A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Study of SHP647 as Maintenance Therapy in Subjects With Moderate to Severe Crohn's Disease (CARMEN CD 307)
Phase: PHASE3
Conditions: Crohn's Disease
Sponsor: Shire

CLINICAL STUDY PROTOCOL 
NCT Number: 
NCT03627091 
Study Title:  
A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy 
and Safety Study of SHP647 as Maintenance Therapy in Subjects With Moderate 
to Severe Crohn’s Disease (CARMEN CD 307) 
Study Number:  
SHP647-307 
Protocol Version and Date:  
Protocol Amendment 3: 17 Sep 2020 
For non-commercial use only

 
PROTOCOL: SHP647-307 
TITLE: 
A Phase 3 Randomized, Double-blind, Placebo-controlled, 
Parallel-group Efficacy and Safety Study of SHP647 as Maintenance 
Therapy in Subjects With Moderate to Severe Crohn’s Disease 
(CARMEN CD 307) 
DRUG: 
Ontamalimab (SHP647) 
IND: 
100,222 
EUDRACT NO.: 
2017-000617-23 
SPONSOR: 
Shire Human Genetic Therapies, Inc. (“Shire”), a wholly owned 
subsidiary of Takeda Pharmaceutical Company 
300 Shire Way, Lexington, MA 02421 US 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
 
, MD 
PROTOCOL 
HISTORY: 
Protocol Amendment 3: 17 Sep 2020 
Protocol Amendment 2: 22 Nov 2019 
Protocol Amendment 1: 23 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

DocuSign Envelope ID: 9063D0EE-E724-425D-8727-19AC0A311C0A 
 
 
Shire 
CONFIDENTIAL 
Page 2 
Ontamalimab 
 
 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
PROTOCOL SIGNATURE PAGE 
Sponsor’s (Shire) Approv
 
Signature:
Date: 
21-Sep-2020 | 21:36:26 JST 
 MD 
Investigator’s Acknowledgement 
I have read this protocol for Shire Study SHP647-307. 
Title: A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and 
Safety Study of SHP647 as Maintenance Therapy in Subjects With Moderate to Severe Crohn’s 
Disease (CARMEN CD 307). 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation guidelines on Good Clinical Practice 
and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the sponsor. 
 
Investigator Name and Address: 
(please hand print or type) 
 
 
 
 
 
Signature:  
Date: 
  
 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 3 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
17 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Protocol Amendment Summary and Rationale: 
The main purpose of SHP647-307 Amendment 3 is to provide an update regarding the early closure of this study 
due to sponsor decision and to provide corresponding updates to the end of treatment procedures, including 
unblinding, as well as to reflect the impact of the early discontinuation of the study on the study objectives, 
endpoints, further assessments, and associated analyses of the data. As ontamalimab will not be further developed, 
most of the non-key secondary endpoints and all of the exploratory endpoints will not be analyzed, and data for the 
associated assessments will not be collected going forward. Due to the early termination of the ontamalimab 
program, the sponsor is providing an option for subjects who are responding to active treatment in this maintenance 
study or who are on placebo and had responded to active treatment in an induction study to continue to receive 
ontamalimab in the long-term safety extension study SHP647-304. Subjects already enrolled in this maintenance 
study and who are responding to active treatment, or who are on placebo and had responded to active treatment in an 
induction study, will be offered the opportunity to continue to receive ontamalimab in Study SHP647-304 provided 
they meet the eligibility criteria under SHP647-304 Amendment 4, which is being implemented concurrently. 
Subjects who received placebo in both the induction and maintenance studies will not be eligible to roll over into 
Study SHP647-304. 
As the eligibility criteria for Study SHP647-304 depend on the blinded treatment assignment in this study, for a 
given subject, there is potential for the treatment assignment in this study to be unblinded at the early termination 
visit when assessing whether the subject may roll over into the SHP647-304 study or should proceed to the safety 
follow-up period. In addition, due to the early discontinuation of the SHP647 program, the SHP647-304 study is 
planned to be unblinded prior to the database lock for this study, which would unblind the treatment assignment in 
this study for a significant portion of subjects. As such, this study will be considered unblinded when the 
SHP647-304 study is unblinded, and the date of study unblinding will be recorded. 
All subjects who discontinue investigational product and are not entering Study SHP647-304 should complete the 
protocol-specified safety follow-period in this study. Note that, with this amendment, the safety follow-up period 
has been reduced from 16 weeks to 12 weeks, based on emergent data on the half-life of ontamalimab (16 days). 
This amendment also provides clarification around home administration of investigational product, a provision that 
has been implemented in response to the World Health Organization (WHO) officially declaring the novel 
Coronavirus a pandemic on 11 March 2020. This amendment incorporates changes to provide flexibility in timing of 
site visits, to identify home healthcare solutions as permitted by local regulations, and to maintain subject safety and 
confidentiality and study integrity in the context of healthcare delivery challenges presented by the COVID-19 
pandemic. 
The significant changes in SHP647-307 Protocol Amendment 3 relative to the previous edition, SHP647-307 
Protocol Amendment 2, are captured below. 
 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 4 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
17 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Protocol Signature Page 
Updated sponsor signatory. 
Administrative change. 
Product Quality Complaints 
Updated the email address for 
product quality complaints. 
Administrative change. 
Global 
Changed the safety follow-up 
period from 16 weeks to 12 weeks. 
Due to the emergent data on the 
half-life of ontamalimab (16 days). 
Table 1, Schedule of Assessments 
Added note to state that after the 
implementation of Amendment 3, 
the subject’s next scheduled visit 
will be the Week 52/ET visit, 
which should be conducted no later 
than 4 weeks (±10 days) from the 
subject’s last study visit prior to 
the implementation of 
SHP647-304 Amendment 4. 
 
 
 
Updated footnotes ‘c’ and ‘d’ to 
reflect early closure of the study 
and issues related to COVID-19 
(or other similar pandemic). 
To specify that due to study closure, 
upon implementation of 
Amendment 3, the subject’s next 
scheduled visit will be the Week 52/ET 
visit and to clarify timing of the 
Week 52/ET visit. 
 
 
 
 
 
 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
Table 1, Schedule of Assessments 
footnote ‘j’ 
Added footnote that in case of a 
DTP situation, some procedures 
will be performed by remote visits 
via virtual communications. 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Table 1, Schedule of Assessments 
footnote ‘l’ 
Added footnote to allow clinical 
laboratory assays (liver function 
testing) to be done by local 
laboratory in case of issues related 
to COVID-19 (or other similar 
pandemic). 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Table 1, Schedule of Assessments 
footnote ‘m’ 
Added footnote to specify that 
subjects performing home 
administrations consecutively for 
3 months will need to perform 
liver function testing locally. 
To comply with the FDA 
requirements. 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 5 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
17 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Table 1, Schedule of Assessments 
footnote ‘q’ 
Added language to clarify that, 
with the early termination of this 
study by the sponsor, colonoscopy 
is optional for subjects who 
received less than 52 weeks of 
treatment. 
To clarify assessments to be done at 
the Week 52/ET visit. 
Table 1, Schedule of Assessments 
footnote ‘z’ 
Addition of details around DTP 
program/provision for home 
administration of investigational 
product. 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Study Synopsis, Objectives 
Section 2, Study Objectives and 
Purpose 
Removed other secondary and 
exploratory objectives. 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
Study Synopsis, Methodology 
Section 3.1, Study Design and Flow 
Chart 
Removed text regarding treatment 
failures. 
Added text on allowing continued 
treatment with ontamalimab for 
subjects benefiting. 
Added text on allowing study 
program to be stopped in case of 
no clinical efficacy. 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
Study Synopsis, Methodology 
Section 3.2, Duration and Study 
Completion Definition 
Added text regarding COVID-19 
(or other similar pandemic). 
Updated subject’s maximum study 
duration from 68 weeks to 
64 weeks. 
Added text regarding early closure 
of study and expected completion 
date of November 2021. 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
Study Synopsis, Site(s) and 
Region(s) 
Section 3.3, Sites and Regions 
Updated number of countries and 
sites in the study. 
Administrative change. 
Section 4.5.1, Subject Withdrawal 
Criteria 
Section 4.5.2, Reasons for 
Withdrawal 
Added text regarding subject 
withdrawal from the study due to 
personal concerns related to 
COVID-19 (or other similar 
pandemic). 
To address the situation if the subject 
withdraws from the study due to a 
pandemic (eg, coronavirus disease 
[COVID-19]) or other future similar 
unexpected public health concerns 
requiring physical distancing that may 
result in subjects missing their visits. 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 6 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
17 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 5, Prior and Concomitant 
Treatment 
Added text around change in 
permitted treatment when the 
subject is known to have been 
infected with the COVID-19 virus 
(Section 5.3). 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Section 6.2.3, Dosing 
Addition of details around DTP 
program/provision for home 
administration of investigational 
product, which has been 
implemented due to the COVID-19 
pandemic situation. 
Added the criteria of delayed 
dosing and missed dosing due to a 
pandemic (eg, coronavirus disease 
[COVID-19]) or other future 
similar unexpected public health 
concerns requiring physical 
distancing that may result in 
subjects missing their visits. 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Section 6.2.4, Unblinding the 
Treatment Assignment 
Added text to describe the 
potential for unblinding of 
treatment assignment, following 
the end of treatment, for those 
subjects who had received placebo 
both in this study and in the 
induction study and who would not 
be eligible for entry into Study 
SHP647-304. 
To note the potential for unblinding of 
treatment assignment due to the 
revised entry criteria for the long-term 
safety extension Study SHP647-304, 
which depends on the subject’s 
treatment assignment in this 
maintenance study. 
Section 6.3.2, Packaging 
Updated the packaging of 
pre-filled syringe from tray to 
foam insert. 
To accurately describe the packaging 
of study drug. 
Section 6.3.3, Storage 
Added the storage condition for the 
investigational product in case of 
DTP program/provision for home 
administration of investigational 
product. 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Section 6.3.4, Special Handling 
Added the special handling of the 
investigational product in case of 
DTP program/provision for home 
administration of investigational 
product. 
To comply with study procedures of as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 7 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
17 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
subjects missing their visits. 
Section 6.4, Drug Accountability 
Added text related to the 
documentation of investigational 
product administration in case of 
DTP program/provision. 
Added text related to shipping of 
used investigational product to the 
site in case of DTP. 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Section 7, Study Procedures 
Added new section to address the 
changes to study procedures due to 
a pandemic (eg, coronavirus 
disease [COVID-19]) or other 
future similar unexpected public 
health concerns requiring physical 
distancing that may result in 
subjects missing their visits 
(Section 7.1). 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Section 7.2.2.1, Visits 2 to 13 
(Weeks 4 to 48) 
Added note that, after the 
implementation of Amendment 3, 
subject’s next scheduled visit will 
be the Week 52/ET visit. 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Section 7.2.2.2, Final On-treatment 
Visits: Visit 14, Parts 1 and 2 
(Week 52/Early Termination) 
Updated the window for the safety 
follow-up visit to ±10 days (from 
±7 days). 
Added text on treatment failures or 
discontinuations from the study 
due to early termination. 
Added note that colonoscopy is not 
required at the ET visit. 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Section 7.2.3, Follow-up Period: 
Visit 15 (Week 64) 
Updated follow-up period visit 
from Week 68 to Week 64 and 
added text regarding COVID-19 
(or other similar pandemic) 
guidance. 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 8 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
17 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 7.3.3.6, Clinical Laboratory 
Evaluations 
Added text to allow clinical 
laboratory assays to be done by 
local laboratory in case of issues 
related to COVID-19 (or other 
similar pandemic). 
Added liver function test (local 
laboratory) for subjects performing 
home administration consecutively 
for 3 months. 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
To comply with the FDA 
requirements. 
Section 7.3.4, Others 
 
 
 
 
 
 
Section 7.3.5, Volume of Blood to 
be Drawn From Each Subject 
Table 4, Volume of Blood to be 
Drawn From Each Subject 
Updated the total blood volume 
drawn from 97 mL to 41 mL. 
 
 
 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
Section 9.4, Statistical Analysis 
Process 
Added text to clarify that changes 
to the planned analyses will be 
described in the statistical analysis 
plan. 
To address the impact of COVID-19 
(or other similar pandemic) on data 
analysis. 
Section 9.5, Planned Interim 
Analysis, Adaptive Design, Data 
Monitoring Committee, and 
Hypersensitivity Adjudication 
Committee 
Updated text regarding the use of a 
DMC until the time of unblinding. 
Removed text describing the 
planned interim analysis for related 
studies and that these may affect 
the current study. 
Added text that there was no 
planned interim analysis or 
adaptive design. 
Removed text on multiplicity 
concerns regarding repeated 
analyses. 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
Section 9.6, Sample Size 
Calculation and Power 
Considerations 
Added text to clarify that the 
power considerations were based 
on a planned sample size of 
983 subjects, which will not be 
attained. 
To clarify that the planned sample size 
will not be attained due to early 
discontinuation of this study. 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 9 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
17 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Endpoints and 
statistical analysis 
Section 9.7, Study Population 
Reduced analysis sets. 
Due to the early discontinuation of the 
study and limited sample size, 
previously planned analyses will no 
longer be conducted. 
Study Synopsis, Endpoints and 
statistical analysis 
Section 9.8, Efficacy Analyses 
Removed other secondary analyses 
and exploratory analyses. 
Updated text on primary efficacy 
endpoint measurements and 
secondary endpoint analyses. 
Due to the early discontinuation of the 
study and limited sample size, 
previously planned analyses will no 
longer be conducted. 
Study Synopsis, Endpoints and 
statistical analysis 
Section 9.10, Other Analyses 
 
 
 
 
Section 10.1.5, Study Suspension, 
Termination, and Completion 
Removed text regarding DMC 
meeting to review induction study 
results. 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
Section 10.2.3.2, Recording, 
Access, and Retention of Source 
Data and Study Documents 
Added sentence on document 
retention requirement in case of 
DTP provision. 
To comply with study procedures as 
per the protocol due to a pandemic 
(eg, coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing that may result in 
subjects missing their visits. 
Throughout protocol 
Minor changes to wording and 
editorial changes. 
To improve clarity, consistency, and 
remove redundancy of text. 
Appendices 
Added Summary of Changes of 
Protocol Amendment 2. 
Removed assessments no longer 
applicable under Amendment 2. 
Administrative change. 
See Appendix 1 for protocol history, including all amendments. 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 10 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must fax or email the Shire 
“Clinical Study Serious Adverse Event and Nonserious AE as Required by the Protocol Form” 
within 24 hours to the Shire Global Drug Safety Department. The fax number and email address 
are provided on the form (sent under separate cover). A copy of this form must also be sent to the 
contract research organization (CRO)/Shire medical monitor using the details below. 
Fax 
 (Global) 
Email 
 
For protocol- or safety-related issues, the investigator must contact the medical monitor via 
the appropriate regional safety hotline (24 hours): 
North America: 
PPD 24 Hour Safety Hotline: RTP 
; Wilmington 
 
PPD 24 Hour Safety Hotline Fax: RTP 
 or 
; 
Wilmington 
 or 
 
Latin America: 
PPD 24 Hour Safety Hotline: 
 
PPD 24 Hour Safety Hotline Fax: 
 
Europe, the Middle East, and Africa; and Asia-Pacific: 
PPD 24 Hour Safety Hotline: 
 
PPD 24 Hour Safety Hotline Fax: 
 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 11 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
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 (US) 
 
For instructions on reporting adverse events related to product complaints, see Section 8.2.2. 
For non-commercial use only

Shire 
CONFIDENTIAL 
Page 12 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ........................................................3 
EMERGENCY CONTACT INFORMATION ..............................................................................10 
PRODUCT QUALITY COMPLAINTS........................................................................................11 
TABLE OF CONTENTS ...............................................................................................................12 
LIST OF TABLES .........................................................................................................................17 
LIST OF FIGURES .......................................................................................................................17 
LIST OF APPENDICES ................................................................................................................17 
ABBREVIATIONS .......................................................................................................................18 
STUDY SYNOPSIS ......................................................................................................................21 
STUDY SCHEDULE ....................................................................................................................27 
1. 
BACKGROUND INFORMATION .......................................................................................31 
1.1 
Indication and Current Treatment Options ...............................................................31 
1.2 
Product Background and Clinical Information ........................................................31 
1.3 
Benefit/Risk Assessment ..........................................................................................32 
2. 
STUDY OBJECTIVES AND PURPOSE ..............................................................................34 
2.1 
Rationale for the Study .............................................................................................34 
2.1.1 Rationale for Subjects Who Responded to Ontamalimab in the Induction 
Study and Who Could Potentially be Randomized to Placebo in the 
Maintenance Study.................................................................................................36 
2.2 
Study Objectives ......................................................................................................37 
2.2.1 Coprimary Objectives ............................................................................................37 
2.2.2 Secondary Objectives .............................................................................................37 
2.2.2.1 
Key Secondary Objectives .....................................................................37 
3. 
STUDY DESIGN ...................................................................................................................38 
3.1 
Study Design and Flow Chart ..................................................................................38 
3.1.1 Rationale for Coprimary Endpoints .......................................................................42 
3.1.2 Rationale for Key Secondary Endpoints ................................................................43 
3.2 
Duration and Study Completion Definition .............................................................47 
3.3 
Sites and Regions .....................................................................................................47 
4. 
STUDY POPULATION .........................................................................................................48 
4.1 
Inclusion Criteria ......................................................................................................48 
4.2 
Exclusion Criteria .....................................................................................................49 
4.3 
Restrictions ...............................................................................................................51 
4.4 
Reproductive Potential .............................................................................................51 
4.4.1 Contraceptive Methods for Female Study Subjects ...............................................52 
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CONFIDENTIAL 
Page 13 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
4.4.2 Contraceptive Methods for Male Study Subjects ..................................................54 
4.5 
Withdrawal of Subjects ............................................................................................54 
4.5.1 Subject Withdrawal Criteria ..................................................................................55 
4.5.2 Reasons for Withdrawal .........................................................................................57 
4.5.3 Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................58 
5. 
PRIOR AND CONCOMITANT TREATMENT ...................................................................59 
5.1 
Prior Treatment ........................................................................................................59 
5.2 
Concomitant Treatment ............................................................................................59 
5.2.1 Permitted Treatment ...............................................................................................59 
5.2.2 Prohibited Treatment .............................................................................................61 
5.2.3 Rescue Therapy ......................................................................................................62 
5.3 
COVID-19 ................................................................................................................62 
6. 
INVESTIGATIONAL PRODUCT ........................................................................................63 
6.1 
Identity of Investigational Product ...........................................................................63 
6.1.1 Blinding the Treatment Assignment ......................................................................63 
6.2 
Administration of Investigational Products ..............................................................63 
6.2.1 Interactive Response Technology for Investigational Product Management ........63 
6.2.2 Allocation of Subjects to Treatment ......................................................................63 
6.2.3 Dosing ....................................................................................................................64 
6.2.4 Unblinding the Treatment Assignment ..................................................................66 
6.3 
Labeling, Packaging, Storage, and Handling ...........................................................66 
6.3.1 Labeling .................................................................................................................66 
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 
Changes to Study Procedures Due to a Pandemic ....................................................70 
7.2 
Study Schedule .........................................................................................................71 
7.2.1 Baseline Visit (Visit 1, Week 0) ............................................................................71 
7.2.2 Treatment Period ....................................................................................................72 
7.2.2.1 
Visits 2 to 13 (Weeks 4 to 48) ................................................................72 
7.2.2.2 
Final On-treatment Visits: Visit 14, Parts 1 and 2 (Week 52/Early 
Termination) ...........................................................................................72 
7.2.2.3 
Unscheduled Visit to Evaluate Potential Treatment Failure With 
CDAI ......................................................................................................73 
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7.2.2.4 
Unscheduled Visit to Evaluate Potential Treatment Failure With 
Colonoscopy ...........................................................................................73 
7.2.3 Follow-up Period: Visit 15 (Week 64)...................................................................74 
7.2.4 Additional Care of Subjects After the Study .........................................................74 
7.3 
Study Evaluations and Procedures ...........................................................................74 
7.3.1 Demographic and Other Baseline Characteristics .................................................75 
7.3.2 Efficacy ..................................................................................................................75 
7.3.2.1 
Patient-reported Outcome – Crohn’s Disease Daily E-diary .................75 
7.3.2.2 
Simple Endoscopic Score for Crohn’s Disease ......................................76 
7.3.2.3 
Crohn’s Disease Activity Index .............................................................77 
7.3.2.4 
Colonoscopy and Histology ...................................................................78 
7.3.3 Safety .....................................................................................................................79 
7.3.3.1 
Medical and Medication History ............................................................79 
7.3.3.2 
Physical Examination (Including Weight) .............................................79 
7.3.3.3 
Targeted Neurological Assessment ........................................................80 
7.3.3.4 
Adverse Event Collection .......................................................................82 
7.3.3.5 
Vital Signs ..............................................................................................82 
7.3.3.6 
Clinical Laboratory Evaluations .............................................................83 
7.3.3.7 
Pregnancy Test and Follicle-stimulating Hormone Test ........................85 
7.3.3.8 
Electrocardiogram ..................................................................................86 
7.3.3.9 
Antidrug Antibodies ...............................................................................86 
7.3.3.10 
Monitoring for Type I and Type III Immune Reactions ........................86 
7.3.3.11 
Evaluation of Increased Gastrointestinal Symptoms .............................87 
7.3.4 Others .....................................................................................................................87 
7.3.4.1 
 .............................................................87 
7.3.5 Volume of Blood to Be Drawn From Each Subject ..............................................88 
8. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................89 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events .......................................................................................................................89 
8.1.1 Severity Categorization ..........................................................................................89 
8.1.2 Relationship Categorization ...................................................................................90 
8.1.3 Adverse Events of Special Interest ........................................................................90 
8.1.3.1 
Hypersensitivity .....................................................................................91 
8.1.4 Outcome Categorization ........................................................................................93 
8.1.5 Symptoms of the Disease Under Study .................................................................93 
8.1.6 Clinical Laboratory and Other Safety Evaluations ................................................93 
8.1.7 Pregnancy ...............................................................................................................94 
8.1.8 Abuse, Misuse, Overdose, and Medication Error ..................................................94 
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8.1.9 Unexpected Adverse Event ....................................................................................95 
8.1.10 Suspected Unexpected Serious Adverse Reaction .................................................96 
8.2 
Serious Adverse Event Procedures ..........................................................................96 
8.2.1 Reference Safety Information ................................................................................96 
8.2.2 Reporting Procedures .............................................................................................96 
8.2.3 Serious Adverse Event Definition .........................................................................97 
8.2.4 Serious Adverse Event Collection Time Frame .....................................................97 
8.2.5 Serious Adverse Event Onset and Resolution Dates .............................................98 
8.2.6 Fatal Outcome ........................................................................................................98 
8.2.7 Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................98 
8.2.8 Safety Monitoring for Potential Cases of Drug-induced Liver Injury ...................99 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS .............................................102 
9.1 
Data Collection .......................................................................................................102 
9.2 
Clinical Data Management .....................................................................................102 
9.3 
Data Handling Considerations ...............................................................................102 
9.4 
Statistical Analysis Process ....................................................................................103 
9.5 
Planned Interim Analysis, Adaptive Design, Data Monitoring Committee, 
and Hypersensitivity Adjudication Committee ......................................................103 
9.6 
Sample Size Calculation and Power Considerations ..............................................104 
9.7 
Study Population ....................................................................................................106 
9.8 
Efficacy Analyses ...................................................................................................107 
9.8.1 Coprimary Efficacy Endpoints ............................................................................107 
9.8.2 Secondary Efficacy Endpoints .............................................................................108 
9.8.2.1 
Key Secondary Efficacy Endpoints ......................................................108 
9.9 
Safety Analyses ......................................................................................................109 
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 ....................................................................111 
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 
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 
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10.2.3.1 
Case Report Forms ...............................................................................112 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study 
Documents ............................................................................................113 
10.2.3.3 
Audit/Inspection ...................................................................................113 
10.2.3.4 
Financial Disclosure .............................................................................114 
10.3 
Ethical Considerations ............................................................................................114 
10.3.1 Informed Consent.................................................................................................114 
10.3.2 Institutional Review Board or Ethics Committee ................................................115 
10.4 
Privacy and Confidentiality ....................................................................................115 
10.5 
Study Results/Publication Policy ...........................................................................116 
11. REFERENCES .....................................................................................................................118 
 
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LIST OF TABLES 
Table 1 
Schedule of Assessments ...............................................................................27 
Table 2 
Glucocorticoid Tapering ................................................................................60 
Table 3 
Quarterly Neurological Assessments ............................................................81 
Table 4 
Volume of Blood to Be Drawn From Each Subject ......................................88 
Table 5 
Clinical Criteria for Diagnosing Anaphylaxis (Type I Hypersensitivity) .....92 
Table 6 
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin .......................................................................................................100 
Table 7 
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints ...................................................................................106 
 
LIST OF FIGURES 
Figure 1 
Overview of Ontamalimab Phase 3 Studies in Crohn’s Disease ...................40 
Figure 2 
Study Design Flow Chart ..............................................................................41 
Figure 3 
Flow Diagram for Quarterly Neurological Assessments ...............................82 
Figure 4 
Potential Immunogenicity of Therapeutic Monoclonal Antibodies ..............91 
 
LIST OF APPENDICES 
Appendix 1 
Protocol History ...........................................................................................121 
Appendix 2 
Scales and Assessments ...............................................................................131 
Appendix 3 
Glucocorticoid Equivalent Doses ................................................................137 
Appendix 4 
Guidance for Diagnosis and Treatment of Increased Gastrointestinal 
Symptoms ....................................................................................................138 
 
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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 
CDEIS 
Crohn’s Disease Endoscopic Index of Severity 
CGHAS 
Colonic Global Histologic Disease Activity Score 
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 
ECCO 
European Crohn’s and Colitis Organisation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
e-diary 
electronic diary 
EIM 
extra-intestinal manifestation 
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 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
hsCRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
ICH 
International Council for Harmonisation 
IgG2κ 
immunoglobulin G2 kappa 
IGHAS 
Ileal Global Histologic Disease Activity Score 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LP 
lumbar puncture 
LTS 
long-term safety extension 
MAdCAM 
mucosal addressin cell adhesion molecule 
MTX 
methotrexate 
NAb 
neutralizing antibody 
NRS 
numerical rating scale 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PFS 
prefilled syringe 
PK 
pharmacokinetic(s) 
PML 
progressive multifocal leukoencephalopathy 
PRO 
patient-reported outcome 
Q4W 
once every 4 weeks 
RSI 
reference safety information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SES-CD 
Simple Endoscopic Score for Crohn’s Disease 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
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UC 
ulcerative colitis 
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STUDY SYNOPSIS 
Protocol number: SHP647-307 
Drug: Ontamalimab (SHP647) 
Title of the study: A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and 
Safety Study of SHP647 as Maintenance Therapy in Subjects With Moderate to Severe Crohn’s Disease 
(CARMEN CD 307) 
Number of subjects (total and for each treatment arm): 
Approximately 983 subjects were planned for enrollment into the study: approximately 776 subjects from active 
induction treatments and approximately 207 subjects from placebo induction groups. A total of 40 subjects have 
been enrolled. 
Investigator(s): Multicenter study 
Site(s) and region(s): 
This study will be conducted in approximately 33 sites in approximately 16 countries. 
Study period (planned): 
2018 to 2021 
Clinical phase: 
3 
Objectives: 
Coprimary: The coprimary objectives of this study are to evaluate the efficacy of ontamalimab as maintenance 
treatment in subjects with moderate to severe Crohn’s disease (CD) based on: 
• 
Clinical remission based on 2-item patient-reported outcome (PRO) (abdominal pain severity and very 
soft stool/liquid stool frequency) 
• 
Enhanced endoscopic response based on centrally read colonoscopy. 
Key Secondary: 
• 
To evaluate the efficacy of ontamalimab as maintenance treatment on clinical remission as measured 
by CD Activity Index (CDAI) 
• 
To evaluate the efficacy of ontamalimab as maintenance treatment on glucocorticoid-free clinical 
remission based on patient-reported clinical signs and symptoms (as measured by 2-item PRO) 
• 
To evaluate the efficacy of ontamalimab as maintenance treatment on clinical remission based on 
abdominal pain severity and very soft stool/liquid stool frequency (alternate thresholds) 
• 
To evaluate the efficacy of ontamalimab on maintenance of clinical remission among subjects in 
clinical remission at baseline of the SHP647-307 study based on patient-reported clinical signs and 
symptoms (as measured by 2-item PRO) 
• 
To evaluate the efficacy of ontamalimab on maintenance of enhanced endoscopic response among 
subjects with enhanced endoscopic response at baseline of the SHP647-307 study based on centrally 
read colonoscopy 
• 
To evaluate the efficacy of ontamalimab as maintenance treatment based on achieving clinical 
remission as well as achieving enhanced endoscopic response in the same subject 
• 
To evaluate the effect of ontamalimab as maintenance treatment on complete endoscopic healing based 
on centrally read colonoscopy. 
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Rationale: 
This study is designed to evaluate the efficacy of ontamalimab as maintenance therapy in subjects with 
moderate to severe CD who fulfilled the efficacy entry criteria of this study including the clinical and/or 
endoscopic response criteria defined in induction Study SHP647-305 or SHP647-306. 
Investigational product, dose, and mode of administration: 
The test product is ontamalimab (SHP647), which will be provided as a sterile aqueous buffered solution for 
subcutaneous (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 in subjects with moderate 
to severe CD who completed participation in an induction study (either SHP647-305 or SHP647-306) and 
fulfilled the efficacy entry criteria of this study. 
This study consists of a 52-week, double-blind treatment period, followed by a 12-week safety follow-up period 
for subjects who either discontinue treatment early or who complete the treatment period and do not enter the 
long-term safety extension (LTS) study (SHP647-304). 
The eligibility of a subject for the study will be assessed based on the study data collected at the Week 16 visit 
of the induction studies (SHP647-305 or SHP647-306), which will be considered as the baseline visit for this 
maintenance study. 
Eligible subjects who received active treatment in one of the induction studies and fulfilled the efficacy entry 
criteria of this study, including achieving endoscopic and/or clinical response, will be randomized as 
follows: subjects who received 25 mg ontamalimab in one of the induction studies will be randomized (1:1) to 
receive either 25 mg ontamalimab or placebo, and subjects who received 75 mg ontamalimab in one of the 
induction studies will be randomized (1:1) to receive either 75 mg ontamalimab or placebo. 
Eligible subjects who received placebo in one of the induction studies and fulfilled the efficacy entry criteria of 
this study, including achieving endoscopic and/or clinical response, will be randomized in a 2:2:1 ratio to 
receive 1 of 3 treatments (25 mg ontamalimab, 75 mg ontamalimab, or placebo, respectively) during this 
maintenance study. 
Subjects will be stratified according to glucocorticoid use at Study SHP647-307 baseline, the subject’s status of 
prior anti-tumor necrosis factor (TNF) treatment (naïve or experienced), and whether or not the subject achieved 
clinical remission by 2-item PRO or enhanced endoscopic response in the induction study. 
Subjects enrolled in this study (SHP647-307) will receive double-blind maintenance treatment in the form of 
SC injections, using a PFS, once every 4 weeks for 52 weeks. Subjects will undergo efficacy, 
, and 
safety assessments. 
Under Amendment 3, subjects who complete the double-blind treatment period, or subjects who are withdrawn 
from the study prior to completing the double-blind treatment period due to early closure of the study by the 
sponsor, may be eligible to enter the LTS study (SHP647-304) provided they meet the eligibility criteria under 
SHP647-304 Amendment 4. Offering treatment in the LTS study after exiting this maintenance study allows 
subjects who benefited from active treatment, in this study or the induction study, to potentially benefit from 
continued treatment at the same dose of ontamalimab or at different dose of ontamalimab if, during the course 
of the SHP647-304 study, one of those doses (25 mg or 75 mg) is determined to be more efficacious based on 
emergent data from the induction studies. However, if there is no evidence of efficacy of either of the doses in 
comparison to placebo in the UC/CD clinical study, the entire program may be stopped, including the LTS 
study. Subjects who are not entering Study SHP647-304 will enter a 12-week safety follow-up period. 
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Inclusion and exclusion criteria: 
Inclusion criteria: 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study: 
1. Subjects and/or their parent or legally authorized representative must have an understanding, ability, and 
willingness to fully comply with study procedures and restrictions. 
2. Subjects must be able to voluntarily provide written, signed, and dated (personally or via a legally 
authorized representative) informed consent and/or assent, as applicable, to participate in the study. 
3. Subjects must have completed the 16-week induction treatment period from Study SHP647-305 or 
SHP647-306 and met the following criteria at baseline in maintenance study SHP647-307: 
a) Meet endoscopic response criteria of a reduction in the Simple Endoscopic Score for CD (SES-CD) 
from induction study (SHP647-305 or SHP647-306) baseline by ≥25% at Week 16 of induction study 
(SHP647-305 or SHP647-306) 
OR 
b) Meet at least 1 of the following 4 criteria at baseline in maintenance Study SHP647-307, in addition to 
no worsening of endoscopic score as measured by SES-CD relative to induction study (SHP647-305 or 
SHP647-306) baseline: 
i. 
Achieving clinical remission as determined by meeting the criteria for clinical remission using 
the 2-item PRO, ie, 2-item PRO subscores of average worst daily abdominal pain ≤3 (based 
on 11-point numerical rating scale [NRS]) over the 7 most recent days* and average daily 
stool type frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the Bristol 
Stool Form Scale (BSFS) over the 7 most recent days*. 
ii. 
A decrease of at least 100 points in CDAI score (CDAI-100) from induction study 
(SHP647-305 or SHP647-306) baseline. 
iii. 
A decrease of ≥30% and at least 2 points from induction study (SHP647-305 or SHP647-306) 
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 induction study (SHP647-305 or SHP647-306) 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*. 
iv. 
A decrease of ≥30% from induction study (SHP647-305 or SHP647-306) 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: (i) not 
worsening from induction study (SHP647-305 or SHP647-306) baseline and/or (ii) 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 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. 
4. 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. 
Exclusion criteria: 
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Subjects who had major protocol deviation(s) (as determined by the sponsor) in induction study 
SHP647-305 or SHP647-306. 
2. Subjects who permanently discontinued investigational product because of an adverse event (AE), 
regardless of relatedness to investigational product, in induction study SHP647-305 or SHP647-306. 
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3. Subjects who are likely to require surgery for CD during the study period, except minor interventions 
(eg, seton placement for anal fistulas). 
4. Subjects are females who became pregnant during induction study SHP647-305 or SHP647-306, females 
who are lactating, females who are planning to become pregnant during the study period, or males or 
females of childbearing potential not agreeing to continue using appropriate contraception methods 
(ie, highly effective methods for female subjects and medically appropriate methods for male subjects, as 
described in Section 4.4 of the protocol) through the conclusion of study participation. 
5. 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. 
6. Subjects who, in the opinion of the investigator or the sponsor, will be uncooperative or unable to comply 
with study procedures. 
7. Subjects who have developed obstructive colonic stricture, or enterovesical or enterovaginal fistulae during 
the induction study (SHP647-305 or SHP647-306). 
8. Subjects who have a newly diagnosed malignancy or recurrence of malignancy (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). 
9. Subjects who have developed 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. 
10. 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. 
11. Subjects with known exposure to Mycobacterium tuberculosis since testing at screening in induction study 
SHP647-305 or SHP647-306 and who have been advised to require treatment for latent or active disease 
but who are without a generally accepted course of treatment. 
12. Subjects with any of the following abnormalities in hematology and/or serum chemistry profiles during the 
evaluation of the last visit in the SHP647-305 or SHP647-306 studies. If the results are considered by the 
investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated once prior 
to enrollment in Study SHP647-307. 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase levels ≥3.0 × the upper limit of normal 
(ULN) 
• 
Total bilirubin level ≥1.5 times the 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. 
13. Subjects who are investigational site staff members or relatives of those site staff members or subjects who 
are sponsor employees directly involved in the conduct of the study. 
14. Subjects who are participating in other investigational studies (other than induction study SHP647-305 or 
SHP647-306) or plan to participate in other investigational studies during Study SHP647-307. 
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Maximum duration of subject involvement in the study: 
• 
Maximum duration of participation: Approximately 64 weeks 
• 
Planned duration of treatment period: 52 weeks 
• 
Planned duration of safety follow-up period: 12 weeks 
Endpoints and statistical analysis: 
Analysis Sets: 
The safety set will consist of all subjects who have received at least 1 dose of investigational product in the 
SHP647-307 study, regardless of treatment received during the induction studies (SHP647-305 and 
SHP647-306). 
The full analysis set (FAS) will consist of all randomized subjects who have received at least 1 dose of 
investigational product in the SHP647-307 study, regardless of treatment received during the induction studies 
(SHP647-305 and SHP647-306). 
Coprimary Efficacy Endpoints: 
The coprimary efficacy endpoints are: 
• 
Clinical remission at the Week 52 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. 
• 
Enhanced endoscopic response at Week 52 as measured by a decrease in SES-CD of at least 50% from 
induction study (SHP647-305 or SHP647-306) baseline. 
The number and percentage of subjects, and the estimate of the common treatment difference along with the 
corresponding unstratified Newcombe 95% confidence interval for each primary endpoint, will be summarized 
by maintenance treatment group at Week 52. Subjects with missing data at Week 52 will be considered failures 
and counted as nonresponders. Due to the early discontinuation of the study before full enrollment and the 
limited sample size, formal statistical testing will not be performed, and therefore, multiplicity adjustment is not 
applicable. 
Key Secondary Efficacy Endpoints: 
The key secondary efficacy endpoints are as follows: 
• 
Clinical remission at the Week 52 visit as measured by CDAI <150. 
• 
Glucocorticoid-free clinical remission at the Week 52 visit, among subjects using glucocorticoids at 
induction study baseline. Glucocorticoid-free clinical remission is defined as clinical remission by 
2-item PRO (as defined for the coprimary endpoint; see Section 9.8.1) in addition to not requiring any 
treatment with glucocorticoids for at least 12 weeks prior to the Week 52 visit. 
• 
Clinical remission at the Week 52 visit as defined by the following: CD daily electronic diary (e-diary) 
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 
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recent 6 or 5 days. If fewer than 5 days are available, the endpoint will be treated as missing. 
• 
Sustained clinical remission, ie, in clinical remission at the SHP647-307 Week 52 visit, among subjects 
who were in clinical remission by 2-item PRO (as defined for the coprimary endpoint) at the time of 
baseline in Study SHP647-307. 
• 
Sustained enhanced endoscopic response, ie, in enhanced endoscopic response at the SHP647-307 
Week 52 visit, among subjects who showed enhanced endoscopic response (as defined for the 
coprimary endpoint) at the time of baseline in Study SHP647-307. 
• 
Both clinical remission by 2-item PRO and enhanced endoscopic response at Week 52 (composite 
endpoint). 
• 
Complete endoscopic healing at Week 52 defined as SES-CD=0-2. 
The key secondary endpoints will be analyzed using the same approach as described for the coprimary endpoint. 
Subjects with missing key secondary endpoint data at the Week 52 visit will be considered failures and counted 
as nonresponders. Due to the early discontinuation of the study before full enrollment and the limited sample 
size, formal statistical testing will not be performed. 
Safety Analyses: 
All safety analyses will be performed using the safety set. Subjects will be analyzed according to the treatment 
they actually received. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. 
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates at the time of or following the first 
exposure to investigational product in the SHP647-307 study. 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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Ontamalimab 
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STUDY SCHEDULE 
Table 1 
Schedule of Assessments 
Study Week 
Baselinea 
Treatment 
Follow-Upb 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52/ETc 
64c 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
(Part 1)d 
14 
(Part 2)d 
15 
Study Day 
1 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
 
364 
±10 days 
448 
Visit Window 
None 
±10 days 
±10 days 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessmente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyf 
IDT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examinationg 
IDT 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Targeted physical examinationg,h 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Targeted neurological assessmenti,j 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Vital signs 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Weighth 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECG 
IDT 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
Contraception checkk 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Laboratory Assessmentsl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
Serum chemistrym 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
Urinalysis 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
FSHn 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine β-hCGo 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
ADA and NAb sampling 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
CD Assessmentsp Including 
Endoscopic Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Colonoscopy (including biopsy)q,r,s 
IDT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xq 
 
SES-CD 
IDT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xq,t 
 
CDAIu 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
PRO e-diary data instruction 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO-CD daily e-diary datav 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Treatment failure assessmentw 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Ontamalimab 
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Table 1 
Schedule of Assessments 
Study Week 
Baselinea 
Treatment 
Follow-Upb 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52/ETc 
64c 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
(Part 1)d 
14 
(Part 2)d 
15 
Study Day 
1 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
 
364 
±10 days 
448 
Visit Window 
None 
±10 days 
±10 days 
Treatment Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of ontamalimab or 
placeboy,z,aa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hypersensitivity monitoringbb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication and 
proceduresh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense stool collection kit for stool 
samplecc 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
ADA=antidrug antibody; β-hCG=beta-human chorionic gonadotropin; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; CLIA=Clinical Laboratory Improvement 
Amendments; DTP=Direct-to-Patient; ECG=electrocardiogram; e-diary=electronic diary; ET=early termination; FSH=follicle-stimulating hormone; IDT=induction study 
(SHP647-305 or SHP647-306); LFT=liver function testing; LTS=long-term safety extension; NAb=neutralizing antibody; PRO=patient-reported outcome; SES-CD=Simple 
Endoscopic Score for Crohn's Disease 
Note: As soon as Amendment 3 is implemented, the subject’s next scheduled visit will be the Week 52/ET visit, which should be conducted no later than 4 weeks (±10 days) from 
the subject’s last study visit prior to implementation of SHP647-304 Amendment 4. 
a 
The Week 16 (Visit 7) assessment from the induction study (SHP647-305 or SHP647-306) will be used as the baseline (Day 1/Week 0) assessments for Study SHP647-307. 
b 
Follow-up is not required if subject is entering the LTS study (SHP647-304) at Week 52/ET (Visit 14). 
c 
Any subject who is prematurely withdrawn from the study (including for treatment failure) should return for the ET visit and then enter into the safety follow-up period if not 
entering the LTS study (SHP647-304). Subjects who enter the safety follow-up period will have a final visit at 12 weeks following the Week 52/ET visit. Both the 
Week 52/ET and 12-week safety follow-up visits are preferred to be on-site visits; however, due to the COVID-19 public health emergency (or other similar pandemic), these 
may also be done at a subject’s home provided a qualified site staff member performs these evaluations following DTP guidance. 
d 
Part 1 of Visit 14 should be scheduled within 10 days (preferably within 5 to 7 days) before Part 2; this will allow sufficient time to obtain the data from the central laboratory 
hematocrit test value in order to be available at Part 2 of the visit. If a central laboratory hematocrit result is available that is not older than 3 weeks, Parts 1 and 2 of Visit 14 
can be performed on the same day; however, the laboratory sampling must be done before the start of colonoscopy preparation. For subjects who meet the criteria for 
treatment failure (as defined in Section 4.5.1), or are discontinuing prior to completing the 52-week treatment period due to early study closure, and will be entering the 
LTS study (SHP647-304), Part 2 of Visit 14 should be scheduled at least 2 weeks after the last dose of investigational product, to allow a sufficient time interval prior to the 
first dose in the LTS study. 
e 
Eligibility will be assessed after the consent form is signed and after induction study SHP647-305 or SHP647-306 Week 16, Visit 7 (Part 3) procedures are completed. 
f 
Medical history for induction study SHP647-305 or SHP647-306 will be used as the baseline medical history data for Study SHP647-307. 
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Table 1 
Schedule of Assessments 
Study Week 
Baselinea 
Treatment 
Follow-Upb 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52/ETc 
64c 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
(Part 1)d 
14 
(Part 2)d 
15 
Study Day 
1 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
 
364 
±10 days 
448 
Visit Window 
None 
±10 days 
±10 days 
g 
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. 
h 
If it is clinically necessary, an unscheduled assessment may be performed for calculation of CDAI after Week 4 in order to evaluate treatment failure; in connection to this, 
blood sampling for hematocrit may be necessary if no value is available from the past 3 weeks (see Section 4.5.1). Unscheduled assessments for CDAI calculation must not be 
performed more than 4 times during the study. 
i 
Subjects will be evaluated to reveal any potential abnormalities in the following neurological domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, cognition/behavior. See Section 7.3.3.3 for further details. 
j 
In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application). 
k 
Contraception check should be performed for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential. See Section 4.4 for 
further details. 
l 
Clinical laboratory assays (LFT) can also be performed by the local laboratory in case of issues related to COVID-19 (or other similar pandemic) and if deemed necessary by 
the investigator to confirm the subject’s safety. In such a case, the investigative site must obtain the local laboratory’s normal ranges as well as a CLIA certificate and the 
investigator must add the local laboratory as appropriate. 
m 
Subjects performing home administrations consecutively for 3 months will need to perform LFT per FDA requirement. It may be done locally if it is not possible to collect 
samples at the central laboratory. 
n 
For confirmation of postmenopausal status in females who have had 12 consecutive months of spontaneous amenorrhea and are ≥51 years of age. This does not need to be 
performed if postmenopausal status was confirmed by FSH in induction study SHP647-305 or SHP647-306. If a female subject’s status has changed to postmenopausal since 
the induction studies (SHP647-305 or SHP647-306), the FSH confirmation test will be done at baseline (Visit 1) of SHP647-307. Once FSH results are received, and if 
postmenopausal status is uncertain, the routine pregnancy testing will continue as planned for the remainder of the study. If postmenopausal status is confirmed, routine 
pregnancy testing is no longer required. 
o 
For females of childbearing potential who are not surgically sterile, do not have confirmed ovarian failure, or do not meet the definition of postmenopausal as described in the 
Section 4.4 and Section 7.3.3.7. 
p 
PRO assessments will be based on subject daily e-diary entries. CDAI score will be calculated based on data collected on patient diary as well as data obtained at the site visit. 
q 
Colonoscopy preparation will be according to local routine (see Section 7.3.2.4). Colonoscopy preparation may be done on the same day as the colonoscopy procedure. 
Note: For subjects discontinued from the study under Amendment 3 and prior to completion of 52 weeks of treatment, colonoscopy is not required (optional) at the ET visit. 
r 
Biopsy samples from each of the segments investigated will be collected for histological evaluation (see Section 7.3.2.4). 
s 
If needed, an unscheduled colonoscopy may be performed as part of treatment failure evaluation. Note: It is recommended that the unscheduled colonoscopy is performed 
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Table 1 
Schedule of Assessments 
Study Week 
Baselinea 
Treatment 
Follow-Upb 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52/ETc 
64c 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
(Part 1)d 
14 
(Part 2)d 
15 
Study Day 
1 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
 
364 
±10 days 
448 
Visit Window 
None 
±10 days 
±10 days 
within 2 weeks after the visit day when either the PRO-based or the CDAI score-based criterion for treatment failure was fulfilled. If the CDAI score-based criterion is 
fulfilled on an unscheduled visit, then the colonoscopy is to be performed either within 2 weeks after the previous regular visit or at the next regular visit. Colonoscopy does 
not need to be repeated at the ET visit if performed earlier as part of treatment failure assessment and treatment failure is confirmed. 
t 
SES-CD score at Week 52/ET will be calculated using the subscores of each of the segments investigated and centrally read for the colonoscopy performed at 
Week 52 (Visit 14, Part 2). 
u 
If it is clinically necessary, an unscheduled CDAI evaluation may be performed any time after Week 4 in order to evaluate treatment failure (see Section 4.5.1). If an 
unscheduled CDAI evaluation is planned after an unscheduled/confirmatory colonoscopy (that did not confirm treatment failure), then the diary data cannot be utilized for 
CDAI calculation earlier than 1 week after the colonoscopy. 
v 
PRO-CD daily e-diary will be available daily throughout the study. Subjects will be required to enter e-diary data every day throughout the study period; see Section 7.3.2.1 
for further details. 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, particularly when 
compliance is below 80% (eg, <12 out of 14 e-diary entries), or lower than the previous visit. 
w 
See Section 4.5.1 of the protocol for definition of treatment failure. 
x 
All patient-reported questionnaires should be completed before completing any other visit assessments. 
y 
Interactive response technology will be used for randomization and dispensation of study treatment. 
z 
In a situation in which a subject is not able to visit the study site due to the COVID-19 public health emergency (or other similar pandemic), DTP investigational product 
administration options may be available, in accordance with local regulations (refer to DTP guidance document). 
aa 
Where applicable, specified procedures and laboratory samples should be collected before investigational product administration. 
bb 
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. 
cc 
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 7.3 for the order in which assessments should be performed. Timing of visits is relative to SHP647-307 baseline (Visit 1). 
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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, extra-intestinal manifestations (EIMs) 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 
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chronic GI inflammation. The α4β7 integrin is the recognized ligand for MAdCAM, and 
expression of this ligand on populations of CD4+ and CD8+ T cells, as well as on subsets of 
B cells, distinguishes them as unique gut homing lymphocytes. 
Ontamalimab (previously known as PF-00547659 and SHP647) is a fully human 
immunoglobulin G2 kappa (IgG2κ) monoclonal antibody that binds to human MAdCAM to 
reduce lymphocyte homing to the gut and GI inflammation. Ontamalimab binds MAdCAM-1 
with high affinity and selectivity that prevents the binding of α4β7+ lymphocytes to 
MAdCAM-expressing sites in the high endothelial venules of the GI tract. 
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 CRP (hsCRP) were observed in all 4 treatment groups over the 12-week 
induction period. Compared to placebo, nominally statistically significant decreases in hsCRP 
were observed in all 3 active treatment groups (7.5 mg, 22.5 mg, and 75 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. 
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The most common serious adverse events (SAEs) across all studies were CD and UC. In 
Study A7281006, the randomized, placebo-controlled induction study in CD, treatment-emergent 
adverse events (TEAEs) were most commonly reported within the GI disorders system organ 
class (SOC) followed by the infections and infestations SOC. The most common all-causality 
TEAEs were CD (worsening and progression of underlying disease), followed by pyrexia, 
headache, and arthralgia, all of which had similar incidences in the placebo treatment group 
compared with the active treatment groups. In Study A7281009, the randomized, 
placebo-controlled induction study in UC, TEAEs were most commonly reported within the 
GI disorders SOC followed by the infections and infestations SOC. The most common 
all-causality TEAE was headache, followed by abdominal pain, nasopharyngitis, UC (worsening 
and progression of underlying disease), and nausea, all with similar incidence between 
placebo- and drug-treated subjects. 
The long-term, open-label safety studies (Studies A7281007 and A7281010) were not 
placebo-controlled but permitted exposure to the investigational product at doses of 75 mg or 
225 mg Q4W for 18 and 36 months, respectively. In Study A7281007, the most common 
all-causality TEAE was CD (worsening or progression), arthralgia, nasopharyngitis, and 
abdominal 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, was 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 to affect lymphocyte homing or surveillance in the CNS. 
This study is designed to evaluate the efficacy of ontamalimab as maintenance therapy in 
subjects with moderate to severe CD who fulfilled the efficacy entry criteria of this study 
including the clinical and/or endoscopic response criteria defined in induction study SHP647-305 
or SHP647-306. 
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. 
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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 immune 
surveillance. 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 
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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. 
2.1.1 
Rationale for Subjects Who Responded to Ontamalimab in the Induction Study 
and Who Could Potentially be Randomized to Placebo in the Maintenance Study 
The design of the maintenance study (SHP647-307) for those who completed active treatment in 
the induction studies (SHP647-305 and SHP647-306) and met entry criteria is one of randomized 
withdrawal, whereby a subject may be randomized to continue treatment on the same dose of 
active treatment or switched to placebo. This design allows for the assessment of the total and 
multidimensional benefits of a new drug, which encompass efficacy, safety, convenience, and 
other factors like the durability of the effect of the drug. Having a similarly selected cohort of 
subjects who are treated with placebo instead of active treatment allows for such an assessment. 
2.1.2 
Rationale for Subjects Who Responded to Placebo in the Induction Study and 
Who Could Potentially be Randomized to Ontamalimab in the Maintenance Study 
As one of the coprimary objectives of this study is clinical remission, rerandomizing 
placebo-treated subjects from the induction studies (SHP647-305 and SHP647-306) who meet 
entry criteria for the maintenance study (SHP647-307) allows for the greatest number of subjects 
to potentially be in clinical remission. Sandborn et al. (2013) demonstrated that the percentage of 
placebo-treated subjects in clinical remission decreases significantly over time compared with 
subjects on active treatment following 52 weeks of treatment with vedolizumab in a maintenance 
study. This finding is consistent with results from subjects with UC who followed a similar dose 
regimen. Rerandomizing placebo-treated subjects who qualify for the maintenance study allows 
for the greatest number of subjects to potentially benefit from treatment with active treatment. 
Additionally, randomized withdrawal of subjects on active treatment and rerandomization of 
placebo-treated subjects entering the maintenance study allows for a full and separate 
investigation of the induction of clinical remission and maintenance of clinical remission effects 
of any potential new treatment for CD, such as ontamalimab. Rerandomizing placebo-treated 
subjects allows for further investigation of long-term safety of ontamalimab. 
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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 as 
maintenance treatment in subjects with moderate to severe CD based on: 
• Clinical remission based on 2-item patient-reported outcome (PRO) (abdominal pain 
severity and very soft stool/liquid stool frequency) 
• Enhanced 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 as maintenance treatment on clinical 
remission as measured by CDAI 
• To evaluate the efficacy of ontamalimab as maintenance treatment on 
glucocorticoid-free clinical remission based on patient-reported clinical signs and 
symptoms (as measured by 2-item PRO) 
• To evaluate the efficacy of ontamalimab as maintenance treatment on clinical 
remission based on abdominal pain severity and very soft stool/liquid stool frequency 
(alternate thresholds) 
• To evaluate the efficacy of ontamalimab on maintenance of clinical remission among 
subjects in clinical remission at baseline of the SHP647-307 study based on 
patient-reported clinical signs and symptoms (as measured by 2-item PRO) 
• To evaluate the efficacy of ontamalimab on maintenance of enhanced endoscopic 
response among subjects with enhanced endoscopic response at baseline of the 
SHP647-307 study based on centrally read colonoscopy 
• To evaluate the efficacy of ontamalimab as maintenance treatment based on achieving 
clinical remission as well as achieving enhanced endoscopic response in the same 
subject 
• To evaluate the effect of ontamalimab as maintenance treatment on complete 
endoscopic healing based on centrally read colonoscopy. 
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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 in subjects 
with moderate to severe CD who completed their participation in an induction study (either 
SHP647-305 or SHP647-306) and fulfilled the efficacy entry criteria of this study. 
Approximately 983 subjects were planned to be enrolled into the study: approximately 
776 subjects from active induction treatments and approximately 207 subjects from placebo 
induction groups. The eligibility of a subject for the study will be assessed based on the study 
data collected at the Week 16 visit of the induction studies (SHP647-305 or SHP647-306), which 
will be considered as the baseline visit for this maintenance study. 
This study consists of a 52-week, double-blind treatment period, followed by a 12-week safety 
follow-up period for subjects who either discontinue treatment early or complete the treatment 
period and do not enter the long-term safety extension (LTS) study (SHP647-304). 
Eligible subjects who received active treatment in one of the induction studies and fulfilled the 
efficacy entry criteria of this study, including achieving endoscopic and/or clinical response, will 
be randomized as follows: subjects who received 25 mg ontamalimab in one of the induction 
studies will be randomized (1:1) to receive either 25 mg ontamalimab or placebo, and subjects 
who received 75 mg ontamalimab in one of the induction studies will be randomized (1:1) to 
receive either 75 mg ontamalimab or placebo. 
Eligible subjects who received placebo in one of the induction studies and fulfilled the efficacy 
entry criteria of this study, including achieving endoscopic and/or clinical response, will be 
randomized in a 2:2:1 ratio to receive 1 of 3 treatments (25 mg ontamalimab, 75 mg 
ontamalimab, or placebo, respectively) during this maintenance study. 
Subjects will be stratified according to glucocorticoid use at Study SHP647-307 baseline, the 
subject’s status of prior anti-TNF treatment (naïve or experienced), and whether or not the 
subject achieved clinical remission by 2-item PRO or enhanced endoscopic response in the 
induction study. 
Subjects enrolled in this study (SHP647-307) will receive double-blind maintenance treatment in 
the form of SC injections, using a prefilled syringe (PFS), Q4W for 52 weeks. Subjects will 
undergo efficacy and safety assessments as detailed in Table 1. 
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Under Amendment 3, subjects who complete the double-blind treatment period, or subjects who 
are withdrawn from the study prior to completing the double-blind treatment period due to early 
closure of the study by the sponsor, may be eligible to enter the LTS study (SHP647-304) 
provided they meet the eligibility criteria under SHP647-304 Amendment 4. Offering treatment 
in the LTS study after exiting this maintenance study allows subjects who benefited from active 
treatment, in this study or the induction study, to potentially benefit from continued treatment at 
the same dose of ontamalimab or at different dose of ontamalimab if, during the course of the 
SHP647-304 study, one of those doses (25 mg or 75 mg) is determined to be more efficacious 
based on emergent data from the induction studies. However, if there is no evidence of efficacy 
of either of the doses in comparison to placebo in the UC/CD clinical study, the entire program 
may be stopped, including the LTS study. Subjects who are not entering Study SHP647-304 will 
enter a 12-week safety follow-up period. 
An overview of the ontamalimab Phase 3 CD studies is shown in Figure 1 and 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-100) 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; Q4W=every 4 weeks; W=week 
a 
Eligible subjects who received placebo in one of the induction studies and fulfilled the efficacy entry criteria in this study will be randomized in a 2:2:1 ratio to receive 
1 of 3 treatments (25 mg ontamalimab, 75 mg ontamalimab, or placebo, respectively). 
b 
With the implementation of Amendment 3, subjects who complete the double-blind treatment period, or subjects who are withdrawn from the study prior to completing the 
double-blind treatment period due to early closure of the study by the sponsor, may be eligible to enter the LTS study (SHP647-304) provided they meet the eligibility criteria 
under SHP647-304 Amendment 4. Subjects who are not entering study SHP647-304 will enter a 12-week safety follow-up period. 
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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 
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 of 
Study SHP647-307 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 
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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. 
Enhanced Endoscopic Response Defined as 50% Improvement in SES-CD Score 
The SES-CD was developed to meet the clinical need for a reliable, easy-to-use endoscopic 
scoring instrument and for its need in research for endoscopic endpoints in studies evaluating 
new agents for CD in the era of mucosal healing and central endoscopy reading (Koutroumpakis 
and Katsanos, 2016). It has been developed as an alternative to CD Endoscopic Index of Severity 
(CDEIS) and is simpler and therefore more suited to routine use. During the validation process, a 
strong correlation between SES-CD and CDEIS (r=0.920) has been seen. In addition, SES-CD 
correlates with clinical parameters and 
. 
A 50% improvement in the endoscopic score will be used as a coprimary endpoint in this study 
as this magnitude of change is 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 
endoscopic response may also provide benefits. 
The benefit of endoscopic response is shown in the ACCENT-1 study (a CD clinical study 
evaluating infliximab in a new long-term treatment regimen), where patients who achieved 
complete mucosal healing (defined as complete absence of mucosal ulceration) after 1 year 
remained in remission for a median of 20 weeks, compared with 19 weeks for patients who 
achieved significant but incomplete mucosal healing and only 4 weeks for patients who 
experienced no healing of ulcers (D'Haens et al., 2002). 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). 
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 
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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. 
Glucocorticoid-free Clinical Remission Based on Patient-reported Clinical Signs and Symptoms 
(2-item PRO) 
First-line therapy for CD typically consists of oral budesonide for mild disease or systemically 
active glucocorticoids for moderate to severe disease. While systemic glucocorticoids can deliver 
rapid symptomatic relief and reduction of inflammation, prolonged steroid administration should 
be avoided given the risk of opportunistic infections and other complications (osteoporosis, 
growth suppression, ulcers, GI bleeding, etc.). As a result, once clinical remission has been 
induced, use of glucocorticoids should be tapered. Clinical remission, as defined above based on 
the 2-item PRO of average daily abdominal pain severity and average daily stool frequency, will 
be measured in subjects who are steroid-free at the end of maintenance or whose steroids use has 
been tapered off for a predefined period at the end of maintenance. Steroid-free is defined as not 
requiring any treatment with glucocorticoids at least 12 weeks prior to the Week 52 visit. The 
12-week window is supported by European Crohn’s and Colitis Organisation (ECCO) guidelines 
and the draft European Medicines Agency (EMA) guidance for CD (CPMP/EWP/2284/99 
Rev. 2). The ECCO Guideline (2016) states the following, under Section 1.1.6 Pattern of relapse: 
“Patients are still considered steroid dependent if they relapse within 3 months of stopping 
steroids. Although these limits are arbitrary, they serve as guidance for clinical practice and may 
be used for uniformity in clinical trials.” In line with this, the draft EMA guidance for CD 
(CPMP/EWP/2284/99 Rev. 2) states that patients can be regarded as steroid dependent if they 
have a relapse within 3 months of stopping steroids.  
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 
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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 
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 Remission Among Subjects in Clinical Remission at Baseline of the SHP647-307 Study, 
Based on Patient-reported Clinical Signs and Symptoms (2-Item PRO) 
Entry into the maintenance study is largely based on subjects in clinical response but not 
necessarily clinical remission to allow for the greatest number of subjects to have the chance to 
benefit from therapy during this maintenance study. However, some subjects will have achieved 
clinical remission at the end of the induction study. In these subjects who have started 
maintenance therapy while in clinical remission, it is important that this remission be maintained 
and stable without relapse. Hence, demonstrating clinical remission, as defined above based on 
the 2-item PRO of average daily abdominal pain severity and average daily stool frequency in 
patients who are in clinical remission at the baseline for Study SHP647-307, is an important 
clinical indicator of durability of treatment effect. 
Enhanced Endoscopic Response Among Subjects with Enhanced Endoscopic Response at 
Baseline of the SHP647-307 Study 
Entry into the maintenance study is largely based on subjects in clinical response or endoscopic 
response (at least 25% reduction in SES-CD score from baseline) to allow for the greatest 
number of subjects to have the chance to benefit from therapy during this maintenance study. 
However, some subjects will have achieved enhanced endoscopic response (at least 
50% reduction in SES-CD score from baseline) at the end of the induction study. In these 
subjects who have started maintenance therapy with enhanced endoscopic response, it is 
important that this is maintained or improved even further. 
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Clinical Remission as Well as Enhanced Endoscopic Response in the Same Subject 
Both clinical remission and endoscopic response to treatment, as defined by enhanced 
endoscopic response above, are important goals of treatment with ontamalimab in this 
maintenance study. However, the correlation between clinical improvement and endoscopic 
improvement is not always strong or straightforward in CD given the transmural involvement of 
the disease. By documenting the treatment effect on the basis of both clinical signs and 
symptoms as well as endoscopic improvement in the same subject, this endpoint offers possibly 
the most comprehensive evidence of benefit of therapy. 
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 1) 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 achieving 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). 
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3.2 
Duration and Study Completion Definition 
Each subject’s final visit in this study will be the Week 52/ET visit, if continuing to the 
LTS study (Study SHP647-304) or at the end of the 12-week safety follow-up period if not 
entering Study SHP647-304. Both the Week 52/ET and 12-week safety follow-up visits are 
preferred to be on-site visits; however, due to a pandemic [eg, coronavirus disease (COVID-19)] 
or other future similar unexpected public health concerns requiring physical distancing that may 
result in subjects missing their visits, these may also be done at a subject’s home provided a 
qualified site staff member performs these evaluations following Direct-to-Patient 
(DTP) guidance. 
A subject’s maximum duration of participation in Study SHP647-307 is expected to be 
approximately 64 weeks: a treatment period of 52 weeks, and a safety follow-up period of 
12 weeks (if applicable). It was expected that the study would be completed in less than 
4.5 years; however, due to early closure by the sponsor, the study is expected to be completed by 
November 2021. 
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 
This study will be conducted in approximately 33 sites in approximately 16 countries. 
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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 have completed the 16-week induction treatment period from 
Study SHP647-305 or SHP647-306 and met the following criteria at baseline in 
maintenance study SHP647-307: 
o Meet endoscopic response criteria of a reduction in SES-CD from induction study 
(SHP647-305 or SHP647-306) baseline by ≥25% at Week 16 of induction study 
(SHP647-305 or SHP647-306) 
OR 
o Meet at least 1 of the following 4 criteria at baseline in maintenance study 
SHP647-307, in addition to no worsening of endoscopic score as measured by 
SES-CD relative to induction study (SHP647-305 or SHP647-306) baseline: 
4. Achieving clinical remission as determined by meeting the criteria for clinical remission 
using the 2-item PRO, ie, 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 type 
frequency ≤2 of type 6/7 (very soft stools/liquid stools) as shown in the BSFS over the 
7 most recent days*. 
5. A decrease of at least 100 points in CDAI score (CDAI-100) from induction study 
(SHP647-305 or SHP647-306) baseline. 
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6. A decrease of ≥30% and at least 2 points from induction study (SHP647-305 or 
SHP647-306) 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 induction study (SHP647-305 or SHP647-306) 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*. 
7. A decrease of ≥30% from induction study (SHP647-305 or SHP647-306) 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: 
(i) not worsening from induction study (SHP647-305 or SHP647-306) baseline and/or 
(ii) 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 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. 
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. 
4.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Subjects who had major protocol deviation(s) (as determined by the sponsor) in induction 
study SHP647-305 or SHP647-306. 
2. Subjects who permanently discontinued investigational product because of an AE, regardless 
of relatedness to investigational product, in induction study SHP647-305 or SHP647-306. 
3. Subjects who are likely to require surgery for CD during the study period, except minor 
interventions (eg, seton placement for anal fistulas). 
4. Subjects are females who became pregnant during induction study SHP647-305 or 
SHP647-306, females who are lactating, females who are planning to become pregnant 
during the study period, or males or females of childbearing potential not agreeing to 
continue using appropriate contraception methods (ie, highly effective methods for female 
and medically appropriate methods for male study subjects, as described in Section 4.4) 
through the conclusion of study participation. 
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5. 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. 
6. Subjects who, in the opinion of the investigator or the sponsor, will be uncooperative or 
unable to comply with study procedures. 
7. Subjects who have developed obstructive colonic stricture, or enterovesical or enterovaginal 
fistulae during the induction study (SHP647-305 or SHP647-306). 
8. Subjects who have a newly diagnosed malignancy or recurrence of malignancy (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). 
9. Subjects who have developed 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. 
10. 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. 
11. Subjects with known exposure to Mycobacterium tuberculosis since testing at screening in 
induction study SHP647-305 or SHP647-306 and who have been advised to require treatment 
for latent or active disease but who are without a generally accepted course of treatment. 
12. Subjects with any of the following abnormalities in hematology and/or serum chemistry 
profiles during the evaluation of the last visit in the SHP647-305 or SHP647-306 studies. 
If the results are considered by the investigator to be transient and inconsistent with the 
subject’s clinical condition, may be repeated once prior to enrollment in Study SHP647-307. 
• 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) 
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• 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. 
13. Subjects who are investigational site staff members or relatives of those site staff members or 
subjects who are sponsor employees directly involved in the conduct of the study. 
14. Subjects who are participating in other investigational studies (other than induction study 
SHP647-305 or SHP647-306) or plan to participate in other investigational studies during 
Study SHP647-307. 
4.3 
Restrictions 
Subjects are encouraged to keep their diet habits constant throughout the study. 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). 
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 
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curve [AUC] from 0 to 672 hours [AUC0-672h] at 6140 µg·h/mL following repeated 
SC administration of 75 mg ontamalimab Q4W), maternal exposure (AUC) in cynomolgus 
monkeys within a similar duration at 30 and 60 mg/kg once every 10 days is approximately 
77 times and 172 times the clinical exposure, respectively. 
To minimize the risk of unintentional exposure of the embryo or fetus in the clinical study, all 
sexually active male and female subjects who, in the opinion of the investigator, are biologically 
capable of having children and with their partners are at risk of pregnancy, must agree to use an 
appropriate form of contraception (ie, highly effective methods for female and medically 
appropriate methods for male study subjects), in accordance with the package 
instructions/leaflet, for the duration of the active treatment period and for at least 16 weeks 
after the last dose of investigational product. 
True abstinence is considered to be a highly effective contraception (ie, a method that results in a 
failure rate of <1% per year) when it is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
declaration of abstinence for the duration of exposure to investigational product, and withdrawal 
are not appropriate methods of contraception. 
During induction studies (SHP647-305 and SHP647-306), 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 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 
At baseline in this study, the childbearing potential of subjects must be re-established and 
documented if the subject’s status has changed since the induction studies (SHP647-305 or 
SHP647-306) (see Section 7.3.3.7). 
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. 
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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. 
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 pregnancy test result at baseline 
(ie, Week 16 of the induction study SHP647-305 or SHP647-306; Week 0 of 
Study SHP647-307). 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 baseline (ie, Week 16 of the induction study SHP647-305 or 
SHP647-306; Week 0 of Study SHP647-307) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation plus 
a barrier method 
• Intrauterine device 
• Intrauterine hormone-releasing system 
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• Bilateral tubal occlusion 
• Male sterilization/vasectomized partner with documented absence of sperm in the 
postvasectomy ejaculate 
• True abstinence (see Section 4.4). 
4.4.2 
Contraceptive Methods for Male Study Subjects 
Contraception is required for all sexually active male subjects, who with their female sexual 
partners, must agree to use 1 of the following appropriate methods of contraception throughout 
the study period and for 16 weeks following the last dose of investigational product. 
Appropriate methods of contraception for male subjects are: 
• Male condom with spermicide; however, if spermicide is not available in the country, 
additional contraception (ie, one of those listed below) must be used in addition to a 
male condom 
• Male sterilization with documented absence of sperm in the postvasectomy ejaculate. 
Appropriate methods for female sexual partners of male subjects are (unless the female sexual 
partner is sterile [surgically or documented nonsurgical sterility]): 
• Use of a highly effective method of contraception listed in Section 4.4.1 OR an 
acceptable method of contraception (failure rate of >1% per year) 
o Female condom with spermicide (use by female sexual partner); however, if 
spermicide is not available in the country, additional contraception (ie, 1 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. 
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If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 52/ET (Visit 14 Part 1 and Part 2) are to be performed. All subjects who discontinue 
investigational product and who are not entering the LTS study (SHP647-304) should also 
undergo the protocol-specified 12-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 
• Meeting the criteria for treatment failure 
• 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. 
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 chooses to withdraw from study participation due to personal concerns related to a 
pandemic (eg, coronavirus disease [COVID-19]) or other future similar unexpected public health 
concerns requiring physical distancing that may result in subjects missing their visits (other than 
a COVID-19-related or other pandemic-related AE), this should be specified as the reason for 
subject withdrawal in the source document. 
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Treatment failure is defined as meeting at least one of the following criteria: 
1. Worsening of at least 30% either in abdominal pain and/or stool frequency scores over the 
7 most recent days compared to the baseline values of Study SHP647-307 resulting in 
abdominal pain and/or stool frequency scores that are greater than or equal to the inclusion 
criteria thresholds (≥5 for abdominal pain and/or ≥4 for stool frequency) of the induction 
study. 
This criterion needs to be met on 2 successive visits. 
2. Worsening of CDAI score by ≥100 points from baseline of Study SHP647-307 and 
CDAI>220 during one of the visits when CDAI is evaluated. This criterion needs to be met 
on at least 1 visit, unlike the 2 successive visits requirement that is necessary for criterion 1 
above. 
If it is clinically necessary, the investigator can decide to perform an unscheduled CDAI 
assessment based on the subject’s reported symptoms and signs any time after Week 4. The 
unscheduled CDAI assessment can be performed no more than 4 times during the study. 
Subjects who meet treatment failure criteria 1 and/or 2 will be considered treatment failures, with 
a need for a confirmatory colonoscopy. If needed, an unscheduled colonoscopy may be 
performed as part of treatment failure evaluation. Note: It is recommended that the unscheduled 
colonoscopy is performed within 2 weeks after the visit day when either the PRO-based or the 
CDAI score-based criterion for treatment failure was fulfilled. If the CDAI score-based criterion 
is fulfilled on an unscheduled visit, then the colonoscopy is to be performed either within 
2 weeks after the previous regular visit or at the next regular visit. 
Colonoscopy does not need to be repeated at the ET visit if performed earlier as part of treatment 
failure assessment and treatment failure is confirmed. 
Treatment failure on endoscopy is defined as worsening of at least 30% on SES-CD scores and at 
least a 2-point increase in comparison to baseline values of Study SHP647-307 and SES-CD >6 
(or ≥4 for isolated ileitis). 
If the endoscopy does not confirm treatment failure, but the CDAI or PRO scores indicate 
treatment failure again for the next visit where CDAI is assessed (either scheduled or 
unscheduled) or for the next visit where PRO is assessed after the nonconfirmatory colonoscopy, 
then the subject will be categorized as a treatment failure without a need for further endoscopy. 
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Other causes of these changes, including viral or bacterial gastroenteritis and Clostridium 
difficile infection must be ruled out by appropriate stool cultures and other laboratory tests 
(see Appendix 4 for further information on testing for C. difficile infection, including diagnostic 
algorithms). If a potential other cause is identified, treatment failure will not be assessed until a 
full course of treatment has been completed or, if untreated, the infection would be expected to 
have resolved based on its natural history. This testing must begin once treatment failure is 
suspected, ie, at the first visit identified as potential treatment failure, to minimize the interval 
either to start treatment or to identify treatment failure. 
Additionally, the investigator, in consultation with the study medical monitor, can use his/her 
clinical judgment to further determine if a particular subject meets criteria for treatment failure. 
Subjects who do not enter the LTS study will continue into the 12-week safety follow-up period. 
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. This includes unavoidable circumstances, such as a pandemic (eg, coronavirus 
disease [COVID-19]) or other future similar unexpected public health concerns requiring 
physical distancing that may result in subjects missing their visits. 
If a subject chooses to withdraw from study participation due to personal concerns related to a 
pandemic (eg, coronavirus disease [COVID-19]) or other future similar unexpected public health 
concerns requiring physical distancing that may result in subjects missing their visits (other than 
a COVID-19-related or other pandemic-related AE), this should be specified as the reason for 
subject withdrawal in the source document. 
Reasons for discontinuation include but are not limited to: 
• Adverse event 
• Protocol deviation 
• Withdrawal by subject 
• Lost to follow-up 
• Treatment failure 
• Other (if “other” is selected, the investigator must specify the reason) 
• Death 
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• Physician decision 
• Pregnancy 
• Screen failure 
• Site terminated by sponsor. 
4.5.3 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point before the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and that they return their electronic diary (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) 
that is ongoing at the time of the baseline visit (Visit 1). It is expected that prior treatment will 
have been recorded during the induction study. 
5.2 
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product in this maintenance study and the end of the 12-week safety follow-up 
period, inclusive. 
5.2.1 
Permitted Treatment 
Subjects must remain on stable doses of permitted CD treatments until completion of the 
Week 52 visit, unless decreases are required because of AEs. Stable doses of the following 
treatments for CD are permitted as concomitant medication: 
• Oral 5-ASA (mesalamine) and sulfasalazine 
• Immunosuppressants (AZA, 6-MP, or MTX) 
• Oral glucocorticoids; however, tapering is mandatory starting on Day 1. As the 
subjects are transferred from induction studies SHP647-305 or SHP647-306, the 
maximum glucocorticoid dose is 20 mg/day of oral prednisone or equivalent 
(Appendix 3) or 9 mg/day of budesonide. Tapering should follow the procedure 
shown in Table 2. 
Note: Rectal 5-ASA and parenteral or rectal glucocorticoids are prohibited (see Section 5.2.2). 
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Table 2 
Glucocorticoid Tapering 
 
First Taper 
Second Taper 
Timing 
Prospectively define glucocorticoid-dependent subjects 
(ie, European Crohn’s and Colitis Organisation)a 
When subject is stable 
Increments 
• 
If daily dose of prednisone is >10 mg:  
Taper by 5 mg/day each 1–2 weeks 
• 
When daily dose of prednisone is ≤10 mg:  
Taper by 2.5 mg/day each 1-2 weeks 
• 
When daily dose of budesonide is up to a 
maximum of 9 mg/day: Taper by 3 mg every 
3 weeks 
• If daily dose of prednisone  
is >5 mg: Taper by 2.5 mg/day 
each week 
• When daily dose of prednisone 
is ≤5 mg: Taper by 1 mg/day 
each week 
Action if unable to 
taper 
Return to SHP647-307 baseline dose 
Return to last effective dose: 
• If >10 mg, exit study 
• If ≤10 mg, remain as failure for 
glucocorticoid-free population. 
a 
Glucocorticoid-dependent subjects are: 
Subjects who are unable to reduce glucocorticoids below the equivalent of prednisone 10 mg/day (or budesonide below 
3 mg/day) within 3 months of starting glucocorticoids, without recurrent active disease 
OR 
Subjects who have a relapse within 3 months of stopping glucocorticoids (Dignass et al., 2012). 
During the glucocorticoid taper, subjects may experience worsening of CD signs or symptoms 
that, in the opinion of the investigator, are attributable to reduction in glucocorticoid dose. If 
signs or symptoms occur, the investigator can instruct the subject to revert to the preceding 
week’s daily dosage. The signs or symptoms leading to this change (eg, increased stool 
frequency, increased rectal bleeding) must be recorded. 
Antidiarrheal opiate drugs such as IMODIUM® (loperamide), LOMOTIL® (diphenoxylate 
hydrochloride and atropine sulfate), tincture of opium, and codeine will be recorded as 
concomitant medications. 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, is 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. 
Routine nonlive vaccinations are allowed during the study. 
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Dietary and herbal supplements and probiotics are allowed in the study, provided they are being 
taken at stable doses 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 (>2 weeks) immediately before Week 52 (Visit 14, Part 1). 
5.2.2 
Prohibited Treatment 
The following common treatments are excluded medications for this study. As the subjects are 
transferred from induction studies SHP647-305 or SHP647-306, during which these treatments 
were also prohibited, no washout period is applicable. 
• Parenterally and rectally administered glucocorticoids 
• Prednisone dose >20 mg/day, budesonide >9 mg/day, or other equivalent oral 
systemic corticosteroid dose 
• Off-label usage of immunosuppressants used in transplantation or other 
nonestablished therapies for CD (eg, mycophenolate mofetil, cyclosporine, 
rapamycin, thalidomide, tofacitinib, or tacrolimus) 
• Rectally administered 5-ASA 
• Bismuth subsalicylate products 
• Anti-TNF treatment and other biologics with immunomodulatory properties including 
biosimilars 
• Anti-integrin or antiadhesion molecule treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab) 
• Lymphocytes apheresis or selective monocyte granulocytes apheresis 
• Live (attenuated) vaccines 
• Fecal microbiota transplantation 
• Any investigational product other than the study drug. 
Treatments not listed in this section may be considered allowable; see Section 5.2.1 for further 
details. 
No new nonpharmacological therapies that might affect bowel habit or GI function should be 
started during the study. 
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Enteral nutrition is not permitted 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 SHP647-307 baseline level, the subject should 
be withdrawn from study treatment and enter the safety follow-up period, and appropriate 
treatment should be given at the discretion of the investigator. 
Subjects who enter the safety follow-up period will no longer need to abstain from the 
medications that were prohibited during the baseline and treatment periods. High-dose 
glucocorticoids and other 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. 
5.3 
COVID-19 
In cases in which the subject is known to have been infected with the COVID-19 virus but does 
not have the disease, he or she should be actively moved to lower doses of prednisone 
(<20 mg/day) or transition to budesonide when feasible. Thiopurines and MTX should be 
temporarily withheld. The study drug should have dosing delayed for 2 weeks while the subject 
is monitored for the development of COVID-19. 
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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 mg 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 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. 
Subjects who fulfill all eligibility criteria and who received active treatment in the induction 
study (SHP647-305 or SHP647-306) will be randomized via a computer-generated 
randomization schedule as follows: subjects who received 25 mg ontamalimab in one of the 
induction studies will be randomized (1:1) to receive either 25 mg ontamalimab or placebo, and 
subjects who received 75 mg ontamalimab in one of the induction studies will be randomized 
(1:1) to receive either 75 mg ontamalimab or placebo. 
Subjects who fulfill all eligibility criteria and who received placebo in the induction study will be 
randomized in a 2:2:1 ratio to receive 1 of 3 treatments (25 mg ontamalimab, 75 mg 
ontamalimab, or placebo, respectively) during this maintenance study. 
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Subjects will be stratified according to glucocorticoid use at SHP647-307 baseline, the subject’s 
status of prior anti-TNF treatment (naïve or experienced), and whether or not the subject 
achieved clinical remission by 2-item PRO or enhanced endoscopic response in the induction 
study. 
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 up to Week 52 (ie, a total of up to 13 doses of investigational 
product). See Section 7.3 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. 
Principal investigators are responsible for ensuring that all study and nonstudy personnel 
identified to administer investigational product are qualified, with documented training and 
delegation of responsibilities prior to their first investigational product administration visit at 
subjects’ homes (see Section 10.2.1). 
In a situation in which a subject is not able to visit the study site due to a pandemic 
(eg, coronavirus disease [COVID-19]) or other future similar unexpected public health concerns 
requiring physical distancing that may result in subjects missing their visits, DTP investigational 
product administration options may be available, in accordance with local regulations (refer to 
DTP guidance document). 
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All subjects and nonstudy personnel performing the investigational product administration must 
receive training in order to receive DTP shipments. Training will include how to identify 
hypersensitivity reactions, inject the IP, and properly dispose of IP after use. Training may be in 
person or via telephone call. All DTP shipments will require pre-administration and 
post-administration calls by the site staff to assess and monitor subject’s health status and safety; 
to review any AEs, concomitant medications, and diary assessments; and to perform the 
neurological questionnaire assessment by the investigator. These calls must be appropriately 
recorded in the source document. 
The personnel that perform study procedures at the subjects’ homes will be delegated, trained, 
and properly supervised by the principal investigator(s) of each site. 
All study and nonstudy personnel will be trained on potential hypersensitivity reactions (Type I 
and Type III) and associated symptoms. 
NOTE: DTP investigational product administration, except when performed by study personnel, 
is NOT ALLOWED for a subject’s first dose of investigational product in this study. 
Investigator-directed delays in dosing due to abnormal laboratory findings or AEs or due to a 
pandemic (eg, coronavirus disease [COVID-19]) or other future similar unexpected public health 
concerns requiring physical distancing that may result in subjects missing their visits should be 
discussed with the medical monitor to determine whether the subject should continue with the 
treatment. Dosing delays up to 8 weeks (2 doses) are allowed, and the subjects are allowed to 
miss a maximum of 2 doses due to COVID-related or other pandemic-related issues (see 
Section 5.3). Sites must receive Shire approvals for each subject meeting the missed/delayed 
dosing criteria. 
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational product is dispensed by qualified staff members. During the COVID-19 public 
health emergency (or other similar pandemic), alternative investigational product delivery to 
study participants may be necessary to avoid unnecessary subject visits to sites while providing 
needed investigational product. Additional investigational product may be dispensed during a 
scheduled study visit or investigational product may be shipped directly from investigational 
sites to participants’ residences by a contracted logistics provider or distributor (DTP shipment) 
in compliance with national laws or temporary national emergency measures and sponsor 
processes. 
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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. 
Due to early termination of the ontamalimab program, the sponsor is providing an option for 
subjects who are responding to active treatment in this maintenance study or who are on placebo 
and had responded to active treatment in an induction study to continue to receive ontamalimab 
in the long-term safety extension study SHP647-304. As this eligibility criterion into 
SHP647-304 depends on the blinded treatment assignment in this study, for these subjects, there 
is a potential for the treatment assignment in this study to be unblinded at the ET visit when 
assessing whether a subject can be a rollover into the SHP647-304 study or proceed to the safety 
follow-up period. The date of the ET visit will be recorded. 
In addition, due to the early discontinuation of the SHP647 program, the SHP647-304 study is 
planned to be unblinded prior to the database lock in this study, which would unblind the 
treatment assignment in this study for a significant portion of subjects. As such, this study will be 
considered unblinded when the SHP647-304 study is unblinded, and the date of study unblinding 
will be recorded. 
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. 
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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 foam insert and 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. In case of a DTP situation, the 
investigational product can be shipped to subject’s home; please refer to DTP guidance for 
further details. 
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. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the investigational 
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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. In case of a DTP situation, the safety of the investigational product will be managed; it 
will be transported via a secured courier or study site personnel with temperature monitoring and 
tracking; please refer to DTP guidance for further details. 
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. In case of a DTP situation, the investigational product 
administration will be documented in the drug administration visit report form (if nonstudy 
personnel administer the investigational product) and in the drug administration log (in case of 
self-administration by the subjects/caregivers/parents). 
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 
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laws must be adhered to for the transfer. In case of a DTP situation, the process for shipping of 
used investigational product to the site is described in the DTP guidance. 
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised. 
With the written agreement of the sponsor, at the end of the study all unused stock may be 
destroyed at the site or a local facility. In this case, destruction records identifying what was 
destroyed, when and how, must be obtained with copies provided to the sponsor. Destruction of 
investigational products must be in accordance with local, state, and national laws. 
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction. 
6.5 
Subject Compliance 
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, cartons) or at 
the individual count level for opened containers/packaging. The pharmacist or delegated team 
member will record details on the drug accountability form. 
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7. STUDY PROCEDURES 
7.1 
Changes to Study Procedures Due to a Pandemic 
The following information provides guidance regarding changes to study procedures that may be 
implemented for study participants or study sites affected by a pandemic (eg, coronavirus disease 
[COVID-19]) or other future similar unexpected public health concerns requiring physical 
distancing that may result in subjects missing their visits. This guidance takes references from 
the US Food and Drug Administration (FDA) Guidance on Conduct of Clinical Trials of Medical 
Products during COVID-19 Public Health Emergency – Guidance for Industry, Investigators, 
and Institutional Review Boards, March 2020, updated 02 July 2020; the European Medicines 
Agency (EMA) Guidance on the Management of Clinical Trials During the COVID-19 
(Coronavirus) Pandemic, Version 3 (28 April 2020); and the EMA Points to consider on 
implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical 
trials, dated 26 June 2020. 
Because a pandemic (eg, COVID-19) may peak in different regions at different times and 
restrictions implemented by local laws and recommendations may vary, any decision on 
procedural changes should be made on a case-by-case basis by the principal investigator in 
consultation with the study team and the medical team as needed, while maintaining subject 
safety and confidentiality as the priority. 
Procedural changes due to COVID-19 (or other similar pandemic) may include the following 
(refer to DTP guidance document for further details): 
• Allow study sites to follow COVID-19 screening requirements per local regulations. 
• Identify which study visits and procedures may be conducted in the clinic or by 
optional home healthcare and evaluations that may be done remotely (eg, Telehealth, 
Telemedicine) (See Table 1). Home healthcare visits will be documented in the study 
records. 
• Allowance of more flexibility around scheduling of study visits and/or allowing some 
assessments to be conducted remotely (See Table 1). 
• For home healthcare visits, collection of clinical laboratory samples (blood specimen 
collection or other diagnostic tests) may be performed by the investigator or qualified 
site staff who can visit the trial participant’s residence. 
• Missed clinic visits or subject withdrawals due to COVID-19 (or other similar 
pandemic) must be recorded in the source document (See Section 4.5.2, Reasons for 
Withdrawal). 
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• ECG procedures: For home healthcare visits, ECGs may be performed by a qualified 
healthcare professional who is authorized/certified to perform such tests routinely. 
• “Remote visits” via virtual communications (eg, TeleHealth application) may be 
performed as a safety check (AE assessment) on subject well-being, concomitant 
medication use, neurological assessments, etc. 
• Allow transfer of study participants to investigational sites away from risk zones or 
closer to their home that are already participating in the trial or to new sites. 
• Deviations from the protocol-specified procedures (eg, not collecting a 
protocol-specified specimen, such as postdose bloodwork) will be recorded as related 
to COVID-19 (or other similar pandemic). 
• Alternative investigational product deliveries may include dispensing additional 
investigational product at clinic visits or DTP delivery of the investigational product 
from the investigational site to subjects in compliance with national laws or 
temporary national emergency measures (See Section 6.2.3, Dosing and Section 6.3, 
Labeling, Packaging, Storage, and Handling). 
7.2 
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. 
7.2.1 
Baseline Visit (Visit 1, Week 0) 
Procedures performed at Week 16 (Visit 7) of the induction studies (SHP647-305 or 
SHP647-306) will be the baseline (Day 1/Week 0) assessments for this maintenance study. The 
baseline visit for this maintenance study will be on the same day as the Week 16 visit of the 
induction study. To be eligible for this maintenance study, subjects must have fulfilled the 
specific entry criteria set up in the induction study (see Section 4.1 and Section 4.2 for a full list 
of inclusion and exclusion criteria, respectively). The assessments and procedures performed 
during the baseline visit are specified in Table 1. 
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. 
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The results of the 2-item PRO, the endoscopic score measured by SES-CD, and CDAI score at 
Week 16/Visit 7 of induction study SHP647-305 or SHP647-306 will be used for 
Week 0/Day 1/Visit 1 of Study SHP647-307 before randomization. 
For eligible subjects, all relevant study information recorded for Week 16 of the induction 
studies will be included in the baseline visit data for this maintenance study. All procedures that 
would lead to the assessment of the subject eligibility criteria for the maintenance study at 
Week 16/Visit 7 in the induction study should have been completed before any other baseline 
visit assessments performed for this maintenance study. 
After eligibility has been confirmed 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. 
7.2.2 
Treatment Period 
7.2.2.1 
Visits 2 to 13 (Weeks 4 to 48) 
The schedule of Visits 2 to 13 during the treatment period, and the assessments and procedures 
to be performed at each visit, are specified in Table 1. 
Note: As soon as Amendment 3 is implemented, the subject’s next scheduled visit will be the 
Week 52/ET visit, which should be conducted no later than 4 weeks (±10 days) from the 
subject’s last study visit prior to implementation of SHP647-304 Amendment 4. 
7.2.2.2 Final On-treatment Visits: Visit 14, Parts 1 and 2 (Week 52/Early Termination) 
The Week 52/ET visit consists of 2 parts. 
Part 1 of Visit 14 should be scheduled within 10 days (preferably within 5 to 7 days) before 
Part 2; this will allow sufficient time to obtain the data from the central laboratory hematocrit test 
value in order to be available at Part 2 of the visit. If a central laboratory hematocrit result is 
available that is not older than 3 weeks, Parts 1 and 2 of Visit 14 can be performed on the same 
day; however, the laboratory sampling must be done before the start of colonoscopy preparation. 
The Week 52/ET assessments and procedures that will take place during Part 1 are specified in 
Table 1. 
Part 2 of Visit 14 will take place on Day 364 ±10 days. The Week 52/ET assessments and 
procedures, including the colonoscopy that will take place during Part 2, are specified in Table 1. 
For subjects who meet the criteria for treatment failure (as defined in Section 4.5.1), or are 
discontinuing prior to completing the 52-week treatment period due to early study closure, and 
will be entering the LTS study (SHP647-304), Part 2 of Visit 14 should be scheduled at least 
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2 weeks after the last dose of investigational product, to allow a sufficient time interval prior to 
the first dose in the LTS study. 
The Week 52/ET visit is preferred to be on-site; however, due to a pandemic (eg, coronavirus 
disease [COVID-19]) or other future similar unexpected public health concerns requiring 
physical distancing that may result in subjects missing their visits, the visit may also be done at a 
subject’s home provided a qualified site staff member performs the evaluations following 
DTP guidance. 
Note: For subjects discontinuing from the study due to early termination of the study by the 
sponsor, clinical response as measured by at least a 100-point reduction in CDAI score 
(CDAI-100 response) from induction study (SHP647-305 or SHP647-306) baseline will be 
evaluated at the ET visit as well. 
Colonoscopy is not required (optional) at the ET visit if the subject has not completed 52 weeks 
of treatment due to early closure of the study (see Section 10.1.5). 
After both parts of Visit 14 have been completed, the subject will either enter the LTS study 
(SHP647-304) or the 12-week safety follow-up period. 
The Week 52 assessments and procedures will also form the ET assessments for any subjects 
who are withdrawn early from the study. 
7.2.2.3 Unscheduled Visit to Evaluate Potential Treatment Failure With CDAI 
An unscheduled visit can be performed at any time after Week 4 if the investigator decides, 
based on patient-reported symptoms and clinical signs, that there is a possibility of treatment 
failure and therefore it is necessary to calculate the CDAI before the scheduled CDAI evaluation. 
During this visit, the investigator performs all the physical examinations and other assessments 
(including blood sampling for hematocrit if there no hematocrit value is available from the past 
3 weeks), reviews the relevant diary data for the past 7 days, calculates the CDAI score if every 
item is available, and makes the decision as to whether or not a confirmatory unscheduled 
colonoscopy is necessary. If the hematocrit value is not available at the time of the visit, the 
patient will be informed via telephone on the outcome. 
7.2.2.4 Unscheduled Visit to Evaluate Potential Treatment Failure With Colonoscopy 
If either the PRO treatment criterion is fulfilled at 2 consecutive scheduled assessments or the 
CDAI treatment failure criterion is fulfilled on at least one occasion (at either a scheduled or an 
unscheduled visit), the investigator will schedule a colonoscopy either within 2 weeks after the 
previous regular visit or, if it is not possible to do so, then for the next scheduled regular visit. 
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7.2.3 
Follow-up Period: Visit 15 (Week 64) 
Subjects who are withdrawn early from the study, or who do not enter the LTS study 
(SHP647-304), should enter the 12-week safety follow-up period for safety monitoring. Subjects 
who are proceeding to the LTS study (SHP647-304) will not enter the safety follow-up period. 
For subjects who complete SHP647-307, safety follow-up will occur 12 weeks following the 
subject’s last visit (Week 52) in the treatment period. 
At the end of the 12-week safety follow-up period, there will be a visit at the site on 
Day 448 ±10 days (for subjects who completed the 52-week treatment period) or 
12 weeks ±10 days after the ET visit (for subjects who are withdrawn early from the study), 
which will form the Week 64 visit (Visit 15). The final 12-week safety follow-up visit is 
preferred to be on-site; however, due to a pandemic (eg, coronavirus disease [COVID-19]) or 
other future similar unexpected public health concerns requiring physical distancing that may 
result in subjects missing their visits, the visit may also be done at a subject’s home provided a 
qualified site staff member performs the evaluations following DTP guidance. 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). 
7.2.4 
Additional Care of Subjects After the Study 
No aftercare is planned for this study. 
7.3 
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. 
When timing of procedures and assessments coincide, the following order should be followed: 
• Patient-reported questionnaires 
• Vital signs and ECG 
• Laboratory sample collection 
• Investigational product administration 
• Colonoscopy (generally performed at a separate visit (see Section 7.3.2.4). 
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Note: Blood and tissue samples may be stored for up to the duration allowed by local 
regulations, but for no longer than 25 years. 
7.3.1 
Demographic and Other Baseline Characteristics 
All relevant demographic and baseline characteristics recorded for the induction studies 
(SHP647-305 or SHP647-306) will be used as the baseline characteristics for this maintenance 
study. 
7.3.2 
Efficacy 
7.3.2.1 
Patient-reported Outcome – Crohn’s Disease Daily E-diary 
Patient-reported CD signs and symptoms data will be collected using a PRO-CD daily e-diary 
(electronic handheld device). The e-diary will be available daily throughout the study. Subjects 
will be required to enter e-diary data every day throughout the study period. 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, particularly when compliance is below 
80% (eg, <12 out of 14 e-diary entries), or lower than the previous visit. 
Subjects will be asked to record the following signs and symptom data, as experienced over the 
previous 24 hours, in the e-diary: 
• 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 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: 
• Visits 2 to 13: 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 14 (Part 2) and at any regular visit (Visit 3 to 13) when a confirmatory 
colonoscopy is performed to evaluate treatment failure: 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. 
7.3.2.2 
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 
Week 52/ET or at an unscheduled colonoscopy to confirm treatment failure will be calculated 
using the subscores of each of the segments investigated and centrally read for the colonoscopy 
performed. 
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). 
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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). 
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) of 
the induction studies (SHP647-305 and SHP647-306) and Week 52/ET of this study 
(SHP647-307) (matching segments approach) will be utilized. 
The SES-CD is presented in Appendix 2. 
7.3.2.3 
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 7.3.2.1 and 
5 components will be recorded at the time points specified in Table 1. 
The CDAI scores at Visits 4, 7, and 10 or at an unscheduled visit for treatment failure evaluation 
will be calculated using the following: 
• Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected every 
day. For the calculation, data from the past 7 days will be utilized in a similar way as 
described for the 2-item PRO (see Section 7.3.2.1) 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 Week 52/ET (Visit 14, Part 2 after all evaluations are complete), or at any of 
the regular visit days (Visits 4, 7, and 10) when a treatment failure confirmatory colonoscopy is 
performed, will be calculated using the following: 
• Components 1 to 3 from subject-reported PRO-CD daily e-diary data collected every 
day. For the calculation, data from the previous 7 days will be utilized before the day 
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of the start of colonoscopy preparation in a similar way as described for the 
2-item PRO (see Section 7.3.2.1) and 
• Components 4 to 8 (weight, medical and physical examination, use of diarrhea 
treatment, and hematocrit value) collected at Part 1 and Part 2 of the Week 52/ET 
visit or at Visits 4, 7, and 10 when colonoscopy is performed for treatment failure 
evaluation. 
The investigator may also perform an unscheduled CDAI assessment based on the subject’s 
reported symptoms in order to evaluate treatment failure (see Section 4.5.1). 
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. 
7.3.2.4 Colonoscopy and Histology 
Colonoscopy will be performed at Visit 14, Part 2 (Table 1) or as an unscheduled visit for 
confirming treatment failure. 
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 when it is not possible after previous partial colectomy/ileocolectomy. An 
incomplete colonoscopy can be accepted for evaluation in exceptional cases, eg, in case of 
impassable stenosis or other CD-related complications as causes 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 the baseline 
colonoscopy in the induction study (SHP647-305 or SHP647-306). 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 
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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 colonoscopy at the Week 52/ET visit or at an unscheduled visit to confirm treatment 
failure by colonoscopy, 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. 
Each biopsy will be stained with hematoxylin and eosin and then digitized for central review 
using the Colonic (CGHAS) and Ileal (IGHAS) Global Histologic Disease Activity Scores 
(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. 
Colonoscopy is not required (optional) at the ET visit if the subject has not completed 52 weeks 
of treatment due to early closure of the study. 
7.3.3 
Safety 
7.3.3.1 Medical and Medication History 
Medical history, including CD history, cardiac history, and smoking history, and prior 
medications will be collected at the screening visit (Visit 1) of induction study SHP647-305 or 
SHP647-306. Concomitant medications and procedures will be documented throughout the 
SHP647-307 study at the time points specified in Table 1; diarrhea medications may also be 
documented at unscheduled visits for the calculation of CDAI, in order to assess treatment 
failure (see Section 4.5.1). 
7.3.3.2 Physical Examination (Including 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); 
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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. 
For SHP647-307, the complete physical examination performed at Week 16 (Visit 7 [Part 3]) of 
induction study SHP647-305 or SHP647-306 will be used as the baseline examination. 
Abnormalities identified during this visit will be documented. Any changes from the baseline 
visit (Week 0) in physical examination findings that are deemed clinically significant in the 
opinion of the investigator are to be recorded as an AE. 
Unscheduled physical examinations and weight measurements may be performed for calculation 
of CDAI in order to evaluate treatment failure (see Section 4.5.1). 
7.3.3.3 
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. 
A step-wise approach for the proposed neurological assessment plan is provided in Table 3. 
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Table 3 
Quarterly Neurological Assessments 
Domain 
Step 1: 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. 
7.3.3.4 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 Week 52 visit or the end of the defined safety follow-up period stated in Section 7.2.3 (See 
Section 8, Adverse and Serious Adverse Events Assessment.) 
7.3.3.5 Vital Signs 
Vital signs will be measured at the time points specified in Table 1. Additional collection times 
or changes to collection times will be permitted, as necessary to ensure appropriate collection of 
safety data. Vital signs include blood pressure, pulse, respiratory rate, and temperature. Vital 
signs should be recorded before laboratory blood samples are collected. 
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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. 
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 1) 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. 
7.3.3.6 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. 
Clinical laboratory assays can also be performed by the local laboratory in case of issues related 
to COVID-19 (or other similar pandemic) and if deemed necessary by the investigator to confirm 
the subject’s safety. In such a case, the investigative site must obtain the local laboratory’s 
normal ranges as well as a CLIA (Clinical Laboratory Improvement Amendments) certificate, 
and the investigator must add the local laboratory as appropriate. 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. 
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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 
Urinalysis 
• 
glucose 
• 
protein 
• 
specific gravity 
• 
pH 
• 
nitrite 
• 
bilirubin 
• 
ketones 
• 
hemoglobin 
• 
urobilinogen 
• 
leukocyte esterase 
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Hematocrit may be measured at unscheduled time points any time after Week 4 for calculation of 
CDAI in order to evaluate treatment failure (see Section 4.5.1). Unscheduled CDAI evaluation 
and related blood sampling for hematocrit cannot be performed more than 4 times during the 
study. 
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 4 for guidance regarding diagnostic 
algorithms. 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 4. 
Subjects performing home administrations consecutively for 3 months will need to perform liver 
function testing per FDA requirement. It may be done locally if it is not possible to collect 
samples at the central laboratory. 
7.3.3.7 Pregnancy Test and Follicle-stimulating Hormone Test 
A urine 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. 
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). This does not need to be performed if 
postmenopausal status was confirmed by FSH in induction study SHP647-305 or SHP647-306. 
If a female subject’s status has changed to postmenopausal since the induction studies 
(SHP647-305 or SHP647-306), the childbearing potential of the subject must be re-established 
and documented (FSH confirmation test) at baseline (Visit 1) of SHP647-307. Once FSH results 
are received, and if postmenopausal status is uncertain, the routine pregnancy testing will 
continue as planned for the remainder of the study. If postmenopausal status is confirmed, 
routine pregnancy testing is no longer required. 
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7.3.3.8 Electrocardiogram 
A 12-lead ECG will be recorded at the time points specified in Table 1. When timings of 
measurements coincide, ECGs should be performed before laboratory blood collection. 
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. 
7.3.3.9 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. 
7.3.3.10 
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. 
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. 
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7.3.3.11 
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 4. If the subject has undergone or is undergoing a glucocorticoid taper, the 
glucocorticoid dose should be increased to the pre-taper dose; when clinically stable, the taper 
may begin again per Table 2. 
Subjects should be assessed for possible treatment failure no earlier than the Week 4 scheduled 
visit. If treatment failure is considered after infectious etiology has been ruled out or treated, 
and/or after increase in the glucocorticoid dose (if appropriate), then the procedures in 
Section 4.5.1 should be followed. 
In each case, the appropriate AE (eg, infection, exacerbation) should be recorded in the subject’s 
source document. 
7.3.4 
Others 
7.3.4.1 
 
 
 
 
 
 
 
 
 
 
 
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7.3.5 
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 
5a 
10 
Serum chemistry 
4 
5 
20 
FSH 
2 
1 
2 
ADA and NAb sampling 
3 
3 
9 
Total mL 
41 
ADA=antidrug antibody; FSH=follicle-stimulating hormone; NAb=neutralizing antibody 
a 
Up to 4 additional samples may be taken at unscheduled visits for measurement of hematocrit, in order to determine the 
Crohn’s Disease Activity Index score for treatment failure assessment. 
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 41 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 Week 52 
or the end of the defined follow-up period stated in Section 7.2.3. 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. Resolved AEs considered to be significant by the 
investigator that occurred in induction studies SHP647-305 or SHP647-306 will be captured as 
part of the SHP647-307 baseline medical history, while ongoing AEs from Studies SHP647-305 
or SHP647-306 will be captured as AEs in SHP647-307 and followed throughout the 
SHP647-307 study. 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. 
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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). 
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 in 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. 
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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. 
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. 
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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 7.2.3. 
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. 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. 
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The categories below are not mutually exclusive; the event can meet more than 1 category. 
• Abuse – Persistent or sporadic intentional intake of investigational product when 
used for a nonmedical purpose (eg, to alter one’s state of consciousness or get high) 
in a manner that may be detrimental to the individual and/or society 
• Misuse – Intentional use of investigational product other than as directed or indicated 
at any dose (Note: this includes a situation where the investigational product is not 
used as directed at the dose prescribed by the protocol) 
• Overdose – Intentional or unintentional administration of investigational product at a 
dose interval that is less than 2 weeks between doses 
• Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of an investigational product. For studies, medication errors are reportable to the 
sponsor only as defined below. 
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
Medication errors should be collected/reported for all products under investigation. 
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error. 
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
There is no specific antidote for overdose with 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. 
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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. 
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. 
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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 emergency department 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 7.2.3 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. 
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In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to 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, 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. 
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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 ≥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 induction 
study (SHP647-305 or SHP647-306) 
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 induction 
study (SHP647-305 or SHP647-306) 
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 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 induction 
study (SHP647-305 or SHP647-306) 
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 ≥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 induction 
study (SHP647-305 or SHP647-306) 
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 electronic case report form (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 
Prior to the unblinding described in Section 6.2.4, 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. 
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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. 
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. 
Note: The overall impact of COVID-19 (or other similar pandemic) on data analyses is unknown 
at the time of the writing of this amendment; details on changes to any analyses or any additional 
analyses to evaluate the impact of COVID-19 (or other similar pandemic) on the study objectives 
will be described in the SAP. 
9.5 
Planned Interim Analysis, Adaptive Design, Data Monitoring Committee, and 
Hypersensitivity Adjudication Committee 
There is no planned interim analysis or adaptive design in this study. 
An external DMC will be established to review the overall safety of the study subjects on an 
ongoing basis. 
Until the time of unblinding, 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 
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authorities as appropriate, of DMC recommendations (which may include summaries of 
aggregate analyses of endpoint events and of safety data that are not endpoints). 
Further details regarding the DMC can be found in the DMC charter, which will be available 
before the administration of investigational product to any subject. Analyses of the data for 
DMC review will be conducted according to the DMC charter and DMC SAP. 
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 
The planned sample size for this maintenance study depends on enrollment from the induction 
studies (SHP647-305 and SHP647-306). Assuming that 50% of subjects receiving ontamalimab 
induction treatments and 40% of subjects receiving placebo induction treatment in 
Studies SHP647-305 and SHP647-306 will be eligible to move into this maintenance study based 
on Week 16 results in the induction studies, an estimated 983 subjects will be eligible to enter 
this maintenance study: 388 subjects from ontamalimab 25 mg induction treatment, 388 subjects 
from ontamalimab 75 mg induction treatment, and 207 subjects from placebo induction 
treatment. Expected rates at Week 16 are based on observed rates from a post hoc analysis of the 
A7281006 study and the literature (Sandborn et al., 2017). 
Graphical methods are used to control the global family-wise Type-I error rate at the 0.05 level 
(2-sided) for the comparisons of the 2 ontamalimab treatment groups with the respective placebo 
group based on induction ontamalimab dose. Alpha is split equally at the 0.025 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 based on assuming a 0.025 (2-sided) significance level for each pairwise 
treatment comparison; 388 subjects previously treated with 25 mg ontamalimab in induction 
studies (1:1 allocation ratio: 194 subjects in the 25 mg ontamalimab treatment group versus 
194 subjects in the placebo group) and 388 subjects previously treated with 75 mg ontamalimab 
in induction studies (1:1 allocation ratio: 194 subjects in the 75 mg ontamalimab treatment group 
versus 194 subjects in the placebo group) were planned. These numbers of subjects would yield 
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an approximately 92% power to detect individual pairwise treatment difference in the first 
coprimary efficacy endpoint, clinical remission at Week 52, of 17% (39% ontamalimab versus 
22% placebo). Expected clinical remission rates by 2-item PRO at Week 52 are based on clinical 
remission by CDAI observed in the vedolizumab pivotal maintenance study (Sandborn et al., 
2013). 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 52 are imputed as failures and 
the above rates account for these subjects. 
With the 388 subjects previously treated for each ontamalimab dose in the induction studies as 
noted above, this number of subjects would yield an approximately 94% power to detect an 
individual pairwise treatment difference in the other coprimary efficacy endpoint, enhanced 
endoscopic response at Week 52, of 17% (35% ontamalimab versus 18% placebo). Expected 
enhanced endoscopic responses rates at Week 52 are based on enhanced endoscopic response 
rates derived from the literature (Feagan et al., 2017). No adjustment for missing data is required 
in these sample size calculations as subjects with missing data for enhanced endoscopic response 
at Week 52 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 89% power assuming a 
correlation of 0.4. 
With the planned sample size of 388 subjects previously treated with 25 mg in induction studies 
and 388 subjects previously treated with 75 mg in induction studies, Table 7 provides the power 
for detecting a treatment difference between a ontamalimab treatment group and the placebo 
group for the key secondary endpoints. 
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Table 7 
Power to Detect the Corresponding Treatment Effect for Key Secondary 
Endpoints 
Key Secondary Endpoint at Week 52 
Ontamalimab Premise 
Placebo Premise 
Power 
Clinical remission by CDAI 
39% 
22% 
0.92 
Glucocorticoid-free clinical remission by 2-item 
PROa 
32% 
16% 
0.67 
Clinical remission by abdominal pain ≤1 and 
stool frequency ≤3 
42% 
27% 
0.80 
Sustained clinical remission by 2-item PROb 
65% 
45% 
0.52 
Sustained enhanced endoscopic responsec 
65% 
40% 
0.90 
Clinical remission by 2-item PRO and enhanced 
endoscopic response 
22% 
10% 
0.84 
Complete endoscopic healing 
10% 
3% 
0.71 
CDAI=Crohn’s Disease Activity Index; PRO=patient-reported outcome 
a 
Based on an anticipated 53% of subjects who will be on corticosteroids at baseline of this study. 
b 
Based on an anticipated 34% of subjects who will be in clinical remission by 2-item PRO at baseline of this study. 
c 
Based on an anticipated 50% of subjects that will be have enhanced endoscopic response at baseline of this study. 
With the early discontinuation of the study, the planned sample size of 983 subjects will not be 
attained, as the final number of subjects enrolled into this study is 40. Formal statistical testing 
will not be performed. 
9.7 
Study Population 
The safety set will consist of all subjects who have received at least 1 dose of investigational 
product in the SHP647-307 study, regardless of treatment received during the induction studies 
(SHP647-305 and SHP647-306). 
The full analysis set (FAS) will consist of all randomized subjects who have received at least 
1 dose of investigational product in the SHP647-307 study, regardless of treatment received 
during the induction studies (SHP647-305 and SHP647-306). 
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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 52 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. 
• Enhanced endoscopic response at Week 52 as measured by a decrease in SES-CD of 
at least 50% from induction study (SHP647-305 or SHP647-306) baseline. 
The number and percentage of subjects, and the estimate of the common treatment difference 
along with the corresponding unstratified Newcombe 95% CI for each primary endpoint, will be 
summarized by treatment group at Week 52. Subjects with missing data at Week 52 will be 
considered failures and counted as nonresponders. Due to the early discontinuation of the study 
before full enrollment and the limited sample size, formal statistical testing will not be 
performed. 
Statistical Testing and Protection of the Type I Error 
Due to the early discontinuation of the study before full enrollment and the limited sample size, 
formal statistical testing will not be performed, and therefore, multiplicity adjustment is not 
applicable. 
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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 52 visit as measured by CDAI <150. 
• Glucocorticoid-free clinical remission at the Week 52 visit, among subjects using 
glucocorticoids at induction study baseline. Glucocorticoid-free clinical remission is 
defined as clinical remission by 2-item PRO (as defined for the coprimary endpoint; 
see Section 9.8.1) in addition to not requiring any treatment with glucocorticoids for 
at least 12 weeks prior to the Week 52 visit. 
• Clinical remission at the Week 52 visit as defined by the following: CD daily e-diary 
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. 
• Sustained clinical remission, ie, in clinical remission at the SHP647-307 Week 52 
visit, among subjects who were in clinical remission by 2-item PRO (as defined for 
the coprimary endpoint) at the time of baseline in Study SHP647-307. 
• Sustained enhanced endoscopic response, ie, in enhanced endoscopic response at the 
SHP647-307 Week 52 visit, among subjects who showed enhanced endoscopic 
response (as defined for the coprimary endpoint) at the time of baseline in 
Study SHP647-307. 
• Both clinical remission by 2-item PRO and enhanced endoscopic response at 
Week 52 (composite endpoint). 
• Complete endoscopic healing at Week 52 defined as SES-CD=0-2. 
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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 52 visit 
will be considered failures and counted as nonresponders. Due to the early discontinuation of the 
study before full enrollment and the limited sample size, formal statistical testing will not be 
performed. 
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 in the SHP647-307 study. 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. 
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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. 
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10.1.3 
Public Posting of Study Information 
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information. 
10.1.4 
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees 
The sponsor will upload the clinical study report to the EudraCT database and will also provide a 
summary of the clinical study report to the CRO for submission to the competent authority of the 
countries concerned as required by local regulatory requirement(s). This requirement will be 
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. 
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If a potential research subject has a primary care physician, the investigator should, with the 
subject’s or subject’s legally authorized representative’s consent and/or assent, as applicable, 
inform them of the subject’s participation in the study. 
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2 
Protocol Adherence and Investigator Agreement 
The investigator and any coinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
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. 
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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 the 
subject’s medical file, subject e-diary, original clinical laboratory reports, and histology and 
pathology reports. 
All key data must be recorded in the subject’s medical records. 
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media. 
The clinical research associate/study monitor (and auditors, IRB/EC or regulatory inspectors) 
may check the 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 Administration [FDA], EMA, UK Medicines and Healthcare products Regulatory Agency) 
or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
Sites are to ensure that all study documents related to DTP are complete, accurate, and retained 
at the site according to the document retention requirements. 
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 
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Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site. 
10.2.3.4 
Financial Disclosure 
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 Code of Federal 
Regulations 54 2(b) (1998). 
10.3 
Ethical Considerations 
10.3.1 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent and/or assent from 
all study subjects before any study-related procedures including screening assessments. All 
consent documentation must be in accordance with applicable regulations and GCP. Each subject 
or the subject’s legally authorized representative, as applicable, is requested to sign and date the 
subject informed consent form or a certified translation if applicable, after the subject has 
received and read (or been read) the written subject information and received an explanation of 
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. 
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10.3.2 
Institutional Review Board or Ethics Committee 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved before site initiation. 
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions. 
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Before implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. 
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents. 
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs. 
10.4 
Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with 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 
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approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities. 
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities. 
10.5 
Study Results/Publication Policy 
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(eg Good Publication Practices 2) when forming a publication steering committee, which is done 
for large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy. 
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish before release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications. 
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form. 
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days before 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application. 
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented. 
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications. 
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Sandora, T. J. and Wilcox, M. H. 2018. Clinical Practice Guidelines for Clostridium 
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Molodecky, N. A., Soon, I. S., Rabi, D. M., Ghali, W. A., Ferris, M., Chernoff, G., Benchimol, 
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incidence and prevalence of the inflammatory bowel diseases with time, based on 
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Evolving Definitions of Remission in Crohn’s Disease. Inflammatory Bowel Diseases, 
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H., Ardizzone, S., Veereman-Wauters, G., Chevaux, J.-B., Allez, M. and Dane 2011. 
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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., 
Branum, A., Brown, S. G., Camargo, C. A., Jr., Cydulka, R., Galli, S. J., Gidudu, J., 
Gruchalla, R. S., Harlor, A. D., Jr., Hepner, D. L., Lewis, L. M., Lieberman, P. L., 
Metcalfe, D. D., O'Connor, R., Muraro, A., Rudman, A., Schmitt, C., Scherrer, D., 
Simons, F. E., Thomas, S., Wood, J. P. and Decker, W. W. 2006. Second symposium on 
the definition and management of anaphylaxis: summary report--Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. The Journal of allergy and clinical immunology, 117, 391-7. 
Sandborn, Feagan, Panes, D'Haens, Colombel, Zhou, Huang, Enejosa, Pangan and Lacerda 2017. 
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. 
Sandborn, W. J., Feagan, B. G., Rutgeerts, P., Hanauer, S., Colombel, J. F., Sands, B. E., Lukas, 
M., Fedorak, R. N., Lee, S., Bressler, B., Fox, I., Rosario, M., Sankoh, S., Xu, J., 
Stephens, K., Milch, C. and Parikh, A. 2013. Vedolizumab as induction and maintenance 
therapy for Crohn's disease. N Engl J Med, 369, 711-21. 
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Schnitzler, F., Fidder, H., Ferrante, M., Noman, M., Arijs, I., Van Assche, G., Hoffman, I., Van 
Steen, K., Vermeire, S. v. and Rutgeerts, P. 2009. Mucosal healing predicts long-term 
outcome of maintenance therapy with infliximab in Crohn's disease Supported by an 
unrestricted scientific grant from Centocor. Fabian Schnitzler received a research grant 
by ECCO (European Crohn's and Colitis Organisation). Inflammatory Bowel Diseases, 
15, 1295-1301. 
Shane, A. L., Mody, R. K., Crump, J. A., Tarr, P. I., Steiner, T. S., Kotloff, K., Langley, J. M., 
Wanke, C., Warren, C. A., Cheng, A. C., Cantey, J. and Pickering, L. K. 2017. 2017 
Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis 
and Management of Infectious Diarrhea. Clinical Infectious Diseases, 65, 1963-1973. 
Shyjan, A. M., Bertagnolli, M., Kenney, C. J. and Briskin, M. J. 1996. Human mucosal addressin 
cell adhesion molecule-1 (MAdCAM-1) demonstrates structural and functional 
similarities to the alpha 4 beta 7-integrin binding domains of murine MAdCAM-1, but 
extreme divergence of mucin-like sequences. J Immunol, 156, 2851-7. 
Siegel, C. A., Whitman, C. B., Spiegel, B. M. R., Feagan, B., Sands, B., Loftus, E. V., 
Panaccione, R., D'Haens, G., Bernstein, C. N., Gearry, R., Ng, S. C., Mantzaris, G. J., 
Sartor, B., Silverberg, M. S., Riddell, R., Koutroubakis, I. E., O'Morain, C., Lakatos, P. 
L., McGovern, D. P. B., Halfvarson, J., Reinisch, W., Rogler, G., Kruis, W., Tysk, C., 
Schreiber, S., Danese, S., Sandborn, W., Griffiths, A., Moum, B. and Gasche, C. 2016. 
Development of an index to define overall disease severity in IBD. Gut, gutjnl-2016-
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. 
Warrington, R., Silviu-Dan, F. and Wong, T. 2018. Drug allergy. Allergy, Asthma & Clinical 
Immunology, 14, 1-11. 
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. 
 
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APPENDIX 1 
PROTOCOL HISTORY  
Document 
Date 
Global/Country/Site Specific 
Protocol Amendment 3 
17 Sep 2020 
Global 
Protocol Amendment 2 
22 Nov 2019 
Global 
Protocol Amendment 1 
23 Aug 2018 
Global 
Original Protocol 
15 Dec 2017 
Global 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/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 complaints 
language with current Shire 
template. 
Study Synopsis, Objectives, Key 
secondary 
Section 2.2.2.1, Key Secondary 
Objectives 
Added that complete endoscopic healing will 
be measured by centrally read endoscopy. 
For clarity. 
Study Synopsis, Exclusion 
Criteria 
Section 4.2, Exclusion Criteria 
Revised exclusion criterion #4 to add that 
lactating females are also excluded. 
To clarify that lactating females 
are excluded. 
Study Synopsis, Exclusion 
Criteria 
Section 4.2, Exclusion Criteria 
Section 4.4, Reproductive 
Potential 
Added the term ‘highly effective methods for 
female and medically appropriate methods for 
male study subjects’ to exclusion criterion #4 
in parentheses after the term ‘appropriate 
contraception methods’. Also added after the 
terms ‘appropriate form of contraception’ and 
‘appropriate method of contraception’ in 
Section 4.4. 
To clarify what is meant by 
appropriate contraception 
methods. 
Study Synopsis, 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. 
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SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Table 1, Schedule of 
Assessments, footnote “d” 
Section 7.2.2.2, Final 
On-treatment Visits: Visit 14, 
Parts 1 and 2 (Week 52/Early 
Termination) 
Revised to extend the window between 
Visit 14 (Part 1) and Visit 14 (Part 2) to 
10 days, although 5 to 7 days is preferable. 
 
 
 
Added that Parts 1 and 2 of Visit 14 can be 
performed on the same day if central 
laboratory hematocrit result is not older than 
3 weeks. 
To allow sufficient time to 
obtain data from the central 
laboratory hematocrit test value 
in order to be available at Part 2 
of the visit. 
 
To reduce the burden on the 
subjects. 
Table 1, Schedule of 
Assessments, footnote “h” 
Added new footnote stating that an 
unscheduled assessment for calculation of 
CDAI may be performed after Week 4 if it is 
clinically necessary; blood sampling for 
hematocrit may be necessary if there is no 
value available from last 3 weeks; and 
unscheduled assessment for CDAI must not 
be performed more than 4 times during the 
study. 
To provide clarity about 
unscheduled assessment for 
calculation of CDAI in order to 
evaluate treatment failure. 
Table 1, Schedule of 
Assessments, footnote “n” 
Section 7.3.2.4, Colonoscopy 
and Histology 
Revised to clarify that colonoscopy 
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 “p” 
Section 4.5.1, Subject 
Withdrawal Criteria 
Added that colonoscopy is to be performed 
either within 2 weeks after the previous 
regular visit or the next regular visit if the 
CDAI based score criterion is fulfilled at an 
unscheduled visit. 
To provide clarity around 
unscheduled colonoscopy with 
respect to CDAI score-based 
criterion. 
Table 1, Schedule of 
Assessments, footnote “r” 
Added new footnote stating that an 
unscheduled CDAI evaluation may be 
performed any time after Week 4 if it is 
clinically necessary; if an unscheduled CDAI 
evaluation is planned after an 
unscheduled/confirmatory colonoscopy, then 
diary data cannot be utilized for CDAI 
calculation earlier than 1 week after 
colonoscopy. 
To provide clarity about 
unscheduled CDAI evaluation 
and use of diary data for CDAI 
calculation in order to evaluate 
treatment failure. 
Table 1, Schedule of 
Assessments, footnote “s” 
Section 7.3.2.1, Patient-reported 
Outcome – Crohn’s Disease 
Daily E-diary 
Updated language to describe availability of 
e-diary throughout the study. 
To provide additional clarity 
around the collection of e-diary 
data. 
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CONFIDENTIAL 
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Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Table 1, Schedule of 
Assessments, footnote “x” 
Section 7.3.3.10, Monitoring for 
Type I and Type III Immune 
Reactions 
Added new row and footnote to Table 1, new 
subsection to Section 7.3.3, and language to 
describe monitoring for hypersensitivity. 
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 3.1, Study Design and 
Flow Chart 
Added new figure (Figure 1, Overview of 
Ontamalimab Phase 3 Studies in Crohn’s 
Disease). 
Added for clarity. 
Section 3.1.2, Rationale for Key 
Secondary Endpoints 
Added that ‘complete endoscopic healing’ 
will be used as a key secondary point. 
Added for clarity. 
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. 
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CONFIDENTIAL 
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Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 4.5.1, Subject 
Withdrawal Criteria 
Added criteria of treatment failure as a reason 
of subject withdrawal. 
 
 
 
 
 
 
 
Changed the term ‘protocol violations’ to 
‘protocol deviations’. 
 
 
Removed the term ‘4 weeks apart’ after the 
term ‘2 successive visits’. 
To clarify that when treatment 
failure criteria are fulfilled the 
subject may be withdrawn from 
the maintenance study and 
either enter into the long-term 
safety follow-up study 
(Study SHP647-304), or the 
16-week safety follow-up 
period. 
 
For consistency with 
Section 4.5.2 (Reasons for 
Withdrawal). 
 
To account for flexibility in the 
time between visits due to the 
existing visit windows. 
Section 4.5.1, Subject 
Withdrawal Criteria 
Section 7.3.2.3, Crohn’s Disease 
Activity Index 
Updated to specify that the investigator may 
perform an unscheduled CDAI assessment 
based on the subject’s reported symptoms. 
To allow treatment failure to be 
assessed at unscheduled visits. 
Section 7.2.2.3, Unscheduled 
Visit to Evaluate Potential 
Treatment Failure With CDAI 
Section 7.2.2.4, Unscheduled 
Visit to Evaluate Potential 
Treatment Failure With 
Colonoscopy 
Added new subsections to Section 7.2.2 to 
describe unscheduled visits to evaluate 
potential treatment failure with CDAI 
(Section 7.2.2.3) and colonoscopy 
(Section 7.2.2.4). 
To allow treatment failure to be 
assessed at unscheduled visits. 
Section 7.3.2.1, Patient-reported 
Outcome – Crohn’s Disease 
Daily E-diary 
Changed the term ‘very soft stools/liquid 
stools’ to ‘very soft stool/liquid stool 
frequency’. 
 
Updated text so that the method for 
calculating 2-item PRO at Visit 14 (Part 2) 
also applies to any regular visit (Visit 3 to 13) 
when a confirmatory colonoscopy is 
performed to evaluate treatment failure. 
For consistency with other 
sections. 
 
 
To allow evaluation of 
treatment failure. 
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Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 7.3.2.2, Simple 
Endoscopic Score for Crohn’s 
Disease 
Updated text so that the method for 
calculation of the SES-CD score at 
week 52/ET also applies to unscheduled 
colonoscopy. 
 
Added reference citation to Daperno et al., 
2004. 
 
 
 
Added the term ileocolectomy along with 
partial colectomy. 
To allow evaluation of 
treatment failure at 
unscheduled visits. 
 
 
To provide additional 
information regarding the 
Simple Endoscopic Score for 
Crohn’s Disease (SES-CD). 
 
For consistency with other 
sections. 
Section 7.3.2.3, Crohn’s Disease 
Activity Index 
Text updated in relation to calculation of 
CDAI scores at an unscheduled visit for 
treatment failure evaluation; at any of the 
regular visit days when a treatment failure 
confirmatory colonoscopy is performed, and 
at any of the visits when colonoscopy is 
performed for treatment failure evaluation.  
To allow evaluation of 
treatment failure. 
Section 7.3.2.4, Colonoscopy 
and Histology 
Sentence updated to read as ‘colonoscopy will 
be performed at Visit 14, Part 2 or as an 
unscheduled visit for confirming treatment 
failure.’ 
To allow colonoscopy for the 
assessment of treatment failure 
at unscheduled visit. 
Section 7.3.3.1, Medical and 
Medication History 
Section 7.3.3.2, Physical 
Examination (Including Weight) 
Section 7.3.3.6, Clinical 
Laboratory Evaluations 
Updated to specify that diarrhea medications, 
physical examination, weight, and hematocrit 
may be determined at unscheduled time 
points for calculation of CDAI. 
To allow treatment failure to be 
assessed between scheduled 
visits as well. 
Table 3, Quarterly Neurological 
Assessments 
Column heading changed from ‘targeted 
neurological history’ to ‘interim neurologic 
history and targeted neurologic examination’. 
To align with language of 
newly proposed electronic case 
report form. 
Section 7.3.3.6, Clinical 
Laboratory Evaluations 
Table 4, Volume of Blood to Be 
Drawn From Each Subject 
Added that unscheduled CDAI evaluation and 
related blood sampling for hematocrit cannot 
be performed more than 4 times during the 
study. 
To clarify the maximum 
number of unscheduled CDAI 
evaluations and related blood 
samples for hematocrit for 
treatment failure assessment. 
Section 7.3.3.6, Clinical 
Laboratory Evaluations 
Section 7.3.3.11, Evaluation of 
Increased Gastrointestinal 
Symptoms 
Added new subsection (Section 7.3.3.11) to 
Section 7.3.3 to describe evaluation of 
increased gastrointestinal symptoms. 
To clarify that infectious 
etiology must be evaluated 
when a subject experience an 
increase in gastrointestinal 
symptoms. 
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Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 7.3.5, Volume of Blood 
to be Drawn from Each Subject 
Decreased serum chemistry sample volume 
from 6 mL to 4 mL. 
 
 
To correct the sample volume 
needed for the serum chemistry 
test and 
 
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. 
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 9.6, Sample Size 
Calculation and Statistical 
Power 
Updated power considerations for complete 
endoscopic healing. 
To accurately reflect the power 
considerations for complete 
endoscopic healing. 
Section 9.8.3, Exploratory 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number  
2 
Amendment Date 
22 Nov 2019 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 10.1.5, Study 
Suspension, Termination, and 
Completion 
Added text to specify that designated meeting 
of the DMC will take place after completion 
of the induction studies for the review of the 
safety and efficacy results of the induction 
studies for the recommendation to the sponsor 
whether to continue or discontinue with the 
maintenance study or long-term study. 
 
Clarified that the end-of-study declaration 
may be made by the sponsor or alternatively 
its representatives. 
To provide clarity around 
continue or discontinue with 
the maintenance study or 
long-term study after the 
completion of the induction 
studies. 
 
 
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 
Minor changes to wording. 
To improve clarity, 
consistency, and remove 
redundancy of text. 
 
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CONFIDENTIAL 
Page 128 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendments 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
17 Aug 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Emergency Contact Information 
Updated the global fax number for 
serious adverse event reporting. 
To provide updated emergency 
contact information. 
Study Synopsis, Inclusion and  
exclusion criteria 
Section 4.1, Inclusion Criteria 
Updated inclusion criterion #3b (ii) to 
indicate that subjects must have a 
decrease of at least 100 points in CDAI 
score (CDAI-100) from induction 
study baseline. 
To align with what has been used 
in more recent clinical trials for 
evaluating response. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Updated exclusion criterion #7 to 
indicate that subjects who developed 
enterovesical or enterovaginal fistulae 
during the induction study 
(SHP647-305 or SHP647-306) would 
be excluded. 
To specify the exclusion of subjects 
who developed such fistulae during 
the induction study. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Updated exclusion criterion #12 to 
indicate that subjects meeting the 
following lab criteria would be 
excluded: 
• 
ALT or AST ≥3×ULN  
• 
Total bilirubin level 
≥1.5 times the ULN (>2 times 
the ULN if subject has a 
known documented history of 
Gilbert’s syndrome) 
Added note to exclusion criterion #12 
to specify that, if platelet count is 
<150,000 cells/mm3, a further 
evaluation should be performed to rule 
out cirrhosis, unless another etiology 
has already been identified. 
To align criteria with FDA 
guidelines. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Updated exclusion criterion #5 to 
indicate the exclusion of subjects who 
do not agree to postpone donation of 
any organ or tissue, including male 
subjects are planning to bank or donate 
sperm and female subjects who are 
planning to harvest or donate eggs, for 
the duration of the study and for 16 
weeks after last dose of investigational 
product. 
To specify the exclusion of subjects 
who do not agree to postpone 
donation of any organ or tissue, 
including sperm banking or 
donation for male subjects and egg 
donation or harvest for female 
subjects, are excluded. 
Study Synopsis, Methodology 
Section 3.1, Study Design and 
Flow Chart 
Figure 2, Study Design Flow Chart 
Added a statement to note that subjects 
who are withdrawn early from the 
study due to fulfilling the criteria for 
treatment failure also may be eligible 
to enter the long-term safety (LTS) 
study, SHP647-304, and to provide 
rationale for this. 
To clarify the subject population 
that may be eligible to enter the 
LTS study and provide rationale for 
offering the opportunity for 
treatment in LTS to subjects who 
meet the criteria for “treatment 
failure” in this study. 
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SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendments 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
17 Aug 2018 
Global/Country/Site Specific 
Global 
Study Synopsis, Key Secondary 
Endpoints 
Section 3.1.2, Rationale for Key 
Secondary Efficacy Endpoints 
Section 9.8.2.1, Key Secondary 
Efficacy Endpoints 
Updated the second key secondary 
efficacy endpoint definition to include 
the stipulated window for not requiring 
any treatment with glucocorticoids (at 
least 12 weeks prior to the Week 52 
visit). 
To clarify the endpoint definition 
for glucocorticoid-free clinical 
remission (based on ECCO and 
EMA guidances). 
Section 1.3, Benefit and Risk 
Assessment 
Added new section describing risks and 
benefits of ontamalimab treatment. 
To provide updated risk and benefit 
information for ontamalimab. 
Section 4.5.1, Subject Withdrawal 
Criteria Schedule of Assessments, 
footnote “n” 
Added a note to specify that if an 
unscheduled colonoscopy is needed for 
treatment failure evaluation, it is 
strongly encouraged that the 
colonoscopy is performed within 
2 weeks after the visit day when either 
the PRO-based or the CDAI score-
based criterion for treatment failure 
was fulfilled. 
To specify the recommended time 
frame within which the 
unscheduled colonoscopy should 
be performed, if needed as part of 
treatment failure evaluation. 
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 6.2.3, Dosing 
Add language to specify that a total of 
up to 13 doses of investigational 
product (IP) will be administered in 
this study. 
To clarify the total number of doses 
of IP to be administered in this 
study. 
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 language to state that diagnosis 
of C. difficile infection should be made 
using the central laboratory and to note 
that guidance regarding diagnostic 
algorithms, if the central laboratory is 
not available, is provided in 
Appendix 4. 
To provide guidance regarding 
laboratory testing for C. difficile 
infection. 
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Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
Protocol Amendments 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
17 Aug 2018 
Global/Country/Site Specific 
Global 
Section 7.2.3.5, Vital Signs 
Removed language that specified 
measuring body temperature orally 
with a digital thermometer or by using 
tympanic temperature. 
To clarify how body temperature 
should be obtained. 
Section 8.2.8, Safety Monitoring 
Rules 
Added new section and table 
describing safety monitoring and 
stopping criteria for elevated hepatic 
blood tests. 
To provide appropriate guidance on 
patients who have been enrolled 
with elevated liver function test 
values or who experience and 
increase in liver function test(s) 
during the study. 
Section 10, Sponsor’s and 
Investigator’s Responsibilities 
Added a statement that compliance 
with the noted regulations and 
guidelines also constitutes compliance 
with the ethical principles described in 
the Declaration of Helsinki. 
To clarify that the study is 
conducted in accordance with the 
ethical principles in the Declaration 
of Helsinki. 
Appendix 4, Guidance for 
Diagnosis and Treatment of 
Increased Gastrointestinal 
Symptoms 
Added new Appendix 4, “Guidance for 
Diagnosis and Treatment of Increased 
Gastrointestinal Symptoms related to 
diagnosis and treatment of C. difficile 
infection.” 
To provide appropriate guidance 
for diagnosis and treatment of 
C. difficile infection. 
Throughout protocol 
Minor changes to wording. 
To improve clarity, consistency, 
and remove redundancy of text. 
 
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Page 131 
Ontamalimab 
SHP647-307 Protocol Amendment 3 
 
17 Sep 2020 
 
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 
• Colonic Global Histologic Disease Score and Ileal Global Histologic Disease Score 
• Patient-reported Outcome – Crohn’s Disease Daily E-diary 
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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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17 Sep 2020 
 
Colonic Global Histologic Disease Score (CGHAS) and Ileal Global Histologic Disease 
Score (IGHAS) 
Scoring system for histological abnormalities in Crohn’s disease mucosal biopsy specimens 
Epithelial damage 
0, Normal 
 
1, Focal pathology 
 
2, Extensive pathology 
Architectural changes 
0, Normal 
 
1, Moderately disturbed (<50%) 
 
2, Severely disturbed (>50%) 
Infiltration of mononuclear cells in the lamina propria 
0, Normal 
 
1, Moderate increase 
 
2, Severe increase 
Infiltration of polymorphonuclear cells in the lamina propria 
0, Normal 
 
1, Moderate increase 
 
2, Severe increase 
Polymorphonuclear cells in epithelium 
1, In surface epithelium 
 
2, Cryptitis 
 
3, Crypt abscess 
Presence of erosion and/or ulcers 
0, No 
 
1, Yes 
Presence of granuloma 
0, No 
 
1, Yes 
No. of biopsy specimens affected* 
0, None (0 of 6) 
 
1, ≤33% (1 or 2 of 6) 
 
2, 33%–66% (3 or 4 of 6) 
 
3, >66% (5 or 6 of 6) 
Note: Each topic is scored independently. Moderate increase is defined as up to twice the number of cells that can normally be 
expected; severe increase is defined as more than twice the normal number of cells. 
* The score for “No. of biopsy specimens affected” will be adapted to 10 biopsies; details will be provided in the statistical 
analysis plan. 
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: ____________ 
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: ____________ 
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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 
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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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 
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 polymerase chain reaction [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 Infectious Diseases Society of America recommendations for 
C. difficile infection (McDonald et al., 2018) or the recent expert review on C. difficile infection 
in IBD (Khanna et al., 2017) should be consulted. 
If C. difficile infection was identified, clinical improvement should be noted within about 5 days 
after the start of treatment. If improvement does not occur, the etiology is most likely an 
IBD flare secondary to C. difficile and treatment failure assessment should proceed per the 
protocol. Another possible explanation is primary failure of C. difficile therapy which is unlikely. 
If an infectious etiology other than C. difficile is identified, it should be managed as appropriate, 
with reference to current clinical guidelines (Shane et al., 2017). 
If any infectious etiology is determined, the site should contact the medical monitor to make him 
or her aware of the diagnosis and to discuss treatment and ongoing study participation. 
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