Sweet’s 
syndrome (acute febrile neutrophilic dermatosis) 
Mercaptopurine (6-MP) 
Inadequate response or loss of response defined as persistent signs and symptoms of active 
disease despite a history of 6-MP use for at least 12 weeks at daily doses ≥0.75 mg/kg, including 
its use as adjunctive therapy or steroid-sparing therapy. 
Intolerance defined as documented treatment discontinuation for AEs suspected to be related to 
6-MP treatment.  
As guidance, the US package insert of a 6-MP product lists the following AEs. Please check the 
respective latest label of your country as well (Purinethol®, 2011):  
Myelosuppression: anemia, leukopenia, and thrombocytopenia 
Embryo-fetal toxicity 
Treatment-related malignancies 
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Renal: hyperuricemia and/or hyperuricosuria 
Gastrointestinal: including hepatotoxicity: elevated transaminases, elevated bilirubin, 
ascites potentially intestinal ulceration, oral lesions, nausea, vomiting, anorexia, 
diarrhea and sprue-like symptoms, pancreatitis 
Miscellaneous: skin rashes, hyperpigmentation, alopecia, drug fever, oligospermia 
Methotrexate (MTX) 
Inadequate response or loss of response: defined as failure to respond to at least one 8-week 
regimen of or maintain remission at doses of at least 15 mg/week, given by the intramuscular or 
subcutaneous route.  
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to 
MTX treatment.  
As guidance, the US package insert of an MTX product lists the following AEs. Please check the 
respective latest label of your country as well (Methotrexate®, 2018): 
Alimentary system: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, 
diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, 
pancreatitis 
Blood and lymphatic system disorders: anemia, aplastic anemia, pancytopenia, 
leukopenia, neutropenia and/or thrombocytopenia, lymphadenopathy and 
lymphoproliferative disorders, hypogammaglobulinemia  
Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic 
events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal 
vein thrombosis, thrombophlebitis, and pulmonary embolus) 
Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, 
speech impairment including dysarthria and aphasia, hemiparesis, paresis and 
convulsions, cognitive dysfunction, mood alteration, unusual cranial sensations, 
leukoencephalopathy, or encephalopathy 
Hepatobiliary: acute (elevated transaminases) and chronic (fibrosis and cirrhosis) 
hepatotoxicity decrease in serum albumin, and liver enzyme elevations 
Infection: opportunistic infections eg, Pneumocystis carinii pneumonia, pneumonia, 
sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, H. simplex hepatitis, 
and disseminated H. simplex 
Musculoskeletal system: stress fracture 
Ophthalmic: conjunctivitis, serious visual changes of unknown etiology 
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Pulmonary system: respiratory fibrosis, respiratory failure, interstitial pneumonitis, 
chronic interstitial obstructive pulmonary disease 
Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, 
alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic 
epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, and 
exfoliative dermatitis 
Urogenital system: severe nephropathy or renal failure, azotemia, cystitis, hematuria; 
defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, 
vaginal discharge, and gynecomastia; infertility, abortion, fetal defects 
Other: nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, 
osteoporosis, sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue 
necrosis and osteonecrosis, anaphylactoid reactions  
ANTI-TNF AGENTS 
Inadequate response or loss of response: defined as persistent signs and symptoms of active 
disease despite at least one 4-week induction regimen with the following minimum doses of:  
• infliximab (5 mg/kg IV, 2 doses at least 2 weeks apart) or  
• adalimumab (one 80 mg SC dose followed by one 40 mg dose at least 2 weeks apart) or 
• golimumab (one 200 mg SC dose followed by 100 mg dose at least 2 weeks apart) 
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to 
anti-TNF agents.  
As guidance, the US package insert of Humira lists the following AEs. Please check the 
respective latest labels for the other anti-TNF agents and the labels of your country as well 
(Humira®, 2017): 
Anaphylaxis or serious allergic reactions: generalized rash and flushing, 
hypersensitivity reactions including angioneurotic edema  
Development of neutralizing autoantibodies 
Body as a whole: pain in extremity, pelvic pain, surgery, thorax pain 
Cardiovascular system: arrhythmia, atrial fibrillation, chest pain, coronary artery 
disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, 
pericardial effusion, pericarditis, syncope, tachycardia, heart failure  
Gastrointestinal: cholecystitis, cholelithiasis, esophagitis, gastroenteritis, 
gastrointestinal hemorrhage, vomiting, nausea, abdominal pain, hepatic reactions 
including acute liver failure, hepatic necrosis  
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Lupus-like syndrome 
Endocrine system: parathyroid disorder  
Hemic and lymphatic system: cytopenias, pancytopenia, agranulocytosis, polycythemia 
Infections: tuberculosis (new and reactivation of latent tuberculosis) and opportunistic 
infections pneumonia, septic arthritis, prosthetic and postsurgical infections, erysipelas, 
cellulitis, diverticulitis, and pyelonephritis 
Metabolic and nutritional disorders: Dehydration, healing abnormal, ketosis, 
paraproteinemia, peripheral edema  
Musculoskeletal system: arthritis, bone disorder, bone fracture (not spontaneous), bone 
necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, tendon 
disorder 
Neoplasia: adenoma 
Nervous system: confusion, paresthesia, subdural hematoma, tremor  
Respiratory system: upper respiratory infection, sinusitis, flu syndrome, asthma, 
bronchospasm, dyspnea, lung function decreased, pleural effusion  
Special senses: cataract  
Thrombosis: thrombosis leg  
Urogenital system: cystitis, kidney calculus, menstrual disorder 
Other: headache, rash, injection site reaction, infusion-related reactions such as fever or 
chills, cardiopulmonary reactions such as chest pain, hypotension, hypertension, or 
dyspnea and/or pruritus or urticaria, back pain, urinary tract infection, hypertension  
TOFACITINIB 
Inadequate response or loss of response: defined as persistent signs and symptoms of active 
disease despite at least an 8-week induction regimen with the following minimum doses of:  
• 5 or 10 mg given orally twice daily for induction for 8 weeks 
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related to 
tofacitinib.  
As guidance, the US package insert of Xeljanz lists the following AEs. Please check the 
respective latest labels for your country as well (XELJANZ®, 2019): 
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Serious infections: upper respiratory tract infections, nasopharyngitis, urinary tract 
infections, pneumonia, cellulitis, Herpes zoster, and urinary tract infection, tuberculosis, 
opportunistic infections (excluding tuberculosis), diverticulitis, gastroenteritis 
Malignancies: solid cancers (lung, breast, gastric, colorectal, renal cell, and prostate), 
lymphoma, malignant melanoma, nonmelanoma skin cancer 
Laboratory abnormalities: lymphopenia, neutropenia, liver enzyme elevations (ALT, 
AST, bilirubin), elevated cholesterol levels (including includes hypercholesterolemia, 
hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, 
low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased), 
serum creatinine elevations, increased blood creatine phosphokinase 
Blood and lymphatic system disorders: anemia 
Metabolism and nutrition disorders: dehydration 
Psychiatric disorders: insomnia 
Nervous system disorders: paresthesia, headache 
Respiratory, thoracic and mediastinal disorders: dyspnea, cough, sinus congestion, 
interstitial lung disease 
Gastrointestinal disorders: abdominal pain, dyspepsia, vomiting, gastritis, nausea, 
diarrhea 
Hepatobiliary disorders: hepatic steatosis 
Skin and subcutaneous tissue disorders: rash, erythema, pruritus, acne 
Musculoskeletal, connective tissue, and bone disorders: musculoskeletal pain, 
arthralgia, tendonitis, joint swelling 
Neoplasms benign, malignant, and unspecified (including cysts and polyps): 
nonmelanoma skin cancers 
General disorders and administration site conditions: pyrexia, fatigue, peripheral 
edema 
Drug hypersensitivity: angioedema, urticarial 
Cardiovascular: pulmonary embolism 
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APPENDIX 5 GUIDANCE FOR DIAGNOSIS AND TREATMENT OF INCREASED 
GASTROINTESTINAL SYMPTOMS  
If, for any reason, the central laboratory is not available, the preferred diagnostic algorithm is to 
use the Alere Quik Chek card test (Figure A1). 
Figure A1 
Algorithm for C. difficile Diagnosis Using the Quick Check Card Test 
 
If the Alere Quik Chek card test is not available, then a diagnosis may be established by 
following either of the algorithms shown in Figure A2 (using PCR for toxin), Figure A3 using 
toxigenic culture) or Figure A4 (using toxigenic culture, followed by PCR). The rationale for the 
method in Figure A3 is that the majority of PCR tests are expected to be negative for toxin, thus 
obviating the need for the test at the central laboratory. The expected turnaround time at the 
central laboratory for a GDH card test is expected to be shorter than that for stool culture for 
C. difficile at the local laboratory. The details of the sensitivity and specificity of these tests were 
reported by Khanna (Khanna et al., 2017). 
When medically reasonable, treatment decisions should be deferred until an etiology has been 
determined. When this is not feasible, management of symptoms should be dictated by the 
clinical situation. 
 
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Figure A2 
Alternative 1 for C. difficile Testing Using Local Laboratory When No Alere 
Quick Chek Card Test is Available 
 
 
Figure A3 
Alternative 2 for C. difficile Testing Using Local Laboratory When No Card 
Test is Available  
 
 
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Figure A4 
Alternative 3 for C. difficile Testing Using Local Laboratory When No Alere 
Quick Chek Card Test is Available 
 
Treatment 
When medically reasonable, treatment decisions should be deferred until an etiology has been 
determined. When this is not feasible, management of symptoms should be dictated by the 
clinical situation. If management requires a prohibited treatment (eg, IV glucocorticoids for 
induction or maintenance studies) the subject should be withdrawn from treatment. 
If treatment has been deferred, once an etiology is determined (eg, C. difficile, disease 
exacerbation, Campylobacter), appropriate treatment should be promptly implemented without 
waiting for a scheduled visit. If the etiology is determined to be C. difficile, treatment guidelines 
conforming to the current Infectious Diseases Society of America recommendations for 
C. difficile infection (McDonald et al., 2018) or the recent expert review on C. difficile infection 
in IBD (Khanna et al., 2017) should be consulted. 
If C. difficile infection was identified, clinical improvement should be noted within about 5 days 
after the start of treatment. If improvement does not occur, the etiology is most likely an IBD 
flare secondary to C. difficile and treatment failure assessment should proceed per the protocol. 
Another possible explanation is primary failure of C. difficile therapy which is unlikely. 
If an infectious etiology other than C. difficile is identified, it should be managed as appropriate, 
with reference to current clinical guidelines (Shane et al., 2017). 
If any infectious etiology is determined, the site should contact the medical monitor to make him 
or her aware of the diagnosis and to discuss treatment and ongoing study participation. 
 
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
NCT Number:   
NCT03259308 
 
Study Title:  
A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group 
Efficacy and Safety Study of SHP647 as Induction Therapy in Subjects with 
Moderate to Severe Ulcerative Colitis (FIGARO UC 302) 
 
Study Number:  
SHP647-302 
 
 
SAP Version and Date:   
Version 2.0:  
 
04 Nov 2020 


STATISTICAL ANALYSIS PLAN
SHP647
PHASE 3
A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel group Efficacy and Safety 
Study of SHP647 as Induction Therapy in Subjects with Moderate to Severe Ulcerative Colitis 
(FIGARO UC 302)
PROTOCOL IDENTIFIER: SHP647-302
Study Sponsor(s):
Shire Human Genetic Therapies, Inc. ("Shire"),
300 Shire Way, Lexington, MA 02421 USA
Author:
, 
, PPD
Protocol:
V1 (06 Jul 2017); Amendment 1, 05 Sep 2018; Amendment 2, 
11 Nov 2019
SAP Version #:
       2.0
SAP Date:
       04 Nov 2020
Status:
Final
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REVISION HISTORY
Version 
Issue Date
Summary of Changes
1.0
13 Aug 2020
Final
2.0
04 Nov 2020
Updated text in Section 6.1.1 and Section 6.2.1.
Minor editorial and formatting changes.
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TABLE OF CONTENTS
REVISION HISTORY.....................................................................................................................2
TABLE OF CONTENTS.................................................................................................................3
LIST OF TABLES...........................................................................................................................6
LIST OF FIGURES .........................................................................................................................6
LIST OF APPENDIX ......................................................................................................................6
ABBREVIATIONS .........................................................................................................................7
1.
INTRODUCTION....................................................................................................................9
2.
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS ...........................................................10
2.1
Objectives.................................................................................................................10
2.1.1
Primary Objective .............................................................................................10
2.1.2
Key Secondary Objectives................................................................................10
2.1.3
Other Secondary Objectives..............................................................................10
2.1.4
Exploratory Objective(s)...................................................................................11
2.2
Estimand(s)...............................................................................................................11
2.3
Endpoints..................................................................................................................15
2.3.1
Primary Endpoint ..............................................................................................15
2.3.2
Key Secondary Endpoints.................................................................................15
2.3.3
Other Secondary Endpoints ..............................................................................15
2.3.4
Exploratory Endpoints ......................................................................................16
3.
STUDY DESIGN ...................................................................................................................18
3.1
General Description..................................................................................................18
3.2
Randomization .........................................................................................................20
3.3
Blinding....................................................................................................................21
3.4
Sample Size and Power Considerations...................................................................21
4.
STATISTICAL ANALYSIS SETS........................................................................................23
4.1
Screened Set .............................................................................................................23
4.2
Randomized Set........................................................................................................23
4.3
Safety Set..................................................................................................................23
4.4
Full Analysis Set ......................................................................................................23
5.
STUDY SUBJECTS...............................................................................................................24
5.1
Disposition of Subjects.............................................................................................24
5.2
Demographic and Other Baseline Characteristics....................................................24
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5.3
Smoking history .......................................................................................................26
5.4
Medical History........................................................................................................26
5.5
Prior Procedures and Medication .............................................................................26
5.6
Concomitant Therapies, Procedures and Medications .............................................27
5.7
Exposure to Investigational Product ........................................................................27
5.8
Measurements of Treatment Compliance.................................................................28
5.9
Protocol Deviations..................................................................................................28
6.
EFFICACY ANALYSES.......................................................................................................29
6.1
Analyses of Primary Efficacy Endpoint(s)...............................................................29
6.1.1
Sensitivity Analyses of Primary Efficacy Endpoint..........................................30
6.2
Analyses of Key Secondary Efficacy Endpoint(s)...................................................30
6.2.1
Sensitivity Analyses of Key Secondary Efficacy Endpoints ............................31
6.3
Analyses of Other Secondary Efficacy Endpoints ...................................................31
6.3.1
Sensitivity Analyses of Other Secondary Efficacy Endpoint(s) .......................34
6.4
Multiplicity Adjustment ...........................................................................................34
6.5
Analyses of Exploratory Endpoint(s).......................................................................35
6.6
Subgroup Analyses...................................................................................................37
7.
SAFETY ANALYSIS ............................................................................................................38
7.1
Adverse Events.........................................................................................................38
7.1.1
Adverse Events of Special Interest and other Potential Risks ..........................38
7.1.1.1
Hypersensitivity .....................................................................................39
7.2
Clinical Laboratory Data..........................................................................................39
7.3
Vital Signs................................................................................................................42
7.4
Electrocardiogram (ECG).........................................................................................43
7.5
Other Safety Data.....................................................................................................44
7.5.1
Targeted Neurological Assessment...................................................................44
7.5.2
Immunogenicity ................................................................................................44
7.5.3
Pregnancy Test and Follicle-stimulating Hormone Test...................................45
7.5.4
Contraception Check.........................................................................................45
7.5.5
Stool Microbiology ...........................................................................................45
7.5.6
Physical Examination........................................................................................45
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10. OTHER ANALYSES .............................................................................................................48
10.1
Coronavirus Pandemic .............................................................................................48
11. INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE.......................49
12. DATA HANDLING CONVENTIONS..................................................................................50
12.1
General Data Reporting Conventions ......................................................................50
12.2
Definition of Visit Windows....................................................................................50
12.3
Derived Efficacy Endpoints .....................................................................................52
12.3.1
Total Mayo Score..............................................................................................52
12.3.2
Partial Mayo Score............................................................................................53
12.3.3
Composite Score ...............................................................................................53
12.3.4
Mucosal Healing ...............................................................................................53
12.3.5
Total Sign/Symptom Score ...............................................................................53
12.3.6
IBDQ Total and Domain Scores .......................................................................54
.....................................................................................55
.......................................................................................55
......................................................................................56
12.3.10
SF-36.................................................................................................................56
12.4
Repeated or Unscheduled Assessments of Safety Parameters.................................57
12.5
Handling of Missing, Unused, and Spurious Data...................................................57
12.5.1
Missing Date of End of Treatment....................................................................57
12.5.2
Missing Date of Ulcerative Colitis Diagnoses..................................................57
12.5.3
Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) .....................................................................................57
12.5.3.1
Incomplete Start Date.............................................................................58
12.5.3.2
Incomplete Stop Date.............................................................................58
12.5.4
Missing Date Information for Adverse Events .................................................59
12.5.4.1
Incomplete Start Date.............................................................................59
12.5.4.2
Incomplete Stop Date.............................................................................59
12.5.5
Missing Severity Assessment for Adverse Events............................................59
12.5.6
Missing Relationship to IP for Adverse Events................................................59
12.5.7
Character Values of Clinical Laboratory Variables..........................................60
13. ANALYSIS SOFTWARE......................................................................................................61
14. CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ..................................................62
15. REFERENCES .......................................................................................................................63
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LIST OF TABLES
Table 1
List of Select Estimands ................................................................................12
Table 2
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints.....................................................................................22
Table 3
Criteria for Potentially Clinically Important Laboratory Tests .....................41
Table 4
Criteria for Potentially Clinically Important Vital Signs ..............................43
Table 5
Criteria for Potentially Clinically Important ECG Values ............................44
Table 6
Visit Windows (Study Day Based) – PRO, Mayo, 
, and 
Endoscopy Assessments................................................................................51
Table 7
Visit Windows (Study Day Based) – ADA and 
 Assessments.................51
Table 8
Visit Windows (Study Day Based) –
, IBDQ, 
, SF-36 
Assessments...................................................................................................51
Table 9
Visit Windows (Study Day Based) – Safety Lab and Vital Sign 
Assessments...................................................................................................52
Table 10
Visit Windows (Study Day Based) – Physical Examination, ECG, 
Neurological Testing, 
, 
 Assessments................................52
Table 11
Proposed Categorized Sign/Symptom Score Conversion Scale....................54
LIST OF FIGURES
Figure 1
Overview of ontamalimab Phase 3 Studies in Ulcerative Colitis..................19
Figure 2
SHP647-302 Study Design Flow Chart.........................................................20
Figure 3
Visualization of Alpha Propagation ..............................................................35
LIST OF APPENDIX
Appendix 1.
Schedule of Activities....................................................................................64
Appendix 2.
Geographic Region........................................................................................69
Appendix 3.
Rescue Therapy for UC.................................................................................70
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ABBREVIATIONS
ADA
anti-drug antibodies
ANCOVA
analysis of covariance
AE
adverse event
BMI
body mass index
BLQ
below the limit of quantification
CI
confidence interval
CDF
cumulative distribution function 
CMH
Cochran-Mantel Haenszel
DMC
data monitoring committee
eCRF
electronic case report form
ECG
electrocardiogram
 
ET
early termination
EOF
End of Follow-up  
EOT
End of Treatment
FAS
full analysis set
FWER
family-wise type I error rate
HEOR
Health Economics and Outcomes Research
HRQL
health-related quality of life
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
informed consent form
LLOQ
lower limit of quantification
IP
investigational product
LOCF
last observation carried forward
LTS
long-term safety extension
NAB
neutralizing antibodies
PCI
potentially clinically important
PDF
probability density function
PML
progressive multifocal leukoencephalopathy
PRO
patient-reported outcome
QoL
quality of life
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REML
restricted maximum likelihood
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous/subcutaneously
SF-36
Short Form-36 Health Survey
SOC
system organ class
TEAE 
treatment-emergent adverse event
TNF
tumor necrosis factor
UC
ulcerative colitis
VAS
visual analogue scale
WHO
World Health Organization
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1.
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of efficacy, safety, and Health Economics and Outcomes Research (HEOR) data, as 
well as descriptive summaries of 
 data, as 
described in Protocol Amendment 2 dated 11 Nov 2019 (original protocol dated 06 Jul 2017 and 
Protocol Amendment 1 dated 05 Sep 2018). Specifications for tables, figures, and listings are 
contained in a separate document. The analysis plans for 
 and HEOR patient-reported 
outcome (PRO) validation are prepared separately.
On May 29, 2020, Takeda announced the decision to discontinue the ontamalimab clinical trial 
program in ulcerative colitis and Crohn's disease. The planned analyses have been update 
reflecting the planned early discontinuation of this study. 
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2.
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS
2.1
Objectives
2.1.1
Primary Objective
To evaluate the efficacy of ontamalimab in inducing remission, based on composite score of 
patient-reported symptoms and centrally read endoscopy, in subjects with moderate to severe 
ulcerative colitis (UC).
2.1.2
Key Secondary Objectives
The key secondary objectives are as follows:

To evaluate the efficacy of ontamalimab in achieving endoscopic remission, based on 
centrally read endoscopy

To evaluate the efficacy of ontamalimab in achieving clinical remission, based on 
composite score of patient-reported symptoms

To evaluate the efficacy of ontamalimab in inducing clinical response, based on 
composite score of patient-reported symptoms and centrally read endoscopy

To evaluate the efficacy of ontamalimab in achieving mucosal healing, based on 
endoscopic and histological assessment using the Geboes Score grading system.
2.1.3
Other Secondary Objectives
The other secondary objectives are as follows:

To evaluate the safety and tolerability of ontamalimab

To evaluate the effect of ontamalimab induction treatment on other clinical and 
endoscopic outcomes (including Mayo-based remission and clinical response, partial 
Mayo score over time, clinical remission over time, endoscopic remission, and deep 
remission)

To evaluate the effect of ontamalimab on abdominal pain, urgency, diarrhea, and absolute 
stool frequency and bleeding scores

To evaluate the effect of ontamalimab on health-related quality of life (as measured by 
the Inflammatory Bowel Disease Questionnaire [IBDQ] and the Short Form-36 Health 
Survey [SF-36])

To evaluate the effect of ontamalimab on incidence of hospitalizations and total inpatient 
days.
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2.1.4
Exploratory Objective(s)
The exploratory objectives of the study are as follows:
2.2
Estimand(s)
The primary, key secondary, and secondary estimands are described in Table 1.
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Table 1
List of Select Estimands
Estimand
Definition
Attributes
A: Population
B: Variable 
C: Strategy for 
addressing 
intercurrent 
event
D: Population-level 
summary
Primary
The primary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 12 in 
remission
16-80 year old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol
Remission at the 
Week 12 visit without 
rescue therapy defined 
in Appendix 3 and
discontinuation  
Composite: 
intercurrent 
events captured in 
variable 
definition. 
Difference in proportions 
of subjects in remission at 
the Week 12 visit between 
each active treatment group 
(ontamalimab 25 mg, 
ontamalimab 75 mg) and 
placebo
Key 
Secondary
1st key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 12 in impact 
on endoscopic 
remission
16-80 year old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol
Endoscopic remission 
at the Week 12 visit, 
defined by centrally 
read endoscopic 
subscore 0 or 1 
(modified, excludes 
friability), at the 
Week 12 visit without 
rescue therapy defined 
in Appendix 3 and 
discontinuation
Composite: 
intercurrent 
events captured in 
variable 
definition. 
Difference in proportions 
of subjects in endoscopic 
remission at the Week 12 
visit between each active 
treatment group 
(ontamalimab 25 mg, 
ontamalimab 75 mg) and 
placebo
Key 
Secondary
2nd key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 12 in impact 
16-80 year old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
Clinical remission at 
the Week 12 visit, 
defined by stool 
frequency subscore of 
0 or 1 with at least a 
1-point change from 
Composite: 
intercurrent 
events captured in 
variable 
definition. 
Difference in proportions 
of subjects in clinical 
remission at the Week 12 
visit between each active 
treatment group 
(ontamalimab 25 mg, 
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Table 1
List of Select Estimands
Estimand
Definition
Attributes
A: Population
B: Variable 
C: Strategy for 
addressing 
intercurrent 
event
D: Population-level 
summary
on clinical remission
stated in the protocol
baseline in stool 
frequency subscore, 
and rectal bleeding 
subscore of 0, at the 
Week 12 visit without 
rescue therapy defined 
in Appendix 3 and 
discontinuation
ontamalimab 75 mg) and 
placebo
Key 
Secondary
3rd key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 12 in impact 
on clinical response
16-80 year old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol
Clinical response at 
the Week 12 visit, 
defined as the 
decrease from baseline 
in the composite score 
of patient-reported 
symptoms using daily 
e-diary and centrally 
read endoscopy of at 
least 2 points and at 
least 30%, with an 
accompanying 
decrease in the 
subscore for rectal 
bleeding ≥1 point or a 
subscore for rectal 
Composite: 
intercurrent 
events captured in 
variable 
definition. 
Difference in proportions 
of subjects with clinical 
response at the Week 12 
visit between each active 
treatment group 
(ontamalimab 25 mg, 
ontamalimab 75 mg) and 
placebo
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Table 1
List of Select Estimands
Estimand
Definition
Attributes
A: Population
B: Variable 
C: Strategy for 
addressing 
intercurrent 
event
D: Population-level 
summary
bleeding ≤1 without 
rescue therapy defined 
in Appendix 3 and 
discontinuation
Key 
Secondary
4th key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 12 in impact 
on mucosal healing
16-80 year old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol
Mucosal healing at the 
Week 12 visit, defined 
as mucosal healing 
based on endoscopic 
and histological 
assessment at the 
Week 12 visit. 
Mucosal healing is 
defined by centrally 
read endoscopic 
subscore 0 or 1 
(modified, excludes 
friability) and 
centrally read Geboes 
score of ≤2 without 
rescue therapy defined 
in Appendix 3 and 
discontinuation
Composite: 
intercurrent 
events captured in 
variable 
definition. 
Difference in proportions 
of subjects with mucosal 
healing at the Week 12 
visit between each active 
treatment group 
(ontamalimab 25 mg, 
ontamalimab 75 mg) and 
placebo
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2.3
Endpoints
2.3.1
Primary Endpoint
The primary efficacy endpoint is remission at the Week 12 visit. Remission is defined as a 
composite score of patient-reported symptoms using daily e-diary and centrally read endoscopy 
as follows:

stool frequency subscore of 0 or 1 with at least a 1-point change from baseline
AND

rectal bleeding subscore of 0
AND

endoscopic subscore of 0 or 1 (modified, excludes friability).
2.3.2
Key Secondary Endpoints

Endoscopic remission, as defined by centrally read endoscopic subscore 0 or 1 (modified, 
excludes friability), at the Week 12 visit.

Clinical remission, as defined by stool frequency subscore of 0 or 1 with at least a 1-point 
change from baseline in stool frequency subscore, and rectal bleeding subscore of 0, at 
the Week 12 visit.

Clinical response based on composite score at the Week 12 visit. Clinical response 
(composite) is defined as a decrease from baseline in the composite score of 
patient-reported symptoms using daily e-diary and centrally read endoscopy of at least 
2 points and at least 30%, with an accompanying decrease in the subscore for rectal 
bleeding ≥1 point or a subscore for rectal bleeding ≤1.

Mucosal healing based on endoscopic and histological assessment at the Week 12 visit. 
Mucosal healing is defined by centrally read endoscopic subscore 0 or 1 (modified, 
excludes friability) and centrally read Geboes score of ≤2.
2.3.3
Other Secondary Endpoints

Remission, defined as a total Mayo score ≤2 with no individual subscore (stool 
frequency, rectal bleeding, endoscopy [modified, excludes friability], and physician’s 
global assessment) exceeding 1, at the Week 12 visit.

Clinical response based on total Mayo score at the Week 12 visit. Clinical response 
(Mayo) is defined as a decrease from baseline in the total Mayo score of at least 3 points 
and at least 30%, with an accompanying decrease in the subscore for rectal bleeding 
≥1 point or a subscore for rectal bleeding ≤1.

Partial Mayo score ≤2 with no individual subscore >1 at the Week 4, 8, and 12 visits. The 
partial Mayo score does not include the endoscopy subscore.
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
Clinical remission as defined by stool frequency subscore of 0 or 1 with at least a 1-point 
change from baseline in stool frequency subscore, and rectal bleeding subscore of 0, at 
Weeks 4 and 8.

Endoscopic remission at the Week 12 visit with endoscopic subscore of 0.

Clinical remission at the Week 4, 8, and 12 visits with both rectal bleeding and stool 
frequency subscores of 0.

Deep remission at the Week 12 visit. Deep remission is defined as both endoscopic and 
rectal bleeding subscores of 0, and stool frequency subscore ≤1 and a centrally read 
Geboes score of ≤2.

Change from baseline at the Week 12 visit in abdominal pain, diarrhea, and urgency item 
scores, absolute stool frequency, absolute rectal bleeding and total sign/symptom score 
based on subject daily e-diary entries (average of rectal bleeding, stool frequency, 
abdominal pain, diarrhea, and urgency).

Change from baseline in IBDQ domain and total (absolute) scores (time frame: Week 0, 
Week 8, up to Week 12, or ET).

Change from baseline in SF-36, version 2, acute (physical and mental component 
summary scores and individual domain scores) to the Week 12/ET visit.

Incidence of all-cause hospitalizations and total inpatient days.
2.3.4
Exploratory Endpoints
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3.
STUDY DESIGN
3.1
General Description
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study designed to 
evaluate the efficacy and safety of ontamalimab in inducing remission in subjects with moderate 
to severe UC.
A total of 740 subjects (296 subjects at 25 mg ontamalimab, 296 subjects at 75 mg ontamalimab, 
and 148 subjects on placebo) are planned for enrollment into the study (Figure 1). Subjects must 
be at least 16 years of age and no more than 80 years of age at the time of signing the informed 
consent/assent form.
The study consists of a screening period up to 6 weeks and a 12-week treatment period. After the 
screening period, eligible subjects will be randomly assigned to receive 1 of 3 treatments (25 mg 
ontamalimab, 75 mg ontamalimab, or placebo) in a 2:2:1 ratio. Randomization will be stratified 
based upon the subject’s status of prior anti- TNF treatment (naive or experienced) and 
glucocorticoid use at baseline (on glucocorticoids at baseline versus not on glucocorticoids at 
baseline). Subjects will receive SC injections of ontamalimab or placebo, using a prefilled 
syringe (PFS), on Week 0/Day 1 (Visit 2), Week 4 (Visit 4), and Week 8 (Visit 5). Subjects will 
undergo efficacy, 
, 
, safety, and health outcome assessments at these visits as 
detailed in Table A1.
At the end of the 12-week treatment period, eligible subjects will be offered the opportunity to 
participate in a double-blind maintenance study (SHP647-303; for subjects who achieve clinical 
response) or an LTS study (SHP647-304; for subjects who do not achieve a clinical response) as 
shown in Figure 1. Subjects who withdraw early from the 12-week treatment period or who do 
not wish to enter the maintenance study (SHP647-303) or LTS study (SHP647-304) will 
continue into a 16-week safety follow-up period. Only those subjects who complete the full 
course of investigational product treatment in the induction studies (SHP647-301 or 
SHP647-302) will be eligible to continue in the maintenance study or LTS study.
The overall study design is shown in Figure 2.
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Figure 1
Overview of ontamalimab Phase 3 Studies in Ulcerative Colitis
a Clinical response is defined as:
1. A decrease from the induction study (SHP647-301 or SHP647-302) baseline in the composite score of patient-reported 
symptoms using daily e-diary and centrally read endoscopy of at least 2 points and at least 30%, with an accompanying decrease 
in the subscore for rectal bleeding ≥1 point or a subscore for rectal bleeding ≤1
OR 
2. A decrease from the induction study (SHP647-301 or SHP647-302) baseline total Mayo score of at least 3 points and at least 
30%, with an accompanying decrease in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of ≤1.
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Figure 2
SHP647-302 Study Design Flow Chart
LTS=long-term safety extension; W=week
a Subjects who withdraw early from the 12-week treatment period or who do not wish to enter the maintenance study 
(SHP647-303) or LTS study (SHP647-304) will continue into a 16-week safety follow-up period.
3.2
Randomization
The actual treatment given to individual subjects is determined by a randomization schedule.
The total Mayo score will be calculated at baseline (Visit 2) before randomization. Endoscopic 
subscore based on the central reader’s assessment will be used to determine eligibility. Subjects 
with a total Mayo score of ≥6, including a centrally read endoscopic subscore ≥2, rectal bleeding 
subscore ≥1, and stool frequency subscore ≥1, and who fulfill all other eligibility criteria, will be 
randomized in a ratio of 2:2:1 via a computer-generated randomization schedule to receive SC 
injections of 25 mg ontamalimab, 75 mg ontamalimab, or placebo, respectively. The 
randomization will be performed centrally and stratified by status of prior anti-TNF therapy 
(2 strata: Naive versus experienced) and glucocorticoid use at baseline (2 strata: on 
glucocorticoids at baseline versus not on glucocorticoids at baseline).
To ensure that the allocation of subjects with prior anti-TNF therapy exposure is similar to that 
observed in Study A7281009, the percentage of subjects with prior anti-TNF therapy exposure 
will be capped at 60% of the sample population. Additionally, in Japan only, enrollment of 
Japanese subjects with prior anti-TNF therapy exposure will be capped at 60%, to ensure 
comparability to the rest of the global study population. There will be no cap on the number of 
anti-TNF Naive subjects randomized.
Subject numbers are assigned to all eligible subjects as they consent to take part in the study. 
Within each site (numbered uniquely within a protocol), the subject number will be assigned to 
subjects according to the sequence of presentation for study participation.
Placebo
25 mg ontamalimab
75 mg ontamalimab
Screening: Up to 
6 weeks
Randomization
Maintenance study 
(SHP647-303)
or
LTS study 
(SHP647-304)
or
W0
W4
W8
Dosing:
Treatment period: 12 weeks
Week 12/End of 
Treatment
16-week safety 
follow-up perioda
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The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment will be 
automatically assigned by the IRT system.
Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment assignment as 
dictated by the study. In these cases, the same investigational product packing identification 
number may not be assigned to more than 1 subject.
3.3
Blinding
This is a double-blind, placebo-controlled study. All investigational and reference product 
(ontamalimab 25 mg, ontamalimab 75 mg, or placebo) will appear identical to protect the study 
blind.
Data that may potentially unblind the treatment assignment (eg, IP serum concentrations, 
antibodies to investigational product, treatment allocation, and IP preparation/accountability 
data) will be handled with special care during the data cleaning and review process. These data 
will be handled in such a way that, before unblinding, any data that may unblind study team 
personnel will be presented as blinded information or otherwise will not be made available. If 
applicable, unblinded data may be made available to quality assurance representatives for the 
purposes of conducting independent drug audits.
Whenever possible, the investigator or sub-investigator should contact the Shire physician and/or 
assigned medical monitor before breaking the blind. It is understood that in an emergency 
situation it may not be possible to communicate with the study team before breaking the blind. 
The safety of the subject should be of primary concern. When the blinding code is broken the 
reasons must be fully documented.
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded on the IRT and the source 
documents. Upon breaking the blind, the subject is withdrawn from the study, but should be 
followed up for safety purposes. The IRT will notify the relevant personnel in the event of any 
code break. Code-break information is held by the pharmacist/designated person at the site.
3.4
Sample Size and Power Considerations
Graphical methods are used to control the global family-wise Type I error rate (FWER) at the 
.05 level (2-sided) for the comparisons of the 2 ontamalimab treatment groups with the placebo 
group. Alpha is initially split equally at the .025 level (2-sided) for each of the pairwise treatment 
comparisons for the primary endpoint. Therefore, the power analysis and sample size estimation 
were calculated based on the chi-square test of proportions using nQuery Advisor Version 7.0 
(Statistical Solutions Ltd, Cork, Ireland) for an individual ontamalimab dose compared with 
placebo.
Power calculations are made based on assuming a .025 (2-sided) significance level for each 
pairwise treatment comparison. Approximately 1346 subjects will be screened to randomize 
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740 subjects (2:2:1 allocation ratio: 296 subjects in the 25 mg ontamalimab treatment group, 
296 subjects in the 75 mg ontamalimab treatment group, and 148 subjects in the placebo group) 
which would yield an approximately 90% power to detect individual pairwise treatment 
difference in the primary efficacy endpoint, remission at Week 12, of 11% (5% placebo versus 
16% ontamalimab).
Expected remission rates at Week 12 are based on observed rates from the A7281009 study and 
placebo remission rates from literature (Feagan et al., 2013; Sandborn et al., 2017). No 
adjustment for missing data is required in these sample size calculations as subjects with missing 
data for remission at Week 12 are imputed as failures and the above rates account for these 
subjects.
With the sample size of 740, Table 2 provides the power for detecting a treatment difference 
between a ontamalimab treatment group and the placebo group for the key secondary endpoints.
Table 2
Power to Detect the Corresponding Treatment Effect for Key Secondary 
Endpoints
Key Secondary Endpoint at Week 12
ontamalimab Premise
Placebo Premise
Power
Endoscopic remission
24%
8%
0.98
Clinical remission
30%
16%
0.85
Clinical response by composite score
50%
35%
0.78
Mucosal healing
15%
5%
0.84
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4.
STATISTICAL ANALYSIS SETS
4.1
Screened Set 
The Screened Set will consist of all subjects who have signed informed consent.
4.2
Randomized Set
The Randomized Set will consist of all subjects in the screened set for whom a randomization 
number has been assigned.
4.3
Safety Set  
The Safety Set will consist of all subjects who have received at least 1 dose of investigational 
product. Analysis will be performed according to the treatment regimen actually received 
regardless of the randomized treatment regimen.
4.4
Full Analysis Set
The Full Analysis Set (FAS) will consist of all subjects in the randomized set who have received 
at least 1 dose of investigational product. Analysis will be performed according to the 
randomized treatment regimen regardless of the treatment regimen actually received.
 
 
 
 
 
 
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5.
STUDY SUBJECTS
5.1
Disposition of Subjects
The number of screened subjects and the number of screen failures will be presented in the 
overall column. The number of subjects included in each analysis set (ie, Randomized, Safety, 
FAS, 
, and 
,) will be summarized by treatment group, ontamalimab all doses and overall. 
The percentage, based on the number of subjects in the Safety Set, will be presented for FAS, 
, and 
 Sets. The study analysis set classifications of each subject will be listed for the 
Screened Set. Subjects excluded from efficacy analysis will be listed for the Randomized Set.
The number and percentage of subjects who completed and prematurely discontinued during the 
treatment and follow-up periods will be presented for each treatment group, ontamalimab all 
doses and overall for the Safety Set. Reasons for premature discontinuation from the treatment 
and follow-up periods as recorded on the termination page of the electronic case report form 
(eCRF) will be summarized (number and percentage) by treatment group, ontamalimab all doses, 
and overall for the Safety Set. The number and percentage of subjects who continued to the 
follow-up period and who continued to SHP647-303 or 304 studies will be presented for each 
treatment group, ontamalimab all doses and overall for the Safety Set. 
The number and percentage of subjects who completed and prematurely discontinued the study 
will be presented for each treatment group, ontamalimab all doses and overall for the Safety Set. 
Subjects who complete 12 weeks treatment and rollover 303/304 or enter and complete safety 
follow-up will be considered completed the study. Reasons for premature discontinuation from 
the study are derived from reasons for premature discontinuation from the treatment and 
follow-up period. For subjects who discontinued from treatment, the reasons for discontinuation 
from the treatment will be presented regardless the status of safety follow up period. For subjects 
who completed the 12 weeks treatment and discontinued from safety follow up period, the 
reasons for discontinuation from the safety follow-up period will be presented. All subjects who 
prematurely discontinued during the treatment period, follow up period and study will be listed 
with their primary reason for discontinuation reason and duration of exposure for the Safety Set. 
In addition, number of subjects screened, randomized and completed will be summarized for 
each site. The duration of enrollment, in days, will be summarized for each site, and overall. 
Duration of enrollment will be calculated as (last date of contact for any subject at that site - the 
first date of informed consent for any subject at that site +1).
5.2
Demographic and Other Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented by each 
treatment group, ontamalimab all doses and overall for the Safety Set and FAS. 
Subject’s age is calculated as the difference between the date of birth and the date of informed 
consent. If day of birth is missing then the day will be imputed as 1, if both the day and month of 
birth are missing then the day will be imputed as 1 and the month will be imputed as 1 (January). 
The following demographic characteristics will be summarized in the following order in the 
tables: age, age category (<18, 18-<65 and >=65; <35 and >=35 ), sex (Male, Female), ethnicity 
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(Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown), region (North America, 
Western Europe, Eastern Europe, Asia (Japan/South Korea), ROW (Africa/Australia/Latin 
America/Middle East) in Appendix 2, race (American Indian or Alaska Native, Asian (Japanese, 
Korean, Other), Black or African American, White, Native Hawaiian or Other Pacific Islander, 
and Other), Japanese Ancestry (Currently living in Japan, Born in Japan and currently living 
outside of Japan for less than 5 years, and Other) and Korean Ancestry (Currently living in 
Korea, Born in Korea and currently living outside of Korea for less than 5 years, and Other). 
Baseline is defined as the last assessment prior to the first administration of the IP unless 
otherwise specified. The following baseline characteristics will be summarized: 

Weight, 

Height, 

Body mass index (BMI), 

UC disease duration and UC disease duration category (<1 years, >=1 - <3 years, >=3 -
<7 years and >=7 years), 

Total Mayo severity and total Mayo severity category (< 6, 6 - <9, and >=9),  

Stool frequency score (0,1,2 and 3), 

Rectal bleeding score (0,1,2 and 3),  

Findings of endoscopy (0,1,2 and 3),  

Physician global assessment (0,1,2 and 3), 

 
 
 

UC disease location (Proctitis, Procto-Sigmoidits, Left-sided Colitis, Extensive 
Colitis/Pancolitis)
Disease duration is the number of years from the date of UC diagnosis to the date of informed 
consent.
The following UC medication history/ use will be summarized.

Immunosuppressant Experienced (Yes vs. No), 

Immunosuppressant Use at Baseline (Yes vs. No), 

5-ASA Use at Baseline (Yes vs. No),

Anti-TNF Experienced (Experienced vs. Naive) (both randomized status and actual 
status), 

Anti-TNF Failure (Yes vs. No), 
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
Anti-TNF Failure Times (Anti-TNF Naive, Anti-TNF Experienced without Failure, 
Failed 1 Anti-TNF Therapy, Failed 2 Anti-TNF Therapies, Failed 3 or more Anti-TNF 
Therapies), 

Glucocorticoid Use at Baseline (Yes vs. No) (both randomized status and actual status),

Glucocorticoid Use at Baseline (Systemic and Topical, Systemic Only, Topical Only, 
None),

Systemic Glucocorticoid Dose at Baseline,

Systemic Glucocorticoid Dose at Baseline Category (<=10 mg, >10 mg), 

Maximum Prior Treatment Experience (Aminosalicylates experienced, Glucocorticoid 
experienced (further broken down into topical glucocorticoid experienced and systemic 
glucocorticoid experienced), Immunosuppressant experienced or Biologic failure, 
Immunosuppressant experienced and Biologic failure),

Glucocorticoid Use at Baseline AND Immunosuppressant Use at Baseline (Both 
Glucocorticoid and Immunosuppressant Use, Only Glucocorticoid Use, Only 
Immunosuppressant Use, Neither Glucocorticoid nor Immunosuppressant Use). 
5.3
Smoking history
Smoking history will be summarized for each treatment group and ontamalimab all doses.
5.4
Medical History
Medical history will be collected at the Screening Visit (Visit 1), including UC history and 
cardiac history. Medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 19.1 2016. The number and percentage of subjects who have 
general medical history will be summarized by each treatment group and ontamalimab all doses, 
system organ class (SOC), and preferred term. General medical history will be listed for the 
Safety Set.
Cardiovascular history information will be summarized by each treatment group and 
ontamalimab all doses. Cardiovascular history will be listed for the Safety Set.
UC history will be listed for the Safety Set.
5.5
Prior Procedures and Medication 
Prior medications will be coded using the World Health Organization (WHO) Drug Dictionary 
dated December 01, 2016.
Prior medication is defined as any medication with the start date prior to the date of the first dose 
of investigational product. Incomplete medication dates will be imputed as described in 
Section 12.5.3. 
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Prior medication for Indication Under Study usage will be summarized by the number and 
percentage of subjects in each treatment group and ontamalimab all doses, for subjects receiving 
each medication within each therapeutic class and preferred term for the Safety Set. Multiple 
medication usage by a subject in the same category will be counted only once. 
All prior medications and medical/surgical procedures will be listed for the Safety Set.
5.6
Concomitant Therapies, Procedures and Medications 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary dated 01 Dec 2016. Concomitant medication is defined as any medication with a start 
date prior to the date of the first dose of IP and continuing after the first dose of IP or with a start 
date between the dates of the first dose of IP and end of treatment date, inclusive. Medication 
that starts after the first dose of SHP647-303/304 IP will be collected in SHP647-303/304 
database and will not be considered as concomitant medication in SHP647-302. Incomplete 
medication dates will be imputed as described in Section 12.5.3. Any medication with a start date 
between the dates of the first dose of IP and end of treatment date, inclusive, or with a start date 
after the end of treatment date (post-treatment) will be considered a post-treatment concomitant 
medication.
Concomitant medication usage will be summarized by the number and percentage of subjects in 
each treatment group and ontamalimab all doses, for subjects receiving each medication within 
each therapeutic class and preferred term for the Safety Set. Multiple medication usage by a 
subject in the same category will be counted only once. Summaries are presented separately for 
“Indication Under Study” and “not for Indication Under Study”.
All medications, medical/surgical procedures and therapies will be listed for the Safety Set.
5.7
Exposure to Investigational Product
Investigational product (ontamalimab or placebo) will be administered SC every four weeks 
(Weeks 0, 4, and 8). Exposure to IP will be summarized by presenting the number of subjects 
who had 1 injection, 2 injections or 3 injections. Number of injections received will be 
summarized in each treatment group and ontamalimab all doses. 
Exposure to IP for the Safety Set will be summarized in terms of treatment duration, which is 
calculated as the number of days from the date of first dose of IP taken to the date of the last 
dose of IP taken + 29 days. Subject years of exposure is calculated as (Date of Last Dose of 
investigational product in this study – Date of First Dose of investigational product in this study 
+29)/365.25. Total subject years of exposure is calculated by summing of each subject years of 
exposure within each column.
Descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented to describe the exposure to IP by each treatment group and ontamalimab all doses.
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5.8
Measurements of Treatment Compliance 
Compliance for the treatment period is defined as the total number of SC injections administered 
from the start of the treatment until the end of the treatment divided by the number of injections 
expected to be taken during that time period, times 100. Percentage compliance will be 
summarized by treatment group.
5.9
Protocol Deviations
Protocol deviations will be recorded by Pharmaceutical Product Development (PPD) separately 
from the clinical database. PPD/Shire will classify significant and nonsignificant protocol 
deviations per the agreed protocol deviation management plan. The Shire study team will review 
the protocol deviations and their classification throughout the study and before treatment 
unblinding and database lock.
For any criteria for protocol deviations that can be completely implemented by a computer 
program, the detailed algorithm will be agreed upon. Details of such algorithms will be included 
in the derived dataset specifications and finalized before treatment unblinding.
Confirmed significant and nonsignificant protocol deviations will be documented in the Protocol 
Deviation tracker for the study. Significant and nonsignificant protocol deviations will be 
summarized by category and site for each treatment group, ontamalimab all doses and overall, 
for the Randomized Set. Significant and nonsignificant protocol deviations will be listed for the 
Randomized Set. 
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6.
EFFICACY ANALYSES
All efficacy analyses will be based on the FAS unless stated otherwise. Baseline for all efficacy 
analyses is defined as the last observed value for the efficacy assessment prior to taking the first 
dose of IP (based on dates or date/times) unless otherwise specified. 
All efficacy analyses will be conducted according to the randomized treatment, regardless of the 
treatment actually received.
All confidence intervals (CIs) will be 2-sided 95% CIs, unless stated otherwise. Control of 
Type I error is discussed in Section 6.4 in detail. 
For continuous endpoints, descriptive summary statistics will be presented by treatment group at 
each scheduled visit and will include the following: n, mean, median, standard deviation, 
minimum and maximum. For binary endpoints, number and percentage of subjects in each 
category will be summarized by treatment group at each scheduled visit. 
6.1
Analyses of Primary Efficacy Endpoint(s)
The primary efficacy endpoint is remission at the Week 12 visit. Remission is defined as a 
composite score of patient-reported symptoms using daily e-diary and centrally read endoscopy 
as follows:

stool frequency subscore of 0 or 1 with at least a 1-point change from baseline
AND

rectal bleeding subscore of 0
AND

endoscopic subscore of 0 or 1 (modified, excludes friability).
The primary efficacy endpoint will be compared for each active treatment group (25 mg or 
75 mg ontamalimab) to the placebo group using a Cochran-Mantel Haenszel (CMH) chi-square 
test stratified by actual status of prior anti-TNF treatment and glucocorticoid use at baseline. 
Subjects with the intercurrent events defined in Section 2.2 and/or with missing remission data at 
the Week 12 will be considered failures and counted as non-remission. The endoscopy score will 
be based on centrally read results.
The primary endpoint will be tested by the following hypothesis:
H0: δ = 0
H1: δ ≠ 0
where δ is the common treatment difference across strata, j=1 to m. The common treatment 
difference is a weighted average of the stratum-specific treatment differences.
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The estimate of the common treatment difference along with the corresponding stratified
Newcombe 95% CI using the method of Yan and Su (2010) and CMH p-value will be presented 
for each active treatment group to placebo comparison.
The proportion of subjects in remission at Week 12 will be plotted by each treatment group; by 
actual status of prior anti-TNF treatment and each treatment group; by actual glucocorticoid use 
at baseline and each treatment group. 
6.1.1
Sensitivity Analyses of Primary Efficacy Endpoint
If significant noncompliance with regulatory requirements during the course of the study is 
detected or reported at any clinical site, additional sensitivity analyses may be conducted on the 
primary efficacy endpoint by using the same approach but excluding all subjects from the 
noncompliant site(s).
6.2
Analyses of Key Secondary Efficacy Endpoint(s) 
Similarly to the primary endpoint, each secondary endpoint will be summarized by treatment 
group. Subjects with the intercurrent events defined in Section 2.2 and/or missing key secondary 
endpoint data at the Week 12 visit are considered failures. Each of the key secondary endpoints 
will be analyzed using the same approach as described for the primary efficacy endpoint using 
the following hypothesis:
H0: δ = 0
H1: δ ≠ 0
Where δ is the common treatment difference across strata, j=1 to m. The common treatment 
difference is a weighted average of the stratum-specific treatment differences.
The estimate of the common treatment difference along with the corresponding stratified 
Newcombe 95% CI using the method of Yan and Su (2010) and CMH p-value will be presented 
for each active treatment group to placebo comparison.
Proportion of subjects achieve secondary endpoint at Week 12 will be plotted by each treatment 
group; by actual status of prior anti-TNF treatment and each treatment group; by actual 
glucocorticoid use at baseline and each treatment group. 
The key secondary efficacy endpoints are:

Endoscopic remission, as defined by centrally read endoscopic subscore 0 or 1 (modified, 
excludes friability), at the Week 12 visit.

Clinical remission, as defined by stool frequency subscore of 0 or 1 with at least a 1-point 
change from baseline in stool frequency subscore, and rectal bleeding subscore of 0, at the 
Week 12 visit. 

Clinical response based on composite score at the Week 12 visit. Clinical response 
(composite) is defined as a decrease from baseline in the composite score of patient-reported 
symptoms using daily e-diary and centrally read endoscopy of at least 2 points and at least 
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30%, with an accompanying decrease in the subscore for rectal bleeding ≥1 point or a 
subscore for rectal bleeding ≤1.

Mucosal healing based on endoscopic and histological assessment at the Week 12 visit. 
Mucosal healing is defined by centrally read endoscopic subscore 0 or 1 (modified, excludes 
friability) and centrally read Geboes score of ≤2.
6.2.1
Sensitivity Analyses of Key Secondary Efficacy Endpoints
If significant noncompliance with regulatory requirements during the course of the study is 
detected or reported at any clinical site, additional sensitivity analyses may be conducted on the 
key secondary endpoints using the same approach but excluding all subjects from the 
noncompliant site(s).
6.3
Analyses of Other Secondary Efficacy Endpoints
Other secondary endpoints will be summarized by descriptive statistics at each visit the endpoint 
is assessed and presented by treatment group. In general, the following analysis methods, where 
specified, will be used to analyze the other secondary endpoints. 
Binary endpoints will be compared for each active treatment group (25 mg or 75 mg 
ontamalimab) to the placebo group using a CMH chi-square test stratified by actual status of 
prior anti-TNF treatment and glucocorticoid use at baseline. Subjects with the intercurrent events 
defined in Section 2.2 and/or missing binary endpoint data at a visit will be considered failures
(Yan and Su, 2010).
The estimate of the common treatment difference along with the corresponding stratified 
Newcombe 95% CI using the method of Yan and Su (2010) and CMH p-value will be presented 
for each active treatment group to placebo comparison.
Continuous endpoints that are measured repeatedly over time will be analyzed using a linear 
repeated measures mixed model with restricted maximum likelihood (REML) estimation. The 
model will include fixed effects for treatment group (categorical), visit (categorical), treatment 
group by visit interaction, actual status of prior anti-TNF treatment (categorical), and 
glucocorticoid use at baseline (categorical); baseline value as a continuous covariate; and 
repeated measures across visit for subject. From this model, estimates of least squares means, 
treatment differences, standard errors, p-values, size effect and 95% CIs for least squares mean 
treatment differences for each visit will be provided. The REML estimation, which is default in 
SAS, will be utilized along with the Kenward-Roger method for estimating the covariance matrix 
and degrees of freedom. The model will use an unstructured covariance type. If the fit of the 
unstructured covariance matrix fails to converge, the following covariance structures will be 
tried in order until convergence is reached: Heterogeneous Toeplitz, Toeplitz, Autoregressive (1) 
and Compound Symmetry.
The other secondary endpoints and analyses are noted below.

Remission, defined as a total Mayo score ≤2 with no individual subscore (stool frequency, 
rectal bleeding, endoscopy [modified, excludes friability], and physician’s global assessment) 
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exceeding 1. A CMH chi-square test that is described in Section 6.3 will be used to compare 
the proportion of subjects with remission for each active treatment group to placebo group in 
remission at Week 12.

Clinical response based on total Mayo score at the Week 12 visit. Clinical response (Mayo) is 
defined as a decrease from baseline in the total Mayo score of at least 3 points and at least 
30%, with an accompanying decrease in the subscore for rectal bleeding ≥1 point or a 
subscore for rectal bleeding ≤1. A CMH chi-square test that is described in Section 6.3 will 
be used to compare the proportion of subjects with clinical response for each active treatment 
group to placebo group with clinical response at Week 12.

Partial Mayo remission, defined as partial mayo score ≤2 with no individual subscore >1 at 
the Weeks 4, 8, and 12 visits. A CMH chi-square test that are described in Section 6.3 will be 
used to compared for the proportion of subjects with partial mayo remission for each active 
treatment group to placebo group in partial mayo remission at Weeks 4, 8, and 12.

Clinical remission as defined by stool frequency subscore of 0 or 1 with at least a 1-point 
change from baseline in stool frequency subscore, and rectal bleeding subscore of 0, at 
Week 4 and 8. A CMH chi-square test that is described in Section 6.3 will be used to 
compare the proportion of subjects with clinical remission for each active treatment group to 
placebo group in clinical remission at Week 4 and Week 8.

Endoscopic remission at the Week 12 visit with endoscopic subscore of 0. A CMH chi-
square test that is described in Section 6.3 will be used to compare the proportion of subjects 
with endoscopic remission for each active treatment group to placebo group in endoscopic 
remission at Week 12.

Clinical remission at the Week 4, 8, and 12 visits with both rectal bleeding and stool 
frequency subscores of 0. A CMH chi-square test that is described in Section 6.3 will be used 
to compare the proportion of subjects with clinical remission for each active treatment group 
to placebo group in clinical remission at Week 4 and Week 8.

Deep remission at the Week 12 visit. Deep remission is defined as both endoscopic and rectal 
bleeding subscores of 0, and stool frequency subscore ≤1 and a centrally read Geboes score 
of ≤2. A CMH chi-square test that is described in Section 6.3 will be used to compare the 
proportion of subjects with deep remission for each active treatment group to placebo group 
in deep remission at Week 12.

The absolute and change from baseline in abdominal pain, urgency, diarrhea, absolute stool 
frequency, and absolute rectal bleeding raw and categorized scores as well as the total 
sign/symptom score based on subject daily e-diary entries (average of rectal bleeding, stool 
frequency, abdominal pain, diarrhea, and urgency) will be summarized by descriptive 
statistics and presented by visits and each treatment group. The linear repeated measures 
mixed model that is described in Section 6.3 will be used to analyze change from baseline in 
the raw, categorized, and total scores with the change from baseline at each timepoint as the 
outcome variable. The cumulative distribution function (CDF) and probability density 
function (PDF) of change from baseline in the above scores at Week 12 will be plotted. The 
proportion of subjects with remission at Week 4, Week 8 and Week 12 will be summarized 
by treatment group and analyzed using a using a logistic regression with the effects of 
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treatment group, actual status of prior anti-TNF treatment and glucocorticoid use at baseline. 
The CDF of subjects in remission at Week 4, Week 8 and Week 12 will be plotted by each 
treatment group. The categorized scoring systems as well as the threshold for remission 
based on the total score will be confirmed after database lock according to the UC 
Patient-Reported Outcome (PRO) SAP and are subject to change after the psychometric 
assessment has been completed.

IBDQ total score and domain scores will be summarized by treatment group at baseline, 
Week 8, and Week 12. Change from baseline will also be summarized by treatment at 
Week 8 and Week 12. IBDQ individual scores, total score, and domain scores will be listed 
at all the visits. The linear repeated measures mixed model that is described in Section 6.3
will be used to analyze change from baseline in IBDQ total score and domain scores at 
Week 8 and Week 12.

Subjects with an improvement of >=16 points in the IBDQ total score will be designated as 
having an improvement in IBDQ total score. The proportion of subjects with IBDQ total 
score improvement at Week 8 and Week 12 will be summarized by treatment group and 
analyzed using logistic regression with the effects of treatment group, actual status of prior 
anti-TNF treatment and glucocorticoid use at baseline. The odds ratio for subjects with IBDQ 
total score improvement for the 25 mg vs placebo group and 75 mg vs placebo group, and the 
associated 95% CIs will be estimated from the models. The CMH chi-square test that is 
described in Section 6.3 will also be used to compare each active treatment group to placebo 
group in IBDQ total score improvement at Week 8 or Week 12. The CDF and PDF of IBDQ 
change from baseline at Week 12 will be plotted. 

Subjects with a total score >=170 will be classified as achieving IBDQ clinical remission. 
The proportion of subjects with IBDQ clinical remission at Week 8 and Week 12 will be 
analyzed using a logistic regression with the effects of treatment group, actual status of prior 
anti-TNF treatment and glucocorticoid use at baseline. The odds ratio for subjects in 
remission for the 25 mg vs placebo group and 75 mg vs placebo group, and the associated 
95% CIs will be estimated from the models. The CMH chi-square test that is described in 
Section 6.3 will also be used to compare each active treatment group to placebo group in 
IBDQ clinical remission at Week 8 or Week 12. 

Each SF-36 domain score, the physical component summary score, and the mental 
component summary score will be summarized by treatment group at baseline, Week 8, and 
Week 12. Change from baseline will also be summarized by treatment at Week 8 and 
Week 12. The linear repeated measures mixed model that is described in Section 6.3 will be 
used to analyze change from baseline in SF-36 domain and component summary scores at 
Week 8 and Week 12. Each SF-36 domain score, the physical component summary score, 
and the mental component summary score will be listed at all the visits.

Descriptive summary statistics of all-cause hospitalizations, gastrointestinal related hospital 
admission, other illness/problem related hospital admission, gastrointestinal related surgical 
procedures during hospital admission will be presented by treatment group during the entire 
treatment period and during the follow-up period, and will include the following: Number of 
Events and Number of Subjects with Events. 

Descriptive summary statistics of total inpatient days will be presented by treatment group 
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during the entire treatment period and during the follow-up period, and will include the 
following: n, mean, median, standard deviation, minimum and maximum.
6.3.1
Sensitivity Analyses of Other Secondary Efficacy Endpoint(s)
No sensitivity analyses of other secondary efficacy endpoints are planned for this study.
6.4
Multiplicity Adjustment
The global FWER for the statistical tests of the primary and key secondary endpoints will be 
strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in Bretz 
et al (2009) will be utilized to propagate α from primary to key secondary endpoints and between 
the two ontamalimab treatment group and placebo comparisons. Alpha is initially split equally at 
the .025 level (2-sided) for each of the pairwise treatment comparisons for the primary endpoint 
(P) and alpha is propagated in a hierarchical manner to each of the 4 key secondary endpoints 
(K1-K4) within a pairwise treatment comparison. A graphical visualization of the α propagation 
is presented in Figure 3. Statistical results with the p-value and significance for the primary and 
each key secondary endpoint will be presented.
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Figure 3
Visualization of Alpha Propagation
Only p-values that are significant according to this graphical approach are inferential and 
statistically significant. All other p-values are descriptive.
6.5
Analyses of Exploratory Endpoint(s) 
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The exploratory endpoints and analysis methods are noted below:
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6.6
Subgroup Analyses
Subgroup analyses are planned for the primary endpoint, the key secondary endpoints and the 
first other secondary endpoint (remission using total Mayo score). These endpoints will be 
derived by using the same strategy for handling intercurrent events and missing data as was done 
for endpoints in the overall population. 
Within subgroups, each endpoint will be summarized by treatment group and will be compared 
for each active treatment group (ontamalimab 25 mg and ontamalimab 75 mg) with the placebo 
group using a Chi-square test. The 95% CI for difference in proportion is based on unstratified 
Wilson CI. 
Subgroup variables are: 

Actual Anti-TNF Experienced (Experienced vs Naive)

Actual Glucocorticoid Use at Baseline (Yes vs No)
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7.
SAFETY ANALYSIS 
The safety analyses will be performed using the Safety Set. Safety variables include AEs, clinical 
laboratory variables, vital signs, electrocardiogram (ECG) variables, Anti-Drug Antibodies 
(ADA) and Neutralizing Antibodies (NAB) variables, and neurological variables. For each safety 
variable, the last value collected prior to the first dose of double-blind IP will be used as baseline 
for all analyses of that safety variable. A Final on-Treatment Assessment will be defined as the 
last valid assessment obtained after baseline and through the end of the treatment visit.
7.1
Adverse Events 
Adverse events will be coded using MedDRA Version 19.1 2016.
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates at the time of or following 
the first exposure to investigational product.
An overall summary of the number of subjects with TEAEs will be presented, including the 
number and percentage of subjects with any TEAEs, serious TEAEs, TEAEs related to 
investigational product, related serious AEs (SAE), and TEAEs leading to discontinuation of 
investigational product, and TEAEs leading to death.
The number of events, incidence, and percentage of subjects reporting TEAEs in each treatment 
group will be presented by treatment group and for ontamalimab all doses;  by preferred term; by 
SOC and preferred term; by SOC, preferred term, and maximum severity. TEAEs considered 
related to IP will also be summarized by SOC and preferred term. If more than 1 AE occurs with 
the same preferred term for the same subject, then the subject will be counted only once for that 
preferred term using the most severe and most related occurrence for the summarization by 
severity and by relationship to investigational product.
Most common TEAE (incidence ≥ 2% in any treatment group) will be summarized by preferred 
term, in each treatment group and for ontamalimab all doses. 
Serious TEAEs, TEAEs leading to discontinuation of the study or study medication and injection 
site adverse events will be summarized by SOC, preferred term, in each treatment group and 
ontamalimab all doses. Adverse events leading to withdrawal, serious AEs, and deaths will be 
similarly summarized or listed.
7.1.1
Adverse Events of Special Interest and other Potential Risks
There is one identified important potential risk of Progressive Multifocal Leukoencephalopathy. 
There are six other identified potential risks: immunotoxicity, immunogenicity, infection, 
vascular and thrombotic events, local tolerability and malignant tumours. Potential risks will be 
summarized by treatment group and for ontamalimab all doses. Important potential risk will be 
listed.
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7.1.1.1
Hypersensitivity
Potential hypersensitivity, serum sickness, vasculitis, and arthus reactions to ontamalimab will be 
regarded as AESIs. 
An external hypersensitivity adjudication committee is established to review reported 
hypersensitivity events and adjudicate whether the event was a hypersensitivity event, which 
Type (Type I or Type III) and recommendations of permanent discontinuation or re-challenge 
with investigational product. Reported hypersensitivity events, adjudicated hypersensitivity 
events and study drug recommendation will be summarized by treatment group and for 
ontamalimab all doses.
The number of events, incidence, and percentage of subjects reporting Treatment-emergent 
hypersensitivity events in each treatment group will be presented by treatment group and for 
ontamalimab all doses; by SOC, preferred term and hypersensitivity type. 
Reported hypersensitivity events and adjudicated hypersensitivity events will be listed for the 
safety set.
7.2
Clinical Laboratory Data
Descriptive statistics for clinical laboratory values (in conventional units) and changes from 
baseline at each assessment time point for quantitative variables will be presented by treatment 
group and for ontamalimab all doses for the following clinical laboratory variables. 
Serum chemistry

alkaline phosphatase 

AST

ALT

total bilirubin

total protein

albumin

glucose 

blood urea nitrogen 

creatinine

sodium 

potassium 

chloride 

calcium

carbon dioxide
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Hematology

hemoglobin 

hematocrit 

mean corpuscular hemoglobin

mean corpuscular hemoglobin concentration

mean corpuscular volume

erythrocyte (red blood cell) count

leukocyte (white blood cell) count

neutrophils

lymphocytes

monocytes

eosinophils

basophils

platelet count
Urinalysis

glucose

protein

specific gravity

pH

nitrite

bilirubin

ketones

hemoglobin

urobilinogen

leukocyte esterase
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 3. The number and percentage of subjects with 
post-baseline PCI values will be tabulated by treatment group. The percentages will be calculated 
relative to the number of subjects with at least 1 post-baseline assessment. The numerator is the 
total number of subjects with at least 1 post-baseline PCI value. A supportive listing of subjects 
with post-baseline PCI values will be provided including the subject number, site, baseline, and 
post-baseline values.
Figures will be presented for hematology and chemistry to show the changes in lab parameters 
over time. Data will be presented as box-and-whisker plots for each treatment group (placebo, 
ontamalimab 25 mg, and ontamalimab 75 mg) at each visit, with one lab parameter per page. 
Shifts (Low, Normal and High) from baseline to each visit will be presented by treatment group 
and for ontamalimab all doses for hematology, chemistry and urinalysis.
All laboratory data will be listed for the Safety Set.
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Table 3
Criteria for Potentially Clinically Important Laboratory Tests
Parameter
Age 
Range
Sex
Outlier Criteriaa
Low
High
Hematology
Hemoglobin
All
<8 g/dL
NA
Hematocrit
All
<32%
NA
Mean Corpuscular 
Hemoglobin
All
<LLN
>ULN
Mean Corpuscular 
Hemoglobin Concentration
All
<LLN
>ULN
Mean Corpuscular Volume
All
<LLN
>ULN
Erythrocyte (red blood cell)
All
<3.0 x 10^6/µL 
NA
Leukocytes (white blood 
cell) 
All
<3.0 x 10^3/µL 
>20 x 10^3/µL 
Neutrophils (Abs)
All
<1.5 x 10^3/µL 
>15 x 10^3/µL 
Neutrophils (%)
All
<40%
NA
Lymphocytes (Abs)
All
NA
NA
Lymphocytes (%)
All
<10%
>50%
Monocytes (Abs)
All
NA
NA
Monocytes (%)
All
NA
>25%
Eosinophils (Abs)
All
NA
NA
Eosinophils (%)
All
NA 
>10%
Basophils (Abs)
All
NA
NA
Basophils (%)
All
NA
>10%
Platelets
All
<75 x 10^3/µL 
>1,000 x 10^3/µL 
Chemistry
Alkaline Phosphatase
All

>2.5 x ULN (or 
alternatively 
>400 U/L)
Aspartate 
Aminotransferase (AST)
All

>2.5 x ULN
Alanine Aminotransferase 
(ALT)
All

>2.5 x ULN
Total Bilirubin 
All

>1.5 x ULN
Total Protein, plasma or 
serum
All
<5 g/dL
>9 g/dL
Albumin
All
<3 g/dL
NA
Glucose (fasting)
All
<55 mg/dL
>160 mg/dL
Blood Urea Nitrogen 
(BUN)
All

>2.5 x ULN (or 
alternatively 
>29.4 mg/dL)
Creatinine, serum
All

>1.5 x ULN (or 
alternatively
>1.98 mg/dL)
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Table 3
Criteria for Potentially Clinically Important Laboratory Tests
Parameter
Age 
Range
Sex
Outlier Criteriaa
Low
High
Sodium
All
<130 mEq/L
>150 mEq/L
Potassium, plasma or 
serum
All
<3 mEq/L
>5.5 mEq/L
Chloride
All
<90 mEq/L
>115 mEq/L
Calcium
All
<8.0 mg/dL
>11.2 mg/dL
Carbon dioxide (NCI uses 
bicarb)
All
NA
NA
DILI Screen (ongoing 
safety monitoring)
All
NA
AST or ALT >3 x 
ULN and
TBL >2 x ULN
Urinalysis
Bilirubin
All
NA
NA
Leukocyte esterase
All
NA
NA
Protein
All
NA
>=2+
Glucose
All
NA
NA
Blood
All
NA
NA
Ketones
All
NA
NA
Nitrite
All
NA
NA
pH
All
NA
NA
Specific gravity
All
NA
NA
Urobilinogen
All
NA
NA
NA=Not Applicable; LLN=Lower limit of normal provided by the laboratory; ULN=Upper limit of normal provided 
by the laboratory, Abs=Absolute, NCI = National Cancer Institute, DILI = Drug Induced Liver Injury.
a If criteria in both directions are shown for a single parameter, then abnormalities in each direction are summarized 
separately.
7.3
Vital Signs
Descriptive statistics for vital signs (eg, systolic and diastolic blood pressure, pulse rate, body 
weight, respiratory rate, and temperature) and their changes from baseline at each post-baseline 
visit and at the end of study will be presented by treatment group and for ontamalimab all doses.
For pulse rate, a post-baseline value is considered as a PCI value if its meets both criteria for 
observed value and change from baseline. For systolic/diastolic blood pressure, a post-baseline 
value is considered as a PCI value if it meets criteria for observed value or change from baseline. 
For weight and BMI, a post-baseline value is considered as a PCI value if it meets criteria for 
change from baseline. The PCI criteria are listed in Table 4. The number and percentage of 
subjects with PCI post-baseline values will be tabulated by each treatment group and 
ontamalimab all doses treatment group. The percentages will be calculated relative to the number 
of subjects with at least 1 post-baseline assessment. The numerator is the total number of 
subjects with at least 1 PCI post-baseline vital sign value. A supportive listing of subjects with 
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post-baseline PCI values will be provided including the subject number, site, baseline, and 
post-baseline values. 
All vital signs data will be listed for the Safety Set.
Table 4
Criteria for Potentially Clinically Important Vital Signs
Vital Sign Parameter
Flag
Criteriaa
Observed Value
Change from Baseline
Systolic blood pressure
(mmHg)
High
180
Increase of 20
Low
90
Decrease of 20
Diastolic blood pressure (mmHg)
High
105
Increase of 15
Low
50
Decrease of 15
Pulse rate
(beats per minute)
High
120
Increase of 15
Low
50
Decrease of 15
Weight (kg)
High
-
Increase of 7%
Low
-
Decrease of 7%
BMI (kg/m2)
High
-
Increase of 10%
Low
<18
Decrease of 10%
Temperature (◦C)
NA
NA
a For pulse rate, a post-baseline value is considered as a PCI value if its meets both criteria for observed value and change from 
baseline. For systolic/diastolic blood pressure, a post-baseline value of is considered as a PCI value if its meets criteria for 
observed value or change from baseline. For weight and BMI, a post-baseline value is considered as a PCI value if it meets 
criteria for change from baseline. NA=Not Applicable.
7.4
Electrocardiogram (ECG)
A central ECG reader will be used. Descriptive statistics for ECG variables (eg, heart rate, PR 
interval, QRS interval, QT interval, and QTc interval using both Bazett and Fridericia 
corrections) and their changes from baseline at each assessment time point will be presented by 
treatment group. ECG interpretation will be summarized by visit. A shift table from baseline to 
Week 12 for ECG Interpretation results will be presented by treatment group and for 
ontamalimab all doses.
ECG variable values will be considered PCI if they meet or exceed the upper limit values listed 
in Table 5. The number and percentage of subjects with post-baseline PCI values will be 
tabulated by treatment group and for ontamalimab all doses. The percentages will be calculated 
relative to the number of subjects with at least 1 post-baseline assessment. The numerator is the 
total number of subjects with at least 1 post-baseline PCI value. 
Listings of ECG data including the central reader’s assessment and investigator's interpretation 
by individual subject will be produced. Separate listings will be produced for subjects with ECG 
results meeting the PCI criteria. Data from unscheduled visits will be listed, but not summarized.
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Table 5
Criteria for Potentially Clinically Important ECG Values
ECG Parameter
Unit
Higher Limit
QRS Interval
msec
150
PR Interval
msec
250
QTc Interval
msec
500
7.5
Other Safety Data
7.5.1
Targeted Neurological Assessment
The targeted neurological evaluation results and neurological consult evaluation results with 
unexplained abnormal neurological findings will be summarized at screening and at each visit 
and by treatment group and for ontamalimab all doses. The number and percentage of subjects 
with targeted neurological exam in each of the neurological domains (vision, motor, tactile 
sensation, coordination/cerebellar function, speech, verbal comprehension, and 
cognition/behavior) will be summarized by the result category (abnormal, normal, not done) at 
each visit and by treatment group and for ontamalimab all doses. The number and percentage of 
subjects who were referred for a neurological consult and the results (no PML, 
leukoencephalopathy, no clinically significant finding, other clinically significant finding, not 
done) will also be summarized by treatment group and for ontamalimab all doses.
7.5.2
Immunogenicity
Presence of Anti-Drug Antibodies (ADAs) will be listed and summarized by visit for each 
treatment group and for ontamalimab all doses.
ADAs will be classified into pre-existing, treatment-induced responses and treatment-boosted 
responses. Pre-existing is defined as a signal detected prior to treatment. Treatment-induced 
responses are defined as a negative pretreatment sample with at least one positive sample at a 
subsequent time point. Treatment-boosted responses are defined as positive pretreatment samples 
that are boosted to a higher level following drug administration. Those categories will be listed 
and summarized for each treatment group and for ontamalimab all doses.
Neutralizing antibodies will be tested on ADA-positive subjects and samples will be defined as 
Nab-Positive or Negative. Presence of neutralizing antibodies will be listed and summarized for 
all ADA-positive subjects by visit for each treatment group and for  ontamalimab all doses.
ADA prevalence will also be calculated and summarized for each treatment group and for 
ontamalimab all doses. ADA prevalence is the proportion of study population having 
drug-reactive antibodies (ADA) at any time point (including pre-existing antibodies) during the 
study.
ADA incidence will be calculated and summarized for each treatment group and for 
ontamalimab all doses. ADA incidence is the proportion of study population found to have 
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developed ADA or boosted their ADA (including pre-existing ADA) at any point during the 
study period  
Listings of positive immunogenicity results and Individual subject immunogenicity data will be 
presented.
7.5.3
Pregnancy Test and Follicle-stimulating Hormone Test
Pregnancy tests are not required for females of nonchildbearing potential. All pregnancy tests 
data will be listed for the Safety Set. 
7.5.4
Contraception Check
Contraception Check should be performed for female subjects of childbearing potential and male 
subjects who are with a partner of childbearing potential. Contraception check results will be 
listed for the Safety Set.
7.5.5
Stool Microbiology
Stool microbiology will be performed at the screening visit (Visit 1) or at any time a subject 
experience an increase in Gastrointestinal symptoms. Stool microbiology data will be listed for 
the Safety Set. 
7.5.6
Physical Examination
Complete and targeted physical examinations will be performed at the time points specified in 
Table A1. Physical examinations results will be listed for the Safety Set.
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10.
OTHER ANALYSES
10.1
Coronavirus Pandemic
The Coronavirus (COVID-19) pandemic of 2019-20 particularly poses risks to the safety of 
subjects enrolled in clinical trials, and the availability and interpretability of data from those 
trials. COVID-19 impacts on individual subjects collected on COVID-19 CRF pages will be 
listed for the Randomized Set. Protocol deviations related to COVID-19 will be listed for the 
Randomized Set.
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11.
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE 
A data monitoring committee (DMC) was set up to review the safety during the course of the 
trial. The DMC will not review efficacy data. 
No interim analyses are planned for this study. 
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12.
DATA HANDLING CONVENTIONS
12.1
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, standard deviation, minimum, and maximum. For the summary statistics of all 
numerical variables, unless otherwise specified, minimum and maximum will be displayed to the 
same level of precision as reported. Mean and median will be displayed to one level of precision 
greater than the data collected. Standard deviation will be displayed to two levels of precision 
greater than the data collected.
Categorical and count variables will be summarized by the number of subjects (n) and the 
percent of subjects in each category. Percentages will be presented with 1 decimal place. When 
count data are presented, the percentage will be suppressed when the count is zero. A row 
denoted “Missing” will be included in count tabulations only if there are missing values. The 
denominator for all percentages will be the number of subjects in that treatment within the 
population of interest, unless otherwise specified.
P-values will generally be presented to 3 decimal places; values less than 0.001 will be presented 
as <0.001.
‘ONTA’ is the acronym of ontamalimab which will be used in output treatment presentation.
12.2
Definition of Visit Windows 
Assessments will be assigned to visits based upon the date the assessment took place regardless 
of the completed CRF page. Assessments will be mapped to visits as outlined in the Table 6, 
Table 7, Table 8, Table 9, and Table 10.
Should there be more than 1 assessment mapped into a given study visit with non-missing 
results, the assessment closest to the planned visit will be used for analysis (referred to as 
analysis visit); in case of ties between observations the later assessment will be used. 
Study day will be calculated as follows 

If the assessment date is on or after the date of first dose of IP: 
Study day = assessment date – first dosing date +1

If the assessment date is before the date of first dose of IP:
Study day = assessment date – first dosing date
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Table 6
Visit Windows (Study Day Based) – PRO, Mayo, 
, and Endoscopy 
Assessments
Visit
Planned Study Day
Start Day of Window
End Day of Window
Baseline
1 
ICF Date
<=1
Week 4
28
2
42
Week 8
56
43
70
Week 12
84
>70
EOT Date
*To accommodate the scheduling of the endoscopy prior to the Week 12 visit, the start day of the 
analysis window will be extended to > 61 for this parameter only if there is a valid assessment of 
stool frequency and rectal bleeding mapped to Week 12.
**
 is not collected before treatment starts. 
Table 7
Visit Windows (Study Day Based) – ADA and 
 Assessments
Visit
Planned Study Day
Start Day of Window
End Day of Window
Baseline
1 
ICF Date
<=1
Week 2
14
2
20
Week 4
28
21
42
Week 8
56
43
70
Week 12
84
>70
EOT Date
Follow-up
EOT Date + 112
EOT Date+1
EOF Date
*
 is not collected at follow-up visit
Table 8
Visit Windows (Study Day Based) –
, IBDQ, 
 SF-36 Assessments
Visit
Planned Study Day
Start Day of Window
End Day of Window
Baseline
1 
ICF Date
<=1
Week 8
56
2
70
Week 12
84
>70
EOT Date
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Table 9
Visit Windows (Study Day Based) – Safety Lab and Vital Sign Assessments
Visit
Planned Study Day
Start Day of Window
End Day of Window
Baseline
1 
ICF Date
<=1
Week 4
28
2
42
Week 8
56
43
70
Week 12
84
>70
EOT Date
Follow-up
EOT Date + 112
EOT Date+1
EOF Date
Table 10
Visit Windows (Study Day Based) – Physical Examination, ECG, Neurological 
Testing, 
, 
 Assessments
Visit
Planned Study Day
Start Day of Window
End Day of Window
Baseline
1 
ICF Date
<=1
Week 12
84
2
EOT Date
Follow-up
EOT Date + 112
EOT Date+1
EOF Date
*Note, ECG, 
, 
do not have scheduled assessments in Follow-up.
12.3
Derived Efficacy Endpoints 
12.3.1
Total Mayo Score
The Mayo score is a measure of UC disease activity. The total Mayo score ranges from 0 to 12 
points and consists of the following 4 subscores, each graded from 0 to 3 with higher scores 
indicating more severe disease:

Stool frequency (0-3)

Rectal bleeding (0-3)

Findings of endoscopy (0-3)

Physician global assessment (PGA, 0-3).
The calculation of the total score requires stool frequency subscore and rectal bleeding subscore, 
reported by subjects in the PRO UC daily e-diary and PGA and the centrally read endoscopic 
subscore.
The Mayo stool frequency and rectal bleeding subscores will be calculated based on each 
subject’s daily e-diary data recorded over the most recent 3 days (consecutive or nonconsecutive) 
of the last 10 days prior to the scheduled visit start date excluding the following days: day of any 
bowel preparation, day of endoscopy, any days between day of bowel preparation and day of
endoscopy, and the 2 days after the day of endoscopy. The most recent 3 days subscores will be 
averaged and rounded to the nearest score according to standard rounding rules. PGA and 
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centrally read endoscopic subscore will be collected at baseline and the Week 12 visit. The total 
mayo score is the sum of the 4 subscores, and will be calculated at baseline and at the Week 12 
visit. 
12.3.2
Partial Mayo Score
The partial Mayo score consists of the Mayo score without the endoscopic subscore and ranges 
from 0 to 9 points.
The calculation of the partial Mayo score requires the stool frequency subscore and the rectal 
bleeding subscore, reported by subjects in the PRO UC daily e-diary and PGA.
The partial mayo score will be calculated at baseline, and the Week 4, Week 8 and Week 12 
visits.
12.3.3
Composite Score
The composite score is a regulatory-authority recommended measure derived from the Mayo 
score omitting the PGA subscore and ranges from 0 to 9 points.
12.3.4
Mucosal Healing
Mucosal healing is based on the endoscopic and histological assessment at the Week 12 visit. 
Mucosal healing is defined by the centrally read endoscopic subscore 0 or 1 (modified, excludes 
friability) and the centrally read Geboes score of ≤2.
Mucosal healing based on endoscopic and histological assessment at the Week 12 visit. Mucosal 
healing is defined by centrally read endoscopic subscore 0 or 1 (modified, excludes friability) 
and 
, with lamina propria neutrophils, 
neutrophils in epithelium, and erosion or ulceration scores of 0.
12.3.5
Total Sign/Symptom Score
Patient-reported UC signs and symptom data will be collected using a daily e-diary starting 
during the screening period. Collection of the daily e-diary data must begin at least 10 days 
before the baseline visit. Subjects will enter data on UC signs and symptoms items using an 
electronic handheld device that will be provided to subjects at the start of the study. Compliance 
is assessed by site staff at each visit. The site staff will instruct the subject on the appropriate use 
of the e-diary, particularly when compliance is below 80% (eg, <23 out of 28 e-diary entries) 
when compared with the previous visit.
Subjects will be asked to record the following signs and symptom data, as experienced over the 
previous 24 hours, in the e diary: 

Stool frequency: Number of Bowel Movements (0-99)

Rectal bleeding severity and frequency: Rectal Bleeding Worst Experience (0-3) and 
Number of Bowel Movements with Blood (0-99)

Diarrhea frequency: Number of Loose Bowel Movements (0-99)
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
Urgency frequency: Number of Bowel Movements with Urgency (0-99)

Abdominal pain worst severity: Worst Abdominal Pain Over the Past 24 Hours (0-10)
Note: In the instrument, if the Number of Bowel Movements is entered as 0, then the rest of 
questions except Worst Abdominal Pain Over the Past 24 Hours question are skipped as they are 
further questions about the bowel movements. These skipped items will be considered as 0 for 
analysis purposes.
Subject’s signs and symptom average scores at each scheduled visit will be calculated based on 
data recorded over the most recent 3 days (consecutive or nonconsecutive) of the last 10 days 
prior to the scheduled visit start date excluding the following days: day of any bowel preparation, 
day of endoscopy, any days between day of bowel preparation and day of endoscopy, and the 
2 days after the day of endoscopy. Daily signs and symptom records will be assigned to visits 
based on visit window in Table 6. The assessment closest to the planned visit day will be used 
for analysis at that visit. 
Number of bowel movements and rectal bleeding worst experience will be used to determine the 
Mayo stool frequency and rectal bleeding subscores, which will be used to calculate the total and 
partial Mayo scores and the composite score. Subject’s signs and symptom average scores of 
number bowel movements with blood, number bowel movements with urgency, number of 
bowel movements and number of loose bowel movements will be converted to same scale as 
shown in Table 11. No conversion will be applied for average scores of worst abdominal pain 
over the past 24 hours. 
Table 11
Proposed Categorized Sign/Symptom Score Conversion Scale
Response
Conversion (applied to each item)
0-2
0
3-5
2.5
6-8
5
9-11
7.5
>=12
10
Total sign/symptom score is the average of the average scores of worst abdominal pain over the 
past 24 hours and the conversion scale values for number of bowel movements blood, number of 
bowel movements with urgency, number of bowel movements and number of loose bowel 
movements, with scale range of 0-10. The categorized and total score scoring systems will be 
confirmed after database lock according to the UC PRO SAP and are subject to change after the 
psychometric assessment has been completed.
12.3.6
IBDQ Total and Domain Scores
The IBDQ is a psychometrically validated patient-reported outcome instrument for measuring 
the disease-specific HRQL in subjects with inflammatory bowel disease, including UC. The 
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IBDQ consists of 32 items (scale: 1-7), which are grouped into 4 domains: bowel function, 
emotional status, systemic symptoms, and social function. Each domain score is calculated as the 
sum of the questions scores within the domain as follows: 

Bowel function – sum of scores for questions (1, 5, 9, 13, 17, 20, 22, 24, 26, 29).

Emotional status - sum of scores for questions (3, 7, 11, 15, 19, 21, 23, 25, 27, 30, 31, 32).

Systemic symptoms - sum of scores for questions (2, 6, 10, 14, 18).

Social function - sum of scores for questions (4, 8, 12, 16, 28).
The IBDQ total score is the sum of scores for all 32 questions and ranges from 32 to 224. For the 
total score and for each domain, a higher score indicates better HRQL. Domain score is missing 
if one or more item scores are missing. Total score is missing if one or more domain scores are 
missing.
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12.3.10
SF-36
The SF-36 (version 2) consists of 36 items that are aggregated into 8 multi-item scales (physical 
functioning, role – physical, bodily pain, general health, vitality, social functioning, role –
emotional, and mental health), with scores ranging from 0 to 100. Higher scores indicate better 
HRQL.
These 8 subscales (domains) will be scored using norm-based methods that have standardized 
the scores to a mean of 50 and a standard deviation of 10 in the general population. The scores 
range from 0 to 100, with a higher score indicating better quality of life. Physical component 
summary and mental component summary scores will be calculated by taking a weighted linear 
combination of the 8 individual subscales.
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The physical component summary of the SF-36 V2.0 consists of these 4 subscales:

Physical functioning

Role-physical

Bodily pain

General health
The mental component summary of the SF-36 V2.0 consists of these 4 subscales:

Vitality

Social functioning

Role-emotional

Mental health
12.4
Repeated or Unscheduled Assessments of Safety Parameters 
Assessments will be assigned to visits based on the date the assessment took place regardless of 
the completed CRF page. Assessments will be mapped to visits as outlined in Table 6, Table 7, 
Table 8, Table 9, and Table 10.
If a subject has more than 1 assessment mapped into a given study visit with non-missing results, 
the assessment closest to the planned visit will be used for analysis. However, all post-baseline 
assessments will be used for PCI value determination. 
12.5
Handling of Missing, Unused, and Spurious Data 
12.5.1
Missing Date of End of Treatment
When the date of the end of treatment is missing for a subject, all efforts should be made to 
obtain the date from the investigator. If it is still missing after all efforts, then the last dose date 
+28 days will be used in the calculation of treatment duration. 
12.5.2
Missing Date of Ulcerative Colitis Diagnoses
If day of diagnosis date is missing, then the day will be imputed as 1; if both the day and month 
of diagnosis date are missing, then the day will be imputed as 1 and the month will be imputed as 
1 (January).
12.5.3
Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures)
For prior or concomitant medications, including rescue medications, incomplete (ie, partially 
missing) start date and/or stop date will be imputed. When the start date and the stop date are 
both incomplete for a subject, impute the start date first.
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12.5.3.1 Incomplete Start Date 
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date.
MISSING DAY AND MONTH

If the year of the incomplete start date is the same as the year of the date of the first dose of 
investigational product, then the day and month of the date of the first dose of IP will be 
assigned to the missing fields

If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields

If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields.
MISSING MONTH ONLY

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
MISSING DAY ONLY

If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of investigational product, then the day of the date of the first dose of 
IP will be assigned to the missing day

If either the year is before the year of the date of the first dose of IP or if both years are the 
same but the month is before the month of the date of the first dose of investigational 
product, then the last day of the month will be assigned to the missing day

If either the year is after the year of the date of the first dose of IP or if both years are the 
same but the month is after the month of the date of the first dose of investigational 
product, then the first day of the month will be assigned to the missing day.
12.5.3.2 Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of IP is missing, then replace it with the last visit date. If the imputed stop date is before the 
start date (imputed or non-imputed start date), then the imputed stop date will be equal to the 
start date.
MISSING DAY AND MONTH

If the year of the incomplete stop date is the same as the year as of the date of the last dose 
of investigational product, then the day and month of the date of the last dose of IP will be 
assigned to the missing fields

If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields
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
If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields.
MISSING MONTH ONLY

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
MISSING DAY ONLY

If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of investigational product, then the day of the date of the last dose of 
IP will be assigned to the missing day

If either the year is before the year of the date of the last dose of IP or if both years are the 
same but the month is before the month of the date of the last dose of investigational 
product, then the last day of the month will be assigned to the missing day

If either the year is after the year of the last dose of IP or if both years are the same but the 
month is after the month of the date of the last dose of investigational product, then the 
first day of the month will be assigned to the missing day.
12.5.4
Missing Date Information for Adverse Events 
For AEs, the default is to only impute incomplete (ie, partially missing) start dates. If start date is 
missing, no imputation will be performed. 
12.5.4.1 Incomplete Start Date 
Follow the same rules as in Section 12.5.3.1.
12.5.4.2 Incomplete Stop Date 
NA
12.5.5
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned. If the severity is missing for an AE starting 
on or after the date of the first dose of investigational product, then a severity of “Severe” will be 
assigned. The imputed values for severity assessment will be used for incidence summaries, 
while the actual values will be used in data listings.
12.5.6
Missing Relationship to IP for Adverse Events 
If the relationship to IP is missing for an AE starting on or after the date of the first dose of 
investigational product, a causality of “Related” will be assigned. The imputed values for 
relationship to double-blind IP will be used for incidence summaries, while the actual values will 
be presented in data listings.
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12.5.7
Character Values of Clinical Laboratory Variables
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, that a character string is reported for a numerical variable, the appropriately 
determined coded value will be used in the statistical analysis. However, the actual values as 
reported in the database will be presented in data listings.
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13.
ANALYSIS SOFTWARE 
Statistical analyses will be performed using Version 9.4 (or newer) of SASon a suitably 
qualified environment. 
To score generic SF-36 health survey outcomes instruments, the QualityMetric Health 
Outcomes™ Scoring Software 5.0 will be used. 
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14.
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL
The following changes to the analysis specified in Protocol Amendment 2 dated 11 Nov 2019 
have been made.
Concomitant medications in the protocol are defined as any medications between first dose of 
investigational product and the end of safety follow-up. For the purposes of analysis, these 
medications have been separated into concomitant medication that include medications taken 
during the treatment period and concomitant post-treatment medications that include medications 
taken after the treatment period ends.
Due to the early discontinuation of the study before full enrollment and the resulting reduction in 
sample size, previously planned supplementary and subgroup analyses were removed. 
- Removed Subgroup for efficacy endpoints beyond the actual randomization factors. 
- Removed supplementary analyses for primary and key secondary efficacy endpoints. 
- Removed Per-protocol Set and Completers Set. 
Added Coronavirus Pandemic Section.
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15.
REFERENCES
Bretz, F., Maurer, W., Brannath, W.and Posch, M. 2009. A graphical approach to sequentially 
rejective multiple test procedures. Stat Med, 28, 586-604.
Feagan, B. G., Rutgeerts, P., Sands, B. E., Hanauer, S., Colombel, J. F., Sandborn, W. J., Van 
Assche, G., Axler, J., Kim, H. J., Danese, S., Fox, I., Milch, C., Sankoh, S., Wyant, T., Xu, J.and
Parikh, A. 2013. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N 
Engl J Med, 369, 699-710.
Sandborn, W. J., Su, C., Sands, B. E., D'Haens, G. R., Vermeire, S., Schreiber, S., Danese, S., 
Feagan, B. G., Reinisch, W., Niezychowski, W., Friedman, G., Lawendy, N., Yu, D., 
Woodworth, D., Mukherjee, A., Zhang, H., Healey, P.and Panes, J. 2017. Tofacitinib as 
Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med, 376, 1723-1736.
Yan, X.and Su, X. 2010. Stratified Wilson and Newcombe Confidence Intervals for Multiple 
Binomial Proportions. Stat Biopharm Res, 2, 329-35. 
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APPENDIX 1.
SCHEDULE OF ACTIVITIES
Table A1
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
Informed consent/assent
X
Eligibility assessment
X
X
Xe
Demographics and medical historyf
X
Complete physical examinationg
X
X
X
Targeted physical examinationg
X
Targeted neurological assessmenth
X
X
X
Vital signsi
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
12-lead ECGi
X
X
X
Chest x-rayj
X
Contraception checkk
X
X
X
X
X
X
X
Laboratory Assessments
Hematology
Xl
X
X
X
X
X
Serum chemistry
Xl
X
X
X
X
X
Urinalysis
Xl
X
X
X
X
X
Stool microbiologym
Xl
HBsAg, HBcAb, HCVAbn
Xl
HIV testing per local regulationo
X
FSHp
Xl
Serum β–hCGq
Xl
Urine β–hCGq
X
X
X
X
X
TB test (PPD or QuantiFERON TB Gold 
Plus)r
Xl
JCV antibody banked samples
X
X
X
X
Xt
Xt
X
Xt
Xt
X
 
Xt
Xt
X
Xu
Xu
Xu
Xu
X
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Table A1
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
ADA and NAb sampling
Xt
X
Xt
Xt
X
X
Endoscopic Procedure
Endoscopy (including biopsy)v
Xv
X
UC Assessments
Total Mayo score
Xw
Xw
Partial Mayo score
X
X
Remission stool frequency and pre-UC stool 
frequency
X
PRO-UC daily e-diary data instruction
X
PRO-UC daily e-diary datax
X
X
X
X
X
X
X
Health Assessmenty
IBDQ
X
X
X
X
X
X
Hospitalizations, inpatient days, 
 
(HRUA)
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36, v2, acute form
X
X
X
X
X
Treatment Procedures
Randomizationz
X
Administration of ontamalimab or placeboz
X
X
X
Hypersensitivity monitoringaa
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Concomitant medications and procedures
X
X
X
X
X
X
X
X
X
Dispense stool collection kit for stool sampleab
X
X
X
ADA=antidrug antibody; β–hCG=beta-human chorionic gonadotropin; 
; ECG=electrocardiogram; 
; e-diary=electronic diary; 
; ET=early termination; FSH=follicle-stimulating hormone; HBcAb=hepatitis B core antibody; 
HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCVAb=hepatitis C virus antibody; HEENT=head, eyes, ears, nose, and throat; 
HIV=human immunodeficiency virus; HRUA=Healthcare Resource Utilization Assessment; IBDQ=Inflammatory Bowel Disease Questionnaire; IGRA= interferon-gamma release 
assay; JCV=John Cunningham virus; LTS=long-term safety extension; 
; NAb=neutralizing antibody; PGA=physician global 
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Table A1
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
assessment;
; 
; PML=progressive multifocal leukoencephalopathy; 
PPD=purified protein derivative; PRO=patient-reported outcome; SF-36 v2=Short Form-36 Health Survey, version 2; TB=tuberculosis; 
 
; UC=ulcerative colitis; 
a
At least 2 visits will be necessary to complete the screening procedures, including endoscopy.
b
Subjects who withdraw early during the treatment period should return for the ET visit and then enter into the safety follow-up period.
c
Participation in the safety follow-up period is not required if subject is entering the maintenance study (SHP647-303) or LTS (SHP647-304) at the completion of the Week 12 
visit. For subjects participating in the 16-week safety follow-up period (not entering the maintenance study or LTS study), the Week 20 (Visit 7) visit will routinely be 
conducted by telephone; however, as an exception the visit can be performed as a study site visit if preferred. The Week 28 (Visit 8) visit will be at the study site.
d
Part 1 of Visit 6 must be completed within 10 days (preferably, within 5 to 7 days) before Part 2; this will allow sufficient time for data from the centrally read endoscopy to be 
available at Part 2 of the visit.
e
The outcome of Visit 6, Part 2 is used to assess eligibility to enroll in the maintenance (SHP647-303) or LTS (SHP647-304) studies. Eligibility for SHP647-303 and 
SHP647-304 will be assessed under those respective protocols.
f
Medical history will include UC history, cardiac history, and smoking history.
g
Complete physical examination includes the review of the following body systems: general appearance, skin, HEENT, heart, lungs, confrontational visual fields (eyes), breast 
(optional), abdomen, external genitalia (optional), extremities, neurologic function, back, and lymph nodes. Targeted physical examination includes the review of the following 
body systems: skin, heart, lungs, confrontational visual fields (eyes), abdomen, and examination of body systems where there are symptom complaints by the subject.
h
Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, speech, 
verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of PML should be excluded. See Section 7.2.7.3 of 
the protocol for further details.
i
Vital signs (including blood pressure, pulse, respiratory rate, and temperature) and 12-lead ECG should be performed before collection of blood samples for laboratory 
assessments and before endoscopic procedure.
j
A chest x-ray performed up to 12 weeks before screening (Visit 1) may be used if available; the official reading must be located in the subject’s source documentation.
k
Contraception check should be performed for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential. See Section 4.4 of 
the protocol for further details.
l
Screening laboratory test results, if considered by the investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated once during the 
screening period for confirmation. Results of repeated tests must be reviewed for eligibility prior to the screening endoscopy procedure.
m
Diagnosis of Clostridium difficile infection should be made using the central laboratory. If for any reason the central laboratory is not available, see Appendix 5 of the protocol
for guidance regarding alternate diagnostic algorithms. When a subject experiences an increase in gastrointestinal symptoms, which could be an exacerbation of disease, an 
infectious etiology must be evaluated including testing for C. difficile as described in Appendix 5 of the protocol.
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Table A1
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
n
Subjects who test negative for HBsAg but positive for HBcAb without HBV DNA may be considered eligible. For subjects who test positive for HBcAb and negative for 
HBsAg, a blood sample should be taken for HBV DNA. Blood for HBV DNA reflex testing is collected for required subjects only. If HBV DNA is positive, these subjects will 
not be eligible.
o
Documentation of a negative HIV test result within 6 months prior to screening will be accepted.
p
For confirmation of postmenopausal status in females who have had 12 consecutive months of spontaneous amenorrhea and are 51 years of age.
q
For females of childbearing potential who are not surgically sterile, do not have confirmed ovarian failure, or do not meet the definition of postmenopausal as described in 
Section 4.4.1 and Section 7.2.7.3 of the protocol.
r
A documented negative IGRA or PPD test within 12 weeks before screening (Visit 1) is acceptable provided that an IGRA result or PPD official reading and method is located 
in the source documentation.
s
A serum sample will be collected and banked. It may be analyzed if a subject shows neurologic symptoms suggestive of PML.
t
The sample must be collected before administration of investigational product.
u
The 
 sample must be collected before administration of investigational product. 
v
Flexible sigmoidoscopy or colonoscopy (if preferred) at screening must be performed on all subjects after the majority of other eligibility criteria (eg, laboratory values) are 
met. Endoscopy must be performed during the screening period within 10 days before baseline (Visit 2), preferably within 5 to 7 days before the baseline visit, to obtain the 
centrally read endoscopic subscore. Biopsy samples will be collected for histological evaluation using the Geboes Score classification for the key secondary efficacy endpoint 
and using the 
. Subjects at risk of colorectal cancer, as defined in exclusion criterion 5 (see Section 4.2 of the 
protocol.), must have a colonoscopy performed at screening, unless the subject has had a surveillance colonoscopy performed within 1 year prior to screening, and any 
adenomatous polyps found at that examination have been excised. Colonoscopy report and pathology report (if biopsies are obtained) from the colonoscopy performed during 
screening or in the prior year confirming no evidence of dysplasia and colon cancer must be available in the source documents.
w
Mayo score will be based on subject daily e-diary entries. The Mayo score at baseline will be calculated based on the stool frequency subscore and rectal bleeding subscore, 
reported by subjects in the PRO-UC daily e-diary and PGA obtained at baseline and the centrally read endoscopic subscore for the endoscopy performed during the screening 
period. The Mayo score at the Week 12 visit will be calculated based on the stool frequency subscore and rectal bleeding subscore reported by subjects in the PRO-UC daily 
e-diary and PGA and the centrally read endoscopic subscore for the endoscopy performed at Week 12, Visit 6 (Part 1). See Section 7.2.2.2 of the protocol for further details.
x
PRO-UC daily e-diary will be collected using a daily e-diary during the treatment period. Collection of the daily e-diary data must begin at least 10 days before the baseline 
visit (Visit 2). The subject should be provided with the handheld device to take home on their first visit. See Section 7.2.7.3 of the protocol for further details. Compliance is 
assessed by site staff at each visit. The site staff will instruct the subject on the appropriate use of the e-diary, particularly when compliance is below 80% (eg, <23 out of 
28 e-diary entries) when compared with the previous visit.
y
All health outcome or patient-reported questionnaires should be completed before completing any other visit assessments.
z
Interactive response technology will be used for randomization and dispensation of study treatment.
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SHP647-302 Statistical Analysis Plan v 2.0
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Table A1
Schedule of Assessments
Study Procedure
Screeninga
Baseline
Treatment
Follow-up
Weeks -6 to -1
Week 0/
Day 1
Week 2
Week 4
Week 8
Week 12/ETb
Week 20c
Week 28c
Visit Number
1
2
3
4
5
6 
(Part 1)d
6 
(Part 2)
7
8
Study Day
-42 to 0
1
14 3
28 3
56 3
84 ±3
140 7
196 7
aa
Beginning at Visit 2, at each visit the subject will be assessed for the presence of Type I and Type III hypersensitivity reactions since the prior visit. If a suspected 
hypersensitivity reaction has occurred, the next dose of investigational product should be withheld if necessary until the precise etiology (investigational product related or not) 
has been determined. If a Type III reaction is suspected, appropriate samples for testing will be collected and stored until the adjudication committee determines whether 
testing is appropriate.
ab
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the visit at which testing will be done.
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APPENDIX 2.
GEOGRAPHIC REGION  
Table A2
Geographic Region
Country
Region
Japan
Asia 
Korea, Republic of
Asia 
Bosnia and Herzegovina
Eastern Europe
Bulgaria
Eastern Europe
Croatia
Eastern Europe
Czech Republic
Eastern Europe
Estonia
Eastern Europe
Hungary
Eastern Europe
Lithuania
Eastern Europe
Poland
Eastern Europe
Romania
Eastern Europe
Russia
Eastern Europe
Serbia
Eastern Europe
Slovakia
Eastern Europe
Ukraine
Eastern Europe
Austria
Western Europe
Belgium
Western Europe
Germany
Western Europe
Greece
Western Europe
Ireland
Western Europe
Italy
Western Europe
Netherlands
Western Europe
Portugal
Western Europe
Spain
Western Europe
Switzerland
Western Europe
United Kingdom
Western Europe
Argentina
ROW
Australia
ROW
Brazil
ROW
Colombia
ROW
Israel
ROW
Lebanon
ROW
Mexico
ROW
New Zealand
ROW
South Africa
ROW
Turkey
ROW
Canada
North America
United States
North America
ROW (Africa/Australia/Latin America/Middle East). Asia (Japan/South Korea)
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APPENDIX 3.
RESCUE THERAPY FOR UC 

Biologics with immunomodulatory properties 
o
Any exposure after first dose 

Non-biologics with immunomodulatory properties

Immunosuppressants
o
After first dose and up to and including Week 8: any increase from baseline for more than 
5 days 
o
After Week 8: Any dose above baseline

5-ASA
o
After first dose and up to and including Week 8: any increase from baseline for more than 
5 days 
o
After Week 8: Any dose above baseline

Other small molecule immunomodulatory active agents
o
Any exposure after first dose

Leukocyte apheresis, other apheresis, and plasma exchange
o
Any exposure after first dose

Systemic glucocorticoids 

Systemic glucocorticoids given via oral or rectal routes of administration
o
After first dose and up to and including Week 8: any increase from baseline for more than 
7 days 
o
After Week 8: Any dose above baseline 

Systemic glucocorticoids given via parenteral routes of administration
o
Any exposure after first dose

Topical Glucocorticoids

Budesonide 
o
Subjects not taking Budesonide at baseline: 

After first dose and up to and including Week 8: more than 9 mg/day for one day 
or any exposure for more than 5 days

After Week 8: Any dose above baseline
o
Subjects taking Budesonide at baseline: 

After first dose and up to and including Week 8: more than 9 mg/day for one day 
or any increase for more than 5 days

After Week 8: Any dose above baseline

Beclomethasone
o
Subjects not taking Beclomethasone at baseline: 

After first dose and up to and including Week 8: more than 5 mg/day for one day 
or any exposure for more than 5 days

After Week 8: Any dose above baseline
o
Subjects taking Beclomethasone at baseline: 
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
After first dose and up to and including Week 8: more than 5 mg/day for one day 
or any increase for more than 5 days

After Week 8: Any dose above baseline
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