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 Crohn's Disease (CARMEN CD 306)
Phase: PHASE3
Conditions: Crohn's Disease
Sponsor: Shire

CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT03566823 
 
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 Crohn’s Disease (CARMEN CD 306) 
 
 
Study Number:  
SHP647-306 
 
 
Protocol Version and Date:  
 
Original Protocol:  
15 Dec 2017 
Amendment 1:  
21 Aug 2018 
Amendment 2:  
22 Nov 2019 

PROTOCOL: SHP647-306
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 Crohn’s Disease
(CARMEN CD 306)
DRUG:
SHP647
IND:
100,222
EUDRACT NO.:
2017-000576-29
SPONSOR:
Shire Human Genetic Therapies, Inc. (“Shire”)
300 Shire Way, Lexington, MA 02421 US
PRINCIPAL/
COORDINATING
INVESTIGATOR:
MD
PROTOCOL 
HISTORY:
Original Protocol: 15 Dec 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  
SHP647-306 
  
15 Dec 2017 
 
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Nonserious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to Shire Global Drug Safety. Applicable fax numbers and e-mail 
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 e-mail 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):
Pharmaceutical Product Development North America:
24 Hour Safety Hotline: RTP 
; Wilmington 
24 Hour Safety Hotline Fax: RTP 
 or 
; 
Wilmington
 or 
Pharmaceutical Product Development Latin America:
24 Hour Safety Hotline: 
24 Hour Safety Hotline Fax: 
Pharmaceutical Product Development Europe, the Middle East, and Africa; and 
Asia-Pacific:
24 Hour Safety Hotline: 
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 8.2.2.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America, the 
European Union, and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (US)
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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 ......................................................................................................................13
STUDY SCHEDULE ....................................................................................................................23
1.
BACKGROUND INFORMATION.......................................................................................28
1.1
Indication and Current Treatment Options...............................................................28
1.2
Product Background and Clinical Information ........................................................28
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................30
2.1
Rationale for the Study.............................................................................................30
2.2
Study Objectives ......................................................................................................32
2.2.1
Coprimary Objectives............................................................................................32
2.2.2
Secondary Objectives.............................................................................................32
2.2.3
Exploratory Objectives ..........................................................................................33
3.
STUDY DESIGN ...................................................................................................................34
3.1
Study Design and Flow Chart ..................................................................................34
3.1.1
Rationale for Coprimary Endpoints.......................................................................36
3.1.2
Rationale for Key Secondary Endpoints................................................................38
3.2
Duration and Study Completion Definition .............................................................40
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 .............................................................................................48
4.4.1
Contraceptive Methods for Female Study Subjects...............................................48
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
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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 Products..............................................................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
7.1.2
Treatment Period....................................................................................................61
7.1.3
Follow-up Period ...................................................................................................62
7.1.4
Additional Care of Subjects after the Study ..........................................................62
7.2
Study Evaluations and Procedures ...........................................................................62
7.2.1
Demographic and Other Baseline Characteristics .................................................63
7.2.2
Efficacy..................................................................................................................63
7.2.3
Safety .....................................................................................................................66
7.2.4
Others.....................................................................................................................72
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
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8.1.4
Symptoms of the Disease Under Study .................................................................77
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................78
8.1.6
Pregnancy...............................................................................................................78
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................79
8.1.8
Unexpected Adverse Event....................................................................................79
8.1.9
Suspected Unexpected Serious Adverse Reaction.................................................80
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
8.2.6
Fatal Outcome........................................................................................................81
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................82
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................83
9.1
Data Collection.........................................................................................................83
9.2
Clinical Data Management.......................................................................................83
9.3
Data Handling Considerations..................................................................................83
9.4
Statistical Analysis Process......................................................................................83
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......84
9.6
Sample Size Calculation and Power Considerations................................................85
9.7
Study Population ......................................................................................................86
9.8
Efficacy Analyses.....................................................................................................86
9.8.1
Coprimary Efficacy Endpoints ..............................................................................87
9.8.2
Secondary Efficacy Endpoints...............................................................................90
9.8.3
Exploratory Efficacy Endpoints.............................................................................92
9.9
Safety Analyses........................................................................................................93
9.10
Other Analyses .........................................................................................................93
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................95
10.1
Sponsor’s Responsibilities .......................................................................................95
10.1.1 Good Clinical Practice Compliance.......................................................................95
10.1.2 Indemnity/Liability and Insurance.........................................................................95
10.1.3 Public Posting of Study Information......................................................................95
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................96
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10.1.5 Study Suspension, Termination, and Completion..................................................96
10.2
Investigator’s Responsibilities .................................................................................96
10.2.1 Good Clinical Practice Compliance.......................................................................96
10.2.2 Protocol Adherence and Investigator Agreement..................................................97
10.2.3 Documentation and Retention of Records.............................................................97
10.3
Ethical Considerations..............................................................................................98
10.3.1 Informed Consent...................................................................................................98
10.3.2 Institutional Review Board or Ethics Committee..................................................99
10.4
Privacy and Confidentiality....................................................................................100
10.5
Study Results/Publication Policy ...........................................................................100
11. REFERENCES .....................................................................................................................102
12. APPENDICES ......................................................................................................................105
Appendix 1
Protocol History ...................................................................................105
Appendix 2
Scales and Assessments .......................................................................106
Appendix 3
Glucocorticoid Equivalent Doses.........................................................138
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LIST OF TABLES
Table 1:
Schedule of Assessments...............................................................................23
Table 2:
Common Excluded Treatments .....................................................................53
Table 3:
Neurological Assessment Plan ......................................................................67
Table 4:
Volume of Blood to Be Drawn From Each Subject......................................74
Table 5:
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints.....................................................................................86
LIST OF FIGURES
Figure 1:
Overview of SHP647 Phase 3 Studies in Crohn’s Disease ...........................35
Figure 2:
Study Design Flow Chart ..............................................................................36
Figure 3:
Flow Diagram for Quarterly Neurological Assessments...............................68
Figure 4:
Visualization of Multiple Testing Strategy ...................................................89
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ABBREVIATIONS
5-ASA
5-aminosalicylic acid
6-MP
6-mercaptopurine
β-hCG
beta-human chorionic gonadotropin
ADA
antidrug antibodies
AE
adverse event
AZA
azathioprine
BSFS
Bristol Stool Form scale
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CI
confidence interval
CMH
Cochran-Mantel Haenszel
CNS
central nervous system
CSF
cerebrospinal fluid
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
FSH
follicle-stimulating hormone
FWER
family-wise type I error rate
GCP
Good Clinical Practice
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCVAb
hepatitis C virus antibody
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HIPAA
Health Insurance Portability and Accountability Act
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
LP
lumbar puncture
LTS
long-term safety extension
MTX
methotrexate
NAb
neutralizing antibody
NRS
numerical rating scale
PCR
polymerase chain reaction 
PFS
prefilled syringe
PML
progressive multifocal leukoencephalopathy
PPD
purified protein derivative
PRO
patient-reported outcome
Q4W
once every 4 weeks
RNA
ribonucleic acid
RSI
reference safety information
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SES-CD
Simple Endoscopic Score for Crohn’s Disease
SF-36
Short Form-36 Health Survey
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SUSAR
serious unexpected serious adverse reaction
TB
tuberculosis
TEAE
treatment-emergent AE
TNF
tumor necrosis factor
ULN
upper limit of normal
US
United States
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STUDY SYNOPSIS
Protocol number: SHP647-306
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 Crohn’s Disease (CARMEN CD 306)
Number of subjects (total and for each treatment arm):
A total of 1032 subjects (387 subjects in the 25 mg SHP647 treatment group, 387 subjects in the 75 mg SHP647 
treatment group, and 258 subjects in the placebo group) 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 approximately 19 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):
2018 to 2021
Clinical phase:
3
Objectives:
Coprimary: The coprimary objectives of this study are to evaluate the efficacy of SHP647 in subjects with 
moderate to severe Crohn’s disease (CD) in:

Inducing clinical remission based on 2-item patient-reported outcome (PRO) (abdominal pain severity and 
very soft stool/liquid stool frequency)

Inducing endoscopic response based on centrally read colonoscopy.
Key secondary:

To evaluate the efficacy of SHP647 in inducing clinical remission as measured by CD Activity Index
CDAI

To evaluate the efficacy of SHP647 in inducing enhanced endoscopic response based on centrally read 
colonoscopy

To evaluate the efficacy of SHP647 in inducing clinical remission based on abdominal pain severity and 
very soft stool/liquid stool frequency (alternate thresholds)

To evaluate the efficacy of SHP647 in inducing clinical response based on patient-reported clinical signs 
and symptoms (as measured by 2-item PRO)

To evaluate the efficacy of SHP647 in inducing clinical remission based on patient-reported clinical signs 
and symptoms (as measured by 2-item PRO) as well as inducing endoscopic response based on centrally 
read colonoscopy in the same subject

To evaluate the efficacy of SHP647 in inducing endoscopic healing based on centrally read colonoscopy.
Other secondary:

To evaluate the safety and tolerability of SHP647

To evaluate the effect of SHP647 induction treatment on other clinical outcomes (clinical response 
defined by CDAI, or clinical remission over time, or change from baseline in frequency in CD-related 
clinical parameters)

To evaluate the effect of SHP647 induction treatment on other endoscopic outcomes

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

To evaluate the impact of SHP647 on incidence of CD-related and other surgeries.
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Rationale:
This study is designed to evaluate the efficacy and safety of SHP647 in inducing clinical remission and endoscopic 
response in subjects with moderate to severe CD.
The CD clinical development program includes 3 completed studies: 1 Phase 1 study (A7281008) and 2 Phase 2 
studies (A7281006 and A7281007). The SHP647 dose selection (25 and 75 mg) for this study is based on data 
from these 3 previous studies, which evaluated the activity of SHP647 in adult patients with moderately to severely 
active CD based on CDAI scores between 220 and 450. The Phase 1 study (A7281008, TOSCA) and Phase 2 
studies (A7281006, OPERA; and A7281007, OPERA II [long-term safety study]) that investigated the safety, 
tolerance, pharmacokinetics, and pharmacodynamic properties of SHP647 support further clinical development of 
SHP647 using subcutaneous (SC) administration in subjects with moderate to severe CD.
Investigational product, dose, and mode of administration:
The test product is SHP647 (a fully human immunoglobulin G2 kappa antihuman mucosal addressin cell adhesion 
molecule [MAdCAM] monoclonal antibody), 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 (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 SHP647.
Methodology:
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the 
efficacy and safety of SHP647 in inducing clinical remission and endoscopic response in subjects with moderate to 
severe CD.
A total of 1032 subjects (387 subjects in the 25 mg SHP647 treatment group, 387 subjects in the 75 mg SHP647 
treatment group, and 258 subjects in the placebo group) 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 16-week treatment period. After the screening period, 
eligible subjects will be randomized to receive 1 of 3 treatments (25 mg SHP647, 75 mg SHP647, or placebo) in a 
3:3:2 ratio. Randomization will be stratified based upon the subject’s status of prior antitumor necrosis factor 
(TNF) treatment (naïve or experienced), glucocorticoid use at baseline (on glucocorticoids at baseline versus not 
on glucocorticoids at baseline), and Simple Endoscopic Score for CD (SES-CD) at baseline (SES-CD ≥17 or 
SES-CD <17). Subjects will receive SC injections of SHP647 or placebo, using a PFS, on Week 0/Day 1 (Visit 2), 
Week 4 (Visit 4), Week 8 (Visit 5), and Week 12 (Visit 6). Subjects will undergo efficacy, 
 
, safety, and health outcome assessments at these visits.
At the end of the 16-week treatment period, subjects will be offered the opportunity to participate in either a 
double-blind maintenance study (SHP647-307; for subjects who fulfill the entry criteria) or a long-term safety 
extension (LTS) study (SHP647-304; for subjects who do not fulfill the entry criteria for Study SHP647-307). 
Subjects who withdraw early from the 16-week treatment period or who do not wish to enter the maintenance 
study (SHP647-307) 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 (SHP647-305 or 
SHP647-306) will be eligible to continue in the maintenance study or LTS study.
A planned interim analysis for the coprimary endpoints will take place after approximately the first 50% of all 
randomized subjects in both the SHP647-305 and SHP647-306 studies have either completed the studies or have 
prematurely withdrawn from the studies. The sample size will be reassessed as part of this interim analysis.
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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 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 active moderate to severe ileal (terminal ileum), ileocolic, or colonic CD at baseline 
(Visit 2) as defined by:
a.
CDAI score between 220 and 450 (inclusive) AND
b.
Presence of ulcerations that are characteristic to CD, as determined by a colonoscopy performed 
during screening, and as defined by the SES-CD >6 (SES-CD ≥4 for isolated ileitis) AND
c.
Meeting the following subscores in the 2-item PRO:
i.
Average of the abdominal pain subscores ≥5 (average worst daily pain on the 11-point 
numerical rating scale [NRS]) over the 7 most recent days out of the 10 days before
colonoscopy preparation (may or may not be contiguous) AND/OR
ii.
Average of the daily stool frequency subscore ≥4 of type 6/7 (very soft stools/liquid 
stools) as shown in the Bristol Stool Form Scale (BSFS) over the 7 most recent days out 
of the 10 days before colonoscopy preparation (may or may not be contiguous).
5.
Subjects must have a documented diagnosis (endoscopic with histology) of CD for 3 months before 
screening. Documented diagnosis is defined as:

A biopsy report to confirm the histological diagnosis AND

A report documenting disease duration based upon prior colonoscopy.
Note: If a biopsy report is not available in the source document at the time of screening, the histology 
report of the biopsy performed mandatorily during the screening colonoscopy should be consistent with 
the CD diagnosis. If the histology diagnosis is not clear at this time point, the subject should not be 
randomized.
6.
Subjects must be willing and able to undergo a colonoscopy during screening after all other inclusion 
criteria have been met.
7.
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 mesalamine (5-aminosalicylic acid [5-ASA]), 
glucocorticoids, immunosuppressants (azathioprine [AZA], 6-mercaptopurine [6-MP], or 
methotrexate [MTX]), or anti-TNF. Subjects who have had an inadequate response to sulfasalazine or 
mesalamine should have also failed at least 1 other conventional treatment such as glucocorticoids.
8.
Subjects receiving any treatment(s) for CD 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.
9.
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, ischemic colitis, infectious colitis, or 
clinical/histologic findings suggestive of ulcerative colitis.
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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 presence of enterovesical (ie, between the bowel and urinary bladder) or enterovaginal 
fistulae.
5.
Subjects with current symptomatic diverticulitis or diverticulosis.
6.
Subjects with obstructive 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 CD during the 
treatment period.
7.
Subjects with past medical history of multiple small bowel resections resulting in clinically significant 
short bowel syndrome.
8.
Subjects requiring total parenteral nutrition.
9.
Subjects with past medical history of bowel surgery resulting in an existing or current stoma. Subjects 
who had a j-pouch are excluded as a j-pouch could result in a stoma.
10. Subjects have had prior treatment with SHP647 (formerly PF-00547659).
11. Subjects with known or suspected intolerance or hypersensitivity to the investigational product(s), closely 
related compounds, or any of the stated ingredients.
12. Subjects have received any nonbiologic treatment with immunomodulatory properties (other than AZA, 
6-MP, or MTX) or continuous antibiotics (>2 weeks) for the treatment of CD within 30 days before 
baseline (Visit 2).
13. Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2).
14. Subjects have received any biologic with immunomodulatory properties (other than anti-TNFs) within 
90 days before baseline (Visit 2).
15. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion molecule).
16. Subjects have received lymphocytes apheresis or selective monocyte granulocytes apheresis within 
60 days before baseline (Visit 2).
17. Subjects have received enteral nutrition treatment within 30 days before baseline (Visit 2).
18. Subjects have received parenteral or rectal glucocorticoids or rectal 5-ASA within 14 days before 
screening colonoscopy.
19. Subjects have taken >20 mg/day of prednisone or equivalent oral systemic corticosteroid dose within 
14 days before baseline (Visit 2) or have taken ≥40 mg/day of prednisone or equivalent oral systemic 
corticosteroid dose within 6 weeks before baseline (Visit 2).
20. 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 screening (Visit 1).
21. Subjects have received a live (attenuated) vaccine within 30 days before the baseline visit (Visit 2).
22. 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 
retest 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).
23. Subjects with abnormal chest x-ray or other imaging findings at screening (Visit 1), such as presence of 
active tuberculosis (TB), general infections, heart failure, or malignancy. (A chest x-ray, computed 
tomography scan, etc., 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.)
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24. Subjects with evidence of active or latent infection with Mycobacterium tuberculosis (TB) who have not 
completed a generally accepted full course of treatment before baseline (Visit 2) 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 baseline (Visit 2). 
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/TB 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.
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 before 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.
25. 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.
26. Subjects with any unexplained symptoms suggestive of progressive multifocal leukoencephalopathy based 
on the targeted neurological assessment during the screening period.
27. Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed.
28. 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.
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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).
29. Subjects who have had significant trauma or major surgery within 4 weeks before screening (Visit 1), or 
with any major elective surgery scheduled to occur during the study.
30. Subjects with evidence of or suspected liver disease, liver injury due to methotrexate or primary 
sclerosing cholangitis.
31. 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 (also referred as 
anti-HBsAg) reflex testing.
32. Subjects with positive hepatitis C antibody with confirmation by HCV-ribonucleic acid polymerase chain 
reaction reflex testing.
33. Subjects with any of the following abnormalities in hematology and/or serum chemistry profiles during 
screening (Visit 1). 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 colonoscopy
procedure.

Alanine aminotransferase and aspartate aminotransferase levels 2.5 times the upper limit of 
normal (ULN)

Total bilirubin level 1.5 times the ULN (except where attributed to elevation in unconjugated 
bilirubin 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 <2 × 109/L (2000 cells/mm3)

Serum creatinine level >1.5 times the ULN or estimated glomerular filtration rate 
<30 mL/min/1.73m2 based on the abbreviated Modification of Diet in Renal Disease Study 
Equation.
34. Subjects with known infection with human immunodeficiency virus, as documented in their medical 
history.
35. 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.
36. Subjects using 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, Fifth Edition 
(including urine drug screen and medical history).
37. 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.
38. Female subjects who are planning to become pregnant during the study period.
39. Male subjects who are planning to donate sperm and do not agree not to do so for the duration of the study 
and through 16 weeks after last dose of investigational product.
40. 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.
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Maximum duration of subject involvement in the study:

Planned duration of screening period: Up to 6 weeks

Planned duration of treatment period: 16 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 protocol deviations that may affect the 
coprimary efficacy endpoints.
The completer set will consist of all subjects in the FAS who have completed the Week 16 assessment for this 
study.
 
 
Coprimary efficacy endpoints:
The coprimary efficacy endpoints are:

Clinical remission at the Week 16 visit as defined by the following: 2-item PRO subscores of average 
worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days and average daily 
stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent 
days. The 7 most recent days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. If fewer than 7 days 
are available, the endpoint will be calculated on all available most recent 6 or 5 days. If fewer than 5 days 
are available, the endpoint will be treated as missing.

Endoscopic response at Week 16 as measured by a decrease in SES-CD of at least 25% from baseline.
The coprimary efficacy endpoints, clinical remission at the Week 16 visit and endoscopic response at the Week 16 
visit, will each 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, glucocorticoid 
use, and SES-CD at baseline for each of the stages of the study (stage 1 includes subjects whose primary efficacy 
data are used in the interim analysis and stage 2 includes all other subjects. Note: classification of stage 1 and 
stage 2 is based on the time of randomization rather than the time of study completion or termination). Subjects 
with missing data at the Week 16 visit will be considered failures and counted as nonresponders.
Weighted inverse normal p-value combination methods are used to combine the p-values from stage 1 and stage 2 
through the following formula:
C(p1, p2) = 1 – Φ[w1 Φ-1(1-p1)+ w2 Φ-1(1-p2)]
Where p1, p2 are the p-values computed from the CMH chi-square test for each stage, wi
2 = ni/(n1 + n2), n1 and n2 are 
the preplanned stage-wise sample sizes that are fixed at the time of the interim analysis based on an original total 
sample size, and Φ denotes the cumulative distribution function of the standard normal distribution (Bretz, et al.,
2009a). Given that there is no possibility of stopping early for efficacy, that any potential stopping for futility of 
either or both doses of SHP647 is nonbinding, and that weights are prespecified, the test statistic C(p1, p2) can be 
compared against the nominal alpha level to assess statistical significance (Chang, 2008).
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The coprimary endpoints will each be tested by the following hypothesis:
H0: δ = 0
H1: δ ≠ 0
Where δ is the common treatment difference across strata. 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 coprimary and key secondary 
endpoints will be strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in 
Bretz et al. (2009b) will be utilized to propagate α from the coprimary endpoints to the key secondary endpoints 
and between the 2 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 coprimary endpoints (P) and alpha is 
propagated in a hierarchical manner to each of the 6 key secondary endpoints (K1–K6) within a pairwise treatment 
comparison. In order to pass alpha between the coprimary endpoints and the first key secondary endpoint, both 
coprimary endpoints must attain statistical significance.
Key secondary efficacy endpoints:
The key secondary efficacy endpoints are as follows:

Clinical remission at the Week 16 visit as measured by a CDAI score of <150.

Enhanced endoscopic response at Week 16 as measured by a decrease in SES-CD of at least 50% from 
baseline.

Clinical remission at the Week 16 visit as defined by the following: 2-item PRO subscores of average 
worst daily abdominal pain ≤1 (based on the 4-point scale) over the 7 most recent days and average daily 
stool frequency ≤3 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent 
days. The 7 most recent days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. If fewer than 7 days 
are available, the endpoint will be calculated on all available most recent 6 or 5 days. If fewer than 5 days 
are available, the endpoint will be treated as missing.

Clinical response at the Week 16 visit as measured by the 2-item PRO and defined as meeting at least 1 of 
the following 2 criteria:
o
A decrease of ≥30% and at least 2 points from baseline in the average daily worst abdominal pain 
over the 7 most recent days*, with the average daily stool frequency of type 6/7 (very soft
stools/liquid stools) either:
(a) Not worsening from baseline
and/or
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average daily stool 
frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent 
days*
o
A decrease of ≥30% from baseline in the average daily stool frequency of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days*, with the average daily worst 
abdominal pain either:
(a) Not worsening from baseline
and/or
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average worst daily
abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days*
*Note: The 7 most recent days may or may not be contiguous during the 10 days of data collection 
before colonoscopy preparation, depending on days to be excluded because of missing data. If fewer
than 7 days are available, the endpoint will be calculated on all available most recent 6 or 5 days. If 
fewer than 5 days are available, the endpoint will be treated as missing.
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
Clinical remission with endoscopic response, ie, both clinical remission by 2-item PRO and endoscopic 
response, as measured by a decrease in SES-CD of at least 25% at Week 16 (composite endpoint)

Complete endoscopic healing at Week 16 defined as SES-CD=0-2.
The key secondary endpoints will be analyzed using the same approach as described for the coprimary endpoints. 
Subjects with missing key secondary endpoint data at the Week 16 visit will be considered failures and counted as 
nonresponders.
Other secondary efficacy endpoints:

Clinical response at the Week 16 visit as measured by at least a 100-point reduction in the CDAI from 
baseline (CDAI-100 response)

Clinical response at the Week 16 visit as measured by at least a 70-point reduction in the CDAI from 
baseline (CDAI-70 response)

Clinical remission over time, as measured by the 2-item PRO

Change from baseline in total stool frequency, rectal bleeding frequency, rectal urgency frequency, nausea 
severity, vomiting frequency, and rectal incontinence frequency scores; and total sign/symptom score 
based on subject daily e-diary entries

Endoscopic healing at Week 16 as measured by SES-CD ≤4 and at least 2-point reduction versus baseline 
and no subscore >1 in any individual variable

Change from baseline in IBDQ domain and total (absolute) scores over time

Change from baseline in SF-36, version 2, acute (physical and mental component summary scores and 
individual domain scores) over time

Incidence of all cause hospitalizations and total inpatient days

Incidence of CD-related surgeries and other surgical procedures during the entire study period.
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 compared between each active treatment group and the placebo group using a 
CMH chi-square test stratified by status of prior anti-TNF treatment, glucocorticoid use at baseline, and 
SES-CD at baseline. The estimate of the common treatment difference along with the corresponding 
stratified Newcombe 95% CI using the method of Yan and Su (2010) and the p-value computed from 
CHM test will be provided. Subjects with missing binary endpoint data at the Week 16 visit will be 
considered failures and counted as nonresponders.

Continuous endpoints that are only measured at baseline and the Week 16 visit will be analyzed using an 
analysis of covariance model with fixed effects for treatment group (categorical), status of prior anti-TNF 
treatment (categorical), glucocorticoid use at baseline (categorical), and SES-CD at baseline (Visit 2)
(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), glucocorticoid use at baseline (categorical), and SES-CD 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 (AEs) 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 and percentage of TEAEs will be calculated 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
Week 16/ETb
Week 
24c
Week
32c
Visit Number
1
(Part 1)a
1
(Part 2)a
2
3
4
5
6
7
(Part 1)b
7
(Part 2)b
7
(Part 3)b
8
9
Study Day
-42 to 0
1
14 3
28 3
56 3
84 3
112 ±3
168 7
224 7
Informed consent/assent
X
Eligibility assessment
X
X
Xd
Demographics and medical 
historye
X
Complete physical 
examinationf
X
X
X
Targeted physical 
examinationf
X
X
X
X
X
Targeted neurological 
assessmentg
X
X
X
Vital signs
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Chest x-rayh
X
Contraception checki
X
X
X
X
X
X
X
X
Laboratory Assessments
Hematology
Xj,k
X
X
X
X
X
X
Serum chemistry
Xj
X
X
X
X
X
X
Urinalysis
Xj
X
X
X
X
X
X
Stool microbiologyl
Xj
HBsAg, HBcAb, HCVAbm
Xj
FSHn
Xj
Serum β-hCGo
Xj
Urine β-hCGo
X
X
X
X
X
X
TB test (PPD or 
QuantiFERON-TB Gold/TB 
Plus)p
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
Week 16/ETb
Week 
24c
Week
32c
Visit Number
1
(Part 1)a
1
(Part 2)a
2
3
4
5
6
7
(Part 1)b
7
(Part 2)b
7
(Part 3)b
8
9
Study Day
-42 to 0
1
14 3
28 3
56 3
84 3
112 ±3
168 7
224 7
JCV antibody banked 
sampleq
X
 
X
X
X
X
X
X
X
X
X
 
X
X
X
X
X
X
X
X
X
ADA and NAb sampling
X
X
X
X
X
X
X
Endoscopic Procedure
Colonoscopy (including 
biopsy)r
X
X
CD Assessments
CDAIs
X
X
X
X
X
PRO-CD daily e-diary data 
instruction
X
PRO-CD daily e-diary datat
X
X
X
X
X
X
X
X
X
X
SES-CDu
X
X
Health Assessmentv
IBDQ
X
X
X
X
X
X
X
X
Hospitalizations, inpatient 
days, 
 (HRUA)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36, version 2, acute
X
X
X
X
X
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
Week 16/ETb
Week 
24c
Week
32c
Visit Number
1
(Part 1)a
1
(Part 2)a
2
3
4
5
6
7
(Part 1)b
7
(Part 2)b
7
(Part 3)b
8
9
Study Day
-42 to 0
1
14 3
28 3
56 3
84 3
112 ±3
168 7
224 7
Treatment Procedures
Randomizationw
X
Administration of SHP647 or 
placebow, x
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Prior medications
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool collection kit 
for stool sampley
X
X
X
Ab=antibody; ADA=antidrug antibodies; β-hCG=beta-human chorionic gonadotropin; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; 
; 
ECG=electrocardiogram; 
; 
; ET=early termination; FSH=follicle-stimulating 
hormone; GDH=glutamate dehydrogenase; HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HCV RNA=hepatitis C virus 
ribonucleic acid; HRUA=Healthcare Resource Utilization Assessment; IBD=inflammatory bowel disease; 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;
; PML=progressive 
multifocal leukoencephalopathy; PPD=purified protein derivative; PRO=patient-reported outcomes; SES-CD=Simple Endoscopic Score for CD; SF-36 v2=Short Form-36 Health 
Survey, version 2; TB=tuberculosis; 
.
a
Screening assessments will take place over more than 1 day (at least 2 visits will be necessary to complete the screening evaluations, including colonoscopy).
b
Subjects who withdraw early during the treatment period should return for the ET visit and then enter into the safety follow-up period. The Week 16 (Visit 7) and ET 
visits consist of 3 parts:
Part 1 of Visit 7 should be scheduled 1 to 3 day(s) before Part 2; this will allow for blood samples to be taken before starting the colonoscopy preparation and before the 
colonoscopy procedure at Part 2 of the visit (Section 7.2.2.4)
Part 2 of Visit 7 should be scheduled preferably 5 to 7 days before Part 3; this will allow sufficient time to obtain the data from the centrally read colonoscopy
Part 3 of Visit 7 will take place on Day 112 ±3 days.
c
Subjects NOT entering the maintenance study (SHP647-307) or LTS (SHP647-304) study at the completion of the Week 16 visit will need to complete the safety 
follow-up assessments. The Week 24 (Visit 8) 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 32 (Visit 9) visit will take place at the study site.
d
The outcome of Visit 7, Part 3 is used to assess eligibility to enroll subjects in the maintenance (SHP647-307) or LTS (SHP647-304) studies. Please refer to the 
respective protocols for further details.
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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
Week 16/ETb
Week 
24c
Week
32c
Visit Number
1
(Part 1)a
1
(Part 2)a
2
3
4
5
6
7
(Part 1)b
7
(Part 2)b
7
(Part 3)b
8
9
Study Day
-42 to 0
1
14 3
28 3
56 3
84 3
112 ±3
168 7
224 7
e
Medical history will include CD history, cardiac history, and smoking history.
f
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; 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 and mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, eyes, abdomen, and examination of body systems 
where there are symptom complaints by the subject.
g
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. 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.
h
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.
i
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.
j
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 before the screening colonoscopy procedure.
k
Hematology samples should be repeated if more than 3 weeks have elapsed before the day of colonoscopy to be able to use the hematocrit central laboratory results for 
the CDAI score calculation at screening.
Note: Hematocrit must NOT be older than 3 weeks before the day of colonoscopy.
l
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 
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.
m
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 (also referred as anti-HBsAg) reflex testing. HCV RNA PCR reflex testing may be performed if the subject is HCVAb positive.
n
For confirmation of postmenopausal status in females who have had 12 consecutive months of spontaneous amenorrhea and are 51 years of age.
o
Female subjects of childbearing potential; serum pregnancy test at screening (Visit 1) and urine pregnancy test at all other time points. 
p
A documented negative PPD test within 12 weeks before baseline (Visit 2) is acceptable provided that an interferon-gamma release assay official reading and method or 
test is located in the source documentation.
q
A serum sample will be collected and banked. It may be analyzed if a subject shows neurological symptoms suggestive of PML.
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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
Week 16/ETb
Week 
24c
Week
32c
Visit Number
1
(Part 1)a
1
(Part 2)a
2
3
4
5
6
7
(Part 1)b
7
(Part 2)b
7
(Part 3)b
8
9
Study Day
-42 to 0
1
14 3
28 3
56 3
84 3
112 ±3
168 7
224 7
r
Colonoscopy preparation will be according to local routine. Colonoscopy must be performed during the screening period within 5 to 7 days before baseline (Visit 2), to 
allow for adequate e-diary data collection for the 2-item PRO and CDAI scores and to obtain the centrally read endoscopic subscore to verify the subject’s eligibility. During the 
colonoscopy at screening (Visit 1, Part 2) and Week 16/ET, 10 biopsies will be collected from the most inflamed area of the mucosa; 2 samples each from the ileum, the 
3 segments of the colon, and the rectum. If the calculated CDAI scores is <220 or >450, the subject will be considered a screen failure and should not proceed with the 
colonoscopy preparation and/or the colonoscopy. 
s
The CDAI score at screening (Visit 1, Part 2) includes subject-reported PRO-CD daily e-diary data collected >10 days before the start of colonoscopy preparation.
The CDAI score at Visits 4, 5, and 6 includes subject-reported PRO-CD daily e-diary data collected >10 days before the visit.
The CDAI score at the Week 16/ET visit will be calculated at Visit 7, Part 3 (after all evaluations are complete) and includes subject-reported PRO-CD daily e-diary data 
collected >10 days before the start of colonoscopy preparation.
Note: All required components (including subject-reported PRO-CD daily e-diary data collected >10 days before the start of colonoscopy preparation and <3 weeks of 
central hematocrit results) should be available to calculate the CDAI scores. See Section 7.2.2.3 for further details.
t
Patient-reported CD clinical signs and symptoms will be collected daily using a PRO-CD daily e-diary (electronic handheld device) starting from the first screening visit; 
however, collection of the daily e-diary data must begin at least 14 days before colonoscopy preparation. Subjects should be provided with the e-diary to take home on their first 
visit. Compliance will be assessed by the site staff and the subject should be retrained on the appropriate use of the e-diary when compliance is below 80% (eg, <23 out of 
28 e-diary entries). If 70% compliance cannot be achieved after repeated instructions during the screening period, noncompliant subjects will be automatically noneligible as they 
will not fulfill inclusion criterion 1 (Section 4.1). If 7 out of the 10 most recent days are not available, then the 2-item PRO cannot be calculated for the subject at screening.
u
The SES-CD score at baseline (Visit 2) and at Week 16/ET will be calculated using subscores of each of the segments investigated and centrally read from the 
colonoscopies performed at screening (Visit 1, Part 2) and Week 16 (Visit 7, Part 2), respectively.
v
All health outcome or patient-reported questionnaires should be completed before completing any other visit assessments.
w
Interactive response technology will be used for randomization and dispensation of study treatment.
x
Where applicable, specified procedures and laboratory samples should be collected before investigational product administration.
y
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
Crohn’s disease (CD) is a chronic, relapsing disease marked by granulomatous inflammation of 
the gastrointestinal (GI) tract. Although the terminal ileum and right colon are the most 
commonly involved sites, CD can affect any part of the GI tract, from the mouth to the perianal 
region. Inflammation is typically transmural (full-thickness), segmental, and discontinuous, and 
symptoms are predominantly determined by the part of bowel or organ involved. Patients 
typically present with symptoms including abdominal pain, diarrhea, rectal bleeding, which may 
be persistent and lead to anemia, and weight loss due to pain on eating and malabsorption. As the 
disease progresses, extraintestinal manifestations and associated conditions can develop, 
including bowel obstruction, fistulas, and stenosis, as well as painful skin ulcerations, eye pain, 
and arthritis.
The incidence of CD is estimated to be up to 12.7 cases per 100,000 persons per year in Europe 
and up to 20.2 cases per 100,000 persons per year in North America. No clear difference in 
incidence has been observed between men and women. Although CD can occur at any age, peak 
incidence has been observed in the second to fourth decades of life, with a second modest rise in 
incidence in the latter decades of life (Molodecky et al., 2012).
Crohn’s disease is a lifelong condition with a serious effect on quality of life. The traditional 
approach to therapy of CD has been the step-up approach usually represented as a pyramid 
where, progressing from mild to severe disease, therapeutic choices proceed step by step from 
less potent drugs at the base of the pyramid to more potent but also more toxic drugs at the top. 
Current treatment primarily consists of symptomatic management with dietary modifications, 
5-aminosalicylic acid (5-ASA), opiates (loperamide), systemic glucocorticoids, 
immunosuppressive agents (azathioprine [AZA], 6-mercaptopurine [6-MP], 
methotrexate [MTX]), and biologic therapy with anti-tumor necrosis factor (TNF) agents or 
anti-integrin agents. Despite recent advances, there is still an unmet need for a safe, effective, 
and durable pharmacological treatment that will induce and maintain clinical remission.
1.2
Product Background and Clinical Information
The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal sites of the 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 (Shyjan et al., 
1996; Briskin et al., 1997; 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.
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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 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 (IB) 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 IgG2κ antihuman MAdCAM monoclonal antibody, is under development 
for the treatment of CD. SHP647 prevents the binding of 47
+ 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 47
+ lymphocytes to the 
MAdCAM receptor and the resultant efficacy in CD is well established (Sandborn et al., 2013). 
SHP647 is differentiated from other molecules targeting the 47-MAdCAM mediated 
lymphocyte trafficking used for the treatment of CD in that SHP647 blocks the interaction of 
47
+ lymphocytes with the MAdCAM receptor by selectively binding to MAdCAM on the 
endothelial cells surface in the gut (and related tissues) while the other molecules target the 
integrins on the infiltrating lymphocytes. Additionally, SHP647 does not bind to the vascular cell 
adhesion molecule (VCAM); therefore, SHP647 is not expected to affect lymphocyte homing or 
surveillance in the CNS or to be an effective treatment for multiple sclerosis.
This study is designed to evaluate the efficacy and safety of SHP647 in inducing clinical 
remission and endoscopic response in subjects with moderate to severe CD.
The CD clinical development program includes 3 completed studies: 1 Phase 1 study 
(A7281008) and 2 Phase 2 studies (A7281006 and A7281007).
Study A7281006 (OPERA) was a parallel, dose-ranging, randomized, double-blind, 
placebo-controlled study in which SHP647 was given as 3 subcutaneous (SC) dose levels (22.5, 
75, and 225 mg) once every 4 weeks (Q4W) over an 8-week period. SHP647 was generally safe 
and well tolerated and there were no deaths. Three placebo-treated subjects and 9 subjects in the 
22.5, 75, and 225 mg SHP647 groups discontinued treatment due to adverse events (AEs). Most 
treatment-emergent AEs (TEAEs) were mild or moderate in severity. Median serum 
concentrations of SHP647 increased with increasing dose. Positive antidrug antibodies (ADA)
status did not appear to impact exposure to SHP647. The CD Activity Index (CDAI) was the 
primary instrument to assess the efficacy of SHP647; no statistically significant differences were 
noted between the active treatment arms and the placebo arm. Therefore, the study did not meet 
its primary endpoint. However, post hoc analysis indicated increased remission rates in subjects 
in the 22.5 mg or 75 mg treatment arms who had higher serum concentrations of high-sensitivity 
C-reactive protein (hsCRP) or higher scores of Simple Endoscopic Score for CD (SES-CD) at 
baseline.
Study A7281008 (TOSCA) was an open-label multi-center, Phase 1 sequential cohort study that 
evaluated the effects of a maximum induction dose of SHP647 on CNS system immune 
surveillance.
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Subjects with inflammatory bowel disease (IBD) (including CD), with or without stoma, who 
failed or were intolerant to both anti-TNF and immunosuppressant therapy and who had 
moderate to severe active disease underwent a lumbar puncture (LP), completed induction 
therapy with 3 doses of 225 mg SHP647 4 weeks apart, and then underwent a second LP 
2 (±1) weeks later. The primary endpoint was the percent change from baseline (pretreatment) in 
absolute lymphocyte count in cerebrospinal fluid (CSF) in subjects with IBD after receiving 
3 doses of 225 mg SHP647. The mean percentage change from baseline in absolute lymphocytes 
in CSF was 61.76% with a median change of 35.2% (range: -70.2% to 267.8%). The 
post-treatment LP/pretreatment LP geometric mean ratio for CSF lymphocytes was 1.33 with the 
lower bound of the 80% confidence interval (CI)=1.13, which was greater than 0.5, supporting 
rejection of the null hypothesis (ie, that the percent decrease in total lymphocytes counts after 
treatment would be ≥50% (equivalent to the geometric mean ratio in total lymphocyte counts 
being ≤0.5). This result supports the hypothesis that SHP647 does not impair trafficking of 
lymphocytes into the CNS and thus should not impair CNS immune surveillance.
Study A7281007 (OPERA II) was a Phase 2 open-label extension study to provide additional 
long-term safety data on subjects with moderate to severe CD who completed Study A7281006 
or Study A7281008 and wished to continue to receive SHP647. SHP647 75 mg (with potential 
dose escalation to 225 mg) SC given every 4 weeks for 72 weeks was generally well tolerated in 
subjects with CD over the treatment period evaluated in this study. In subjects with positive 
ADA or neutralizing antibody (NAb) status, exposure to SHP647 was not affected. Serum 
concentrations of SHP647 in this study were consistent with what was predicted based on the 
Feeder Study A7281006. There were 2 deaths in the study: 1 subject died of multiple organ 
dysfunction syndromes in the treatment period and 1 subject died of metastatic neoplasm in the 
follow-up period. Neither death was reported as related to treatment with the study drug by the 
investigators. The most frequently reported serious adverse event (SAE) was CD in either the 
treatment period or the follow-up period. The system organ class with the most subjects 
experiencing TEAEs was GI disorders. Although Study A7281007 was not placebo controlled, 
the exploratory efficacy results (based on the modified Harvey Bradshaw Index) indicated that 
the effect of SHP647 on disease activity was maintained over the duration of treatment.
The SHP647 dose selection (25 and 75 mg) for this study is based on data from these 3 previous 
studies, which evaluated the activity of SHP647 in adult patients with moderately to severely 
active CD based on CDAI scores between 220 and 450. The results of a post hoc analysis of 
remission rate by baseline elevated serum concentration of hsCRP suggested that the greatest 
treatment effect was at a dose of 22.5 mg. Similarly, post hoc analysis of remission rates by 
endoscopic severity assessed using the Simple Endoscopic Score for CD (SES-CD) suggested 
best efficacy at a dose of 75 mg. Therefore, both dosage regimens 25 and 75 mg Q4W have been 
selected for the Phase 3 testing. The Phase 1 study (A7281008, TOSCA) and Phase 2 studies
(A7281006, OPERA; and A7281007, OPERA II [long-term safety study]) that investigated the 
safety, tolerance, pharmacokinetics, and pharmacodynamic properties of SHP647 support further 
clinical development of SHP647 using SC administration in subjects with moderate to severe 
CD.
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2.2
Study Objectives
2.2.1
Coprimary Objectives
The coprimary objectives of this study are to evaluate the efficacy of SHP647 in subjects with 
moderate to severe CD in:

Inducing clinical remission based on 2-item patient-reported outcome (PRO) (abdominal 
pain severity and very soft stool/liquid stool frequency)

Inducing endoscopic response based on centrally read colonoscopy.
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 inducing clinical remission as measured by CDAI

To evaluate the efficacy of SHP647 in inducing enhanced endoscopic response based on 
centrally read colonoscopy

To evaluate the efficacy of SHP647 in inducing clinical remission based on abdominal 
pain severity and very soft stool/liquid stool frequency (alternate thresholds)

To evaluate the efficacy of SHP647 in inducing clinical response based on 
patient-reported clinical signs and symptoms (as measured by 2-item PRO)

To evaluate the efficacy of SHP647 in inducing clinical remission based on 
patient-reported clinical signs and symptoms (as measured by 2-item PRO) as well as 
inducing endoscopic response based on centrally read colonoscopy in the same subject

To evaluate the efficacy of SHP647 in inducing endoscopic healing based on centrally 
read colonoscopy.
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 (clinical 
response defined by CDAI, or clinical remission over time, or change from baseline in 
frequency in CD-related clinical parameters)

To evaluate the effect of SHP647 induction treatment on other endoscopic outcomes

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

To evaluate the impact of SHP647 on incidence of CD-related and other surgeries.
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2.2.3
Exploratory Objectives
The exploratory objectives 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 clinical remission and endoscopic 
response in subjects with moderate to severe CD.
At study initiation, a total of 1032 subjects (387 subjects in the 25 mg SHP647 treatment group, 
387 subjects in the 75 mg SHP647 treatment group, and 258 subjects in the placebo group) 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 16-week treatment period. After the 
screening period, eligible subjects will be randomized to receive 1 of 3 treatments 
(25 mg SHP647, 75 mg SHP647, or placebo) in a 3:3:2 ratio. Randomization will be stratified 
based upon the subject’s status of prior anti-TNF treatment (naïve or experienced), 
glucocorticoid use at baseline (on glucocorticoids at baseline versus not on glucocorticoids at 
baseline), and SES-CD at baseline (SES-CD ≥17 or SES-CD <17). 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), Week 8 (Visit 5), and Week 12 (Visit 6). Subjects will undergo efficacy, 
, 
, safety, and health outcome assessments at these visits and at 
the time points specified in Table 1.
At the end of the 16-week treatment period, subjects will be offered the opportunity to participate 
in either a double-blind maintenance study (SHP647-307; for subjects who fulfill the entry 
criteria) or a long-term safety extension (LTS) study (SHP647-304; for subjects who do not 
fulfill the entry criteria for Study SHP647-307) as shown in Figure 1. Subjects who withdraw 
early from the 16-week treatment period or who do not wish to enter the maintenance study 
(SHP647-307) 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 (SHP647-305 or SHP647-306) will be eligible to continue in the 
maintenance study or LTS study.
A planned interim analysis for the coprimary endpoints will take place after approximately the 
first 50% of all randomized subjects in both the SHP647-305 and SHP647-306 studies have 
either completed the studies or have prematurely withdrawn from the studies. The sample size 
will be reassessed as part of this interim analysis. See Section 9.5 for further details of the 
planned interim analysis.
The overall study design is shown in Figure 2.
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Figure 1:
Overview of SHP647 Phase 3 Studies in Crohn’s Disease
BSFS=Bristol Stool Form Scale; CD=Crohn’s disease; CDAI= CDAI=Crohn’s Disease Activity Index; NRS=numerical rating 
scale; PRO=patient-reported outcomes; SES-CD=Simple Endoscopic Score for Crohn's Disease.
a
Responders are subjects who either:
(a) Meet endoscopic response criteria of a reduction in SES-CD from baseline by ≥25% at Week 16
OR
(b) Meet at least 1 of the following 4 criteria at Week 16 in addition to no worsening of endoscopic score as measured by 
SES-CD relative to induction study baseline (SHP647-305 or SHP647-306):
1.
Subject is in clinical remission as determined by meeting the criteria for clinical remission using the 2-item PRO, 
ie, 2-item PRO subscore of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days and 
average daily stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days.*
2.
Subject has a decrease of at least 70 points in CDAI score (CDAI-70) from baseline.
3.
Subject has a decrease of ≥30% and at least 2 points from baseline in the average daily worst abdominal pain over the 
7 most recent days*, with the average daily stool frequency of type 6/7 (very soft stools/liquid stools) either: (i) not worsening 
from baseline and/or (ii) meeting the criteria for clinical remission, ie, 2-item PRO subscore of average daily stool frequency 
≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days.*
4.
Subject has a decrease of ≥30% from baseline in the average daily stool frequency of type 6/7 (very soft stools/liquid 
stools) as shown in the BSFS over the 7 most recent days*, with the average daily worst abdominal pain either: (a) not worsening 
from baseline and/or (b) meeting the criteria for clinical remission, ie, 2-item PRO subscore of average worst daily abdominal 
pain ≤3 (based on 11-point NRS) over the 7 most recent days*.
*Note: The 7 most recent days may or may not be contiguous during the 10 days of data collection before colonoscopy 
preparation, depending on days to be excluded because of missing data. If fewer than 7 days are available, the criterion will be 
calculated on all available most recent 6 or 5 days. If fewer than 5 days are available, the criterion will be treated as missing.
Placebo 
25 mg
75 mg
Non-Respondersa
Induction
(SHP647-305, SHP647-306) 
Maintenance
(SHP647-307) 
Long-term Safety 
Extension
(SHP647-304) 
25 mg
Placebo
75 mg
Placebo
Placebo
Respondersa
Respondersa
Respondersa
75 mg
25 mg
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Figure 2:
Study Design Flow Chart
LTS=long-term safety extension; W=week.
aSubjects who withdraw early from the 16-week treatment period or who do not wish to enter the maintenance study 
(SHP647-307) or LTS study (SHP647-304) will continue into a 16-week safety follow-up period.
Note: A planned interim analysis for the coprimary endpoints will take place after approximately the first 50% of all randomized
subjects in both the SHP647-305 and SHP647-306 studies have either completed the studies or have prematurely withdrawn from 
the studies.
3.1.1
Rationale for Coprimary Endpoints
In this study, clinical remission, as measured by a decrease below prespecified thresholds in the
2-item PRO (abdominal pain severity and very soft stool/liquid stool frequency [as shown in the 
Bristol Stool Form Scale, BSFS]), and enhanced endoscopic response, as measured by a decrease 
in SES-CD, will be the primary instruments to assess the efficacy of SHP647.
Rationale for Abdominal Pain Severity
Abdominal pain is one of the most common symptoms of CD, with the cause likely to be 
multifactorial. In the CDAI, which was the most commonly used primary endpoint in CD studies 
in the past, the degree of abdominal pain was based on a 4-point scale, with scores ranging from 
0 (none) to 3 (severe). However, the new standard is to use the 11-point numerical rating scale 
(NRS) instead for the degree of abdominal pain. The limitation is that the 4-point and the 
11-point scales are not directly comparable. Numerous studies across a variety of conditions 
have examined cutoff scores for mild, moderate, and severe pain based on the 11-point pain 
NRS, with the findings across studies generally converging on a cutoff score of 4 (reflecting the 
maximum score indicating mild pain) and a score of 5 (reflecting the minimum score indicating 
moderate pain). To ensure that clinical remission criteria for abdominal pain are both clinically 
meaningful and fall definitively within the mild pain range on the NRS based on the literature, a 
remission subscore of ≤3 (a minimum improvement of at least 2 points is required for subjects 
who enter the study with moderate abdominal pain [subscore of ≥5]) will be used as part of the 
coprimary endpoints. 
Placebo
25 mg SHP647
75 mg SHP647
Screening: Up to 
6 weeks
Randomization
Maintenance study 
(SHP647-307)
or
LTS study 
(SHP647-304)
or
16-week safety 
follow-up perioda
W0
W4
Dosing:
Treatment period: 16 weeks
Week 16/End of 
Treatment
W8
W12
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This definition is further supported by a study conducted in a similar condition (irritable bowel 
syndrome) that examined the minimal clinically important difference on the 11-point NRS for 
abdominal pain (Spiegel et al., 2009) as well as post hoc analyses of the Phase 2 data from the 
SHP647 program (Study A7281006, OPERA).
Rationale for Very Soft Stool/Liquid Stool Frequency
Diarrhea is the most common sign in the presentation of CD, affecting approximately 85% of 
patients with a diagnosis of CD. In the CDAI, the number of liquid or soft stools (each day for 
7 days) is used with a multiplier of 2. The coprimary endpoints for clinical remission in studies 
SHP647-305 and SHP647-306 requires the use of a definition without any such multiplying 
factor and will use the BSFS for defining the very soft or liquid stools according to types 6 and 7, 
respectively. A retrospective study of PROs in CD based on data from randomized controlled 
studies using rifaximin and methotrexate showed that a mean daily stool frequency score of 
≤1.5 had an area under the receiving operating characteristic curve of 0.79 (Khanna et al., 2015) 
and provided a potential cutoff for defining remission as measured by CDAI. In a recent study to 
select the attributes determining overall disease severity and to rank the importance of and to 
score these individual attributes for both CD and UC based on specialist opinion, a sample of at
least 10 loose stools per week was considered as an attribute contributing to overall disease 
severity in CD (Siegel et al., 2016). Based on post hoc analyses of the Phase 2 data in the 
SHP647 program (Study A7281006, OPERA) and by choosing the population of subjects 
satisfying the moderate to severe CD inclusion criteria, various cutoffs were explored and a stool 
frequency ≤2.0 was found to be optimal in terms of treatment separation while still allowing for 
a reasonable threshold for remission. Based on these and other recent data that support this 
cutoff, an average daily stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) has been 
chosen as the stool frequency criterion for clinical remission.
Endoscopic Response
Endoscopic response is defined in 2 ways:

25% reduction in SES-CD score (“endoscopic response”)

50% reduction in SES-CD score (“enhanced endoscopic response”).
“Endoscopic response” will be used as a coprimary endpoint and “enhanced endoscopic 
response” will be used as a key secondary endpoint in this study as these magnitudes of changes 
are likely to be clinically relevant.
Mucosal healing or “endoscopic healing” is considered to be a pivotal long-term target in the 
treatment of CD; however, partial healing or endoscopic response may also provide benefits. 
Endoscopic response can be an important indicator that the mucosal inflammation has decreased 
as an effect of the investigational product. Some treatments may result in a partial initial 
response, even though at a later stage a complete response may occur. Median duration of 
remission after 1 year treatment with infliximab was similar in subjects achieving complete 
absence of mucosal ulcer to subjects who achieved significant but incomplete mucosal healing 
(D'Haens et al., 2002). 
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The benefit of endoscopic response was also shown in the SONIC study; the presence of 
endoscopic response (defined in that study as at least a 50% decrease in endoscopic score at 
Week 26 of treatment) identified subjects most likely to be in corticosteroid-free clinical 
remission at Week 50 (Ferrante et al., 2013). The proportion of patients requiring major 
abdominal surgery in a single-center cohort study with infliximab was similar with complete 
healing or with partial healing. (Schnitzler et al., 2009; Panaccione et al., 2013). Subjects with 
such a treatment response should be identified by endoscopic assessment in order not to 
misclassify them as nonresponders and underestimate the response to the treatment.
3.1.2
Rationale for Key Secondary Endpoints
Clinical Remission Defined by CDAI Score
Conventionally, a CDAI score of <150 has been used to define clinical remission. While there 
has been widespread use of the CDAI over a long period of time, the items do not contribute 
equally to the score, and symptom items reported by subjects are not specific for CD and are not 
sensitive for inflammation seen at colonoscopy. There has been movement away from using the 
CDAI by regulatory authorities to the use of PROs and objective measures of disease such as 
endoscopy (Williet et al., 2014). However, for benchmarking or for comparative effectiveness 
purposes, CDAI endpoints are expected to be used.
Although this has been the established gold-standard for clinical remission to date, CDAI suffers 
from requiring complex calculations across 8 individual items including subjective elements.
Clinical Remission Defined by Average Worst Daily Abdominal Pain ≤1 (Based on the 4-point 
Scale) and Average Daily Stool Frequency ≤3 of Type 6/7
The CDAI has been the traditionally used measure to assess clinical response and clinical 
remission in CD. In the CDAI, the degree of abdominal pain is one of 8 variables and is used 
with a multiplier of 5 in the overall score. Importantly, it is based on a 4-point scale, with scores 
ranging from 0 (none) to 3 (severe). With the shift to the new endpoint as evident from the 
coprimary endpoint of clinical remission in this study, it is still important to allow for a frame of 
reference to the existing standard for response, based on the CDAI components. A daily average 
abdominal pain threshold of ≤1 will help achieve this as 1 on the 4-point scale corresponds to 
mild abdominal pain. Although direct mapping between the scales has not been established, this 
will approximate to a score of 3 on the 11-point NRS scale, as this falls within the mild pain 
range on the NRS based on the literature.
Based on post hoc analyses of the Phase 2 data in the SHP647 program, regulatory requirements, 
and treatment separation assumptions, a threshold for the average daily stool frequency ≤2 of
type 6/7 (very soft stools/liquid stools) was chosen for the coprimary endpoint of clinical 
remission. However, given the limited data available for this endpoint, recent evidence from 
literature suggesting that thresholds ≤3 are likely to be quite stringent (Sandborn et al., 2017),
and the refractory nature of the disease in those with moderate to severe CD, it is also important 
to assess the effects of treatment using a more realistic measure. Hence, for this key secondary 
endpoint of clinical remission, average daily stool frequency ≤3 of type 6/7 (very soft 
stools/liquid stools) has been chosen as the appropriate threshold.
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Clinical Response
The goal of measuring clinical remission is to have a sensitive clinical measure to assess the 
complete absence of symptoms or the stabilization of noninflammatory symptoms. However, as 
response and remission are considered to be on a continuum of improvement or response to 
treatment, clinical remission is generally the chosen measurement over clinical response.
Therefore, clinical remission is used as coprimary endpoint and clinical response is used as a 
key secondary endpoint in this study.
Clinical response is defined in Section 9.8.2.1. For both clinical response criteria, an additional 
requirement is that the symptom not being used to assess clinical response (ie, abdominal pain 
severity or very soft stool/liquid stool frequency) must remain unchanged/not worsen from the 
baseline score, or meet the criteria for clinical remission for that item of the 2-item PRO (either a 
2-item PRO subscore of average daily stool frequency ≤2 of type 6/7 [very soft stools/liquid 
stools] as shown in the BSFS or average worst daily abdominal pain ≤3 [based on 11-point NRS]
over the 7 most recent days).
The rationale for needing to meet at a minimum clinical response definition for either abdominal 
pain severity or very soft stool/liquid stool frequency (and not necessarily both) is based on the 
supposition that a lack of improvement in 1 of these symptoms is not necessarily an indicator of 
eventual lack of response (as assessed by the stricter clinical remission criterion). Based on 
Phase 2 data, it has been observed that the magnitude of placebo response rate can be higher for 
abdominal pain than for stool frequency. Therefore, the additional criterion of at least a 2-point 
decrease in abdominal pain severity from baseline is required for assessing clinical response for 
abdominal pain. Overall, the definition of clinical response used for this study has been chosen to 
allow for the maximal pool of subjects to be assessed for the effect of treatment and, if 
appropriate, the continuation of therapy in the maintenance study (SHP647-307).
Composite Score Endpoint of Both Clinical Remission by 2-item PRO and Endoscopic Response 
at Week 16
In theory, as the degree of inflammation decreases due to the effect of treatment, both clinical 
signs and symptoms of CD as well as endoscopic appearance can improve. However, in any 
given subject, the rates of clinical improvement and endoscopic improvement may not be the 
same. There are reasons for this discrepancy when evaluating clinical and endoscopic 
improvement in the same time period, including clinical symptoms not being well correlated to 
the mucosal inflammation. Due to the transmural feature of the disease, symptoms can 
correspond to the inflammation in some of the other gut layers as well. Previous clinical studies
and clinical observations indicate that the improvement of clinical signs and symptoms and the 
improvement in endoscopic appearance may not go hand in hand. Significant clinical 
improvement can precede significant endoscopic improvement. The healing process of the gut 
mucosa may take a long time and may depend on the baseline severity of the endoscopic 
appearance, which may not be in line with the actual baseline severity of the symptoms. 
Therefore, when evaluating clinical remission together with endoscopic endpoints, improvement 
in endoscopic scores could be more relevant than evaluating mucosal healing in the induction 
phase. 
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For these reasons, the key secondary composite endpoint (which takes into account both clinical 
and endoscopic response to treatment in the same subject) consists of the evaluation of the 
clinical remission together with the endoscopic response.
Complete Endoscopic Healing
Endoscopic healing will be defined in 2 ways:

Endoscopic healing defined by SES-CD ≤4 and at least a 2-point reduction versus 
baseline (Visit 2) and no subscore >1 in any individual variable

Complete endoscopic healing defined by SES-CD=0-2.
There is no uniformly accepted definition for endoscopic healing in CD and several different 
terminologies are used to describe the same endoscopic appearance defined by a certain 
endoscopic score (eg, endoscopic remission and mucosal healing). Endoscopic healing or 
mucosal healing is predominantly defined by the absence of mucosal ulcerations in CD during 
endoscopic assessment of intestinal inflammation (Atreya and Neurath, 2017). The International 
Organization for the study of Inflammatory Bowel Disease technical review on endoscopic 
indices for CD clinical studies defined complete endoscopic healing as SES-CD=0-2 (Vuitton et 
al., 2016). Some studies introduced SES-CD ≤4 as “endoscopic remission”. The more stringent 
endpoint of “complete endoscopic healing” will be used as a key secondary endpoint in this 
study. Even in case of complete endoscopic healing, there may still be ongoing histological 
activity in many cases and it may not always reflect healing of all layers of the tissue, as 
endoscopy only addresses mucosal rather than transmural healing (Atreya and Neurath, 2017).
The importance of inducing endoscopic healing is that it may be associated with long-term 
symptomatic remission; longer relapse-free interval; reduced frequency of hospitalizations, 
complications, and surgical resections; and the potential for a significant improvement in quality 
of life (Peyrin-Biroulet et al., 2011).
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 16), if 
continuing to Study SHP647-307 or SHP647-304, or at the end of the safety follow-up period 
(Week 32), 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 38 weeks: a screening period of up to 6 weeks, a treatment period of 16 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.
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3.3
Sites and Regions
It is anticipated that the study will be conducted in approximately 19 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 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 active moderate to severe ileal (terminal ileum), ileocolic, or colonic 
CD at baseline (Visit 2) as defined by:
a.
CDAI score between 220 and 450 (inclusive) AND
b. Presence of ulcerations that are characteristic to CD, as determined by a 
colonoscopy performed during screening, and as defined by the SES-CD >6
(SES-CD ≥4 for isolated ileitis) AND
c.
Meeting the following subscores in the 2-item PRO:
i. Average of the abdominal pain subscores ≥5 (average worst daily pain on 
the 11-point NRS) over the 7 most recent days out of the 10 days before
colonoscopy preparation (may or may not be contiguous) AND/OR
ii. Average of the daily stool frequency subscore ≥4 of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days out 
of the 10 days before colonoscopy preparation (may or may not be 
contiguous).
5. Subjects must have a documented diagnosis (endoscopic with histology) of CD for 
≥3 months before screening. Documented diagnosis is defined as:
A biopsy report to confirm the histological diagnosis AND
A report documenting disease duration based upon prior colonoscopy.
Note: If a biopsy report is not available in the source document at the time of screening, 
the histology report of the biopsy performed mandatorily during the screening 
colonoscopy should be consistent with the CD diagnosis. If the histology diagnosis is 
not clear at this time point, the subject should not be randomized.
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6. Subjects must be willing and able to undergo a colonoscopy during screening after all 
other inclusion criteria have been met.
7. 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 mesalamine 
(5-ASA), glucocorticoids, immunosuppressants (AZA, 6-MP, or MTX), or anti-TNF.
Subjects who have had an inadequate response to sulfasalazine or mesalamine should 
have also failed at least 1 other conventional treatment such as glucocorticoids.
8. Subjects receiving any treatment(s) for CD 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.
9. 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, ischemic colitis, infectious 
colitis, or clinical/histologic findings suggestive of ulcerative colitis.
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 presence of enterovesical (ie, between the bowel and urinary bladder) or 
enterovaginal fistulae.
5. Subjects with current symptomatic diverticulitis or diverticulosis.
6. Subjects with obstructive 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 CD during the treatment period.
7. Subjects with past medical history of multiple small bowel resections resulting in 
clinically significant short bowel syndrome.
8. Subjects requiring total parenteral nutrition.
9. Subjects with past medical history of bowel surgery resulting in an existing or current 
stoma. Subjects who had a j-pouch are excluded as a j-pouch could result in a stoma.
10. Subjects have had prior treatment with SHP647 (formerly PF-00547659).
11. Subjects with known or suspected intolerance or hypersensitivity to the investigational 
product(s), closely related compounds, or any of the stated ingredients.
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12. Subjects have received any nonbiologic treatment with immunomodulatory properties 
(other than AZA, 6-MP, or MTX) or continuous antibiotics (>2 weeks) for the treatment 
of CD within 30 days before baseline (Visit 2).
13. Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2).
14. Subjects have received any biologic with immunomodulatory properties (other than 
anti-TNFs) within 90 days before baseline (Visit 2).
15. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, 
vedolizumab, efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion 
molecule).
16. Subjects have received lymphocytes apheresis or selective monocyte granulocytes 
apheresis within 60 days before baseline (Visit 2).
17. Subjects have received enteral nutrition treatment within 30 days before 
baseline (Visit 2).
18. Subjects have received parenteral or rectal glucocorticoids or rectal 5-ASA within 
14 days before screening colonoscopy.
19. Subjects have taken >20 mg/day of prednisone or equivalent oral systemic corticosteroid 
dose within 14 days before baseline (Visit 2) or have taken ≥40 mg/day of prednisone or 
equivalent oral systemic corticosteroid dose within 6 weeks before baseline (Visit 2).
20. 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 
screening (Visit 1).
21. Subjects have received a live (attenuated) vaccine within 30 days before 
baseline (Visit 2).
22. 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 retest 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 baseline (Visit 2).
23. Subjects with abnormal chest x-ray or other imaging findings at screening (Visit 1), such 
as presence of active tuberculosis (TB), general infections, heart failure, or malignancy. 
(A chest x-ray, computed tomography scan, etc., 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).
24. Subjects with evidence of active or latent infection with Mycobacterium tuberculosis
(TB) who have not completed a generally accepted full course of treatment before 
baseline (Visit 2) are excluded. All other subjects must have either the Mantoux (purified 
protein derivative [PPD]) tuberculin skin test or interferon-gamma release assay (IGRA) 
performed.
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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 baseline (Visit 2). 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/TB 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.
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 3 months before 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.
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25. 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.
26. Subjects with any unexplained symptoms suggestive of progressive multifocal 
leukoencephalopathy (PML) based on the targeted neurological assessment during the 
screening period (Section 7.2.3.3).
27. Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are 
allowed.
28. 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).
29. Subjects who have had significant trauma or major surgery within 4 weeks before 
screening (Visit 1), or with any major elective surgery scheduled to occur during the 
study.
30. Subjects with evidence of or suspected liver disease, liver injury due to methotrexate or 
primary sclerosing cholangitis.
31. 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 (also referred as anti-HBsAg) reflex testing.
32. Subjects with positive hepatitis C antibody (HCVAb) with confirmation by 
HCV-ribonucleic acid (RNA) polymerase chain reaction (PCR) reflex testing.
33. Subjects with any of the following abnormalities in hematology and/or serum chemistry 
profiles during screening (Visit 1). 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 colonoscopy procedure.
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Alanine aminotransferase and aspartate aminotransferase levels 2.5 times the 
upper limit of normal (ULN)
Total bilirubin level 1.5 times the ULN (except where attributed to elevation in 
unconjugated bilirubin 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 <2 × 109/L (2000 cells/mm3)
Serum creatinine level >1.5 times the ULN or estimated glomerular filtration rate 
<30 mL/min/1.73m2 based on the abbreviated Modification of Diet in Renal 
Disease Study Equation.
34. Subjects with a known infection with human immunodeficiency virus, as documented in 
their medical history.
35. 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.
36. Subjects using 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, Fifth Edition (including urine drug screen and medical history).
37. 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.
38. Female subjects who are planning to become pregnant during the study period.
39. Male subjects who are planning to donate sperm and do not agree not to do so for the 
duration of the study and through 16 weeks after last dose of investigational product.
40. 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

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 (Section 5.2).
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
Smoking is considered to be a risk factor for CD. Reports have shown that smoking is not 
only related to the onset, relapse, and exacerbation of CD, but also that smoking cessation 
lowers the postoperative recurrence rate (Ueno et al., 2013). Subjects should inform the 
investigator of any changes to their smoking habits during the study (including starting or 
stopping smoking). Use of nicotine patches should be recorded as concomitant 
medication (Section 5.2.1).
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.
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 one 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 a 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.
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
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 (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
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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 16/early termination (ET) (Visit 7) 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 active treatment include but are not limited 
to:

AEs

SAEs

Protocol violations

Failure to return for visits.
A subject should be withdrawn from study treatment:

If a new therapy is initiated for CD, or

If a subject undergoes surgery for CD.
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.
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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:

AE

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 one 
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 CD during the 90 days 
before screening must also be recorded.
Subjects must have had an inadequate response to, or lost response to, or had intolerance to at 
least 1 conventional treatment such as sulfasalazine or 5-ASA, glucocorticoids, 
immunosuppressants (AZA, 6-MP, or MTX), or anti-TNF.
Inadequate response:
The subject experiences continued disease activity despite 
treatment with an adequate therapeutic dose and treatment course 
(dictated by the product label and international CD therapeutic 
guidelines)
Loss of response:
The subject experiences relapse after an initial clinical response or 
remission
Intolerance:
The subject has a history of having experienced an unacceptable or 
dose limiting toxicity associated with the use of the agent.
All prior and concomitant CD-specific treatments will be recorded. The subject’s entire history 
of biologic CD-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 of this study, inclusive.
5.2.1
Permitted Treatment
Subjects must remain on stable doses of permitted CD treatments until completion of the 
Week 16 visit, unless decreases are required because of AEs. Stable doses of the following 
treatments for CD are permitted as concomitant medication:

Oral sulfasalazine or 5-ASA, 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 [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 baseline (Visit 2). After baseline (Visit 2), a stable dose of 
20 mg/day prednisone or equivalent oral systemic corticosteroid dose is allowed. Steroids 
may be decreased due to AEs.
Note: Rectal 5-ASA and parenteral or rectal glucocorticoids are prohibited from within 14 days 
before screening colonoscopy.
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Antidiarrheal opiate drugs such as IMODIUM® (loperamide), LOMOTIL® (diphenoxylate 
hydrochloride and atropine sulfate), tincture of opium, and codeine will be recorded. Subjects 
must be using such products in a stable regimen for at least 2 weeks before randomization at 
baseline (Visit 2). Reported use of any antidiarrheal opiate medicines will assist the investigator 
response to Question 5 of the CDAI.
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-containing preparations should be recorded as concomitant medication.
Antibiotics are permitted, with the exception of antibiotics used to treat the underlying disease or 
any continuous antibiotic treatment exceeding 2 weeks within 30 days before starting PRO-CD 
daily e-diary data collection in the screening period or before Week 16 (Visit 7, Part 1).
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
Excluded 
without any 
timeframe
Minimum Required Number of Days Before 
Baseline (Visit 2)
Treatment
14 days
30 days
60 days
90 days
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 
propertiesc
X
Anti-TNF treatment
X
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Table 2:
Common Excluded Treatments
Excluded 
without any 
timeframe
Minimum Required Number of Days Before 
Baseline (Visit 2)
Treatment
14 days
30 days
60 days
90 days
Lymphocytes apheresis or selective monocyte 
granulocytes apheresis
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 colonoscopy (Section 4.2, exclusion criterion 18).
b Or 5 half-lives if longer.
c Off-label usage of immunosuppressants used in transplantation or other nonestablished therapies for CD (eg, mycophenolate 
mofetil, cyclosporine, rapamycin, thalidomide, tofacitinib, or tacrolimus)
Treatments not listed in Table 2 may be considered allowable; see Section 5.2.1 for further 
details.
In addition to the treatment listed in Table 2, the following common treatments are excluded 
medications for this study:

Prednisone dose >20 mg/day, budesonide >9 mg/day, or other equivalent oral systemic 
corticosteroid dose

Bismuth subsalicylate products

Fecal macrobiota transplantation.
No new nonpharmacological therapies that might affect bowel habit or GI function should be 
started during the study.
Enteral nutrition is not permitted from within 30 days of baseline (Visit 2) or at any time during 
the study.
5.2.3
Rescue Therapy
Subjects must maintain their stable dose of background CD 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 CD above the SHP647-305 or SHP647-306 
baseline (Visit 2), 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 (Visit 2) and treatment periods. High-dose 
glucocorticoids and other CD 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 (a fully human IgG2k antihuman MAdCAM monoclonal antibody), 
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 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 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 Products
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.
Eligible subjects will be randomized in a ratio of 3:3:2 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), glucocorticoid use at baseline (2 strata: on glucocorticoids at 
baseline versus not on glucocorticoids at baseline), and SES-CD at baseline (2 strata: 
SES-CD ≥17 at baseline versus SES-CD <17 at baseline).
To ensure that the allocation of subjects with prior anti-TNF therapy exposure is similar to that 
observed in previous studies, the percentage of subjects with prior exposure to treatment with 
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.
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.
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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.
6.2.3
Dosing
Investigational product (SHP647 or placebo) will be administered subcutaneously by qualified 
site personnel Q4W (Weeks 0, 4, 8, and 12). 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 (SHP647-305 or SHP647-306) 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.
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.
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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 United States [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 
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. 
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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.
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.
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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 (unplanned visits) in addition to those listed on the schedule 
of assessments (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 first dose of investigational product 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 will take place over more than 1 day (at least 2 visits will be necessary to 
complete the screening evaluations, including colonoscopy).
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 one 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 only. 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 before the screening colonoscopy procedure.
Hematology samples should be repeated if more than 3 weeks have elapsed before the day of 
colonoscopy to be able to use the hematocrit central laboratory results for the CDAI score 
calculation at screening. Hematocrit must not be older than 3 weeks before the day of 
colonoscopy.
Collection of the daily e-diary data must begin at least 14 days before colonoscopy preparation. 
Colonoscopy preparation will be according to local routine.
Colonoscopy must be performed on all subjects after the majority of other eligibility criteria 
(eg, laboratory values and 2-item PRO and CDAI scores) are met. It must be performed during
the screening period within 5 to 7 days before baseline (Visit 2), to allow for adequate e-diary 
data collection for the 2-item PRO and CDAI scores and to obtain the centrally read endoscopic
subscore to verify the subject’s eligibility (Section 7.2.2.4). If the calculated CDAI scores is 
<220 or >450, the subject will be considered a screen failure and should not proceed with the 
colonoscopy preparation and/or the colonoscopy. All colonoscopies will be evaluated using the 
SES-CD (Appendix 2).
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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 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 (Visit 2) 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 receive 1 of the 3 treatments 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
Visits 3, 4, 5, and 6 (Weeks 2, 4, 8, and 12)
Visits 3, 4, 5, and 6 are scheduled to take place on Day 14 ±3 days (Week 2), Day 28 ±3 days 
(Week 4), Day 56 ±3 days (Week 8), and Day 84 ±3 days (Week 12), respectively. The 
assessments and procedures specified in Table 1 will be performed.
7.1.2.2
Final On-treatment Visit: Visit 7, Parts 1, 2, and 3
(Week 16/Early Termination)
The Week 16/ET visit (Visit 7) consists of 3 parts.
Part 1 of Visit 7 should be scheduled 1 to 3 day(s) before Part 2; this will allow for blood 
samples to be taken before starting the colonoscopy preparation and before the colonoscopy 
procedure at Part 2 of the visit. The Week 16/ET assessments and procedures that will take place 
during Part 1 are specified in Table 1.
Part 2 of Visit 7 should be scheduled preferably within 5 to 7 days before Part 3; this will allow 
sufficient time to obtain the data from the centrally read colonoscopy. The Week 16/ET 
assessments and procedures that will take place during Part 2 are specified in Table 1.
Part 3 of Visit 7 will take place on Day 112 ±3 days. The Week 16/ET assessments and 
procedures that will take place during Part 3 are specified in Table 1.
At Part 3 of Visit 7, after review of CD assessments, health outcome assessments, and safety 
assessments, it will be determined whether the subject should enroll in the maintenance 
(SHP647-307) or LTS (SHP647-304) studies or enter the follow-up period of this study. Entry 
into the maintenance or LTS studies is dependent upon whether the subject fulfills the efficacy 
entry criteria of the maintenance study (SHP647-307), including achieving endoscopic and/or 
clinical response, and whether the subject agrees to participate.
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The Week 16 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
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 period for safety monitoring.
During the safety follow-up period, the Week 24 visit (Visit 8) will take place on 
Day 168 ±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 224 ±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; this visit will form the Week 32 visit (Visit 9). The assessments 
and procedures specified in Table 1 will be performed, including querying for SAEs, AEs, and 
concomitant medications and treatments. All AEs and SAEs that are not resolved at the time of 
this visit will be followed to closure (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 wellbeing 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

Investigational product administration

Colonoscopy is performed at a separate visit (Section 7.2.2.4).
Note: Blood and tissue samples may be stored for up to, 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 screening (Visit 1).
7.2.2
Efficacy
7.2.2.1
Patient-reported Outcome – Crohn’s Disease Daily E-diary
Patient-reported CD clinical signs and symptom data will be collected daily using a PRO-CD 
daily e-diary (electronic handheld device) starting from the first screening visit; however, 
collection of the daily e-diary data must begin at least 14 days before colonoscopy preparation. 
Subjects will enter data on CD signs and symptoms items using the e-diary, which will be 
provided to subjects at the start of the study. Compliance will be assessed by site staff at each 
visit. The site staff will instruct the subject on the appropriate use of the e-diary when 
compliance is below 80% (eg, <23 out of 28 e-diary entries). If 70% compliance cannot be 
achieved after repeated instructions during the screening period, noncompliant subjects will be 
automatically noneligible as they will not fulfill inclusion criterion 1 (Section 4.1).
Subjects will be asked to record the following signs and symptom data, as experienced over the 
previous 24 hours, in the e-diary:

Abdominal pain severity (numeric rating scale [NRS])

Very soft stool/liquid stool frequency (as shown by BSFS type 6/7)

Total stool frequency

Rectal bleeding frequency

Rectal urgency frequency

Nausea severity

Vomiting frequency

Incontinence frequency

Abdominal pain used in CDAI

General wellbeing.
The first 2 items (abdominal pain severity and very soft stool/liquid stool frequency) will be used 
to calculate the 2-item PRO. The 2-item PRO will be calculated using the following criteria:

Screening: the 2-item PRO will be calculated based on the 7 most recent days during the 
10 days of data collection before the colonoscopy preparation. If 7 out of the 10 most 
recent days are not available, then the 2-item PRO cannot be calculated for the subject at 
screening.

Visits 3, 4, 5, and 6: the 2-item PRO will be calculated based on the 7 most recent days 
during the 10 days of data collection before the visit. If fewer than 7 days are available, 
the 2-item PRO will be calculated on all available most recent 6 or 5 days. If fewer than 
5 days are available, the 2-item PRO will be treated as missing.
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
Visit 7 (Part 3): the 2-item PRO will be calculated based on the 7 most recent days during 
the 10 days of data collection before the colonoscopy preparation. If fewer than 7 days 
are available, the 2-item PRO will be calculated on all available most recent 6 or 5 days. 
If fewer than 5 days are available, the 2-item PRO will be treated as missing.
For all 2-item PRO calculations, the 7 most recent days may or may not be contiguous during the 
10 days of data collection depending on days to be excluded because of missing data. 
The PRO-CD daily e-diary is presented in Appendix 2.
7.2.2.2
Simple Endoscopic Score for Crohn’s Disease
The SES-CD will be performed at the time points specified in Table 1. The SES-CD score at 
baseline (Visit 2) and at Week 16/ET will be calculated using subscores of each of the segments 
investigated and centrally read from the colonoscopies performed at screening (Visit 1, Part 2) 
and Week 16 (Visit 7, Part 2), respectively.
The SES-CD is a simple scoring system based on 4 endoscopic variables (presence and size of 
ulcers, proportion of surface covered by ulcers, proportion of affected surface, and presence and 
severity of stenosis [narrowing]) measured in the same 5 ileocolonic segments as the CD index 
of severity. Overall, values on the SES-CD range from 0 to 56, with higher values indicating 
more severe disease. The 4 endoscopic variables are scored from 0 to 3 in each bowel segment 
(ileum, right/transverse/left colon, and rectum):

Presence and size of ulcers (none = score 0; diameter 0.1–0.5 cm = score 1; 
0.5–2 cm = score 2; diameter >2 cm = score 3)

Extent of ulcerated surface (none = 0; <10% =1; 10%–30% = 2; >30% = 3); extent of 
affected surface (none = 0; <50% = 1; 50%–75% = 2; >75% = 3)

Presence and type of narrowings (none = 0; single, can be passed = 1; multiple, 
can be passed = 2; cannot be passed = 3).
A complete colonoscopy is required (including visualization of the terminal ileum). 
The maximum stenosis score in a segment distal to another evaluable segment cannot exceed 2, 
so that the stenosis scores cannot exceed a total of 11 (Reinisch et al., 2017).
Evidence of active inflammation and ulceration is required at screening (Visit 1), in the form of a 
centrally read score of at least 1 in one or more ileocolonic segments in the Presence of Ulcers 
component of the SES-CD, as well as a total score of >6.
Study videos will be scored separately by 2 central readers who are blinded to the treatment. 
If the central readers’ scores are not in agreement, there will be a third adjudication read to select 
the correct read from the first 2 scores. Results of the central reading of the videos will be 
communicated to sites within 5 business days.
For the evaluation of efficacy, in cases where 1 or 2 segments cannot be fully evaluated by 
central endoscopic readers, ileocolonic segments that are evaluable during screening (Visit 1) 
and Week 16/ET (matching segments approach) will be utilized.
The SES-CD is presented in Appendix 2.
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7.2.2.3
Crohn’s Disease Activity Index
The CDAI is a composite measure with 8 components; 3 components (abdominal pain severity, 
very soft stool/liquid stool frequency, and general wellbeing) will be self-reported by the subject 
and will be recorded as part of the daily e-diary, as described in Section 7.2.2.1 and
5 components will be recorded at the time points specified in Table 1.
The CDAI score at screening (Visit 1, Part 2) will be calculated using the following:

Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected >10 days 
before the start of colonoscopy preparation using the same most recent 7 of 10 days as 
described for the 2-item PRO (Section 7.2.2.1) and

Components 4 to 8 (weight, medical and physical examination, use of diarrhea treatment, 
and hematocrit value) collected during screening (Visit 1) Part 1. Note: Hematology 
samples should be repeated if more than 3 weeks have elapsed before the day of 
colonoscopy to be able to use the hematocrit central laboratory results for the CDAI score 
calculation at screening. Hematocrit must not be older than 3 weeks before the day of 
colonoscopy.
The CDAI scores at Visits 4, 5, and 6 will be calculated using the following:

Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected >10 days 
before the visit using the same most recent 7 or 10 days as described for the 2-item PRO 
(Section 7.2.2.1) and

Components 4 to 8 (weight, medical and physical examination, use of diarrhea treatment,
and hematocrit value) collected at the visit.
The CDAI score at the Week 16/ET visit will be calculated at Visit 7, Part 3 (after all evaluations 
are complete), using the following:

Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected >10 days 
before the start of colonoscopy preparation using the same most recent 7 or 10 days as 
described for the 2-item PRO (Section 7.2.2.1) and

Components 4 to 8 (weight, medical and physical examination, use of diarrhea treatment,
and hematocrit value) collected at Part 1 and Part 3 of the Week 16/ET visit, where 
assessed.
Change in CDAI has been used as a primary endpoint in multiple pivotal studies in the CD 
indication. The algorithm for calculating the CDAI score was first published by William Best 
and colleagues (Best et al., 1976).
The CDAI is presented in Appendix 2.
7.2.2.4
Colonoscopy and Histology
Colonoscopy will be performed at the time points specified in Table 1.
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Bowel preparation regimens typically incorporate dietary modifications along with oral 
cathartics. Typically, the standard dose of a bowel preparation is split between the day before 
and the morning of the procedure. In this study, bowel preparation and colonoscopy are to be 
conducted per local routine; however, sodium phosphate based preparations should be avoided, 
as such regimens can produce mucosal changes that mimic IBD.
In general, a complete colonoscopy should be performed; this includes visualization of the 
rectum, sigmoid colon, left colon, transverse colon, right colon, ileocecal valve, and the terminal 
ileum. At screening, an incomplete colonoscopy will not be accepted; only a few exceptions will 
be evaluated on a case by case basis (eg. presence of impassable narrowing without any clinical 
signs of bowel obstruction and when the same time the investigated segments provide the 
SES-CD score required for inclusion). Similarly, a complete colonoscopy is the aim at 
Week 16/ET, with the exception of the presence of impassable stenosis or other CD-related 
complications as cause of failure to complete the colonoscopy procedure.
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 colonoscopy. 
To achieve consistency in capturing and assessing endoscopic video recordings, each 
participating site will use an integrated hardware/software solution and associated tools for the 
capture and transmission of endoscopy video recordings for central reading. Nonreadable 
endoscopic images, as assessed by the investigator, should not be sent for central reading. The 
colonoscopy 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 the colonoscopy at screening (Visit 1, Part 2) and Week 16/ET, 10 biopsies will be 
collected from the most inflamed area of the mucosa: 2 samples each from the ileum, the 
3 segments of the colon, and the rectum. Colonoscopy and biopsy procedures will be defined in a 
colonoscopy instructions manual and/or reference card(s), on which all sites will be trained. 
Colonoscopy results will be reviewed by a central reader.
 
 
(Appendix 2). Biopsies for conventional histologic assessment will be collected in formalin and 
shipped to the central laboratory. The central laboratory will register all biopsies and create 
paraffin blocks. Blocks will be batched and shipped on an agreed schedule to specialty 
laboratory, where tissue processing (sectioning, hematoxylin and eosin staining, and affixation to 
glass slides), digitalization, and uploading of images will occur. All images for a subject will be 
scored by the same qualified central pathologists blinded to the subject and treatment sequence 
information, according to the scoring modality.
7.2.3
Safety
7.2.3.1
Medical and Medication History
Medical history will be documented at screening (Visit 1), including CD history, cardiac history, 
and smoking history. Prior and concomitant medications and procedures will also be documented
at the time points specified in Table 1.
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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; 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 and 
mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, 
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, neurological examination(s), 
targeted to the abnormal domain, will be performed by the investigator or qualified personnel.
Subjects with any unexplained positive neurological assessment item at screening that is 
suggestive of PML should be excluded from enrollment in the study (exclusion criterion 25, 
Section 4.2).
The neurological assessment plan is summarized in Table 3.
Table 3:
Neurological Assessment Plan
Domain
Step 1: Targeted Neurological
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
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Table 3:
Neurological Assessment Plan
Domain
Step 1: Targeted Neurological
History
Step 2: If Abnormal Response
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 7s, 
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 study or the defined follow-up period stated in Section 7.1.3 (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.
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 or Fahrenheit. 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. 
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.
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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 (also referred as 
anti-HBsAg) if HBsAg is negative and HBcAb 
is positive

hepatitis C virus antibody (HCVAb)

HCV ribonucleic acid polymerase chain 
reaction if HCVAb is positive
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 electronic case report form (eCRF) 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 TB test (PPD or QuantiFERON-TB Gold/TB Plus) will be performed at the screening visit 
(Visit 1). A documented negative PPD test within 12 weeks before baseline (Visit 2) is 
acceptable provided that an IGRA official reading and method or test is located in the source 
documentation.
A serum sample will be collected and banked for John Cunningham virus antibody testing at 
baseline (Visit 2). It may be analyzed if a subject shows neurological 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/TB 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.
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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, will confirm 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 and Neutralizing Antibodies
A blood sample for measurement of 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.
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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, including CD. The IBDQ consists of 
32 items, which are grouped into 4 domains: bowel, systemic, emotional, and social function 
(Irvine et al., 1994). The 4 domains are scored as follows:

Bowel function: 10 to 70

Systemic function: 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.
 
 
 
 
 
The 
 is presented in Appendix 2.
 
 
The 
 and 
 are presented in Appendix 2.
 
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Short Form-36 Health Survey (Version 2, 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. Information regarding Crohn’s disease-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
The volume of blood to be drawn from each subject is summarized in Table 4.
Table 4:
Volume of Blood to Be Drawn From Each Subject
Assessment
Sample Volume (mL)
Number of Samples
Total Volume (mL)
Hematology
2
7
14
Serum chemistry
6
7
42
HBsAg
2
1
2
HBcAb
2
1
2
HCV Ab
2
1
2
FSH
2
1
2
Serum β-hCGa
2
1
2
TB test (QuantiFERON-TB 
Gold/TB Plus or PPD)
3
1
3
JCV antibody banked sample
3.5
1
3.5
2
3
6
5
3
15
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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)
 
4
3
12
 
3
6
18
ADA and NAb sampling
3
7
21
Total (mL)
144.5
Ab=antibody; ADA=antidrug antibodies; β-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
β-hCG testing for female subjects only.
c
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 144.5 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.
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 if the investigator considers such symptoms of disease progression related to 
the investigational product.
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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 Drug Safety 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 Nonserious 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 
Nonserious 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 β-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.
8.1.8
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.
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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.
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 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 Shire Global Drug 
Safety 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 (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 Nonserious 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 Drug Safety. A copy of the 
Shire Clinical Study Serious Adverse Event and Nonserious 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
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. 
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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 one 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 Drug Safety 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 Shire Global Drug 
Safety 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). 
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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 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® software Version 9.3 or higher 
(SAS Institute Inc, Cary, NC, US).
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, and Data Monitoring Committee
A planned interim analysis for the coprimary endpoints will take place after approximately the 
first 50% of all randomized subjects in both the SHP647-305 and SHP647-306 studies have 
either completed the studies or have prematurely withdrawn from the studies. Recruitment will 
not pause for this interim analysis. The purpose of the unblinded interim analysis is to reassess 
the appropriateness of the premises used for the coprimary endpoints when the study was 
designed. There is no possibility to stop early for overwhelming efficacy as the studies must 
continue in order to enroll an appropriate number of subjects in the SHP647-307 study. The 
reassessment of sample size will be performed using conditional power methods. Results at the 
interim analysis may be futile for one or both of the SHP647 doses and lead to the 
discontinuation of that dose for CD or the SHP647 CD program. Full details of the interim 
analysis, the guidelines for increasing the sample size, and futility rules to stop a dose will be 
included in a prespecified interim analysis SAP. The interim analysis SAP will be finalized 
before the interim analysis is conducted.
The planned interim analysis will be conducted by an external independent statistical group and 
given to the independent Interim Analysis Review Committee; the individuals involved in the 
day-to-day conduct of the study will not be involved in the interim analysis nor have access to 
the results of the interim analysis. The sponsor will only be notified by the Interim Analysis 
Review Committee of recommendations to modify the SHP647 CD program according to the 
guidelines specified in the interim analysis SAP.
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).
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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 coprimary endpoints. 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 to 
placebo.
Power calculations are made based on assuming a .025 (2-sided) significance level for each 
pairwise treatment comparison, 1720 subjects will be screened to randomize 1032 subjects in a 
3:3:2 allocation ratio: 387 subjects in the 25 mg SHP647 treatment group, 387 subjects in the 
75 mg SHP647 treatment group, and 258 subjects in the placebo group. These numbers of 
subjects would yield an approximately 93% power to detect individual pairwise treatment 
difference in the first coprimary efficacy endpoint, clinical remission by 2-item PRO at Week 16, 
of 10% (17.5% SHP647 versus 7.5% placebo). Expected clinical remission rates by 2-item PRO 
at Week 16 are based on observed rates from a post hoc analysis of the A7281006 study and 
placebo remission rates from literature (Sandborn et al., 2017). No adjustment for missing data is 
required in these sample size calculations as subjects with missing data for clinical remission by 
2-item PRO at Week 16 are imputed as failures and the above rates account for these subjects.
With the 1032 subjects in allocation noted above, this number of subjects would yield an 
approximately 94% power to detect individual pairwise treatment difference in the other 
coprimary efficacy endpoint, endoscopic response at Week 16, of 12.5% (27.5% SHP647 versus 
15% placebo). Expected endoscopic response rates at Week 16 are based on observed rates from 
a post hoc analysis of the A7281006 study and also endoscopic response rates from literature 
(Sandborn et al., 2017). No adjustment for missing data is required in these sample size 
calculations as subjects with missing data for endoscopic response at Week 16 are imputed as 
failures and the above rates account for these subjects.
The overall power for the coprimary endpoints will be approximately 87% assuming no 
correlation between the tests on the endpoints and approximately 90% assuming a correlation of 
0.4.
With the sample size of 1032 subjects, Table 5 provides the power for detecting a treatment 
difference between a SHP647 treatment group and the placebo group for the key secondary 
endpoints.
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Table 5:
Power to Detect the Corresponding Treatment Effect for Key Secondary 
Endpoints
Key Secondary Endpoint at Week 16
SHP647 Premise
Placebo Premise
Power
Clinical remission by CDAI
26.5%
15%
0.90
Enhanced endoscopic response
25%
13%
0.94
Clinical remission by abdominal pain 
≤1 and stool frequency ≤3
24%
14%
0.81
Clinical response by 2-item PRO
52.5%
40%
0.81
Clinical remission by 2-item PRO and 
endoscopic response
11%
4.5%
0.77
Complete endoscopic healing
6%
2%
0.58
CDAI=Crohn’s Disease Activity Index; PRO=patient-reported outcome.
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 set will consist of all subjects in the FAS who do not have protocol deviations 
that may affect the coprimary efficacy endpoints.
The completer set will consist of all subjects in the FAS who have completed the Week 16
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
Coprimary Efficacy Endpoints
The coprimary efficacy endpoints are:

Clinical remission at the Week 16 visit as defined by the following: 2-item PRO 
subscores of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the 
7 most recent days and average daily stool frequency ≤2 of type 6/7 (very soft
stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent 
days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. 
If fewer than 7 days are available, the endpoint will be calculated on all available most 
recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as
missing.

Endoscopic response at Week 16 as measured by a decrease in SES-CD of at least 25% 
from baseline.
The coprimary efficacy endpoints, clinical remission at the Week 16 visit and endoscopic 
response at the Week 16 visit, will each 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, glucocorticoid use, and SES-CD at baseline for 
each of the stages of the study (stage 1 includes subjects whose primary efficacy data are used in 
the interim analysis and stage 2 includes all other subjects. Note: classification of stage 1 and 
stage 2 is based on the time of randomization rather than the time of study completion or 
termination). Subjects with missing data at the Week 16 visit will be considered failures and 
counted as nonresponders.
Weighted inverse normal p-value combination methods are used to combine the p-values from 
stage 1 and stage 2 through the following formula:
C(p1, p2) = 1 – Φ[w1 Φ-1(1-p1)+ w2 Φ-1(1-p2)]
Where p1, p2 are the p-values computed from the CMH chi-square test for each stage, 
wi
2 = ni/(n1 + n2), n1 and n2 are the preplanned stage-wise sample sizes that are fixed at the time of 
the interim analysis based on an original total sample size, and Φ denotes the cumulative 
distribution function of the standard normal distribution (Bretz et al., 2009a). Given that there is 
no possibility of stopping early for efficacy, that any potential stopping for futility of either or 
both doses of SHP647 is nonbinding, and that weights are prespecified, the test statistic C(p1, p2) 
can be compared against the nominal alpha level to assess statistical significance (Chang and 
Chow, 2008).
The coprimary endpoints will each be tested by the following hypothesis:
H0: δ = 0
H1: δ ≠ 0
Where δ is the common treatment difference across strata. 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 the p-value computed from the 
p-value combination method will be presented for each active treatment group to placebo 
comparison for each endpoint.
Sensitivity analyses to explore the impact of missing data on the coprimary efficacy endpoints
and key secondary endpoints 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 coprimary endpoints including, but not 
limited to gender, prior anti-TNF treatment, glucocorticoid use at baseline, SES-CD at baseline, 
region, age group, randomization stratum, and other important subgroups. A full list of important 
subgroups will be described in 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. The estimate of the treatment difference, along with the corresponding 
Newcombe (hybrid-score) 95% CI and chi-square test p-value, will be presented.
Statistical Testing and Protection of the Type I Error
The global FWER for the statistical tests of the coprimary and key secondary endpoints will be 
strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in 
Bretz et al. (2009b) will be utilized to propagate α from the coprimary endpoints to the 
key secondary endpoints and between the 2 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 coprimary endpoints (P) and alpha is propagated in a hierarchical manner to 
each of the 6 key secondary endpoints (K1–K6) within a pairwise treatment comparison. In order 
to pass alpha between the coprimary endpoints and the first key secondary endpoint, both 
coprimary endpoints must attain statistical significance. A graphical visualization of the 
α propagation is presented in Figure 4.
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Figure 4:
Visualization of Multiple Testing Strategy
K=key secondary endpoint; P=coprimary endpoints.
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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 Endpoints
The key secondary efficacy endpoints are as follows:

Clinical remission at the Week 16 visit as measured by a CDAI score of <150.

Enhanced endoscopic response at Week 16 as measured by a decrease in SES-CD of at 
least 50% from baseline.

Clinical remission at the Week 16 visit as defined by the following: 2-item PRO 
subscores of average worst daily abdominal pain ≤1 (based on the 4-point scale) over the 
7 most recent days and average daily stool frequency ≤3 of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent 
days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. 
If fewer than 7 days are available, the endpoint will be calculated on all available most 
recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as 
missing.

Clinical response at the Week 16 visit as measured by the 2-item PRO and defined as 
meeting at least 1 of the following 2 criteria:
o
A decrease of ≥30% and at least 2 points from baseline in the average daily worst 
abdominal pain over the 7 most recent days*, with the average daily stool frequency 
of type 6/7 (very soft stools/liquid stools) either:
(a) Not worsening from baseline
and/or
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average 
daily stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the 
BSFS over the 7 most recent days*
o
A decrease of ≥30% from baseline in the average daily stool frequency of type 6/7
(very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days*, 
with the average daily worst abdominal pain either:
(a) Not worsening from baseline
and/or
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average 
worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days*
*Note: The 7 most recent days may or may not be contiguous during the 10 days of 
data collection before colonoscopy preparation, depending on days to be excluded 
because of missing data. If fewer than 7 days are available, the endpoint will be 
calculated on all available most recent 6 or 5 days. If fewer than 5 days are available, 
the endpoint will be treated as missing.
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
Clinical remission with endoscopic response, ie, both clinical remission by 2-item PRO 
and endoscopic response, as measured by a decrease in SES-CD of at least 25% at 
Week 16 (composite endpoint)

Complete endoscopic healing at Week 16 defined as SES-CD=0-2.
Similar to the coprimary endpoints, the 6 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 
coprimary endpoints. Subjects with missing key secondary endpoint data at the Week 16 visit 
will be considered failures and counted as nonresponders.
9.8.2.2
Other Secondary Efficacy Endpoints
The other secondary endpoints are as follows:

Clinical response at the Week 16 visit as measured by at least a 100-point reduction in the 
CDAI from baseline (CDAI-100 response)

Clinical response at the Week 16 visit as measured by at least a 70-point reduction in the 
CDAI from baseline (CDAI-70 response)

Clinical remission over time, as measured by the 2-item PRO

Change from baseline in total stool frequency, rectal bleeding frequency, rectal urgency 
frequency, nausea severity, vomiting frequency, and rectal incontinence frequency 
scores; and total sign/symptom score based on subject daily e-diary entries

Endoscopic healing at Week 16 as measured by SES-CD ≤4 and at least 2-point reduction 
versus baseline and no subscore >1 in any individual variable

Change from baseline in IBDQ domain and total (absolute) scores over time

Change from baseline in SF-36, version 2, acute (physical and mental component 
summary scores and individual domain scores) over time

Incidence of all cause hospitalizations and total inpatient days

Incidence of CD-related surgeries and other surgical procedures during the entire study 
period.
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 compared between each active treatment group and the placebo 
group using a CMH chi-square test stratified by status of prior anti-TNF treatment, 
glucocorticoid use at baseline, and SES-CD at baseline. 
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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 the p-value computed 
from CHM test will be provided. Subjects with missing binary endpoint data at the 
Week 16 visit will be considered failures and counted as nonresponders.

Continuous endpoints that are only measured at baseline and the Week 16 visit will be 
analyzed using an analysis of covariance model with fixed effects for treatment group 
(categorical), status of prior anti-TNF treatment (categorical), glucocorticoid use at 
baseline (categorical), and SES-CD 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), 
glucocorticoid use at baseline (categorical), and SES-CD 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.
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 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.
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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.
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 and percentage of TEAEs will be 
calculated 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.
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 Good Clinical Practice (GCP) guidelines 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 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 guidelines
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 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.
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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 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). 
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 Food and 
Drug [FDA], European Medicines Agency [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 US 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. 
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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 
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 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. 
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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 
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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312648.
Spiegel, B., Bolus, R., Harris, L. A., Lucak, S., Naliboff, B., Esrailian, E., Chey, W. D., Lembo, 
A., Karsan, H., Tillisch, K., Talley, J., Mayer, E. and Chang, L. 2009. Measuring irritable 
bowel syndrome patient-reported outcomes with an abdominal pain numeric rating scale. 
Aliment Pharmacol Ther, 30, 1159-70.
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.
Ueno, F., Matsui, T., Matsumoto, T., Matsuoka, K., Watanabe, M. and Hibi, T. 2013. Evidence-
based clinical practice guidelines for Crohn’s disease, integrated with formal consensus 
of experts in Japan. Journal of Gastroenterology, 48, 31-72.
Vuitton, L., Marteau, P., Sandborn, W. J., Levesque, B. G., Feagan, B., Vermeire, S., Danese, S., 
D'Haens, G., Lowenberg, M., Khanna, R., Fiorino, G., Travis, S., Mary, J. Y. and Peyrin-
Biroulet, L. 2016. IOIBD technical review on endoscopic indices for Crohn's disease 
clinical trials. Gut, 65, 1447-1455.
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.
Williet, N., Sandborn, W. and Peyrin–Biroulet, L. 2014. Patient-Reported Outcomes as Primary 
End Points in Clinical Trials of Inflammatory Bowel Disease. Clinical Gastroenterology 
and Hepatology, 12, 1246-1256.e6.
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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12.
APPENDICES
APPENDIX 1
PROTOCOL HISTORY 
Document
Date
Global/Country/Site Specific
Original Protocol
15 Dec 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:

Simple Endoscopic Score for Crohn’s Disease

Crohn’s Disease Activity Index


Patient-reported Outcome Crohn’s Disease daily e-diary

Inflammatory Bowel Disease Questionnaire





Short Form-36 Health Survey

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Simple Endoscopic Score for Crohn’s Disease (SES-CD)
SITE WORKSHEET: Simple Endoscopic Score for Crohn’s Disease (SES-CD)
’
Presence and type o f narrowing s
None
Single, can be passed
Multiple, can be passed
Cannot be passed
Extent of affected surface
Unaffected segment
< 50%
50 – 75%
>75%
Extent of ulcerated surface
None
< 10%
10 – 30%
> 30%
Endoscopy Finding
Ileum
Right 
Colon
Transverse 
Colon
Left 
Colon
Rectum
Presence and size o f ulcers
N one
Apthous ulcers (Ø 0.1 to 0.5 c m)
Large ulcers (Ø 0.5 to 2 cm)
Very large ulcers (Ø > 2 cm)
Cannot be passed
Multiple, can be 
passed
Singl e, can be 
passed
N one
Presence of 
N arrowing
>75%
50-75%
<50%
U naffected segment
Affected surface
>30%
10-30%
<10%
N one
U lcerated surface
Very large ulcers 
(>2 cm)
Large ulcers
(0.5 to 2 cm)
Apththous ulcers 
(0.1 to 0.5 cm)
N one
Size of Ulcers
Variable
Sim ple Endoscopic Score for Crohn ’s Disease values
Definitions of Simple Endoscopic Score for Crohn
’
Cannot be passed
Multiple, can be 
passed
Singl e, can be 
passed
N one
Presence of 
N arrowing
>75%
50-75%
<50%
U naffected segment
Affected surface
>30%
10-30%
<10%
N one
U lcerated surface
Very large ulcers 
(>2 cm)
Large ulcers
(0.5 to 2 cm)
Apththous ulcers 
(0.1 to 0.5 cm)
N one
Size of Ulcers
Variable
Sim ple Endoscopic Score for Crohn ’s Disease values
Definitions of Simple Endoscopic Score for Crohn’s Disease
Site #
Investigator
Sub ject ID
Visit Date
(mmm dd yyyy)
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Crohn’s Disease Activity Index (CDAI)
CDAI=Crohn’s Disease Activity Index; ePRO=electronic patient-reported outcome; Hct=hematocrit.
Note: Variable 5: This variable covers taking medication for symptomatic relief from diarrhea, eg, bulking agents, opiates etc.
Variable 7: Absolute deviation of hematocrit is the difference in hematocrit from standard. A male subject with a hematocrit of 
40% has an absolute deviation of 7. Each percentage deviation has a value of 6 points. If hematocrit subtotal is <0, enter 0. 
Variable 8: This variable is based on Metropolitan Life Tables (these are programmed into the ePRO device).
Percent deviation from standard weight is (1 - weight/standard weight) × 100; therefore, positive percent deviation represents 
weight loss, which adds points to the CDAI. Percentage deviation from standard weight = 1 point for each percent deviation. If 
body weight subtotal is less than -10, enter -10.
CDAI Interpretation:

0-149 points: Asymptomatic remission (Note: subjects requiring steroids to remain asymptomatic are not considered to 
be in remission but are referred to as being “steroid dependent”)

150-220 points: Mild to moderate active CD

221-450 points: Moderate to severe active CD

>451 points: Severely active to fulminant disease.
CDAI online estimator: http://www.ibdjohn.com/cdai/
Sources: Best et al., 1976; Best et al., 1979.
Crohn’s Disease Activity Index (CDAI)
CDAI 
Score
X 1
Body weight (1-weight/standard weight) X 100                                   
(add or subtract according to sign)
8
X 6
Hematocrit [Males: 47-Hct (%), Females: 42-Hct (%)]
7
X 10
Abdominal mass (0 = no, 2 = questionable, 5 = definite)
6
X 30
Use of diphenoxylate or loperamide for diarrhea (0 = no, 1 = yes)
5
X 20
Number of listed complications [arthritis or arthralgia, iritis or uveitis, 
erythema nodosum or pyoderma gangrenosum or aphthous
stomatitis, anal fissure or  fistula or abscess, other fistula, fever     
over 37.8oC (100oF)]
4
X 7
General well-being (0 = generally well, 1 = slightly under par,             
2 = poor, 3 = very poor, 4 = terrible)
3
X 5
Abdominal pain (0 = none, 1 = mild, 2 = moderate, 3 = severe)
2
X 2
No. of liquid or soft stools (each day for 7 days)
1
Total
Multiplier
Variable Description
Variable 
No.
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Reference: D'Haens et al., 1998.
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Patient-reported Outcomes – Crohn’s Disease Daily E-diary Version 1
1.
Please rate your worst abdominal pain over the past 24 hours.
0     1     2     3     4     5     6     7     8     9     10
      No pain
Worst imaginable pain
2.
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: ____________
The next question asks about the number of liquid or very soft stools you had in the past 
24 hours. Liquid or very soft stools are defined as Type 6 and Type 7 in the chart below.
3.
You indicated you had X bowel movements in the past 24 hours. Of these, how many were 
liquid or very soft?
Enter number of liquid or very soft bowel movements: ____________
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4.
You indicated you had X bowel movements in the past 24 hours. Of these, how many had 
blood, either in the stool, the toilet bowel, or on the toilet paper?
Enter number of bowel movements with blood: ____________
5.
You indicated you had X bowel movements in the past 24 hours. How many of these 
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 feeling of nausea (feeling sick to your stomach or like you might 
throw up) over the past 24 hours.
None
Mild
Moderate
Severe
7.
How many vomiting episodes did you have in the past 24 hours? An episode includes one or 
multiple heaves (including dry heaves) in quick succession followed by a break in vomiting.
Enter number of vomiting episodes: ____________
8.
How many bowel incontinence episodes (losing control of your bowels before reaching the 
toilet) did you have in the past 24 hours?
Enter number of bowel incontinence episodes: ______________
9.
Please rate your abdominal pain over the past 24 hours.
None
Mild
Moderate
Severe
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10. How would you rate your general wellbeing over the past 24 hours?
Generally well
Slightly below par
Poor
Very poor
Terrible
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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 2 weeks? Please indicate 
how frequent your bowel movements have been during the last 2 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 (Version 2), Acute Form
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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 strennous sports ...................... D 1 .••••••••.••• D 2 ••••••.•••••• D • 
!-.!oderate activities, snch as moving a table. pushing 
a vacuum cleaner. bowling, or playing golf ............................ D 1 .••••••••.••• D 2 ••••••.•••••• D • 
Lifting or carrying groceries .................................................... D 1 .••••••••.••• D 2 ••••••.•••••• D 2 
ct 
Climbing several flights of stairs ............................................. D 1 .••••••••.••• D 2 ••••••.•••••• D 2 
Climbing one flight of stairs .................................................... D 1 .••••••••.••• D 2 ••••••.•••••• D 2 
1 Bending, kneeling, or stooping ................................................ D 1 .••••••••.••• D 2 ••••••.•••••• D 2 
2 
Walking more than a mile ........................................................ D 1 .••••••••.••• D 2 ••••••.•••••• D 2 
h 
Walking several hundred yards ............................................... D 1 .••••••••.••• D, ............. D 2 
Walking one hundred yards ..................................................... D 1 .••••••••.••• D 2 ••••••.•••••• D 2 
Bathing or dressing yourself .................................................... D 1 .••••••••.••• D 2 ••••••.•••••• D 2 
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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4. 
During the past week, how much of the time haYe 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 
time 
Most of 
the time 
Some of 
the time 
A little of 
None of 
the 
the time 
other activities ................................. 0 L ............. o c .............. o c .............. oL .......... 0 0 
' 
Accomplished less than you 
would like ........................................ 0 L ............. O 2 .............. 0 3 .............. 0 , ............. 0 s 
Were limited in the kind of 
work or other activities .................... D 1 •••••••••••••• 0 : .............. 0 o ••••••••••.••• D -+ ••••••••••••• D s 
d 
Had difficultv perfonning the 
work or other activities (for 
example, ittookextradfmt) ........... O L ............. O 2 .............. 0 3 .............. 0, ............. 0 s 
5. During the past week, how much of the time haYe 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 
time 
Most of 
the time 
Some of 
the time 
A little of 
None of 
the 
the time 
other activities ................................. 0 L ............. O c .............. O z .............. O L 
.......... 0 s 
t 
Accomplished less than you 
would like ........................................ 0 L ............. O 2 .............. 0 3 .............. 0 , ............. 0 s 
Did work or other activities 
less carefully than usual.. ................. 0 L ............. O z .............. O z .............. 0 L 
.......... 0 3 
SF-36v2® Health Survey© 199::!. ::!000 l\Iedical Outcomes Trust and Qualityl\Jetric Incorporated. All rights reserved 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)l 
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Shire
CONFIDENTIAL
Page 131
Protocol 
SHP647-306
15 Dec 2017
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 
T 
03 
Quite a bit 
T 
04 
Extremely 
T 
Ds 
7. How much bodill: pain have you had during the past week? 
!\one 
Very mild 
Mild 
Moderate 
Severe 
Very severe 
T 
T 
T 
T 
T 
T 
o, 
Dz 
Dz 
04 
Ds 
De 
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 
T 
04 
S.F-36v21[) Health Survey 19 l!J92, 2000 1\ledical Outcomes Trust and QualityMetric Incorporated. All rights reserved. 
SF -36® is a re.gistered trademark of Medical Outcomes Trust. 
ISF-36v2® He;lth Survey Acute, United States (English)) 
T 
Ds 
For non-commercial use only

Shire
CONFIDENTIAL
Page 132
Protocol 
SHP647-306
15 Dec 2017
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 
2 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)) 
For non-commercial use only

Shire
CONFIDENTIAL
Page 133
Protocol 
SHP647-306
15 Dec 2017
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 • .............. 0 o .............. O o 
I mn as healthy as 
anybody I koow .............................. 0 1 ............ 0 2 ............. 0 • ............. 0 , ............. 0 o 
I expect my health to 
get worse ......................................... 0 1 .............. 0 2 ............. 0 2 .............. 0 ............... 0 s 
ct 
My health is excellent ..................... 0 1 .............. 0 2 ............. 0 • .............. 0 o .............. O o 
Thank you for completing these questions! 
SF -36v2® Health Survey© 1992. 2000 Medical Outcomes Trmt and QualityMetric Incorporated. All rights reserved. 
SF -36® is a registered trademark of Medical Outcomes Tmst. 
(SF-36v2® Health Survey Acute. United States (English)) 
For non-commercial use only

Shire
CONFIDENTIAL
Page 134
Protocol 
SHP647-306
15 Dec 2017
 
 
 
 
 
For non-commercial use only

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CONFIDENTIAL
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SHP647-306
15 Dec 2017
 
 
 
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CONFIDENTIAL
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SHP647-306
15 Dec 2017
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15 Dec 2017
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15 Dec 2017
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
For non-commercial use only

 
 
 
PROTOCOL: SHP647-306 
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 Crohn’s Disease 
(CARMEN CD 306) 
DRUG: 
SHP647 
IND: 
100,222 
EUDRACT NO.: 
2017-000576-29 
SPONSOR: 
Shire Human Genetic Therapies, Inc. (“Shire”) 
300 Shire Way, Lexington, MA 02421 US 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
 MD 
PROTOCOL 
HISTORY: 
Protocol Amendment 1: 21 Aug 2018 
Original Protocol: 15 Dec 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 
Page2 
SHP647-306 Protocol Amendment 1 
SHP647-306 
21 Aug 2018 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
 MD, 
 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP647-306. 
Title: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and 
Safety Study ofSHP647 as Induction Therapy in Subjects With Moderate to Severe Crohn's 
Disease (CARMEN CD 306). 
I have fully discussed the objective(s) ofthis study and the contents of this protocol with the 
sponsor's representative. 
I understand that the infmmation 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 
infmmation 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 
tetmination 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: 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 3 
SHP647-306 Protocol Amendment 1 
SHP647-306 
 
21 Aug 2018 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 1 
Amendment Date 
21 Aug 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Emergency Contact 
 
Information
Updated global fax number for Shire Global 
Drug Safety 
To provide updated emergency 
contact information 
, Inclusion 
Study Synopsis
and exclusion criteria 
Section 4.1, Inclusion 
Criteria 
Updated inclusion criterion #4c to indicate that 
subjects must have abdominal pain subscores ≥2 
on the 4-point severity scale (used in the CDAI), 
in addition to abdominal pain subscores ≥5 on 
the 11-point numerical rating scale. 
To collect additional data for 
abdominal pain at study entry 
using the 0-3 CDAI severity scale. 
Study Synopsis, Inclusion 
and exclusion criteria 
Section 4.1, Inclusion 
Criteria 
Section 5.1, Prior 
 
Treatment
Updated inclusion criterion #7 to add hyperlink 
to Section 5.1 in which “inadequate response to, 
lost response to, or intolerance to at least 1 
conventional treatment” (eg, sulfasalazine, 
mesalamine, glucocorticoids, 
 
immunosuppressants, or anti-TNF) is defined.
To cross-reference section where 
 
prior treatments are defined.
, Inclusion 
Study Synopsis
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. 
, Inclusion 
Study Synopsis
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Updated exclusion criterion #24 to clarify that 
subjects with a history of Mycobacterium 
tuberculosis (TB) infection who have not 
completed a generally accepted full course of 
treatment before baseline will also be excluded. 
To further define the exclusion of 
subjects with any history of 
positive TB. 
, Inclusion 
Study Synopsis
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Updated exclusion criterion #30 to indicate that 
subjects with cirrhosis with or without 
decompensation will be excluded. 
To further define the exclusion of 
subjects with compromised liver 
function. 
, Inclusion 
Study Synopsis
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Moved exclusion of subjects with primary 
sclerosing cholangitis from exclusion criterion 
#30 to new criterion #31.  
To further define the exclusion of 
subjects with compromised liver 
function. 
, Inclusion 
Study Synopsis
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Updated exclusion criterion #32 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 
DBA, may be eligible for the 
study. 
, Inclusion 
Study Synopsis
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Updated exclusion criterion #33 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 (in 
case of spontaneous viral 
clearance or previously treated 
and cured). 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 4 
SHP647-306 Protocol Amendment 1 
SHP647-306 
 
21 Aug 2018 
 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 1 
Amendment Date 
21 Aug 2018 
Global/Country/Site Specific 
Global 
, Inclusion 
Study Synopsis
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Updated exclusion criterion #34 to indicate that 
subjects meeting the following lab criteria would 
be excluded: 
• 
ALT or AST ≥3×ULN  
• 
Total bilirubin ≥1.5×ULN or >2×ULN 
if the subject has a known documented 
history of Gilbert’s syndrome  
Added note to exclusion criterion #34 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 
Table 1, Schedule of 
Assessments, footnote ‘n’ 
Section 4.2, Exclusion 
 
Criteria
Added new exclusion criterion #35 to clarify 
that documentation of HIV status should be 
 
performed within 6 months of screening.
To clarify the timing of acceptable 
 
documentation of HIV status.
, Inclusion 
Study Synopsis
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Updated exclusion criterion #36 to include 
exclusion of subjects with abuse of medicinal 
marijuana. Deleted former exclusion criterion 
#36 related to medicinal marijuana dependency.  
To indicate that subjects with 
medicinal marijuana abuse would 
be excluded.  
, Inclusion 
Study Synopsis
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Updated exclusion criterion #39 to indicate the 
exclusion of 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 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, are excluded. 
Section 1.3, Benefit/Risk 
Assessment 
Added new section describing risk and benefits 
of SHP647 treatment. 
To provide updated risk and 
benefit information for SHP647. 
Section 3.1.1, Rationale for 
Coprimary Endpoints 
Added text describing results from recent trial 
with upadacitinib and from Phase 2 OPERA 
study with SHP647 as supporting rationale for 
the coprimary endpoint of endoscopic response. 
To provide additional supporting 
rationale for the co-primary 
endpoint of endoscopic response. 
Table 1, Schedule of 
Assessments: footnote ‘l’ 
Section 7.2.3.6, Clinical 
Laboratory Evaluations 
Appendix 5 
Updated SOA footnote ‘l’ and added 
Appendix 5 to clarify that diagnosis of C. 
difficile infection should be made using the 
central laboratory.  
Added diagnostic algorithms and relevant 
information related to C. difficile testing and 
diagnosis. 
To provide appropriate guidance 
regarding laboratory testing for C. 
difficile infection. 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 5 
SHP647-306 Protocol Amendment 1 
SHP647-306 
 
21 Aug 2018 
 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 1 
Amendment Date 
21 Aug 2018 
Global/Country/Site Specific 
Global 
Table 1, Schedule of 
 footnote ‘n’ 
Assessments:
Added new row to SOA and footnote ‘n’ to 
indicate HIV tests may be performed at local 
laboratories (per local requirements), or 
centrally, if documentation of a negative HIV 
test within 6 months of screening is unavailable. 
To clarify the timing of acceptable 
documentation of HIV status. 
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 5.2.1, Permitted 
 
Treatment
Added language to specify that any antidiarrheal 
opiate drugs must be taken at stable doses for 
the duration of the study unless dose reduction 
or discontinuation is required due to clinical 
improvement or adverse event, and that 
escalation of the dose after dose reduction, or re-
initiation after drug discontinuation, is not 
 
allowed.
To clarify that concomitant 
antidiarrheal opiate drugs are 
permitted if taken at stable doses 
for the duration of the study, with 
dose reduction or discontinuation 
allowed only if required due to 
clinical improvement or adverse 
 
event.
Section 7.2, Study 
Procedures 
Added language to specify that the duration of 
blood and tissue sample storage is dependent on 
local regulations. 
To clarify that local regulations 
should be considered for duration 
of blood and tissue sample 
storage. 
7.2.3.6
Section 
, Clinical 
 
Laboratory Evaluations
Added HIV and HBV DNA samples to virology 
 
table.
To reflect new eligibility criteria 
regarding HIV testing and HBV 
 
DNA reflex testing.
7.2.5
Section 
, Volume of 
Blood to be Drawn from 
 
Each Subject
Added 2 new rows to Table 4 for collection of 
HBV DNA and HIV samples. Increased TB test 
 
sample volume by 1 mL.
To reflect changes in eligibility 
criteria regarding HIV testing and 
HBV DNA reflex testing and to 
correct the sample volume needed 
 
for the TB test.  
Section 8.2.8, Safety 
Monitoring  
Table 5 
Added new section and table describing safety 
monitoring and stopping criteria for elevated 
hepatic blood tests.  
To provide appropriate guidance 
on subjects who have been 
enrolled with elevated liver 
function test or who have elevated 
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. 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 6 
SHP647-306 Protocol Amendment 1 
SHP647-306 
 
21 Aug 2018 
 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 1 
Amendment Date 
21 Aug 2018 
Global/Country/Site Specific 
Global 
Appendix 4, Determination 
of Failure or Intolerance to 
Prior Treatment for 
Crohn’s Disease 
Added new appendix section, “Determination of 
Inadequate Response/Loss of Response or 
Intolerance to Prior Treatment for Crohn’s 
Disease” to provide guidance as related to 
inclusion criterion #7 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 
Diagnosis and Treatment of 
Increased Gastrointestinal 
Symptoms 
Added new Appendix 5, “Guidance for 
Diagnosis and 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.  
 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 7 
SHP647-306 Protocol Amendment 1 
SHP647-306 
 
21 Aug 2018 
 
EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Nonserious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to the Shire Global Drug Safety Department. Applicable fax 
numbers and e-mail 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 e-mail 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): 
Pharmaceutical Product Development North America: 
24 Hour Safety Hotline: RTP 
; Wilmington 
 
24 Hour Safety Hotline Fax: RTP 
 or 
; 
Wilmington 
 or 
 
Pharmaceutical Product Development Latin America: 
24 Hour Safety Hotline: 
 
24 Hour Safety Hotline Fax: 
 
Pharmaceutical Product Development Europe, the Middle East, and Africa; and 
Asia-Pacific: 
24 Hour Safety Hotline: 
 
24 Hour Safety Hotline Fax: 
 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 8 
SHP647-306 Protocol Amendment 1 
SHP647-306 
 
21 Aug 2018 
 
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 8.2.2. 
Please use the information below as applicable to report the Product Quality Complaint: 
Origin of Product Quality Complaint 
E-mail Address 
North and South America, the 
European Union, and Rest of World 
 
 
Telephone numbers (provided for reference if needed): 
Shire, Lexington, MA (US) 
 
 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 9 
SHP647-306 Protocol Amendment 1 
SHP647-306 
 
21 Aug 2018 
 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ...........................................................................................2 
EMERGENCY CONTACT INFORMATION ...........................................................................7 
PRODUCT QUALITY COMPLAINTS ....................................................................................8 
TABLE OF CONTENTS ..........................................................................................................9 
LIST OF TABLES ................................................................................................................. 14 
LIST OF FIGURES ................................................................................................................ 14 
ABBREVIATIONS ................................................................................................................ 15 
STUDY SYNOPSIS ............................................................................................................... 18 
STUDY SCHEDULE ............................................................................................................. 28 
1. 
BACKGROUND INFORMATION.................................................................................. 33 
1.1 
Indication and Current Treatment Options ........................................................... 33 
1.2 
Product Background and Clinical Information ..................................................... 33 
1.3 
Benefit/Risk Assessment .................................................................................... 34 
2. 
STUDY OBJECTIVES AND PURPOSE ......................................................................... 36 
2.1 
Rationale for the Study ....................................................................................... 36 
2.2 
Study Objectives ................................................................................................ 38 
2.2.1 
Coprimary Objectives ...................................................................................... 38 
2.2.2 
Secondary Objectives ....................................................................................... 38 
2.2.2.1 
Key Secondary Objectives ................................................................. 38 
2.2.2.2 
Other Secondary Objectives............................................................... 38 
2.2.3 
Exploratory Objectives..................................................................................... 39 
3. 
STUDY DESIGN ............................................................................................................ 40 
3.1 
Study Design and Flow Chart ............................................................................. 40 
3.1.1 
Rationale for Coprimary Endpoints................................................................... 42 
3.1.2 
Rationale for Key Secondary Endpoints ............................................................ 44 
3.2 
Duration and Study Completion Definition.......................................................... 46 
3.3 
Sites and Regions ............................................................................................... 47 
4. 
STUDY POPULATION .................................................................................................. 48 
4.1 
Inclusion Criteria................................................................................................ 48 
4.2 
Exclusion Criteria .............................................................................................. 49 
4.3 
Restrictions ........................................................................................................ 54 
4.4 
Reproductive Potential ....................................................................................... 54 
4.4.1 
Contraceptive Methods for Female Study Subjects ............................................ 55 
4.4.2 
Contraceptive Methods for Male Study Subjects ............................................... 55 
4.5 
Withdrawal of Subjects ...................................................................................... 56 
4.5.1 
Subject Withdrawal Criteria ............................................................................. 56 
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Shire 
CONFIDENTIAL 
Page 10 
SHP647-306 Protocol Amendment 1 
SHP647-306 
 
21 Aug 2018 
 
4.5.2 
Reasons for Withdrawal ................................................................................... 57 
4.5.3 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit ............................... 57 
5. 
PRIOR AND CONCOMITANT TREATMENT ............................................................... 58 
5.1 
Prior Treatment .................................................................................................. 58 
5.2 
Concomitant Treatment ...................................................................................... 58 
5.2.1 
Permitted Treatment......................................................................................... 58 
5.2.2 
Prohibited Treatment........................................................................................ 59 
5.2.3 
Rescue Therapy ............................................................................................... 60 
6. 
INVESTIGATIONAL PRODUCT ................................................................................... 61 
6.1 
Identity of Investigational Product ...................................................................... 61 
6.1.1 
Blinding the Treatment Assignment .................................................................. 61 
6.2 
Administration of Investigational Products .......................................................... 61 
6.2.1 
Interactive Response Technology for Investigational Product Management ........ 61 
6.2.2 
Allocation of Subjects to Treatment .................................................................. 61 
6.2.3 
Dosing ............................................................................................................. 62 
6.2.4 
Unblinding the Treatment Assignment .............................................................. 62 
6.3 
Labeling, Packaging, Storage, and Handling........................................................ 63 
6.3.1 
Labeling .......................................................................................................... 63 
6.3.2 
Packaging ........................................................................................................ 63 
6.3.3 
Storage ............................................................................................................ 63 
6.3.4 
Special Handling.............................................................................................. 64 
6.4 
Drug Accountability ........................................................................................... 64 
6.5 
Subject Compliance............................................................................................ 65 
7. 
STUDY PROCEDURES.................................................................................................. 66 
7.1 
Study Schedule .................................................................................................. 66 
7.1.1 
Screening Period .............................................................................................. 66 
7.1.1.1 
Screening Visit (Visit 1) .................................................................... 66 
7.1.1.2 
Baseline Visit (Visit 2, Week 0) ......................................................... 67 
7.1.2 
Treatment Period ............................................................................................. 67 
7.1.2.1 
Visits 3, 4, 5, and 6 (Weeks 2, 4, 8, and 12) ........................................ 67 
7.1.2.2 
Final On-treatment Visit: Visit 7, Parts 1, 2, and 3 
(Week 16/Early Termination) ............................................................ 67 
7.1.3 
Follow-up Period ............................................................................................. 68 
7.1.4 
Additional Care of Subjects after the Study ....................................................... 68 
7.2 
Study Evaluations and Procedures....................................................................... 68 
7.2.1 
Demographic and Other Baseline Characteristics .............................................. 69 
7.2.2 
Efficacy ........................................................................................................... 69 
7.2.2.1 
Patient-reported Outcome – Crohn’s Disease Daily E-diary ................ 69 
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CONFIDENTIAL 
Page 11 
SHP647-306 Protocol Amendment 1 
SHP647-306 
 
21 Aug 2018 
 
7.2.2.2 
Simple Endoscopic Score for Crohn’s Disease ................................... 70 
7.2.2.3 
Crohn’s Disease Activity Index ......................................................... 71 
7.2.2.4 
Colonoscopy and Histology ............................................................... 71 
7.2.3 
Safety .............................................................................................................. 72 
7.2.3.1 
Medical and Medication History ........................................................ 72 
7.2.3.2 
Physical Examination (Including Height and Weight) ......................... 73 
7.2.3.3 
Targeted Neurological Assessment .................................................... 73 
7.2.3.4 
Adverse Event Collection .................................................................. 75 
7.2.3.5 
Vital Signs ........................................................................................ 75 
7.2.3.6 
Clinical Laboratory Evaluations ......................................................... 75 
7.2.3.7 
Pregnancy Test and Follicle-stimulating Hormone Test ...................... 77 
7.2.3.8 
Electrocardiogram ............................................................................. 77 
7.2.3.9 
Chest X-ray....................................................................................... 77 
7.2.3.10 
Antidrug Antibodies and Neutralizing Antibodies............................... 78 
7.2.4 
Others.............................................................................................................. 78 
 
 
 
 
7.2.4.3 
Health-related Quality of Life Assessments ........................................ 78 
7.2.4.4 
Healthcare Resource Utilization Assessments..................................... 80 
7.2.5 
Volume of Blood to Be Drawn From Each Subject............................................ 80 
8. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT .................................. 82 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events................................................................................................................ 82 
8.1.1 
Severity Categorization .................................................................................... 82 
8.1.2 
Relationship Categorization.............................................................................. 83 
8.1.3 
Outcome Categorization ................................................................................... 83 
8.1.4 
Symptoms of the Disease Under Study ............................................................. 83 
8.1.5 
Clinical Laboratory and Other Safety Evaluations ............................................. 84 
8.1.6 
Pregnancy ........................................................................................................ 84 
8.1.7 
Abuse, Misuse, Overdose, and Medication Error ............................................... 85 
8.1.8 
Unexpected Adverse Event............................................................................... 85 
8.1.9 
Suspected Unexpected Serious Adverse Reaction.............................................. 86 
8.2 
Serious Adverse Event Procedures ...................................................................... 86 
8.2.1 
Reference Safety Information ........................................................................... 86 
8.2.2 
Reporting Procedures ....................................................................................... 86 
8.2.3 
Serious Adverse Event Definition ..................................................................... 86 
8.2.4 
Serious Adverse Event Collection Time Frame ................................................. 87 
8.2.5 
Serious Adverse Event Onset and Resolution Dates........................................... 87 
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8.2.6 
Fatal Outcome ................................................................................................. 87 
8.2.7 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting......................................................................................................... 88 
8.2.8 
Safety Monitoring for Potential Cases of Drug-induced Liver Injury .................. 88 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS ............................................ 91 
9.1 
Data Collection .................................................................................................. 91 
9.2 
Clinical Data Management ................................................................................. 91 
9.3 
Data Handling Considerations ............................................................................ 91 
9.4 
Statistical Analysis Process................................................................................. 91 
9.5 
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee...... 92 
9.6 
Sample Size Calculation and Power Considerations............................................. 93 
9.7 
Study Population ................................................................................................ 94 
9.8 
Efficacy Analyses .............................................................................................. 94 
9.8.1 
Coprimary Efficacy Endpoints.......................................................................... 95 
9.8.2 
Secondary Efficacy Endpoints .......................................................................... 98 
9.8.2.1 
Key Secondary Efficacy Endpoints .................................................... 98 
9.8.2.2 
Other Secondary Efficacy Endpoints .................................................. 99 
9.8.3 
Exploratory Efficacy Endpoints ...................................................................... 100 
9.9 
Safety Analyses................................................................................................ 101 
9.10 
Other Analyses................................................................................................. 101 
 
 
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...................................... 103 
10.1 
Sponsor’s Responsibilities ................................................................................ 103 
10.1.1 Good Clinical Practice Compliance ................................................................ 103 
10.1.2 Indemnity/Liability and Insurance .................................................................. 103 
10.1.3 Public Posting of Study Information ............................................................... 103 
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees ...................................... 104 
10.1.5 Study Suspension, Termination, and Completion............................................. 104 
10.2 
Investigator’s Responsibilities .......................................................................... 104 
10.2.1 Good Clinical Practice Compliance ................................................................ 104 
10.2.2 Protocol Adherence and Investigator Agreement ............................................. 105 
10.2.3 Documentation and Retention of Records ....................................................... 105 
10.2.3.1 
Case Report Forms .......................................................................... 105 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study 
Documents ...................................................................................... 105 
10.2.3.3 
Audit/Inspection.............................................................................. 106 
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10.2.3.4 
Financial Disclosure ........................................................................ 106 
10.3 
Ethical Considerations ...................................................................................... 106 
10.3.1 Informed Consent .......................................................................................... 106 
10.3.2 Institutional Review Board or Ethics Committee ............................................. 107 
10.4 
Privacy and Confidentiality .............................................................................. 108 
10.5 
Study Results/Publication Policy ...................................................................... 108 
11. REFERENCES .............................................................................................................. 110 
12. APPENDICES............................................................................................................... 114 
Appendix 1 
Protocol History .............................................................................. 115 
Appendix 2 
Scales and Assessments ................................................................... 116 
Appendix 3 
Glucocorticoid Equivalent Doses ..................................................... 148 
Appendix 4 
Determination of Inadequate Response/Loss of Response or 
intolerance to prior treatment for Crohn’s Disease ............................................. 149 
Appendix 5 
Guidance for Diagnosis and Treatment of Increased 
Gastrointestinal Symptoms ............................................................................... 157 
 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments .......................................................................... 28 
Table 2: 
Common Excluded Treatments ................................................................. 59 
Table 3: 
Neurological Assessment Plan .................................................................. 73 
Table 4: 
Volume of Blood to Be Drawn From Each Subject .................................... 80 
Table 5: 
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin .................................................................................................. 89 
Table 6: 
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints ................................................................................ 94 
 
LIST OF FIGURES 
Figure 1: 
Overview of SHP647 Phase 3 Studies in Crohn’s Disease.......................... 41 
Figure 2: 
Study Design Flow Chart.......................................................................... 42 
Figure 3: 
Flow Diagram for Quarterly Neurological Assessments ............................. 74 
Figure 4: 
Visualization of Multiple Testing Strategy ................................................ 97 
 
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ABBREVIATIONS 
5-ASA 
5-aminosalicylic acid 
6-MP 
6-mercaptopurine 
β-hCG 
beta-human chorionic gonadotropin 
ADA 
antidrug antibodies 
AE 
adverse event 
AZA 
azathioprine 
BSFS 
Bristol Stool Form scale 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
 
 
CI 
confidence interval 
CMH 
Cochran-Mantel Haenszel 
CNS 
central nervous system 
 
 
CSF 
cerebrospinal fluid 
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 
FSH 
follicle-stimulating hormone 
FWER 
family-wise type I error rate 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
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HCV 
hepatitis C virus 
HCVAb 
hepatitis C virus antibody 
HCVRNA 
hepatitis C ribonucleic acid 
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 
LP 
lumbar puncture 
LTS 
long-term safety extension 
 
 
MTX 
methotrexate 
NAb 
neutralizing antibody 
NRS 
numerical rating scale 
PCR 
polymerase chain reaction  
 
 
PFS 
prefilled syringe 
 
 
 
 
 
 
PML 
progressive multifocal leukoencephalopathy 
PPD 
purified protein derivative 
PRO 
patient-reported outcome 
Q4W 
once every 4 weeks 
RSI 
reference safety information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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SC 
subcutaneous 
SES-CD 
Simple Endoscopic Score for Crohn’s disease 
SF-36 
Short Form-36 Health Survey 
SOC 
system organ class 
SUSAR 
serious 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 
VCAM 
vascular cell adhesion molecule 
 
 
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STUDY SYNOPSIS 
Protocol number: SHP647-306 
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 Crohn’s Disease (CARMEN CD 306) 
Number of subjects (total and for each treatment arm): 
A total of 1032 subjects (387 subjects in the 25 mg SHP647 treatment group, 387 subjects in the 75 mg SHP647 
treatment group, and 258 subjects in the placebo group) 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 approximately 19 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): 
2018 to 2021 
Clinical phase: 
3 
Objectives: 
Coprimary: The coprimary objectives of this study are to evaluate the efficacy of SHP647 in subjects with 
moderate to severe Crohn’s disease (CD) in: 
• 
Inducing clinical remission based on 2-item patient-reported outcome (PRO) (abdominal pain severity and 
very soft stool/liquid stool frequency) 
• 
Inducing endoscopic response based on centrally read colonoscopy. 
Key secondary: 
• 
To evaluate the efficacy of SHP647 in inducing clinical remission as measured by CD Activity Index 
 
CDAI 
• 
To evaluate the efficacy of SHP647 in inducing enhanced endoscopic response based on centrally read 
colonoscopy 
• 
To evaluate the efficacy of SHP647 in inducing clinical remission based on abdominal pain severity and 
very soft stool/liquid stool frequency (alternate thresholds) 
• 
To evaluate the efficacy of SHP647 in inducing clinical response based on patient-reported clinical signs 
and symptoms (as measured by 2-item PRO) 
• 
To evaluate the efficacy of SHP647 in inducing clinical remission based on patient-reported clinical signs 
and symptoms (as measured by 2-item PRO) as well as inducing endoscopic response based on centrally 
read colonoscopy in the same subject 
• 
To evaluate the efficacy of SHP647 in inducing endoscopic healing based on centrally read colonoscopy. 
Other secondary: 
• 
To evaluate the safety and tolerability of SHP647 
• 
To evaluate the effect of SHP647 induction treatment on other clinical outcomes (clinical response 
defined by CDAI, or clinical remission over time, or change from baseline in frequency in CD-related 
clinical parameters) 
• 
To evaluate the effect of SHP647 induction treatment on other endoscopic outcomes 
• 
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 
• 
To evaluate the impact of SHP647 on incidence of CD-related and other surgeries. 
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Rationale: 
This study is designed to evaluate the efficacy and safety of SHP647 in inducing clinical remission and endoscopic 
response in subjects with moderate to severe CD. 
The CD clinical development program includes 3 completed studies: 1 Phase 1 study (A7281008) and 2 Phase 2 
studies (A7281006 and A7281007). The SHP647 dose selection (25 mg and 75 mg) for this study is based on data 
from these 3 previous studies, which evaluated the activity of SHP647 in adult patients with moderately to severely 
active CD based on CDAI scores between 220 and 450. The Phase 1 study (A7281008, TOSCA) and Phase 2 
studies (A7281006, OPERA; and A7281007, OPERA II [long-term safety study]) that investigated the safety, 
tolerance, pharmacokinetics, and pharmacodynamic properties of SHP647 support further clinical development of 
SHP647 using subcutaneous (SC) administration in subjects with moderate to severe CD. 
Investigational product, dose, and mode of administration: 
The test product is SHP647 (a fully human immunoglobulin G2 kappa antihuman mucosal addressin cell adhesion 
molecule [MAdCAM] monoclonal antibody), 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 mg or 75 mg). 
Additional information is provided in the current SHP647 investigator’s brochure (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 SHP647. 
Methodology: 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the 
efficacy and safety of SHP647 in inducing clinical remission and endoscopic response in subjects with moderate to 
severe CD. 
A total of 1032 subjects (387 subjects in the 25 mg SHP647 treatment group, 387 subjects in the 75 mg SHP647 
treatment group, and 258 subjects in the placebo group) 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 16-week treatment period. After the screening period, 
eligible subjects will be randomized to receive 1 of 3 treatments (25 mg SHP647, 75 mg SHP647, or placebo) in a 
3:3:2 ratio. Randomization will be stratified based upon the subject’s status of prior antitumor necrosis factor 
(TNF) treatment (naïve or experienced), glucocorticoid use at baseline (on glucocorticoids at baseline versus not 
on glucocorticoids at baseline), and Simple Endoscopic Score for CD (SES-CD) at baseline (SES-CD ≥17 or 
SES-CD <17). Subjects will receive SC injections of SHP647 or placebo, using a PFS, on Week 0/Day 1 (Visit 2), 
Week 4 (Visit 4), Week 8 (Visit 5), and Week 12 (Visit 6). Subjects will undergo efficacy, 
 
, safety, and health outcome assessments at these visits. 
At the end of the 16-week treatment period, subjects will be offered the opportunity to participate in either a 
double-blind maintenance study (SHP647-307; for subjects who fulfill the entry criteria) or a long-term safety 
extension (LTS) study (SHP647-304; for subjects who do not fulfill the entry criteria for Study SHP647-307). 
Subjects who withdraw early from the 16-week treatment period or who do not wish to enter the maintenance 
study (SHP647-307) 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 (SHP647-305 or 
SHP647-306) will be eligible to continue in the maintenance study or LTS study. 
A planned interim analysis for the coprimary endpoints will take place after approximately the first 50% of all 
randomized subjects in both the SHP647-305 and SHP647-306 studies have either completed the studies or have 
prematurely withdrawn from the studies. The sample size will be reassessed as part of this interim analysis. 
 
 
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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 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 active moderate to severe ileal (terminal ileum), ileocolic, or colonic CD at baseline 
(Visit 2) as defined by: 
a. CDAI score between 220 and 450 (inclusive) AND 
b. Presence of ulcerations that are characteristic to CD, as determined by a colonoscopy performed 
during screening, and as defined by the SES-CD >6 (SES-CD ≥4 for isolated ileitis) AND 
c. Meeting the following subscores in the 2-item PRO: 
i. Abdominal pain subscore ≥5 (average worst daily pain on the 11-point numerical rating 
scale [NRS]) AND abdominal pain subscore ≥2 (average daily pain on the 4-point 
abdominal pain variable of CDAI) over the 7 most recent days out of the 10 days before 
colonoscopy preparation (may or may not be contiguous) AND/OR 
ii. Average of the daily stool frequency subscore ≥4 of type 6/7 (very soft stools/liquid 
stools) as shown in the Bristol Stool Form Scale (BSFS) over the 7 most recent days out 
of the 10 days before colonoscopy preparation (may or may not be contiguous). 
5. Subjects must have a documented diagnosis (endoscopic with histology) of CD for ≥3 months before 
screening. Documented diagnosis is defined as: 
• A biopsy report to confirm the histological diagnosis AND 
• A report documenting disease duration based upon prior colonoscopy. 
Note: If a biopsy report is not available in the source document at the time of screening, a biopsy must be 
performed during the screening colonoscopy and the histology report should be consistent with the CD 
diagnosis. If the histology diagnosis is not clear at this time point, the subject should not be randomized. 
6. Subjects must be willing and able to undergo a colonoscopy during screening after all other inclusion 
criteria have been met. 
7. 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 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). Subjects who have had an 
inadequate response to sulfasalazine or mesalamine should have also failed at least 1 other conventional 
treatment such as glucocorticoids. 
8. Subjects receiving any treatment(s) for CD 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. 
9. 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 ulcerative colitis. 
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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 presence of enterovesical (ie, between the bowel and urinary bladder) or enterovaginal 
fistulae. 
5. Subjects with current symptomatic diverticulitis or diverticulosis. 
6. Subjects with obstructive 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 CD during the 
treatment period. 
7. Subjects with past medical history of multiple small bowel resections resulting in clinically significant 
short bowel syndrome. 
8. Subjects requiring total parenteral nutrition. 
9. Subjects with past medical history of bowel surgery resulting in an existing or current stoma. Subjects 
who had a j-pouch are excluded as a j-pouch could result in a stoma. 
10. Subjects have had prior treatment with SHP647 (formerly PF-00547659). 
11. Subjects with known or suspected intolerance or hypersensitivity to the investigational product(s), closely 
related compounds, or any of the stated ingredients. 
12. Subjects have received any nonbiologic treatment with immunomodulatory properties (other than AZA, 
6-MP, or MTX) or continuous antibiotics (>2 weeks) for the treatment of CD within 30 days before 
baseline (Visit 2). 
13. Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2). 
14. Subjects have received any biologic with immunomodulatory properties (other than anti-TNFs) within 
90 days before baseline (Visit 2). 
15. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion molecule). 
16. Subjects have received lymphocytes apheresis or selective monocyte granulocytes apheresis within 
60 days before baseline (Visit 2). 
17. Subjects have received enteral nutrition treatment within 30 days before baseline (Visit 2). 
18. Subjects have received parenteral or rectal glucocorticoids or rectal 5-ASA within 14 days before 
screening colonoscopy. 
19. Subjects have taken >20 mg/day of prednisone or equivalent oral systemic corticosteroid dose within 
14 days before baseline (Visit 2) or have taken ≥40 mg/day of prednisone or equivalent oral systemic 
corticosteroid dose within 6 weeks before baseline (Visit 2). 
20. 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 screening (Visit 1). 
21. Subjects have received a live (attenuated) vaccine within 30 days before the baseline visit (Visit 2). 
22. 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 
retest 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). 
23. Subjects with abnormal chest x-ray or other imaging findings at screening (Visit 1), such as presence of 
active tuberculosis (TB), general infections, heart failure, or malignancy. (A chest x-ray, computed 
tomography scan, etc., 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.) 
24. 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 baseline 
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(Visit 2) 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 baseline (Visit 2). 
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 
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. 
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 before 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. 
25. 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. 
26. Subjects with any unexplained symptoms suggestive of progressive multifocal leukoencephalopathy based 
on the targeted neurological assessment during the screening period. 
27. Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed. 
28. 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). 
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• 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). 
29. Subjects who have had significant trauma or major surgery within 4 weeks before screening (Visit 1), or 
with any major elective surgery scheduled to occur during the study. 
30. Subjects with evidence of cirrhosis with or without decompensation (ie, esophageal varices, hepatic 
encephalopathy, portal hypertension, ascites). 
31. Subjects with primary sclerosing cholangitis. 
32. 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). 
33. Subjects with chronic hepatitis C (HCV) (positive HCVAb and hepatitis C ribonucleic acid [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]). 
34. Subjects with any of the following abnormalities in hematology and/or serum chemistry profiles during 
screening (Visit 1). 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 colonoscopy 
procedure. 
• Alanine aminotransferase and aspartate aminotransferase levels ≥3 × 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/1.73m2 
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. 
35. 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. 
36. 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 of any kind including abuse of 
medicinal marijuana (cannabis). 
37. 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. 
38. Female subjects who are planning to become pregnant during the study period. 
39. 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. 
40. 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. 
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Maximum duration of subject involvement in the study: 
• 
Planned duration of screening period: Up to 6 weeks 
• 
Planned duration of treatment period: 16 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 protocol deviations that may affect the 
coprimary efficacy endpoints. 
The completer set will consist of all subjects in the FAS who have completed the Week 16 assessment for this 
study. 
 
 
 
 
Coprimary efficacy endpoints: 
The coprimary efficacy endpoints are: 
• 
Clinical remission at the Week 16 visit as defined by the following: 2-item PRO subscores of average 
worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days and average daily 
stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent 
days. The 7 most recent days may or may not be contiguous during the 10 days of data collection before 
 
colonoscopy preparation, depending on days to be excluded because of missing data. If fewer than 7 days 
are available, the endpoint will be calculated on all available most recent 6 or 5 days. If fewer than 5 days 
are available, the endpoint will be treated as missing. 
• 
Endoscopic response at Week 16 as measured by a decrease in SES-CD of at least 25% from baseline. 
The coprimary efficacy endpoints, clinical remission at the Week 16 visit and endoscopic response at the Week 16 
visit, will each 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, glucocorticoid 
use, and SES-CD at baseline for each of the stages of the study (stage 1 includes subjects whose primary efficacy 
data are used in the interim analysis and stage 2 includes all other subjects. Note: classification of stage 1 and 
stage 2 is based on the time of randomization rather than the time of study completion or termination). Subjects 
with missing data at the Week 16 visit will be considered failures and counted as nonresponders. 
Weighted inverse normal p-value combination methods are used to combine the p-values from stage 1 and stage 2 
through the following formula: 
C(p1, p2) = 1 – Φ[w1 Φ-1(1-p1)+ w2 Φ-1(1-p2)] 
Where p1, p2 are the p-values computed from the CMH chi-square test for each stage, wi
2
 = ni/(n1 + n2), n1 and n2 are 
the preplanned stage-wise sample sizes that are fixed at the time of the interim analysis based on an original total 
sample size, and Φ denotes the cumulative distribution function of the standard normal distribution (Bretz, et al., 
2009a). Given that there is no possibility of stopping early for efficacy, that any potential stopping for futility of 
either or both doses of SHP647 is nonbinding, and that weights are prespecified, the test statistic C(p1, p2) can be 
compared against the nominal alpha level to assess statistical significance (Chang, 2008). 
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The coprimary endpoints will each be tested by the following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
Where δ is the common treatment difference across strata. 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 coprimary and key secondary 
endpoints will be strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in 
Bretz et al. (2009b) will be utilized to propagate α from the coprimary endpoints to the key secondary endpoints 
and between the 2 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 coprimary endpoints (P) and alpha is 
propagated in a hierarchical manner to each of the 6 key secondary endpoints (K1–K6) within a pairwise treatment 
comparison. In order to pass alpha between the coprimary endpoints and the first key secondary endpoint, both 
coprimary endpoints must attain statistical significance. 
Key secondary efficacy endpoints: 
The key secondary efficacy endpoints are as follows: 
• 
Clinical remission at the Week 16 visit as measured by a CDAI score of <150. 
• 
Enhanced endoscopic response at Week 16 as measured by a decrease in SES-CD of at least 50% from 
baseline. 
• 
Clinical remission at the Week 16 visit as defined by the following: 2-item PRO subscores of average 
daily abdominal pain ≤1 (based on the 4-point scale) over the 7 most recent days and average daily stool 
frequency ≤3 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days. 
The 7 most recent days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. If fewer than 7 days 
are available, the endpoint will be calculated on all available most recent 6 or 5 days. If fewer than 5 days 
are available, the endpoint will be treated as missing. 
• 
Clinical response at the Week 16 visit as measured by the 2-item PRO and defined as meeting at least 1 of 
the following 2 criteria: 
 
o
A decrease of ≥30% and at least 2 points from baseline in the average daily worst abdominal pain 
over the 7 most recent days*, with the average daily stool frequency of type 6/7 (very soft 
stools/liquid stools) either: 
(a) Not worsening from baseline 
and/or 
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average daily stool 
frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent 
days* 
 
o
A decrease of ≥30% from baseline in the average daily stool frequency of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days*, with the average daily worst 
abdominal pain either: 
(a) Not worsening from baseline 
and/or 
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average worst daily 
abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days* 
*Note: The 7 most recent days may or may not be contiguous during the 10 days of data collection 
before colonoscopy preparation, depending on days to be excluded because of missing data. If fewer 
than 7 days are available, the endpoint will be calculated on all available most recent 6 or 5 days. If 
fewer than 5 days are available, the endpoint will be treated as missing. 
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• 
Clinical remission with endoscopic response, ie, both clinical remission by 2-item PRO and endoscopic 
response, as measured by a decrease in SES-CD of at least 25% at Week 16 (composite endpoint) 
• 
Complete endoscopic healing at Week 16 defined as SES-CD=0-2. 
The key secondary endpoints will be analyzed using the same approach as described for the coprimary endpoints. 
Subjects with missing key secondary endpoint data at the Week 16 visit will be considered failures and counted as 
nonresponders. 
Other secondary efficacy endpoints: 
• 
Clinical response at the Week 16 visit as measured by at least a 100-point reduction in the CDAI from 
baseline (CDAI-100 response) 
• 
Clinical response at the Week 16 visit as measured by at least a 70-point reduction in the CDAI from 
baseline (CDAI-70 response) 
• 
Clinical remission over time, as measured by the 2-item PRO 
• 
Change from baseline in total stool frequency, rectal bleeding frequency, rectal urgency frequency, nausea 
severity, vomiting frequency, and rectal incontinence frequency scores; and total sign/symptom score 
based on subject daily e-diary entries 
• 
Endoscopic healing at Week 16 as measured by SES-CD ≤4 and at least 2-point reduction versus baseline 
and no subscore >1 in any individual variable 
• 
Change from baseline in IBDQ domain and total (absolute) scores over time 
• 
Change from baseline in SF-36, version 2, acute (physical and mental component summary scores and 
individual domain scores) over time 
• 
Incidence of all cause hospitalizations and total inpatient days 
• 
Incidence of CD-related surgeries and other surgical procedures during the entire study period. 
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 compared between each active treatment group and the placebo group using a 
CMH chi-square test stratified by status of prior anti-TNF treatment, glucocorticoid use at baseline, and 
SES-CD at baseline. The estimate of the common treatment difference along with the corresponding 
stratified Newcombe 95% CI using the method of Yan and Su (2010) and the p-value computed from 
CHM test will be provided. Subjects with missing binary endpoint data at the Week 16 visit will be 
considered failures and counted as nonresponders. 
• 
Continuous endpoints that are only measured at baseline and the Week 16 visit will be analyzed using an 
analysis of covariance model with fixed effects for treatment group (categorical), status of prior anti-TNF 
treatment (categorical), glucocorticoid use at baseline (categorical), and SES-CD at baseline (Visit 2) 
(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), glucocorticoid use at baseline (categorical), and SES-CD 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 and percentage of TEAEs will be calculated 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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 28 ±3 
56 ±3 84 ±3 
 
 
112 ±3 
168 ±7 
224 ±7 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
X 
 
 
 
 
 
 
Xd 
 
 
Demographics and medical 
historye 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examinationf 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Targeted physical 
examinationf 
 
X 
X 
 
X 
X 
X 
 
 
 
 
 
Targeted neurological 
assessmentg 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Vital signs 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
12-lead ECG 
X 
 
X 
 
 
 
 
 
 
X 
 
 
Chest x-rayh 
X 
 
 
 
 
 
 
 
 
 
 
 
Contraception checki 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
X 
Laboratory Assessments 
Hematology 
Xj,k 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Serum chemistry 
Xj 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Urinalysis 
Xj 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Stool microbiologyl 
Xj 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, HBcAb, HCVAbm 
Xj 
 
 
 
 
 
 
 
 
 
 
 
HIV testing per local 
regulationn 
X 
 
 
 
 
 
 
 
 
 
 
 
FSHo 
Xj 
 
 
 
 
 
 
 
 
 
 
 
Serum β-hCGp 
Xj 
 
 
 
 
 
 
 
 
 
 
 
Urine β-hCGp 
 
 
X 
 
X 
X 
X 
 
 
X 
 
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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 28 ±3 
56 ±3 84 ±3 
 
 
112 ±3 
168 ±7 
224 ±7 
TB test (PPD or 
QuantiFERON-TB Gold 
Plus)q 
X 
 
 
 
 
 
 
 
 
 
 
 
JCV antibody banked 
sampler 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
ADA and NAb sampling 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Endoscopic Procedure 
Colonoscopy (including 
biopsy)s 
 
X 
 
 
 
 
 
 
X 
 
 
 
CD Assessments 
CDAIt 
 
X 
 
 
X 
X 
X 
 
 
X 
 
 
PRO-CD daily e-diary data 
instruction 
X 
 
 
 
 
 
 
 
 
 
 
 
PRO-CD daily e-diary datau 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
SES-CDv 
 
 
X 
 
 
 
 
 
 
X 
 
 
Health Assessmentw 
IBDQ 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
Hospitalizations, inpatient 
days, 
 (HRUA) 
 
 
 
 
X 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
SF-36, version 2, acute 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 28 ±3 
56 ±3 84 ±3 
 
 
112 ±3 
168 ±7 
224 ±7 
Treatment Procedures 
Randomizationx 
 
 
X 
 
 
 
 
 
 
 
 
 
Administration of SHP647 or 
placebox,y 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior medications 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
and procedures 
X 
X 
X 
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; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; 
; 
ECG=electrocardiogram; 
; 
; ET=early termination; FSH=follicle-stimulating 
hormone; GDH=glutamate dehydrogenase; HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HCV RNA=hepatitis C virus 
ribonucleic acid; HRUA=Healthcare Resource Utilization Assessment; IBD=inflammatory bowel disease; 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; 
; PML=progressive 
multifocal leukoencephalopathy; PPD=purified protein derivative; PRO=patient-reported outcomes; SES-CD=Simple Endoscopic Score for CD; SF-36 v2=Short Form-36 Health 
Survey, version 2; TB=tuberculosis; 
. 
a 
Screening assessments will take place over more than 1 day (at least 2 visits will be necessary to complete the screening evaluations, including colonoscopy). 
b 
Subjects who withdraw early during the treatment period should return for the ET visit and then enter into the safety follow-up period. The Week 16 (Visit 7) and ET visits 
consist of 3 parts: 
 •
Part 1 of Visit 7 should be scheduled 1 to 3 day(s) before Part 2; this will allow for blood samples to be taken before starting the colonoscopy preparation and before the 
colonoscopy procedure at Part 2 of the visit (Section 7.2.2.4) 
 •
Part 2 of Visit 7 should be scheduled preferably 5 to 7 days before Part 3; this will allow sufficient time to obtain the data from the centrally read colonoscopy 
 •
Part 3 of Visit 7 will take place on Day 112 ±3 days. 
c 
Subjects NOT entering the maintenance study (SHP647-307) or LTS (SHP647-304) study at the completion of the Week 16 visit will need to complete the safety follow-up 
assessments. The Week 24 (Visit 8) 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 32 (Visit 9) visit will take place at the study site. 
d 
The outcome of Visit 7, Part 3 is used to assess eligibility to enroll subjects in the maintenance (SHP647-307) or LTS (SHP647-304) studies. Please refer to the respective 
protocols for further details. 
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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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 28 ±3 
56 ±3 84 ±3 
 
 
112 ±3 
168 ±7 
224 ±7 
e 
Medical history will include CD history, cardiac history, and smoking history. 
f 
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; 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 and mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, eyes, abdomen, and examination of body 
systems where there are symptom complaints by the subject. 
g 
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. 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. 
h 
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. 
i 
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. 
j 
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 before the screening colonoscopy procedure. 
k 
Hematology samples should be repeated if more than 3 weeks have elapsed before the day of colonoscopy to be able to use the hematocrit central laboratory results for the 
CDAI score calculation at screening. 
 
Note: Hematocrit must NOT be older than 3 weeks before the day of colonoscopy. 
l 
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. 
m 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. 
n 
Testing may be performed at the site’s local laboratory in accordance with country requirements, or at the central laboratory. Documentation of a negative HIV test result 
within 6 months prior to screening will be accepted. 
o 
For confirmation of postmenopausal status in females who have had 12 consecutive months of spontaneous amenorrhea and are ≥51 years of age. 
p 
Female subjects of childbearing potential; serum pregnancy test at screening (Visit 1) and urine pregnancy test at all other time points.  
q 
A documented negative PPD test within 12 weeks before baseline (Visit 2) is acceptable provided that an interferon-gamma release assay official reading and method or test is 
located in the source documentation. 
r 
A serum sample will be collected and banked. It may be analyzed if a subject shows neurological symptoms suggestive of PML. 
 
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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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 28 ±3 
56 ±3 84 ±3 
 
 
112 ±3 
168 ±7 
224 ±7 
s 
Colonoscopy preparation will be according to local routine. Colonoscopy must be performed during the screening period within 5 to 7 days before baseline (Visit 2), to allow 
for adequate e-diary data collection for the 2-item PRO and CDAI scores and to obtain the centrally read endoscopic subscore to verify the subject’s eligibility. During the 
colonoscopy at screening (Visit 1, Part 2) and Week 16/ET, 10 biopsies will be collected from the most inflamed area of the mucosa; 2 samples each from the ileum, the 
3 segments of the colon, and the rectum. If the calculated CDAI scores is <220 or >450, the subject will be considered a screen failure and should not proceed with the 
colonoscopy preparation and/or the colonoscopy.  
t 
The CDAI score at screening (Visit 1, Part 2) includes subject-reported PRO-CD daily e-diary data collected >10 days before the start of colonoscopy preparation. 
 
The CDAI score at Visits 4, 5, and 6 includes subject-reported PRO-CD daily e-diary data collected >10 days before the visit. 
 
The CDAI score at the Week 16/ET visit will be calculated at Visit 7, Part 3 (after all evaluations are complete) and includes subject-reported PRO-CD daily e-diary data 
collected >10 days before the start of colonoscopy preparation. 
 
Note: All required components (including subject-reported PRO-CD daily e-diary data collected >10 days before the start of colonoscopy preparation and <3 weeks of central 
hematocrit results) should be available to calculate the CDAI scores. See Section 7.2.2.3 for further details. 
u 
Patient-reported CD clinical signs and symptoms will be collected daily using a PRO-CD daily e-diary (electronic handheld device) starting during the screening period; 
however, collection of the daily e-diary data must begin at least 10 days before colonoscopy preparation. Subjects should be provided with the e-diary to take home on their 
first visit. Compliance will be assessed by the site staff and the subject should be retrained on the appropriate use of the e-diary when compliance is below 80% (eg, <23 out of 
28 e-diary entries). If 70% compliance cannot be achieved after repeated instructions during the screening period, noncompliant subjects will be automatically noneligible as 
they will not fulfill inclusion criterion 1 (Section 4.1). If 7 out of the 10 most recent days are not available, then the 2-item PRO cannot be calculated for the subject at 
screening. 
v 
The SES-CD score at baseline (Visit 2) and at Week 16/ET will be calculated using subscores of each of the segments investigated and centrally read from the colonoscopies 
performed at screening (Visit 1, Part 2) and Week 16 (Visit 7, Part 2), respectively. 
w All health outcome or patient-reported questionnaires should be completed before completing any other visit assessments. 
x 
Interactive response technology will be used for randomization and dispensation of study treatment. 
y 
Where applicable, specified procedures and laboratory samples should be collected before investigational product administration. 
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 
Crohn’s disease (CD) is a chronic, relapsing disease marked by granulomatous inflammation of 
the gastrointestinal (GI) tract. Although the terminal ileum and right colon are the most 
commonly involved sites, CD can affect any part of the GI tract, from the mouth to the perianal 
region. Inflammation is typically transmural (full-thickness), segmental, and discontinuous, and 
symptoms are predominantly determined by the part of bowel or organ involved. Patients 
typically present with symptoms including abdominal pain, diarrhea, rectal bleeding, which may 
be persistent and lead to anemia, and weight loss due to pain on eating and malabsorption. As the 
disease progresses, extraintestinal manifestations and associated conditions can develop, 
including bowel obstruction, fistulas, and stenosis, as well as painful skin ulcerations, eye pain, 
and arthritis. 
The incidence of CD is estimated to be up to 12.7 cases per 100,000 persons per year in Europe 
and up to 20.2 cases per 100,000 persons per year in North America. No clear difference in 
incidence has been observed between men and women. Although CD can occur at any age, peak 
incidence has been observed in the second to fourth decades of life, with a second modest rise in 
incidence in the latter decades of life (Molodecky et al., 2012). 
Crohn’s disease is a lifelong condition with a serious effect on quality of life. The traditional 
approach to therapy of CD has been the step-up approach usually represented as a pyramid 
where, progressing from mild to severe disease, therapeutic choices proceed step by step from 
less potent drugs at the base of the pyramid to more potent but also more toxic drugs at the top. 
Current treatment primarily consists of symptomatic management with dietary modifications, 
5-aminosalicylic acid (5-ASA), opiate antidiarrheal drugs (loperamide), systemic 
glucocorticoids, immunosuppressive agents (azathioprine [AZA], 6-mercaptopurine [6-MP], 
methotrexate [MTX]), and biologic therapy with anti-tumor necrosis factor (TNF) or 
anti-integrin agents. Despite recent advances, there is still an unmet need for a safe, effective, 
and durable pharmacological treatment that will induce and maintain clinical remission. 
1.2 
Product Background and Clinical Information 
The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal sites of the 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 (Shyjan et al., 
1996; Briskin et al., 1997; 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. 
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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 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. 
1.3 
Benefit/Risk Assessment 
SHP647 has been evaluated in Phase 1 and Phase 2 clinical studies in subjects with CD and UC. 
In study A7281006 in subjects with CD, induction treatment with SHP647 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 (CDAI)-70 response rate at Week 8 or 
Week 12. Post hoc analyses did suggest evidence of drug effect in subjects with a higher 
inflammatory state at baseline (as indicated by higher serum CRP concentrations or higher 
endoscopic disease activity as measured by SES-CD). In Study A7281009 in subjects with UC, 
induction treatment with SHP647 at doses of 7.5 mg, 22.5 mg, or 75 mg every 4 weeks resulted 
in 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 the induction study A7281006 in subjects with CD, compared to placebo, nominally 
statistically significant decreases 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 3 active treatment groups (7.5 mg, 22.5 mg, and 75 mg) over the 12-week 
induction period. Compared to placebo, nominally statistically significant decreased in hsCRP 
were observed in all 3 active treatment groups 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 Week 8 and Week 12, consistent 
with the predicted mechanism of action. In the UC induction study, A7281009, decreases in fecal 
calprotectin were observed in all groups, including placebo; however, there were no nominally 
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 nominally significant differences were 
observed in active treatment vs placebo. 
The most common 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 when 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. 
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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. 
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 central 
nervous system (CNS) immune surveillance. No evidence of progressive multifocal 
leukoencephalopathy (PML) or myocarditis has been observed. 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 (IB) 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 IgG2κ antihuman MAdCAM monoclonal antibody, is under development 
for the treatment of CD. 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 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 CD is well established 
(Sandborn et al., 2013). SHP647 is differentiated from other molecules targeting the 
α4β7-MAdCAM mediated lymphocyte trafficking used for the treatment of CD in that SHP647 
blocks the interaction of α4β7
+ lymphocytes with the MAdCAM receptor by selectively binding 
to MAdCAM on the endothelial cells surface in the gut (and related tissues) while the other 
molecules target the integrins on the infiltrating lymphocytes. Additionally, SHP647 does not 
bind to the vascular cell adhesion molecule (VCAM); therefore, SHP647 is not expected to affect 
lymphocyte homing or surveillance in the CNS or to be an effective treatment for multiple 
sclerosis. 
This study is designed to evaluate the efficacy and safety of SHP647 in inducing clinical 
remission and endoscopic response in subjects with moderate to severe CD. 
The CD clinical development program includes 3 completed studies: 1 Phase 1 study 
(A7281008) and 2 Phase 2 studies (A7281006 and A7281007). 
Study A7281006 (OPERA) was a parallel, dose-ranging, randomized, double-blind, 
placebo-controlled study in which SHP647 was given as 3 subcutaneous (SC) dose levels 
(22.5 mg, 75 mg, and 225 mg) once every 4 weeks (Q4W) over an 8-week period. SHP647 was 
generally safe and well tolerated and there were no deaths. Three placebo-treated subjects and 
9 subjects in the 22.5 mg, 75 mg, and 225 mg SHP647 groups discontinued treatment due to 
adverse events (AEs). Most TEAEs were mild or moderate in severity. Median serum 
concentrations of SHP647 increased with increasing dose. Positive antidrug antibodies (ADA) 
status did not appear to impact exposure to SHP647. The CDAI was the primary instrument to 
assess the efficacy of SHP647; no statistically significant differences were noted between the 
active treatment arms and the placebo arm. Therefore, the study did not meet its primary 
endpoint. However, post hoc analysis indicated increased remission rates in subjects in the 
22.5 mg or 75 mg treatment arms who had higher serum concentrations of high-sensitivity 
C-reactive protein (hsCRP) or higher scores of Simple Endoscopic Score for CD (SES-CD) at 
baseline. 
Study A7281008 (TOSCA) was an open-label multi-center, Phase 1 sequential cohort study that 
evaluated the effects of a maximum induction dose of SHP647 on CNS system immune 
surveillance. 
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Subjects with inflammatory bowel disease (IBD) (including CD), with or without stoma, who 
failed or were intolerant to both anti-TNF and immunosuppressant therapy and who had 
moderate to severe active disease underwent a lumbar puncture (LP), completed induction 
therapy with 3 doses of 225 mg SHP647 4 weeks apart, and then underwent a second LP 
2 (±1) weeks later. The primary endpoint was the percent change from baseline (pretreatment) in 
absolute lymphocyte count in cerebrospinal fluid (CSF) in subjects with IBD after receiving 
3 doses of 225 mg SHP647. The mean percentage change from baseline in absolute lymphocytes 
in CSF was 61.76% with a median change of 35.2% (range: -70.2% to 267.8%). The 
post-treatment LP/pretreatment LP geometric mean ratio for CSF lymphocytes was 1.33 with the 
lower bound of the 80% confidence interval (CI)=1.13, which was greater than 0.5, supporting 
rejection of the null hypothesis (ie, that the percent decrease in total lymphocytes counts after 
treatment would be ≥50% (equivalent to the geometric mean ratio in total lymphocyte counts 
being ≤0.5). This result supports the hypothesis that SHP647 does not impair trafficking of 
lymphocytes into the CNS and thus should not impair CNS immune surveillance. 
Study A7281007 (OPERA II) was a Phase 2 open-label extension study to provide additional 
long-term safety data on subjects with moderate to severe CD who completed Study A7281006 
or Study A7281008 and wished to continue to receive SHP647. SHP647 75 mg (with potential 
dose escalation to 225 mg) SC given every 4 weeks for 72 weeks was generally well tolerated in 
subjects with CD over the treatment period evaluated in this study. In subjects with positive 
ADA or neutralizing antibody (NAb) status, exposure to SHP647 was not affected. Serum 
concentrations of SHP647 in this study were consistent with what was predicted based on the 
Feeder Study A7281006. There were 2 deaths in the study: 1 subject died of multiple organ 
dysfunction syndromes in the treatment period and 1 subject died of metastatic neoplasm in the 
follow-up period. Neither death was reported as related to treatment with the study drug by the 
investigators. The most frequently reported SAE was CD in either the treatment period or the 
follow-up period. The system organ class with the most subjects experiencing TEAEs was GI 
disorders. Although Study A7281007 was not placebo controlled, the exploratory efficacy results 
(based on the modified Harvey Bradshaw Index) indicated that the effect of SHP647 on disease 
activity was maintained over the duration of treatment. 
The SHP647 dose selection (25 mg and 75 mg) for this study is based on data from these 
3 previous studies, which evaluated the activity of SHP647 in adult patients with moderately to 
severely active CD based on CDAI scores between 220 and 450. The results of a post hoc 
analysis of remission rate by baseline elevated serum concentration of hsCRP suggested that the 
greatest treatment effect was at a dose of 22.5 mg. Similarly, post hoc analysis of remission rates 
by endoscopic severity assessed using the SES-CD suggested best efficacy at a dose of 75 mg. 
Therefore, both dosage regimens 25 mg and 75 mg Q4W have been selected for the Phase 3 
testing. The Phase 1 study (A7281008, TOSCA) and Phase 2 studies (A7281006, OPERA; and 
A7281007, OPERA II [long-term safety study]) that investigated the safety, tolerance, 
pharmacokinetics, and pharmacodynamic properties of SHP647 support further clinical 
development of SHP647 using SC administration in subjects with moderate to severe CD. 
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2.2 
Study Objectives 
2.2.1 
Coprimary Objectives 
The coprimary objectives of this study are to evaluate the efficacy of SHP647 in subjects with 
moderate to severe CD in: 
 •
Inducing clinical remission based on 2-item patient-reported outcome (PRO) (abdominal 
pain severity and very soft stool/liquid stool frequency) 
 •
Inducing endoscopic response based on centrally read colonoscopy. 
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 inducing clinical remission as measured by CDAI 
 •
To evaluate the efficacy of SHP647 in inducing enhanced endoscopic response based on 
centrally read colonoscopy 
 •
To evaluate the efficacy of SHP647 in inducing clinical remission based on abdominal 
pain severity and very soft stool/liquid stool frequency (alternate thresholds) 
 •
To evaluate the efficacy of SHP647 in inducing clinical response based on 
patient-reported clinical signs and symptoms (as measured by 2-item PRO) 
 •
To evaluate the efficacy of SHP647 in inducing clinical remission based on 
patient-reported clinical signs and symptoms (as measured by 2-item PRO) as well as 
inducing endoscopic response based on centrally read colonoscopy in the same subject 
 •
To evaluate the efficacy of SHP647 in inducing endoscopic healing based on centrally 
read colonoscopy. 
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 (clinical 
response defined by CDAI, or clinical remission over time, or change from baseline in 
frequency in CD-related clinical parameters) 
 •
To evaluate the effect of SHP647 induction treatment on other endoscopic outcomes 
 •
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 
 •
To evaluate the impact of SHP647 on incidence of CD-related and other surgeries. 
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2.2.3 
Exploratory Objectives 
The exploratory objectives 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 clinical remission and endoscopic 
response in subjects with moderate to severe CD. 
At study initiation, a total of 1032 subjects (387 subjects in the 25 mg SHP647 treatment group, 
387 subjects in the 75 mg SHP647 treatment group, and 258 subjects in the placebo group) 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 16-week treatment period. After the 
screening period, eligible subjects will be randomized to receive 1 of 3 treatments 
(25 mg SHP647, 75 mg SHP647, or placebo) in a 3:3:2 ratio. Randomization will be stratified 
based upon the subject’s status of prior anti-TNF treatment (naïve or experienced), 
glucocorticoid use at baseline (on glucocorticoids at baseline versus not on glucocorticoids at 
baseline), and SES-CD at baseline (SES-CD ≥17 or SES-CD <17). 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), Week 8 (Visit 5), and Week 12 (Visit 6). Subjects will undergo efficacy, 
, 
, safety, and health outcome assessments at these visits and at 
the time points specified in Table 1. 
At the end of the 16-week treatment period, subjects will be offered the opportunity to participate 
in either a double-blind maintenance study (SHP647-307; for subjects who fulfill the entry 
criteria) or a long-term safety extension (LTS) study (SHP647-304; for subjects who do not 
fulfill the entry criteria for Study SHP647-307) as shown in Figure 1. Subjects who withdraw 
early from the 16-week treatment period or who do not wish to enter the maintenance study 
(SHP647-307) 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 (SHP647-305 or SHP647-306) will be eligible to continue in the 
maintenance study or LTS study. 
A planned interim analysis for the coprimary endpoints will take place after approximately the 
first 50% of all randomized subjects in both the SHP647-305 and SHP647-306 studies have 
either completed the studies or have prematurely withdrawn from the studies. The sample size 
will be reassessed as part of this interim analysis. See Section 9.5 for further details of the 
planned interim analysis. 
The overall study design is shown in Figure 2. 
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Figure 1: Overview of SHP647 Phase 3 Studies in Crohn’s Disease 
 
BSFS=Bristol Stool Form Scale; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; NRS=numerical rating scale; 
PRO=patient-reported outcomes; SES-CD=Simple Endoscopic Score for Crohn's Disease. 
a Responders are subjects who either: 
(a) Meet endoscopic response criteria of a reduction in SES-CD from baseline by ≥25% at Week 16 
OR 
(b) Meet at least 1 of the following 4 criteria at Week 16 in addition to no worsening of endoscopic score as measured by 
SES-CD relative to induction study baseline (SHP647-305 or SHP647-306): 
1. Subject is in clinical remission as determined by meeting the criteria for clinical remission using the 2-item PRO, ie, 2-item 
PRO subscore of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days and average daily 
stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days.* 
2. Subject has a decrease of at least 100 points in CDAI score (CDAI-70) from baseline. 
3. Subject has a decrease of ≥30% and at least 2 points from baseline in the average daily worst abdominal pain over the 7 most 
recent days*, with the average daily stool frequency of type 6/7 (very soft stools/liquid stools) either: (i) not worsening from 
baseline and/or (ii) meeting the criteria for clinical remission, ie, 2-item PRO subscore of average daily stool frequency ≤2 of 
type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days.* 
4. Subject has a decrease of ≥30% from baseline in the average daily stool frequency of type 6/7 (very soft stools/liquid stools) as 
shown in the BSFS over the 7 most recent days*, with the average daily worst abdominal pain either: (a) not worsening from 
baseline and/or (b) meeting the criteria for clinical remission, ie, 2-item PRO subscore of average worst daily abdominal pain ≤3 
(based on 11-point NRS) over the 7 most recent days*. 
*Note: The 7 most recent days may or may not be contiguous during the 10 days of data collection before colonoscopy 
preparation, depending on days to be excluded because of missing data. If fewer than 7 days are available, the criterion will be 
calculated on all available most recent 6 or 5 days. If fewer than 5 days are available, the criterion will be treated as missing. 
Placebo 
25 mg
75 mg
Non-Respondersa
Induction
(SHP647-305, SHP647-306) 
Maintenance
(SHP647-307) 
Long-term Safety 
Extension
(SHP647-304) 
25 mg
Placebo
75 mg
Placebo
Placebo
Respondersa
Respondersa
Respondersa
75 mg
25 mg
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Figure 2: Study Design Flow Chart 
 
LTS=long-term safety extension; W=week. 
a Subjects who withdraw early from the 16-week treatment period or who do not wish to enter the maintenance study 
(SHP647-307) or LTS study (SHP647-304) will continue into a 16-week safety follow-up period. 
Note: A planned interim analysis for the coprimary endpoints will take place after approximately the first 50% of all randomized 
subjects in both the SHP647-305 and SHP647-306 studies have either completed the studies or have prematurely withdrawn from 
the studies. 
3.1.1 
Rationale for Coprimary Endpoints 
In this study, clinical remission, as measured by a decrease below prespecified thresholds in the 
2-item PRO (abdominal pain severity and very soft stool/liquid stool frequency [as shown in the 
Bristol Stool Form Scale, BSFS]), and enhanced endoscopic response, as measured by a decrease 
in SES-CD, will be the primary instruments to assess the efficacy of SHP647. 
Rationale for Abdominal Pain Severity 
Abdominal pain is one of the most common symptoms of CD, with the cause likely to be 
multifactorial. In the CDAI, which was the most commonly used primary endpoint in CD studies 
in the past, the degree of abdominal pain was based on a 4-point scale, with scores ranging from 
0 (none) to 3 (severe). However, the new standard is to use the 11-point numerical rating scale 
(NRS) instead for the degree of abdominal pain. The limitation is that the 4-point and the 
11-point scales are not directly comparable. Numerous studies across a variety of conditions 
have examined cutoff scores for mild, moderate, and severe pain based on the 11-point pain 
NRS, with the findings across studies generally converging on a cutoff score of 4 (reflecting the 
maximum score indicating mild pain) and a score of 5 (reflecting the minimum score indicating 
moderate pain). To ensure that clinical remission criteria for abdominal pain are both clinically 
meaningful and fall definitively within the mild pain range on the NRS based on the literature, a 
remission subscore of ≤3 (a minimum improvement of at least 2 points is required for subjects 
who enter the study with moderate abdominal pain [subscore of ≥5]) will be used as part of the 
coprimary endpoints. 
Placebo 
25 mg SHP647 
75 mg SHP647 
Screening: Up to 
6 weeks 
Randomization 
Maintenance study 
(SHP647-307) 
or 
LTS study 
(SHP647-304) 
or 
16-week safety 
follow-up perioda 
W0 
W4 
Dosing:
@
Treatment period: 16 weeks 
Week 16/End of 
Treatment 
W8 
W12 
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This definition is further supported by a study conducted in a similar condition (irritable bowel 
syndrome) that examined the minimal clinically important difference on the 11-point NRS for 
abdominal pain (Spiegel et al., 2009) as well as post hoc analyses of the Phase 2 data from the 
SHP647 program (Study A7281006, OPERA). 
Rationale for Very Soft Stool/Liquid Stool Frequency 
Diarrhea is the most common sign in the presentation of CD, affecting approximately 85% of 
patients with a diagnosis of CD. In the CDAI, the number of liquid or soft stools (each day for 
7 days) is used with a multiplier of 2. The coprimary endpoints for clinical remission in studies 
SHP647-305 and SHP647-306 requires the use of a definition without any such multiplying 
factor and will use the BSFS for defining the very soft or liquid stools according to types 6 and 7, 
respectively. A retrospective study of PROs in CD based on data from randomized controlled 
studies using rifaximin and methotrexate showed that a mean daily stool frequency score of 
≤1.5 had an area under the receiving operating characteristic curve of 0.79 (Khanna et al., 2015) 
and provided a potential cutoff for defining remission as measured by CDAI. In a recent study to 
select the attributes determining overall disease severity and to rank the importance of and to 
score these individual attributes for both CD and UC based on specialist opinion, a sample of at 
least 10 loose stools per week was considered as an attribute contributing to overall disease 
severity in CD (Siegel et al., 2016). Based on post hoc analyses of the Phase 2 data in the 
SHP647 program (Study A7281006, OPERA) and by choosing the population of subjects 
satisfying the moderate to severe CD inclusion criteria, various cutoffs were explored and a stool 
frequency ≤2.0 was found to be optimal in terms of treatment separation while still allowing for 
a reasonable threshold for remission. Based on these and other recent data that support this 
cutoff, an average daily stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) has been 
chosen as the stool frequency criterion for clinical remission. 
Endoscopic Response 
Endoscopic response is defined in 2 ways: 
• 25% reduction in SES-CD score (“endoscopic response”) 
• 50% reduction in SES-CD score (“enhanced endoscopic response”). 
“Endoscopic response” will be used as a coprimary endpoint and “enhanced endoscopic 
response” will be used as a key secondary endpoint in this study as these magnitudes of changes 
are likely to be clinically relevant. In the recent trial with upadacitinib, the magnitude of 
difference between the different doses of the active drug and placebo at Week 16 was reported to 
be 9-36% for endoscopic response and 10-20% for enhanced endoscopic response (Sandborn et 
al., 2017). In the post hoc analysis of the Phase 2 OPERA study with SHP647 the magnitude of 
difference between the active treatment arms and placebo showed a similar pattern (higher for 
the endoscopic response than for enhanced endoscopic response) (D’Haens et al., 2018). 
Mucosal healing or “endoscopic healing” is considered to be a pivotal long-term target in the 
treatment of CD; however, partial healing or endoscopic response may also provide benefits. 
Endoscopic response can be an important indicator that the mucosal inflammation has decreased 
as an effect of the investigational product. 
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Some treatments may result in a partial initial response, even though at a later stage a complete 
response may occur. Median duration of remission after 1 year treatment with infliximab was 
similar in subjects achieving complete absence of mucosal ulcer to subjects who achieved 
significant but incomplete mucosal healing (D'Haens et al., 2002). The benefit of endoscopic 
response was also shown in the SONIC study; the presence of endoscopic response (defined in 
that study as at least a 50% decrease in endoscopic score at Week 26 of treatment) identified 
subjects most likely to be in corticosteroid-free clinical remission at Week 50 (Ferrante et al., 
2013). The proportion of patients requiring major abdominal surgery in a single-center cohort 
study with infliximab was similar with complete healing or with partial healing. (Schnitzler et 
al., 2009; Panaccione et al., 2013). Subjects with such a treatment response should be identified 
by endoscopic assessment in order not to misclassify them as nonresponders and underestimate 
the response to the treatment. 
3.1.2 
Rationale for Key Secondary Endpoints 
Clinical Remission Defined by CDAI Score 
Conventionally, a CDAI score of <150 has been used to define clinical remission. While there 
has been widespread use of the CDAI over a long period of time, the items do not contribute 
equally to the score, and symptom items reported by subjects are not specific for CD and are not 
sensitive for inflammation seen at colonoscopy. There has been movement away from using the 
CDAI by regulatory authorities to the use of PROs and objective measures of disease such as 
endoscopy (Williet et al., 2014). However, for benchmarking or for comparative effectiveness 
purposes, CDAI endpoints are expected to be used. 
Although this has been the established gold-standard for clinical remission to date, CDAI suffers 
from requiring complex calculations across 8 individual items including subjective elements. 
Clinical Remission Defined by Average Daily Abdominal Pain ≤1 (Based on the 4-point Scale) 
and Average Daily Stool Frequency ≤3 of Type 6/7 
The CDAI has been the traditionally used measure to assess clinical response and clinical 
remission in CD. In the CDAI, the degree of abdominal pain is one of 8 variables and is used 
with a multiplier of 5 in the overall score. Importantly, it is based on a 4-point scale, with scores 
ranging from 0 (none) to 3 (severe). With the shift to the new endpoint as evident from the 
coprimary endpoint of clinical remission in this study, it is still important to allow for a frame of 
reference to the existing standard for response, based on the CDAI components. A daily average 
abdominal pain threshold of ≤1 will help achieve this as 1 on the 4-point scale corresponds to 
mild abdominal pain. Although direct mapping between the scales has not been established, this 
will approximate to a score of 3 on the 11-point NRS scale, as this falls within the mild pain 
range on the NRS based on the literature. 
Based on post hoc analyses of the Phase 2 data in the SHP647 program, regulatory requirements, 
and treatment separation assumptions, a threshold for the average daily stool frequency ≤2 of 
type 6/7 (very soft stools/liquid stools) was chosen for the coprimary endpoint of clinical 
remission. However, given the limited data available for this endpoint, recent evidence from 
literature suggesting that thresholds ≤3 are likely to be quite stringent (Sandborn et al., 2017), 
and the refractory nature of the disease in those with moderate to severe CD, it is also important 
to assess the effects of treatment using a more realistic measure. 
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Hence, for this key secondary endpoint of clinical remission, average daily stool frequency ≤3 of 
type 6/7 (very soft stools/liquid stools) has been chosen as the appropriate threshold. 
Clinical Response 
The goal of measuring clinical remission is to have a sensitive clinical measure to assess the 
complete absence of symptoms or the stabilization of noninflammatory symptoms. However, as 
response and remission are considered to be on a continuum of improvement or response to 
treatment, clinical remission is generally the chosen measurement over clinical response. 
Therefore, clinical remission is used as coprimary endpoint and clinical response is used as a 
key secondary endpoint in this study. 
Clinical response is defined in Section 9.8.2.1. For both clinical response criteria, an additional 
requirement is that the symptom not being used to assess clinical response (ie, abdominal pain 
severity or very soft stool/liquid stool frequency) must remain unchanged/not worsen from the 
baseline score, or meet the criteria for clinical remission for that item of the 2-item PRO (either a 
2-item PRO subscore of average daily stool frequency ≤2 of type 6/7 [very soft stools/liquid 
stools] as shown in the BSFS or average worst daily abdominal pain ≤3 [based on 11-point NRS] 
over the 7 most recent days). 
The rationale for needing to meet at a minimum clinical response definition for either abdominal 
pain severity or very soft stool/liquid stool frequency (and not necessarily both) is based on the 
supposition that a lack of improvement in 1 of these symptoms is not necessarily an indicator of 
eventual lack of response (as assessed by the stricter clinical remission criterion). Based on 
Phase 2 data, it has been observed that the magnitude of placebo response rate can be higher for 
abdominal pain than for stool frequency. Therefore, the additional criterion of at least a 2-point 
decrease in abdominal pain severity from baseline is required for assessing clinical response for 
abdominal pain. Overall, the definition of clinical response used for this study has been chosen to 
allow for the maximal pool of subjects to be assessed for the effect of treatment and, if 
appropriate, the continuation of therapy in the maintenance study (SHP647-307). 
Composite Score Endpoint of Both Clinical Remission by 2-item PRO and Endoscopic Response 
at Week 16 
In theory, as the degree of inflammation decreases due to the effect of treatment, both 
clinical signs and symptoms of CD as well as endoscopic appearance can improve. 
However, in any given subject, the rates of clinical improvement and endoscopic 
improvement may not be the same. There are reasons for this discrepancy when evaluating 
clinical and endoscopic improvement in the same time period, including clinical symptoms 
not being well correlated to the mucosal inflammation. Due to the transmural feature of the 
disease, symptoms can correspond to the inflammation in some of the other gut layers as 
well. Previous clinical studies and clinical observations indicate that the improvement of 
clinical signs and symptoms and the improvement in endoscopic appearance may not go hand 
in hand. Significant clinical improvement can precede significant endoscopic improvement. 
The healing process of the gut mucosa may take a long time and may depend on the baseline 
severity of the endoscopic appearance, which may not be in line with the actual baseline severity 
of the symptoms. 
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Therefore, when evaluating clinical remission together with endoscopic endpoints, improvement 
in endoscopic scores could be more relevant than evaluating mucosal healing in the induction 
phase. For these reasons, the key secondary composite endpoint (which takes into account both 
clinical and endoscopic response to treatment in the same subject) consists of the evaluation of 
the clinical remission together with the endoscopic response. 
Complete Endoscopic Healing 
Endoscopic healing will be defined in 2 ways: 
 •
Endoscopic healing defined by SES-CD ≤4 and at least a 2-point reduction versus 
baseline (Visit 2) and no subscore >1 in any individual variable 
 •
Complete endoscopic healing defined by SES-CD=0-2. 
There is no uniformly accepted definition for endoscopic healing in CD and several different 
terminologies are used to describe the same endoscopic appearance defined by a certain 
endoscopic score (eg, endoscopic remission and mucosal healing). Endoscopic healing or 
mucosal healing is predominantly defined by the absence of mucosal ulcerations in CD during 
endoscopic assessment of intestinal inflammation (Atreya and Neurath, 2017). The International 
Organization for the study of Inflammatory Bowel Disease technical review on endoscopic 
indices for CD clinical studies defined complete endoscopic healing as SES-CD=0-2 (Vuitton et 
al., 2016). Some studies introduced SES-CD ≤4 as “endoscopic remission”. The more stringent 
endpoint of “complete endoscopic healing” will be used as a key secondary endpoint in this 
study. Even in case of complete endoscopic healing, there may still be ongoing histological 
activity in many cases and it may not always reflect healing of all layers of the tissue, as 
endoscopy only addresses mucosal rather than transmural healing (Atreya and Neurath, 2017). 
The importance of inducing endoscopic healing is that it may be associated with long-term 
symptomatic remission; longer relapse-free interval; reduced frequency of hospitalizations, 
complications, and surgical resections; and the potential for a significant improvement in quality 
of life (Peyrin-Biroulet et al., 2011). 
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 16), if 
continuing to Study SHP647-307 or SHP647-304, or at the end of the safety follow-up period 
(Week 32), 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 38 weeks: a screening period of up to 6 weeks, a treatment period of 16 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. 
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3.3 
Sites and Regions 
It is anticipated that the study will be conducted in approximately 19 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 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 active moderate to severe ileal (terminal ileum), ileocolic, or colonic 
CD at baseline (Visit 2) as defined by: 
a. CDAI score between 220 and 450 (inclusive) AND 
b. Presence of ulcerations that are characteristic to CD, as determined by a 
colonoscopy performed during screening, and as defined by the SES-CD >6 
(SES-CD ≥4 for isolated ileitis) AND 
c. Meeting the following subscores in the 2-item PRO: 
i. Abdominal pain subscore ≥5 (average worst daily pain on the 11-point 
NRS) AND abdominal pain subscore ≥2 (average daily pain on the 4-point 
abdominal pain variable of CDAI) over the 7 most recent days out of the 
10 days before colonoscopy preparation (may or may not be contiguous) 
AND/OR 
ii. Average of the daily stool frequency subscore ≥4 of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days out 
of the 10 days before colonoscopy preparation (may or may not be 
contiguous). 
5. Subjects must have a documented diagnosis (endoscopic with histology) of CD for 
≥3 months before screening. Documented diagnosis is defined as: 
• A biopsy report to confirm the histological diagnosis AND 
• A report documenting disease duration based upon prior colonoscopy. 
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Note: If a biopsy report is not available in the source document at the time of screening, 
a biopsy must be performed during the screening colonoscopy and the histology report 
should be consistent with the CD diagnosis. If the histology diagnosis is not clear at this 
time point, the subject should not be randomized. 
6. Subjects must be willing and able to undergo a colonoscopy during screening after all 
other inclusion criteria have been met. 
7. 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 mesalamine 
(5-ASA), glucocorticoids, immunosuppressants (AZA, 6-MP, or MTX), or anti-TNF 
(refer to Appendix 4 for guidance). Subjects who have had an inadequate response to 
sulfasalazine or mesalamine should have also failed at least 1 other conventional 
treatment such as glucocorticoids. 
8. Subjects receiving any treatment(s) for CD 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. 
9. 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 ulcerative colitis. 
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 presence of enterovesical (ie, between the bowel and urinary bladder) or 
enterovaginal fistulae. 
5. Subjects with current symptomatic diverticulitis or diverticulosis. 
6. Subjects with obstructive 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 CD during the treatment period. 
7. Subjects with past medical history of multiple small bowel resections resulting in 
clinically significant short bowel syndrome. 
8. Subjects requiring total parenteral nutrition. 
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9. Subjects with past medical history of bowel surgery resulting in an existing or current 
stoma. Subjects who had a j-pouch are excluded as a j-pouch could result in a stoma. 
10. Subjects have had prior treatment with SHP647 (formerly PF-00547659). 
11. Subjects with known or suspected intolerance or hypersensitivity to the investigational 
product(s), closely related compounds, or any of the stated ingredients. 
12. Subjects have received any nonbiologic treatment with immunomodulatory properties 
(other than AZA, 6-MP, or MTX) or continuous antibiotics (>2 weeks) for the treatment 
of CD within 30 days before baseline (Visit 2). 
13. Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2). 
14. Subjects have received any biologic with immunomodulatory properties (other than 
anti-TNFs) within 90 days before baseline (Visit 2). 
15. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, 
vedolizumab, efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion 
molecule). 
16. Subjects have received lymphocytes apheresis or selective monocyte granulocytes 
apheresis within 60 days before baseline (Visit 2). 
17. Subjects have received enteral nutrition treatment within 30 days before 
baseline (Visit 2). 
18. Subjects have received parenteral or rectal glucocorticoids or rectal 5-ASA within 
14 days before screening colonoscopy. 
19. Subjects have taken >20 mg/day of prednisone or equivalent oral systemic corticosteroid 
dose within 14 days before baseline (Visit 2) or have taken ≥40 mg/day of prednisone or 
equivalent oral systemic corticosteroid dose within 6 weeks before baseline (Visit 2). 
20. 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 
screening (Visit 1). 
21. Subjects have received a live (attenuated) vaccine within 30 days before 
baseline (Visit 2). 
22. 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 retest 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 baseline (Visit 2). 
23. Subjects with abnormal chest x-ray or other imaging findings at screening (Visit 1), such 
as presence of active tuberculosis (TB), general infections, heart failure, or malignancy. 
(A chest x-ray, computed tomography scan, etc., 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). 
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24. 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 baseline (Visit 2) 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 baseline (Visit 2). 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 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. 
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. 
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• A chest x-ray performed within 3 months before 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. 
25. 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. 
26. Subjects with any unexplained symptoms suggestive of progressive multifocal 
leukoencephalopathy (PML) based on the targeted neurological assessment during the 
screening period (Section 7.2.3.3). 
27. Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are 
allowed. 
28. 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). 
29. Subjects who have had significant trauma or major surgery within 4 weeks before 
screening (Visit 1), or with any major elective surgery scheduled to occur during the 
study. 
30. Subjects with evidence of cirrhosis with or without decompensation (ie, esophageal 
varices, hepatic encephalopathy, portal hypertension, ascites).  
31. Subjects with primary sclerosing cholangitis. 
32. 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. 
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33. Subjects with chronic hepatitis C (HCV) (positive HCVAb and hepatitis C ribonucleic 
acid [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]). 
34. Subjects with any of the following abnormalities in hematology and/or serum chemistry 
profiles during screening (Visit 1). 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 colonoscopy procedure. 
• Alanine aminotransferase and aspartate aminotransferase levels ≥3 × 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/1.73m2 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. 
35. 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. 
36. 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 of any kind 
including abuse of medicinal marijuana (cannabis). 
37. 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. 
38. Female subjects who are planning to become pregnant during the study period. 
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39. 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. 
40. 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 
• 
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 (Section 5.2). 
• 
Smoking is considered to be a risk factor for CD. Reports have shown that smoking is not 
only related to the onset, relapse, and exacerbation of CD, but also that smoking cessation 
lowers the postoperative recurrence rate (Ueno et al., 2013). Subjects should inform the 
investigator of any changes to their smoking habits during the study (including starting or 
stopping smoking). Use of nicotine patches should be recorded as concomitant 
medication (Section 5.2.1). 
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. 
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 one 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. 
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4.4.1 
Contraceptive Methods for Female Study Subjects 
Sexually active females of childbearing potential must already be using a 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 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Male sterilization/vasectomized partner with documented absence of sperm in the 
postvasectomy ejaculate 
• 
True abstinence (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. 
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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 16/early termination (ET) (Visit 7) 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: 
• 
AEs 
• 
SAEs 
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• 
Pregnancy  
• 
Protocol violations 
• 
Failure to return for visits. 
A subject should be withdrawn from study treatment: 
• 
If a new therapy is initiated for CD, or 
• 
If a subject undergoes surgery for CD. 
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: 
• 
AE 
• 
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 one 
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 CD during the 90 days 
before screening must also be recorded. 
All prior and concomitant CD-specific treatments will be recorded. The subject’s entire history 
of biologic CD-specific treatments will be recorded. 
Subjects must have had an inadequate response to, or lost response to, or had intolerance to at 
least 1 conventional treatment such as sulfasalazine or 5-ASA, glucocorticoids, 
immunosuppressants (AZA, 6-MP, or MTX), or anti-TNF agents (Lichtenstein et al., 2018). 
Please refer to Appendix 4 for guidance on defining prior treatment failure and intolerance to 
prior treatment for CD. 
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 of this study, inclusive. 
5.2.1 
Permitted Treatment 
Subjects must remain on stable doses of permitted CD treatments until completion of the 
Week 16 visit, unless decreases are required because of AEs. Stable doses of the following 
treatments for CD are permitted as concomitant medication: 
• 
Oral sulfasalazine or 5-ASA, 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 [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 baseline (Visit 2). After baseline (Visit 2), a stable dose of 
20 mg/day prednisone or equivalent oral systemic corticosteroid dose is allowed. Steroids 
may be decreased due to AEs. 
Note: Rectal 5-ASA and parenteral or rectal glucocorticoids are prohibited from within 14 days 
before screening colonoscopy. 
Antidiarrheal opiate drugs such as IMODIUM® (loperamide), LOMOTIL® (diphenoxylate 
hydrochloride and atropine sulfate), tincture of opium, and codeine will be recorded as 
concomitant medications. Subjects must be using such products in a stable regimen for at least 
2 weeks before randomization at baseline (Visit 2). Reported use of any antidiarrheal opiate 
medicines will assist the investigator response to Question 5 of the CDAI. Reported use of 
antidiarrheal opiate medicines will assist the investigator response to Question 5 of the CDAI. 
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Antidiarrheal opiate drugs must be taken at stable doses for the duration of the study unless dose 
reduction or discontinuation is required due to clinical improvement of AE. However, escalations 
of the dose after dose reduction or re-initiation after drug discontinuation are not allowed (see 
Section 5.2.3).  
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-containing preparations should be recorded as concomitant medication. 
Antibiotics are permitted, with the exception of antibiotics used to treat the underlying disease or 
any continuous antibiotic treatment exceeding 2 weeks within 30 days before starting PRO-CD 
daily e-diary data collection in the screening period or before Week 16 (Visit 7, Part 1). 
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 
 
Excluded 
without any 
timeframe 
Minimum Required Number of Days Before 
Baseline (Visit 2) 
Treatment 
 
14 days 
30 days 
60 days 
90 days 
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 
propertiesc 
 
 
X 
 
 
Anti-TNF treatment 
 
 
 
X 
 
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Table 2: 
Common Excluded Treatments 
 
Excluded 
without any 
timeframe 
Minimum Required Number of Days Before 
Baseline (Visit 2) 
Treatment 
 
14 days 
30 days 
60 days 
90 days 
Lymphocytes apheresis or selective monocyte 
granulocytes apheresis 
 
 
 
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 colonoscopy (Section 4.2, exclusion criterion 18). 
 
b Or 5 half-lives if longer. 
 c Usage of immunosuppressants, eg used in transplantation or in autoimmune diseases that are not established therapies for CD 
(eg, mycophenolate mofetil, cyclosporine, rapamycin, thalidomide, tofacitinib, or tacrolimus). 
 
Treatments not listed in Table 2 may be considered allowable; see Section 5.2.1 for further 
details. 
In addition to the treatment listed in Table 2, the following common treatments are excluded 
medications for this study: 
• 
Prednisone dose >20 mg/day, budesonide >9 mg/day, or other equivalent oral systemic 
corticosteroid dose 
• 
Bismuth subsalicylate products 
• 
Fecal microbiota transplantation. 
No new nonpharmacological therapies that might affect bowel habit or GI function should be 
started during the study. 
Enteral nutrition is not permitted from within 30 days of baseline (Visit 2) or at any time during 
the study. 
5.2.3 
Rescue Therapy 
Subjects must maintain their stable dose of background CD 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 CD above the SHP647-305 or SHP647-306 baseline (Visit 2), 
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 (Visit 2) and treatment periods. High-dose 
glucocorticoids and other CD 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 (a fully human IgG2k antihuman MAdCAM monoclonal antibody), 
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 mg or 75 mg). Additional information is 
provided in the current SHP647 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 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 Products 
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. 
Eligible subjects will be randomized in a ratio of 3:3:2 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), glucocorticoid use at baseline (2 strata: on glucocorticoids at 
baseline versus not on glucocorticoids at baseline), and SES-CD at baseline (2 strata: 
SES-CD ≥17 at baseline versus SES-CD <17 at baseline). 
To ensure that the allocation of subjects with prior anti-TNF therapy exposure is similar to that 
observed in previous studies, the percentage of subjects with prior exposure to treatment with 
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. 
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. 
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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. 
6.2.3 
Dosing 
Investigational product (SHP647 or placebo) will be administered subcutaneously by qualified 
site personnel Q4W (Weeks 0, 4, 8, and 12). 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 (SHP647-305 or SHP647-306) 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. 
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. 
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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 United States [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 
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. 
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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. 
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. 
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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 (unplanned visits) in addition to those listed on the schedule 
of assessments (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 first dose of investigational product 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 will take place over more than 1 day (at least 2 visits will be necessary to 
complete the screening evaluations, including colonoscopy). 
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 one 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 only. 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 before the screening colonoscopy procedure. 
Hematology samples should be repeated if more than 3 weeks have elapsed before the day of 
colonoscopy to be able to use the hematocrit central laboratory results for the CDAI score 
calculation at screening. Hematocrit must not be older than 3 weeks before the day of 
colonoscopy. 
Collection of the daily e-diary data must begin at least 10 days before colonoscopy preparation. 
Colonoscopy preparation will be according to local routine. 
Colonoscopy must be performed on all subjects after the majority of other eligibility criteria 
(eg, laboratory values and 2-item PRO and CDAI scores) are met. It must be performed during 
the screening period within 5 to 7 days before baseline (Visit 2), to allow for adequate e-diary 
data collection for the 2-item PRO and CDAI scores and to obtain the centrally read endoscopic 
subscore to verify the subject’s eligibility (Section 7.2.2.4). If the calculated CDAI scores is 
<220 or >450, the subject will be considered a screen failure and should not proceed with the 
colonoscopy preparation and/or the colonoscopy. All colonoscopies will be evaluated using the 
SES-CD (Appendix 2). 
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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 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 (Visit 2) 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 receive 1 of the 3 treatments 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 
Visits 3, 4, 5, and 6 (Weeks 2, 4, 8, and 12) 
Visits 3, 4, 5, and 6 are scheduled to take place on Day 14 ±3 days (Week 2), Day 28 ±3 days 
(Week 4), Day 56 ±3 days (Week 8), and Day 84 ±3 days (Week 12), respectively. The 
assessments and procedures specified in Table 1 will be performed. 
7.1.2.2 
Final On-treatment Visit: Visit 7, Parts 1, 2, and 3 
(Week 16/Early Termination) 
The Week 16/ET visit (Visit 7) consists of 3 parts. 
Part 1 of Visit 7 should be scheduled 1 to 3 day(s) before Part 2; this will allow for blood 
samples to be taken before starting the colonoscopy preparation and before the colonoscopy 
procedure at Part 2 of the visit. The Week 16/ET assessments and procedures that will take place 
during Part 1 are specified in Table 1. 
Part 2 of Visit 7 should be scheduled preferably within 5 to 7 days before Part 3; this will allow 
sufficient time to obtain the data from the centrally read colonoscopy. The Week 16/ET 
assessments and procedures that will take place during Part 2 are specified in Table 1. 
Part 3 of Visit 7 will take place on Day 112 ±3 days. The Week 16/ET assessments and 
procedures that will take place during Part 3 are specified in Table 1. 
At Part 3 of Visit 7, after review of CD assessments, health outcome assessments, and safety 
assessments, it will be determined whether the subject should enroll in the maintenance 
(SHP647-307) or LTS (SHP647-304) studies or enter the follow-up period of this study. Entry 
into the maintenance or LTS studies is dependent upon whether the subject fulfills the efficacy 
entry criteria of the maintenance study (SHP647-307), including achieving endoscopic and/or 
clinical response, and whether the subject agrees to participate. 
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The Week 16 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 
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 period for safety monitoring. 
During the safety follow-up period, the Week 24 visit (Visit 8) will take place on 
Day 168 ±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 224 ±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; this visit will form the Week 32 visit (Visit 9). The assessments 
and procedures specified in Table 1 will be performed, including querying for SAEs, AEs, and 
concomitant medications and treatments. All AEs and SAEs that are not resolved at the time of 
this visit will be followed to closure (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 wellbeing 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 
• Investigational product administration 
• Colonoscopy is performed at a separate visit (Section 7.2.2.4). 
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 screening (Visit 1). 
7.2.2 
Efficacy 
7.2.2.1 
Patient-reported Outcome – Crohn’s Disease Daily E-diary 
Patient-reported CD clinical signs and symptom data will be collected daily using a PRO-CD 
daily e-diary (electronic handheld device) starting during the screening period; however, 
collection of the daily e-diary data must begin at least 10 days before colonoscopy preparation. 
Subjects will enter data on CD signs and symptoms items using the e-diary, which will be 
provided to subjects at the start of the study. Compliance will be assessed by site staff at each 
visit. The site staff will instruct the subject on the appropriate use of the e-diary when 
compliance is below 80% (eg, <23 out of 28 e-diary entries). If 70% compliance cannot be 
achieved after repeated instructions during the screening period, noncompliant subjects will be 
automatically noneligible as they will not fulfill inclusion criterion 1 (Section 4.1). 
Subjects will be asked to record the following signs and symptom data, as experienced over the 
previous 24 hours, in the e-diary: 
• 
Abdominal pain severity (NRS) 
• 
Very soft stool/liquid stool frequency (as shown by BSFS type 6/7) 
• 
Total stool frequency 
• 
Rectal bleeding frequency 
• 
Rectal urgency frequency 
• 
Nausea severity 
• 
Vomiting frequency 
• 
Incontinence frequency 
• 
Abdominal pain used in CDAI 
• 
General wellbeing. 
The first 2 items (abdominal pain severity and very soft stool/liquid stool frequency) will be used 
to calculate the 2-item PRO. The 2-item PRO will be calculated using the following criteria: 
• 
Screening: the 2-item PRO will be calculated based on the 7 most recent days during the 
10 days of data collection before the colonoscopy preparation. If 7 out of the 10 most 
recent days are not available, then the 2-item PRO cannot be calculated for the subject at 
screening. 
• 
Visits 3, 4, 5, and 6: the 2-item PRO will be calculated based on the 7 most recent days 
during the 10 days of data collection before the visit. If fewer than 7 days are available, 
the 2-item PRO will be calculated on all available most recent 6 or 5 days. If fewer than 
5 days are available, the 2-item PRO will be treated as missing. 
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• 
Visit 7 (Part 3): the 2-item PRO will be calculated based on the 7 most recent days during 
the 10 days of data collection before the colonoscopy preparation. If fewer than 7 days 
are available, the 2-item PRO will be calculated on all available most recent 6 or 5 days. 
If fewer than 5 days are available, the 2-item PRO will be treated as missing. 
For all 2-item PRO calculations, the 7 most recent days may or may not be contiguous during the 
10 days of data collection depending on days to be excluded because of missing data. 
The PRO-CD daily e-diary is presented in Appendix 2. 
7.2.2.2 
Simple Endoscopic Score for Crohn’s Disease 
The SES-CD will be performed at the time points specified in Table 1. The SES-CD score at 
baseline (Visit 2) and at Week 16/ET will be calculated using subscores of each of the segments 
investigated and centrally read from the colonoscopies performed at screening (Visit 1, Part 2) 
and Week 16 (Visit 7, Part 2), respectively. 
The SES-CD is a simple scoring system based on 4 endoscopic variables (presence and size of 
ulcers, proportion of surface covered by ulcers, proportion of affected surface, and presence and 
severity of stenosis [narrowing]) measured in the same 5 ileocolonic segments as the CD index 
of severity. Overall, values on the SES-CD range from 0 to 56, with higher values indicating 
more severe disease. The 4 endoscopic variables are scored from 0 to 3 in each bowel segment 
(ileum, right/transverse/left colon, and rectum): 
• 
Presence and size of ulcers (none = score 0; diameter 0.1–0.5 cm = score 1;  
0.5–2 cm = score 2; diameter >2 cm = score 3) 
• 
Extent of ulcerated surface (none = 0; <10% =1; 10%–30% = 2; >30% = 3); extent of 
affected surface (none = 0; <50% = 1; 50%–75% = 2; >75% = 3) 
• 
Presence and type of narrowings (none = 0; single, can be passed = 1; multiple, 
can be passed = 2; cannot be passed = 3). 
A complete colonoscopy is required (including visualization of the terminal ileum). 
The maximum stenosis score in a segment distal to another evaluable segment cannot exceed 2, 
so that the stenosis scores cannot exceed a total of 11 (Reinisch et al., 2017). 
Evidence of active inflammation and ulceration is required at screening (Visit 1), in the form of a 
centrally read score of at least 1 in one or more ileocolonic segments in the Presence of Ulcers 
component of the SES-CD, as well as a total score of >6. 
Study videos will be scored separately by 2 central readers who are blinded to the treatment. 
If the central readers’ scores are not in agreement, there will be a third adjudication read to select 
the correct read from the first 2 scores. Results of the central reading of the videos will be 
communicated to sites within 5 business days. 
For the evaluation of efficacy, in cases where 1 or 2 segments cannot be fully evaluated by 
central endoscopic readers, ileocolonic segments that are evaluable during screening (Visit 1) 
and Week 16/ET (matching segments approach) will be utilized. 
The SES-CD is presented in Appendix 2. 
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7.2.2.3 
Crohn’s Disease Activity Index 
The CDAI is a composite measure with 8 components; 3 components (abdominal pain severity, 
very soft stool/liquid stool frequency, and general wellbeing) will be self-reported by the subject 
and will be recorded as part of the daily e-diary, as described in Section 7.2.2.1 and 
5 components will be recorded at the time points specified in Table 1. 
The CDAI score at screening (Visit 1, Part 2) will be calculated using the following: 
• 
Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected >10 days 
before the start of colonoscopy preparation using the same most recent 7 of 10 days as 
described for the 2-item PRO (Section 7.2.2.1) and 
• 
Components 4 to 8 (weight, medical and physical examination, use of diarrhea treatment, 
and hematocrit value) collected during screening (Visit 1) Part 1. Note: Hematology 
samples should be repeated if more than 3 weeks have elapsed before the day of 
colonoscopy to be able to use the hematocrit central laboratory results for the CDAI score 
calculation at screening. Hematocrit must not be older than 3 weeks before the day of 
colonoscopy. 
The CDAI scores at Visits 4, 5, and 6 will be calculated using the following: 
• 
Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected >10 days 
before the visit using the same most recent 7 or 10 days as described for the 2-item PRO 
(Section 7.2.2.1) and 
• 
Components 4 to 8 (weight, medical and physical examination, use of diarrhea treatment, 
and hematocrit value) collected at the visit. 
The CDAI score at the Week 16/ET visit will be calculated at Visit 7, Part 3 (after all evaluations 
are complete), using the following: 
• 
Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected >10 days 
before the start of colonoscopy preparation using the same most recent 7 or 10 days as 
described for the 2-item PRO (Section 7.2.2.1) and 
• 
Components 4 to 8 (weight, medical and physical examination, use of diarrhea treatment, 
and hematocrit value) collected at Part 1 and Part 3 of the Week 16/ET visit, where 
assessed. 
Change in CDAI has been used as a primary endpoint in multiple pivotal studies in the CD 
indication. The algorithm for calculating the CDAI score was first published by William Best 
and colleagues (Best et al., 1976). 
The CDAI is presented in Appendix 2. 
7.2.2.4 
Colonoscopy and Histology 
Colonoscopy will be performed at the time points specified in Table 1. 
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Bowel preparation regimens typically incorporate dietary modifications along with oral 
cathartics. Typically, the standard dose of a bowel preparation is split between the day before 
and the morning of the procedure. In this study, bowel preparation and colonoscopy are to be 
conducted per local routine; however, sodium phosphate based preparations should be avoided, 
as such regimens can produce mucosal changes that mimic IBD. 
In general, a complete colonoscopy should be performed; this includes visualization of the 
rectum, sigmoid colon, left colon, transverse colon, right colon, ileocecal valve, and the terminal 
ileum. At screening, an incomplete colonoscopy will not be accepted; only a few exceptions will 
be evaluated on a case by case basis (eg. presence of impassable narrowing without any clinical 
signs of bowel obstruction and when the same time the investigated segments provide the 
SES-CD score required for inclusion). Similarly, a complete colonoscopy is the aim at 
Week 16/ET, with the exception of the presence of impassable stenosis or other CD-related 
complications as cause of failure to complete the colonoscopy procedure. 
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 colonoscopy. 
To achieve consistency in capturing and assessing endoscopic video recordings, each 
participating site will use an integrated hardware/software solution and associated tools for the 
capture and transmission of endoscopy video recordings for central reading. Nonreadable 
endoscopic images, as assessed by the investigator, should not be sent for central reading. The 
colonoscopy 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 the colonoscopy at screening (Visit 1, Part 2) and Week 16/ET, 10 biopsies will be 
collected from the most inflamed area of the mucosa: 2 samples each from the ileum, the 
3 segments of the colon, and the rectum. Colonoscopy and biopsy procedures will be defined in a 
colonoscopy instructions manual and/or reference card(s), on which all sites will be trained. 
Colonoscopy results will be reviewed by a central reader. 
 
(
). Biopsies for conventional histologic assessment will be collected in formalin and 
Appendix 2
shipped to the central laboratory. The central laboratory will register all biopsies and create 
paraffin blocks. Blocks will be batched and shipped on an agreed schedule to specialty 
laboratory, where tissue processing (sectioning, hematoxylin and eosin staining, and affixation to 
glass slides), digitalization, and uploading of images will occur. All images for a subject will be 
scored by the same qualified central pathologists blinded to the subject and treatment sequence 
information, according to the scoring modality. 
7.2.3 
Safety 
7.2.3.1 
Medical and Medication History 
Medical history will be documented at screening (Visit 1), including CD history, cardiac history, 
and smoking history. Prior and concomitant medications and procedures will also be documented 
at the time points specified in Table 1. 
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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; 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 and 
mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, 
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, neurological examination(s), 
targeted to the abnormal domain, will be performed by the investigator or qualified personnel. 
Subjects with any unexplained positive neurological assessment item at screening that is 
suggestive of PML should be excluded from enrollment in the study (exclusion criterion 25, 
Section 4.2). 
The neurological assessment plan is summarized in Table 3. 
Table 3: 
Neurological Assessment Plan 
Domain 
Step 1: Targeted Neurological 
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 
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Table 3: 
Neurological Assessment Plan 
Domain 
Step 1: Targeted Neurological 
History 
Step 2: If Abnormal Response 
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 7s, 
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 study or the defined follow-up period stated in Section 7.1.3 (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. 
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. 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. 
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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 reflex testing if HBsAg is 
negative and HBcAb is positive 
• 
hepatitis C virus antibody (HCVAb) 
• 
HCV ribonucleic acid polymerase chain 
reaction 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 electronic case report form (eCRF) database. 
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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 the 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 baseline (Visit 2) is 
acceptable provided that an IGRA official reading and method or test is located in the source 
documentation. 
A serum sample will be collected and banked for John Cunningham virus antibody testing at 
baseline (Visit 2). It may be analyzed if a subject shows neurological 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. 
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, will confirm 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. 
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7.2.3.10 
Antidrug Antibodies and Neutralizing Antibodies 
A blood sample for measurement of 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 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 CD. The IBDQ consists of 
32 items, which are grouped into 4 domains: bowel, systemic, emotional, and social function 
(Irvine et al., 1994). The 4 domains are scored as follows: 
• 
Bowel function: 10 to 70 
• 
Systemic function: 5 to 35 
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• 
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. 
 
 
 
 
 
The 
 is presented in Appendix 2. 
 
 
 
The 
 and 
 are presented in Appendix 2. 
 
 
 
 
Short Form-36 Health Survey (Version 2, 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. 
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7.2.4.4 
Healthcare Resource Utilization Assessments 
Hospitalizations, inpatient days, and 
 will be recorded at the time points specified in 
Table 1. Information regarding Crohn’s disease-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 
The volume of blood to be drawn from each subject is summarized in Table 4. 
Table 4: 
Volume of Blood to Be Drawn From Each Subject 
Assessment 
Sample Volume (mL) 
Number of Samples 
Total Volume (mL) 
Hematology 
2 
7 
14 
Serum chemistry 
6 
7 
42 
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 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 
 
 
3 
6 
18 
ADA and NAb sampling 
3 
7 
21 
Total (mL) 
153.5 
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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) 
Ab=antibody; ADA=antidrug antibodies; β-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 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 153.5 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 
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 if the investigator considers such symptoms of disease progression related to 
the investigational product. 
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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 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 Nonserious 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 
Nonserious 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 β-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. 
8.1.8 
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. 
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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. 
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 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 (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 Nonserious 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 the Shire Global Drug Safety 
Department. A copy of the Shire Clinical Study Serious Adverse Event and Nonserious 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 
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. 
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• 
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 one 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. 
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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 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 48-72 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 (SHP647-305 or SHP647-306) 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≥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 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 ≥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 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 ≥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 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 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 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 2-3 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® software Version 9.3 or higher 
(SAS Institute Inc, Cary, NC, US). 
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, and Data Monitoring Committee 
A planned interim analysis for the coprimary endpoints will take place after approximately the 
first 50% of all randomized subjects in both the SHP647-305 and SHP647-306 studies have 
either completed the studies or have prematurely withdrawn from the studies. Recruitment will 
not pause for this interim analysis. The purpose of the unblinded interim analysis is to reassess 
the appropriateness of the premises used for the coprimary endpoints when the study was 
designed. There is no possibility to stop early for overwhelming efficacy as the studies must 
continue in order to enroll an appropriate number of subjects in the SHP647-307 study. The 
reassessment of sample size will be performed using conditional power methods. Results at the 
interim analysis may be futile for one or both of the SHP647 doses and lead to the 
discontinuation of that dose for CD or the SHP647 CD program. Full details of the interim 
analysis, the guidelines for increasing the sample size, and futility rules to stop a dose will be 
included in a prespecified interim analysis SAP. The interim analysis SAP will be finalized 
before the interim analysis is conducted. 
The planned interim analysis will be conducted by an external independent statistical group and 
given to the independent Interim Analysis Review Committee; the individuals involved in the 
day-to-day conduct of the study will not be involved in the interim analysis nor have access to 
the results of the interim analysis. The sponsor will only be notified by the Interim Analysis 
Review Committee of recommendations to modify the SHP647 CD program according to the 
guidelines specified in the interim analysis SAP. 
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). 
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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 coprimary endpoints. 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 to 
placebo. 
Power calculations are made based on assuming a .025 (2-sided) significance level for each 
pairwise treatment comparison, 1720 subjects will be screened to randomize 1032 subjects in a 
3:3:2 allocation ratio: 387 subjects in the 25 mg SHP647 treatment group, 387 subjects in the 
75 mg SHP647 treatment group, and 258 subjects in the placebo group. These numbers of 
subjects would yield an approximately 93% power to detect individual pairwise treatment 
difference in the first coprimary efficacy endpoint, clinical remission by 2-item PRO at Week 16, 
of 10% (17.5% SHP647 versus 7.5% placebo). Expected clinical remission rates by 2-item PRO 
at Week 16 are based on observed rates from a post hoc analysis of the A7281006 study and 
placebo remission rates from literature (Sandborn et al., 2017). No adjustment for missing data is 
required in these sample size calculations as subjects with missing data for clinical remission by 
2-item PRO at Week 16 are imputed as failures and the above rates account for these subjects. 
With the 1032 subjects in allocation noted above, this number of subjects would yield an 
approximately 94% power to detect individual pairwise treatment difference in the other 
coprimary efficacy endpoint, endoscopic response at Week 16, of 12.5% (27.5% SHP647 versus 
15% placebo). Expected endoscopic response rates at Week 16 are based on observed rates from 
a post hoc analysis of the A7281006 study and also endoscopic response rates from literature 
(Sandborn et al., 2017). No adjustment for missing data is required in these sample size 
calculations as subjects with missing data for endoscopic response at Week 16 are imputed as 
failures and the above rates account for these subjects. 
The overall power for the coprimary endpoints will be approximately 87% assuming no 
correlation between the tests on the endpoints and approximately 90% assuming a correlation of 
0.4. 
With the sample size of 1032 subjects, Table 6 provides the power for detecting a treatment 
difference between a SHP647 treatment group and the placebo group for the key secondary 
endpoints. 
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Table 6: 
Power to Detect the Corresponding Treatment Effect for Key Secondary 
Endpoints 
Key Secondary Endpoint at Week 16 
SHP647 Premise 
Placebo Premise 
Power 
Clinical remission by CDAI 
26.5% 
15% 
0.90 
Enhanced endoscopic response 
25% 
13% 
0.94 
Clinical remission by abdominal pain 
≤1 and stool frequency ≤3 
24% 
14% 
0.81 
Clinical response by 2-item PRO 
52.5% 
40% 
0.81 
Clinical remission by 2-item PRO and 
endoscopic response 
11% 
4.5% 
0.77 
Complete endoscopic healing 
6% 
2% 
0.58 
CDAI=Crohn’s Disease Activity Index; PRO=patient-reported outcome. 
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 set will consist of all subjects in the FAS who do not have protocol deviations 
that may affect the coprimary efficacy endpoints. 
The completer set will consist of all subjects in the FAS who have completed the Week 16 
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 
Coprimary Efficacy Endpoints 
The coprimary efficacy endpoints are: 
• Clinical remission at the Week 16 visit as defined by the following: 2-item PRO 
subscores of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the 
7 most recent days and average daily stool frequency ≤2 of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent 
days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. 
If fewer than 7 days are available, the endpoint will be calculated on all available most 
recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as 
missing. 
• Endoscopic response at Week 16 as measured by a decrease in SES-CD of at least 25% 
from baseline. 
The coprimary efficacy endpoints, clinical remission at the Week 16 visit and endoscopic 
response at the Week 16 visit, will each 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, glucocorticoid use, and SES-CD at baseline for 
each of the stages of the study (stage 1 includes subjects whose primary efficacy data are used in 
the interim analysis and stage 2 includes all other subjects. Note: classification of stage 1 and 
stage 2 is based on the time of randomization rather than the time of study completion or 
termination). Subjects with missing data at the Week 16 visit will be considered failures and 
counted as nonresponders. 
Weighted inverse normal p-value combination methods are used to combine the p-values from 
stage 1 and stage 2 through the following formula: 
C(p1, p2) = 1 – Φ[w1 Φ-1(1-p1)+ w2 Φ-1(1-p2)] 
Where p1, p2 are the p-values computed from the CMH chi-square test for each stage, 
wi
2 = ni/(n1 + n2), n1 and n2 are the preplanned stage-wise sample sizes that are fixed at the time of 
the interim analysis based on an original total sample size, and Φ denotes the cumulative 
distribution function of the standard normal distribution (Bretz et al., 2009a). Given that there is 
no possibility of stopping early for efficacy, that any potential stopping for futility of either or 
both doses of SHP647 is nonbinding, and that weights are prespecified, the test statistic C(p1, p2) 
can be compared against the nominal alpha level to assess statistical significance (Chang and 
Chow, 2008). 
The coprimary endpoints will each be tested by the following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
Where δ is the common treatment difference across strata. 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 the p-value computed from the 
p-value combination method will be presented for each active treatment group to placebo 
comparison for each endpoint. 
Sensitivity analyses to explore the impact of missing data on the coprimary efficacy endpoints 
and key secondary endpoints 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 coprimary endpoints including, but not 
limited to gender, prior anti-TNF treatment, glucocorticoid use at baseline, SES-CD at baseline, 
region, age group, randomization stratum, and other important subgroups. A full list of important 
subgroups will be described in 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. The estimate of the treatment difference, along with the corresponding 
Newcombe (hybrid-score) 95% CI and chi-square test p-value, will be presented. 
Statistical Testing and Protection of the Type I Error 
The global FWER for the statistical tests of the coprimary and key secondary endpoints will be 
strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in 
Bretz et al. (2009b) will be utilized to propagate α from the coprimary endpoints to the 
key secondary endpoints and between the 2 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 coprimary endpoints (P) and alpha is propagated in a hierarchical manner to 
each of the 6 key secondary endpoints (K1–K6) within a pairwise treatment comparison. In order 
to pass alpha between the coprimary endpoints and the first key secondary endpoint, both 
coprimary endpoints must attain statistical significance. A graphical visualization of the 
α propagation is presented in Figure 4. 
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Figure 4: Visualization of Multiple Testing Strategy 
 
K=key secondary endpoint; P=coprimary endpoints. 
 
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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 Endpoints 
The key secondary efficacy endpoints are as follows: 
• Clinical remission at the Week 16 visit as measured by a CDAI score of <150. 
• Enhanced endoscopic response at Week 16 as measured by a decrease in SES-CD of at 
least 50% from baseline. 
• Clinical remission at the Week 16 visit as defined by the following: 2-item PRO 
subscores of average daily abdominal pain ≤1 (based on the 4-point scale) over the 
7 most recent days and average daily stool frequency ≤3 of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent 
days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. 
If fewer than 7 days are available, the endpoint will be calculated on all available most 
recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as 
missing. 
• Clinical response at the Week 16 visit as measured by the 2-item PRO and defined as 
meeting at least 1 of the following 2 criteria: 
 
o
A decrease of ≥30% and at least 2 points from baseline in the average daily worst 
abdominal pain over the 7 most recent days*, with the average daily stool frequency 
of type 6/7 (very soft stools/liquid stools) either: 
(a) Not worsening from baseline 
and/or 
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average 
daily stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the 
BSFS over the 7 most recent days* 
 
o
A decrease of ≥30% from baseline in the average daily stool frequency of type 
6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days*, 
with the average daily worst abdominal pain either: 
(a) Not worsening from baseline 
and/or 
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average 
worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days* 
*Note: The 7 most recent days may or may not be contiguous during the 10 days of 
data collection before colonoscopy preparation, depending on days to be excluded 
because of missing data. If fewer than 7 days are available, the endpoint will be 
calculated on all available most recent 6 or 5 days. If fewer than 5 days are available, 
the endpoint will be treated as missing. 
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• Clinical remission with endoscopic response, ie, both clinical remission by 2-item PRO 
and endoscopic response, as measured by a decrease in SES-CD of at least 25% at 
Week 16 (composite endpoint) 
• Complete endoscopic healing at Week 16 defined as SES-CD=0-2. 
Similar to the coprimary endpoints, the 6 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 
coprimary endpoints. Subjects with missing key secondary endpoint data at the Week 16 visit 
will be considered failures and counted as nonresponders. 
9.8.2.2 
Other Secondary Efficacy Endpoints 
The other secondary endpoints are as follows: 
• Clinical response at the Week 16 visit as measured by at least a 100-point reduction in the 
CDAI from baseline (CDAI-100 response) 
• Clinical response at the Week 16 visit as measured by at least a 70-point reduction in the 
CDAI from baseline (CDAI-70 response) 
• Clinical remission over time, as measured by the 2-item PRO 
• Change from baseline in total stool frequency, rectal bleeding frequency, rectal urgency 
frequency, nausea severity, vomiting frequency, and rectal incontinence frequency 
scores; and total sign/symptom score based on subject daily e-diary entries 
• Endoscopic healing at Week 16 as measured by SES-CD ≤4 and at least 2-point reduction 
versus baseline and no subscore >1 in any individual variable 
• Change from baseline in IBDQ domain and total (absolute) scores over time 
• Change from baseline in SF-36, version 2, acute (physical and mental component 
summary scores and individual domain scores) over time 
• Incidence of all cause hospitalizations and total inpatient days 
• Incidence of CD-related surgeries and other surgical procedures during the entire study 
period. 
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 compared between each active treatment group and the placebo 
group using a CMH chi-square test stratified by status of prior anti-TNF treatment, 
glucocorticoid use at baseline, and SES-CD at baseline. 
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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 the p-value computed 
from CHM test will be provided. Subjects with missing binary endpoint data at the 
Week 16 visit will be considered failures and counted as nonresponders. 
• Continuous endpoints that are only measured at baseline and the Week 16 visit will be 
analyzed using an analysis of covariance model with fixed effects for treatment group 
(categorical), status of prior anti-TNF treatment (categorical), glucocorticoid use at 
baseline (categorical), and SES-CD 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), 
glucocorticoid use at baseline (categorical), and SES-CD 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. 
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 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. 
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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. 
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 and percentage of TEAEs will be 
calculated 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. 
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) guidelines 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 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 guidelines 
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 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. 
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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 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). 
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 Food and 
Drug [FDA], European Medicines Agency [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 US 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. 
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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 
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 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. 
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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 
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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Atreya, R.and Neurath, M. F. 2017. Current and Future Targets for Mucosal Healing in 
Inflammatory Bowel Disease. Visceral Medicine, 33, 82-88. 
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Best, W. R., Becktel, J. M.and Singleton, J. W. 1979. Rederived values of the eight coefficients 
of the Crohn's Disease Activity Index (CDAI). Gastroenterology, 77, 843-6. 
Best, W. R., Becktel, J. M., Singleton, J. W.and Kern, F. 1976. Development of a Crohn's 
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Bretz, F., Koenig, F., Brannath, W., Glimm, E.and Posch, M. 2009a. Adaptive designs for 
confirmatory clinical trials. Statistics in Medicine, 28, 1181-1217. 
Bretz, F., Maurer, W., Brannath, W.and Posch, M. 2009b. 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.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. 
 
 
 
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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. 
Chang, M.and Chow, S. C. 2008. Adaptive design methods in clinical trials - a review. Orphanet 
journal of rare diseases, 3, 11. 
D'Haens, G., Noman, M., Baert, F.and et al. 2002. Endoscopic healing after infliximab treatment 
for Crohn's disease provides a longer time to relapse [abstract]. Gastroenterology, 122, 
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D'Haens, G. R., Geboes, K., Peeters, M., Baert, F., Penninckx, F.and Rutgeerts, P. 1998. Early 
Lesions of Recurrent Crohn’s Disease Caused by Infusion of Intestinal Contents in 
Excluded Ileum. Gastroenterol, 114, 262-7. 
D’Haens, G., Gorelick, K., Wang, Y., Cataldi, F.and Sandborn, W. 2018. The anti-MAdCAM-1 
antibody SHP647 in Crohn’s disease:endoscopic effects of induction therapy. DDW. 
Ferrante, M., Colombel, J., Sandborn, W., Reinisch, W., Mantzaris, G., Kornbluth, A., 
Rachmilewitz, D., Lichtiger, S., D'Haens, G., Van der Woude, C., Danese, S., Diamond, 
R., Oortwijn, A., Tang, K., Miller, M., Cornillie, F.and Rutgeerts, P. 2013. Validation of 
Endoscopic Activity Scores in Patients With Crohn's Disease Based on a Post Hoc 
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Humira® 2017. US Prescribing Information. 
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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, R., Zou, G., D'Haens, G., Feagan, B. G., Sandborn, W. J., Vandervoort, M. K., Rolleri, 
R. L., Bortey, E., Paterson, C., Forbes, W. P.and Levesque, B. G. 2015. A retrospective 
analysis: the development of patient reported outcome measures for the assessment of 
Crohn's disease activity. Alimentary Pharmacology & Therapeutics, 41, 77-86. 
Khanna, S., Shin, A.and Kelly, C. 2017. Management of Clostridium difficile Infection in 
Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates 
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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. 
Lichtenstein, G. R., Loftus, E., Isaacs, K., Regueiro, M., Gerson, L.and Sands, B. 2018. ACG 
Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol, 113, 
481-517. 
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. 
Panaccione, R., Colombel, J.-F., Louis, E., Peyrin-Biroulet, L.and Sandborn, W. J. 2013. 
Evolving Definitions of Remission in Crohn’s Disease. Inflammatory Bowel Diseases, 
19, 1645-1653. 
Peyrin-Biroulet, L., Ferrante, M., Magro, F., Campbell, S., Franchimont, D., Fidder, H., Strid, 
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Purinethol® 2011. US Prescribing Information. 
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Characterisation of Mucosal Healing with Adalimumab Treatment in Patients with 
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Safety and Efficacy of ABT-494 (Upadacitinib), an Oral Jak1 Inhibitor, as Induction 
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Vuitton, L., Marteau, P., Sandborn, W. J., Levesque, B. G., Feagan, B., Vermeire, S., Danese, S., 
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12. APPENDICES 
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PROTOCOL HISTORY  
Appendix 1
Document 
Date 
Global/Country/Site Specific 
Protocol Amendment 1 
21 Aug 2018 
Global 
Original Protocol 
15 Dec 2017 
Global 
 
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SCALES AND ASSESSMENTS 
Appendix 2
The following scales/assessments will be used in the study and are provided in this appendix: 
• Simple Endoscopic Score for Crohn’s Disease 
• Crohn’s Disease Activity Index 
• 
 
• Patient-reported Outcome Crohn’s Disease daily e-diary 
• Inflammatory Bowel Disease Questionnaire 
• 
 
• 
 
• 
 
• 
 
• Short Form-36 Health Survey 
• 
 
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Simple Endoscopic Score for Crohn’s Disease (SES-CD) 
 
SITE WORKSHEET: Simple Endoscopic Score for Crohn’s Disease (SES-CD) 
’ 
Presence and type of narrowings
None
Single, can be passed 
Multiple, can be passed 
Cannot be passed 
Extent of affected surface 
Unaffected segment 
< 50% 
50 – 75% 
>75% 
Extent of ulcerated surface 
None 
< 10% 
10 – 30% 
> 30% 
Endoscopy Finding 
Ileum 
Right 
Colon 
Transverse
Colon 
Left 
Colon 
Rectum 
Presence and size of ulcers 
None
Apthous ulcers ( Ø 0.1 to 0.5 cm) 
Large ulcers ( Ø 0.5 to 2 cm) 
Very large ulcers ( Ø > 2 cm) 
Cannot be passed 
Multiple, can be 
passed 
Single, can be 
passed 
None 
Presence of 
Narrowing
>75% 
50 - 75% 
<50% 
Unaffected segment 
Affected surface 
>30% 
10 - 30% 
<10% 
None 
Ulcerated surface
Very large ulcers 
(>2 cm) 
Large ulcers 
( 0.5 to 2 cm) 
Apththous ulcers 
(  0.1 to 0.5 cm) 
None 
Size of Ulcers 
Variable
Simple Endoscopic Score for Crohn ’ s Disease values 
Definitions of Simple Endoscopic Score for Crohn 
’ 
Cannot be passed 
Multiple, can be 
passed 
Single, can be 
passed 
None 
Presence of 
Narrowing
>75% 
50 - 75% 
<50% 
Unaffected segment 
Affected surface 
>30% 
10 - 30% 
<10% 
None 
Ulcerated surface
Very large ulcers 
(>2 cm) 
Large ulcers 
( 0.5 to 2 cm) 
Apththous ulcers 
(  0.1 to 0.5 cm) 
None 
Size of Ulcers 
Variable
Simple Endoscopic Score for Crohn ’ s Disease values 
Definitions of Simple Endoscopic Score for Crohn’s Disease 
 
 
Site # 
Investigator
Subject ID 
Visit Date 
(mmm dd yyyy) 
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Crohn’s Disease Activity Index (CDAI) 
 
CDAI=Crohn’s Disease Activity Index; ePRO=electronic patient-reported outcome; Hct=hematocrit. 
Note: Variable 5: This variable covers taking medication for symptomatic relief from diarrhea, eg, bulking agents, opiates etc. 
Variable 7: Absolute deviation of hematocrit is the difference in hematocrit from standard. A male subject with a hematocrit of 
40% has an absolute deviation of 7. Each percentage deviation has a value of 6 points. If hematocrit subtotal is <0, enter 0. 
Variable 8: This variable is based on Metropolitan Life Tables (these are programmed into the ePRO device). 
Percent deviation from standard weight is (1 - weight/standard weight) × 100; therefore, positive percent deviation represents 
weight loss, which adds points to the CDAI. Percentage deviation from standard weight = 1 point for each percent deviation. If 
body weight subtotal is less than -10, enter -10. 
CDAI Interpretation: 
• 
0-149 points: Asymptomatic remission (Note: subjects requiring steroids to remain asymptomatic are not considered to 
be in remission but are referred to as being “steroid dependent”) 
• 
150-220 points: Mild to moderate active CD 
• 
221-450 points: Moderate to severe active CD 
• 
>451 points: Severely active to fulminant disease. 
CDAI online estimator: http://www.ibdjohn.com/cdai/ 
Sources: Best et al., 1976; Best et al., 1979. 
 
Crohn’s Disease Activity Index (CDAI)
CDAI 
Score
X 1
Body weight (1-weight/standard weight) X 100                                   
(add or subtract according to sign)
8
X 6
Hematocrit [Males: 47-Hct (%), Females: 42-Hct (%)]
7
X 10
Abdominal mass (0 = no, 2 = questionable, 5 = definite)
6
X 30
Use of diphenoxylate or loperamide for diarrhea (0 = no, 1 = yes)
5
X 20
Number of listed complications [arthritis or arthralgia, iritis or uveitis, 
erythema nodosum or pyoderma gangrenosum or aphthous
stomatitis, anal fissure or  fistula or abscess, other fistula, fever     
over 37.8oC (100oF)]
4
X 7
General well-being (0 = generally well, 1 = slightly under par,             
2 = poor, 3 = very poor, 4 = terrible)
3
X 5
Abdominal pain (0 = none, 1 = mild, 2 = moderate, 3 = severe)
2
X 2
No. of liquid or soft stools (each day for 7 days)
1
Total
Multiplier
Variable Description
Variable 
No.
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Reference: D'Haens et al., 1998. 
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Patient-reported Outcomes – Crohn’s Disease Daily E-diary Version 1 
 
1.
Please rate your worst abdominal pain over the past 24 hours. 
0 1 2 3 4 5 6 7 8 9 10 
 No pain 
 
 
 
 
 
Worst imaginable pain 
 
2.
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: ____________ 
The next question asks about the number of liquid or very soft stools you had in the past 
24 hours. Liquid or very soft stools are defined as Type 6 and Type 7 in the chart below. 
 
 
3.
You indicated you had X bowel movements in the past 24 hours. Of these, how many were 
liquid or very soft? 
Enter number of liquid or very soft bowel movements: ____________ 
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4.
You indicated you had X bowel movements in the past 24 hours. Of these, how many had 
blood, either in the stool, the toilet bowel, or on the toilet paper? 
Enter number of bowel movements with blood: ____________ 
 
5.
You indicated you had X bowel movements in the past 24 hours. How many of these 
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 feeling of nausea (feeling sick to your stomach or like you might 
throw up) over the past 24 hours. 
None 
Mild 
Moderate 
Severe 
 
7.
How many vomiting episodes did you have in the past 24 hours? An episode includes one or 
multiple heaves (including dry heaves) in quick succession followed by a break in vomiting. 
Enter number of vomiting episodes: ____________ 
 
8.
How many bowel incontinence episodes (losing control of your bowels before reaching the 
toilet) did you have in the past 24 hours? 
Enter number of bowel incontinence episodes: ______________ 
 
9.
Please rate your abdominal pain over the past 24 hours. 
None 
Mild 
Moderate 
Severe 
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10. How would you rate your general wellbeing over the past 24 hours? 
Generally well 
Slightly below par 
Poor 
Very poor 
Terrible 
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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 2 weeks? Please indicate 
how frequent your bowel movements have been during the last 2 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 (Version 2), Acute Form 
 
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GLUCOCORTICOID EQUIVALENT DOSES 
Appendix 3
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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DETERMINATION OF INADEQUATE RESPONSE/LOSS OF 
Appendix 4
RESPONSE OR INTOLERANCE TO PRIOR TREATMENT FOR CROHN’S 
DISEASE 
The information below should serve as guidance. Local therapeutic standards and investigator 
judgment should be used. 
AMINOSALICYLATES 
Mesalamine (5-ASA) 
Inadequate response or loss of response: Although the use of mesalamine in UC is well 
established (eg, induction treatment up to 4.8 g/day up to 8 weeks) and based upon evidence-
based criteria, its use in CD is not well established. Oral mesalamine has not consistently been 
demonstrated to be effective compared with placebo for induction of remission and achieving 
mucosal healing in patients with active CD. Similarly, topical mesalamine is of limited benefit in 
CD (Lichtenstein et al., 2018). For the purpose of this study, inadequate response or loss of 
response is defined as signs and symptoms of persistently active disease despite a history of 
mesalamine use 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 
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, 
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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.  
Sulfasalazine (SSZ): 
Inadequate response or loss of response: Although the use of sulfasalazine in UC is accepted 
(eg, induction treatment up to 4 g/day up to 8 weeks) its use in CD is not well established.  
For the purpose of this study, inadequate response or loss of response is defined as signs and 
symptoms of persistently active disease despite a history of sulfasalazine use for at least 8 weeks 
at daily doses of 4 g/day. 
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related 
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, Guillian-Barre 
syndrome, peripheral neuropathy, mental depression, vertigo, hearing loss, insomnia, 
ataxia, hallucinations, tinnitus, and drowsiness. 
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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. 
GLUCOCORTICOIDS 
Inadequate response or loss of response: Signs and symptoms of persistently 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 prednisone 10 mg daily orally on 2 separate 
occasions.  
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related 
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 
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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. 
IMMUNOSUPPRESSANTS 
Azathioprine (AZA) 
Inadequate response or loss of response: Signs and symptoms of persistently 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, myalgias, 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).  
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Mercaptopurine (6-MP) 
Inadequate response or loss of response: Signs and symptoms of persistently 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 
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 
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: 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 
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  
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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 
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: Anti-TNF agents are rapid in onset of effect, with 
benefit often noted within 2 weeks of initiating therapy. As a result, assessment of inadequate 
response may be done sooner than with immunosuppressants. These include signs and symptoms 
of persistently 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 
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• certolizumab pegol (400 mg SC, 2 doses at least 2 weeks apart) or recurrence of 
symptoms during maintenance therapy. (approved for CD in US) 
Intolerance: defined as documented treatment discontinuation for AEs suspected to be related 
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  
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  
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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  
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GUIDANCE FOR DIAGNOSIS AND TREATMENT OF 
Appendix 5
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, 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. 
 
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PROTOCOL: SHP647-306 
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 Crohn’s Disease 
(CARMEN CD 306) 
DRUG: 
Ontamalimab (SHP647) 
IND: 
100,222 
EUDRACT NO.: 
2017-000576-29 
SPONSOR: 
Shire Human Genetic Therapies, Inc. (“Shire”) 
300 Shire Way, Lexington, MA 02421 
USA 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
, MD 
PROTOCOL 
HISTORY: 
Protocol Amendment 2: 22 Nov 2019 
Protocol Amendment 1: 21 Aug 2018 
Original Protocol: 15 Dec 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 
SHP647-306 Protocol Amendment 2 
Ontamalimab 
CONFIDENTIAL 
Page2 
22 Nov 2019 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
 MD, 
 
Date: 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP647-306. 
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 Crohn's 
Disease (CARMEN CD 306). 
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 ofmy 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: 
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Shire 
CONFIDENTIAL 
Page 3 
SHP647-306 Protocol Amendment 2 
Ontamalimab 
  
22 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 
22 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, Inclusion 
Criteria 
Section 4.1, Inclusion Criteria 
Section 7.1.1.1, Screening Visit 
(Visit 1) 
Section 7.2.2, Efficacy 
Reordered inclusion criteria #4a, 4b and 4c so 
that the colonoscopy is last. Clarified that the 
subject must meet inclusion criteria #4a and 
4b (CDAI score and PRO subscores) prior to 
the colonoscopy (criterion #4c) being 
performed. 
To clarify the order of 
assessments to prevent 
unnecessary colonoscopies 
being performed. 
Study Synopsis, Inclusion 
Criteria 
Section 4.1, Inclusion Criteria 
Section 4.4, Reproductive 
Potential 
Revised inclusion criterion #9 to add “highly 
effective methods for female and medically 
appropriate methods for male study subjects” 
in parentheses after “appropriate 
contraception”. Also added this language 
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 
Section 4.2, Exclusion Criteria 
Revised exclusion criterion #6 to clarify that 
subjects with obstructive colonic stricture are 
excluded if it is clinically significant. 
Updated exclusion criterion #6 to state that 
subjects who have undergone previous 
colonic resection or ileocolectomy are 
excluded unless it was at least 6 months 
before screening and they have at least 25 cm 
of colon remaining (previously all subjects 
who had undergone previous colonic 
resection were excluded.) 
To provide clarity regarding 
the exclusion around prior 
bowel surgeries. 
As ileocolectomy or partial 
colectomy is common in 
Crohn’s disease, the population 
previously defined in the 
protocol has been too 
restrictive and thus could not 
reflect the broader Crohn’s 
disease population. There is no 
reason to believe that 
ontamalimab would work 
differently after ileocolectomy 
or partial colectomy. The 
length of the remaining colon is 
required to be at least 25 cm in 
order to be able to evaluate and 
score the mucosal 
inflammation appropriately. 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 4 
SHP647-306 Protocol Amendment 2 
Ontamalimab 
  
22 Nov 2019 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/Region/Country/Site 
Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Exclusion 
Criteria 
Section 4.2, Exclusion Criteria 
Revised exclusion criterion #19 to state that 
subjects who have taken >9 mg/day of 
budesonide within 14 days before baseline 
(Visit 2) are excluded. 
To clarify the allowed doses of 
steroids. 
Study Synopsis, Exclusion 
Criteria 
Section 4.2, Exclusion Criteria 
Updated exclusion criterion #36 to include 
‘dependency’ along with substance/drug 
abuse for any kind of abuse including 
medicinal marijuana (cannabis). 
For clarity. 
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 “b” 
Section 7.1.2.2, Final 
On-treatment Visit: Visit 7, 
Parts 1, 2, and 3 (Week 16/Early 
Termination) 
Revised to clarify that, for the colonoscopies 
required at ET/Week 16, the specified blood 
sampling should be taken before colonoscopy 
preparation. 
To clarify the order of 
procedures. 
Table 1, Schedule of 
Assessments, footnote “l” 
Section 7.2.3.6, Clinical 
Laboratory Evaluations 
Section 7.2.3.12, Evaluation of 
Increased Gastrointestinal 
Symptoms 
Added new subsection (7.2.3.12) to 
Section 7.2.3 to describe 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 “s” 
Section 7.1.1.1, Screening Visit 
(Visit 1) 
Section 7.2.2.4, Colonoscopy 
Revised to clarify that, for the colonoscopies 
required at screening and ET/Week 16, the 
preparation may be done on the same day as 
the colonoscopy procedure. 
To reduce logistical burden 
around the colonoscopy 
requirements.  
Table 1, Schedule of 
Assessments, footnote “s” 
Section 7.1.1.1, Screening Visit 
(Visit 1) 
Revised to extend the window between the 
screening colonoscopy procedure and 
baseline (Visit 2) from 5-7 days to 10 days; 
however, within 5 to 7 days is stated as being 
preferable. 
Updated to indicate that colonoscopy 
preparation may be done on the same day as 
the colonoscopy procedure. 
Updated screen failure criteria to include 
PRO scores. 
To allow sites to receive 
SES-CD results in time to 
schedule randomization within 
the eligibility window. 
To provide additional 
flexibility on timing of 
colonoscopy preparation. 
For consistency with inclusion 
criterion #4. 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 5 
SHP647-306 Protocol Amendment 2 
Ontamalimab 
  
22 Nov 2019 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/Region/Country/Site 
Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Table 1, Schedule of 
Assessments, footnote “z” 
Section 7.2.3.11, Monitoring for 
Type I and Type III Immune 
Reactions 
Added new row and footnote 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. 
Section 4.4, Reproductive 
Potential  
Updated text to reflect results of an enhanced 
pre-and postnatal development (ePPND) 
toxicity study in nonhuman primates. 
To reflect preliminary results 
from an ePPND toxicity study 
of ontamalimab in nonhuman 
primates, which indicated that, 
at the dose levels tested 
(30 mg/kg 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 are 
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 
Changed the term ‘protocol violations’ to 
‘protocol deviations’. 
For consistency with 
Section 4.5.2 (Reasons for 
Withdrawal). 
Section 5.1, Prior Treatment 
Updated to specify that prior and concomitant 
Crohn’s disease-specific treatments from the 
previous 10 years will be recorded rather than 
all prior and concomitant Crohn’s disease-
specific treatments. 
For consistency with 
Study SHP647-301. 
Section 5.2.1, Permitted 
Treatment 
Updated text on permitted use of antibiotics 
to align with exclusion criterion #12. 
For consistency. 
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Shire 
CONFIDENTIAL 
Page 6 
SHP647-306 Protocol Amendment 2 
Ontamalimab 
  
22 Nov 2019 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/Region/Country/Site 
Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 7.1.1.1, Screening Visit 
(Visit 1) 
Changed the term ‘first dose of 
investigational product’ to ‘baseline visit 
(Visit 2)’. 
For consistency with other 
sections. 
Section 7.2.2.2, Simple 
Endoscopic Score for Crohn’s 
Disease 
Added reference citation to Daperno et al., 
2004. 
To provide additional 
information regarding the 
Simple Endoscopic Score for 
Crohn’s Disease (SES-CD). 
Section 7.2.2.2, Simple 
Endoscopic Score for Crohn’s 
Disease 
Section 7.2.2.4, Colonoscopy 
and Histology 
Updated text to clarify that a complete 
colonoscopy (including visualization of the 
terminal ileum) and collection of biopsies 
from all bowel segments may not be possible 
due to impassable stenosis or previous partial 
colectomy/ileocolectomy. If a complete 
colonoscopy is not possible, the aim is to 
visualize the remaining colon and, if it exists, 
the terminal ileum. 
To clarify the colonoscopy 
procedure if the subject has 
undergone partial 
colectomy/ileocolectomy. 
Section 7.2.3.3, Targeted 
Neurological Assessment 
Updated column heading in Table 3 from 
Targeted Neurological History’ to ‘Interim 
Neurologic History and Targeted Neurologic 
Examination.’ 
To align with language of 
newly proposed electronic case 
report form. 
Section 7.2.5, Volume of Blood 
to be Drawn From Each Subject 
Decreased serum chemistry sample volume 
from 6 mL to 4 mL. 
Increased 
 volume 
from 3 mL to 5 mL. 
To correct the sample volume 
needed for the serum chemistry 
test and for the 
. 
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 time frame 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.  
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Shire 
CONFIDENTIAL 
Page 7 
SHP647-306 Protocol Amendment 2 
Ontamalimab 
  
22 Nov 2019 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/Region/Country/Site 
Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 9.5, Planned Interim 
Analysis, Adaptive Design, Data 
Monitoring Committee, and 
Hypersensitivity Adjudication 
Committee 
Added text to specify that an 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 
For the endpoint ‘
 
.’ 
Deleted reference to
 
 
.’ 
For consistency with other 
Phase 3 ontamalimab studies. 
 
To correctly describe
 
 
Section 10.1.5, Study 
Suspension, Termination, and 
Completion 
Clarified that the end-of study declaration 
may be made by the sponsor or alternatively 
its representatives. 
To improve clarity. 
Appendix 2, Scales and 
Assessments 
Updated the example SES-CD worksheet. 
To provide the scoring values 
for the SES-CD endoscopic 
variables and clarify how the 
scores are recorded for each 
ileocolonic segment. 
Throughout protocol 
Updated ‘SHP647’ to ‘ontamalimab” 
throughout the protocol. 
 
Updated with minor changes to wording. 
To reflect that ontamalimab is 
the international nonproprietary 
name for SHP647. 
To improve clarity, 
consistency, and remove 
redundancy of text.  
See Appendix 1 for protocol history, including all amendments. 
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Shire 
CONFIDENTIAL 
Page 8 
SHP647-306 Protocol Amendment 2 
Ontamalimab 
  
22 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: 
 
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Shire 
CONFIDENTIAL 
Page 9 
SHP647-306 Protocol Amendment 2 
Ontamalimab 
  
22 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. 
 
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Shire 
CONFIDENTIAL 
Page 10 
SHP647-306 Protocol Amendment 2 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ........................................................3 
EMERGENCY CONTACT INFORMATION ................................................................................8 
PRODUCT QUALITY COMPLAINTS..........................................................................................9 
TABLE OF CONTENTS ...............................................................................................................10 
LIST OF TABLES .........................................................................................................................15 
LIST OF FIGURES .......................................................................................................................15 
LIST OF APPENDICES ................................................................................................................15 
ABBREVIATIONS .......................................................................................................................16 
STUDY SYNOPSIS ......................................................................................................................19 
STUDY SCHEDULE ....................................................................................................................29 
1. 
BACKGROUND INFORMATION .......................................................................................35 
1.1 
Indication and Current Treatment Options ...............................................................35 
1.2 
Product Background and Clinical Information ........................................................35 
1.3 
Benefit/Risk Assessment ..........................................................................................36 
2. 
STUDY OBJECTIVES AND PURPOSE ..............................................................................38 
2.1 
Rationale for the Study .............................................................................................38 
2.2 
Study Objectives .......................................................................................................40 
2.2.1 Coprimary Objectives ............................................................................................40 
2.2.2 Secondary Objectives .............................................................................................40 
2.2.2.1 
Key Secondary Objectives .....................................................................40 
2.2.2.2 
Other Secondary Objectives ...................................................................40 
2.2.3 Exploratory Objectives ..........................................................................................41 
3. 
STUDY DESIGN ...................................................................................................................42 
3.1 
Study Design and Flow Chart ..................................................................................42 
3.1.1 Rationale for Coprimary Endpoints .......................................................................44 
3.1.2 Rationale for Key Secondary Endpoints ................................................................46 
3.2 
Duration and Study Completion Definition .............................................................48 
3.3 
Sites and Regions .....................................................................................................49 
4. 
STUDY POPULATION .........................................................................................................50 
4.1 
Inclusion Criteria ......................................................................................................50 
4.2 
Exclusion Criteria .....................................................................................................51 
4.3 
Restrictions ...............................................................................................................56 
4.4 
Reproductive Potential .............................................................................................56 
4.4.1 Contraceptive Methods for Female Study Subjects ...............................................57 
4.4.2 Contraceptive Methods for Male Study Subjects ..................................................58 
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CONFIDENTIAL 
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4.5 
Withdrawal of Subjects ............................................................................................59 
4.5.1 Subject Withdrawal Criteria ..................................................................................59 
4.5.2 Reasons for Withdrawal .........................................................................................60 
4.5.3 Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................60 
5. 
PRIOR AND CONCOMITANT TREATMENT ...................................................................61 
5.1 
Prior Treatment .........................................................................................................61 
5.2 
Concomitant Treatment ............................................................................................61 
5.2.1 Permitted Treatment ...............................................................................................61 
5.2.2 Prohibited Treatment .............................................................................................62 
5.2.3 Rescue Therapy ......................................................................................................64 
6. 
INVESTIGATIONAL PRODUCT ........................................................................................65 
6.1 
Identity of Investigational Product ...........................................................................65 
6.1.1 Blinding the Treatment Assignment ......................................................................65 
6.2 
Administration of Investigational Products ..............................................................65 
6.2.1 Interactive Response Technology for Investigational Product Management ........65 
6.2.2 Allocation of Subjects to Treatment ......................................................................65 
6.2.3 Dosing ....................................................................................................................66 
6.2.4 Unblinding the Treatment Assignment ..................................................................66 
6.3 
Labeling, Packaging, Storage, and Handling ...........................................................67 
6.3.1 Labeling .................................................................................................................67 
6.3.2 Packaging ...............................................................................................................67 
6.3.3 Storage ...................................................................................................................67 
6.3.4 Special Handling ....................................................................................................68 
6.4 
Drug Accountability .................................................................................................68 
6.5 
Subject Compliance ..................................................................................................69 
7. 
STUDY PROCEDURES ........................................................................................................70 
7.1 
Study Schedule .........................................................................................................70 
7.1.1 Screening Period ....................................................................................................70 
7.1.1.1 
Screening Visit (Visit 1) .........................................................................70 
7.1.1.2 
Baseline Visit (Visit 2; Week 0) ............................................................71 
7.1.2 Treatment Period ....................................................................................................71 
7.1.2.1 
Visits 3, 4, 5, and 6 (Weeks 2, 4, 8, and 12) ..........................................71 
7.1.2.2 
Final On-treatment Visit: Visit 7, Parts 1, 2, and 3 
(Week 16/Early Termination) ................................................................71 
7.1.3 Follow-up Period ...................................................................................................72 
7.1.4 Additional Care of Subjects After the Study .........................................................72 
7.2 
Study Evaluations and Procedures ...........................................................................72 
7.2.1 Demographic and Other Baseline Characteristics .................................................73 
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7.2.2 Efficacy ..................................................................................................................73 
7.2.2.1 
Patient-reported Outcome – Crohn’s Disease Daily E-diary .................73 
7.2.2.2 
Simple Endoscopic Score for Crohn’s Disease ......................................74 
7.2.2.3 
Crohn’s Disease Activity Index .............................................................75 
7.2.2.4 
Colonoscopy and Histology ...................................................................76 
7.2.3 Safety .....................................................................................................................77 
7.2.3.1 
Medical and Medication History ............................................................77 
7.2.3.2 
Physical Examination (Including Height and Weight) ..........................77 
7.2.3.3 
Targeted Neurological Assessment ........................................................78 
7.2.3.4 
Adverse Event Collection .......................................................................79 
7.2.3.5 
Vital Signs ..............................................................................................79 
7.2.3.6 
Clinical Laboratory Evaluations .............................................................80 
7.2.3.7 
Pregnancy Test and Follicle-stimulating Hormone Test ........................81 
7.2.3.8 
Electrocardiogram ..................................................................................82 
7.2.3.9 
Chest X-ray ............................................................................................82 
7.2.3.10 
Antidrug Antibodies ...............................................................................82 
7.2.3.11 
Monitoring for Type I and Type III Immune Reactions ........................82 
7.2.3.12 
Evaluation of Increased Gastrointestinal Symptoms .............................83 
7.2.4 Others .....................................................................................................................83 
 
 
 
 
7.2.4.3 
Health-related Quality-of-life Assessments ...........................................84 
7.2.4.4 
Healthcare Resource Utilization Assessments .......................................85 
7.2.5 Volume of Blood to Be Drawn From Each Subject ..............................................86 
8. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................87 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events .......................................................................................................................87 
8.1.1 Severity Categorization ..........................................................................................87 
8.1.2 Relationship Categorization ...................................................................................88 
8.1.3 Adverse Events of Special Interest ........................................................................88 
8.1.3.1 
Hypersensitivity .....................................................................................88 
8.1.4 Outcome Categorization ........................................................................................91 
8.1.5 Symptoms of the Disease Under Study .................................................................91 
8.1.6 Clinical Laboratory and Other Safety Evaluations ................................................91 
8.1.7 Pregnancy ...............................................................................................................91 
8.1.8 Abuse, Misuse, Overdose, and Medication Error ..................................................92 
8.1.9 Unexpected Adverse Event ....................................................................................93 
8.1.10 Suspected Unexpected Serious Adverse Reaction .................................................93 
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8.2 
Serious Adverse Event Procedures ...........................................................................93 
8.2.1 Reference Safety Information ................................................................................93 
8.2.2 Reporting Procedures .............................................................................................93 
8.2.3 Serious Adverse Event Definition .........................................................................94 
8.2.4 Serious Adverse Event Collection Time Frame .....................................................94 
8.2.5 Serious Adverse Event Onset and Resolution Dates .............................................95 
8.2.6 Fatal Outcome ........................................................................................................95 
8.2.7 Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................95 
8.2.8 Safety Monitoring for Potential Cases of Drug-induced Liver Injury ...................96 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................98 
9.1 
Data Collection .........................................................................................................98 
9.2 
Clinical Data Management .......................................................................................98 
9.3 
Data Handling Considerations ..................................................................................98 
9.4 
Statistical Analysis Process ......................................................................................98 
9.5 
Planned Interim Analysis, Adaptive Design, Data Monitoring Committee, and 
Hypersensitivity Adjudication Committee ...............................................................99 
9.6 
Sample Size Calculation and Power Considerations ..............................................100 
9.7 
Study Population ....................................................................................................101 
9.8 
Efficacy Analyses ...................................................................................................102 
9.8.1 Coprimary Efficacy Endpoints ............................................................................102 
9.8.2 Secondary Efficacy Endpoints .............................................................................105 
9.8.2.1 
Key Secondary Efficacy Endpoints ......................................................105 
9.8.2.2 
Other Secondary Efficacy Endpoints ...................................................106 
9.8.3 Exploratory Efficacy Endpoints ...........................................................................107 
9.9 
Safety Analyses ......................................................................................................108 
9.10 
Other Analyses .......................................................................................................108 
 
 
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .........................................110 
10.1 
Sponsor’s Responsibilities .....................................................................................110 
10.1.1 Good Clinical Practice Compliance .....................................................................110 
10.1.2 Indemnity/Liability and Insurance .......................................................................110 
10.1.3 Public Posting of Study Information ....................................................................110 
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees .........................................111 
10.1.5 Study Suspension, Termination, and Completion................................................111 
10.2 
Investigator’s Responsibilities ...............................................................................111 
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10.2.1 Good Clinical Practice Compliance .....................................................................111 
10.2.2 Protocol Adherence and Investigator Agreement ................................................112 
10.2.3 Documentation and Retention of Records ...........................................................112 
10.2.3.1 
Case Report Forms ...............................................................................112 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study 
Documents ............................................................................................112 
10.2.3.3 
Audit/Inspection ...................................................................................113 
10.2.3.4 
Financial Disclosure .............................................................................113 
10.3 
Ethical Considerations ............................................................................................113 
10.3.1 Informed Consent.................................................................................................113 
10.3.2 Institutional Review Board or Ethics Committee ................................................114 
10.4 
Privacy and Confidentiality ....................................................................................115 
10.5 
Study Results/Publication Policy ...........................................................................115 
11. REFERENCES .....................................................................................................................117 
 
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LIST OF TABLES 
Table 1 
Schedule of Assessments ...............................................................................29 
Table 2 
Common Excluded Treatments .....................................................................63 
Table 3 
Quarterly Neurological Assessment ..............................................................78 
Table 4 
Volume of Blood to Be Drawn From Each Subject ......................................86 
Table 5 
Clinical Criteria for Diagnosing Anaphylaxis (Type I Hypersensitivity) .....90 
Table 6 
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin .........................................................................................................96 
Table 7 
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints ...................................................................................101 
 
LIST OF FIGURES 
Figure 1 
Overview of Ontamalimab Phase 3 Studies in Crohn’s Disease ...................43 
Figure 2 
Study Design Flow Chart ..............................................................................44 
Figure 3 
Flow Diagram for Quarterly Neurological Assessments ...............................79 
Figure 4 
Potential Immunogenicity of Therapeutic Monoclonal Antibodies ..............89 
Figure 5 
Visualization of Multiple Testing Strategy .................................................104 
 
LIST OF APPENDICES 
Appendix 1 
Protocol History ...........................................................................................121 
Appendix 2 
Scales and Assessments ...............................................................................125 
Appendix 3 
Glucocorticoid Equivalent Doses ................................................................158 
Appendix 4 
Determination of Inadequate Response/Loss of Response or 
Intolerance to Prior Treatment for Crohn’s Disease ....................................159 
Appendix 5 
Guidance for Diagnosis and Treatment of Increased Gastrointestinal 
Symptoms ....................................................................................................167 
 
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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 
BSFS 
Bristol Stool Form Scale 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
 
 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
 
 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
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 
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FSH 
follicle-stimulating hormone 
FWER 
family-wise Type I error rate 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
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 
LP 
lumbar puncture 
LTS 
long-term safety extension 
 
 
MTX 
methotrexate 
NAb 
neutralizing antibody 
NRS 
numerical rating scale 
PCR 
polymerase chain reaction  
 
PFS 
prefilled syringe 
 
 
 
 
 
PML 
progressive multifocal leukoencephalopathy 
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PP 
per protocol 
PPD 
purified protein derivative 
PRO 
patient-reported outcome 
Q4W 
once every 4 weeks 
RSI 
reference safety information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SES-CD 
Simple Endoscopic Score for Crohn’s disease 
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 
 
 
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STUDY SYNOPSIS 
Protocol number: SHP647-306 
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 Crohn’s Disease (CARMEN CD 306) 
Number of subjects (total and for each treatment arm): 
A total of 1032 subjects (387 subjects in the 25 mg ontamalimab treatment group, 387 subjects in the 75 mg 
ontamalimab treatment group, and 258 subjects in the placebo group) 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 approximately 19 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): 
2018 to 2021 
Clinical phase: 
3 
Objectives: 
Coprimary: The coprimary objectives of this study are to evaluate the efficacy of ontamalimab in subjects with 
moderate to severe Crohn’s disease (CD) in: 
• 
Inducing clinical remission based on 2-item patient-reported outcome (PRO) (abdominal pain severity and 
very soft stool/liquid stool frequency) 
• 
Inducing endoscopic response based on centrally read colonoscopy. 
Key secondary: 
• 
To evaluate the efficacy of ontamalimab in inducing clinical remission as measured by CD Activity Index 
(CDAI) 
• 
To evaluate the efficacy of ontamalimab in inducing enhanced endoscopic response based on centrally read 
colonoscopy 
• 
To evaluate the efficacy of ontamalimab in inducing clinical remission based on abdominal pain severity 
and very soft stool/liquid stool frequency (alternate thresholds) 
• 
To evaluate the efficacy of ontamalimab in inducing clinical response based on patient-reported clinical 
signs and symptoms (as measured by 2-item PRO) 
• 
To evaluate the efficacy of ontamalimab in inducing clinical remission based on patient-reported clinical 
signs and symptoms (as measured by 2-item PRO) as well as inducing endoscopic response based on 
centrally read colonoscopy in the same subject 
• 
To evaluate the efficacy of ontamalimab in inducing endoscopic healing based on centrally read 
colonoscopy. 
Other secondary: 
• 
To evaluate the safety and tolerability of ontamalimab 
• 
To evaluate the effect of ontamalimab induction treatment on other clinical outcomes (clinical response 
defined by CDAI, or clinical remission over time, or change from baseline in frequency in CD-related 
clinical parameters) 
• 
To evaluate the effect of ontamalimab induction treatment on other endoscopic outcomes 
• 
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 
• 
To evaluate the impact of ontamalimab on incidence of CD-related and other surgeries. 
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Rationale: 
This study is designed to evaluate the efficacy and safety of ontamalimab in inducing clinical remission and 
endoscopic response in subjects with moderate to severe CD. 
The CD clinical development program includes 3 completed studies: 1 Phase 1 study (A7281008) and 2 Phase 2 
studies (A7281006 and A7281007). The ontamalimab dose selection (25 mg and 75 mg) for this study is based on 
data from these 3 previous studies, which evaluated the activity of ontamalimab in adult patients with moderately to 
severely active CD based on CDAI scores between 220 and 450. The Phase 1 study (A7281008, TOSCA) and 
Phase 2 studies (A7281006, OPERA; and A7281007, OPERA II [long-term safety study]) that investigated the 
safety, tolerance, pharmacokinetics (PK), and pharmacodynamic (PD) properties of ontamalimab support further 
clinical development of ontamalimab using subcutaneous (SC) administration in subjects with moderate to severe 
CD. 
Investigational product, dose, and mode of administration: 
The test product is ontamalimab (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 ontamalimab 
solution for injection at an appropriate concentration to provide the intended dose of drug (25 mg 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: 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the 
efficacy and safety of ontamalimab in inducing clinical remission and endoscopic response in subjects with 
moderate to severe CD. 
A total of 1032 subjects (387 subjects in the 25 mg ontamalimab treatment group, 387 subjects in the 75 mg 
ontamalimab treatment group, and 258 subjects in the placebo group) 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 16-week treatment period. After the screening period, 
eligible subjects will be randomized to receive 1 of 3 treatments (25 mg ontamalimab, 75 mg ontamalimab, or 
placebo) in a 3:3:2 ratio. Randomization will be stratified based upon the subject’s status of prior antitumor necrosis 
factor (TNF) treatment (naïve or experienced), glucocorticoid use at baseline (on glucocorticoids at baseline versus 
not on glucocorticoids at baseline), and Simple Endoscopic Score for CD (SES-CD) at baseline (SES-CD ≥17 or 
SES-CD <17). Subjects will receive SC injections of ontamalimab or placebo, using a PFS, on Week 0/Day 1 
(Visit 2), Week 4 (Visit 4), Week 8 (Visit 5), and Week 12 (Visit 6). Subjects will undergo efficacy, 
, 
, 
safety, and health outcome assessments at these visits. 
At the end of the 16-week treatment period, subjects will be offered the opportunity to participate in either a 
double-blind maintenance study (SHP647-307; for subjects who fulfill the entry criteria) or a long-term safety 
extension (LTS) study (SHP647-304; for subjects who do not fulfill the entry criteria for Study SHP647-307). 
Subjects who withdraw early from the 16-week treatment period or who do not wish to enter the maintenance study 
(SHP647-307) 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 (SHP647-305 or 
SHP647-306) will be eligible to continue in the maintenance study or LTS study. 
A planned interim analysis for the coprimary endpoints will take place after approximately the first 50% of all 
randomized subjects in both the SHP647-305 and SHP647-306 studies have either completed the studies or have 
prematurely withdrawn from the studies. The sample size will be reassessed as part of this interim analysis. 
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. 
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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 active moderate to severe ileal (terminal ileum), ileocolic, or colonic CD at baseline 
(Visit 2) as defined by: 
a. 
CDAI score between 220 and 450 (inclusive) AND 
b. Meeting the following subscores in the 2-item PRO: 
i. Abdominal pain subscore ≥5 (average worst daily pain on the 11-point numerical rating 
scale [NRS]) AND abdominal pain subscore ≥2 (average daily pain on the 4-point 
abdominal pain variable of CDAI) over the 7 most recent days out of the 10 days before 
colonoscopy preparation (may or may not be contiguous) AND/OR 
ii. Average of the daily stool frequency subscore ≥4 of type 6/7 (very soft stools/liquid 
stools) as shown in the Bristol Stool Form Scale (BSFS) over the 7 most recent days out 
of the 10 days before colonoscopy preparation (may or may not be contiguous). 
AND 
c. 
Presence of ulcerations that are characteristic to CD, as determined by a colonoscopy performed 
during screening, and as defined by the SES-CD >6 (SES-CD ≥4 for isolated ileitis) 
Note that the subject must be confirmed as meeting the CDAI score and PRO subscore requirements before 
a colonoscopy is done. 
5. Subjects must have a documented diagnosis (endoscopic with histology) of CD for ≥3 months before 
screening. Documented diagnosis is defined as: 
• A biopsy report in which the description of the histological findings is consistent with the CD 
diagnosis AND 
• A report documenting disease duration based upon prior colonoscopy. 
Note: If a biopsy report is not available in the source document at the time of screening, a biopsy must be 
performed during the screening colonoscopy and the histology report should be consistent with the CD 
diagnosis. If the histology description does not support the CD diagnosis at this time point, the subject 
should not be randomized. 
6. Subjects must be willing and able to undergo a colonoscopy during screening after all other inclusion 
criteria have been met. 
7. 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 mesalamine (5-aminosalicylic acid [5-ASA]), 
glucocorticoids, immunosuppressants (azathioprine [AZA], 6-mercaptopurine [6-MP], or 
methotrexate [MTX]), or anti-TNF (see Appendix 4 of the protocol for guidance). Subjects who have had 
an inadequate response to sulfasalazine or mesalamine should have also failed at least 1 other conventional 
treatment such as glucocorticoids. 
8. Subjects receiving any treatment(s) for CD 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. 
9. 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 ulcerative colitis. 
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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 presence of enterovesical (ie, between the bowel and urinary bladder) or enterovaginal 
fistulae. 
5. Subjects with current symptomatic diverticulitis or diverticulosis. 
6. Subjects with clinically significant obstructive colonic stricture, or who have a history of bowel surgery 
within 6 months before screening, or who are likely to require surgery for CD during the treatment period. 
Subjects who have undergone previous colonic resection or ileocolectomy more than 6 months before 
screening must have at least 25 cm of colon remaining. 
7. Subjects with past medical history of multiple small bowel resections resulting in clinically significant short 
bowel syndrome. 
8. Subjects requiring total parenteral nutrition. 
9. Subjects with past medical history of bowel surgery resulting in an existing or current stoma. Subjects who 
had a j-pouch are excluded as a j-pouch could result in a stoma. 
10. Subjects have had prior treatment with ontamalimab (formerly PF-00547659; SHP647). 
11. Subjects with known or suspected intolerance or hypersensitivity to the investigational product(s), closely 
related compounds, or any of the stated ingredients. 
12. Subjects have received any nonbiologic treatment with immunomodulatory properties (other than AZA, 
6-MP, or MTX) or continuous antibiotics (>2 weeks) for the treatment of CD within 30 days before 
baseline (Visit 2). 
13. Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2). 
14. Subjects have received any biologic with immunomodulatory properties (other than anti-TNFs) within 
90 days before baseline (Visit 2). 
15. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion molecule). 
16. Subjects have received lymphocytes apheresis or selective monocyte granulocytes apheresis within 60 days 
before baseline (Visit 2). 
17. Subjects have received enteral nutrition treatment within 30 days before baseline (Visit 2). 
18. Subjects have received parenteral or rectal glucocorticoids or rectal 5-ASA within 14 days before screening 
colonoscopy. 
19. Subjects have taken >20 mg/day of prednisone, >9 mg/day of budesonide, or equivalent oral systemic 
corticosteroid dose within 14 days before baseline (Visit 2) or have taken ≥40 mg/day of prednisone or 
equivalent oral systemic corticosteroid dose within 6 weeks before baseline (Visit 2). 
20. 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 screening (Visit 1). 
21. Subjects have received a live (attenuated) vaccine within 30 days before the baseline visit (Visit 2). 
22. 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 retest 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). 
23. Subjects with abnormal chest x-ray or other imaging findings at screening (Visit 1), such as presence of 
active tuberculosis (TB), general infections, heart failure, or malignancy. (A chest x-ray, computed 
tomography scan, etc., 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.) 
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24. 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 baseline (Visit 2) 
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 the IGRA 
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. 
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 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. 
25. 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. 
26. 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). 
27. Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed. 
28. 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 
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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). 
29. Subjects who have had significant trauma or major surgery within 4 weeks before screening (Visit 1), or 
with any major elective surgery scheduled to occur during the study. 
30. Subjects with evidence of cirrhosis with or without decompensation (ie, esophageal varices, hepatic 
encephalopathy, portal hypertension, ascites).  
31. Subjects with primary sclerosing cholangitis. 
32. 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. 
33. 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]). 
34. Subjects with any of the following abnormalities in hematology and/or serum chemistry profiles during 
screening (Visit 1). 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 colonoscopy 
procedure. 
• 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. 
35. 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.  
36. 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). 
37. 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. 
38. Female subjects who are planning to become pregnant during the study period. 
39. 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 
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duration of the study and through 16 weeks after last dose of investigational product. 
40. 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: 16 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 coprimary efficacy endpoints. 
The completer set will consist of all subjects in the FAS who have completed the Week 16 assessment for this study. 
 
 
Coprimary efficacy endpoints: 
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 coprimary efficacy endpoints are: 
• 
Clinical remission at the Week 16 visit as defined by the following: 2-item PRO subscores of average worst 
daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days and average daily stool 
frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days. 
The 7 most recent days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. If fewer than 7 days 
are available, the endpoint will be calculated on all available most recent 6 or 5 days. If fewer than 5 days 
are available, the endpoint will be treated as missing. 
• 
Endoscopic response at Week 16 as measured by a decrease in SES-CD of at least 25% from baseline. 
The coprimary efficacy endpoints, clinical remission at the Week 16 visit and endoscopic response at the Week 16 
visit, will each 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, 
glucocorticoid use, and SES-CD at baseline for each of the stages of the study (stage 1 includes subjects whose 
primary efficacy data are used in the interim analysis and stage 2 includes all other subjects. Note: classification of 
stage 1 and stage 2 is based on the time of randomization rather than the time of study completion or termination). 
Subjects with missing data at the Week 16 visit will be considered failures and counted as nonresponders. 
Weighted inverse normal p-value combination methods are used to combine the p-values from stage 1 and stage 2 
through the following formula: 
C(p1, p2) = 1 – Φ[w1 Φ-1(1-p1)+ w2 Φ-1(1-p2)] 
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Where p1, p2 are the p-values computed from the CMH chi-square test for each stage, wi2 = ni/(n1 + n2), n1 and n2 are 
the preplanned stage-wise sample sizes that are fixed at the time of the interim analysis based on an original total 
sample size, and Φ denotes the cumulative distribution function of the standard normal distribution (Bretz, et al., 
2009a). Given that there is no possibility of stopping early for efficacy, that any potential stopping for futility of 
either or both doses of ontamalimab is nonbinding, and that weights are prespecified, the test statistic C(p1, p2) can 
be compared against the nominal alpha level to assess statistical significance (Chang and Chow, 2008). 
The coprimary endpoints will each be tested by the following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
Where δ is the common treatment difference across strata. 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 coprimary and key secondary 
endpoints will be strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in Bretz et 
al. (2009b) will be utilized to propagate α from the coprimary endpoints to the 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 coprimary endpoints (P) and alpha is propagated in 
a hierarchical manner to each of the 6 key secondary endpoints (K1–K6) within a pairwise treatment comparison. In 
order to pass alpha between the coprimary endpoints and the first key secondary endpoint, both coprimary endpoints 
must attain statistical significance. 
Key secondary efficacy endpoints: 
The key secondary efficacy endpoints are as follows: 
• 
Clinical remission at the Week 16 visit as measured by a CDAI score of <150. 
• 
Enhanced endoscopic response at Week 16 as measured by a decrease in SES-CD of at least 50% from 
baseline. 
• 
Clinical remission at the Week 16 visit as defined by the following: 2-item PRO subscores of average daily 
abdominal pain ≤1 (based on the 4-point scale) over the 7 most recent days and average daily stool 
frequency ≤3 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days. 
The 7 most recent days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. If fewer than 7 days 
are available, the endpoint will be calculated on all available most recent 6 or 5 days. If fewer than 5 days 
are available, the endpoint will be treated as missing. 
• 
Clinical response at the Week 16 visit as measured by the 2-item PRO and defined as meeting at least 1 of 
the following 2 criteria: 
o 
A decrease of ≥30% and at least 2 points from baseline in the average daily worst abdominal pain over 
the 7 most recent days*, with the average daily stool frequency of type 6/7 (very soft stools/liquid 
stools) either: 
(a) Not worsening from baseline 
and/or 
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average daily stool 
frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent 
days* 
o 
A decrease of ≥30% from baseline in the average daily stool frequency of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days*, with the average daily worst 
abdominal pain either: 
(a) Not worsening from baseline 
and/or 
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average worst daily 
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abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days* 
*Note: The 7 most recent days may or may not be contiguous during the 10 days of data collection 
before colonoscopy preparation, depending on days to be excluded because of missing data. If fewer 
than 7 days are available, the endpoint will be calculated on all available most recent 6 or 5 days. If 
fewer than 5 days are available, the endpoint will be treated as missing. 
• 
Clinical remission with endoscopic response, ie, both clinical remission by 2-item PRO and endoscopic 
response, as measured by a decrease in SES-CD of at least 25% at Week 16 (composite endpoint) 
• 
Complete endoscopic healing at Week 16 defined as SES-CD=0-2. 
The key secondary endpoints will be analyzed using the same approach as described for the coprimary endpoints. 
Subjects with missing key secondary endpoint data at the Week 16 visit will be considered failures and counted as 
nonresponders. 
Other secondary efficacy endpoints: 
• 
Clinical response at the Week 16 visit as measured by at least a 100-point reduction in the CDAI from 
baseline (CDAI-100 response) 
• 
Clinical response at the Week 16 visit as measured by at least a 70-point reduction in the CDAI from 
baseline (CDAI-70 response) 
• 
Clinical remission over time, as measured by the 2-item PRO 
• 
Change from baseline in total stool frequency, rectal bleeding frequency, rectal urgency frequency, nausea 
severity, vomiting frequency, and rectal incontinence frequency scores; and total sign/symptom score based 
on subject daily electronic diary entries 
• 
Endoscopic healing at Week 16 as measured by SES-CD ≤4 and at least 2-point reduction versus baseline 
and no subscore >1 in any individual variable 
• 
Change from baseline in IBDQ domain and total (absolute) scores over time 
• 
Change from baseline in SF-36, version 2, acute (physical and mental component summary scores and 
individual domain scores) over time 
• 
Incidence of all cause hospitalizations and total inpatient days 
• 
Incidence of CD-related surgeries and other surgical procedures during the entire study period. 
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 compared between each active treatment group and the placebo group using a 
CMH chi-square test stratified by status of prior anti-TNF treatment, glucocorticoid use at baseline, and 
SES-CD at baseline. 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 the p-value 
computed from CHM test will be provided. Subjects with missing binary endpoint data at the Week 16 visit 
will be considered failures and counted as nonresponders. 
• 
Continuous endpoints that are only measured at baseline and the Week 16 visit will be analyzed using an 
analysis of covariance model with fixed effects for treatment group (categorical), status of prior anti-TNF 
treatment (categorical), glucocorticoid use at baseline (categorical), and SES-CD at baseline (Visit 2) 
(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), glucocorticoid use at baseline (categorical), and SES-CD 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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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 (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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
84 ±3 
 
 
112 ±3 
168 ±7 
224 ±7 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
X 
 
 
 
 
 
 
Xd 
 
 
Demographics and medical 
historye 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examinationf 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Targeted physical 
examinationf 
 
X 
X 
 
X 
X 
X 
 
 
 
 
 
Targeted neurological 
assessmentg 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Vital signs 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
12-lead ECG 
X 
 
X 
 
 
 
 
 
 
X 
 
 
Chest x-rayh 
X 
 
 
 
 
 
 
 
 
 
 
 
Contraception checki 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
X 
Laboratory Assessments 
Hematology 
Xj,k 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Serum chemistry 
Xj 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Urinalysis 
Xj 
 
X 
 
X 
X 
X 
X 
 
 
 
X 
Stool microbiologyl 
Xj 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, HBcAb, HCVAbm 
Xj 
 
 
 
 
 
 
 
 
 
 
 
HIV testing per local 
regulationn 
X 
 
 
 
 
 
 
 
 
 
 
 
FSHo 
Xj 
 
 
 
 
 
 
 
 
 
 
 
Serum β-hCGp 
Xj 
 
 
 
 
 
 
 
 
 
 
 
Urine β-hCGp 
 
 
X 
 
X 
X 
X 
 
 
X 
 
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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
84 ±3 
 
 
112 ±3 
168 ±7 
224 ±7 
TB test (PPD or 
QuantiFERON-TB Gold 
Plus)q 
X 
 
 
 
 
 
 
 
 
 
 
 
JCV antibody banked 
sampler 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
ADA and NAb sampling 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Endoscopic Procedure 
Colonoscopy (including 
biopsy)s 
 
X 
 
 
 
 
 
 
X 
 
 
 
CD Assessments 
CDAIt 
 
X 
 
 
X 
X 
X 
 
 
X 
 
 
PRO-CD daily e-diary data 
instruction 
X 
 
 
 
 
 
 
 
 
 
 
 
PRO-CD daily e-diary datau 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
SES-CDv 
 
 
X 
 
 
 
 
 
 
X 
 
 
Health Assessmentw 
IBDQ 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
Hospitalizations, inpatient 
days, 
 (HRUA) 
 
 
 
 
X 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
SF-36, version 2, acute 
 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
84 ±3 
 
 
112 ±3 
168 ±7 
224 ±7 
Treatment Procedures 
Randomizationx 
 
 
X 
 
 
 
 
 
 
 
 
 
Administration of 
ontamalimab or placebox, y 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
Hypersensitivity monitoringz 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior medications 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
and procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense stool collection kit 
for stool sampleaa 
X 
 
 
 
 
X 
X 
 
 
 
 
 
ADA=antidrug antibody; β-hCG=beta-human chorionic gonadotropin; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; 
; 
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; 
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; 
 
; 
; PML=progressive multifocal leukoencephalopathy; PPD=purified protein derivative; 
PRO=patient-reported outcome; SES-CD=Simple Endoscopic Score for CD; SF-36 v2=Short Form-36 Health Survey, version 2; TB=tuberculosis; 
 
 
a 
Screening assessments will take place over more than 1 day (at least 2 visits will be necessary to complete the screening evaluations, including colonoscopy).  
b 
Subjects who withdraw early during the treatment period should return for the ET visit and then enter into the safety follow-up period. The Week 16 (Visit 7) and ET visits 
consist of 3 parts: 
• 
Part 1 of Visit 7 can either be done on the same day as Part 2 or be done up to 3 day(s) before Part 2. If Parts 1 and 2 are done on the same day, blood samples must 
be taken before starting the colonoscopy preparation 
• 
Part 2 of Visit 7 must be completed within 10 days (preferably within 5 to 7 days) before Part 3; this will allow sufficient time to obtain the data from the centrally 
read colonoscopy 
• 
Part 3 of Visit 7 will take place on Day 112 ±3 days. 
c 
Subjects NOT entering the maintenance study (SHP647-307) or LTS (SHP647-304) study at the completion of the Week 16 visit will need to complete the safety follow-up 
assessments. The Week 24 (Visit 8) 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 32 (Visit 9) visit will take place at the study site. 
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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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
84 ±3 
 
 
112 ±3 
168 ±7 
224 ±7 
d 
The outcome of Visit 7, Part 3 is used to assess eligibility to enroll subjects in the maintenance (SHP647-307) or LTS (SHP647-304) studies. Please refer to the respective 
protocols for further details. 
e 
Medical history will include CD history, cardiac history, and smoking history. 
f 
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; 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 and mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, eyes, abdomen, and examination of body 
systems where there are symptom complaints by the subject. 
g 
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. 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. 
h 
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. 
i 
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. 
j 
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 before the screening colonoscopy procedure. 
k 
Hematology samples should be repeated if more than 3 weeks have elapsed before the day of colonoscopy to be able to use the hematocrit central laboratory results for the 
CDAI score calculation at screening. 
 
Note: Hematocrit must NOT be older than 3 weeks before the day of colonoscopy. 
l 
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 
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. 
m 
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. 
n 
Testing may be performed at the site’s local laboratory in accordance with country requirements, or at the central laboratory. Documentation of a negative HIV test result 
within 6 months prior to screening will be accepted. 
o 
For confirmation of postmenopausal status in females who have had 12 consecutive months of spontaneous amenorrhea and are ≥51 years of age. 
p 
Female subjects of childbearing potential; serum pregnancy test at screening (Visit 1) and urine pregnancy test at all other time points.  
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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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
84 ±3 
 
 
112 ±3 
168 ±7 
224 ±7 
q 
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. 
r 
A serum sample will be collected and banked. It may be analyzed if a subject shows neurological symptoms suggestive of PML. 
s 
Colonoscopy preparation will be according to local routine (see Section 7.2.2.4). Colonoscopy must be performed during the screening period, preferably within 5 to 7 days but 
no later than 10 days before baseline (Visit 2), to allow for adequate e-diary data collection for the 2-item PRO and CDAI scores and to obtain the centrally read endoscopic 
subscore to verify the subject’s eligibility. Colonoscopy preparation may be done on the same day as the colonoscopy procedure. During the colonoscopy at screening (Visit 1, 
Part 2) and Week 16/ET, 10 biopsies will be collected from the most inflamed area of the mucosa; 2 samples each from the ileum, the 3 segments of the colon, and the rectum 
except when it is not possible due to impassable stenosis or previous partial colectomy/ileocolectomy. If the calculated CDAI scores is <220 or >450, or the PRO scores are 
outside the eligibility thresholds, the subject will be considered a screen failure and should not proceed with the colonoscopy preparation and/or the colonoscopy. 
t 
The CDAI score at screening (Visit 1, Part 2) includes subject-reported PRO-CD daily e-diary data collected >10 days before the start of colonoscopy preparation. 
 
The CDAI score at Visits 4, 5, and 6 includes subject-reported PRO-CD daily e-diary data collected >10 days before the visit. 
 
The CDAI score at the Week 16/ET visit will be calculated at Visit 7, Part 3 (after all evaluations are complete) and includes subject-reported PRO-CD daily e-diary data 
collected >10 days before the start of colonoscopy preparation. 
 
Note: All required components (including subject-reported PRO-CD daily e-diary data collected >10 days before the start of colonoscopy preparation and <3 weeks of central 
hematocrit results) should be available to calculate the CDAI scores. See Section 7.2.2.3 for further details. 
u 
Patient-reported CD clinical signs and symptoms will be collected daily using a PRO-CD daily e-diary (electronic handheld device) starting during the screening period; 
however, collection of the daily e-diary data must begin at least 10 days before colonoscopy preparation. Subjects should be provided with the e-diary to take home on their 
first visit. Compliance will be assessed by the site staff and the subject should be retrained on the appropriate use of the e-diary when compliance is below 80% (eg, <23 out of 
28 e-diary entries). If at least 70% compliance cannot be achieved after repeated instructions during the screening period, noncompliant subjects will be automatically 
noneligible as they will not fulfill inclusion criterion 1 (see Section 4.1). If 7 out of the 10 most recent days are not available, then the 2-item PRO cannot be calculated for the 
subject at screening. 
v 
The SES-CD score at baseline (Visit 2) and at Week 16/ET will be calculated using subscores of each of the segments investigated and centrally read from the colonoscopies 
performed at screening (Visit 1, Part 2) and Week 16 (Visit 7, Part 2), respectively. 
w 
All health outcome or patient-reported questionnaires should be completed before completing any other visit assessments. 
x 
Interactive response technology will be used for randomization and dispensation of study treatment. 
y 
Where applicable, specified procedures and laboratory samples should be collected before investigational product administration. 
z 
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.  
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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 
Week 16/ETb 
Week 
24c 
Week 
32c 
Visit Number 
1 
(Part 1)a 
1 
(Part 2)a 
2 
3 
4 
5 
6 
7 
(Part 1)b 
7 
(Part 2)b 
7 
(Part 3)b 
8 
9 
Study Day 
-42 to 0 
1 
14 ±3 
28 ±3 
56 ±3 
84 ±3 
 
 
112 ±3 
168 ±7 
224 ±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 
Crohn’s disease (CD) is a chronic, relapsing disease marked by granulomatous inflammation of 
the gastrointestinal (GI) tract. Although the terminal ileum and right colon are the most 
commonly involved sites, CD can affect any part of the GI tract, from the mouth to the perianal 
region. Inflammation is typically transmural (full-thickness), segmental, and discontinuous, and 
symptoms are predominantly determined by the part of bowel or organ involved. Patients 
typically present with symptoms including abdominal pain, diarrhea, rectal bleeding, which may 
be persistent and lead to anemia, and weight loss due to pain on eating and malabsorption. As the 
disease progresses, extraintestinal manifestations and associated conditions can develop, 
including bowel obstruction, fistulas, and stenosis, as well as painful skin ulcerations, eye pain, 
and arthritis. 
The incidence of CD is estimated to be up to 12.7 cases per 100,000 persons per year in Europe 
and up to 20.2 cases per 100,000 persons per year in North America. No clear difference in 
incidence has been observed between men and women. Although CD can occur at any age, peak 
incidence has been observed in the second to fourth decades of life, with a second modest rise in 
incidence in the latter decades of life (Molodecky et al., 2012). 
Crohn’s disease is a lifelong condition with a serious effect on quality of life. The traditional 
approach to therapy of CD has been the step-up approach usually represented as a pyramid 
where, progressing from mild to severe disease, therapeutic choices proceed step by step from 
less potent drugs at the base of the pyramid to more potent but also more toxic drugs at the top. 
Current treatment primarily consists of symptomatic management with dietary modifications, 
5-aminosalicylic acid (5-ASA), opiates (loperamide), systemic glucocorticoids, 
immunosuppressive agents (azathioprine [AZA], 6-mercaptopurine [6-MP], 
methotrexate [MTX]), and biologic therapy with anti-tumor necrosis factor (TNF) agents or 
anti-integrin agents. Despite recent advances, there is still an unmet need for a safe, effective, 
and durable 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 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 (Shyjan et al., 
1996; Briskin et al., 1997; 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. 
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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. 
1.3 
Benefit/Risk Assessment 
Ontamalimab has been evaluated in Phase 1 and Phase 2 clinical studies in subjects with CD and 
ulcerative colitis (UC). 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 (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 C-reactive protein 
(CRP) or Simple Endoscopic Score for CD (SES-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 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 
high-sensitivity (hs)CRP 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. In the UC induction study, 
A7281009, decreases in fecal calprotectin were observed in all groups, including placebo; 
however, there were no nominally statistically significant differences in the decrease in fecal 
calprotectin between any dose level of ontamalimab 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 
nominally significant differences were observed in active treatment vs placebo. 
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. 
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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 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 CD. 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 CD is well established (Sandborn et al., 2013). 
Ontamalimab is differentiated from other molecules used for the treatment of CD in that it blocks 
the interaction of α4β7+ lymphocytes with 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 and safety of ontamalimab in inducing clinical 
remission and endoscopic response in subjects with moderate to severe CD. 
The CD clinical development program includes 3 completed studies: 1 Phase 1 study 
(A7281008) and 2 Phase 2 studies (A7281006 and A7281007). 
Study A7281006 (OPERA) was a parallel, dose-ranging, randomized, double-blind, 
placebo-controlled study in which ontamalimab was given as 3 subcutaneous (SC) dose levels 
(22.5 mg, 75 mg, and 225 mg) Q4W over an 8-week period. Ontamalimab was generally safe 
and well tolerated and there were no deaths. Three placebo-treated subjects and 9 subjects in the 
22.5 mg, 75 mg, and 225 mg ontamalimab groups discontinued treatment due to adverse events 
(AEs). Most TEAEs were mild or moderate in severity. Median serum concentrations of 
ontamalimab increased with increasing dose. Positive antidrug antibody (ADA) status did not 
appear to impact exposure to ontamalimab. The CDAI was the primary instrument to assess the 
efficacy of ontamalimab; no statistically significant differences were noted between the active 
treatment arms and the placebo arm. Therefore, the study did not meet its primary endpoint. 
However, post hoc analysis indicated increased remission rates in subjects in the 22.5 mg or 
75 mg treatment arms who had higher serum concentrations of hsCRP or higher scores of 
SES-CD at baseline. 
Study A7281008 (TOSCA) was an open-label multi-center, Phase 1 sequential cohort study that 
evaluated the effects of a maximum induction dose of ontamalimab on CNS system immune 
surveillance.  
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Subjects with inflammatory bowel disease (IBD) (including CD), with or without stoma, who 
failed or were intolerant to both anti-TNF and immunosuppressant therapy and who had 
moderate to severe active disease underwent a lumbar puncture (LP), completed induction 
therapy with 3 doses of 225 mg ontamalimab 4 weeks apart, and then underwent a second LP 
2 (±1) weeks later. The primary endpoint was the percent change from baseline (pretreatment) in 
absolute lymphocyte count in cerebrospinal fluid (CSF) in subjects with IBD after receiving 
3 doses of 225 mg ontamalimab. The mean percentage change from baseline in absolute 
lymphocytes in CSF was 61.76% with a median change of 35.2% (range: -70.2% to 267.8%). 
The post-treatment LP/pretreatment LP geometric mean ratio for CSF lymphocytes was 1.33 
with the lower bound of the 80% confidence interval (CI)=1.13, which was greater than 0.5, 
supporting rejection of the null hypothesis (ie, that the percent decrease in total lymphocytes 
counts after treatment would be ≥50% (equivalent to the geometric mean ratio in total 
lymphocyte counts being ≤0.5). This result supports the hypothesis that ontamalimab does not 
impair trafficking of lymphocytes into the CNS and thus should not impair CNS immune 
surveillance. 
Study A7281007 (OPERA II) was a Phase 2 open-label extension study to provide additional 
long-term safety data on subjects with moderate to severe CD who completed Study A7281006 
or Study A7281008 and wished to continue to receive ontamalimab. Ontamalimab 75 mg (with 
potential dose escalation to 225 mg) SC given Q4W for 72 weeks was generally well tolerated in 
subjects with CD over the treatment period evaluated in this study. In subjects with positive 
ADA or neutralizing antibody (NAb) status, exposure to ontamalimab was not affected. Serum 
concentrations of ontamalimab in this study were consistent with what was predicted based on 
the Feeder Study A7281006. There were 2 deaths in the study: 1 subject died of multiple organ 
dysfunction syndromes in the treatment period and 1 subject died of metastatic neoplasm in the 
follow-up period. Neither death was reported as related to treatment with the investigational 
product by the investigators. The most frequently reported SAE was CD in either the treatment 
period or the follow-up period. The SOC with the most subjects experiencing TEAEs was GI 
disorders. Although Study A7281007 was not placebo controlled, the exploratory efficacy results 
(based on the modified Harvey Bradshaw Index) indicated that the effect of ontamalimab on 
disease activity was maintained over the duration of treatment. 
The ontamalimab dose selection (25 mg and 75 mg) for this study is based on data from these 
3 previous studies, which evaluated the activity of ontamalimab in adult patients with moderately 
to severely active CD based on CDAI scores between 220 and 450. The results of a post hoc 
analysis of remission rate by baseline elevated serum concentration of hsCRP suggested that the 
greatest treatment effect was at a dose of 22.5 mg. Similarly, post hoc analysis of remission rates 
by endoscopic severity assessed using the SES-CD suggested best efficacy at a dose of 75 mg. 
Therefore, both dosage regimens 25 mg and 75 mg Q4W have been selected for the Phase 3 
testing. The Phase 1 study (A7281008, TOSCA) and Phase 2 studies (A7281006, OPERA; and 
A7281007, OPERA II [long-term safety study]) that investigated the safety, tolerance, PK, and 
pharmacodynamic (PD) properties of ontamalimab support further clinical development of 
ontamalimab using SC administration in subjects with moderate to severe CD. 
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2.2 
Study Objectives 
2.2.1 
Coprimary Objectives 
The coprimary objectives of this study are to evaluate the efficacy of ontamalimab in subjects 
with moderate to severe CD in: 
• Inducing clinical remission based on 2-item patient-reported outcome (PRO) (abdominal 
pain severity and very soft stool/liquid stool frequency) 
• Inducing endoscopic response based on centrally read colonoscopy. 
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 inducing clinical remission as measured by 
CDAI 
• To evaluate the efficacy of ontamalimab in inducing enhanced endoscopic response 
based on centrally read colonoscopy 
• To evaluate the efficacy of ontamalimab in inducing clinical remission based on 
abdominal pain severity and very soft stool/liquid stool frequency (alternate thresholds) 
• To evaluate the efficacy of ontamalimab in inducing clinical response based on 
patient-reported clinical signs and symptoms (as measured by 2-item PRO) 
• To evaluate the efficacy of ontamalimab in inducing clinical remission based on 
patient-reported clinical signs and symptoms (as measured by 2-item PRO) as well as 
inducing endoscopic response based on centrally read colonoscopy in the same subject 
• To evaluate the efficacy of ontamalimab in inducing endoscopic healing based on 
centrally read colonoscopy. 
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 outcomes 
(clinical response defined by CDAI, or clinical remission over time, or change from 
baseline in frequency in CD-related clinical parameters) 
• To evaluate the effect of ontamalimab induction treatment on other endoscopic outcomes 
• 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 
• To evaluate the impact of ontamalimab on incidence of CD-related and other surgeries. 
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2.2.3 
Exploratory Objectives 
The exploratory objectives 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 clinical remission and endoscopic 
response in subjects with moderate to severe CD. 
A total of 1032 subjects (387 subjects in the 25 mg ontamalimab treatment group, 387 subjects in 
the 75 mg ontamalimab treatment group, and 258 subjects in the placebo group) 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 16-week treatment period. After the 
screening period, eligible subjects will be randomized to receive 1 of 3 treatments 
(25 mg ontamalimab, 75 mg ontamalimab, or placebo) in a 3:3:2 ratio. Randomization will be 
stratified based upon the subject’s status of prior anti-TNF treatment (naïve or experienced), 
glucocorticoid use at baseline (on glucocorticoids at baseline versus not on glucocorticoids at 
baseline), and SES-CD at baseline (SES-CD ≥17 or SES-CD <17). 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), Week 8 (Visit 5), and Week 12 (Visit 6). Subjects will undergo 
efficacy, 
, 
, safety, and health outcome assessments at these visits as detailed in 
Table 1. 
At the end of the 16-week treatment period, subjects will be offered the opportunity to participate 
in either a double-blind maintenance study (SHP647-307; for subjects who fulfill the entry 
criteria) or a long-term safety extension (LTS) study (SHP647-304; for subjects who do not 
fulfill the entry criteria for Study SHP647-307) as shown in Figure 1. Subjects who withdraw 
early from the 16-week treatment period or who do not wish to enter the maintenance study 
(SHP647-307) 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 (SHP647-305 or SHP647-306) will be eligible to continue in the 
maintenance study or LTS study. 
A planned interim analysis for the coprimary endpoints will take place after approximately the 
first 50% of all randomized subjects in both the SHP647-305 and SHP647-306 studies have 
either completed the studies or have prematurely withdrawn from the studies. The sample size 
will be reassessed as part of this interim analysis. See Section 9.5 for further details of the 
planned interim analysis. 
The overall study design is shown in Figure 2. 
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Figure 1 
Overview of Ontamalimab Phase 3 Studies in Crohn’s Disease 
 
BSFS=Bristol Stool Form Scale; CDAI= Crohn’s Disease Activity Index; NRS=numerical rating scale; PRO=patient-reported 
outcome; SES-CD=Simple Endoscopic Score for Crohn’s Disease 
a Responders are subjects who either: 
(a) Meet endoscopic response criteria of a reduction in SES-CD from baseline by ≥25% at Week 16 
OR 
(b) Meet at least 1 of the following 4 criteria at Week 16 in addition to no worsening of endoscopic score as measured by 
SES-CD relative to induction study baseline (SHP647-305 or SHP647-306): 
1. Subject is in clinical remission as determined by meeting the criteria for clinical remission using the 2-item PRO, ie, 2-item 
PRO subscore of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days and average daily 
stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days.* 
2. Subject has a decrease of at least 100 points in CDAI score (CDAI-70) from baseline. 
3. Subject has a decrease of ≥30% and at least 2 points from baseline in the average daily worst abdominal pain over the 7 most 
recent days*, with the average daily stool frequency of type 6/7 (very soft stools/liquid stools) either: (i) not worsening from 
baseline and/or (ii) meeting the criteria for clinical remission, ie, 2-item PRO subscore of average daily stool frequency ≤2 of 
type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days.* 
4. Subject has a decrease of ≥30% from baseline in the average daily stool frequency of type 6/7 (very soft stools/liquid stools) as 
shown in the BSFS over the 7 most recent days*, with the average daily worst abdominal pain either: (a) not worsening from 
baseline and/or (b) meeting the criteria for clinical remission, ie, 2-item PRO subscore of average worst daily abdominal pain 
≤3 (based on 11-point NRS) over the 7 most recent days*. 
*Note: The 7 most recent days may or may not be contiguous during the 10 days of data collection before colonoscopy 
preparation, depending on days to be excluded because of missing data. If fewer than 7 days are available, the criterion will be 
calculated on all available most recent 6 or 5 days. If fewer than 5 days are available, the criterion will be treated as missing. 
Placebo 
25 mg
75 mg
Non-Respondersa
Induction
(SHP647-305, SHP647-306) 
Maintenance
(SHP647-307) 
Long-term Safety 
Extension
(SHP647-304) 
25 mg
Placebo
75 mg
Placebo
Placebo
Respondersa
Respondersa
Respondersa
75 mg
25 mg
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Figure 2 
Study Design Flow Chart 
 
LTS=long-term safety extension; W=week 
a Subjects who withdraw early from the 16-week treatment period or who do not wish to enter the maintenance study 
(SHP647-307) or LTS study (SHP647-304) will continue into a 16-week safety follow-up period. 
Note: A planned interim analysis for the coprimary endpoints will take place after approximately the first 50% of all randomized 
subjects in both the SHP647-305 and SHP647-306 studies have either completed the studies or have prematurely withdrawn from 
the studies. 
 
3.1.1 
Rationale for Coprimary Endpoints 
In this study, clinical remission, as measured by a decrease below prespecified thresholds in the 
2-item PRO (abdominal pain severity and very soft stool/liquid stool frequency [as shown in the 
Bristol Stool Form Scale, BSFS]), and enhanced endoscopic response, as measured by a decrease 
in SES-CD, will be the primary instruments to assess the efficacy of ontamalimab. 
Rationale for Abdominal Pain Severity 
Abdominal pain is one of the most common symptoms of CD, with the cause likely to be 
multifactorial. In the CDAI, which was the most commonly used primary endpoint in CD studies 
in the past, the degree of abdominal pain was based on a 4-point scale, with scores ranging from 
0 (none) to 3 (severe). However, the new standard is to use the 11-point numerical rating scale 
(NRS) instead for the degree of abdominal pain. The limitation is that the 4-point and the 
11-point scales are not directly comparable. Numerous studies across a variety of conditions 
have examined cutoff scores for mild, moderate, and severe pain based on the 11-point pain 
NRS, with the findings across studies generally converging on a cutoff score of 4 (reflecting the 
maximum score indicating mild pain) and a score of 5 (reflecting the minimum score indicating 
moderate pain). To ensure that clinical remission criteria for abdominal pain are both clinically 
meaningful and fall definitively within the mild pain range on the NRS based on the literature, a 
remission subscore of ≤3 (a minimum improvement of at least 2 points is required for subjects 
who enter the study with moderate abdominal pain [subscore of ≥5]) will be used as part of the 
coprimary endpoints. This definition is further supported by a study conducted in a similar 
Placebo 
25 mg ontamalimab 
75 mg ontamalimab 
Screening: Up to 
6 weeks 
Randomization 
Maintenance study 
(SHP647-307) 
or 
LTS study 
(SHP647-304) 
or 
16-week safety 
follow-up perioda 
W0 
W4 
Dosing:
Treatment period: 16 weeks 
Week 16/End of 
Treatment 
W8 
W12 
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condition (irritable bowel syndrome) that examined the minimal clinically important difference 
on the 11-point NRS for abdominal pain (Spiegel et al., 2009) as well as post hoc analyses of the 
Phase 2 data from the ontamalimab program (Study A7281006, OPERA). 
Rationale for Very Soft Stool/Liquid Stool Frequency 
Diarrhea is the most common sign in the presentation of CD, affecting approximately 85% of 
patients with a diagnosis of CD. In the CDAI, the number of liquid or soft stools (each day for 
7 days) is used with a multiplier of 2. The coprimary endpoints for clinical remission in studies 
SHP647-305 and SHP647-306 requires the use of a definition without any such multiplying 
factor and will use the BSFS for defining the very soft or liquid stools according to types 6 and 7, 
respectively. A retrospective study of PROs in CD based on data from randomized controlled 
studies using rifaximin and MTX showed that a mean daily stool frequency score of ≤1.5 had an 
area under the receiving operating characteristic curve of 0.79 (Khanna et al., 2015) and 
provided a potential cutoff for defining remission as measured by CDAI. In a recent study to 
select the attributes determining overall disease severity and to rank the importance of and to 
score these individual attributes for both CD and UC based on specialist opinion, a sample of at 
least 10 loose stools per week was considered as an attribute contributing to overall disease 
severity in CD (Siegel et al., 2016). Based on post hoc analyses of the Phase 2 data in the 
ontamalimab program (Study A7281006, OPERA) and by choosing the population of subjects 
satisfying the moderate to severe CD inclusion criteria, various cutoffs were explored and a stool 
frequency ≤2.0 was found to be optimal in terms of treatment separation while still allowing for 
a reasonable threshold for remission. Based on these and other recent data that support this 
cutoff, an average daily stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) has been 
chosen as the stool frequency criterion for clinical remission. 
Endoscopic Response 
Endoscopic response is defined in 2 ways: 
• 25% reduction in SES-CD score (“endoscopic response”) 
• 50% reduction in SES-CD score (“enhanced endoscopic response”). 
“Endoscopic response” will be used as a coprimary endpoint and “enhanced endoscopic 
response” will be used as a key secondary endpoint in this study as these magnitudes of changes 
are likely to be clinically relevant. In the recent trial with upadacitinib, the magnitude of 
difference between the different doses of the active drug and placebo at Week 16 was reported to 
be 9% to 36% for endoscopic response and 10% to 20% for enhanced endoscopic response 
(Sandborn et al., 2017). In the post hoc analysis of the Phase 2 OPERA study with ontamalimab 
the magnitude of difference between the active treatment arms and placebo showed a similar 
pattern (higher for the endoscopic response than for enhanced endoscopic response) (D'Haens et 
al., 2018). 
Mucosal healing or “endoscopic healing” is considered to be a pivotal long-term target in the 
treatment of CD; however, partial healing or endoscopic response may also provide benefits. 
Endoscopic response can be an important indicator that the mucosal inflammation has decreased 
as an effect of the investigational product. Some treatments may result in a partial initial 
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response, even though at a later stage a complete response may occur. Median duration of 
remission after 1 year treatment with infliximab was similar in subjects achieving complete 
absence of mucosal ulcer to subjects who achieved significant but incomplete mucosal healing 
(D'Haens et al., 2002).  
The benefit of endoscopic response was also shown in the SONIC study; the presence of 
endoscopic response (defined in that study as at least a 50% decrease in endoscopic score at 
Week 26 of treatment) identified subjects most likely to be in corticosteroid-free clinical 
remission at Week 50 (Ferrante et al., 2013). The proportion of patients requiring major 
abdominal surgery in a single-center cohort study with infliximab was similar with complete 
healing or with partial healing. (Schnitzler et al., 2009; Panaccione et al., 2013). Subjects with 
such a treatment response should be identified by endoscopic assessment in order not to 
misclassify them as nonresponders and underestimate the response to the treatment. 
3.1.2 
Rationale for Key Secondary Endpoints 
Clinical Remission Defined by CDAI Score 
Conventionally, a CDAI score of <150 has been used to define clinical remission. While there 
has been widespread use of the CDAI over a long period of time, the items do not contribute 
equally to the score, and symptom items reported by subjects are not specific for CD and are not 
sensitive for inflammation seen at colonoscopy. There has been movement away from using the 
CDAI by regulatory authorities to the use of PROs and objective measures of disease such as 
endoscopy (Williet et al., 2014). However, for benchmarking or for comparative effectiveness 
purposes, CDAI endpoints are expected to be used. 
Although this has been the established gold-standard for clinical remission to date, CDAI suffers 
from requiring complex calculations across 8 individual items including subjective elements. 
Clinical Remission Defined by Average Daily Abdominal Pain ≤1 (Based on the 4-point Scale) 
and Average Daily Stool Frequency ≤3 of Type 6/7 
The CDAI has been the traditionally used measure to assess clinical response and clinical 
remission in CD. In the CDAI, the degree of abdominal pain is one of 8 variables and is used 
with a multiplier of 5 in the overall score. Importantly, it is based on a 4-point scale, with scores 
ranging from 0 (none) to 3 (severe). With the shift to the new endpoint as evident from the 
coprimary endpoint of clinical remission in this study, it is still important to allow for a frame of 
reference to the existing standard for response, based on the CDAI components. A daily average 
abdominal pain threshold of ≤1 will help achieve this as 1 on the 4-point scale corresponds to 
mild abdominal pain. Although direct mapping between the scales has not been established, this 
will approximate to a score of 3 on the 11-point NRS scale, as this falls within the mild pain 
range on the NRS based on the literature. 
Based on post hoc analyses of the Phase 2 data in the ontamalimab program, regulatory 
requirements, and treatment separation assumptions, a threshold for the average daily stool 
frequency ≤2 of type 6/7 (very soft stools/liquid stools) was chosen for the coprimary endpoint 
of clinical remission. However, given the limited data available for this endpoint, recent evidence 
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from literature suggesting that thresholds ≤3 are likely to be quite stringent (Sandborn et al., 
2017), and the refractory nature of the disease in those with moderate to severe CD, it is also 
important to assess the effects of treatment using a more realistic measure. Hence, for this key 
secondary endpoint of clinical remission, average daily stool frequency ≤3 of type 6/7 (very soft 
stools/liquid stools) has been chosen as the appropriate threshold. 
Clinical Response 
The goal of measuring clinical remission is to have a sensitive clinical measure to assess the 
complete absence of symptoms or the stabilization of noninflammatory symptoms. However, as 
response and remission are considered to be on a continuum of improvement or response to 
treatment, clinical remission is generally the chosen measurement over clinical response. 
Therefore, clinical remission is used as coprimary endpoint and clinical response is used as a 
key secondary endpoint in this study. 
Clinical response is defined in Section 9.8.2.1. For both clinical response criteria, an additional 
requirement is that the symptom not being used to assess clinical response (ie, abdominal pain 
severity or very soft stool/liquid stool frequency) must remain unchanged/not worsen from the 
baseline score, or meet the criteria for clinical remission for that item of the 2-item PRO (either a 
2-item PRO subscore of average daily stool frequency ≤2 of type 6/7 [very soft stools/liquid 
stools] as shown in the BSFS or average worst daily abdominal pain ≤3 [based on 11-point NRS] 
over the 7 most recent days). 
The rationale for needing to meet at a minimum clinical response definition for either abdominal 
pain severity or very soft stool/liquid stool frequency (and not necessarily both) is based on the 
supposition that a lack of improvement in 1 of these symptoms is not necessarily an indicator of 
eventual lack of response (as assessed by the stricter clinical remission criterion). Based on 
Phase 2 data, it has been observed that the magnitude of placebo response rate can be higher for 
abdominal pain than for stool frequency. Therefore, the additional criterion of at least a 2-point 
decrease in abdominal pain severity from baseline is required for assessing clinical response for 
abdominal pain. Overall, the definition of clinical response used for this study has been chosen to 
allow for the maximal pool of subjects to be assessed for the effect of treatment and, if 
appropriate, the continuation of therapy in the maintenance study (SHP647-307). 
Composite Score Endpoint of Both Clinical Remission by 2-item PRO and Endoscopic Response 
at Week 16 
In theory, as the degree of inflammation decreases due to the effect of treatment, both clinical 
signs and symptoms of CD as well as endoscopic appearance can improve. However, in any 
given subject, the rates of clinical improvement and endoscopic improvement may not be the 
same. There are reasons for this discrepancy when evaluating clinical and endoscopic 
improvement in the same time period, including clinical symptoms not being well correlated to 
the mucosal inflammation. Due to the transmural feature of the disease, symptoms can 
correspond to the inflammation in some of the other gut layers as well. Previous clinical studies 
and clinical observations indicate that the improvement of clinical signs and symptoms and the 
improvement in endoscopic appearance may not go hand in hand. Significant clinical 
improvement can precede significant endoscopic improvement. The healing process of the gut 
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mucosa may take a long time and may depend on the baseline severity of the endoscopic 
appearance, which may not be in line with the actual baseline severity of the symptoms. 
Therefore, when evaluating clinical remission together with endoscopic endpoints, improvement 
in endoscopic scores could be more relevant than evaluating mucosal healing in the induction 
phase. For these reasons, the key secondary composite endpoint (which takes into account 
both clinical and endoscopic response to treatment in the same subject) consists of the evaluation 
of the clinical remission together with the endoscopic response. 
Complete Endoscopic Healing 
Endoscopic healing will be defined in 2 ways: 
• Endoscopic healing defined by SES-CD ≤4 and at least a 2-point reduction versus 
baseline (Visit 2) and no subscore >1 in any individual variable 
• Complete endoscopic healing defined by SES-CD=0-2. 
There is no uniformly accepted definition for endoscopic healing in CD and several different 
terminologies are used to describe the same endoscopic appearance defined by a certain 
endoscopic score (eg, endoscopic remission and mucosal healing). Endoscopic healing or 
mucosal healing is predominantly defined by the absence of mucosal ulcerations in CD during 
endoscopic assessment of intestinal inflammation (Atreya and Neurath, 2017). The International 
Organization for the study of Inflammatory Bowel Disease technical review on endoscopic 
indices for CD clinical studies defined complete endoscopic healing as SES-CD=0-2 (Vuitton et 
al., 2016). Some studies introduced SES-CD ≤4 as “endoscopic remission”. The more stringent 
endpoint of “complete endoscopic healing” will be used as a key secondary endpoint in this 
study. Even in case of complete endoscopic healing, there may still be ongoing histological 
activity in many cases and it may not always reflect healing of all layers of the tissue, as 
endoscopy only addresses mucosal rather than transmural healing (Atreya and Neurath, 2017). 
The importance of inducing endoscopic healing is that it may be associated with long-term 
symptomatic remission; longer relapse-free interval; reduced frequency of hospitalizations, 
complications, and surgical resections; and the potential for a significant improvement in quality 
of life (Peyrin-Biroulet et al., 2011). 
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 16), if 
continuing to Study SHP647-307 or SHP647-304, or at the end of the safety follow-up period 
(Week 32), 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 38 weeks: a screening period of up to 6 weeks, a treatment period of 16 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. 
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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 approximately 19 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 active moderate to severe ileal (terminal ileum), ileocolic, or colonic 
CD at baseline (Visit 2) as defined by: 
a. CDAI score between 220 and 450 (inclusive) AND 
b. Meeting the following subscores in the 2-item PRO: 
i. Abdominal pain subscore ≥5 (average worst daily pain on the 11-point 
NRS) and abdominal pain subscore ≥2 (average daily pain on the 4-point 
abdominal pain variable of CDAI) over the 7 most recent days out of the 
10 days before colonoscopy preparation (may or may not be contiguous) 
AND/OR 
ii. Average of the daily stool frequency subscore ≥4 of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days out 
of the 10 days before colonoscopy preparation (may or may not be 
contiguous) 
AND 
c. Presence of ulcerations that are characteristic to CD, as determined by a 
colonoscopy performed during screening, and as defined by the SES-CD >6 
(SES-CD ≥4 for isolated ileitis)  
Note that the subject must be confirmed as meeting the CDAI score and PRO subscore 
requirements before a colonoscopy is done.  
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5. Subjects must have a documented diagnosis (endoscopic with histology) of CD for 
≥3 months before screening. Documented diagnosis is defined as: 
• A biopsy report in which the description of the histological findings is consistent 
with the CD diagnosis AND 
• A report documenting disease duration based upon prior colonoscopy. 
Note: If a biopsy report is not available in the source document at the time of screening, 
a biopsy must be performed during the screening colonoscopy and the histology report 
should be consistent with the CD diagnosis. If the histology description does not support 
the CD diagnosis at this time point, the subject should not be randomized. 
6. Subjects must be willing and able to undergo a colonoscopy during screening after all 
other inclusion criteria have been met. 
7. 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 mesalamine 
(5-ASA), glucocorticoids, immunosuppressants (AZA, 6-MP, or MTX), or anti-TNF 
(see Appendix 4 for guidance). Subjects who have had an inadequate response to 
sulfasalazine or mesalamine should have also failed at least 1 other conventional 
treatment such as glucocorticoids. 
8. Subjects receiving any treatment(s) for CD 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. 
9. 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 UC. 
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 presence of enterovesical (ie, between the bowel and urinary bladder) or 
enterovaginal fistulae. 
5. Subjects with current symptomatic diverticulitis or diverticulosis. 
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6. Subjects with clinically significant obstructive colonic stricture, or who have a history of 
bowel surgery within 6 months before screening, or who are likely to require surgery for 
CD during the treatment period. Subjects who have undergone previous colonic resection 
or ileocolectomy more than 6 months before screening must have at least 25 cm of colon 
remaining. 
7. Subjects with past medical history of multiple small bowel resections resulting in 
clinically significant short bowel syndrome. 
8. Subjects requiring total parenteral nutrition. 
9. Subjects with past medical history of bowel surgery resulting in an existing or current 
stoma. Subjects who had a j-pouch are excluded as a j-pouch could result in a stoma. 
10. Subjects have had prior treatment with ontamalimab (formerly PF-00547659; SHP647). 
11. Subjects with known or suspected intolerance or hypersensitivity to the investigational 
product(s), closely related compounds, or any of the stated ingredients. 
12. Subjects have received any nonbiologic treatment with immunomodulatory properties 
(other than AZA, 6-MP, or MTX) or continuous antibiotics (>2 weeks) for the treatment 
of CD within 30 days before baseline (Visit 2). 
13. Subjects have received anti-TNF treatment within 60 days before baseline (Visit 2). 
14. Subjects have received any biologic with immunomodulatory properties (other than 
anti-TNFs) within 90 days before baseline (Visit 2). 
15. Subjects have ever received anti-integrin/adhesion molecule treatment (eg, natalizumab, 
vedolizumab, efalizumab, etrolizumab, or any other investigational anti-integrin/adhesion 
molecule). 
16. Subjects have received lymphocytes apheresis or selective monocyte granulocytes 
apheresis within 60 days before baseline (Visit 2). 
17. Subjects have received enteral nutrition treatment within 30 days before 
baseline (Visit 2). 
18. Subjects have received parenteral or rectal glucocorticoids or rectal 5-ASA within 
14 days before screening colonoscopy. 
19. Subjects have taken >20 mg/day of prednisone, >9 mg/day of budesonide, or equivalent 
oral systemic corticosteroid dose (see Appendix 3) within 14 days before baseline 
(Visit 2) or have taken ≥40 mg/day of prednisone or equivalent oral systemic 
corticosteroid dose within 6 weeks before baseline (Visit 2). 
20. 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 
screening (Visit 1). 
21. Subjects have received a live (attenuated) vaccine within 30 days before the baseline visit 
(Visit 2). 
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22. 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 retest 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). 
23. Subjects with abnormal chest x-ray or other imaging findings at screening (Visit 1), such 
as presence of active tuberculosis (TB), general infections, heart failure, or malignancy. 
(A chest x-ray, computed tomography scan, etc., 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). 
24. 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 baseline (Visit 2) 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 the IGRA 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. 
25. 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. 
26. Subjects with any unexplained symptoms suggestive of PML based on the targeted 
neurological assessment during the screening period (see Section 7.2.3.3). 
27. Subjects with a transplanted organ. Skin grafts to treat pyoderma gangrenosum are 
allowed. 
28. 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). 
29. Subjects who have had significant trauma or major surgery within 4 weeks before the 
screening (Visit 1), or with any major elective surgery scheduled to occur during the 
study. 
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30. Subjects with evidence of cirrhosis with or without decompensation (ie, esophageal 
varices, hepatic encephalopathy, portal hypertension, ascites).  
31. Subjects with primary sclerosing cholangitis. 
32. 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. 
33. 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]). 
34. Subjects with any of the following abnormalities in hematology and/or serum chemistry 
profiles during screening (Visit 1). 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 colonoscopy 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) 
• 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. 
35. 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.  
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36. 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). 
37. 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. 
38. Female subjects who are planning to become pregnant during the study period. 
39. 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. 
40. 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 
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). 
Smoking is considered to be a risk factor for CD. Reports have shown that smoking is not only 
related to the onset, relapse, and exacerbation of CD, but also that smoking cessation lowers the 
postoperative recurrence rate (Ueno et al., 2013). Subjects should inform the investigator of any 
changes to their smoking habits during the study (including starting or stopping smoking). Use of 
nicotine patches should be recorded as concomitant medication (see Section 5.2.1). 
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 
(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. 
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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 screening, 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 
• Male sterilization/vasectomized partner 
• Implantable progesterone-only hormonal contraception associated with inhibition of 
ovulation. 
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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 screening (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: 
• 
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. 
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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 16/early termination (ET; Visit 7) 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 
• 
Failure to return for visits. 
A subject should be withdrawn from study treatment: 
• 
If a new therapy is initiated for CD, or 
• 
If a subject undergoes surgery for CD. 
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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 CD during the 90 days 
before screening must also be recorded. 
Prior and concomitant CD-specific treatments from the previous 10 years will be recorded. The 
subject’s entire history of biologic CD-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 (Lichtenstein et al., 2018). 
Please see Appendix 4 for guidance on defining prior treatment failure and intolerance to prior 
treatment for CD. 
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 of this study, inclusive. 
5.2.1 
Permitted Treatment 
Subjects must remain on stable doses of permitted CD treatments until completion of the 
Week 16 visit, unless decreases are required because of AEs. Stable doses of the following 
treatments for CD are permitted as concomitant medication: 
• 
Oral sulfasalazine or 5-ASA, 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 baseline (Visit 2). After baseline (Visit 2), a stable dose of 
20 mg/day prednisone or equivalent oral systemic corticosteroid dose is allowed. Steroids 
may be decreased due to AEs. 
Note: Rectal 5-ASA and parenteral or rectal glucocorticoids are prohibited from within 14 days 
before screening colonoscopy. 
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Antidiarrheal opiate drugs such as IMODIUM® (loperamide), LOMOTIL® (diphenoxylate 
hydrochloride and atropine sulfate), tincture of opium, and codeine will be recorded as 
concomitant medications. Subjects must be using such products in a stable regimen for at least 
2 weeks before randomization at baseline (Visit 2). Reported use of any antidiarrheal opiate 
medicines will assist the investigator response to Question 5 of the CDAI. Antidiarrheal opiate 
drugs must be taken at stable doses for the duration of the study unless dose reduction or 
discontinuation is required due to clinical improvement of AE. However, escalations of the dose 
after dose reduction or re-initiation after drug discontinuation are not allowed (see Section 5.2.3).  
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-containing preparations should be recorded as concomitant medication. 
Antibiotics are permitted, with the exception of antibiotics used to treat the underlying disease 
exceeding 2 weeks within 30 days before baseline (Visit 2) or before Week 16 (Visit 7, Part 1). 
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. 
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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 
propertiesc 
 
 
X 
 
 
Anti-TNF treatment 
 
 
 
X 
 
Lymphocytes apheresis or selective monocyte 
granulocytes apheresis 
 
 
 
X 
 
Biologics with immunomodulatory properties 
(other than anti-TNFs) including biosimilars 
 
 
 
 
X 
5-ASA=5-aminosalicylic acid; 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 colonoscopy (see Section 4.2, exclusion criterion 18). 
b Or 5 half-lives if longer. 
c Usage of immunosuppressants, eg used in transplantation or in autoimmune diseases that are not established therapies for CD 
(eg, mycophenolate mofetil, cyclosporine, rapamycin, thalidomide, tofacitinib, or tacrolimus). 
Treatments not listed in Table 2 may be considered allowable; see Section 5.2.1 for further 
details. 
In addition to the treatments listed in Table 2, the following common treatments are excluded 
medications for this study: 
• 
Prednisone dose >20 mg/day, budesonide >9 mg/day, or other equivalent oral systemic 
corticosteroid dose 
• 
Bismuth subsalicylate products 
• 
Fecal microbiota transplantation. 
No new nonpharmacological therapies that might affect bowel habit or GI function should be 
started during the study. 
Enteral nutrition is not permitted from within 30 days of baseline (Visit 2) or at any time during 
the study. 
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5.2.3 
Rescue Therapy 
Subjects must maintain their stable dose of background CD 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 CD above the SHP647-305 or SHP647-306 baseline (Visit 2), 
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 (Visit 2) and treatment periods. High-dose 
glucocorticoids and other CD 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 Products 
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. 
Eligible subjects will be randomized in a ratio of 3:3:2 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), glucocorticoid use at baseline (2 strata: on 
glucocorticoids at baseline versus not on glucocorticoids at baseline), and SES-CD at baseline 
(2 strata: SES-CD ≥17 at baseline versus SES-CD <17 at baseline). 
To ensure that the allocation of subjects with prior anti-TNF therapy exposure is similar to that 
observed in previous studies, the percentage of subjects with prior exposure to treatment with 
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. 
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. 
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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. 
6.2.3 
Dosing 
Investigational product (ontamalimab or placebo) will be administered subcutaneously by 
qualified site personnel Q4W (Weeks 0, 4, 8, and 12). 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 (SHP647-305 or SHP647-306) 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. 
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. 
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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 
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. 
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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. 
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. 
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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 assessments (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 
will take place over more than 1 day (at least 2 visits will be necessary to complete the screening 
procedures, including colonoscopy). 
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 colonoscopy procedure. 
Hematology samples should be repeated if more than 3 weeks have elapsed before the day of 
colonoscopy to be able to use the hematocrit central laboratory results for the CDAI score 
calculation at screening. Hematocrit must not be older than 3 weeks before the day of 
colonoscopy. 
Collection of the daily e-diary data must begin at least 10 days before colonoscopy preparation. 
Note that the subject must be confirmed as meeting the CDAI and PRO subscore requirements 
per inclusion criteria 4a and 4b before a colonoscopy is done. Colonoscopy preparation will be 
according to local routine. 
Colonoscopy during the screening period must be performed preferably within 5 to 7 days, but 
no later than 10 days before baseline (Visit 2), to allow for adequate e-diary data collection for 
the 2-item PRO and CDAI scores and to obtain the centrally read endoscopic subscore to verify 
the subject’s eligibility (see Section 7.2.2.4). Colonoscopy preparation may be done on the same 
day as the colonoscopy procedure. If the calculated CDAI scores is <220 or >450, or the PRO 
scores are outside the eligibility thresholds, the subject will be considered a screen failure and 
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should not proceed with the colonoscopy preparation and/or the colonoscopy. All colonoscopies 
will be evaluated using the SES-CD (see Appendix 2). 
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. 
7.1.1.2 
Baseline Visit (Visit 2; Week 0) 
The baseline visit (Visit 2) 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 
Visits 3, 4, 5, and 6 (Weeks 2, 4, 8, and 12) 
Visits 3, 4, 5, and 6 are scheduled to take place on Day 14 ±3 days (Week 2), Day 28 ±3 days 
(Week 4), Day 56 ±3 days (Week 8), and Day 84 ±3 days (Week 12), respectively. The 
assessments and procedures specified in Table 1 will be performed. 
7.1.2.2 
Final On-treatment Visit: Visit 7, Parts 1, 2, and 3 
(Week 16/Early Termination) 
The Week 16/ET visit (Visit 7) consists of 3 parts. 
Part 1 of Visit 7 can either be done on the same day as Part 2 or be done up to 3 day(s) before 
Part 2. If Parts 1 and 2 are done on the same day, blood samples must be taken before starting the 
colonoscopy preparation. The Week 16/ET assessments and procedures that will take place 
during Part 1 are specified in Table 1. 
Part 2 of Visit 7 must be completed within 10 days (preferably within 5 to 7 days) before Part 3; 
this will allow sufficient time to obtain the data from the centrally read colonoscopy. The 
Week 16/ET assessments and procedures that will take place during Part 2 are specified in 
Table 1. 
Part 3 of Visit 7 will take place on Day 112 ±3 days. The Week 16/ET assessments and 
procedures that will take place during Part 3 are specified in Table 1. 
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At Part 3 of Visit 7, after review of CD assessments, health outcome assessments, and safety 
assessments, it will be determined whether the subject should enroll in the maintenance 
(SHP647-307) or LTS (SHP647-304) studies or enter the follow-up period of this study. Entry 
into the maintenance or LTS studies is dependent upon whether the subject fulfills the efficacy 
entry criteria of the maintenance study (SHP647-307), including achieving endoscopic and/or 
clinical response, and whether the subject agrees to participate. 
The Week 16 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 
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 period for safety monitoring. 
During the safety follow-up period, the Week 24 visit (Visit 8) will take place on 
Day 168 ±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 224 ±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; this visit will form the Week 32 visit (Visit 9). 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, that 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. 
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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 
• Investigational product administration 
• Colonoscopy is performed at a separate visit (see Section 7.2.2.4). 
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 screening (Visit 1). 
7.2.2 
Efficacy 
7.2.2.1 
Patient-reported Outcome – Crohn’s Disease Daily E-diary 
Patient-reported CD clinical signs and symptom data will be collected daily using a PRO-CD 
daily e-diary (electronic handheld device) starting during the screening period; however, 
collection of the daily e-diary data must begin at least 10 days before colonoscopy preparation. 
Subjects will enter data on CD signs and symptoms items using the e-diary, which will be 
provided to subjects at the start of the study. Compliance will be assessed by site staff at each 
visit. The site staff will instruct the subject on the appropriate use of the e-diary when 
compliance is below 80% (eg, <23 out of 28 e-diary entries). If at least 70% compliance cannot 
be achieved after repeated instructions during the screening period, noncompliant subjects will 
be automatically noneligible as they will not fulfill inclusion criterion 1 (see Section 4.1). 
Subjects will be asked to record the following signs and symptom data, as experienced over the 
previous 24 hours, in the e-diary: 
• 
Abdominal pain severity (numeric rating scale [NRS]) 
• 
Very soft stool/liquid stool frequency (as shown by BSFS type 6/7) 
• 
Total stool frequency 
• 
Rectal bleeding frequency 
• 
Rectal urgency frequency 
• 
Nausea severity 
• 
Vomiting frequency 
• 
Incontinence frequency 
• 
Abdominal pain used in CDAI 
• 
General well-being. 
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The first 2 items (abdominal pain severity and very soft stool/liquid stool frequency) will be used 
to calculate the 2-item PRO. The 2-item PRO will be calculated using the following criteria: 
• 
Screening: the 2-item PRO will be calculated based on the 7 most recent days during the 
10 days of data collection before the colonoscopy preparation. If 7 out of the 10 most 
recent days are not available, then the 2-item PRO cannot be calculated for the subject at 
screening. Note that the subject must be confirmed as meeting the PRO subscore 
requirements at screening before a colonoscopy is done. 
• 
Visits 3, 4, 5, and 6: the 2-item PRO will be calculated based on the 7 most recent days 
during the 10 days of data collection before the visit. If fewer than 7 days are available, 
the 2-item PRO will be calculated on all available most recent 6 or 5 days. If fewer than 
5 days are available, the 2-item PRO will be treated as missing. 
• 
Visit 7 (Part 3): the 2-item PRO will be calculated based on the 7 most recent days during 
the 10 days of data collection before the colonoscopy preparation. If fewer than 7 days 
are available, the 2-item PRO will be calculated on all available most recent 6 or 5 days. 
If fewer than 5 days are available, the 2-item PRO will be treated as missing. 
For all 2-item PRO calculations, the 7 most recent days may or may not be contiguous during the 
10 days of data collection depending on days to be excluded because of missing data. 
The PRO-CD daily e-diary is presented in Appendix 2. 
7.2.2.2 
Simple Endoscopic Score for Crohn’s Disease 
The SES-CD will be performed at the time points specified in Table 1. The SES-CD score at 
baseline (Visit 2) and at Week 16/ET will be calculated using subscores of each of the segments 
investigated and centrally read from the colonoscopies performed at screening (Visit 1, Part 2) 
and Week 16 (Visit 7, Part 2), respectively. 
The SES-CD is a simple scoring system based on 4 endoscopic variables (presence and size of 
ulcers, proportion of surface covered by ulcers, proportion of affected surface, and presence and 
severity of stenosis [narrowing]) measured in the same 5 ileocolonic segments as the CD index 
of severity (Daperno et al., 2004). Overall, values on the SES-CD range from 0 to 56, with 
higher values indicating more severe disease. The 4 endoscopic variables are scored from 0 to 3 
in each bowel segment (ileum, right/transverse/left colon, and rectum): 
• 
Presence and size of ulcers (none = score 0; diameter 0.1–0.5 cm = score 1;  
0.5–2 cm = score 2; diameter >2 cm = score 3) 
• 
Extent of ulcerated surface (none = 0; <10% =1; 10%–30% = 2; >30% = 3); extent of 
affected surface (none = 0; <50% = 1; 50%–75% = 2; >75% = 3) 
• 
Presence and type of narrowings (none = 0; single, can be passed = 1; multiple, 
can be passed = 2; cannot be passed = 3). 
A complete colonoscopy is required (including visualization of the terminal ileum except when it 
is not possible due to impassable stenosis or previous partial colectomy/ileocolectomy). The 
maximum stenosis score in a segment distal to another evaluable segment cannot exceed 2, so 
that the stenosis scores cannot exceed a total of 11 (Reinisch et al., 2017). 
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Evidence of active inflammation and ulceration is required at screening (Visit 1), in the form of a 
centrally read score of at least 1 in one or more ileocolonic segments in the Presence of Ulcers 
component of the SES-CD, as well as a total score of >6. 
Study videos will be scored separately by 2 central readers who are blinded to the treatment. 
If the central readers’ scores are not in agreement, there will be a third adjudication read to select 
the correct read from the first 2 scores. Results of the central reading of the videos will be 
communicated to sites within 5 business days. 
For the evaluation of efficacy, in cases where 1 or 2 segments cannot be fully evaluated by 
central endoscopic readers, ileocolonic segments that are evaluable during screening (Visit 1) 
and Week 16/ET (matching segments approach) will be utilized. 
The SES-CD is presented in Appendix 2. 
7.2.2.3 
Crohn’s Disease Activity Index 
The CDAI is a composite measure with 8 components; 3 components (abdominal pain severity, 
very soft stool/liquid stool frequency, and general well-being) will be self-reported by the subject 
and will be recorded as part of the daily e-diary, as described in Section 7.2.2.1 and 
5 components will be recorded at the time points specified in Table 1. 
The CDAI score at screening (Visit 1, Part 2) will be calculated using the following: 
• 
Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected >10 days 
before the start of colonoscopy preparation using the same most recent 7 of 10 days as 
described for the 2-item PRO (see Section 7.2.2.1) and 
• 
Components 4 to 8 (weight, medical and physical examination, use of diarrhea treatment, 
and hematocrit value) collected during screening (Visit 1) Part 1. Note: Hematology 
samples should be repeated if more than 3 weeks have elapsed before the day of 
colonoscopy to be able to use the hematocrit central laboratory results for the CDAI score 
calculation at screening. Hematocrit must not be older than 3 weeks before the day of 
colonoscopy. 
Note that the subject must be confirmed as meeting the CDAI score requirements at screening 
before a colonoscopy is done. 
The CDAI scores at Visits 4, 5, and 6 will be calculated using the following: 
• 
Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected >10 days 
before the visit using the same most recent 7 or 10 days as described for the 2-item PRO 
(see Section 7.2.2.1) and 
• 
Components 4 to 8 (weight, medical and physical examination, use of diarrhea treatment, 
and hematocrit value) collected at the visit. 
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The CDAI score at the Week 16/ET visit will be calculated at Visit 7, Part 3 (after all evaluations 
are complete), using the following: 
• 
Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected >10 days 
before the start of colonoscopy preparation using the same most recent 7 or 10 days as 
described for the 2-item PRO (see Section 7.2.2.1) and 
• 
Components 4 to 8 (weight, medical and physical examination, use of diarrhea treatment, 
and hematocrit value) collected at Part 1 and Part 3 of the Week 16/ET visit, where 
assessed. 
Change in CDAI has been used as a primary endpoint in multiple pivotal studies in the CD 
indication. The algorithm for calculating the CDAI score was first published by William Best 
and colleagues (Best et al., 1976). 
The CDAI is presented in Appendix 2. 
7.2.2.4 
Colonoscopy and Histology 
Colonoscopy will be performed at the time points specified in Table 1. 
Bowel preparation regimens typically incorporate dietary modifications along with oral 
cathartics. Typically, the standard dose of a bowel preparation is split between the day before 
and the morning of the procedure; however, bowel preparation can be done entirely on the 
morning of the procedure. In this study, bowel preparation and colonoscopy are to be conducted 
per local routine; however, sodium phosphate based preparations must be avoided, as such 
regimens can produce mucosal changes that mimic IBD. 
In general, a complete colonoscopy should be performed; this includes visualization of the 
rectum, sigmoid colon, left colon, transverse colon, right colon, ileocecal valve, and the terminal 
ileum (except after partial colectomy/ileocolectomy when the aim is to visualize the remaining 
colon and, if it exists, the terminal ileum). At screening, incomplete colonoscopy will be 
accepted only on a case by case basis (eg, presence of impassable narrowing without any clinical 
signs of bowel obstruction and when the same time the investigated segments provide the 
SES-CD score required for inclusion). Similarly, a complete colonoscopy is the aim at 
Week 16/ET, with the exception of the presence of impassable stenosis or other CD-related 
complications as cause of failure to complete the colonoscopy procedure. 
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 colonoscopy. To 
achieve consistency in capturing and assessing endoscopic video recordings, each participating 
site will use an integrated hardware/software solution and associated tools for the capture and 
transmission of endoscopy video recordings for central reading. Nonreadable endoscopic images, 
as assessed by the investigator, should not be sent for central reading. The colonoscopy report 
and any photographs and/or video recordings taken during the procedure per local custom should 
be filed in the subject’s medical record. 
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During the colonoscopy at screening (Visit 1, Part 2) and Week 16/ET, 10 biopsies will be 
collected from the most inflamed area of the mucosa: 2 samples each from the ileum, the 
3 segments of the colon, and the rectum except when it is not possible due to impassable stenosis 
or previous partial colectomy/ileocolectomy. Colonoscopy and biopsy procedures will be defined 
in a colonoscopy instructions manual and/or reference card(s), on which all sites will be trained. 
Colonoscopy results will be reviewed by a central reader. 
 
 
(see Appendix 2). Biopsies for conventional histologic assessment will be collected in formalin 
and shipped to the central laboratory. The central laboratory will register all biopsies and create 
paraffin blocks. Blocks will be batched and shipped on an agreed schedule to specialty 
laboratory, where tissue processing (sectioning, hematoxylin and eosin staining, and affixation to 
glass slides), digitalization, and uploading of images will occur. All images for a subject will be 
scored by the same qualified central pathologists blinded to the subject and treatment sequence 
information, according to the scoring modality. 
7.2.3 
Safety 
7.2.3.1 
Medical and Medication History 
Medical history will be documented at screening (Visit 1), including CD history, cardiac history, 
and smoking history. Prior and concomitant medications and procedures will also be documented 
at the time points specified in Table 1. 
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; 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 and 
mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, 
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 screening 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, neurological 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 25, Section 4.2). 
A step-wise approach for the proposed neurological assessment plan is provided in Table 3.  
Table 3 
Quarterly Neurological Assessment 
Domain 
Step 1: Interim Neurological 
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 7s, 
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.  
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. 
Targeted Neuro 
history per Table 
Review of Consult 
and test results by 
blinded DMC members 
Review by full DMC 
No 
~-.i probe deeper 
Yes '---'-----~ 
No 
~ -----.i Targeted exam 
Yes 
Urgent Neuro referral i.----------c--c---~ 
- ---, 
to rule out PML 
Yes 
IND Safety Report as appropriate 
Treatment as clinically appropriate 
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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 
 
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 
 
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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 electronic case report form (eCRF) database. 
Stool microbiology will be performed at screening (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, 
please see Appendix 5 for guidance regarding diagnostic algorithms. 
A TB test (PPD or QuantiFERON-TB Gold Plus) will be performed at screening (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 neurological 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 screening 
(Visit 1); all other pregnancy tests will be urine tests. 
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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 ADAs and NAbs will be collected at the time points specified 
in Table 1. Blood samples must be collected before 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 AEs of special interest (AESIs) related to 
hypersensitivity. 
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. 
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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; if the AEs are assessed as related to the formation of circulating 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 IBD, including CD. The IBDQ consists of 32 items, which are grouped 
into 4 domains: bowel function, systemic symptoms, emotional status, 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. 
 
 
 
 
 
 
 
 
 
The 
 is presented in Appendix 2. 
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The 
 and 
 are presented in Appendix 2. 
 
 
 
Short Form-36 Health Survey (Version 2, 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. 
The SF-36 is presented in Appendix 2. 
 
 
 
 
 
 
 
 
 
 
The TSQM is presented in Appendix 2. 
7.2.4.4 
Healthcare Resource Utilization Assessments 
Hospitalizations, inpatient days, and 
 will be recorded at the time points specified in 
Table 1. Information regarding CD-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 
The volume of blood to be drawn from each subject is summarized in Table 4. 
Table 4 
Volume of Blood to Be Drawn From Each Subject 
Assessment 
Sample Volume (mL) 
Number of Samples 
Total Volume (mL) 
Hematology 
2 
7 
14 
Serum chemistry 
4 
7 
28 
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 
6 
30 
ADA and NAb sampling 
3 
7 
21 
Total mL 
151.5 
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 151.5 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). 
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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. 
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 describes 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 Serious Adverse 
Event and Nonserious AE as Required by the Protocol Form” and within the time frame 
mandated for SAEs (see Section 8.2.2). 
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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 
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 assay 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. 
Potential 
Potential 
lnunuuogtnidt~.; 
ImmuuogeukilJ 
High 
Lower 
Muline 
Chimeric 
Humanized 
Fulk Human 
0% Human 
65% Human 
90% Human 
99% Humau 
,, l( 
Jl 
Generic Suffix 
-omab 
-ximab 
-zumab 
-umab 
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Table 5 
Clinical Criteria for Diagnosing Anaphylaxis (Type I Hypersensitivity) 
Anaphylaxis is highly likely when the first criterion below and at least 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 ONE 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 source document. 
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 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
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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, 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. 
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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 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 (SHP647-305 or SHP647-306) 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® software Version 9.3 or higher 
(SAS Institute Inc, 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 
A planned interim analysis for the coprimary endpoints will take place after approximately the 
first 50% of all randomized subjects in both the SHP647-305 and SHP647-306 studies have 
either completed the studies or have prematurely withdrawn from the studies. Recruitment will 
not pause for this interim analysis. The purpose of the unblinded interim analysis is to reassess 
the appropriateness of the premises used for the coprimary endpoints when the study was 
designed. There is no possibility to stop early for overwhelming efficacy as the studies must 
continue in order to enroll an appropriate number of subjects in the SHP647-307 study. The 
reassessment of sample size will be performed using conditional power methods. Results at the 
interim analysis may be futile for one or both of the ontamalimab doses and lead to the 
discontinuation of that dose for CD or the ontamalimab CD program. Full details of the interim 
analysis, the guidelines for increasing the sample size, and futility rules to stop a dose will be 
included in a prespecified interim analysis SAP. The interim analysis SAP will be finalized 
before the interim analysis is conducted. 
The planned interim analysis will be conducted by an external independent statistical group and 
given to the independent Interim Analysis Review Committee; the individuals involved in the 
day-to-day conduct of the study will not be involved in the interim analysis nor have access to 
the results of the interim analysis. The sponsor will only be notified by the Interim Analysis 
Review Committee of recommendations to modify the ontamalimab CD program according to 
the guidelines specified in the interim analysis SAP. 
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). 
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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. 
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 coprimary endpoints. 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 to placebo. 
Power calculations are made based on assuming a .025 (2-sided) significance level for each 
pairwise treatment comparison, 1720 subjects will be screened to randomize 1032 subjects in a 
3:3:2 allocation ratio: 387 subjects in the 25 mg ontamalimab treatment group, 387 subjects in 
the 75 mg ontamalimab treatment group, and 258 subjects in the placebo group. These numbers 
of subjects would yield an approximately 93% power to detect individual pairwise treatment 
difference in the first coprimary efficacy endpoint, clinical remission by 2-item PRO at Week 16, 
of 10% (17.5% ontamalimab versus 7.5% placebo). Expected clinical remission rates by 2-item 
PRO at Week 16 are based on observed rates from a post hoc analysis of the A7281006 study 
and placebo remission rates from literature (Sandborn et al., 2017). No adjustment for missing 
data is required in these sample size calculations as subjects with missing data for clinical 
remission by 2-item PRO at Week 16 are imputed as failures and the above rates account for 
these subjects. 
With the 1032 subjects in allocation noted above, this number of subjects would yield an 
approximately 94% power to detect individual pairwise treatment difference in the other 
coprimary efficacy endpoint, endoscopic response at Week 16, of 12.5% (27.5% ontamalimab 
versus 15% placebo). Expected endoscopic response rates at Week 16 are based on observed 
rates from a post hoc analysis of the A7281006 study and also endoscopic response rates from 
literature (Sandborn et al., 2017). No adjustment for missing data is required in these sample size 
calculations as subjects with missing data for endoscopic response at Week 16 are imputed as 
failures and the above rates account for these subjects. 
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The overall power for the coprimary endpoints will be approximately 87% assuming no 
correlation between the tests on the endpoints and approximately 90% assuming a correlation of 
0.4. 
With the sample size of 1032 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 16 
Ontamalimab Premise 
Placebo Premise 
Power 
Clinical remission by CDAI 
26.5% 
15% 
0.90 
Enhanced endoscopic response 
25% 
13% 
0.94 
Clinical remission by abdominal pain ≤1 
and stool frequency ≤3 
24% 
14% 
0.81 
Clinical response by 2-item PRO 
52.5% 
40% 
0.81 
Clinical remission by 2-item PRO and 
endoscopic response 
11% 
4.5% 
0.77 
Complete endoscopic healing 
6% 
2% 
0.58 
CDAI=Crohn’s Disease Activity Index; PRO=patient-reported outcome 
 
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 coprimary efficacy endpoints. 
The completer set will consist of all subjects in the FAS who have completed the Week 16 
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 
Coprimary Efficacy Endpoints 
The coprimary efficacy endpoints are: 
• Clinical remission at the Week 16 visit as defined by the following: 2-item PRO 
subscores of average worst daily abdominal pain ≤3 (based on 11-point NRS) over the 
7 most recent days and average daily stool frequency ≤2 of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent 
days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. 
If fewer than 7 days are available, the endpoint will be calculated on all available most 
recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as 
missing. 
• Endoscopic response at Week 16 as measured by a decrease in SES-CD of at least 25% 
from baseline. 
The coprimary efficacy endpoints, clinical remission at the Week 16 visit and endoscopic 
response at the Week 16 visit, will each 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, glucocorticoid use, and SES-CD at baseline 
for each of the stages of the study (stage 1 includes subjects whose primary efficacy data are 
used in the interim analysis and stage 2 includes all other subjects. Note: classification of stage 1 
and stage 2 is based on the time of randomization rather than the time of study completion or 
termination). Subjects with missing data at the Week 16 visit will be considered failures and 
counted as nonresponders. 
Weighted inverse normal p-value combination methods are used to combine the p-values from 
stage 1 and stage 2 through the following formula: 
C(p1, p2) = 1 – Φ[w1 Φ-1(1-p1)+ w2 Φ-1(1-p2)] 
Where p1, p2 are the p-values computed from the CMH chi-square test for each stage, 
wi2 = ni/(n1 + n2), n1 and n2 are the preplanned stage-wise sample sizes that are fixed at the time of 
the interim analysis based on an original total sample size, and Φ denotes the cumulative 
distribution function of the standard normal distribution (Bretz et al., 2009a). Given that there is 
no possibility of stopping early for efficacy, that any potential stopping for futility of either or 
both doses of ontamalimab is nonbinding, and that weights are prespecified, the test statistic 
C(p1, p2) can be compared against the nominal alpha level to assess statistical significance 
(Chang and Chow, 2008). 
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The coprimary endpoints will each be tested by the following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
Where δ is the common treatment difference across strata. 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 the p-value computed from the 
p-value combination method will be presented for each active treatment group to placebo 
comparison for each endpoint. 
Sensitivity/supplementary analyses to explore the impact of missing data on the coprimary 
efficacy endpoints and key secondary endpoints 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 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 coprimary endpoints including, but not 
limited to gender, prior anti-TNF treatment, glucocorticoid use at baseline, SES-CD at baseline, 
region, age group, randomization stratum, and other important subgroups. A full list of important 
subgroups will be described in 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. The estimate of the treatment difference, along with the 
corresponding Newcombe (hybrid-score) 95% CI and chi-square test p-value, will be presented. 
Statistical Testing and Protection of the Type I Error 
The global FWER for the statistical tests of the coprimary and key secondary endpoints will be 
strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in 
Bretz et al. (2009b) will be utilized to propagate α from the coprimary endpoints to the 
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 coprimary endpoints (P) and alpha is propagated in a hierarchical 
manner to each of the 6 key secondary endpoints (K1–K6) within a pairwise treatment 
comparison. In order to pass alpha between the coprimary endpoints and the first key secondary 
endpoint, both coprimary endpoints must attain statistical significance. A graphical visualization 
of the α propagation is presented in Figure 5. 
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Figure 5 
Visualization of Multiple Testing Strategy 
 
K=key secondary endpoint; P=coprimary endpoints 
 
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 Endpoints 
The key secondary efficacy endpoints are as follows: 
• Clinical remission at the Week 16 visit as measured by a CDAI score of <150. 
• Enhanced endoscopic response at Week 16 as measured by a decrease in SES-CD of at 
least 50% from baseline. 
• Clinical remission at the Week 16 visit as defined by the following: 2-item PRO 
subscores of average daily abdominal pain ≤1 (based on the 4-point scale) over the 
7 most recent days and average daily stool frequency ≤3 of type 6/7 (very soft 
stools/liquid stools) as shown in the BSFS over the 7 most recent days. The 7 most recent 
days may or may not be contiguous during the 10 days of data collection before 
colonoscopy preparation, depending on days to be excluded because of missing data. 
If fewer than 7 days are available, the endpoint will be calculated on all available most 
recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as 
missing. 
• Clinical response at the Week 16 visit as measured by the 2-item PRO and defined as 
meeting at least 1 of the following 2 criteria: 
o A decrease of ≥30% and at least 2 points from baseline in the average daily worst 
abdominal pain over the 7 most recent days*, with the average daily stool frequency 
of type 6/7 (very soft stools/liquid stools) either: 
(a) Not worsening from baseline 
and/or 
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average 
daily stool frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the 
BSFS over the 7 most recent days* 
o A decrease of ≥30% from baseline in the average daily stool frequency of type 6/7 
(very soft stools/liquid stools) as shown in the BSFS over the 7 most recent days*, 
with the average daily worst abdominal pain either: 
(a) Not worsening from baseline 
and/or 
(b) Meeting the criteria for clinical remission, ie, 2-item PRO subscore of average 
worst daily abdominal pain ≤3 (based on 11-point NRS) over the 7 most recent days* 
*Note: The 7 most recent days may or may not be contiguous during the 10 days of data 
collection before colonoscopy preparation, depending on days to be excluded because of 
missing data. If fewer than 7 days are available, the endpoint will be calculated on all 
available most recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be 
treated as missing. 
• Clinical remission with endoscopic response, ie, both clinical remission by 2-item PRO 
and endoscopic response, as measured by a decrease in SES-CD of at least 25% at 
Week 16 (composite endpoint) 
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• Complete endoscopic healing at Week 16 defined as SES-CD=0-2. 
Similar to the coprimary endpoints, the 6 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 
coprimary endpoints. Subjects with missing key secondary endpoint data at the Week 16 visit 
will be considered failures and counted as nonresponders. 
9.8.2.2 
Other Secondary Efficacy Endpoints 
The other secondary endpoints are as follows: 
• Clinical response at the Week 16 visit as measured by at least a 100-point reduction in the 
CDAI from baseline (CDAI-100 response) 
• Clinical response at the Week 16 visit as measured by at least a 70-point reduction in the 
CDAI from baseline (CDAI-70 response) 
• Clinical remission over time, as measured by the 2-item PRO 
• Change from baseline in total stool frequency, rectal bleeding frequency, rectal urgency 
frequency, nausea severity, vomiting frequency, and rectal incontinence frequency 
scores; and total sign/symptom score based on subject daily e-diary entries 
• Endoscopic healing at Week 16 as measured by SES-CD ≤4 and at least 2-point reduction 
versus baseline and no subscore >1 in any individual variable 
• Change from baseline in IBDQ domain and total (absolute) scores over time 
• Change from baseline in SF-36, version 2, acute (physical and mental component 
summary scores and individual domain scores) over time 
• Incidence of all cause hospitalizations and total inpatient days 
• Incidence of CD-related surgeries and other surgical procedures during the entire study 
period. 
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: 
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• Binary endpoints will be compared between each active treatment group and the placebo 
group using a CMH chi-square test stratified by status of prior anti-TNF treatment, 
glucocorticoid use at baseline, and SES-CD at baseline. The estimate of the common 
treatment difference along with the corresponding stratified Newcombe 95% CI using the 
method of Yan and Su (2010) and the p-value computed from CHM test will be provided. 
Subjects with missing binary endpoint data at the Week 16 visit will be considered 
failures and counted as nonresponders.  
• Continuous endpoints that are only measured at baseline and the Week 16 visit will be 
analyzed using an analysis of covariance model with fixed effects for treatment group 
(categorical), status of prior anti-TNF treatment (categorical), glucocorticoid use at 
baseline (categorical), and SES-CD 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), 
glucocorticoid use at baseline (categorical), and SES-CD 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. 
9.8.3 
Exploratory Efficacy Endpoints 
The exploratory endpoints are as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Exploratory efficacy endpoints will be summarized with descriptive statistics and presented by 
treatment group 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. 
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. 
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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 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 Food and 
Drug Administration [FDA], European Medicines Agency [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. 
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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 
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. REFERENCES 
 
 
 
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Ferrante, M., Colombel, J., Sandborn, W., Reinisch, W., Mantzaris, G., Kornbluth, A., 
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Endoscopic Activity Scores in Patients With Crohn's Disease Based on a Post Hoc 
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Castells, M. 2018. Hypersensitivity reactions to therapeutic monoclonal antibodies: 
Phenotypes and endotypes. J Allergy Clin Immunol, 142, 159-170 e2. 
Khanna, R., Zou, G., D'Haens, G., Feagan, B. G., Sandborn, W. J., Vandervoort, M. K., Rolleri, 
R. L., Bortey, E., Paterson, C., Forbes, W. P. and Levesque, B. G. 2015. A retrospective 
analysis: the development of patient reported outcome measures for the assessment of 
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Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates 
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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. 
Lichtenstein, G. R., Loftus, E., Isaacs, K., Regueiro, M., Gerson, L. and Sands, B. 2018. ACG 
Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol, 113, 
481-517. 
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. 
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incidence and prevalence of the inflammatory bowel diseases with time, based on 
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Panaccione, R., Colombel, J.-F., Louis, E., Peyrin-Biroulet, L. and Sandborn, W. J. 2013. 
Evolving Definitions of Remission in Crohn’s Disease. Inflammatory Bowel Diseases, 
19, 1645-1653. 
Peyrin-Biroulet, L., Ferrante, M., Magro, F., Campbell, S., Franchimont, D., Fidder, H., Strid, 
H., Ardizzone, S., Veereman-Wauters, G., Chevaux, J.-B., Allez, M. and Dane 2011. 
Results from the 2nd Scientific Workshop of the ECCO (I): Impact of mucosal healing on 
the course of inflammatory bowel disease. Journal of Crohn’s and Colitis, 5, 477-483. 
Purinethol® 2011. US Prescribing Information. 
Reinisch, W., Colombel, J.-F., D’Haens, G., Sandborn, W. J., Rutgeerts, P., Geboes, K., 
Petersson, J., Eichner, S., Zhou, Q., Robinson, A. M., Read, H. A. and Thakkar, R. 2017. 
Characterisation of Mucosal Healing with Adalimumab Treatment in Patients with 
Moderately to Severely Active Crohn’s Disease: Results from the EXTEND Trial. 
Journal of Crohn’s and Colitis, 11, 425-434. 
Sampson, H. A., Munoz-Furlong, A., Campbell, R. L., Adkinson, N. F., Jr., Bock, S. A., 
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the definition and management of anaphylaxis: summary report--Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
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Safety and Efficacy of ABT-494 (Upadacitinib), an Oral Jak1 Inhibitor, as Induction 
Therapy in Patients with Crohn's Disease: Results from Celest. Gastroenterology, 152, 
S1308-S1309. 
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therapy for Crohn's disease. N Engl J Med, 369, 711-21. 
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Steen, K., Vermeire, S. v. and Rutgeerts, P. 2009. Mucosal healing predicts long-term 
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APPENDIX 1 
PROTOCOL HISTORY  
Document 
Date 
Global/Country/Site Specific 
Protocol Amendment 2 
22 Nov 2019 
Global 
Protocol Amendment 1 
21 Aug 2018 
Global 
Original Protocol 
15 Dec 2017 
Global 
 
Protocol Amendments 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
1 
Amendment Date 
21 Aug 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Emergency contact 
information 
Updated global fax number for Shire Global 
Drug Safety 
To provide updated emergency 
contact information 
Study Synopsis, Inclusion 
and 
exclusion criteria 
Section 4.1, Inclusion 
Criteria 
Updated inclusion criterion #4c to indicate that 
subjects must have abdominal pain subscores ≥2 
on the 4-point severity scale (used in the CDAI), 
in addition to abdominal pain subscores ≥5 on 
the 11-point numerical rating scale. 
To collect additional data for 
abdominal pain at study entry 
using the 0-3 CDAI severity scale. 
 
Study Synopsis, Inclusion 
and exclusion criteria 
Section 4.1, Inclusion 
Criteria 
Section 5.1, Prior 
Treatment 
Updated inclusion criterion #7 to add hyperlink 
to Section 5.1 in which “inadequate response to, 
lost response to, or intolerance to at least 1 
conventional treatment” (eg, sulfasalazine, 
mesalamine, glucocorticoids, 
immunosuppressants, or anti-TNF) is defined. 
To cross-reference section where 
prior treatments are defined. 
Study Synopsis, Inclusion 
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Updated exclusion criterion #1 to indicate that 
subjects with nonsteroidal 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 
Updated exclusion criterion #24 to clarify that 
subjects with a history of Mycobacterium 
tuberculosis (TB) infection who have not 
completed a generally accepted full course of 
treatment before baseline will also 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 
Updated exclusion criterion #30 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 #30 to new criterion #31.  
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 #32 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 
DBA, may be eligible for the 
study. 
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Protocol Amendments 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
1 
Amendment Date 
21 Aug 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 #33 to indicate that 
subjects with chronic hepatitis C without 
evidence of HCV RNA within 12 weeks of 
baseline may be considered eligible. 
To clarify that subjects with 
chronic hepatitis C, without 
HCV RNA, may be eligible for 
the study (in case of spontaneous 
viral clearance or previously 
treated and cured). 
Study Synopsis, Inclusion 
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Updated exclusion criterion #34 to indicate that 
subjects meeting the following lab criteria would 
be excluded: 
• 
ALT or AST ≥3×ULN  
• 
Total bilirubin ≥1.5×ULN or >2×ULN 
if the subject has a known documented 
history of Gilbert’s syndrome  
Added note to exclusion criterion #34 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 
Table 1, Schedule of 
Assessments, footnote ‘n’ 
Section 4.2, Exclusion 
Criteria 
Added new exclusion criterion #35 to clarify 
that documentation of HIV status should be 
performed within 6 months of screening. 
To clarify the timing of acceptable 
documentation of HIV status. 
Study Synopsis, Inclusion 
and exclusion criteria 
Section 4.2, Exclusion 
Criteria 
Updated exclusion criterion #36 to include 
exclusion of subjects with abuse of medicinal 
marijuana. Deleted former exclusion 
criterion #36 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 #39 to indicate the 
exclusion of 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 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, are excluded. 
Section 1.3, Benefit/Risk 
Assessment 
Added new section describing risk and benefits 
of SHP647 treatment. 
To provide updated risk and 
benefit information for SHP647. 
Section 3.1.1, Rationale for 
Coprimary Endpoints 
Added text describing results from recent trial 
with upadacitinib and from Phase 2 OPERA 
study with SHP647 as supporting rationale for 
the coprimary endpoint of endoscopic response. 
To provide additional supporting 
rationale for the coprimary 
endpoint of endoscopic response. 
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Protocol Amendments 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
1 
Amendment Date 
21 Aug 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Table 1, Schedule of 
Assessments, footnote ‘l’ 
Section 7.2.3.6, Clinical 
Laboratory Evaluations 
Appendix 5 
Updated SOA footnote ‘l’ and added 
Appendix 5 to clarify that diagnosis of 
C. difficile infection should be made using the 
central laboratory.  
Added diagnostic algorithms and relevant 
information related to C. difficile testing and 
diagnosis. 
To provide appropriate guidance 
regarding laboratory testing for 
C. difficile infection. 
Table 1, Schedule of 
Assessments, footnote ‘n’  
Added new row to SOA and footnote ‘n’ to 
indicate HIV tests may be performed at local 
laboratories (per local requirements), or 
centrally, if documentation of a negative HIV 
test within 6 months of screening is unavailable. 
To clarify the timing of acceptable 
documentation of HIV status. 
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 5.2.1, Permitted 
Treatment 
Added language to specify that any antidiarrheal 
opiate drugs must be taken at stable doses for 
the duration of the study unless dose reduction 
or discontinuation is required due to clinical 
improvement or adverse event, and that 
escalation of the dose after dose reduction, or re-
initiation after drug discontinuation, is not 
allowed. 
To clarify that concomitant 
antidiarrheal opiate drugs are 
permitted if taken at stable doses 
for the duration of the study, with 
dose reduction or discontinuation 
allowed only if required due to 
clinical improvement or adverse 
event. 
Section 7.2, Study 
Procedures 
Added language to specify that the duration of 
blood and tissue sample storage is dependent on 
local regulations. 
To clarify that local regulations 
should be considered for duration 
of blood and tissue sample 
storage. 
Section 7.2.3.6, Clinical 
Laboratory Evaluations 
Added HIV and HBV DNA samples to virology 
table. 
To reflect new eligibility criteria 
regarding HIV testing and HBV 
DNA reflex testing. 
Section 7.2.5, Volume of 
Blood to be Drawn from 
Each Subject 
Added 2 new rows to Table 4 for collection of 
HBV DNA and HIV samples. Increased TB test 
sample volume by 1 mL. 
To reflect changes in eligibility 
criteria regarding HIV testing and 
HBV DNA reflex testing and to 
correct the sample volume needed 
for the TB test.  
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Protocol Amendments 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
1 
Amendment Date 
21 Aug 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by 
Change 
Description of Change 
Rationale 
Section 8.2.8, Safety 
Monitoring 
Table 5 
Added new section and table describing safety 
monitoring and stopping criteria for elevated 
hepatic blood tests.  
To provide appropriate guidance 
on subjects who have been 
enrolled with elevated liver 
function test or who have elevated 
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. 
Appendix 4, Determination 
of Failure or Intolerance to 
Prior Treatment for 
Crohn’s Disease 
Added new appendix section, “Determination of 
Inadequate Response/Loss of Response or 
Intolerance to Prior Treatment for Crohn’s 
Disease” to provide guidance as related to 
inclusion criterion #7 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 
Diagnosis and Treatment of 
Increased Gastrointestinal 
Symptoms 
Added new Appendix 5, “Guidance for 
Diagnosis and 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: 
• Simple Endoscopic Score for Crohn’s Disease 
• Crohn’s Disease Activity Index 
• 
 
• Patient-reported Outcome – Crohn’s Disease Daily E-diary 
• Inflammatory Bowel Disease Questionnaire 
• 
 
• 
 
• 
 
• 
 
• Short Form-36 Health Survey 
• 
 
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Simple Endoscopic Score for Crohn’s Disease (SES-CD) 
SITE WORKSHEET: Simple Endoscopic Score for Crohn’s Disease (SES-CD) 
Site # 
Investigator 
Subject ID 
Visit Date 
(dd mmm yyyy) 
 
 
 
 
 
Definitions of Simple Endoscopic Score for Crohn’s Disease 
 
Score 
Variable 
0 
1 
2 
3 
Size of ulcers 
None 
Aphthous ulcers 
(∅ 0.1 to 0.5 cm) 
Large ulcers 
(∅ 0.5 to 2 cm) 
Very large ulcers 
(∅ >2 cm) 
Ulcerated surface 
None 
<10% 
10–30% 
>30% 
Affected surface 
Unaffected segment 
<50% 
50–75% 
>75% 
Presence of narrowing 
None 
Single, can be passed 
Multiple, can be passed 
Cannot be passed 
 
 
Ileum 
Right 
colon 
Transverse 
colon 
Left colon 
Rectum 
Total 
Presence and size of ulcers  (0–3) 
 
 
 
 
 
 
Extent of ulcerated surface  (0–3) 
 
 
 
 
 
 
Extent of affected surface 
(0–3) 
 
 
 
 
 
 
Presence and type of narrowing(s) (0–3) 
 
 
 
 
 
 
 
SES-CD = 
 
 
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Crohn’s Disease Activity Index (CDAI) 
 
CDAI=Crohn’s Disease Activity Index; ePRO=electronic patient-reported outcome; Hct=hematocrit 
Note: Variable 5: This variable covers taking medication for symptomatic relief from diarrhea, eg, bulking agents, opiates etc. 
Variable 7: Absolute deviation of hematocrit is the difference in hematocrit from standard. A male subject with a hematocrit of 
40% has an absolute deviation of 7. Each percentage deviation has a value of 6 points. If hematocrit subtotal is <0, enter 0. 
Variable 8: This variable is based on Metropolitan Life Tables (these are programmed into the ePRO device). 
Percent deviation from standard weight is (1 - weight/standard weight) × 100; therefore, positive percent deviation represents 
weight loss, which adds points to the CDAI. Percentage deviation from standard weight = 1 point for each percent deviation. If 
body weight subtotal is less than -10, enter -10. 
CDAI Interpretation: 
• 
0-149 points: Asymptomatic remission (Note: subjects requiring steroids to remain asymptomatic are not considered to 
be in remission but are referred to as being “steroid dependent”) 
• 
150-220 points: Mild to moderate active Crohn’s disease 
• 
221-450 points: Moderate to severe active Crohn’s disease 
• 
>451 points: Severely active to fulminant disease. 
CDAI online estimator: http://www.ibdjohn.com/cdai/ 
Sources: Best et al., 1976; Best et al., 1979. 
 
Crohn’s Disease Activity Index (CDAI)
CDAI 
Score
X 1
Body weight (1-weight/standard weight) X 100                                   
(add or subtract according to sign)
8
X 6
Hematocrit [Males: 47-Hct (%), Females: 42-Hct (%)]
7
X 10
Abdominal mass (0 = no, 2 = questionable, 5 = definite)
6
X 30
Use of diphenoxylate or loperamide for diarrhea (0 = no, 1 = yes)
5
X 20
Number of listed complications [arthritis or arthralgia, iritis or uveitis, 
erythema nodosum or pyoderma gangrenosum or aphthous
stomatitis, anal fissure or  fistula or abscess, other fistula, fever     
over 37.8oC (100oF)]
4
X 7
General well-being (0 = generally well, 1 = slightly under par,             
2 = poor, 3 = very poor, 4 = terrible)
3
X 5
Abdominal pain (0 = none, 1 = mild, 2 = moderate, 3 = severe)
2
X 2
No. of liquid or soft stools (each day for 7 days)
1
Total
Multiplier
Variable Description
Variable 
No.
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. 
Reference: D'Haens et al., 1998. 
 
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Patient-reported Outcomes – Crohn’s Disease Daily E-diary Version 1 
1. 
Please rate your worst abdominal pain over the past 24 hours. 
0     1     2     3     4     5     6     7     8     9     10 
      No pain 
 
 
 
 
 
Worst imaginable pain 
2. 
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: ____________ 
The next question asks about the number of liquid or very soft stools you had in the past 
24 hours. Liquid or very soft stools are defined as Type 6 and Type 7 in the chart below. 
 
3. 
You indicated you had X bowel movements in the past 24 hours. Of these, how many were 
liquid or very soft? 
Enter number of liquid or very soft bowel movements: ____________ 
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4. 
You indicated you had X bowel movements in the past 24 hours. Of these, how many had 
blood, either in the stool, the toilet bowel, or on the toilet paper? 
Enter number of bowel movements with blood: ____________ 
5. 
You indicated you had X bowel movements in the past 24 hours. How many of these 
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 feeling of nausea (feeling sick to your stomach or like you might 
throw up) over the past 24 hours. 
None 
Mild 
Moderate 
Severe 
7. 
How many vomiting episodes did you have in the past 24 hours? An episode includes one or 
multiple heaves (including dry heaves) in quick succession followed by a break in vomiting. 
Enter number of vomiting episodes: ____________ 
8. 
How many bowel incontinence episodes (losing control of your bowels before reaching the 
toilet) did you have in the past 24 hours? 
Enter number of bowel incontinence episodes: ______________ 
9. 
Please rate your abdominal pain over the past 24 hours. 
None 
Mild 
Moderate 
Severe 
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10. How would you rate your general well-being over the past 24 hours? 
Generally well 
Slightly below par 
Poor 
Very poor 
Terrible 
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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 (Version 2), 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 INADEQUATE RESPONSE/LOSS OF 
RESPONSE OR INTOLERANCE TO PRIOR TREATMENT FOR 
CROHN’S DISEASE 
The information below should serve as guidance. Local therapeutic standards and investigator 
judgment should be considered. 
AMINOSALICYLATES 
Mesalamine (5-ASA) 
Inadequate response or loss of response: Although the use of mesalamine in UC is well 
established (eg, induction treatment up to 4.8 g/day up to 8 weeks) and based upon 
evidence-based criteria, its use in CD is not well established. Oral mesalamine has not 
consistently been demonstrated to be effective compared with placebo for induction of remission 
and achieving mucosal healing in patients with active CD. Similarly, topical mesalamine is of 
limited benefit in CD (Lichtenstein et al., 2018). For the purpose of this study, inadequate 
response or loss of response is 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, 
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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 
Sulfasalazine (SSZ) 
Inadequate response or loss of response: Although the use of sulfasalazine in UC is accepted 
(eg, induction treatment up to 4 g/day up to 8 weeks), its use in CD is not well established.  
For the purpose of this study, inadequate response or loss of response is defined as persistent 
signs and symptoms of active disease despite treatment with at least one 8-week induction 
regimen at a daily dose of 4 g/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 
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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. 
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 
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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. 
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 
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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 
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): 
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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 
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  
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ANTI-TNF AGENTS 
Inadequate response or loss of response: Anti-TNF agents are rapid in onset of effect, with 
benefit often noted within 2 weeks of initiating therapy. As a result, assessment of inadequate 
response may be done sooner than with immunosuppressants. These include 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 
• certolizumab pegol (400 mg SC, 2 doses at least 2 weeks apart) or recurrence of 
symptoms during maintenance therapy (approved for CD in the United States). 
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  
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 
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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  
 
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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. 
PCR (-) 
I 
Not C. diff -
I NoAE 
' 
' 
,~ 
No 
GOH(-) 
GOH(+) 
Increased GI 
Yes 
Card test: 
Toxin A/8 (-) -
PCR for 
symptoms beyond 
GOH& 
. Tox A+B 
-
subject's historical 
Tox A+B 
range 
GOH(+) 
Toxin A/8 (+) 
C. diff 
PCR (+) 
-
infection -
present 
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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  
 
 
I NoAE I 
Not C. diff 
§] 
' 
PCR(-) 
I 
Increased GI 
symptoms beyond 
-
PCR for 
subject's historical 
- ToxA& B 
range 
I PCR (+) I 
" 
C. diff 
infection 
present 
I NoAE I 
Not C. diff 
'~ 
No 
t 
Culture(-) 
I 
Increased GI 
C diff 
symptoms beyond 
Yes 
- toxigenic 
subject's historical 
culture 
range 
I 
Culture(+) 
! 
C. diff 
infection 
present 
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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, 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 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. 
PCR(-) 
I NoAE I 
Not C. diff ..;: 
' 
No 
Culture(-) 
Increased GI 
symptoms beyond 
Yes 
-
C diff 
Culture(+) 
-
PCR for 
subject's historical 
culture 
Tox A+B 
range 
C. diff 
PCR (+) 
infection 
. 
present 
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