Clinical trial NCT03290781
Conditions: Ulcerative Colitis
Keywords: Ulcerative colitis
Sponsor: Shire
Start date: 2018-04-04; Completion date: 2021-07-01
Enrollment: 366 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:

Arms: arm 1: Participants will receive 25 milligram (mg) of ontamalimab or placebo and achieved a clinical response in one of the induction studies (SHP647-301 \[NCT03259334\] and SHP647-302 \[NCT03259308\]) will receive 25 mg of ontamalimab as maintenance treatment subcutaneously using a prefilled syringe once in every 4 weeks (Q4W) up to Week 52. arm 2: Participants will receive 75 mg of ontamalimab or placebo and achieved a clinical response in one of the induction studies (SHP647-301 \[NCT03259334\] and SHP647-302 \[NCT03259308\]) will receive 75 mg of ontamalimab as maintenance treatment subcutaneously using a prefilled syringe Q4W up to Week 52. arm 3: Participants will receive 25 mg or 75 mg ontamalimab or placebo matched to ontamalimab in the induction studies (SHP647-301 \[NCT03259334\] and SHP647-302 \[NCT03259308\]) will receive placebo matched to ontamalimab as maintenance treatment subcutaneously using a prefilled syringe Q4W up to Week 52.
Interventions: intervention 1: Ontamalimab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 1 milliliter (mL) of ontamalimab sterile aqueous buffered solution at an appropriate oncentration to provide an intended dose of drug (25 or 75 mg). intervention 2: Participants will receive 1 mL of sterile aqueous buffered solution.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT03290781 
 
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 Ulcerative Colitis (FIGARO UC 303) 
 
 
Study Number:  
SHP647-303 
 
 
Protocol Version and Date:  
Protocol Amendment 3: 17 Sep 2020 


 
PROTOCOL: SHP647-303 
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 Ulcerative Colitis 
(FIGARO UC 303) 
DRUG: 
Ontamalimab (SHP647) 
IND: 
100,222 
EUDRACT NO.: 
2017-000573-37 
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: 11 Nov 2019 
Protocol Amendment 1: 11 Sep 2018 
Original Protocol: 10 Jul 2017 
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire. 


o
DocuSign Envelope ID: D3A593D3-077B-4142-8EB8-6AEB31BD476C 
 
 
Shire 
CONFIDENTIAL 
Page 2 
Ontamalimab 
 
 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
 
Sponsor's (Shire) Appr 
PROTOCOL SIGNATURE PAGE 
 
Signature: 
Date: 
21-Sep-2020 I 21:35:37 JST 
, MD 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP647-303. 
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 
Ulcerative Colitis (FIGARO UC 303). 
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: 
  
 


Shire 
CONFIDENTIAL 
Page 3 
Ontamalimab 
SHP647-303 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 SHP647-303 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 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 SHP647-303 Protocol Amendment 3 relative to the previous edition, SHP647-303 
Protocol Amendment 2, are captured below. 


Shire 
CONFIDENTIAL 
Page 4 
Ontamalimab 
SHP647-303 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 ‘i’ 
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. 


Shire 
CONFIDENTIAL 
Page 5 
Ontamalimab 
SHP647-303 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 
Table 1, Schedule of Assessments 
footnote ‘r’ 
Added language to clarify that, 
with the early termination of this 
study by the sponsor, endoscopy 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 ‘x’ 
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 
Reduced other secondary 
objectives and removed 
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. 


Shire 
CONFIDENTIAL 
Page 6 
Ontamalimab 
SHP647-303 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 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 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 
subjects missing their visits. 


Shire 
CONFIDENTIAL 
Page 7 
Ontamalimab 
SHP647-303 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 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 endoscopy 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. 


Shire 
CONFIDENTIAL 
Page 8 
Ontamalimab 
SHP647-303 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 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 47 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 
696 subjects, which will not be 
attained. 
To clarify that the planned sample size 
will not be attained due to early 
discontinuation of this study. 
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. 


Shire 
CONFIDENTIAL 
Page 9 
Ontamalimab 
SHP647-303 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 
Study Synopsis, Endpoints and 
statistical analysis 
Section 9.8, Efficacy Analyses 
Reduced other secondary analyses 
and removed exploratory analyses. 
Updated text on sensitivity 
analyses, 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. 


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CONFIDENTIAL 
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Ontamalimab 
SHP647-303 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: 
 


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CONFIDENTIAL 
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Ontamalimab 
SHP647-303 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 AEs related to product complaints, see Section 8.2.2. 


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CONFIDENTIAL 
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Ontamalimab 
SHP647-303 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 ......................................................................................................................20 
STUDY SCHEDULE ....................................................................................................................26 
1. 
BACKGROUND INFORMATION .......................................................................................30 
1.1 
Indication and Current Treatment Options ...............................................................30 
1.2 
Product Background and Clinical Information ........................................................30 
1.3 
Benefit/Risk Assessment ..........................................................................................31 
2. 
STUDY OBJECTIVES AND PURPOSE ..............................................................................33 
2.1 
Rationale for the Study .............................................................................................33 
2.2 
Study Objectives ......................................................................................................35 
2.2.1 Primary Objective ..................................................................................................35 
2.2.2 Secondary Objectives .............................................................................................35 
2.2.2.1 
Key Secondary Objectives .....................................................................35 
2.2.2.2 
Other Secondary Objectives ...................................................................35 
3. 
STUDY DESIGN ...................................................................................................................36 
3.1 
Study Design and Flow Chart ..................................................................................36 
3.1.1 Rationale for Primary Endpoint .............................................................................40 
3.1.2 Rationale for Key Secondary Endpoints ................................................................40 
3.1.3 Rationale for Treatment Failure .............................................................................41 
3.2 
Duration and Study Completion Definition .............................................................41 
3.3 
Sites and Regions .....................................................................................................42 
4. 
STUDY POPULATION .........................................................................................................43 
4.1 
Inclusion Criteria ......................................................................................................43 
4.2 
Exclusion Criteria .....................................................................................................44 
4.3 
Restrictions ...............................................................................................................45 
4.4 
Reproductive Potential .............................................................................................45 
4.4.1 Contraceptive Methods for Female Study Subjects ...............................................46 


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SHP647-303 Protocol Amendment 3 
 
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4.4.2 Contraceptive Methods for Male Study Subjects ..................................................48 
4.5 
Withdrawal of Subjects ............................................................................................48 
4.5.1 Subject Withdrawal Criteria ..................................................................................49 
4.5.1.1 
Definition of Treatment Failure .............................................................50 
4.5.1.2 
Assessing for Treatment Failure ............................................................50 
4.5.1.3 
After Treatment for Infectious Etiology .................................................51 
4.5.2 Reasons for Withdrawal .........................................................................................51 
4.5.3 Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................52 
5. 
PRIOR AND CONCOMITANT TREATMENT ...................................................................53 
5.1 
Prior Treatment ........................................................................................................53 
5.2 
Concomitant Treatment ............................................................................................53 
5.2.1 Permitted Treatment ...............................................................................................53 
5.2.2 Prohibited Treatment .............................................................................................55 
5.2.3 Rescue Therapy ......................................................................................................55 
5.3 
COVID-19 ................................................................................................................56 
6. 
INVESTIGATIONAL PRODUCT ........................................................................................57 
6.1 
Identity of Investigational Product ...........................................................................57 
6.1.1 Blinding the Treatment Assignment ......................................................................57 
6.2 
Administration of Investigational Product ...............................................................57 
6.2.1 Interactive Response Technology for Investigational Product Management ........57 
6.2.2 Allocation of Subjects to Treatment ......................................................................57 
6.2.3 Dosing ....................................................................................................................58 
6.2.4 Unblinding the Treatment Assignment ..................................................................60 
6.3 
Labeling, Packaging, Storage, and Handling ...........................................................61 
6.3.1 Labeling .................................................................................................................61 
6.3.2 Packaging ...............................................................................................................61 
6.3.3 Storage ...................................................................................................................61 
6.3.4 Special Handling ....................................................................................................62 
6.4 
Drug Accountability .................................................................................................62 
6.5 
Subject Compliance ..................................................................................................63 
7. 
STUDY PROCEDURES ........................................................................................................64 
7.1 
Changes to Study Procedures Due to a Pandemic ....................................................64 
7.2 
Study Schedule .........................................................................................................65 
7.2.1 Baseline Visit 1 (Week 0/Day 1) ...........................................................................65 
7.2.2 Treatment Period ....................................................................................................66 
7.2.2.1 
Visits 2 to 13 (Weeks 4 to 48) ................................................................66 
7.2.2.2 
Final On-treatment Visits: Visit 14, Parts 1 and 2 (Week 52/Early 
Termination) ...........................................................................................66 


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7.2.3 Follow-up Period: Visit 15 (Week 64)...................................................................68 
7.2.4 Additional Care of Subjects After the Study .........................................................68 
7.3 
Study Evaluations and Procedures ...........................................................................68 
7.3.1 Demographic and Other Baseline Characteristics .................................................69 
7.3.2 Efficacy ..................................................................................................................69 
7.3.2.1 
Endoscopy and Histology .......................................................................69 
7.3.2.2 
Mayo Score ............................................................................................70 
7.3.2.3 
Patient-reported Outcome – Ulcerative Colitis Daily E-diary ...............71 
7.3.3 Safety .....................................................................................................................72 
7.3.3.1 
Medical and Medication History ............................................................72 
7.3.3.2 
Physical Examination (Including Weight) .............................................72 
7.3.3.3 
Targeted Neurological Assessment ........................................................72 
7.3.3.4 
Adverse Event Collection .......................................................................74 
7.3.3.5 
Vital Signs ..............................................................................................75 
7.3.3.6 
Clinical Laboratory Evaluations .............................................................75 
7.3.3.7 
Pregnancy Test and Follicle-stimulating Hormone Test ........................77 
7.3.3.8 
Electrocardiogram ..................................................................................77 
7.3.3.9 
Antidrug Antibodies ...............................................................................78 
7.3.3.10 
Monitoring for Type I and Type III Immune Reactions ........................78 
7.3.3.11 
Evaluation of Increased Gastrointestinal Symptoms .............................79 
7.3.4 Others .....................................................................................................................79 
7.3.4.1 
 .............................................................79 
7.3.5 Volume of Blood to Be Drawn from Each Subject ...............................................80 
8. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................81 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events .......................................................................................................................81 
8.1.1 Severity Categorization ..........................................................................................81 
8.1.2 Relationship Categorization ...................................................................................82 
8.1.3 Adverse Events of Special Interest ........................................................................82 
8.1.3.1 
Hypersensitivity .....................................................................................83 
8.1.4 Outcome Categorization ........................................................................................85 
8.1.5 Symptoms of the Disease Under Study .................................................................85 
8.1.6 Clinical Laboratory and Other Safety Evaluations ................................................85 
8.1.7 Pregnancy ...............................................................................................................86 
8.1.8 Abuse, Misuse, Overdose, and Medication Error ..................................................87 
8.1.9 Unexpected Adverse Event ....................................................................................88 
8.1.10 Suspected Unexpected Serious Adverse Reaction .................................................88 
8.2 
Serious Adverse Event Procedures ..........................................................................88 


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8.2.1 Reference Safety Information ................................................................................88 
8.2.2 Reporting Procedures .............................................................................................88 
8.2.3 Serious Adverse Event Definition .........................................................................89 
8.2.4 Serious Adverse Event Collection Time Frame .....................................................90 
8.2.5 Serious Adverse Event Onset and Resolution Dates .............................................90 
8.2.6 Fatal Outcome ........................................................................................................90 
8.2.7 Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................91 
8.2.8 Safety Monitoring for Potential Cases of Drug-induced Liver Injury ...................91 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................94 
9.1 
Data Collection .........................................................................................................94 
9.2 
Clinical Data Management .......................................................................................94 
9.3 
Data Handling Considerations .................................................................................94 
9.4 
Statistical Analysis Process ......................................................................................95 
9.5 
Planned Interim Analysis, Adaptive Design, Data Monitoring Committee, 
and Hypersensitivity Adjudication Committee ........................................................95 
9.6 
Sample Size Calculation and Power Considerations ................................................96 
9.7 
Study Population ......................................................................................................98 
9.8 
Efficacy Analyses .....................................................................................................99 
9.8.1 Primary Efficacy Endpoint ....................................................................................99 
9.8.2 Secondary Efficacy Endpoints .............................................................................102 
9.8.2.1 
Key Secondary Efficacy Endpoints ......................................................102 
9.8.2.2 
Other Secondary Efficacy Endpoints ...................................................103 
9.9 
Safety Analyses ......................................................................................................104 
9.10 
Other Analyses .......................................................................................................105 
9.10.1 
 ................................................................................105 
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .........................................106 
10.1 
Sponsor’s Responsibilities .....................................................................................106 
10.1.1 Good Clinical Practice Compliance .....................................................................106 
10.1.2 Indemnity/Liability and Insurance .......................................................................106 
10.1.3 Public Posting of Study Information ....................................................................107 
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees .........................................107 
10.1.5 Study Suspension, Termination, and Completion................................................107 
10.2 
Investigator’s Responsibilities ...............................................................................107 
10.2.1 Good Clinical Practice Compliance .....................................................................107 
10.2.2 Protocol Adherence and Investigator Agreement ................................................108 
10.2.3 Documentation and Retention of Records ...........................................................109 


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10.2.3.1 
Case Report Forms ...............................................................................109 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study 
Documents ............................................................................................109 
10.2.3.3 
Audit/Inspection ...................................................................................110 
10.2.3.4 
Financial Disclosure .............................................................................110 
10.3 
Ethical Considerations ............................................................................................110 
10.3.1 Informed Consent.................................................................................................110 
10.3.2 Institutional Review Board or Ethics Committee ................................................111 
10.4 
Privacy and Confidentiality ....................................................................................112 
10.5 
Study Results/Publication Policy ...........................................................................113 
11. REFERENCES .....................................................................................................................115 


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LIST OF TABLES 
Table 1 
Schedule of Assessments ...............................................................................26 
Table 2 
Criteria for Symptomatic Worsening of Treatment Failure (Must be 
Met at Each of 2 Sequential Visits) E-diary Entries ......................................50 
Table 3 
Glucocorticoid Tapering ................................................................................54 
Table 4 
Quarterly Neurological Assessments ............................................................73 
Table 5 
Volume of Blood to Be Drawn from Each Subject .......................................80 
Table 6 
Clinical Criteria for Diagnosing Anaphylaxis (Type I Hypersensitivity) .....84 
Table 7 
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin .........................................................................................................92 
Table 8 
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints .....................................................................................98 
 
LIST OF FIGURES 
Figure 1 
Overview of Ontamalimab Phase 3 Ulcerative Colitis Studies .....................38 
Figure 2 
Study Design Flow Chart ..............................................................................39 
Figure 3 
Flow Diagram for Quarterly Neurological Assessments ...............................74 
Figure 4 
Potential Immunogenicity of Therapeutic Monoclonal Antibodies ..............83 
Figure 5 
Visualization of Alpha Propagation ............................................................101 
 
LIST OF APPENDICES 
Appendix 1 
Protocol History ...........................................................................................117 
Appendix 2 
Scales and Assessments ...............................................................................126 
Appendix 3 
Glucocorticoid Equivalent Doses ................................................................131 
Appendix 4 
Guidance for Diagnosis and Treatment of Increased Gastrointestinal 
Symptoms ....................................................................................................132 


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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 
AUC 
area under the concentration-time curve 
AZA 
azathioprine 
β-hCG 
beta-human chorionic gonadotropin 
CD 
Crohn’s disease 
CI 
confidence interval 
CMH 
Cochran-Mantel Haenszel 
CNS 
central nervous system 
CRA 
clinical research associate 
CRO 
contract research organization 
CRP 
C-reactive protein 
DMC 
data monitoring committee 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
e-diary 
electronic diary 
EMA 
European Medicines Agency 
ET 
early termination 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FWER 
family-wise Type-I error rate 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
hsCRP 
high-sensitivity C-reactive protein 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 


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ICH 
International Council for Harmonisation 
IgG2κ 
immunoglobulin G2 kappa 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IV 
intravenous(ly) 
LTS 
long-term safety extension 
MAdCAM 
mucosal addressin cell adhesion molecule 
MTX 
methotrexate 
NAb 
neutralizing antibody 
 
PFS 
prefilled syringe 
PGA 
physician global assessment 
 
PML 
progressive multifocal leukoencephalopathy 
PRO 
patient-reported outcome 
Q4W 
once every 4 weeks 
RB 
rectal bleeding 
RSI 
reference safety information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SF 
stool frequency 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
UC 
ulcerative colitis 


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STUDY SYNOPSIS 
Protocol number: SHP647-303 
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 Ulcerative Colitis 
(FIGARO UC 303) 
Number of subjects (total and for each treatment arm): 
Approximately 696 subjects were planned for enrollment into the study: approximately 592 subjects from active 
induction treatments and approximately 104 subjects from placebo induction groups. A total of 366 subjects have 
been enrolled. 
Investigator(s): Multicenter study. 
Site(s) and Region(s): 
This study will be conducted in approximately 164 sites in approximately 31 countries. 
Study period (planned): 
2018 to 2021 
Clinical phase: 
3 
Objectives: 
Primary: To evaluate the efficacy of ontamalimab as maintenance treatment of remission, based on composite score 
of patient-reported symptoms and centrally read endoscopy, in subjects with moderate to severe ulcerative colitis 
(UC). 
Key Secondary: 
• 
To evaluate the efficacy of ontamalimab on endoscopic remission, based on centrally read endoscopy 
• 
To evaluate the efficacy of ontamalimab on clinical remission, based on composite score of patient-reported 
symptoms 
• 
To evaluate the efficacy of ontamalimab on maintenance of remission among subjects in remission at baseline 
of the SHP647-303 study, based on composite score of patient-reported symptoms and centrally read 
endoscopy 
• 
To evaluate the efficacy of ontamalimab on clinical response, based on composite score of patient-reported 
symptoms and centrally read endoscopy 
• 
To evaluate the efficacy of ontamalimab on mucosal healing, based on a centrally read endoscopic and 
histological assessment using the Geboes Score grading system 
• 
To evaluate the efficacy of ontamalimab on glucocorticoid-free clinical remission 
• 
To evaluate the efficacy of ontamalimab on glucocorticoid-free remission. 
Other Secondary: 
• 
To evaluate the effect of ontamalimab maintenance treatment on other clinical and endoscopic outcomes 
(Mayo-based remission, clinical remission over time, and sustained endoscopic remission) 
Rationale: This study is designed to evaluate the efficacy and safety of ontamalimab as maintenance therapy in 
subjects with moderate to severe UC who achieved clinical response in induction study SHP647-301 or 
SHP647-302. 


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Investigational product, dose, and mode of administration: 
The test product is ontamalimab, which will be provided as a sterile aqueous buffered solution for 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 UC who completed their participation in an induction study (either SHP647-301 or SHP647-302) and 
achieved a clinical response. 
Clinical response is defined as: 
1) A decrease from the induction study (SHP647-301 or SHP647-302) baseline in the composite score of 
patient-reported symptoms using daily electronic diary (e-diary) and centrally read endoscopy of at least 
2 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding (RB) ≥1 point 
or a subscore for RB ≤1 
OR 
2) A decrease from the induction study (SHP647-301 or SHP647-302) baseline in total Mayo score of at least 
3 points and at least 30%, with an accompanying decrease in the RB subscore of at least 1 point or an 
absolute RB subscore of 0 or 1. 
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 12 visit of the 
induction studies (SHP647-301 or SHP647-302), which will be considered as the baseline visit for this maintenance 
study. 
Eligible subjects who received active treatment in 1 of the induction studies and achieved a clinical response will be 
randomly assigned as follows: subjects who received 25 mg ontamalimab in 1 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 
1 of the induction studies will be randomized (1:1) to receive either 75 mg ontamalimab or placebo. 
Eligible subjects who received placebo in 1 of the induction studies and achieved a clinical response will be 
randomly assigned 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 SHP647-303 baseline, the subject’s status of prior 
anti-tumor necrosis factor (TNF) treatment (naïve or experienced), and the degree of clinical response in the 
induction study (whether remission is achieved or not). 
Subjects enrolled in this study (SHP647-303) will receive double-blind maintenance treatment in the form of 
SC injections, using a PFS, once every 4 weeks (Q4W) for 52 weeks. Subjects will undergo efficacy, 
 
 and safety assessments. 
Patient-reported UC signs and symptom data (including SF, RB severity and frequency, diarrhea frequency, urgency 
frequency, and abdominal pain worst severity) will be collected using an e-diary daily. The Mayo score is a measure 
of UC disease activity consisting of the following 4 subscores: SF, RB, findings of endoscopy, and physician global 
assessment (PGA). The partial Mayo score consists of the Mayo score without the endoscopic subscores. The 
composite score is a recommended measure consisting of the Mayo score without the PGA subscore, and will be 
used for the primary efficacy endpoint. The Mayo scores and composite score will be based on subject daily e-diary 
entries. 


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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. 
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 to participate in the study. 
3. Subjects must have completed the 12-week induction treatment period from study SHP647-301 or SHP647-302. 
4. Subjects must have achieved clinical response in induction study SHP647-301 or SHP647-302. Clinical 
response is defined as: 
1) A decrease from the induction study (SHP647-301 or SHP647-302) baseline in the composite score of 
patient-reported symptoms using daily e-diary and centrally read endoscopy of at least 2 points and at least 
30%, with an accompanying decrease in the subscore for RB ≥1 point or a subscore for RB ≤1 
OR 
2) A decrease from the induction study (SHP647-301 or SHP647-302) baseline in total Mayo score of at least 
3 points and at least 30%, with an accompanying decrease in the RB subscore of at least 1 point or an 
absolute RB subscore of 0 or 1. 
For eligibility assessment, clinical response will be determined based on the centrally read endoscopy 
performed during screening and at Week 12 of induction study SHP647-301 or SHP647-302. 
5. Subjects receiving any treatment(s) for UC described in Section 5.2.1 are eligible provided they have been, and 
are anticipated to be, on a stable dose for the designated period of time. 
Exclusion Criteria: 
Subjects are excluded from the study if any of the following criteria are met: 
1. Subjects who had major protocol deviation(s) (as determined by the sponsor) in induction study SHP647-301 or 
SHP647-302. 
2. Subjects who permanently discontinued investigational product because of an adverse event (AE), regardless of 
relatedness to investigational product, in induction study SHP647-301 or SHP647-302. 
3. Subjects who are likely to require surgery for UC during the study period. 
4. Subjects are females who became pregnant during induction study SHP647-301 or SHP647-302, females who 
are planning to become pregnant during the study period, or males or females of childbearing potential not 
agreeing to continue appropriate contraception methods (ie, highly effective methods for female and medically 
appropriate methods for male study subjects) 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.  


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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 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). 
8. 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. 
9. 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. 
10. Subjects with known exposure to Mycobacterium tuberculosis (TB) since testing at screening in induction study 
SHP647-301 or SHP647-302 and who are without a generally accepted course of treatment. 
11. 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. 
12. Subjects who are participating in or plan to participate in other investigational studies (other than induction 
study SHP647-301 or SHP647-302) during Study SHP647-303. 
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: 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 
SHP647-303 study, regardless of treatment received during the induction studies (SHP647-301 and SHP647-302). 
The ontamalimab responder full analysis set (FAS) will consist of all subjects in the randomized set who have 
received at least 1 dose of investigational product in the SHP647-303 study and who were previously treated with 
ontamalimab in the induction studies. 
The placebo responder FAS will consist of all subjects in the randomized set who have received at least 1 dose of 
investigational product in the SHP647-303 study and who were previously treated with placebo in the induction 
studies. 
 
 
Primary Efficacy Endpoint: 
Unless otherwise specified, all efficacy analyses will be based on the ontamalimab responder FAS and subjects will 
be analyzed according to their randomized treatment, regardless of the treatment they actually received. 
The primary efficacy endpoint is remission at the Week 52 visit. Remission is defined as a composite score of 
patient-reported symptoms using daily e-diary and centrally read endoscopy as follows: 
• 
stool frequency subscore of 0 or 1 with at least a 1-point change from induction (SHP647-301 or 
SHP647-302) baseline 
AND 


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• 
rectal bleeding subscore of 0 
AND 
• 
endoscopic subscore of 0 or 1 (modified, excludes friability). 
The primary efficacy endpoint will be compared for each active treatment group (25 mg or 75 mg ontamalimab) to 
the corresponding placebo group (25 mg in induction placebo group or 75 mg in induction placebo group; placebo 
groups are not pooled) using a Cochran-Mantel Haenszel (CMH) chi-square test stratified by status of glucocorticoid 
use at SHP647-303 baseline, prior anti-TNF treatment, and the degree of clinical response in the induction studies 
(whether remission is achieved or not). Subjects with missing remission data at Week 52 will be considered failures 
and counted as nonresponders. The endoscopy score will be based on centrally read results. 
The primary efficacy endpoint will be tested by the following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
Where δ is the common treatment difference across strata, j=1 to m. The common treatment difference is a weighted 
average of the stratum-specific treatment differences. 
The estimate of the common treatment difference along with the corresponding stratified Newcombe 95% 
confidence interval (CI) using the method of Yan and Su (2010) and CMH p-value will be presented for each active 
treatment group to placebo comparison. 
Adjustments for multiplicity 
The global family-wise Type-I error rate (FWER) for the statistical tests of the primary and key secondary endpoints 
will be strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in Bretz et al. (2009) 
will be utilized to propagate α from primary to key secondary endpoints and between the 2 ontamalimab treatment 
group and placebo comparisons. Alpha is initially split equally at the .025 level (2-sided) for each of the pairwise 
treatment comparisons for the primary endpoint (P) and alpha is propagated in a hierarchical manner to each of the 
7 key secondary endpoints (K1-K7) within a pairwise treatment comparison. 
Key Secondary Efficacy Endpoints: 
• 
Endoscopic remission, as defined by centrally read endoscopic subscore 0 or 1 (modified, excludes 
friability), at the Week 52 visit. 
• 
Clinical remission as defined by SF subscore of 0 or 1 with at least a 1-point change from induction study 
(SHP647-301 or SHP647-302) baseline in SF subscore, and RB subscore of 0, at the Week 52 visit. 
• 
Sustained remission, ie, in remission at the SHP647-303 Week 52 visit, among subjects who were in 
remission at the time of baseline in study SHP647-303. Remission is defined as a composite score of 
patient-reported symptoms using daily e-diary and centrally read endoscopy, with SF subscore of 0 or 1 
with at least a 1-point change from induction study (SHP647-301 or SHP647-302) baseline, and RB 
subscore of 0, and endoscopic subscore of 0 or 1 (modified, excludes friability). 
• 
Clinical response based on composite score at the Week 52 visit. Clinical response (composite) is defined 
as a decrease from induction study (SHP647-301 or SHP647-302) baseline in the composite score of 
subject-reported symptoms using daily e-diary and centrally read endoscopy of at least 2 points and at least 
30%, with an accompanying decrease in the subscore for RB ≥1 point or a subscore for RB ≤1. 
• 
Mucosal healing, based on endoscopic and histologic assessment, at the Week 52 visit. Mucosal healing is 
defined by centrally read endoscopic subscore 0 or 1 (modified, excludes friability) and centrally read 
Geboes score of ≤2. 
• 
Glucocorticoid-free clinical remission at Week 52, among subjects using glucocorticoids at induction study 
baseline. Glucocorticoid-free clinical remission is defined as clinical remission in addition to not requiring 
any treatment with glucocorticoids for at least 4 weeks prior to the Week 52 visit. Clinical remission is 
defined as SF subscore of 0 or 1 with at least a 1-point change from induction study (SHP647-301 or 


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SHP647-302) baseline in SF subscore, and RB subscore of 0, at the Week 52 visit. 
• 
Glucocorticoid-free remission at Week 52, among subjects using glucocorticoids at induction study 
baseline. Glucocorticoid-free remission is defined as remission in addition to not requiring any treatment 
with glucocorticoids for at least 4 weeks prior to the Week 52 visit. Remission is defined as a composite 
score of subject-reported symptoms using daily e-diary and endoscopy, with SF subscore of 0 or 1 with at 
least a 1-point change from induction study (SHP647-301 or SHP647-302) baseline, and RB subscore of 0, 
and endoscopic subscore of 0 or 1 (modified, excludes friability). 
Similar to the primary endpoints, the key secondary efficacy endpoints will all be tested by the following 
hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
The key secondary endpoints will be analyzed using the same approach as described for the primary endpoint. 
Subjects with missing key secondary endpoint data at the Week 52 visit will be considered failures and counted as 
nonresponders. 
Other Secondary Efficacy Endpoints: 
• 
Remission defined as a total Mayo score of ≤2 with no individual subscore (SF, RB, endoscopy [modified, 
excludes friability], and PGA) exceeding 1, at Week 52. 
• 
Clinical remission over time with both RB and SF subscores of 0. 
• 
Sustained endoscopic remission ie, in endoscopic remission at the SHP647-303 Week 52 visit among 
subjects who were in remission at the time of baseline in Study SHP647-303, as defined by a centrally read 
endoscopic subscore of 0 or 1 (modified, excludes friability). 
Other secondary efficacy endpoints will be summarized by descriptive statistics and presented by treatment group 
for the ontamalimab responder FAS. The other secondary endpoints will be analyzed using the same approach as 
described for the primary endpoint. Subjects with missing other secondary endpoint data at a visit will be considered 
failures and counted as nonresponders at that visit. The other secondary endpoints will be summarized separately for 
the placebo responder FAS by treatment group without inferential methods, as described for the primary endpoint. 
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 SHP647-303 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. 
 


Shire 
CONFIDENTIAL 
Page 26 
Ontamalimab 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
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 
(Pt 1)d 
14 
(Pt 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 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Targeted neurological assessmenth,i 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Vital signsj 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
12-lead ECGj 
IDT 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
Contraception checkk 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Laboratory Assessmentsl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Serum chemistrym 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Urinalysis 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Stool microbiologyn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSHo 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine β–hCGp 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
IDT 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
IDT 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
ADA and NAb samplingq 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Endoscopic Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endoscopy (including biopsy)r 
IDT 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
 
 
UC Assessmentss 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Mayo score 
IDT 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xt 
 
Partial Mayo score 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
PRO-UC e-diary data instruction 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Shire 
CONFIDENTIAL 
Page 27 
Ontamalimab 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
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 
(Pt 1)d 
14 
(Pt 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 
PRO-UC daily e-diary datau 
IDT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Treatment Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationv 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of ontamalimab or 
placebov,w,x 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hypersensitivity monitoringy 
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 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense stool collection kit for stool 
samplez 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
ADA=antidrug antibody; β-hCG=beta-human chorionic gonadotropin; CLIA=Clinical Laboratory Improvement Amendments; 
; DTP=Direct-to-Patient; 
ECG=electrocardiogram; e-diary=electronic diary; ET=early termination; FSH=follicle-stimulating hormone; HEENT=head, eyes, ears, nose, and throat; IDT=induction study 
(SHP647-301 or SHP647-302); LFT=liver function testing; LTS=long-term safety extension; NAb=neutralizing antibody; PRO=patient-reported outcome; Pt=part; UC=ulcerative 
colitis 
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 the implementation of SHP647-304 Amendment 4. 
a 
The Week 12 assessment from the induction study (SHP647-301 or SHP647-302) will be used as the baseline (Day 1/Week 0) assessments for Study SHP647-303. 
b 
No follow-up is required if subject is entering the LTS study (SHP647-304) at the Week 52/ET visit (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 must be completed within 10 days (preferably, within 5 to 7 days) before Part 2; this will allow sufficient time for data from the centrally read endoscopy to 
be available at Part 2 of the visit. For subjects who meet the criteria for treatment failure (as defined in Section 4.5.1.1) 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 SHP647-301 or SHP647-302 Week 12, Visit 6 (Part 2) procedures are completed. 
f 
Medical history for induction study SHP647-301 or SHP647-302 will be used as the baseline medical history data for Study SHP647-303. 


Shire 
CONFIDENTIAL 
Page 28 
Ontamalimab 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
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 
(Pt 1)d 
14 
(Pt 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, HEENT, heart, lungs, confrontational visual fields (eyes), breast 
(optional), abdomen, external genitalia (optional), extremities, neurologic function, back, and lymph nodes. A targeted physical examination only includes the review of the 
following body systems: skin, heart, lungs, confrontational visual fields (eyes), abdomen, and examination of body systems where there are symptom complaints by the 
subject. 
h 
Subject will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, speech, 
verbal comprehension, and cognition/behavior. See Section 7.3.3.3 for further details. 
i 
In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application). 
j 
Vital signs (including blood pressure, pulse, respiratory rate, and temperature) and 12-lead ECG should be performed prior to the collection of blood samples for laboratory 
assessments. 
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 
When a subject experiences an increase in gastrointestinal symptoms, which could be an exacerbation of disease, an infectious etiology must be evaluated including testing for 
Clostridium difficile as described in Appendix 4. 
o 
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 SHP647-301 or SHP647-302. If a female subject’s status has changed to postmenopausal since 
the induction studies (SHP647-301 or SHP647-302), the FSH confirmation test will be done at baseline (Visit 1) of SHP647-303. 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. 
p 
For females of childbearing potential that are not surgically sterile, do not have confirmed ovarian failure, or do not meet the definition of postmenopausal as described in 
Section 4.4.1 and Section 7.3.3.7. 
q 
Samples must be collected before administration of investigational product at that visit. 
r 
Flexible sigmoidoscopy or colonoscopy (if preferred). Biopsy samples will be collected for histological evaluation using the Geboes Score classification and 
 
 Note: For subjects discontinued from the study under Amendment 3 and prior to the completion of 52 weeks of treatment, endoscopy is not required 
(optional) at the ET visit. 


Shire 
CONFIDENTIAL 
Page 29 
Ontamalimab 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
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 
(Pt 1)d 
14 
(Pt 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 
s 
Mayo and PRO-UC assessments will be based on the subject’s daily e-diary entries. 
t 
The total Mayo score at Week 52/ET (Visit 14, Part 2) will be calculated based on the centrally read endoscopic subscore for the endoscopy performed at Week 52 (Visit 14, 
Part 1). 
u 
PRO-UC daily e-diary will be available throughout the study. Subjects will be required to enter e-diary data daily. See Section 7.3.2.3 for further details. Compliance is 
assessed by site staff at each visit. The site staff will instruct the subject on the appropriate use of the e-diary, particularly when compliance is below 80% (eg, <8 out of 
10 diary entries) when compared with the previous visit. 
v 
All patient-reported questionnaires should be completed before completing any other visit assessments. 
w 
Interactive response technology will be used for randomization and dispensation of study treatment. 
x 
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). 
y 
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. 
z 
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the visit at which testing will be done. 
Note: See Section 7.3 for the order in which assessments should be performed. Timing of visits is relative to SHP647-303 baseline (Visit 1). 
 


Shire 
CONFIDENTIAL 
Page 30 
Ontamalimab 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
1. 
BACKGROUND INFORMATION 
1.1 
Indication and Current Treatment Options 
Ulcerative colitis (UC) is a chronic, relapsing disease marked by ulceration and inflammation of 
the colonic mucosa and submucosa. Initially it usually involves the rectum but may extend 
proximally to involve a portion of, or the entirety of, the colon. In the early stages, hemorrhagic 
and erythematous tissue is observed, progressing to mucosal ulceration with purulent exudates in 
severe cases. The ulceration pattern is continuous and may extend the entire length of the colon. 
Perforation of the bowel wall causing ileus and peritonitis can occur with transmural extension of 
the ulceration. Bloody diarrhea with or without mucus and lower abdominal pain with periods of 
remission and exacerbation are the most common symptoms. 
The incidence of UC is estimated to be up to 24.3 cases per 100,000 persons per year in Europe 
and up to 19.2 cases per 100,000 persons per year in North America. No clear difference in 
incidence has been observed between men and women. Although UC can occur at any age, peak 
incidence has been observed in the second to fourth decades of life (Molodecky et al., 2012). 
Ulcerative colitis is a lifelong condition with a serious effect on the quality of life. 
Current treatment primarily consists of symptomatic management with dietary modifications and 
opiate antidiarrheal drugs (loperamide), as well as disease modifying agents such as 
5-aminosalicylic acid (5-ASA), systemic glucocorticoids, immunosuppressive agents 
(azathioprine [AZA]/6-mercaptopurine [6-MP], cyclosporine), and biologic therapy with 
anti-tumor necrosis factor (TNF) or anti-integrin agents. Despite recent advances, there is still an 
unmet need for an effective pharmacological treatment that will induce and maintain remission. 
1.2 
Product Background and Clinical Information 
The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal sites of the 
gastrointestinal (GI) tract is influenced by the endothelial expression of mucosal addressin cell 
adhesion molecule (MAdCAM). MAdCAM is a member of the immunoglobulin super family of 
cell adhesion molecules and is mostly expressed on the cell surface of high endothelial venules 
of organized intestinal lymphoid tissue such as Peyer’s patches and mesenteric lymph nodes 
(Shyjan et al., 1996; Briskin et al., 1997; Liaskou et al., 2011). MAdCAM plays a role in gut 
immune surveillance, and also appears to facilitate excessive lymphocyte infiltration under 
conditions of chronic GI inflammation. The α4β7 integrin is the recognized ligand for MAdCAM, 
and expression of this ligand on populations of CD4+ and CD8+ T cells, as well as on subsets of 
B cells, distinguishes them as unique gut homing lymphocytes. 


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Page 31 
Ontamalimab 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
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 UC and 
Crohn’s disease (CD). In UC study A7281009, induction with ontamalimab at doses of 7.5 mg, 
22.5 mg, or 75 mg once every 4 weeks (Q4W) resulted in statistically significantly higher 
proportions of subjects in remission at Week 12 based on total Mayo score (both locally and 
centrally read) when compared with placebo treatment. In CD study A7281006, induction with 
ontamalimab did not meet the primary endpoint; no statistically significant differences were 
observed between the active treatment arms and the placebo arm in CD Activity Index-70 
response rate at Week 8 or Week 12. Post hoc analyses suggested evidence of drug effect in 
subjects with more inflammation at baseline, as indicated by higher serum concentrations of 
C-reactive protein (CRP) or Simple Endoscopic Score for CD. 
In UC induction study A7281009, decreases in fecal calprotectin were observed in all groups, 
including placebo; however, there were no statistically significant differences in the decrease in 
fecal calprotectin between any dose level of ontamalimab and placebo. Decreases in 
high-sensitivity CRP (hsCRP) were also observed in all 4 treatment groups; however, other than 
the 75 mg dose group at Week 12, no statistically significant differences were observed in active 
treatment versus placebo. In the induction study A7281006 in subjects with CD, compared to 
placebo, nominally statistically significant decreases in fecal calprotectin were observed in the 
75 mg group at Week 8 and in the 22.5 mg and 75 mg groups at Week 12. Generally, decreases 
from baseline in hsCRP were observed in all 4 treatment groups over the 12-week induction 
period. Compared to placebo, nominally statistically significant decreases in hsCRP were 
observed in all 3 active treatment groups (22.5 mg, 75 mg, and 225 mg) at Week 12. There was 
no evidence of a dose response for either of these parameters. A nominally statistically 
significant increase was observed in circulating β7+ central memory T lymphocytes at Weeks 8 
and 12, consistent with the predicted mechanism of action. 


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Page 32 
Ontamalimab 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
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. 


Shire 
CONFIDENTIAL 
Page 33 
Ontamalimab 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
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 UC. Ontamalimab prevents the binding of α4β7+ lymphocytes to 
MAdCAM-expressing sites with high affinity and selectivity. Principal sites of MAdCAM 
expression on normal tissue include intestine, pancreas, stomach, esophagus, spleen, and to a 
lesser extent lung, liver, and bladder but not the CNS (Steffen et al., 1996). 
Although selective targeting of the MAdCAM receptors is a novel approach, the basic 
interference of lymphocyte homing by preventing the binding of these α4β7+ lymphocytes to the 
MAdCAM receptor and the resultant efficacy in UC is well established (Feagan et al., 2013). 
Ontamalimab is differentiated from other molecules used for the treatment of UC in that it blocks 
the interaction of α4β7+ lymphocytes to the MAdCAM receptor by selectively binding to 
MAdCAM in the gut (and related tissues) whereas other molecules only target the integrins on 
the infiltrating lymphocytes. Additionally, ontamalimab does not bind to the vascular cell 
adhesion molecule; therefore, ontamalimab is not expected to be an effective treatment for 
multiple sclerosis, or affect lymphocyte homing or surveillance in the CNS. 
This study is designed to evaluate the efficacy of ontamalimab as maintenance therapy in 
subjects with moderate to severe UC who achieved clinical response in induction study 
SHP647-301 or SHP647-302. 
Ontamalimab has been investigated in subjects with moderate to severe UC in 3 completed 
studies: 2 dose-finding studies (A7281001 and A7281009) and an open-label long-term safety 
extension (LTS) study (A7281010), which was ongoing at the time of the original protocol and 
has since completed. Phase 1 study A7281001 evaluated both single (0.03–10.0 mg/kg 
intravenous [IV]; 3.0 mg/kg subcutaneous [SC]) and multiple doses (0.1–3.0 mg/kg IV; 
0.3 and 1.0 mg/kg SC) of ontamalimab in subjects with UC. Safety evaluation revealed a safety 
profile for ontamalimab similar to that of placebo, with no pattern of adverse events (AEs) 
suggestive of increased risk of opportunistic infections or CNS effects, and no evidence of 
adverse effects on laboratory parameters, electrocardiograms (ECGs), vital signs, or neurological 
function. Events leading to withdrawal were due to exacerbations of the underlying UC. 


Shire 
CONFIDENTIAL 
Page 34 
Ontamalimab 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
Study A7281009 was a Phase 2b proof-of-concept (randomized, double-blind, 
placebo-controlled, parallel, dose-ranging) study designed to evaluate the efficacy, safety, and 
PK of ontamalimab in subjects with moderate to severe UC. Treatment was assigned in 
a 1:1:1:1:1 ratio to dose levels of 7.5, 22.5, 75, or 225 mg ontamalimab or placebo administered 
SC Q4W at Weeks 0, 4, and 8. The primary endpoint of the study was the proportion of subjects 
in clinical remission at Week 12, with remission defined as a total Mayo score of ≤2 with no 
individual subscore >1 (see Appendix 2 for details of the Mayo score). More subjects were in 
clinical remission at Week 12 in ontamalimab-treated groups than in the placebo group, with 
statistical significance achieved for the 7.5, 22.5, and 75 mg doses (Vermeire et al., 2017). Based 
upon the total Mayo score with a centrally read endoscopic severity component, the increase in 
clinical remission rates over placebo at Week 12 for the 7.5, 22.5, and 75 mg doses were 
8.0% (p=.043), 12.8% (p=.010), and 11.8% (p=.012), respectively. When the clinical remission 
rate at Week 12 was analyzed by stratum of previous anti-TNF exposure (experienced or naïve), 
a similar trend was observed across dose levels in both the anti-TNF experienced and anti-TNF 
naïve subjects. There was no evidence of an adverse safety signal, and there was no increase in 
the frequency of infections in MAdCAM-bearing tissues as evidenced by similar rates of 
nasopharyngitis among treatment arms. 
Based on the efficacy and safety data in Study A7281009 and the systemic population PK and 
pharmacodynamic (PD) modeling and simulation, clinical remission, clinical response and 
mucosal healing rates were higher in subjects with UC receiving doses of 22.5 and 75 mg Q4W 
than in those receiving doses of 7.5 mg and 225 mg Q4W. The induction responses were not 
demonstrated either at Week 4 or Week 8 but were observed at Week 12 regardless of dose level. 
No difference in the clinical responses between a 22.5 mg dose and a 25 mg dose is expected 
based on the current understanding of the mode of action of ontamalimab and clinical 
observations to date. To better understand the exposure (dose)-response relationship in this 
population and understand individual patient exposure needs, the 25 mg and 75 mg doses (Q4W) 
will be tested in the Phase 3 program. Therefore, SC doses of 25 mg or 75 mg of ontamalimab or 
placebo on Day 1 (Week 0), Week 4, and Week 8 are recommended for the Phase 3 induction 
studies SHP647-301 and SHP647-302. The Phase 1 study A7281001, which investigated the 
safety, tolerance, PK, and PD properties of ontamalimab, supports further clinical development 
of ontamalimab using SC administration. 


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CONFIDENTIAL 
Page 35 
Ontamalimab 
SHP647-303 Protocol Amendment 3 
 
17 Sep 2020 
 
2.2 
Study Objectives 
2.2.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of ontamalimab as maintenance 
treatment of remission, based on composite score of patient-reported symptoms and centrally 
read endoscopy, in subjects with moderate to severe UC. 
2.2.2 
Secondary Objectives 
2.2.2.1 
Key Secondary Objectives 
The key secondary objectives of the study are as follows: 
• To evaluate the efficacy of ontamalimab on endoscopic remission, based on centrally 
read endoscopy 
• To evaluate the efficacy of ontamalimab on clinical remission, based on composite 
score of patient-reported symptoms 
• To evaluate the efficacy of ontamalimab on maintenance of remission among subjects 
in remission at baseline of the SHP647-303 study, based on composite score of 
patient-reported symptoms and centrally read endoscopy 
• To evaluate the efficacy of ontamalimab on clinical response, based on composite 
score of patient-reported symptoms and centrally read endoscopy 
• To evaluate the efficacy of ontamalimab on mucosal healing, based on a centrally 
read endoscopic and histological assessment using the Geboes Score grading system 
• To evaluate the efficacy of ontamalimab on glucocorticoid-free clinical remission 
• To evaluate the efficacy of ontamalimab on glucocorticoid-free remission. 
2.2.2.2 
Other Secondary Objectives 
The other secondary objectives are as follows: 
• To evaluate the effect of ontamalimab maintenance treatment on other clinical and 
endoscopic outcomes (Mayo-based remission, clinical remission over time, and 
sustained endoscopic remission) 


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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 UC who completed their participation in an induction study (either 
SHP647-301 or SHP647-302) and achieved a clinical response. 
Clinical response is defined as: 
1. A decrease from induction study (SHP647-301 or SHP647-302) baseline in the composite 
score of patient-reported symptoms using daily electronic diary (e-diary) and centrally read 
endoscopy of at least 2 points and at least 30%, with an accompanying decrease in the 
subscore for rectal bleeding (RB) ≥1 point or a subscore for RB ≤1 
OR 
2. A decrease from induction study (SHP647-301 or SHP647-302) baseline in total Mayo score 
of at least 3 points and at least 30%, with an accompanying decrease in the RB subscore of at 
least 1 point or an absolute RB subscore of 0 or 1. 
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 LTS study (SHP647-304). 
Approximately 696 subjects were planned to be enrolled into the study (Figure 1): approximately 
592 subjects from active induction treatments and approximately 104 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 12 visit of the induction studies, which will be considered as the 
baseline visit for this maintenance study. 
Eligible subjects who received active treatment in 1 of the induction studies and achieved a 
clinical response will be randomly assigned as follows: subjects who received 25 mg 
ontamalimab in 1 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 1 of the induction 
studies will be randomized (1:1) to receive either 75 mg ontamalimab or placebo. 
Eligible subjects who received placebo in 1 of the induction studies and achieved a clinical 
response will be randomly assigned 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 SHP647-303 baseline, the subject’s 
status of prior anti-TNF treatment (naïve or experienced), and the degree of clinical response in 
the induction study (whether remission is achieved or not). 
Subjects enrolled in this study (SHP647-303) 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. 
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. 
The overall study design is shown in Figure 2. 


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Figure 1 
Overview of Ontamalimab Phase 3 Ulcerative Colitis Studies 
 
e-diary=electronic diary; RB=rectal bleeding 
a 
Clinical response in the induction studies (SHP647-301 and SHP467-302) is defined as: 
1. A decrease from the induction study (SHP647-301 or SHP647-302) baseline in the composite score of 
patient-reported symptoms using daily e-diary and centrally read endoscopy of at least 2 points and at least 
30%, with an accompanying decrease in the subscore for RB ≥1 point or a subscore for RB ≤1 
OR 
2. A decrease from the induction study (SHP647-301 or SHP647-302) baseline in total Mayo score of at least 
3 points and at least 30%, with an accompanying decrease in the RB subscore of ≥1 point or an absolute RB 
subscore of ≤1. 


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Figure 2 
Study Design Flow Chart 
 
LTS=long-term safety extension; Q4W=once every 4 weeks. 
a 
Eligible subjects who received placebo in 1 of the induction studies and achieved a clinical response will be randomly assigned 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. 
Treatment assignment 
in induction study 
SHP647-301 or 
SHP647-302: 
Treatment period: 52 weeks 
25 mg 
ontamalimab 
75 mg 
ontamalimab 
Dosing: Q4W 
Placebo 
25 mg 
ontamalimab 
Placebo 
75 mg 
ontamalimab 
Placebo 
25 mg 
ontamalimab 
75 mg 
ontamalimab 
Placebo 
1:1 
1:1 
2:2:1a 
Treatment period: 12 weeks 
Dosing: Q4W 
12-week safety 
follow-up periodb 
Week 52/End of 
Treatment 
Randomization 
into SHP647-303 
LTS Study 
(SHP647-304)b 


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3.1.1 
Rationale for Primary Endpoint 
The Mayo score has historically been used as the primary endpoint for pivotal studies of agents 
intended to treat UC. Over the past decade, health authority thinking regarding efficacy 
endpoints for UC has evolved such that the traditional total Mayo score is no longer 
recommended. Current regulatory guidance (US Food and Drug Administration [FDA] 
Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry [Draft], 2016; European 
Medicines Agency [EMA] Guideline on the Development of New Medicinal Products for the 
Treatment of Ulcerative Colitis [Draft], 2016) includes a dual measurement of patient-reported 
signs and symptoms outcomes (SF and RB), and clinician-reported endoscopic outcomes 
(scoring any endoscopy with evidence of friability as a 2), including histology. Per agreement 
with health authorities, these 3 outcomes will be reported as a composite score. 
Data will be collected to calculate the total Mayo score using both the traditional and modified 
endoscopy subscore as a sensitivity analysis and to estimate the impact of the modification on 
the primary endpoint. 
3.1.2 
Rationale for Key Secondary Endpoints 
The first 2 key secondary endpoints are included to comply with EMA advice to support the 
composite primary endpoint with a key secondary analysis, where the patient-reported symptoms 
and clinician-reported endoscopy are analyzed as “co-primary.” 
The third endpoint, maintenance of remission, is used to demonstrate that the induction of 
remission is maintained over 52 weeks. This endpoint is used to support the maintenance of 
remission indication. 
The clinical response endpoint is based on the new composite score, and also represents 1 of the 
entry criteria for the maintenance study. This endpoint has not been previously tested. 
Mucosal healing as a key secondary endpoint comprises both endoscopic and histologic 
components as recommended in the draft FDA and EMA guidance on UC (FDA Ulcerative 
Colitis: Clinical Trial Endpoints Guidance for Industry [Draft], 2016; EMA Guideline on the 
Development of New Medicinal Products for the Treatment of Ulcerative Colitis [Draft], 2016). 
The Geboes Score (see Appendix 2) will be used to evaluate histologic remission and to 
complement the endoscopic subscore in the assessment of mucosal healing for the key secondary 
endpoint. 


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The key secondary endpoints of glucocorticoid-free clinical remission and glucocorticoid-free 
remission are the ultimate treatment goals for all patients with UC (EMA Guideline on the 
Development of New Medicinal Products for the Treatment of Ulcerative Colitis [Draft], 2016). 
3.1.3 
Rationale for Treatment Failure 
To avoid confounding this study with rescue treatment, changes or additions to background 
therapy for UC are not permitted (except for glucocorticoid tapering and dose reductions for 
subject safety). Ulcerative colitis is a disease with considerable variability in symptoms, and 
changes in treatment usually are not warranted for fluctuations of limited severity or duration. 
However, when the increase in symptoms is clinically significant and sustained, treatment failure 
may be declared (see Section 4.5.1.1). In this setting “treatment failure” is not meant to imply 
lack of drug efficacy, but rather to provide a timely escape mechanism for subjects whose 
disease is not adequately controlled by investigational product (which could be placebo) plus 
background therapy (eg, limited dose of systemic glucocorticoids). Subjects who meet the 
criteria for treatment failure will exit the study early and have an option to enter the LTS study 
SHP647-304 to receive active treatment with ontamalimab as well as rescue therapy, or to 
complete an early termination (ET) visit after which study-prohibited treatments may be used as 
clinically appropriate. 
Treatment failure assessment may begin no earlier than the Week 4 scheduled visit. 
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 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 is expected to be approximately 64 weeks. It was 
expected that the study would be completed in approximately 3.5 years; however, due to early 
closure by the sponsor, the study is expected to be completed by November 2021. 


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The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit or contact, 
whichever is later. The study completion date is used to ascertain timing for study results posting 
and reporting. 
3.3 
Sites and Regions 
This study will be conducted in approximately 164 sites in approximately 31 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 12-week induction treatment period from 
Study SHP647-301 or SHP647-302. 
4. Subjects must have achieved clinical response in induction study SHP647-301 or 
SHP647-302. Clinical response is defined as: 
o A decrease from the induction study (SHP647-301 or SHP647-302) baseline in the 
composite score of patient-reported symptoms using daily e-diary and centrally read 
endoscopy of at least 2 points and at least 30%, with an accompanying decrease in 
the subscore for RB ≥1 point or a subscore for RB ≤1 
OR 
o A decrease from the induction study (SHP647-301 or SHP647-302) baseline in total 
Mayo score of at least 3 points and at least 30%, with an accompanying decrease in 
the RB subscore of at least 1 point or an absolute RB subscore of 0 or 1. 
For eligibility assessment, clinical response will be determined based on the centrally read 
endoscopy performed during screening and at Week 12 of induction study SHP647-301 or 
SHP647-302. 
5. Subjects receiving any treatment(s) for UC described in Section 5.2.1 are eligible provided 
they have been, and are anticipated to be, on a stable dose for the designated period of time. 


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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 SHP647-301 or SHP647-302. 
2. Subjects who permanently discontinued investigational product because of an AE, regardless 
of relatedness to investigational product, in induction study SHP647-301 or SHP647-302. 
3. Subjects who are likely to require surgery for UC during the study period. 
4. Subjects are females who became pregnant during induction study SHP647-301 or 
SHP647-302, 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) through the conclusion of study participation 
(see Section 4.4). 
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 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). 
8. 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. 
9. Subjects with any other severe acute or chronic medical or psychiatric condition or 
laboratory or ECG abnormality that may increase the risk associated with study participation 
or investigational product administration or may interfere with the interpretation of study 
results and, in the judgment of the investigator, would make the subject inappropriate for 
entry into this study. 


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10. Subjects with known exposure to Mycobacterium tuberculosis (TB) since testing at screening 
in induction study SHP647-301 or SHP647-302 and who are without a generally accepted 
course of treatment. 
11. 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. 
12. Subjects who are participating in or plan to participate in other investigational studies (other 
than induction study SHP647-301 or SHP647-302) during Study SHP647-303. 
4.3 
Restrictions 
Smoking can have an influence on the severity of UC disease symptoms. Subjects should inform 
the investigator of any changes to their smoking habits during the study; however, these data will 
not be captured in the electronic case report form (eCRF). Use of nicotine patches should be 
recorded as concomitant medication (see Section 5.2). 
For the purposes of this protocol, dietary supplements (such as vitamins, minerals, purified food 
substances, and herbals with pharmaceutical properties) are considered to be concomitant 
medications (see Section 5.2). 
4.4 
Reproductive Potential 
The potential effects of ontamalimab on embryofetal or postnatal development have not been 
assessed in humans. Preliminary results from an enhanced pre-and postnatal development 
toxicity study of ontamalimab in nonhuman primates indicated that, at the dose levels tested 
(30 and 60 mg/kg), infant losses were increased in ontamalimab-exposed animals when 
compared both to control animals in the study and to the historical control animal data from the 
testing facility. The relevance of this finding to humans is unknown but cannot be excluded. 
Based on the exposure in the Phase 2 clinical study A7281009 (area under the concentration-time 
curve [AUC] from 0 to 672 hours [AUC0-672h] at 6140 µg∙h/mL following repeated 
SC administration of 75 mg SHP647 Q4W), maternal exposure (AUC) in cynomolgus monkeys 
within a similar duration at 30 and 60 mg/kg once every 10 days is approximately 77 times and 
172 times the clinical exposure, respectively. 
To minimize the risk of unintentional exposure of the embryo or fetus in the clinical study, all 
sexually active male and female subjects who, in the opinion of the investigator, are biologically 
capable of having children and with their partners are at risk of pregnancy, must agree to use an 
appropriate form of contraception (ie, highly effective methods for female and medically 


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appropriate methods for male study subjects), in accordance with the package 
instructions/leaflet, for the duration of the active treatment period and for at least 16 weeks after 
the last dose of investigational product. 
True abstinence is considered to be a highly effective contraception (ie, a method that results in a 
failure rate of <1% per year) when it is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
declaration of abstinence for the duration of exposure to investigational product, and withdrawal 
are not appropriate methods of contraception. 
During the induction studies (SHP647-301 and SHP647-302), the investigator or designee in 
consultation with the subject will confirm the subject’s childbearing potential status. For subjects 
of childbearing potential, it must be confirmed and documented that the subject has selected the 
most appropriate method of contraception (ie, highly effective methods for female and medically 
appropriate methods for male study subjects) from the permitted list of contraception methods. 
Subjects must affirm the consistent and correct use of at least 1 of these selected methods. 
Regular contraception check discussions will take place at the time points specified in Table 1 
(ie, at each site visit) and will be documented. In addition, the subject must be instructed to call 
the site immediately if the selected contraception method is discontinued or if pregnancy is 
known or suspected. 
4.4.1 
Contraceptive Methods for Female Study Subjects 
At baseline (Visit 1) 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 (SHP647-301 or 
SHP647-302) (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. 
Contraception methods with low user dependency should preferably be used, in particular when 
contraception is introduced as a result of participation in the clinical study. The following highly 
effective contraceptive methods are considered to be methods with low user dependency: 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 


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• Male sterilization/vasectomized partner 
• Implantable progesterone-only hormonal contraception associated with inhibition of 
ovulation. 
Female subjects should be in 1 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 12 of the induction study SHP647-301 or SHP647-302; Week 0 of 
Study SHP647-303). 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 12 of the induction study SHP647-301 or 
SHP647-302; Week 0 of Study SHP647-303) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation plus 
a barrier method 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Male sterilization/vasectomized partner with documented absence of sperm in the 
postvasectomy ejaculate 
• True abstinence (see Section 4.4). 


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4.4.2 
Contraceptive Methods for Male Study Subjects 
Contraception is required for all sexually active male subjects, who with their female sexual 
partners must agree to use one of the following appropriate methods of contraception throughout 
the study period and for 16 weeks following the last dose of investigational product. 
Appropriate methods of contraception for male subjects are: 
• Male condom with spermicide; however, if spermicide is not available in the country, 
additional contraception (ie, 1 of those listed below) must be used in addition to a 
male condom. 
• Male sterilization with documented absence of sperm in the postvasectomy ejaculate. 
o 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. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 52/ET (Visit 14) are to be performed. All subjects who discontinue investigational product 
and who are not entering the LTS study (SHP647-304) should also undergo the 


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protocol-specified 12-week safety follow-up period. In the event that subjects are unable to 
attend in person for the safety 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 UC, or 
• If a subject undergoes surgery for UC. 
Subjects who withdraw from study treatment due to an increase in disease symptoms may see 
nonstudy-related physicians for treatment and may receive treatments prohibited during the 
treatment periods of this study. 
If a subject 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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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. 
4.5.1.1 
Definition of Treatment Failure 
Treatment failure is declared when 3 conditions are met: 
• E-diary documented sustained* symptomatic worsening that includes RB 
• No other etiology (ie, infection) can be identified 
• Endoscopy confirms disease activity. 
*Sustained: for at least 1 week if the RB score has increased by ≥2 points, or at least 2 weeks if 
the RB score has increased by <2 points. 
If treatment failure is not confirmed, subjects may continue with their next scheduled visit. 
4.5.1.2 
Assessing for Treatment Failure 
Treatment failure assessment may begin no earlier than the Week 4 scheduled visit. 
All subjects will be monitored for potential symptomatic worsening at every visit. Initiation of 
assessment for treatment failure requires the presence of worsening in SF, RB, or both. Rectal 
bleeding must be present for a diagnosis of treatment failure, although it need not have 
worsened. Criteria for symptomatic worsening are shown in Table 2. 
Table 2 
Criteria for Symptomatic Worsening of Treatment Failure (Must be Met at 
Each of 2 Sequential Visits) E-diary Entries 
Increase of at least 1 point over baseline in each domain (SF and RB) 
OR 
Increase in RB score ≥2 points over baseline, regardless of SF 
OR 
Increase in SF score ≥2 points over baseline with presence of RB 
OR 
Current SF or RB score of 3 points and an increase from baseline in the other ≥1 domain 
OR 
Current SF score of 3 and a RB score of 3 
RB=rectal bleeding; SF=stool frequency 


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Subjects who experience rapid symptomatic worsening and need an unscheduled evaluation 
between visits will additionally be assessed for treatment failure. Other (eg, infectious) etiologies 
of symptomatic worsening must be ruled out by assessment of appropriate stool samples 
(see Appendix 4 for Clostridium difficile testing). If a potential other cause is identified, 
treatment failure will not be assessed until a full course of treatment has been completed (or clear 
lack of response is identified) or if untreated, the infection would be expected to have resolved 
based on its natural history. 
If no other etiology is confirmed, increased e-diary scores must still be present at a confirmatory 
visit for potential treatment failure assessment. Note that while criteria must be met at each visit, 
it is not required that the same criteria are met at both visits. If testing for infectious agents does 
not reveal an etiology, an endoscopy must be scheduled to confirm the treatment failure. The 
timing of the endoscopy (ie, before or after the confirmatory visit) will depend on the 
investigator’s assessment of urgency. 
The endoscopy will confirm the presence of treatment failure if either of the following is present: 
• An endoscopic subscore that has increased by at least 1 point over baseline in this 
maintenance study 
OR 
• An endoscopic subscore of at least 2. 
4.5.1.3 
After Treatment for Infectious Etiology 
If a subject completed an initial assessment for treatment failure and an infectious etiology was 
identified and appropriately treated, they should be assessed for the efficacy of the treatment. If 
despite treatment they continue to meet treatment failure criteria based on e-diary criteria, they 
should proceed immediately to endoscopy. 
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. 


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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 eCRF. 
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 
• 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 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 UC treatments until completion of the 
Week 52 visit, unless decreases are required because of AEs. Stable doses of the following 
treatments for UC are permitted as concomitant medication: 
• Oral 5-ASA (mesalamine) and sulfasalazine 
• Immunosuppressants (AZA, 6-MP, methotrexate [MTX]) 
• Oral glucocorticoids; however, tapering is mandatory starting on Day 1. As the 
subjects are transferred from induction studies SHP647-301 or SHP647-302, the 
maximum systemic glucocorticoid dose is 20 mg/day of oral prednisone or equivalent 
(see Appendix 3), and the maximum dose of topically active glucocorticoid is 
9 mg/day of oral budesonide or 5 mg/day of oral beclomethasone. Tapering should 
follow the procedure shown in Table 3. 
Note: Rectal 5-ASA and parenteral or rectal glucocorticoids are prohibited. 


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Table 3 
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 >10 mg: 
Taper by 5 mg/day each 1-2 weeks 
• 
When daily dose 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 SHP647-303 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 UC 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 SF, increased 
RB) must be recorded. 
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. 
Dietary and herbal supplements and probiotics are allowed in the study, provided they are being 
taken at stable doses at the time of the baseline visit (Visit 1) and for the duration of the study. 
They should be recorded as concomitant medications. 
Use of nicotine patches should be recorded as concomitant medication. 


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5.2.2 
Prohibited Treatment 
The following common treatments are excluded medications for this study. As the subjects are 
transferred from induction studies SHP647-301 or SHP647-302, during which these treatments 
were also prohibited, no washout period is applicable. 
• Anti-integrin or antiadhesion molecule treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab) 
• Parenteral and rectally administered glucocorticoids 
• Rectally administered 5-ASA 
• Anti-TNF treatment and other biologics with immunomodulatory properties 
• Live (attenuated) vaccines 
• Any nonbiologic treatment with immunomodulatory properties (other than their 
current background UC treatment) 
• Leukocyte apheresis or selective lymphocyte, monocyte, or granulocyte apheresis or 
plasma exchange. 
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. 
5.2.3 
Rescue Therapy 
Subjects must maintain their stable dose of background UC treatment, unless dose reduction or 
discontinuation are required due to associated AEs. If a subject requires initiation of a new 
therapy or increase in glucocorticoids for UC above the SHP647-303 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 follow-up period will no longer need to abstain from the medications that 
were prohibited during the baseline and treatment periods. High-dose glucocorticoids and other 
UC treatments will be allowed. Biologics or nonbiologic immunosuppressants should not be 
initiated during the safety follow-up period without prior discussion with the sponsor study 
physician or designee due to the long half-life of ontamalimab. 


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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 Product 
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. 
The composite score and total Mayo score will be calculated at baseline (Week 12/Visit 6 of 
induction study SHP647-301 or SHP647-302 will be used for Week 0/Day 1/Visit 1 of 
Study SHP647-303) before randomization. Endoscopic subscore based on the central reader’s 
assessment will be used to determine eligibility. 
Subjects who are qualified as a clinical responder, who fulfill all other eligibility criteria, and 
who received active treatment in the induction study (SHP647-301 or SHP647-302) will be 
randomized via a computer-generated randomization schedule as follows: subjects who received 


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25 mg ontamalimab in 1 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 1 of the 
induction studies will be randomized (1:1) to receive either 75 mg ontamalimab or placebo. 
Subjects who are qualified as a clinical responder, who fulfill all other eligibility criteria, and 
who received placebo in the induction study will be randomly assigned 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 SHP647-303 baseline, the subject’s 
status of prior anti-TNF treatment (naïve or experienced), and the degree of clinical response in 
the induction study (whether remission is achieved or not). 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Individual subject treatment is 
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. 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. 


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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). 
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. 


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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. 
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. 


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6.3 
Labeling, Packaging, Storage, and Handling 
6.3.1 
Labeling 
The sponsor will provide the investigator with packaged investigational product labeled in 
accordance with specific country regulatory requirements. All investigational product is labeled 
with a minimum of the following: protocol number, medication identification number, dosage 
form (including product name and quantity in pack), directions for use, storage conditions, 
expiry date (if applicable), batch number and/or packaging reference, the statements “For clinical 
trial use only” and/or “CAUTION: New Drug – Limited by Federal (or US) Law to 
Investigational Use”, and the sponsor’s name and address. 
Additional labels may be applied in order to meet local or institutional requirements, but must 
not: 
• Contradict the clinical study label 
• Obscure the clinical study label 
• Identify the study subject by name. 
Additional labels may not be added without the sponsor’s prior written agreement. 
6.3.2 
Packaging 
Investigational product is packaged in the following labeled containers: PFS with nominal fill 
volume of 1 mL. The PFS will be packaged in a 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 


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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 
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. 


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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 
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. 


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• 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). 
• 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 activities (Table 1), in order to conduct evaluations or assessments required to 
protect the well-being of the subject. 
7.2.1 
Baseline Visit 1 (Week 0/Day 1) 
Procedures performed at Week 12 (Visit 6) of the induction studies (SHP647-301 or 
SHP647-302) 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 12 visit of the 
induction study. To be eligible for this maintenance study, subjects must have achieved a clinical 
response 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. 


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A screen failure is a subject who has given informed consent or assent, as applicable (and whose 
parents or legally authorized representatives have given informed consent, as applicable), failed 
to meet the inclusion criteria and/or met at least 1 of the exclusion criteria, and has not been 
randomized or administered investigational product. 
The composite score and total Mayo score will be calculated at baseline of the SHP647-303 
study (Week 12/Visit 6 of the induction studies; used for Week 0/Day 1/Visit 1 of the 
maintenance studies) before randomization. 
For eligible subjects, all relevant study information recorded for Week 12 of the induction 
studies will be included in the baseline visit data for this maintenance study. The health outcome 
assessments completed at Week 12 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 must be completed within 10 days (preferably, within 5 to 7 days) before 
Part 2; this will allow sufficient time for data from the centrally read endoscopy to be available at 
Part 2 of the visit. The Week 52/ET assessments and procedures that will take place during Part 1 
are specified in Table 1. 


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Part 2 of Visit 14 will take place on Day 364 ±10 days. The Week 52/ET assessments and 
procedures 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 4.5.1.1), 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. 
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, treatment response will be evaluated at the ET visit as well. Treatment response will be 
based on the following criteria: 
• Clinical composite score that has decreased by ≥2 points and ≥30%, with an 
accompanying decrease in the subscore for RB ≥1 point or a subscore for RB ≤1 from 
induction study (SHP647-301 or SHP647-302) baseline OR 
• Composite score that has decreased by ≥30% and ≥3 points compared to the higher 
baseline value for induction or maintenance studies from induction study 
(SHP647-301 or SHP647-302) baseline. 
Endoscopy 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. 


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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 SHP647-303, 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 


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• Endoscopy (generally performed at a separate visit; see Section 7.3.2.1) 
• Investigational product administration. 
Note: Blood and tissue samples may be stored for up to the duration allowed by local regulations 
but for no longer than 25 years. 
7.3.1 
Demographic and Other Baseline Characteristics 
All relevant demographic and baseline characteristics recorded for the induction studies 
(SHP647-301 or SHP647-302) will be used as the baseline characteristics for this maintenance 
study. 
7.3.2 
Efficacy 
The primary efficacy endpoint is remission at the Week 52 visit. Remission is defined as a 
composite score of patient-reported symptoms using daily e-diary and centrally read endoscopy 
as described in Section 9.8.1. 
7.3.2.1 
Endoscopy and Histology 
Endoscopy will be performed at the time points specified in Table 1 and will consist of either 
flexible sigmoidoscopy or colonoscopy (if preferred). 
If it is necessary, bowel preparation should be conducted as per local routine. The position of the 
endoscope will be based on the length of the instrument at various levels of insertion as well as 
the morphological features of the intestine as seen during the baseline endoscopy in the induction 
study (SHP647-301 or SHP647-302). The endoscopy report and any photographs and/or video 
recordings taken during the procedure per local custom should be filed in the subject’s medical 
record. 
During endoscopy, 2 biopsy samples will be collected from the most inflamed area of the 
sigmoid colon at Week 52/ET. Endoscopy and biopsy procedures will be defined in an 
endoscopy instructions manual and/or reference card(s), on which all sites will be trained. 
Endoscopy results will be reviewed by a central reader. 
Biopsy samples will be centrally-reviewed using the Geboes Score classification system and 
 (see Appendix 2) for the evaluation of histological disease 
severity in UC with higher numbers corresponding to more inflammation. The Geboes score will 


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be used for the key and other secondary efficacy evaluations and 
 
 
Endoscopy 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. 
7.3.2.2 
Mayo Score 
The Mayo score is a measure of UC disease activity. Mayo scores (total or partial) will be 
recorded at the time points specified in Table 1. 
The total Mayo score ranges from 0 to 12 points and consists of the following 4 subscores, each 
graded from 0 to 3 with higher scores indicating more severe disease (see Appendix 2): 
• Stool frequency (0-3) 
• Rectal bleeding (0-3) 
• Findings of endoscopy (0-3) 
• Physician global assessment (PGA; 0-3). 
The partial Mayo score consists of the Mayo score without the endoscopic subscores and ranges 
from 0 to 9 points. 
The composite score is a recommended measure consisting of the Mayo score without the 
PGA subscore and ranges from 0 to 9 points. The composite score will be used for the primary 
efficacy endpoint. 
Calculation of the total and partial Mayo scores and composite score requires a self-assessment 
by the subject for SF and the amount of blood in the stool. These data on SF and RB will be 
captured in the patient-reported outcome (PRO)-UC daily e-diary (see Section 7.3.2.3) as 
experienced over the previous 24 hours. 
The Mayo SF and RB subscores will be calculated based on each subject’s e-diary data recorded 
over the most recent 3 days (consecutive or nonconsecutive) of the last 10 days prior to the visit, 
excluding the following days: day of any bowel preparation, day of endoscopy, any days 
between day of bowel preparation and day of endoscopy, and the 2 days after the day of 
endoscopy. 


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The mucosal appearance during the sigmoidoscopic portion of the endoscopic examination will 
be assessed for the Mayo endoscopic subscore based on the scoring system provided in the 
protocol (see Appendix 2). The endoscopic appearance will be read by both the study site 
investigator and a central reader through video recorded during the procedure. Centrally read 
endoscopic subscores will be used for both eligibility and efficacy analyses. 
The PGA acknowledges the 3 other criteria: the subject’s recollection of abdominal discomfort 
and general sense of well-being and other observations (such as physical findings and the 
subject’s performance status). The endoscopic subscore and the PGA must be performed by a 
physician qualified to perform endoscopy; it is recommended that the same physician performs 
all such assessments for a particular subject throughout the study, and that the same physician 
who performed the assessments during the induction study does so during the current study. 
7.3.2.3 
Patient-reported Outcome – Ulcerative Colitis Daily E-diary 
Patient-reported UC signs and symptoms data will be collected using a daily e-diary that will be 
available throughout the study. Subjects will be required to enter data on UC signs and 
symptoms items using an electronic handheld device. 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, <8 out of 10 diary entries) when compared with the 
previous visit. 
Subjects will be asked to record the following signs and symptom data, as experienced over the 
previous 24 hours, in the e-diary: 
• Stool frequency 
• Rectal bleeding severity and frequency 
• Diarrhea frequency 
• Urgency frequency 
• Abdominal pain worst severity. 
The full PRO-UC e-diary consists of 6 items. The first 2 items (SF and RB severity) will be used 
to determine the Mayo SF and RB subscores, which will be used to calculate the total and partial 
Mayo scores and the composite score. The PRO-UC e-diary is presented in Appendix 2. 


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7.3.3 
Safety 
7.3.3.1 
Medical and Medication History 
Medical history, including UC history, cardiac history, and smoking history, and prior 
medications will be collected at the screening visit (Visit 1) of induction study SHP647-301 or 
SHP647-302. Concomitant medications and procedures will be documented throughout the 
SHP647-303 study. 
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; confrontational visual 
fields (eyes); breast (optional); abdomen; external genitalia (optional); extremities; neurologic 
function; back; and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin, heart, lungs, confrontational visual fields (eyes), abdomen, and 
examination of body systems where there are symptom complaints by the subject. 
Weight will be measured at the time points specified in Table 1. 
The complete physical examination performed at Week 12 (Visit 6) of induction study 
SHP647-301 or SHP647-302 will be the baseline examination of Study SHP647-303. 
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. 
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, neurologic examination(s), 
targeted to the abnormal domain, will be performed by an investigator or qualified personnel. 


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A step-wise approach for the proposed neurological assessment plan is provided in Table 4. 
Table 4 
Quarterly Neurological Assessments 
Domain 
Step 1: Interim Neurologic History 
and Targeted Neurological 
Examination 
Step 2: If Abnormal Response 
Vision 
Diplopia or visual/visual field loss 
Perform visual field assessment 
Motor 
Major motor weakness (eg, legs, arms) 
Test leg strength (hopping, foot tapping), 
finger tapping, pronator drift, and 
bilateral muscle strength 
Tactile sensation 
Paresthesia, anesthesia in any domain 
(peripheral, central) 
Pinprick test 
Coordination/Cerebellar 
Clumsiness, difficulty with walking, 
writing, or fine motor skills, etc. 
Finger-nose, heel-shin, heel-toe walk, 
writing sample, draw a clock 
Speech 
Dysarthria, expressive aphasia 
Naming objects, repeat multipart phrase, 
observe for dysarthria or aphasia 
Verbal comprehension 
Agnosia, receptive aphasia 
Test to follow routine commands, 
eg, close eyes, touch finger to ear 
Cognition/Behavior 
New onset of difficulties with memory or 
thinking, important changes in behavior 
Recall 3 objects over 1 minute, serial 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 defined safety follow-up period stated in Section 7.2.3 (See Section 8, Adverse and 
Serious Adverse Events Assessment). 


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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. 
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 patient (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 
• 
aspartate aminotransferase 
• 
alanine aminotransferase 
• 
total bilirubin 
• 
total protein 
• 
albumin 
• 
glucose 
• 
blood urea nitrogen 
• 
creatinine 
• 
sodium 
• 
potassium 
• 
chloride 
• 
calcium 
• 
carbon dioxide 
Hematology 
• 
hemoglobin 
• 
hematocrit 
• 
mean corpuscular hemoglobin 
• 
mean corpuscular hemoglobin 
concentration 
• 
mean corpuscular volume 
• 
erythrocyte (red blood cell) count 
• 
leukocyte (white blood cell) count 
• 
neutrophils 
• 
lymphocytes 
• 
monocytes 
• 
eosinophils 
• 
basophils 
• 
platelet count 
Urinalysis 
• 
glucose 
• 
protein 
• 
specific gravity 
• 
pH 
• 
nitrite 
• 
bilirubin 
• 
ketones 
• 
hemoglobin 
• 
urobilinogen 
• 
leukocyte esterase 


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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 SHP647-301 or SHP647-302. 
If a female subject’s status has changed to postmenopausal since the induction studies 
(SHP647-301 or SHP647-302), the childbearing potential of the subject must be re-established 
and documented (FSH confirmation test) at baseline (Visit 1) of SHP647-303. 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. 
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. 


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A central ECG reader will be used in this study. The eligibility of the subject is based on the 
assessment of the ECG by the investigator. If abnormal results are observed following 
assessment by the central reader, the investigator, in consultation with the appointed sponsor or 
contract research organization (CRO) medical monitor, reconfirms subject eligibility to continue. 
7.3.3.9 
Antidrug Antibodies 
Blood samples for measurement of antidrug antibodies (ADAs) and neutralizing antibodies 
(NAbs) will be collected at the time points specified in Table 1. Blood samples must be collected 
before the administration of investigational product at that visit. 
7.3.3.10 
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 adverse events 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 assess the case 
and finalize recommendation of permanent discontinuation or rechallenge with investigational 
product. 
Subjects who experience an AE suggestive of the presence of circulating immune complexes 
formation (eg, fever, rash [including hives], arthralgia, myalgia, vasculitis, Arthus reaction, 
general ill feeling, itching, and swollen lymph nodes) will have the related AEs reviewed by the 
adjudication committee and if the AEs are assessed as related to formation of circulating of 
immune complexes and not related to underlying disease, blood samples will be collected and 
stored at the central laboratory. Tests will be performed as confirmatory of presence of 
circulating immune complexes at the request of the adjudication committee. 
Further details of hypersensitivity reactions as AESIs are provided in Section 8.1.3.1. 


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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 3. 
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 4.5.1.1 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 5. 
Table 5 
Volume of Blood to Be Drawn from Each Subject 
Assessment 
Sample Volume (mL) 
Number of Samples 
Total Volume (mL) 
Hematology 
2 
5 
10 
Serum chemistry 
4 
5 
20 
FSH 
2 
1 
2 
ADA and NAb sampling 
3 
3 
9 
 
 
 
2 
3 
6 
Total mL 
47 
ADA=antidrug antibody; 
; FSH=follicle-stimulating hormone; NAb=neutralizing antibody 
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 47 mL. When more than 1 blood assessment is to be done at the time point/period, 
if they require the same type of tube, the assessments may be combined. 


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8. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(International Council for Harmonisation [ICH] Guidance E2A 1995). 
All AEs are collected from the time the informed consent and/or assent is signed until the end of 
the defined safety follow-up period stated in Section 7.2.3. Where possible, a diagnosis rather 
than a list of symptoms should be recorded. Resolved AEs considered to be significant by the 
investigator that occurred in induction studies SHP647-301 or SHP647-302 will be captured as 
part of the SHP647-303 baseline medical history, while ongoing AEs from Studies SHP647-301 
or SHP647-302 will be captured as AEs in SHP647-303 and followed throughout the 
SHP647-303 study. If a diagnosis has not been made, then each symptom should be listed 
individually. All AEs should be captured in the subject’s source documents. 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 describe 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 SAE and 
Nonserious AE as Required by the Protocol Form” and within the time frame mandated for 
SAEs (see Section 8.2.2). 
It is well known that the administration of foreign proteins can cause immune responses 
including hypersensitivity reactions such as anaphylaxis and serum sickness. Other immune 
responses to foreign proteins include the development of ADAs and NAbs. 
Monoclonal antibodies have been used in human therapeutics since the 1980s. The first 
monoclonal antibody approved for human use (ORTHOCLONE OKT3®), was a murine protein 
which caused rapid production of NAbs. Since then, much effort has been expended to reduce 
the immunogenicity of these useful therapeutic proteins by reducing the extent of “foreignness” 
from chimeric antibodies such as infliximab, to humanized antibodies such as vedolizumab, and 
finally to fully human antibodies such as adalimumab and ontamalimab (Isabwe et al., 2018) (see 
Figure 4). 
Figure 4 
Potential Immunogenicity of Therapeutic Monoclonal Antibodies 
 
Ontamalimab is a fully human antibody of the immunoglobulin G2 subclass. In Phase 1 and 
Phase 2 clinical trials of ontamalimab, in which over 700 subjects were treated for up to 3 years, 
there has been no case of anaphylaxis. There have been 2 reported cases of drug 
hypersensitivity: serum sickness attributed to concomitant administration of penicillin; and a 
reaction characterized by dyspnea, facial erythema, and chest pain with onset 2 days after 
administration of the fifth dose of ontamalimab. The latter event mimicked a reaction that the 
subject had previously experienced after 4 doses of infliximab. In addition, low titer activity has 
been observed in ADA assays, including pretreatment samples and placebo-treated subjects, and 
no subject has had a 2-fold or greater increase in ADA titer. Analysis of PK and clinical 


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parameters has shown no difference between subjects whose ADA assays results are positive as 
compared with those whose are negative. 
Nonetheless the possibility of a hypersensitivity reaction occurring after drug exposure cannot be 
fully ruled out. The reactions of concern are Type I (anaphylaxis) and Type III (immune 
complex) reactions. The clinical presentation of anaphylactic reactions is described in Table 6. 
Table 6 
Clinical Criteria for Diagnosing Anaphylaxis (Type I Hypersensitivity) 
Anaphylaxis is highly likely when below criterion and at least any one of the following criteria a and b are 
fulfilled: 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both 
(eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST 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, 


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samples for laboratory assessment will be obtained and stored. Tests will be performed if the 
diagnosis is confirmed and requested by the adjudication committee. 
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. 


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The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE. 
8.1.7 
Pregnancy 
All pregnancies are to be reported from the time informed consent is signed until the end of the 
defined safety 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. 


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8.1.8 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category. 
• Abuse – Persistent or sporadic intentional intake of investigational product when 
used for a nonmedical purpose (eg, to alter one’s state of consciousness or get high) 
in a manner that may be detrimental to the individual and/or society 
• Misuse – Intentional use of investigational product other than as directed or indicated 
at any dose (Note: this includes a situation where the investigational product is not 
used as directed at the dose prescribed by the protocol) 
• Overdose – Intentional or unintentional administration of investigational product at a 
dose interval that is less than 2 weeks between doses 
• Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of an investigational product. For studies, medication errors are reportable to the 
sponsor only as defined below. 
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
Medication errors should be collected/reported for all products under investigation. 
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. 


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8.1.9 
Unexpected Adverse Event 
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not consistent with 
the term, representation, or description used in the reference safety information (RSI). 
“Unexpected” also refers to the AEs that are mentioned in the IB as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation. 
The expectedness of AEs will be determined by the sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed, but 
not on the basis of what might be anticipated from the pharmacological properties of a product. 
8.1.10 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is defined as any suspected adverse 
reaction to study treatment (ie, including active comparators) that is both serious and unexpected. 
The event(s) must meet all of the following: 
• Suspected adverse reaction 
• Serious 
• Unexpected 
• Assessed as related to study treatment. 
8.2 
Serious Adverse Event Procedures 
8.2.1 
Reference Safety Information 
The reference for safety information for this study is Section 6.8 of the ontamalimab IB, which 
the sponsor has provided under separate cover to all investigators. 
8.2.2 
Reporting Procedures 
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the CRO/Shire medical monitor within 24 hours of the first 
awareness of the event. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors (see Section 8.1.8) unless they result in 
an SAE. 


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The investigator must complete, sign, and date the Shire “Clinical Study Serious Adverse Event 
and Nonserious AE as Required by the Protocol Form” and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested) and fax or email the form to the Shire Global 
Drug Safety Department. A copy of the Shire “Clinical Study Serious Adverse Event and 
Nonserious AE as Required by the Protocol Form” (and any applicable follow-up reports) must 
also be sent to the CRO/Shire medical monitor using the details specified in the emergency 
contact information section of the protocol. 
8.2.3 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 
• Results in death. 
• Is life-threatening. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
Note: Hospitalizations, which are the result of elective or previously scheduled 
surgery for pre-existing conditions, which have not worsened after initiation of 
treatment, should not be classified as SAEs. For example, an admission for a 
previously scheduled ventral hernia repair would not be classified as an SAE; 
however, complication(s) resulting from a hospitalization for an elective or 
previously scheduled surgery that meet(s) serious criteria must be reported as SAE(s). 
• Results in persistent or significant disability/incapacity. 
• Is a congenital abnormality/birth defect. 
• Is an important medical event. 
Note: Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency department or at home; blood dyscrasias or convulsions that do not 


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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 safety 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. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event. 
8.2.5 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate. 
8.2.6 
Fatal Outcome 
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 


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8.2.7 
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The sponsor or the CRO is responsible for notifying the relevant regulatory authorities, 
US central institutional review boards (IRBs), and European Union (EU) central ethics 
committees (ECs) of related, unexpected SAEs (ie, SUSARs). 
In addition, the CRO is responsible for notifying active sites of all related, unexpected SAEs 
(ie, SUSARs) occurring during all interventional studies across the ontamalimab program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required. 
8.2.8 
Safety Monitoring for Potential Cases of Drug-induced Liver Injury 
The following safety monitoring and stopping criteria are provided for elevated hepatic blood 
tests based on normal and elevated baseline alanine aminotransferase (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 7 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 7 
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 
(SHP647-301 or SHP647-302) 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 productb 
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 
(SHP647-301 or SHP647-302) 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 productb 
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. 
Note: subjects who entered the induction 
study (SHP647-301 or SHP647-302) with 
HBcAb with or without HBsAb would 
need evaluation with HBV DNA to rule 
out HBV reactivation.c 


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Table 7 
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 productb 
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. 
Note: Subjects who entered the induction 
study (SHP647-301 or SHP647-302) 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 2-3 days before the investigational product is 
interrupted. 
c 
If HBV DNA positive, antivirals would need to be started as soon as possible. 
Source: Adapted from Chalasani and Regev, 2016. 


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9. 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1 
Data Collection 
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered in the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. It is expected that site personnel will complete the eCRF 
entry within approximately 3 business days of the subject’s visit. 
9.2 
Clinical Data Management 
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 
9.3 
Data Handling Considerations 
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® Version 9.3 or higher (SAS Institute, 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. 


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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 
authorities as appropriate, of DMC recommendations (which may include summaries of 
aggregate analyses of endpoint events and of safety data that are not endpoints). 
Further details regarding the DMC can be found in the DMC charter, which will be available 
before the administration of investigational product to any subject. Analyses of the data for DMC 
review will be conducted according to the DMC charter and the DMC SAP. Because no formal 
hypothesis testing for safety assessments is planned, multiplicity concerns regarding repeated 
analyses are not applicable. 
An external hypersensitivity adjudication committee will be established to review data from 
subjects who experience a suspected Type I or Type III hypersensitivity reaction in order to 
confirm the nature and etiology of the reaction, to determine whether testing should be 
performed on stored blood samples, and to finalize recommendations of permanent 
discontinuation or rechallenge with investigational product. Further details regarding the 
adjudication committee can be found in the adjudication charter. 
9.6 
Sample Size Calculation and Power Considerations 
The planned sample size for this maintenance study depends on enrollment from the induction 
studies (SHP647-301 and SHP647-302). Assuming that 50% of subjects receiving ontamalimab 
induction treatments and 35% of subjects receiving placebo induction treatment in 
Studies SHP647-301 and SHP647-302 will have a clinical response at Week 12, an estimated 
696 subjects will be eligible to enter this maintenance study: 296 subjects from ontamalimab 
25 mg induction treatment, 296 subjects from ontamalimab 75 mg induction treatment, and 
104 subjects from placebo induction treatment. Expected clinical response rates at Week 12 are 
based on observed rates from the A7281009 study. 
This study is designed to have approximately 85% power for the primary endpoint to detect an 
individual pairwise treatment difference at a highly statistically persuasive level (ie, a 
p-value ≤.001). However, an alpha of 0.05 (2-sided) will be used as the overall Type-I error rate 
for the purposes of demonstration of efficacy in this study and declaring study success. The 
power will be reported for both Type-I error thresholds (0.05 and 0.001). 


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Graphical methods are used to control the global family-wise Type-I error rate (FWER) 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. Therefore, the power 
analysis and sample size estimation was calculated based on the chi-square test of proportions 
using nQuery Advisor Version 7.0 (Statistical Solutions Ltd, Cork, Ireland) for an individual 
ontamalimab dose compared with placebo. 
Power calculations are based on assuming a .025 (2-sided) significance level for each pairwise 
treatment comparison; 296 subjects previously treated with 25 mg ontamalimab in induction 
(1:1 allocation ratio: 148 subjects in 25 mg ontamalimab treatment group vs. 148 subjects in the 
placebo group) and 296 subjects treated with 75 mg ontamalimab in induction (1:1 allocation 
ratio: 148 subjects in the 75 mg ontamalimab treatment group vs. 148 subjects in the placebo 
group) were planned. These numbers would yield an approximately 98% power (85% for 
alpha = 0.001) to detect individual pairwise treatment difference in the primary efficacy 
endpoint, remission at Week 52, of 23% (15% placebo versus 38% ontamalimab). Expected 
remission rates at Week 52 were based on observed rates from an analysis of Study A7281010, 
which was ongoing at the time of the original protocol and placebo remission rates from 
literature (Feagan et al., 2013; Sandborn et al., 2017). No adjustment for missing data is required 
in these sample size calculations as subjects with missing data for remission at Week 52 are 
imputed as failures and the above rates account for these subjects. 
With the planned sample size of 296 subjects previously treated with 25 mg in induction and 
296 subjects previously treated with 75 mg in induction, Table 8 provides the power for 
detecting a treatment difference between ontamalimab treatment group and the placebo group for 
the key secondary endpoints. 


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Table 8 
Power to Detect the Corresponding Treatment Effect for Key Secondary 
Endpoints 
Key Secondary Endpoint at 
Week 52 
SHP647 Premise 
Placebo 
Premise 
Power 
(alpha = .05) 
Power 
(alpha = .001) 
Endoscopic remission 
42.5% 
15% 
0.99 
0.97 
Clinical remission 
60% 
32% 
0.99 
0.92 
Maintenance of remissiona 
65% 
25% 
0.96 
0.68 
Clinical response by composite score 
50% 
25% 
0.98 
0.84 
Mucosal healing 
30% 
13% 
0.91 
0.53 
Glucocorticoid-free clinical remissionb 
50% 
19% 
0.98 
0.79 
Glucocorticoid-free remissionb 
45% 
14% 
0.99 
0.84 
a 
Based on an anticipated 32% of subjects who will be in remission at baseline of this study. 
b 
Based on an anticipated 58% of subjects who will be on corticosteroids at baseline of this study. 
With the early discontinuation of the study, the planned sample size of 696 subjects will not be 
attained as the final number of subjects enrolled into this study is 366. Formal statistical testing 
of the primary and key secondary endpoints will still be conducted despite not reaching the 
planned sample size and power levels. 
9.7 
Study Population 
The safety set will consist of all subjects who have received at least 1 dose of investigational 
product in the SHP647-303 study, regardless of treatment received during the induction studies 
(SHP647-301 and SHP647-302). 
The ontamalimab responder full analysis set (FAS) will consist of all subjects in the randomized 
set who have received at least 1 dose of investigational product in the SHP647-303 study and 
who were previously treated with ontamalimab in the induction studies. 
The placebo responder FAS will consist of all subjects in the randomized set who have received 
at least 1 dose of investigational product in the SHP647-303 study and who were previously 
treated with placebo in the induction studies. 
 
 


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9.8 
Efficacy Analyses 
Unless otherwise specified, all efficacy analyses will be based on the ontamalimab responder 
FAS and subjects will be analyzed according to their randomized treatment, regardless of the 
treatment they actually received. 
9.8.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is remission at the Week 52 visit. Remission is defined as a 
composite score of patient-reported symptoms using daily e-diary and centrally read endoscopy 
as follows: 
• Stool frequency subscore of 0 or 1 with at least a 1-point change from induction 
(SHP647-301 or SHP647-302) baseline 
AND 
• Rectal bleeding subscore of 0 
AND 
• Endoscopic subscore of 0 or 1 (modified, excludes friability). 
The primary efficacy endpoint will be compared for each active treatment group (25 mg or 
75 mg ontamalimab) to the corresponding placebo group (25 mg in induction placebo group or 
75 mg in induction placebo group; placebo groups are not pooled) using a Cochran-Mantel 
Haenszel (CMH) chi-square test stratified by status of glucocorticoid use at SHP647-303 
baseline, prior anti-TNF treatment, and the degree of clinical response in the induction studies 
(whether remission is achieved or not). Subjects with missing remission data at Week 52 will be 
considered failures and counted as nonresponders. The endoscopy score will be based on 
centrally read results. 
The primary efficacy endpoint will be tested by the following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
Where δ is the common treatment difference across strata, j=1 to m. The common treatment 
difference is a weighted average of the stratum-specific treatment differences. 


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The estimate of the common treatment difference along with the corresponding stratified 
Newcombe 95% confidence interval (CI) using the method of Yan and Su (2010) and CMH 
p-value will be presented for each active treatment group to placebo comparison. 
A sensitivity analysis will be performed on the subgroup of subjects that had the opportunity to 
complete 52 weeks of this study prior to the implementation of Amendment 3 at their site. 
The primary efficacy endpoint will be summarized separately for the placebo responder FAS by 
treatment group without inferential methods. The number and percentage of subjects, and the 
estimate of the common treatment difference along with the corresponding unstratified 
Newcombe 95% CI, will be summarized by treatment group at Week 52. Subjects with missing 
data at Week 52 will be considered failures and counted as nonresponders. 
Adjustments for multiplicity 
The global FWER for the statistical tests of the primary and key secondary endpoints will be 
strongly controlled at .05 (2-sided). To control the FWER, graphical methods discussed in 
Bretz et al. (2009) will be utilized to propagate α from primary to key secondary endpoints and 
between the 2 ontamalimab treatment group and placebo comparisons. Alpha is initially split 
equally at the .025 level (2-sided) for each of the pairwise treatment comparisons for the primary 
endpoint (P) and alpha is propagated in a hierarchical manner to each of the 7 key secondary 
endpoints (K1-K7) within a pairwise treatment comparison. A graphical visualization of the 
α propagation is presented in Figure 5. 


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Figure 5 
Visualization of Alpha Propagation 
 


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Only p-values that are significant according to this graphical approach are inferential and 
statistically significant. All other p-values are descriptive. 
9.8.2 
Secondary Efficacy Endpoints 
9.8.2.1 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are as follows: 
• Endoscopic remission, as defined by centrally read endoscopic subscore 0 or 
1 (modified, excludes friability), at the Week 52 visit. 
• Clinical remission as defined by SF subscore of 0 or 1 with at least a 1-point change 
from induction study (SHP647-301 or SHP647-302) baseline in SF subscore, and 
RB subscore of 0, at the Week 52 visit. 
• Sustained remission, ie, in remission at the SHP647-303 Week 52 visit, among 
subjects who were in remission at the time of baseline in study SHP647-303. 
Remission is defined as a composite score of patient-reported symptoms using daily 
e-diary and centrally read endoscopy, with SF subscore of 0 or 1 with at least a 
1-point change from induction study (SHP647-301 or SHP647-302) baseline, and 
RB subscore of 0, and endoscopic subscore of 0 or 1 (modified, excludes friability). 
• Clinical response based on composite score at the Week 52 visit. Clinical response 
(composite) is defined as a decrease from induction study (SHP647-301 or 
SHP647-302) baseline in the composite score of subject-reported symptoms using 
daily e-diary and centrally read endoscopy of at least 2 points and at least 30%, with 
an accompanying decrease in the subscore for RB ≥1 point or a subscore for RB ≤1. 
• Mucosal healing, based on endoscopic and histologic assessment, at the Week 52 
visit. Mucosal healing is defined by centrally read endoscopic subscore 0 or 
1 (modified, excludes friability) and centrally read Geboes score of ≤2. 
• Glucocorticoid-free clinical remission at Week 52, among subjects using 
glucocorticoids at induction study baseline. Glucocorticoid-free clinical remission is 
defined as clinical remission in addition to not requiring any treatment with 
glucocorticoids for at least 4 weeks prior to the Week 52 visit. Clinical remission is 
defined as SF subscore of 0 or 1 with at least a 1-point change from induction study 
(SHP647-301 or SHP647-302) baseline in SF subscore, and RB subscore of 0, at the 
Week 52 visit. 


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• Glucocorticoid-free remission at Week 52, among subjects using glucocorticoids at 
induction study baseline. Glucocorticoid-free remission is defined as remission in 
addition to not requiring any treatment with glucocorticoids for at least 4 weeks prior 
to the Week 52 visit. Remission is defined as a composite score of subject-reported 
symptoms using daily e-diary and endoscopy, with SF subscore of 0 or 1 with at least 
a 1-point change from induction study (SHP647-301 or SHP647-302) baseline, and 
RB subscore of 0, and endoscopic subscore of 0 or 1 (modified, excludes friability). 
Similar to the primary endpoints, the key secondary efficacy endpoints will all be tested by the 
following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
The key secondary endpoints will be analyzed using the same approach as described for the 
primary endpoint. Subjects with missing key secondary endpoint data at the Week 52 visit will 
be considered failures and counted as nonresponders. 
In addition, the same sensitivity analysis as described for the primary endpoint will be repeated 
for the key secondary endpoints. The key secondary endpoints will be summarized separately for 
the placebo responder FAS by treatment group without inferential methods as described for the 
primary endpoint. 
9.8.2.2 
Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints are as follows: 
• Remission defined as a total Mayo score of ≤2 with no individual subscore (SF, RB, 
endoscopy [modified, excludes friability], and PGA) exceeding 1, at Week 52. 
• Clinical remission over time with both RB and SF subscores of 0. 
• Sustained endoscopic remission ie, in endoscopic remission at the SHP647-303 
Week 52 visit among subjects who were in remission at the time of baseline in 
Study SHP647-303, as defined by a centrally read endoscopic subscore of 0 or 
1 (modified, excludes friability). 


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Other secondary efficacy endpoints will be summarized by descriptive statistics and presented by 
treatment group for the ontamalimab responder FAS. The other secondary endpoints will be 
analyzed using the same approach as described for the primary endpoint. Subjects with missing 
other secondary endpoint data at a visit will be considered failures and counted as nonresponders 
at that visit. The other secondary endpoints will be summarized separately for the placebo 
responder FAS by treatment group without inferential methods, as described for the primary 
endpoint. 
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 SHP647-303 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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9.10 Other Analyses 
9.10.1 
 
 
 
 
 
 
 
 
 


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10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate. 
10.1 
Sponsor’s Responsibilities 
10.1.1 
Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996) and 
E6 R2 (2017), EU Directive 2001/20/EC, as well as all applicable national and local laws and 
regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The sponsor ensures that local regulatory authority requirements are met before and during the 
study (including annual safety reporting, ie, Development Safety Update Reports). The sponsor 
(or a nominated designee) is responsible for the preparation, submission, and confirmation of 
receipt of any regulatory authority approvals required before release of investigational product 
for shipment to the site. 
10.1.2 
Indemnity/Liability and Insurance 
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines. 


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The sponsor ensures that suitable clinical study insurance coverage is in place before the start of 
the study. An insurance certificate is supplied to the CRO and investigator as necessary. 
10.1.3 
Public Posting of Study Information 
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information. 
10.1.4 
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees 
The sponsor will upload the clinical study report to the EudraCT database and will also provide a 
summary of the clinical study report to the CRO for submission to the competent authority of the 
countries concerned as required by local regulatory requirement(s). This requirement will be 
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. 


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The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent 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. 


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10.2.3 
Documentation and Retention of Records 
10.2.3.1 
Case Report Forms 
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded in eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. The eCRFs must be completed 
by the investigator or designee as stated in the site delegation log. 
All data in the eCRF will have a separate source (eg, paper or electronic PRO); no data will be 
recorded directly in the eCRF. 
All data sent to the sponsor must be endorsed by the investigator. 
The clinical research associate (CRA)/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 CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, x-rays etc). Nonstudy site personnel will not 
disclose any personal information or personal medical information. 


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These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
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 
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. 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 


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and responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time. 
The principal investigator provides the sponsor with a copy of the consent form that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor before 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) before study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor. 
10.3.2 
Institutional Review Board or Ethics Committee 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved before site initiation. 
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions. 
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Before implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. 
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents. 


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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 
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. 


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10.5 
Study Results/Publication Policy 
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(eg, Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2-4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a noncommercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy. 
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish before release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications. 
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form. 
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days before 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application. 


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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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Butcher, E. C., Kassam, N., Mackay, C. R., Newman, W. and Ringler, D. J. 1997. Human 
mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract 
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Chalasani, N. and Regev, A. 2016. Drug-Induced Liver Injury in Patients With Preexisting 
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Assche, G., Axler, J., Kim, H. J., Danese, S., Fox, I., Milch, C., Sankoh, S., Wyant, T., 
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Geboes, K., Riddell, R., Ost, A., Jensfelt, B., Persson, T. and Lofberg, R. 2000. A reproducible 
grading scale for histological assessment of inflammation in ulcerative colitis. Gut, 47, 
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Isabwe, G. A. C., Garcia Neuer, M., de Las Vecillas Sanchez, L., Lynch, D. M., Marquis, K. and 
Castells, M. 2018. Hypersensitivity reactions to therapeutic monoclonal antibodies: 
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Khanna, S., Shin, A. and Kelly, C. 2017. Management of Clostridium difficile Infection in 
Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates 
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Lacy, C., Armstrong, L., Goldman, M. and Lance, L. 2001-2002. Drug Information Handbook, 
Cleveland, OH, LexiComp, Inc. 
Liaskou, E., Karikoski, M., Reynolds, G. M., Lalor, P. F., Weston, C. J., Pullen, N., Salmi, M., 
Jalkanen, S. and Adams, D. H. 2011. Regulation of mucosal addressin cell adhesion 
molecule 1 expression in human and mice by vascular adhesion protein 1 amine oxidase 
activity. Hepatology, 53, 661-72. 
McDonald, L. C., Gerding, D. N., Johnson, S., Bakken, J. S., Carroll, K. C., Coffin, S. E., 
Dubberke, E. R., Garey, K. W., Gould, C. V., Kelly, C., Loo, V., Shaklee Sammons, J., 
Sandora, T. J. and Wilcox, M. H. 2018. Clinical Practice Guidelines for Clostridium 
difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases 
Society of America (IDSA) and Society for Healthcare Epidemiology of America 
(SHEA). Clinical Infectious Diseases, 66, e1-e48. 
Molodecky, N. A., Soon, I. S., Rabi, D. M., Ghali, W. A., Ferris, M., Chernoff, G., Benchimol, 
E. I., Panaccione, R., Ghosh, S., Barkema, H. W. and Kaplan, G. G. 2012. Increasing 
incidence and prevalence of the inflammatory bowel diseases with time, based on 
systematic review. Gastroenterology, 142, 46-54.e42; quiz e30. 
 


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Sampson, H. A., Munoz-Furlong, A., Campbell, R. L., Adkinson, N. F., Jr., Bock, S. A., 
Branum, A., Brown, S. G., Camargo, C. A., Jr., Cydulka, R., Galli, S. J., Gidudu, J., 
Gruchalla, R. S., Harlor, A. D., Jr., Hepner, D. L., Lewis, L. M., Lieberman, P. L., 
Metcalfe, D. D., O'Connor, R., Muraro, A., Rudman, A., Schmitt, C., Scherrer, D., 
Simons, F. E., Thomas, S., Wood, J. P. and Decker, W. W. 2006. Second symposium on 
the definition and management of anaphylaxis: summary report--Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. The Journal of allergy and clinical immunology, 117, 391-7. 
Sandborn, W. J., Su, C., Sands, B. E., D'Haens, G. R., Vermeire, S., Schreiber, S., Danese, S., 
Feagan, B. G., Reinisch, W., Niezychowski, W., Friedman, G., Lawendy, N., Yu, D., 
Woodworth, D., Mukherjee, A., Zhang, H., Healey, P. and Panes, J. 2017. Tofacitinib as 
Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med, 376, 1723-
1736. 
Schroeder, K. W., Tremaine, W. J. and Ilstrup, D. M. 1987. Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J 
Med, 317, 1625-9. 
Shane, A. L., Mody, R. K., Crump, J. A., Tarr, P. I., Steiner, T. S., Kotloff, K., Langley, J. M., 
Wanke, C., Warren, C. A., Cheng, A. C., Cantey, J. 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. 
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. 
Vermeire, S., Sandborn, W. J., Danese, S., Hebuterne, X., Salzberg, B. A., Klopocka, M., 
Tarabar, D., Vanasek, T., Gregus, M., Hellstern, P. A., Kim, J. S., Sparrow, M. P., 
Gorelick, K. J., Hinz, M., Ahmad, A., Pradhan, V., Hassan-Zahraee, M., Clare, R., 
Cataldi, F. and Reinisch, W. 2017. Anti-MAdCAM antibody (PF-00547659) for 
ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-
controlled trial. Lancet. 
Warrington, R., Silviu-Dan, F. and Wong, T. 2018. Drug allergy. Allergy, Asthma & Clinical 
Immunology, 14, 1-11. 
Yan, X. and Su, X. 2010. Stratified Wilson and Newcombe Confidence Intervals for Multiple 
Binomial Proportions. Stat Biopharm Res, 2, 329-35. 
 


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APPENDIX 1 
PROTOCOL HISTORY 
Document 
Date 
Global/Country/Site Specific 
Protocol Amendment 3 
17 Sep 2020 
Global 
Protocol Amendment 2 
11 Nov 2019 
Global 
Protocol Amendment 1 
11 Sep 2018 
Global 
Original Protocol 
10 Jul 2017 
Global 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
11 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Product Quality Complaints 
Updated language regarding 
reporting of product quality 
complaints. 
To align product quality complaints 
language with current Shire template. 
Study Synopsis, Number of 
Subjects (total and for each 
treatment arm) 
Section 3.1, Study Design and Flow 
Chart 
Section 9.6, Sample Size 
Calculation and Power 
Considerations 
Updated sample size projections. 
 
 
 
 
Updated sample size projections 
and power considerations. 
To reflect a decrease in the sample size 
due to a reduction in the targeted 
power to detect an individual pairwise 
treatment difference at a highly 
statistically persuasive level (ie, a 
p-value ≤.001) in the primary endpoint 
from 90% to 85% for feasibility 
reasons. 
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 inclusion 
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, Analysis Sets 
Section 9.7, Study Population 
 
 
 
 
 


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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
11 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Other Secondary 
Efficacy Endpoints 
Section 9.8.2.2, Other Secondary 
Efficacy Endpoints 
For the endpoint “Change from 
induction study (SHP647-301 or 
SHP647-302) baseline in 
abdominal pain, diarrhea and 
urgency item scores, absolute SF, 
absolute RB and total 
sign/symptom score based on 
subject daily e-diary entries (sum 
of RB, SF, abdominal pain, 
diarrhea, and urgency)”, revised 
the text in parentheses to read 
“(average of RB, SF, abdominal 
pain, diarrhea, and urgency)”. 
To correctly describe the scoring of 
patient-reported UC sign and symptom 
data. 
Study Synopsis, Safety Analyses 
Section 9.9, Safety Analyses 
Added that adverse events of 
special interest will be summarized 
by treatment group. 
To include analysis of adverse events 
of special interest. 
Table 1, Schedule of Assessments 
Added PRO-UC daily e-diary data 
collection at Visit 14 (Part 2). 
To reflect that e-diary data are to be 
collected through Visit 14 (Part 2) in 
order to calculate the primary 
endpoint. 
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 the coloscopy procedure 
at Visit 14 (Part 1) and Visit 14 
(Part 2) to 10 days, although 5 to 
7 days is preferable. 
To allow sufficient time for data from 
the centrally read endoscopy to be 
available at Part 2 of Visit 14. 
Table 1, Schedule of Assessments – 
footnote “k” 
Section 7.3.3.6, Clinical Laboratory 
Evaluations 
Section 7.3.3.11, Evaluation of 
Increased Gastrointestinal 
Symptoms 
Added new subsection to 
Section 7.2.3 and language to 
describe evaluation of increased 
gastrointestinal symptoms. 
To clarify that infectious etiology must 
be evaluated when a subject 
experiences an increase in 
gastrointestinal symptoms. 
Table 1, Schedule of Assessments –
footnote “r” 
Section 7.3.2.3, Patient-reported 
Outcome – Ulcerative Colitis Diary 
Updated language to describe 
availability of e-diary throughout 
the study. 
To provide the additional clarity 
around the collection of e-diary data. 
Table 1, Schedule of Assessments – 
footnote “u” 
Section 7.3.3.10, Monitoring for 
Type I and Type III Immune 
Reactions 
Added new row to Table 1, new 
subsection to Section 7.2.3, and 
language to describe the 
monitoring for hypersensitivity. 
To address Food and Drug 
Administration (FDA) 
recommendation to evaluate the risk of 
hypersensitivity reactions in the 
Phase 3 studies and aid in the 
collection of relevant safety data. 


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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
11 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 2.1, Rationale for the Study 
Revised to describe 
Study A7281010 as a completed 
study. 
To reflect that Study A7281010 has 
been completed. 
Section 3.1.3, Rationale for 
Treatment Failure 
Added new subsection to provide 
rationale for defining treatment 
failure. 
To clarify the rationale for defining 
treatment failure. 
Section 4.4, Reproductive Potential 
Updated text to reflect results of an 
enhanced pre- and postnatal 
development (ePPND) toxicity 
study in nonhuman primates. 
Updated information to reflect 
preliminary results from an ePPND 
toxicity study of ontamalimab in 
nonhuman primates, which indicated 
that at the dose levels tested (30 and 
60 mg/kg), infant losses were 
increased in ontamalimab-exposed 
animals when compared both to 
control animals in the study and to the 
historical control animal data from the 
testing facility. 
The relevance of this finding to 
humans is unknown but cannot be 
excluded. 
Results of the ePPND study were 
reported in the ontamalimab 
Investigator’s Brochure Edition 8.0. 
Section 4.4.1, Contraceptive 
Methods for Female Study Subjects 
Added text to specify that 
contraception methods with low 
user dependency should preferably 
be used, in particular when 
contraception is introduced as a 
result of participation in the 
clinical study. 
To align with guidance document 
“Recommendations related to 
contraception and pregnancy testing in 
clinical trials” of Clinical Trial 
Facilitation Group. 
Section 4.5.1, Subject Withdrawal 
Criteria 
Added treatment failure to the list 
of reasons for subject withdrawal. 
To reflect that treatment failure may be 
a reason for subject withdrawal. 
Section 4.5.1, Subject Withdrawal 
Criteria 
The term ‘protocol violations’ has 
been changed to ‘protocol 
deviations’. 
For consistency with Section 4.5.2 
(Reasons for Withdrawal). 
Section 4.5.1.1, Definition of 
Treatment Failure Assessment 
Section 4.5.1.2, Assessing for 
Treatment Failure 
Section 4.5.1.3, After Treatment for 
Infectious Etiology 
Added language to more clearly 
define treatment failure criteria and 
assessment. 
To modify definition of symptomatic 
worsening of treatment failure and to 
accelerate the timing of the assessment 
visits to shorten the period during 
which increased symptoms are 
evaluated to permit even earlier 
withdrawal from maintenance and 
transition to long-term safety study. 


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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
11 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 5.2.1, Permitted Treatment 
Added that oral beclomethasone up 
to a maximum of 5 mg/day is 
permitted. 
To reflect that beclomethasone is a 
topically active oral glucocorticoid 
used in certain regions as standard of 
care for ulcerative colitis. 
Table 4, 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 7.3.4.3, Health-related 
Quality of Life Assessments 
Changed the term ‘dimensions’ to 
‘domains’. 
For consistency. 
Section 7.3.5, Volume of Blood to 
Be Drawn from Each Subject 
 
 
 
Section 8.1.3, Adverse Events of 
Special Interest 
Added new subsection to describe 
classification of hypersensitivity as 
an adverse event of special 
interest. 
To address FDA recommendation to 
evaluate the risk of hypersensitivity 
reactions in the Phase 3 studies and aid 
in the collection of relevant safety 
data. 
Section 8.1.7, Pregnancy 
Added text to specify that in cases 
of pregnancy, where the outcome 
is a live birth, the vital status and 
clinical condition of the infant 
should be obtained and 
documented at 1 year postpartum. 
To extend the timeframe for follow-up 
of pregnancy outcomes for female 
study participants or partners of male 
study participants, in response to 
preliminary findings of the ePPND 
study. 
Section 9.5, Planned Interim 
Analysis, Adaptive Design, Data 
Monitoring Committee, and 
Hypersensitivity Adjudication 
Committee 
Added text to specify that external 
hypersensitivity adjudication 
committee will be established to 
review data from subjects who 
experience a suspected Type I or 
Type III hypersensitivity reaction. 
To address FDA recommendation to 
evaluate the risk of hypersensitivity 
reactions in the Phase 3 studies and aid 
in the collection of relevant safety 
data. 
Section 9.8.3, Exploratory 
 
Endpoints 
For the endpoint, 
 
 
 
 
 
 
 
 
Appendix 2, Scales and 
Assessments 
 
 
 
 
Section 10.1.5, Study Suspension, 
Termination, and Completion 
To clarify that the end-of-study 
declaration may be made by the 
sponsor or alternatively its 
representatives. 
Added for clarity. 


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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
11 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Throughout protocol 
‘SHP647’ was updated to 
‘ontamalimab’ throughout the 
protocol. 
To reflect that ontamalimab is the 
international nonproprietary name for 
SHP647. 
Throughout protocol 
Minor changes to wording and 
editorial changes. 
To improve clarity, consistency, and 
remove redundancy of text. 
 


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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
11 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Emergency Contact Information 
Section 8.2.2, Reporting Procedures 
Section 8.2.4, Serious Adverse 
Event Collection Time Frame 
Replaced “Shire Global 
Pharmacovigilance” with “the Shire 
Global Drug Safety Department.” 
Updated the global fax number and 
email address for serious adverse 
event reporting. 
To provide updated emergency 
contact information. 
The updated email address was 
updated in accordance with 
SHP647-303 Protocol Administrative 
Change Memo #5, dated 
04 May 2018. 
Product Quality Complaints 
Updated the email address for 
reporting of product complaints that 
originate in the European Union and 
Rest of World. The email address 
now is the same for all regions. 
To provide updated information for 
reporting of product complaints. 
Study Synopsis, Site(s) and 
Region(s) 
Section 3.3, Sites and Regions 
Revised the anticipated number of 
study sites from 350 to 420 and 
number of countries from 33 to 37. 
To provide a revised projection for 
the number of study sites and 
countries expected to participate. 
Study Synopsis, Objectives, Other 
Secondary 
Section 2.2.2.2, Other Secondary 
Objectives 
Added text to clarify the endpoints 
associated with “other clinical 
outcomes” and “health-related 
quality of life.” 
To clarify the measures that support 
those objectives. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.1, Inclusion Criteria 
Section 4.2, Exclusion Criteria 
Combined language regarding 
eligibility of subjects of 
reproductive potential, from 
inclusion criterion #5 and exclusion 
criterion #4 and deleted inclusion 
criterion #6 as it was redundant. 
To remove redundant language 
regarding eligibility of subjects of 
reproductive potential. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Exclusion Criteria 
Updated exclusion criterion #5 to 
indicate the exclusion of female 
subjects who do not agree to refrain 
from donating or harvesting eggs. 
To exclude female subjects who do 
not agree to refrain from egg donation 
or harvest for the duration of the 
study and for 16 weeks after last dose 
of investigational product. 
Study Synopsis, Methodology 
Section 3.1, Study Design and 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. 
To clarify the subject population that 
may be eligible to enter the LTS 
study. 
Study Synopsis, Endpoints and 
statistical analysis, Analysis Sets 
Section 9.7, Study Population 
Revised definition for full analysis 
set, 
 
or clarity. 
For clarity and consistency of how 
these are defined across the Phase 3 
protocols. 


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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
11 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Endpoints and 
statistical analysis, Analysis Sets 
Section 9.8.1, Primary Efficacy 
Endpoint 
Section 9.8.2, Secondary Efficacy 
Endpoints 
Section 9.8.3, Exploratory 
 
Endpoints 
Removed “subjects with” and 
“proportion of subjects with” from 
the 
 endpoints where 
applicable. 
Made other edits to provide clarity 
around the statistical models for 
these analyses. 
To describe the endpoints correctly. 
Study Synopsis, Safety Analyses 
Section 9.9, Safety Analyses 
Added further details on planned 
summary presentations for the 
safety analyses. 
Clarified definition of TEAE. 
For clarity. 
Schedule of Assessments 
 
 
 
 
 
For clarity. 
Schedule of Assessments, footnote 
“d” 
Section 7.1.1.2, Final On-treatment 
Visits: Visit 14, Parts 1 and 2 
(Week 52/Early Termination) 
Added statement to clarify that, for 
subjects who meet the criteria for 
treatment failure 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 the first dose in the 
LTS study. 
To clarify timing of the Week 52/ET 
visit (Visit 14, Part 2) for subjects 
who fulfill the criteria for treatment 
failure and will be entering the LTS 
study. 
Schedule of Assessments, footnote 
 
Section 2.2.3, Exploratory 
Objectives 
Section 7.2.2.1, Endoscopy and 
Histology 
Section 9.8.3, Exploratory 
 
Endpoints 
Appendix 2, Scales and 
Assessments 
 
 
 
 
 
 
 
 
 
Section 1.3, Benefit and Risk 
Assessment 
Added new section describing 
benefit and risk of SHP647 
treatment. 
To provide a summary of benefit and 
risk information for SHP647. 
Section 4.4, Reproductive Potential 
Made edits to clarify the appropriate 
methods of contraception for female 
and male subjects of reproductive 
potential. 
To clarify language regarding 
appropriate contraceptive methods for 
subjects of reproductive potential. 


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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
11 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 4.5.1, Subject Withdrawal 
Criteria Section 
Added pregnancy to the list of 
reasons a subject may be withdrawn 
from study treatment. 
For clarity and consistency with 
language in Section 8.1.6. 
Section 5.2.2, Prohibited Treatment 
Added the following to the list of 
prohibited treatments: 
• 
Any nonbiologic treatment with 
immunomodulatory properties 
(other than their current 
background UC treatment) 
• 
Leukocyte apheresis or 
selective lymphocyte, 
monocyte, or granulocyte 
apheresis or plasma exchange. 
For alignment with prohibited 
treatments in the UC induction 
studies, SHP647-301 and 
SHP647-302. 
Section 7.2, Study Evaluations and 
Procedures 
Added statement that blood and 
tissue samples may be stored for up 
to the duration allowed by local 
regulations, but for no longer than 
25 years. 
 
Revised from “blood sample 
collection” to “laboratory sample 
collection” to clarify that this 
includes other sample collection, 
eg, urine. 
Moved investigational product 
administration to the last bullet 
point in the ordering of procedures. 
To provide clarity regarding the 
length of time that blood and tissue 
samples may be stored. This change 
was made with SHP647-303 Protocol 
Administrative Change Memo #2 
(dated 07 Sep 2017). 
To improve clarity. 
 
 
 
To improve clarity. 
Section 7.2.3.6, Clinical Laboratory 
Evaluations 
Added information on laboratory 
testing for C. difficile infection, 
including diagnostic algorithms. 
To provide appropriate guidance 
regarding laboratory testing for 
C. difficile infection. 
Section 8.1.8, Unexpected Adverse 
Event 
Section 8.1.9, Suspected 
Unexpected Serious Adverse 
Reaction 
Added definitions of unexpected 
adverse event and suspected 
unexpected serious adverse reaction. 
To define unexpected adverse event 
and suspected unexpected serious 
adverse reaction. 
Section 8.2.7, Regulatory Agency, 
Institutional Review Board, Ethics 
Committee, and Site Reporting 
Added text to clarify that “related, 
unexpected SAEs” refers to 
“SUSARs.” 
To clarify that “related, unexpected 
SAEs” refers to “SUSARs.” 
Section 8.2.8, Safety Monitoring for 
Potential Cases of Drug-induced 
Liver Injury 
Added new section describing 
safety monitoring and stopping 
algorithms for elevated hepatic 
blood tests. 
To provide appropriate guidance on 
patients who have been enrolled with 
elevated liver function test values or 
who experience and increase in liver 
function test(s) during the study. 


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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
11 Sep 2018 
Global/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 10, Sponsor’s and 
Investigator’s Responsibilities 
Added a statement that compliance 
with the noted regulations and 
guidelines also constitutes 
compliance with the ethical 
principles described in the 
Declaration of Helsinki. 
To clarify that the study is conducted 
in accordance with the ethical 
principles in the Declaration of 
Helsinki. 
Section 10.1.1, Good Clinical 
Practice Compliance 
Added language to clarify that the 
sponsor will ensure that local 
regulatory requirements are met 
during the study, including annual 
safety reporting, ie, Development 
Safety Update Reports. 
To clarify language regarding 
regulatory reporting requirements. 
Appendix 2, Mayo Scoring System 
for Assessment of Ulcerative Colitis 
Activity 
Added a footnote (“c”) to the Mayo 
Scoring System for Assessment of 
Ulcerative Colitis Activity to clarify 
that the “findings on endoscopy” 
scoring represents the modified 
endoscopy subscore and that data 
will be collected to calculate the 
total Mayo score using both the 
modified endoscopy subscore and 
traditional endoscopy subscore, 
which will be used as a sensitivity 
analysis and to estimate the impact 
of the modification on the primary 
endpoint. 
To provide clarity regarding Mayo 
Scoring System and use of the 
modified and traditional endoscopy 
scores. This change was described in 
SHP647-303 Protocol Administrative 
Change Memo #2 (dated 
07 Sep 2017). 
Appendix 2, Scales and 
Assessments 
 
 
 
 
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 updated 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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APPENDIX 2 
SCALES AND ASSESSMENTS 
The following scales/assessments will be used in the study and are provided in this appendix: 
• Mayo scoring system 
• Geboes score grading system 
• 
 
• PRO-UC diary 
For questionnaires, only language-specific validated versions will be used. 


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Mayo Scoring System for Assessment of Ulcerative Colitis Activity 
Stool frequencya 
0 = Normal number of stools for this subject 
1 = 1 to 2 stools more than normal 
2 = 3 to 4 stools more than normal 
3 = 5 or more stools more than normal 
Subscore, 0 to 3 
Rectal bleedingb 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood (more than just streaks) or streaks of blood with stool most of the time 
3 = Blood alone passes 
Subscore, 0 to 3 
Findings on endoscopyc 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) 
2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration) 
Subscore, 0 to 3 
Physician’s global assessmentd 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
Subscore, 0 to 3 
The total Mayo score ranges from 0 to 12, with higher scores indicating more severe disease. 
a 
Each subject serves as his or her own control to establish the degree of abnormality of the stool frequency. 
b 
The daily bleeding score represents the most severe bleeding of the day. 
c 
Findings on endoscopy scoring represents the modified endoscopy subscore (value of 1 does not include friability). 
d 
The physician’s global assessment acknowledges the 3 other criteria, the subject’s daily recollection of abdominal 
discomfort and general sense of well-being, and other observations, such as physical findings and the subject’s performance 
status. 
Note: Data will be collected to calculate the total Mayo score using both the modified endoscopy subscore and traditional 
endoscopy subscore (value of 1 including mild friability) as a sensitivity analysis and to estimate the impact of the modification 
on the primary endpoint. 
Source: Schroeder et al., 1987. 


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Geboes Score Grading System 
Grade 0 – Structural (architectural change) 
Subgrades 
 
0.0 
No abnormality 
0.1 
Mild abnormality 
0.2 
Mild or moderate diffuse or multifocal abnormalities 
0.3 
Severe diffuse or multifocal abnormalities 
Grade 1 – Chronic inflammatory infiltrate 
Subgrades 
 
1.0 
No increase 
1.1 
Mild but unequivocal increase 
1.2 
Moderate increase 
1.3 
Marked increase 
Grade 2A – Lamina propria eosinophils 
Subgrades 
 
2A.0 
No increase 
2A.1 
Mild but unequivocal increase 
2A.2 
Moderate increase 
2A.3 
Marked increase 
Grade 2B – Lamina propria neutrophils 
Subgrades 
 
2B.0 
None 
2B.1 
Mild but unequivocal increase 
2B.2 
Moderate increase 
2B.3 
Marked increase 
Grade 3 – Neutrophils in epithelium 
Subgrades 
 
3.0 
None 
3.1 
<5% crypts involved 
3.2 
<50% crypts involved 
3.3 
>50% crypts involved 
Grade 4 – Crypt destruction 
Subgrades 
 
4.0 
None 
4.1 
Probable – local excess of neutrophils in part of crypt 
4.2 
Probable – marked attenuation 
4.3 
Unequivocal crypt destruction 
Grade 5 – Erosion or ulceration 
Subgrades 
 
5.0 
No erosion, ulceration, or granulation tissue 
5.1 
Recovering epithelium + adjacent inflammation 
5.2 
Probable erosion - focally stripped 
5.3 
Unequivocal erosion 
5.4 
Ulcer or granulation tissue 
Source: Geboes et al., 2000 
 


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Patient-reported Outcome – Ulcerative Colitis (PRO-UC) Diary Version 1 
Item # 
Item 
1. 
Please indicate how often you had a bowel movement over the past 24 hours. A bowel movement is 
defined as a trip to the toilet and passing stool (liquid, soft, or solid), passing blood only, passing 
blood and mucus, or passing mucus only. 
 
Enter number of bowel movements passed: 
2. 
Please rate your worst experience of rectal bleeding over the past 24 hours. 
No blood seen 
Streaks of blood with stool less than half of the time 
Obvious blood (more than just streaks) or streaks of blood with stool most of the time 
Blood alone passes 
3. 
You indicated you had X bowel movements in the past 24 hours. Of these, how many had blood, 
either in the stool, in the toilet bowl, or on the toilet paper? 
 
Enter number of bowel movements with blood: 
4. 
You indicated you had X bowel movements in the past 24 hours. Of these, how many were loose or 
watery? 
 
Enter number of loose or watery bowel movements: 
5. 
You indicated you had X bowel movements in the past 24 hours. How many of those involved 
urgency (having to suddenly rush to the toilet to make it on time)? 
 
Enter number of bowel movements with urgency:  
6. 
Please rate your worst abdominal pain over the past 24 hours. 
0-10 numeric rating scale, with 0 anchor at “No pain” and 10 at “Worst Imaginable Pain” 
 


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17 Sep 2020 
 
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 PCR for toxin), Figure A3 (using 
toxigenic culture) or Figure A4 (using toxigenic culture, followed by PCR). The rationale for the 
method in Figure A3 is that the majority of PCR tests are expected to be negative for toxin, thus 
obviating the need for the test at the central laboratory. The expected turnaround time at the 
central laboratory for a GDH card test is expected to be shorter than that for stool culture for 
C. difficile at the local laboratory. The details of the sensitivity and specificity of these tests were 
reported by Khanna (Khanna et al., 2017). 
When medically reasonable, treatment decisions should be deferred until an etiology has been 
determined. When this is not feasible, management of symptoms should be dictated by the 
clinical situation. 


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Figure A2 
Alternative 1 for C. difficile Testing Using Local Laboratory When No Alere 
Quick Chek Card Test is Available 
 
 
Figure A3 
Alternative 2 for C. difficile Testing Using Local Laboratory When No Card 
Test is Available 
 
 


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

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
NCT Number:   
NCT03290781 
 
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 Ulcerative Colitis (FIGARO UC 303) 
 
 
Study Number:  
SHP647-303 
 
 
SAP Version and Date:   
Version 3:  
 
23 Jun 2021 


 
 
STATISTICAL ANALYSIS PLAN 
SHP647 
PHASE 3 
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 Ulcerative Colitis (FIGARO UC 303) 
PROTOCOL IDENTIFIER: SHP647-303 
 
Study Sponsor(s): 
Shire Human Genetic Therapies, Inc. (“Shire”), 
300 Shire Way, Lexington, MA 02421 USA 
Author: 
 
       
, 
, PPD 
Protocol: 
 
       V1 (10 Jul 2017) 
 
 
       Amendment 1 (11 Sep 2018) 
 
 
       Amendment 2 (11 Nov 2019) 
 
 
       Amendment 3 (17 Sep 2020) 
SAP Version #: 
       3 
SAP Date: 
 
       23 Jun 2021 
Status: 
                   Final 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303 
    23 Jun 2021 
REVISION HISTORY 
Version 
Issue Date 
Summary of Changes 
1.0 
22 Oct 2020 
Final Document 
2.0 
20 Nov 2020 
Updated text in Section 6.1.1 and Section 6.2.1. 
Minor editorial and formatting changes. 
 
2.1 
13 Jan 2021 
Updated Tables 6, 7 and 9 to adjust Study Day 
start and end dates 
3 
23 Jun 2021 
Updated text in Section 5.3, Section 9, and 
Section 12.1. Fixed a hyperlink that does not 
work properly. 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303 
    23 Jun 2021 
TABLE OF CONTENTS 
REVISION HISTORY................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................ 3 
ABBREVIATIONS ..................................................................................................... 8 
1.INTRODUCTION.................................................................................................. 10 
2.OBJECTIVES, ESTIMANDS, AND ENDPOINTS ............................................... 10 
2.1 
Objectives................................................................................................... 10 
2.1.1 Primary Objective ................................................................................ 10 
2.1.2 Key Secondary Objectives .................................................................... 10 
2.1.3 Other Secondary Objectives.................................................................. 11 
2.2 
Estimands ................................................................................................... 11 
2.3 
Endpoints ................................................................................................... 21 
2.3.1 Primary Endpoint ................................................................................. 21 
2.3.2 Key Secondary Endpoints..................................................................... 21 
2.3.3 Other Secondary Endpoints .................................................................. 22 
2.3.4 
 ................................................................ 23 
3.STUDY DESIGN.................................................................................................... 23 
3.1 
General Description .................................................................................... 23 
3.2 
Randomization............................................................................................ 28 
3.3 
Blinding ..................................................................................................... 29 
3.4 
Sample Size and Power Considerations........................................................ 30 
4.STATISTICAL ANALYSIS SETS ........................................................................ 32 
4.1 
Screened Set ............................................................................................... 32 
4.2 
Randomized Set .......................................................................................... 32 
4.3 
Safety Set ................................................................................................... 32 
4.4 
Ontamalimab Responder Full Analysis Set .................................................. 32 
4.5 
Placebo Responder Full Analysis Set ........................................................... 32 
4.6 
 ................................................................................. 32 
5.STUDY SUBJECTS ............................................................................................... 33 
5.1 
Disposition of Subjects................................................................................ 33 


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5.2 
Demographic and Other Baseline Characteristics ......................................... 34 
5.3 
Medical History .......................................................................................... 37 
5.4 
Prior Medications........................................................................................ 37 
5.5 
Concomitant Therapies, Procedures and Medications ................................... 37 
5.6 
Exposure to Investigational Product ............................................................. 38 
5.7 
Measurements of Treatment Compliance ..................................................... 38 
5.8 
Protocol Deviations..................................................................................... 39 
6.EFFICACY ANALYSES ....................................................................................... 40 
6.1 
Analyses of Primary Efficacy Endpoint ....................................................... 40 
6.1.1 Sensitivity Analyses of Primary Efficacy Endpoint................................ 41 
6.1.2 Supplementary Analyses of Primary Efficacy Endpoint ......................... 42 
6.2 
Analyses of Key Secondary Efficacy Endpoints ........................................... 42 
6.2.1 Sensitivity Analyses of Key Secondary Efficacy Endpoints ................... 44 
6.2.2 Supplementary Analyses of Key Secondary Efficacy Endpoints............. 44 
6.3 
Analyses of Other Secondary Efficacy Endpoints ......................................... 44 
6.3.1 Sensitivity Analyses of Other Secondary Efficacy Endpoints ................. 45 
6.3.2 Supplementary Analyses of Other Secondary Efficacy Endpoints .......... 45 
6.4 
Multiplicity Adjustment .............................................................................. 45 
6.5 
Subgroup Analyses ..................................................................................... 47 
7.SAFETY ANALYSIS ............................................................................................. 47 
7.1 
Adverse Events ........................................................................................... 47 
7.1.1 Adverse Events of Special Interest and Other Potential Risks................. 48 
7.1.1.1 Hypersensitivity .......................................................................... 48 
7.2 
Clinical Laboratory Data ............................................................................. 49 
7.3 
Pregnancy Test and Follicle-stimulating Hormone Test ................................ 52 
7.4 
Vital Signs .................................................................................................. 52 
7.5 
Electrocardiogram (ECG) ............................................................................ 53 
7.6 
Other Safety Data........................................................................................ 54 
7.6.1 Targeted Neurological Assessment ....................................................... 54 
7.6.2 Immunogenicity ................................................................................... 54 
7.6.3 Contraception Check ............................................................................ 55 
7.6.4 Physical Examination ........................................................................... 55 
8.
 ..................................................................... 55 
8.1 
..................................................................................... 55 


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8.2 
................................... 55 
8.3 
 ........................................................................ 56 
8.4 
................................................ 56 
9.
................................................................... 56 
10.OTHER ANALYSES ........................................................................................... 56 
10.1 
Coronavirus Pandemic ................................................................................ 56 
11.INTERIM ANALYSIS/DATA MONITORING (REVIEW) COMMITTEE ...... 57 
12.DATA HANDLING CONVENTIONS................................................................. 57 
12.1 
General Data Reporting Conventions ........................................................... 57 
12.2 
Definition of Treatment Failure ................................................................... 57 
12.3 
Definition of Visit Windows........................................................................ 58 
12.4 
Derived Efficacy Endpoints ......................................................................... 60 
12.4.1 Total Mayo Score ................................................................................. 60 
12.4.2 Composite Score .................................................................................. 61 
12.4.3 Mucosal Healing .................................................................................. 61 
12.4.4 Total Sign/Symptom Score ................................................................... 61 
12.5 
Repeated or Unscheduled Assessments of Safety Parameters ........................ 63 
12.6 
Handling of Missing, Unused, and Spurious Data......................................... 63 
12.6.1 Missing Date of End of Treatment ........................................................ 63 
12.6.2 Missing Date of Ulcerative Colitis Diagnoses........................................ 63 
12.6.3 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ......................................................................... 64 
12.6.3.1 Incomplete Start Date ............................................................. 64 
12.6.3.1.1 Missing Day and Month................................................... 64 
12.6.3.1.2 Missing Month Only........................................................ 64 
12.6.3.1.3 Missing Day Only ........................................................... 64 
12.6.3.2 Incomplete Stop Date.............................................................. 65 
12.6.3.2.1 Missing Day and Month................................................... 65 
12.6.3.2.2 Missing Month Only........................................................ 65 
12.6.3.2.3 Missing Day Only ........................................................... 65 
12.6.4 Missing Date Information for Adverse Events ....................................... 66 
12.6.4.1 Incomplete Start Date ............................................................. 66 
12.6.4.2 Incomplete Stop Date.............................................................. 66 
12.6.5 Missing Severity Assessment for Adverse Events .................................. 66 


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12.6.6 Missing Relationship to IP for Adverse Events ...................................... 66 
12.6.7 Character Values of Clinical Laboratory Variables ................................ 66 
13.ANALYSIS SOFTWARE .................................................................................... 67 
14.CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ................................ 67 
15.REFERENCES .................................................................................................... 68 
16.APPENDICES...................................................................................................... 69 
16.1 
Schedule of Activities Prior to Amendment 3............................................... 69 
16.2 
Schedule of Activities Under Amendment 3................................................. 74 
16.3 
Geographic Regions .................................................................................... 78 
16.4 
UC Medication History or Use Subgroup Identification................................ 80 
16.5 
Rescue Therapy for Ulcerative Colitis.......................................................... 83 
16.6 
Treatment Groups ....................................................................................... 87 
 
 
 


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Table 1:  
List of Select Estimands ................................................................... 12 
Table 2: 
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints........................................................................ 31 
Table 3: 
Criteria for Potentially Clinically Important Laboratory Tests ............ 50 
Table 4: 
Criteria for Potentially Clinically Important Vital Signs..................... 53 
Table 5: 
Criteria for Potentially Clinically Important ECG Values .................. 54 
Table 6:  
Visit Windows (Study Day Based) – PRO, Mayo, and Endoscopy 
Assessments .................................................................................... 58 
Table 7:  
Visit Windows (Study Day Based) – ADA Assessments.................... 59 
Table 8:  
Visit Windows (Study Day Based) – 
 and ECG Assessments ........ 59 
Table 9:  
Visit Windows (Study Day Based) – Safety Lab, Vital Sign, Physical 
Examination, and Neurological Testing Assessments ........................ 60 
Table 10  Proposed Categorized Sign/Symptom Score Conversion Scale .......... 63 
Table 11  Geographic Regions ......................................................................... 78 
 
 
 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303 
    23 Jun 2021 
ABBREVIATIONS 
 
ADA 
anti-drug antibody 
ANCOVA 
analysis of covariance 
AE 
adverse event 
BMI 
body mass index 
BLQ 
below the limit of quantification 
CI 
confidence interval 
CDF 
cumulative distribution function 
CMH 
Cochran-Mantel Haenszel 
CRO 
contract research organization 
 
 
DMC 
data monitoring committee 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
 
 
 
 
 
 
ET 
early termination 
EOF 
End of Follow-up 
EOT 
End of Treatment 
FAS 
full analysis set 
FWER 
family-wise type I error rate 
HEOR 
Health Economics and Outcomes Research 
HRQL 
health-related quality of life 
HRUA 
Healthcare Resource Utilization Analyses 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICF 
informed consent form 
LLOQ 
lower limit of quantification 
IP 
investigational product 
LOCF 
last observation carried forward 
LTS 
long-term safety extension 
NAb 
neutralizing antibodies 
 
 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNT 
maintenance study 
PCI 
potentially clinically important 
 
 
PDF 
probability density function 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303 
    23 Jun 2021 
PGA 
physician global assessment 
 
 
 
 
 
 
PML 
progressive multifocal leukoencephalopathy 
PRO 
patient-reported outcome 
Q4W 
once every 4 weeks 
QoL 
quality of life 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RB 
rectal bleeding 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous/subcutaneously 
SF 
stool frequency 
SF-36 
Short Form-36 Health Survey 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
 
 
UC 
ulcerative colitis 
VAS 
visual analogue scale 
WHO 
World Health Organization 
 
 
 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303 
    23 Jun 2021 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy and safety, as well as descriptive summaries of 
 data and Health Economics and Outcomes Research (HEOR) 
data, as described in Protocol Amendment 3 dated 17 Sep 2020 (original protocol dated 
10 Jul 2017). Specifications for tables, figures, and listings are contained in a separate 
document. The analysis plans for 
 and HEOR patient-reported outcome (PRO) 
validation, if performed, are prepared separately. 
On May 29, 2020, Takeda announced the decision to discontinue the ontamalimab 
clinical trial program in ulcerative colitis (UC) and Crohn’s disease (CD). The planned 
analyses reflect the early discontinuation of this study. 
2. 
OBJECTIVES, ESTIMANDS, AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objective 
The primary objective of the study is to evaluate the efficacy of ontamalimab as 
maintenance treatment of remission, based on composite score of patient-reported 
symptoms and centrally read endoscopy, in subjects with moderate to severe UC. 
2.1.2 Key Secondary Objectives 
The key secondary objectives are as follows: 
• To evaluate the efficacy of ontamalimab on endoscopic remission, based on centrally 
read endoscopy. 
• To evaluate the efficacy of ontamalimab on clinical remission, based on composite 
score of patient-reported symptoms. 
• To evaluate the efficacy of ontamalimab on maintenance of remission among subjects 
in remission at baseline of the SHP647-303 study, based on composite score of 
patient-reported symptoms and centrally read endoscopy. 
• To evaluate the efficacy of ontamalimab on clinical response, based on composite 
score of patient-reported symptoms and centrally read endoscopy. 


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• To evaluate the efficacy of ontamalimab on mucosal healing, on a centrally read 
endoscopic and histological assessment using the Geboes Score grading system. 
• To evaluate the efficacy of ontamalimab on glucocorticoid-free clinical remission. 
• To evaluate the efficacy of ontamalimab on glucocorticoid-free remission. 
2.1.3 Other Secondary Objectives 
The other secondary objective is: 
• To evaluate the effect of ontamalimab maintenance treatment on other clinical and 
endoscopic outcomes (Mayo-based remission, clinical remission over time, and 
sustained endoscopic remission). 
2.2 
Estimands 
The primary and key secondary estimands are described in Table 1. 
 


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Protocol Number: SHP647-303                                                                                                                                                                                  23 Jun 2021 
Table 1: List of Select Estimands 
Estimand 
Definition 
Attributes 
A: Population 
B: Variable 
C: Strategy for 
Addressing 
Intercurrent 
Event 
D: Population-level Summary 
Primary 
The primary estimand 
is the effect of 
ontamalimab 
compared to placebo 
at Week 52 in 
remission. 
16- to 80-year-old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol 
Remission at the 
Week 52 visit 
without treatment 
failure or rescue 
therapy defined in 
Appendix 16.5 or 
discontinuation 
Composite: 
intercurrent 
events captured 
in variable 
definition 
Difference in proportions of subjects 
in remission at the Week 52 visit 
between each active treatment group 
(25 mg or 75 mg ontamalimab) and 
the corresponding placebo (25 mg in 
induction placebo group or 75 mg in 
induction placebo group; placebo 
groups are not pooled) 
Key 
Secondary 
1st key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 52 in impact 
on endoscopic 
remission. 
16- to 80-year-old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol 
Endoscopic remission 
at the Week 52 visit, 
defined by centrally 
read endoscopic 
subscore 0 or 1 
(modified, excludes 
friability), at the 
Week 52 visit 
without treatment 
failure or rescue 
therapy defined in 
Appendix 16.5 or 
discontinuation 
Composite: 
intercurrent 
events captured 
in variable 
definition 
Difference in proportions of subjects 
in endoscopic remission at the 
Week 52 visit between each active 
treatment group (25 mg or 75 mg 
ontamalimab) and the corresponding 
placebo (25 mg in induction placebo 
group or 75 mg in induction placebo 
group; placebo groups are not 
pooled) 


Shire                                                                                                   CONFIDENTIAL                                                                                      Page 13 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                                                                                                  23 Jun 2021 
Estimand 
Definition 
Attributes 
A: Population 
B: Variable 
C: Strategy for 
Addressing 
Intercurrent 
Event 
D: Population-level Summary 
Key 
Secondary 
2nd key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 52 in impact 
on clinical remission. 
16- to 80-year-old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol 
Clinical remission at 
the Week 52 visit, 
defined by stool 
frequency subscore of 
0 or 1 with at least a 
1-point change from 
induction study 
(SHP647-301 or 
SHP647-302) 
baseline in stool 
frequency subscore, 
and rectal bleeding 
subscore of 0, at the 
Week 52 visit 
without treatment 
failure or rescue 
therapy defined in 
Appendix 16.5 or 
discontinuation 
Composite: 
intercurrent 
events captured 
in variable 
definition 
Difference in proportions of subjects 
in clinical remission at the Week 52 
visit between each active treatment 
group (25 mg or 75 mg 
ontamalimab) and the corresponding 
placebo (25 mg in induction placebo 
group or 75 mg in induction placebo 
group; placebo groups are not 
pooled) 


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Protocol Number: SHP647-303                                                                                                                                                                                  23 Jun 2021 
Key 
Secondary 
3rd key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 52 in impact 
on sustained 
remission. 
16- to 80-year-old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol 
Sustained remission 
defined as in 
remission at the 
SHP647-303 
Week 52 visit, 
without treatment 
failure or rescue 
therapy defined in 
Appendix 16.5 or 
discontinuation, 
among subjects who 
were in remission at 
the time of baseline 
in 
Study SHP647-303. 
Remission is defined 
as a composite score 
of patient-reported 
symptoms using daily 
e-diary and centrally 
read endoscopy, with 
stool frequency 
subscore of 0 or 1 
with at least a 1-point 
change from 
induction study 
(SHP647-301 or 
SHP647-302) 
Composite: 
intercurrent 
events captured 
in variable 
definition 
Difference in proportions of subjects 
with sustained remission at the 
Week 52 visit between each active 
treatment group (25 mg or 75 mg 
ontamalimab) and the corresponding 
placebo (25 mg in induction placebo 
group or 75 mg in induction placebo 
group; placebo groups are not 
pooled) 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                                                                                                  23 Jun 2021 
Estimand 
Definition 
Attributes 
A: Population 
B: Variable 
C: Strategy for 
Addressing 
Intercurrent 
Event 
D: Population-level Summary 
baseline, and rectal 
bleeding subscore of 
0, and endoscopic 
subscore of 0 or 1 
(modified, excludes 
friability). 
Key 
Secondary 
4th key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 52 in impact 
on clinical response 
based on composite 
score. 
16- to 80-year-old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol 
Clinical response at 
the Week 52 visit, 
defined as a decrease 
from induction study 
(SHP647-301 or 
SHP647-302) 
baseline in the 
composite score of 
subject-reported 
symptoms using daily 
e-diary and centrally 
read endoscopy of at 
least 2 points and at 
least 30%, with an 
accompanying 
decrease in the 
Composite: 
intercurrent 
events captured 
in variable 
definition 
Difference in proportions of subjects 
with clinical response at the Week 52 
visit between each active treatment 
group (25 mg or 75 mg 
ontamalimab) and the corresponding 
placebo (25 mg in induction placebo 
group or 75 mg in induction placebo 
group; placebo groups are not 
pooled) 


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Estimand 
Definition 
Attributes 
A: Population 
B: Variable 
C: Strategy for 
Addressing 
Intercurrent 
Event 
D: Population-level Summary 
subscore for rectal 
bleeding ≥1 point or a 
subscore for rectal 
bleeding ≤1 without 
treatment failure or 
rescue therapy 
defined in 
Appendix 16.5 or 
discontinuation 
Key 
Secondary 
5th key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 52 in impact 
on mucosal healing. 
16- to 80-year-old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol 
Mucosal healing at 
the Week 52 visit, 
defined as centrally 
read endoscopic 
subscore 0 or 1 
(modified, excludes 
friability) and 
centrally read Geboes 
score of ≤2 without 
treatment failure or 
rescue therapy 
defined in 
Composite: 
intercurrent 
events captured 
in variable 
definition 
Difference in proportions of subjects 
with mucosal healing at the Week 52 
visit between each active treatment 
group (25 mg or 75 mg 
ontamalimab) and the corresponding 
placebo (25 mg in induction placebo 
group or 75 mg in induction placebo 
group; placebo groups are not 
pooled) 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                                                                                                  23 Jun 2021 
Estimand 
Definition 
Attributes 
A: Population 
B: Variable 
C: Strategy for 
Addressing 
Intercurrent 
Event 
D: Population-level Summary 
Appendix 16.5 or 
discontinuation. 
Key 
Secondary 
6th key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 52 in impact 
on glucocorticoid-
free clinical 
remission. 
16- to 80-year-old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol 
Glucocorticoid-free 
clinical remission at 
the Week 52 visit, 
among subjects using 
glucocorticoids at 
induction study 
baseline, defined as 
clinical remission in 
addition to not 
requiring any 
treatment with 
glucocorticoids for at 
least 4 weeks prior to 
the Week 52 visit. 
Clinical remission is 
defined as stool 
frequency subscore of 
0 or 1 with at least a 
1-point change from 
induction study 
Composite: 
intercurrent 
events captured 
in variable 
definition 
Difference in proportions of subjects 
with glucocorticoid-free clinical 
remission at the Week 52 visit 
between each active treatment group 
(25 mg or 75 mg ontamalimab) and 
the corresponding placebo (25 mg in 
induction placebo group or 75 mg in 
induction placebo group; placebo 
groups are not pooled) 


Shire                                                                                                   CONFIDENTIAL                                                                                      Page 18 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                                                                                                  23 Jun 2021 
Estimand 
Definition 
Attributes 
A: Population 
B: Variable 
C: Strategy for 
Addressing 
Intercurrent 
Event 
D: Population-level Summary 
(SHP647-301 or 
SHP647-302) 
baseline in stool 
frequency subscore, 
and rectal bleeding 
subscore of 0, at the 
Week 52 visit, 
without treatment 
failure or rescue 
therapy defined in 
Appendix 16.5 or 
discontinuation. 


Shire                                                                                                   CONFIDENTIAL                                                                                      Page 19 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                                                                                                  23 Jun 2021 
Key 
Secondary 
7th key secondary 
estimand is the effect 
of ontamalimab 
compared to placebo 
at Week 52 in impact 
on glucocorticoid-
free remission. 
16- to 80-year-old 
adolescents and 
adults with UC 
defined through 
inclusion and 
exclusion criteria as 
stated in the protocol 
Glucocorticoid-free 
remission at the 
Week 52 visit, among 
subjects using 
glucocorticoids at 
induction study 
baseline, defined as 
remission in addition 
to not requiring any 
treatment with 
glucocorticoids for at 
least 4 weeks prior to 
the Week 52 visit. 
Remission is defined 
as a composite score 
of subject-reported 
symptoms using daily 
e-diary and 
endoscopy, with stool 
frequency subscore of 
0 or 1 with at least a 
1-point change from 
induction study 
(SHP647-301 or 
SHP647-302) 
baseline, and rectal 
bleeding subscore of 
0, and endoscopic 
Composite: 
intercurrent 
events captured 
in variable 
definition 
Difference in proportions of subjects 
with glucocorticoid-free remission at 
the Week 52 visit between each 
active treatment group (25 mg or 
75 mg ontamalimab) and the 
corresponding placebo (25 mg in 
induction placebo group or 75 mg in 
induction placebo group; placebo 
groups are not pooled) 


Shire                                                                                                   CONFIDENTIAL                                                                                      Page 20 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                                                                                                  23 Jun 2021 
Estimand 
Definition 
Attributes 
A: Population 
B: Variable 
C: Strategy for 
Addressing 
Intercurrent 
Event 
D: Population-level Summary 
subscore of 0 or 1 
(modified, excludes 
friability), without 
treatment failure or 
rescue therapy 
defined in 
Appendix 16.5 or 
discontinuation. 
 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
 
2.3 
Endpoints 
2.3.1 Primary Endpoint 
The primary efficacy endpoint is remission at the Week 52 visit. Remission is defined as 
a composite score of patient-reported symptoms using daily e-diary and centrally read 
endoscopy as follows: 
• Stool frequency (SF) subscore of 0 or 1 with at least a 1-point change from 
induction (SHP647-301 or SHP647-302) baseline 
AND 
• Rectal bleeding (RB) subscore of 0 
AND 
• Endoscopic subscore of 0 or 1 (modified, excludes friability). 
2.3.2 Key Secondary Endpoints 
• Endoscopic remission, as defined by centrally read endoscopic subscore 0 or 1 
(modified, excludes friability), at the Week 52 visit. 
• Clinical remission, as defined by SF subscore of 0 or 1 with at least a 1-point 
change from induction study (SHP647-301 or SHP647-302) baseline in 
SF subscore, and RB subscore of 0, at the Week 52 visit. 
• Sustained remission, ie, in remission at the SHP647-303 Week 52 visit, among 
subjects who were in remission at the time of baseline in Study SHP647-303. 
Remission is defined as a composite score of patient-reported symptoms using 
daily e-diary and centrally read endoscopy, with SF subscore of 0 or 1 with at 
least a 1-point change from induction study (SHP647-301 or SHP647-302) 
baseline, and RB subscore of 0, and endoscopic subscore of 0 or 1 (modified, 
excludes friability). 
• Clinical response based on composite score at the Week 52 visit. Clinical 
response (composite) is defined as a decrease from induction study 
(SHP647-301 or SHP647-302) baseline in the composite score of 
subject-reported symptoms using daily e-diary and centrally read endoscopy of 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
 
at least 2 points and at least 30%, with an accompanying decrease in the 
subscore for RB ≥1 point or a subscore for RB ≤1. 
• Mucosal healing based on endoscopic and histological assessment at the 
Week 52 visit. Mucosal healing is defined by centrally read endoscopic 
subscore 0 or 1 (modified, excludes friability) and centrally read Geboes score 
of ≤2. 
• Glucocorticoid-free clinical remission at Week 52, among subjects using 
glucocorticoids at induction study (SHP647-301 or SHP647-302) baseline. 
Glucocorticoid-free clinical remission is defined as clinical remission in 
addition to not requiring any treatment with glucocorticoids for at least 4 weeks 
prior to the Week 52 visit. Clinical remission is defined as SF subscore of 0 or 1 
with at least a 1-point change from induction study (SHP647-301 or 
SHP647-302) baseline in SF subscore, and RB subscore of 0, at the Week 52 
visit. 
• Glucocorticoid-free remission at Week 52, among subjects using 
glucocorticoids at induction study (SHP647-301 or SHP647-302) baseline. 
Glucocorticoid-free remission is defined as remission in addition to not 
requiring any treatment with glucocorticoids for at least 4 weeks prior to the 
Week 52 visit. Remission is defined as a composite score of subject-reported 
symptoms using daily e-diary and endoscopy, with SF subscore of 0 or 1 with at 
least a 1-point change from induction study (SHP647-301 or SHP647-302) 
baseline, and RB subscore of 0, and endoscopic subscore of 0 or 1 (modified, 
excludes friability). 
2.3.3 Other Secondary Endpoints 
• Remission defined as a total Mayo score of ≤2 with no individual subscore (SF, 
RB, endoscopy [modified, excludes friability], and physician’s global 
assessment [PGA]) exceeding 1, at Week 52. 
• Clinical remission over time with both RB and SF subscores of 0. 
• Sustained endoscopic remission, ie, in endoscopic remission at the SHP647-303 
Week 52 visit among subjects who were in remission at the time of baseline in 
Study SHP647-303, as defined by a centrally read endoscopic subscore of 0 or 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
 
1 (modified, excludes friability). 
2.3.4 
 
 
 
 
 
3. 
STUDY DESIGN 
3.1 
General Description 
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study in 
subjects with moderate to severe UC who completed their participation in an induction 
study (either SHP647-301 or SHP647-302) and achieved a clinical response. 
Clinical response is defined as: 
1) A decrease from induction study (SHP647-301 or SHP647-302) baseline in the 
composite score of patient-reported symptoms using daily electronic diary (e-diary) and 
centrally read endoscopy of at least 2 points and at least 30%, with an accompanying 
decrease in the subscore for rectal bleeding ≥1 point or a subscore for rectal bleeding ≤1 
OR 
2) A decrease from induction study (SHP647-301 or SHP647-302) baseline in total Mayo 
score of at least 3 points and at least 30%, with an accompanying decrease in the rectal 
bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. 
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). 
Approximately 696 subjects will be enrolled into the study. Approximately 592 subjects 
from active induction treatments and approximately 104 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 12 visit of the induction studies, which will be considered as the 
baseline visit for this maintenance study. 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
 
Eligible subjects who received active treatment in one of the induction studies and 
achieved a clinical response will be randomly assigned 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 achieved a 
clinical response will be randomly assigned 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 SHP647-303 baseline, the 
subject’s status of prior anti-TNF treatment (naïve or experienced), and the degree of 
clinical response in the induction study (whether remission is achieved or not). 
Subjects enrolled in this study (SHP647-303) will receive double-blind maintenance 
treatment in the form of SC injections, using a prefilled syringe (PFS), every 4 weeks for 
52 weeks. Subjects will undergo efficacy, 
 
and safety assessments as detailed in Section 16.2. 
Under Protocol 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 UC studies is shown in Figure 1, and the 
overall study design is shown in Figure 2. 




Shire                                                                                                       CONFIDENTIAL 
                                                        Page 26 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                    
 
 
 
 
23 Jun 2021 
Figure 2 Study Design Flow Chart 
 
LTS=long-term safety extension; Q4W=every 4 weeks. 
Treatment assignment 
in induction study 
SHP647-301 or 
SHP647-302: 
Treatment period: 52 weeks 
25 mg 
ontamalimab 
75 mg 
ontamalimab 
Dosing: Q4W 
Placebo 
25 mg 
ontamalimab 
Placebo 
75 mg 
ontamalimab 
Placebo 
25 mg 
ontamalimab 
75 mg 
ontamalimab 
Placebo 
1:1 
1:1 
2:2:1a 
Treatment period: 12 weeks 
Dosing: Q4W 
12-week safety 
follow-up periodb 
Week 52/End of 
Treatment 
Randomization 
into SHP647-303 
LTS study 
(SHP647-304)b 


Shire                                                                                                       CONFIDENTIAL 
                                                        Page 27 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                    
 
 
 
 
23 Jun 2021 
a 
Eligible subjects who received placebo in one of the induction studies and achieved a clinical response will be randomly assigned in a 2:2:1 ratio to 
receive one of 3 treatments (25 mg SHP647, 75 mg SHP647, or placebo, respectively). 
b 
With the implementation of Protocol 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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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
3.2 
Randomization 
The actual treatment given to individual subjects is determined by a randomization 
schedule. 
The composite score and total Mayo score will be calculated at baseline (Week 12/Visit 6 
of induction study SHP647-301 or SHP647-302 will be used for Week 0/Day 1/Visit 1 of 
Study SHP647-303) before randomization. Endoscopic subscore based on the central 
reader’s assessment will be used to determine eligibility. 
Subjects who are qualified as a clinical responder, who fulfill all other eligibility criteria, 
and who received active treatment in the induction study (SHP647-301 or SHP647-302) 
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 are qualified as a clinical responder, who fulfill all other eligibility criteria, 
and who received placebo in the induction study will be randomly assigned in a 
2:2:1 ratio to receive one 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 SHP647-303 (maintenance; 
MNT) baseline defined in Appendix 16.4, the subject’s status of prior anti-TNF treatment 
(naïve or experienced), and the degree of clinical response in the induction study 
(whether remission is achieved or not). 
The randomization number represents a unique number corresponding to investigational 
product (IP) allocated to the subject, once eligibility has been determined. Individual 
subject treatment is 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 IP packing identification 
number may not be assigned to more than one subject. 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
3.3 
Blinding 
This is a double-blind, placebo-controlled study. All investigational and reference 
product (ontamalimab 25 mg, ontamalimab 75 mg, or placebo) will appear identical to 
protect the study blind. 
Data that may potentially unblind the treatment assignment (eg, IP serum concentrations, 
antibodies to IP, treatment allocation, and IP preparation/accountability data) will be 
handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, before unblinding, any data that may unblind study team 
personnel will be presented as blinded information or otherwise will not be made 
available. If applicable, unblinded data may be made available to quality assurance 
representatives for the purposes of conducting independent drug audits. 
Whenever possible, the investigator or sub-investigator should contact the Shire 
physician and/or assigned medical monitor before breaking the blind. It is understood that 
in an emergency situation it may not be possible to communicate with the study team 
before breaking the blind. The safety of the subject should be of primary concern. When 
the blinding code is broken the reasons must be fully documented. 
In the event that the treatment assignment is broken, the date, the signature of the person 
who broke the code, and the reason for breaking the code are recorded on the IRT and the 
source documents. Upon breaking the blind, the subject is withdrawn from the study, but 
should be followed up for safety purposes. The IRT will notify the relevant personnel in 
the event of any code break. Code-break information is held by the pharmacist/designated 
person at the site. 
Due to early termination of the ontamalimab program, the sponsor is providing an option 
for subjects who had responded to active treatment (in this maintenance study or in the 
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 early termination 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 early termination visit will be recorded. 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
In addition, due to the early discontinuation of the SHP647 program, the SHP647-304 
study is planned to 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. 
3.4 
Sample Size and Power Considerations 
The planned sample size for this maintenance study depends on enrollment from the 
induction studies (SHP647-301 and SHP647-302). Assuming that 50% of subjects 
receiving ontamalimab induction treatments and 35% of subjects receiving placebo 
induction treatment in Studies SHP647-301 and SHP647-302 will have a clinical 
response at Week 12, an estimated 696 subjects will be eligible to enter this maintenance 
study: 296 subjects from ontamalimab 25 mg induction treatment, 296 subjects from 
ontamalimab 75 mg induction treatment, and 104 subjects from placebo induction 
treatment. Expected clinical response rates at Week 12 are based on observed rates from 
the A7281009 study. 
This study is designed to have approximately 85% power for the primary endpoint to 
detect an individual pairwise treatment difference at a highly statistically persuasive level 
(ie, a p-value ≤.001). However, an alpha of .05 (2-sided) will be used as the overall Type-
I error rate for the purposes of demonstration of efficacy in this study and declaring study 
success. The power will be reported for both Type-I error thresholds (.05 and .001). 
Graphical methods are used to control the global family-wise Type-I error rate (FWER) 
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 .025 level (2-sided) for each of the pairwise treatment comparisons. 
Therefore, the power analysis and sample size estimation were calculated based on the 
chi-square test of proportions using nQuery Advisor Version 7.0 for an individual 
ontamalimab dose compared to placebo. 
Power calculations are based on assuming a .025 (2-sided) significance level for each 
pairwise treatment comparison, 296 subjects previously treated with 25 mg ontamalimab 
in induction (1:1 allocation ratio: 148 subjects in 25 mg ontamalimab treatment group vs. 
148 subjects in the placebo group) and 296 subjects treated with 75 mg ontamalimab in 
induction (1:1 allocation ratio: 148 subjects in the 75 mg ontamalimab treatment group 
vs. 148 subjects in the placebo group) would yield an approximately 98% power (85% 
for alpha = .001) to detect individual pairwise treatment difference in the primary 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
efficacy endpoint, remission at Week 52, of 23% (15% placebo versus 38% 
ontamalimab). Expected remission rates at Week 52 were based on observed rates from 
an analysis of Study A7281010, which was ongoing at the time of the original protocol 
and placebo remission rates from literature (Feagan et al. 2013; Sandborn et al. 2017). No 
adjustment for missing data is required in these sample size calculations as subjects with 
missing data for remission at Week 52 are imputed as failures and the above rates 
account for these subjects. 
With the planned sample size of 296 subjects previously treated with 25 mg in induction 
and 296 subjects previously treated with 75 mg in induction, Table 2 provides the power 
for detecting a treatment difference between an ontamalimab treatment group and the 
placebo group for the key secondary endpoints. 
With the early discontinuation of the study, the planned sample size of 696 subjects will 
not be attained as the final number of subjects enrolled into this study is 366. Formal 
statistical testing of the primary and key secondary endpoints will still be conducted 
despite not reaching the planned sample size and power levels. 
Table 2: 
Power to Detect the Corresponding Treatment Effect for Key 
Secondary Endpoints 
Key Secondary Endpoint at 
Week 12 
SHP647 
Assumption 
Placebo 
Assumption 
Power 
(alpha = .05) 
Power 
(alpha = .001) 
Endoscopic remission 
42.5% 
15% 
0.99 
0.97 
Clinical remission 
60% 
32% 
0.99 
0.92 
Maintenance of remissiona 
65% 
25% 
0.96 
0.68 
Clinical response by composite 
score 
50% 
25% 
0.98 
0.84 
Mucosal healing 
30% 
13% 
0.91 
0.53 
Glucocorticoid-free clinical 
remissionb 
50% 
19% 
0.98 
0.79 
Glucocorticoid-free remissionb 
45% 
14% 
0.99 
0.84 
a 
Based on an anticipated 32% of subjects who will be in remission at baseline of this study. 
b 
Based on an anticipated 58% of subjects who will be on corticosteroids at baseline of this study. 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
4. 
STATISTICAL ANALYSIS SETS 
4.1 
Screened Set 
The Screened Set will consist of all subjects who have signed an informed consent 
document for the SHP647-303 study, regardless of treatment received during the 
induction studies (SHP647-301 and SHP647-302). 
4.2 
Randomized Set 
The Randomized Set will consist of all subjects in the screened set for whom a SHP647-
303 randomization number has been assigned, regardless of treatment received during the 
induction studies (SHP647-301 and SHP647-302). Analyses will be performed according 
to the randomized treatment regimen regardless of the treatment regimen actually 
received. 
4.3 
Safety Set 
The Safety Set will consist of all subjects who have received at least 1 dose of IP in the 
SHP647-303 study, regardless of treatment received during the induction studies 
(SHP647-301 and SHP647-302). Analyses will be performed according to the treatment 
regimen actually received regardless of the randomized treatment regimen. 
4.4 
Ontamalimab Responder Full Analysis Set 
The Ontamalimab Responder Full Analysis Set (FAS) will consist of all subjects in the 
randomized set who receive at least 1 dose of IP in the SHP647-303 study and who were 
previously treated with ontamalimab in the induction studies. Analyses will be performed 
according to the randomized treatment regimen regardless of the treatment regimen 
actually received. 
4.5 
Placebo Responder Full Analysis Set 
The Placebo Responder FAS will consist of all subjects in the randomized set who 
receive at least 1 dose of IP in the SHP647-303 study who were previously treated with 
placebo in the induction studies. Analyses will be performed according to the randomized 
treatment regimen regardless of the treatment regimen actually received. 
4.6 
 
 
 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
 
 
5. 
STUDY SUBJECTS 
Outputs will be presented by treatment groups as listed in Appendix 16.6. 
5.1 
Disposition of Subjects 
The number of screened subjects will be presented in the overall column. The number of 
subjects included in each analysis set (ie, Randomized, Safety, Ontamalimab Responder 
FAS, Placebo Responder FAS, and
) will be summarized by treatment groups as listed 
in Appendix 16.6. The percentage, based on the number of subjects in the Safety set, will 
be presented for Ontamalimab Responder FAS, Placebo Responder FAS, and 
 subject 
sets. The study analysis set classifications of each subject will be listed for the Screened 
Set. 
The number and percentage of subjects who completed and prematurely discontinued 
during the treatment and follow-up periods and reasons for premature discontinuation 
from the treatment and follow-up periods as recorded on the termination page of the 
electronic case report form (eCRF) will be summarized (number and percentage) by 
treatment group as listed in Appendix 16.6 for the Safety Set. The number and percentage 
of subjects who continued to the follow-up period and who continued to SHP647-304 
study will be presented by treatment group as listed in Appendix 16.6 for the Safety Set. 
The number and percentage of subjects who completed and prematurely discontinued the 
study will be presented by treatment group as listed in Appendix 16.6 for the Safety Set. 
Subjects who complete 52 weeks of treatment and roll over to the SHP647-304 study or 
enter and complete the safety follow-up period will be considered completed the study. 
Reasons for premature discontinuation from the study are derived from reasons for 
premature discontinuation from the treatment and follow-up periods. For subjects who 
discontinued from treatment, the reasons for discontinuation from the treatment will be 
presented regardless the status of safety follow-up period. For subjects who completed 
52 weeks of treatment and discontinued from the safety follow-up period, the reasons for 
discontinuation from the safety follow-up period will be presented. All subjects who 
prematurely discontinued during the treatment period, follow-up period, and study will be 
listed with their primary reason for discontinuation and duration of exposure for the 
Safety Set. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
In addition, number of subjects screened, randomized, and completed will be summarized 
for each site. The duration of enrollment, in days, will be summarized for each site and 
overall. Duration of enrollment will be calculated as (last date of contact for any subject 
at that site - the first date of informed consent for any subject at that site + 1). 
5.2 
Demographic and Other Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group as listed in Appendix 16.6 for the Safety Set, Ontamalimab Responder 
FAS, and Placebo Responder FAS. 
Subject’s age is from the induction study (SHP647-301 or SHP647-302), which is 
calculated as the difference between the date of birth and the date of informed consent in 
the induction study. If day of birth is missing then the day will be imputed as 1, if both 
the day and month of birth are missing then the day will be imputed as 1 and the month 
will be imputed as 1 (January). The following demographic characteristics will be 
summarized in the following order in the tables: age, age category (<18, 18 to <65 and 
≥65; <35 and ≥35 ), sex (Male, Female), ethnicity (Hispanic or Latino, Not Hispanic or 
Latino, Not Reported, Unknown), region (North America, Western Europe, Eastern 
Europe, Asia (Japan/South Korea), ROW (Africa/Australia/Latin America/Middle East), 
race (American Indian or Alaska Native, Asian (Japanese, Korean, Other), Black or 
African American, White, Native Hawaiian or Other Pacific Islander, and Other), 
Japanese ancestry (Currently living in Japan, Born in Japan and currently living outside 
of Japan for less than 5 years, and Other), and Korean ancestry (Currently living in 
Korea, Born in Korea and currently living outside of Korea for less than 5 years, and 
Other). 
Baseline is defined as the last assessment prior to the first administration of the IP in the 
induction study (SHP647-301 or SHP647-302) unless otherwise specified. Maintenance 
(MNT; SHP647-303) baseline is defined as the value for the assessment collected at the 
Week 12 visit of the induction study. The following baseline characteristics will be 
summarized: 
• Weight, 
• Height, 
• Body mass index (BMI), 
• UC disease duration and UC disease duration category (<1 year,  
≥1 to <3 years, ≥3 to <7 years and ≥7 years) 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
Disease duration is calculated as the number of years from the date of UC 
diagnosis to the date of informed consent in the induction study (SHP647-301 or 
SHP647-302), 
• UC disease location (Proctitis, Procto-Sigmoidits, Left-sided Colitis, Extensive 
Colitis/Pancolitis), 
• Total Mayo severity and total Mayo severity category (<6, 6 to <9, and ≥9), 
• Total Mayo severity and total Mayo severity category at MNT baseline (<6,  
6 to <9 and ≥9), 
• Stool frequency score (0, 1, 2, and 3), 
• Stool frequency score at MNT baseline (0, 1, 2, and 3), 
• Rectal bleeding score (0, 1, 2, and 3), 
• Rectal bleeding score at MNT baseline (0, 1, and 2), 
• Findings of endoscopy (0, 1, 2, and 3), 
• Findings of endoscopy at MNT baseline (0, 1, 2, and 3), 
• Physician global assessment (0, 1, 2, and 3), 
• Physician global assessment at MNT baseline (0, 1, 2, and 3), 
 
 
 
 
 
 
 
The following UC medication history/use will be summarized: 
• Immunosuppressant Experienced (Yes, No), 
• Anti-TNF Failure (Yes, No), 
• Anti-TNF Failure Times (Anti-TNF Naïve, Anti-TNF Experienced without 
Failure, Failed 1 anti-TNF therapy, Failed 2 anti-TNF therapies, Failed 3 or more 
anti-TNF therapies), 
• Anti-TNF Experienced (Experienced vs. Naïve) (both randomized status and 
actual status), 
• Maximum Prior Treatment Experience (Aminosalicylates experienced, 
Glucocorticoid experienced (further broken down into topical glucocorticoid 
experienced and systemic glucocorticoid experienced), Immunosuppressant 
experienced or Biologic failure, Immunosuppressant experienced and Biologic 
failure), 
• Glucocorticoid Use at Baseline(Yes, No) (actual status), 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
• Glucocorticoid Use at MNT Baseline (Yes, No) (both randomized status and 
actual status), 
• Immunosuppressant Use at MNT baseline (Yes, No), 
• Glucocorticoid Use at MNT baseline AND Immunosuppressant Use at MNT 
baseline (Both Glucocorticoid and Immunosuppressant Use, Only Glucocorticoid 
Use, Only Immunosuppressant Use, Neither Glucocorticoid nor 
Immunosuppressant Use), 
• Glucocorticoid Use at MNT baseline (Systemic or Topical, Systemic only, 
Topical only, None), 
• Systemic Glucocorticoid Dose at MNT Baseline, 
• Systemic Glucocorticoid Dose at MNT Baseline Category (≤10, >10), 
• 5-ASA Use at MNT baseline (Yes, No). 
The following outcomes from the induction study will be summarized: 
• The actual treatment received in the induction study (Placebo, Ontamalimab 
25 mg, Ontamalimab 75 mg), 
• Clinical Response (Yes, No), 
• Remission at MNT baseline (both randomized and actual status) (Yes, No), 
• Endoscopic remission at MNT baseline (Yes, No), 
• Clinical remission at MNT baseline (Yes, No), 
• Clinical response by composite score at Week 12 (Yes, No), 
• Mucosal healing at MNT baseline (Yes, No), 
• Clinical response by total Mayo score at MNT baseline (Yes, No). 
Smoking history will be recorded in the eCRF at the Screening Visit (Visit 1) in the 
induction study (SHP647-301 or SHP647-302) and will be summarized by treatment 
group as listed in Appendix 16.6. Smoking history will be listed for the Safety Set. 
Duration of smoking will be calculated as (substance use end date – substance use start 
date + 1). If substance use end date is missing, then it will be imputed as the 
randomization date.  


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
5.3 
Medical History 
Medical history will be collected at the Screening Visit (Visit 1) in the induction study 
(SHP647-301 or SHP647-302) and baseline visit in the SHP647-303 study, and will be 
listed for the Safety Set. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 19.1 2016 or newer. The induction study medical history will be 
summarized by the number and percentage of subjects for each treatment group as listed 
in Appendix 16.6, system organ class (SOC), and preferred term. 
Cardiovascular history will be collected at the Screening Visit (Visit 1) in the induction 
study (SHP647-301 or SHP647-302) and will be summarized by treatment group as listed 
in Appendix 16.6 for the Safety Set. Cardiovascular history will be listed for the Safety 
Set. 
UC history will be collected at the Screening Visit (Visit 1) in the induction study 
(SHP647-301 or SHP647-302) and will be listed for the Safety Set. 
5.4 
Prior Medications  
Prior medications will be coded using the World Health Organization (WHO) Drug 
Dictionary dated December 01, 2016 or newer. 
Prior medication is defined as any medication with start date prior to the date of the first 
dose of IP in the SHP647-303 study, and which is ongoing at the time of the baseline visit 
in the SHP647-303 study . Incomplete medication dates will be imputed as described in 
Section 12.6.3. 
All prior medications will be listed for the Safety Set. 
5.5 
Concomitant Therapies, Procedures and Medications 
Concomitant medications will be coded using the WHO Drug Dictionary dated 
01 Dec 2016. 
Concomitant medication is defined as any medication with a start date prior to the dates 
of the first dose of IP in the SHP647-303 study and continuing after the first dose of IP in 
the SHP647-303 study or with a start date between the dates of the first dose of IP in the 
SHP647-303 study and end of treatment date, inclusive. Medication that starts after the 
first dose of SHP647-304 IP will be collected in the SHP647-304 database and will not 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
be considered as concomitant medication in SHP647-303. Incomplete medication dates 
will be imputed as described in Section 12.6.3. Any medication with a start date between 
the dates of the first dose of IP and EOT date in SHP647-303, inclusive, or with a start 
date after the EOT date (post-treatment) in SHP647-303 will be considered a post-
treatment concomitant medication. 
Concomitant medication usage will be summarized by the number and percentage of 
subjects by treatment group as listed in Appendix 16.6, for subjects receiving each 
medication within each therapeutic class and preferred term for the Safety Set. Multiple 
medication usage by a subject in the same category will be counted only once. 
Summaries are presented separately for “Indication Under Study” and “not for Indication 
Under Study”. 
All concomitant medications, medical/surgical procedures, and therapies will be listed for 
the Safety Set. 
5.6 
Exposure to Investigational Product 
Investigational product (ontamalimab or placebo) will be administered SC every 4 weeks 
(from Week 0 to Week 48). Exposure to IP in the SHP647-303 study will be summarized 
by presenting the number of subjects who had 1 injection, 2 injections, 3 injections, etc. 
Number of injections received will be summarized by treatment groups as listed in 
Appendix 16.6. The administration records by visit will be listed for the Safety Set. 
Exposure to IP in the SHP647-303 study for the Safety Set will be summarized in terms 
of treatment duration, which is calculated as the number of days from the date of first 
dose of IP taken in the SHP647-303 study to the date of the last dose of IP taken in the 
SHP647-303 study + 29 days. Subject years of exposure is calculated as (Date of last 
dose of IP in the SHP647-303 study – date of first dose of IP in the SHP647-303 study + 
29)/365.25. Total subject years of exposure is calculated by summing the subject years of 
exposure for all subjects within each column. 
Descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) 
will be presented to describe the exposure to IP in the SHP647-303 study by treatment 
group as listed in Appendix 16.6. 
5.7 
Measurements of Treatment Compliance 
Compliance for the treatment period is defined as the total number of SC injections 
administered from the start of the treatment in the SHP647-303 study until the end of 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
treatment in the SHP647-303 study divided by the number of injections expected to be 
taken during that time period, times 100. Percent compliance will be summarized by 
treatment group as listed in Appendix 16.6. Percent compliance will be listed for the 
Safety Set. 
5.8 
Protocol Deviations 
Protocol deviations will be recorded by Pharmaceutical Product Development (PPD) 
separately from the clinical database. PPD/Shire will classify significant and 
nonsignificant protocol deviations per the agreed protocol deviation management plan. 
The Shire study team will review the protocol deviations and their classification 
throughout the study and before treatment unblinding and database lock. 
For any criteria for protocol deviations that can be completely implemented by a 
computer program, the detailed algorithm will be agreed upon. Details of such algorithms 
will be included in the derived dataset specifications and finalized before treatment 
unblinding. 
Confirmed significant and nonsignificant protocol deviations will be documented in the 
Protocol Deviation tracker for the study. Significant and nonsignificant protocol 
deviations will be summarized by category, site, and treatment group as listed in 
Appendix 16.6, for the Randomized Set. Significant and nonsignificant protocol 
deviations will be listed for the Randomized Set. The protocol deviations related to 
COVID-19 will be listed separately for the Randomized Set.  


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
6. 
EFFICACY ANALYSES 
All efficacy analyses will be based on Ontamalimab Responder FAS unless stated 
otherwise. Baseline for all efficacy analyses is defined as the last observed value for the 
efficacy assessment prior to taking the first dose of IP (based on dates or date/times) in 
the induction study (SHP647-301 or SHP647-302) unless otherwise specified. 
Maintenance baseline for all efficacy analyses is defined as the value for the efficacy 
assessment collected at the Week 12 visit of the induction study. 
The collected data shown in Appendix 16.1 but removed from Appendix 16.2 will be 
listed for the FAS including Inflammatory Bowel Disease Questionnaire questions, Short 
Form-36 Health Survey form, hospitalizations,
 
 
 
All efficacy analyses will be conducted according to the randomized treatment, regardless 
of the treatment actually received. 
All confidence intervals (CIs) will be 2-sided 95% CIs, unless stated otherwise. 
For continuous endpoints, descriptive summary statistics will be presented by treatment 
group at each scheduled visit and will include the following: n, mean, median, standard 
deviation, minimum, and maximum. For binary endpoints, number and percentage of 
subjects in each category will be summarized by treatment group at each scheduled visit. 
Due to the early discontinuation of the study before full enrollment and the limited 
sample size, planned efficacy analyses have been updated. 
6.1 
Analyses of Primary Efficacy Endpoint 
The primary efficacy endpoint is remission at the Week 52 visit. Remission is defined as 
a composite score of patient-reported symptoms using daily e-diary and centrally read 
endoscopy as follows: 
• Stool frequency subscore of 0 or 1 with at least a 1-point change from induction 
(SHP647-301 or SHP647-302) baseline 
AND 
• Rectal bleeding subscore of 0 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
AND 
• Endoscopic subscore of 0 or 1 (modified, excludes friability), based on centrally 
read results. 
The primary efficacy endpoint will be compared for each active treatment group (25 mg 
or 75 mg ontamalimab) to the corresponding placebo group (25 mg in induction placebo 
group or 75 mg in induction placebo group; placebo groups are not pooled) using a 
Cochran-Mantel Haenszel (CMH) chi-square test stratified by actual status of 
glucocorticoid use at MNT (SHP647-303) baseline, prior anti-TNF treatment, and the 
degree of clinical response in the induction studies (whether remission is achieved or 
not). Subjects with the intercurrent events defined in Section 2.2 and/or with missing 
remission data at Week 52 will be considered failures and counted as nonresponders. 
Subjects with treatment failure will also be counted as nonresponders. Subjects with 
missing induction baseline value in SF subscore will be counted as remission if both SF 
and RB subscores are 0 and endoscopic subscore are either 0 or 1 at Week 52. The 
endoscopy score will be based on centrally read results. 
The primary endpoint will be tested by the following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
where δ is the common treatment difference across strata, j=1 to m. The common 
treatment difference is a weighted average of the stratum-specific treatment differences. 
The estimate of the common treatment difference along with the corresponding stratified 
Newcombe 95% CI using the method of Yan and Su (2010) and CMH p-value will be 
presented for each active treatment group to the corresponding placebo group 
comparison. 
6.1.1 
Sensitivity Analyses of Primary Efficacy Endpoint 
A sensitivity analysis will be performed using the CMH testing described in Section 6.1, 
including only the subset of subjects who had the opportunity to complete 52 weeks of 
treatment in the SHP647-303 study prior to the implementation of Protocol Amendment 3 
at their site. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
The primary efficacy endpoint will be summarized separately for the placebo responder 
FAS by treatment group without inferential methods. The number and percentage of 
subjects, and the estimate of the common treatment difference along with the 
corresponding unstratified Newcombe 95% CI, will be summarized by treatment group at 
Week 52. Subjects with missing data at Week 52 will be considered failures and counted 
as nonresponders. 
In addition, if significant noncompliance with regulatory requirements during the course 
of the study is detected or reported at any clinical site, additional sensitivity analyses may 
be conducted on the primary efficacy endpoint by using the same approach but excluding 
all subjects from the noncompliant site(s). 
6.1.2 
Supplementary Analyses of Primary Efficacy Endpoint 
No supplementary analyses of the primary efficacy endpoint are planned for this study. 
6.2 
Analyses of Key Secondary Efficacy Endpoints 
Similarly to the primary endpoint, each secondary endpoint will be summarized by 
treatment group. Subjects with the intercurrent events defined in Section 2.2 and/or 
missing key secondary endpoint data at the Week 52 visit are considered failures. Each of 
the key secondary endpoints will be analyzed using the same approach as described for 
the primary efficacy endpoint using the following hypothesis: 
H0: δ = 0 
H1: δ ≠ 0 
Where δ is the common treatment difference across strata, j=1 to m. The common 
treatment difference is a weighted average of the stratum-specific treatment differences. 
The estimate of the common treatment difference along with the corresponding stratified 
Newcombe 95% CI using the method of Yan and Su (2010) and CMH p-value will be 
presented for each active treatment group to corresponding placebo group (25 mg in 
induction placebo group or 75 mg in induction placebo group; placebo groups are not 
pooled) comparison. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
The key secondary efficacy endpoints are: 
• Endoscopic remission, as defined by centrally read endoscopic subscore 0 or 1 
(modified, excludes friability), at the Week 52 visit. 
• Clinical remission as defined by stool frequency subscore of 0 or 1 with at least 
a 1-point change from induction study (SHP647-301 or SHP647-302) baseline 
in SF subscore, and RB subscore of 0, at the Week 52 visit. Subjects with 
missing induction baseline value in SF subscore will be counted as clinical 
remission if both SF and RB subscores are 0 at Week 52. 
• Sustained remission, ie, in remission at the SHP647-303 Week 52 visit, among 
subjects who were in remission at the time of MNT baseline (the observed 
value for the efficacy assessment at Week 12 in induction study). Remission is 
defined in Section 6.1. 
• Clinical response based on composite score at the Week 52 visit. Clinical 
response (composite) is defined as a decrease from induction study 
(SHP647-301 or SHP647-302) baseline in the composite score of subject-
reported symptoms using daily e-diary and centrally read endoscopy of at least 
2 points and at least 30%, with an accompanying decrease in the subscore for 
rectal bleeding ≥1 point or a subscore for rectal bleeding ≤1. Subjects with 
missing induction baseline value in the composite score but in remission by 
composite score will be counted as clinical response. 
• Mucosal healing based on endoscopic and histologic assessment, at the 
Week 52 visit. Mucosal healing is defined by centrally read endoscopic 
subscore 0 or 1 (modified, excludes friability) and centrally read Geboes score 
of ≤2. 
• Glucocorticoid-free clinical remission at Week 52, among subjects using 
glucocorticoids at the MNT baseline. Glucocorticoid-free clinical remission is 
defined as clinical remission in addition to not requiring any treatment with 
glucocorticoids for at least 4 weeks prior to the Week 52 visit. Clinical 
remission is defined in second bullet above. 
• Glucocorticoid-free remission at Week 52, among subjects using 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
glucocorticoids at the MNT baseline. Glucocorticoid-free remission is defined 
as remission in addition to not requiring any treatment with glucocorticoids for 
at least 4 weeks prior to the Week 52 visit. Remission is defined in Section 6.1. 
6.2.1 
Sensitivity Analyses of Key Secondary Efficacy Endpoints 
A sensitivity analysis will be performed using the CMH testing described in Section 6.1, 
including only the subset of subjects who had the opportunity to complete 52 weeks of 
treatment in the SHP647-303 study prior to the implementation of Protocol Amendment 3 
at their site. 
Additionally, the key secondary endpoints will be summarized separately for the Placebo 
Responder FAS by treatment group without inferential methods. 
In addition, if significant noncompliance with regulatory requirements during the course 
of the study is detected or reported at any clinical site, additional sensitivity analyses may 
be conducted on the key secondary endpoints using the same approach but excluding all 
subjects from the noncompliant site(s). 
6.2.2 
Supplementary Analyses of Key Secondary Efficacy Endpoints 
No supplementary analyses of the key secondary efficacy endpoints are planned for this 
study. 
6.3 
Analyses of Other Secondary Efficacy Endpoints 
Other secondary endpoints will be summarized by descriptive statistics at each visit the 
endpoint is assessed and presented by treatment group for the Ontamalimab Responder 
FAS. The other secondary endpoints will be analyzed using the same approach as 
described for the primary endpoint. Subjects with missing other secondary endpoint data 
at the Week 52 visit will be considered failures and counted as nonresponders. These 
endpoints also will be summarized for the Placebo Responder FAS by treatment group 
without inferential methods. 
The other secondary endpoints and analyses are noted below. 
• Remission, defined as a total Mayo score ≤2 with no individual subscore (SF, 
RB, endoscopy [modified, excludes friability], and physician’s global 
assessment) exceeding 1, at Week 52. A CMH chi-square test that is described 
in Section 6.3 will be used to compare the proportion of subjects with remission 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
for each active treatment group to placebo group (25 mg in induction placebo 
group or 75 mg in induction placebo group; placebo groups are not pooled) at 
Week 52. 
• Clinical remission over time with both RB and SF subscores of 0. A CMH 
chi-square test that is described in Section 6.3 will be used to compare the 
proportion of subjects with clinical remission for each active treatment group to 
placebo group (25 mg in induction placebo group or 75 mg in induction placebo 
group; placebo groups are not pooled) over time. 
• Sustained endoscopic remission, ie, in endoscopic remission at the SHP647-303 
Week 52 visit among subjects who were in remission at the time of MNT 
baseline, as defined by a centrally read endoscopic subscore of 0 or 1 (modified, 
excludes friability). A CMH chi-square test that is described in Section 6.3 will 
be used to compare the proportion of subjects with sustained endoscopic 
remission for each active treatment group to placebo group (25 mg in induction 
placebo group or 75 mg in induction placebo group; placebo groups are not 
pooled) at Week 52. 
6.3.1 
Sensitivity Analyses of Other Secondary Efficacy Endpoints 
No sensitivity analyses of other secondary efficacy endpoints are planned for this study. 
6.3.2 
Supplementary Analyses of Other Secondary Efficacy Endpoints 
No supplementary analyses of other secondary efficacy endpoints are planned for this 
study. 
6.4 
Multiplicity Adjustment 
The global FWER for the statistical tests of the primary and key secondary endpoints will 
be strongly controlled at .05 (2-sided). To control the FWER, graphical methods 
discussed in Bretz et al. (2009) will be utilized to propagate α from primary to key 
secondary endpoints and between the 2 ontamalimab treatment groups and placebo 
comparisons. Alpha is initially split equally at the .025 level (2-sided) for each of the 
pairwise treatment comparisons for the primary endpoint (P) and alpha is propagated in a 
hierarchical manner to each of the 7 key secondary endpoints (K1-K7) within a pairwise 
treatment comparison. A graphical visualization of the α propagation is presented in 
Figure 3. 


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Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
Figure 3: Visualization of Alpha Propagation 
 
 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
Only p-values that are significant according to this graphical approach are inferential and 
statistically significant. All other p-values are descriptive. 
6.5 
Subgroup Analyses 
No subgroup analyses are planned for this study. 
7. 
SAFETY ANALYSIS 
The safety analyses will be performed using the Safety Set. Safety variables include 
adverse events (AEs), clinical laboratory variables, vital signs, electrocardiogram (ECG) 
variables, anti-drug antibody (ADA) and neutralizing antibody (NAb) variables, and 
neurological variables. For each safety variable, the last value collected prior to the first 
dose of double-blind IP in induction study (SHP647-301 or SHP647-302) will be used as 
baseline for all analyses of that safety variable. A final on-treatment assessment will be 
defined as the last valid assessment obtained after MNT baseline and through the end of 
treatment visit. 
Safety outputs will be presented by treatment group listed in Appendix 16.6. The primary 
set will present data by SHP647-303 treatment, regardless of the treatment in the 
induction study. The secondary set will present data by both the induction study treatment 
and the SHP647-303 study treatment. 
7.1 
Adverse Events 
Adverse events will be coded using MedDRA Version 19.1 2016. 
Treatment-emergent AEs (TEAEs) are defined as AEs with start dates at the time of or 
following the first exposure to IP in the SHP647-303 study. 
An overall summary of the number of subjects with TEAEs will be presented, including 
the number and percentage of subjects with any TEAEs, serious TEAEs, TEAEs related 
to IP, related serious AEs (SAEs), TEAEs leading to discontinuation of IP, TEAEs 
leading to study discontinuation, and TEAEs leading to death. 
The number of events, incidence, and percentage of subjects reporting TEAEs will be 
presented by treatment group as listed in Appendix 16.6; by preferred term; by SOC and 
preferred term; and by SOC, preferred term, and maximum severity. Treatment-emergent 
AEs considered related to IP will also be summarized by SOC and preferred term. If 
more than one AE occurs with the same preferred term for the same subject, then the 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
subject will be counted only once for that preferred term using the most severe and most 
related occurrence for the summarization by severity and by relationship to IP. 
The most common TEAEs (incidence ≥2% in any treatment group) will be summarized 
by preferred term in descending frequency by treatment group as listed in Appendix 16.6. 
Serious TEAEs, TEAEs leading to discontinuation of the study or study medication, and 
injection site AEs will be summarized by SOC, preferred term, and treatment group as 
defined in Appendix 16.6. Adverse events leading to withdrawal, serious AEs, and deaths 
will be similarly summarized or listed. 
7.1.1 
Adverse Events of Special Interest and Other Potential Risks 
There is one identified important potential risk of Progressive Multifocal 
Leukoencephalopathy. There are 6 other identified potential risks: immunotoxicity, 
immunogenicity, infection, vascular and thrombotic events, local tolerability, and 
malignant tumors. Potential risks will be summarized by treatment group as listed in 
Appendix 16.6. Important potential risks will be listed. 
7.1.1.1 
Hypersensitivity 
Potential hypersensitivity reactions such as serum sickness, vasculitis, or Arthus reactions 
to ontamalimab will be regarded as adverse events of special interest (AESI). An external 
hypersensitivity adjudication committee is established to review reported hypersensitivity 
events and adjudicate whether the event was a hypersensitivity event, which type (Type I 
or Type III) of event it was, and recommendations of permanent discontinuation or 
re-challenge with IP. Reported hypersensitivity events, adjudicated hypersensitivity 
events, and study drug recommendation will be summarized by treatment groups as listed 
in Appendix 16.6. 
The number of hypersensitivity reactions and percentage of subjects with hypersensitivity 
reactions as adjudicated will be summarized by treatment group and ontamalimab all 
doses; and by SOC, preferred term, and hypersensitivity type. Reported hypersensitivity 
events and adjudicated hypersensitivity events will be listed for the Safety Set. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
7.2 
Clinical Laboratory Data 
Descriptive statistics for clinical laboratory values (in conventional units) and changes 
from induction study (SHP647-301 or SHP647-302) baseline at each assessment time 
point for quantitative variables will be presented by treatment group as listed in 
Appendix 16.6 for the following clinical laboratory variables. The number and 
percentage of subjects for qualitative variables in urinalysis will be presented by 
treatment group as listed in Appendix 16.6 in the Safety Set. 
Serum chemistry 
 
• alkaline phosphatase 
• aspartate aminotransferase (AST) 
• alanine aminotransferase (ALT) 
• total bilirubin 
• total protein 
• albumin 
• glucose 
• blood urea nitrogen 
• creatinine 
• sodium 
• potassium 
• chloride 
• calcium 
• carbon dioxide 
 
 
Hematology 
 
• hemoglobin 
• hematocrit 
• mean corpuscular hemoglobin 
• mean corpuscular hemoglobin 
concentration 
• mean corpuscular volume 
• erythrocyte (red blood cell) count 
• leukocyte (white blood cell) 
count 
• neutrophils 
• lymphocytes 
• monocytes 
• eosinophils 
• basophils 
• platelet count 
 
 






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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
Table 3: 
Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
Age 
Range 
Sex 
Outlier Criteriaa 
Low 
High 
Blood 
All 
 
NA 
NA 
Ketones 
All 
 
NA 
NA 
Nitrite 
All 
 
NA 
NA 
pH 
All 
 
NA 
NA 
Specific gravity 
All 
 
NA 
NA 
Urobilinogen 
All 
 
NA 
NA 
LLN=lower limit of normal provided by the laboratory; NA=not applicable; ULN=upper limit of normal 
provided by the laboratory. 
a If criteria in both directions are shown for a single parameter, then abnormalities in each direction are 
summarized separately. 
7.3 
Pregnancy Test and Follicle-stimulating Hormone Test 
Pregnancy tests are not required for females of nonchildbearing potential. All pregnancy 
tests data will be listed for the Safety Set. 
7.4 
Vital Signs 
Descriptive statistics for vital signs (eg, systolic and diastolic blood pressure, pulse rate, 
body weight, respiratory rate, and temperature) and their changes from induction study 
(SHP647-301 or SHP647-302) baseline at each post-baseline visit and at the end of the 
study will be presented by treatment group as listed in Appendix 16.6. 
For pulse rate, a post-MNT baseline value is considered as a PCI value if its meets both 
criteria for observed value and change from induction study (SHP647-301 or 
SHP647-302) baseline. For systolic/diastolic blood pressure, a post-MNT baseline value 
is considered as a PCI value if it meets criteria for observed value or change from 
induction study (SHP647-301 or SHP647-302) baseline. For weight and BMI, a post-
MNT baseline value is considered as a PCI value if it meets criteria for change from 
induction study (SHP647-301 or SHP647-302) baseline. The PCI criteria are listed in 
Table 4. The number and percentage of subjects with PCI post-MNT baseline values will 
be tabulated by treatment group as listed in Appendix 16.6. The percentages will be 
calculated relative to the number of subjects with induction study (SHP647-301 or 
SHP647-302) baseline and at least 1 post-MNT baseline assessment. The numerator is 
the total number of subjects with at least 1 PCI post-MNT baseline vital sign value. A 
supportive listing of subjects with post-MNT baseline PCI values will be provided 
including the subject number, site, induction study (SHP647-301 or SHP647-302) 
baseline, MNT baseline, and post-MNT baseline values. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
All vital signs data will be listed for the Safety Set. 
7.5 
Electrocardiogram (ECG) 
A central ECG reader will be used. Descriptive statistics for ECG variables (eg, heart 
rate, PR interval, QRS interval, QT interval, QTc interval, QTcB, and QTcF) and their 
changes from induction study (SHP647-301 or SHP647-302) baseline at each assessment 
time point will be presented by treatment group as listed in Appendix 16.6. 
Electrocardiogram interpretation will be summarized by visit. A shift table from 
induction study (SHP647-301 or SHP647-302) baseline to each visit for qualitative 
ECG results will be presented by treatment group as listed in Appendix 16.6. 
Electrocardiogram variable values will be considered PCI if they meet or exceed the 
upper limit values listed in Table 5. The number and percentage of subjects with 
available induction study (SHP647-301 or SHP647-302) baseline values and post-MNT 
baseline PCI values will be tabulated by treatment group as listed in Appendix 16.6. The 
percentages will be calculated relative to the number of subjects with available induction 
study (SHP647-301 or SHP647-302) baseline values and at least 1 post-MNT baseline 
assessment. The numerator is the total number of subjects with at least 1 post-MNT 
baseline PCI value. 
Table 4: 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Flag 
Criteriaa 
Observed Value 
Change from MNT 
Baseline 
Systolic blood pressure 
(mmHg) 
High 
180 
Increase of 20 
Low 
90 
Decrease of 20 
Diastolic blood pressure 
(mmHg) 
High 
105 
Increase of 15 
Low 
50 
Decrease of 15 
Pulse rate 
(beats per minute) 
High 
120 
Increase of 15 
Low 
50 
Decrease of 15 
Weight (kg) 
High 
- 
Increase of 7% 
Low 
- 
Decrease of 7% 
BMI (kg/m2) 
High 
- 
Increase of 10% 
 
Low 
<18 
Decrease of 10% 
Temp. (◦C) 
 
NA 
NA 
a For pulse rate, a post-baseline value is considered as a PCI value if its meets both criteria for observed value and 
change from MNT baseline. For systolic/diastolic blood pressure, a post-baseline value is considered as a PCI value 
if it meets criteria for observed value or change from MNT baseline. For weight and BMI, a post-baseline value is 
considered as a PCI value if it meets criteria for change from MNT baseline. 


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Listings of ECG data including the central reader’s assessment and investigator’s 
interpretation by individual subject will be produced. Separate listings will be produced 
for subjects with ECG results meeting the PCI criteria. Data from unscheduled visits will 
be listed, but not summarized. 
Table 5: 
Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
Higher Limit 
QRS Interval 
msec 
150 
PR Interval 
msec 
250 
QTc Interval 
msec 
500 
ECG=electrocardiogram 
7.6 
Other Safety Data 
7.6.1 
Targeted Neurological Assessment 
The targeted neurological examination and neurological consult evaluation results with 
unexplained abnormal neurological findings will be summarized at screening and at each 
visit and by treatment group as listed in Appendix 16.6. The number and percentage of 
subjects with targeted neurological examination in each of the neurological domains 
(vision, motor, tactile sensation, coordination/cerebellar function, speech, verbal 
comprehension, and cognition/behavior) will be summarized by the result category 
(abnormal, normal, not done) at each visit and by treatment group as listed in 
Appendix 16.6. The number and percentage of subjects who were referred for a 
neurological consultation and the results (no PML, PML, no clinically significant finding, 
other clinically significant finding, not done, other) will also be summarized by treatment 
group as listed in Appendix 16.6. The neurological evaluation and consultation results 
will be listed for the Safety Set. 
7.6.2 
Immunogenicity 
Presence of ADAs will be listed and summarized by visit for each treatment group as 
listed in Appendix 16.6. 
Anti-drug antibodies will be classified into pre-existing, treatment-induced responses, 
and treatment-boosted responses. Pre-existing is defined as a signal detected prior to 
treatment. Treatment-induced responses are defined as a negative pretreatment sample 
with at least 1 positive sample at a subsequent time point. Treatment-boosted responses 
are defined as positive pretreatment samples that are boosted to a higher level following 
drug administration. Those categories will be listed and summarized by treatment group 
as listed in Appendix 16.6. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
Neutralizing antibodies will be tested on ADA-positive subjects, and samples will be 
defined as NAb-positive or -negative. Presence of NAbs will be listed and summarized 
for all ADA-positive subjects by visit for each treatment group as listed in 
Appendix 16.6. 
Anti-drug antibody prevalence will also be calculated and summarized by treatment 
group as listed in Appendix 16.6. Antidrug antibody prevalence is the proportion of study 
population having drug-reactive antibodies (ADA) at any time point (including 
pre-existing antibodies) during the study. 
Anti-drug antibody incidence will be calculated and summarized by treatment group as 
listed in Appendix 16.6. Anti-drug antibody incidence is the proportion of study 
population found to have developed ADA or boosted their ADA (including pre-existing 
ADA) at any point during the study period. 
Listings of positive immunogenicity results and individual subject immunogenicity data 
will be presented. 
7.6.3 
Contraception Check 
Contraception check should be performed for female subjects of childbearing potential 
and male subjects who are with a partner of childbearing potential. Contraception check 
results will be listed for the Safety Set. 
7.6.4 
Physical Examination 
Complete and targeted physical examinations will be performed at the time points 
specified in Appendix 16.1. Physical examination results will be listed for the Safety Set. 
8. 
 
8.1 
 
 
 
8.2 
 
 
 
 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
8.3 
 
 
8.4 
 
 
9. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
10. 
OTHER ANALYSES 
10.1 
Coronavirus Pandemic 
The coronavirus (COVID-19) pandemic of 2019-20 particularly poses risks to the safety 
of subjects enrolled in clinical trials, and the availability and interpretability of data from 
those trials. COVID-19 impacts on individual subjects collected on COVID-19 CRF 
pages will be listed for the Randomized set. Protocol deviations related to COVID-19 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
will be listed for the Randomized Set. The study disruptions related to COVID-19 will be 
listed for the Safety Set. 
11. 
INTERIM ANALYSIS/DATA MONITORING (REVIEW) COMMITTEE 
A data monitoring committee (DMC) was set up to review the safety during the course of 
the study. The DMC will not review efficacy data until the time of unblinding. No 
interim analyses are planned for this study. 
12. 
DATA HANDLING CONVENTIONS 
12.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: n, 
mean, median, standard deviation, minimum, and maximum. For the summary statistics 
of all numerical variables, unless otherwise specified, minimum and maximum will be 
displayed to the same level of precision as reported. Mean and median will be displayed 
to 1 level of precision greater than the data collected. Standard deviation will be 
displayed to 2 levels of precision greater than the data collected. 
Categorical and count variables will be summarized by the number of subjects (n) and the 
percentage of subjects in each category. Percentages will be presented to 1 decimal place. 
When count data are presented, the percentage will be suppressed when the count is zero. 
A row denoted “Missing” will be included in count tabulations only if there are missing 
values. The denominator for all percentages will be the number of subjects in that 
treatment within the population of interest, unless otherwise specified. 
P-values will generally be presented to 3 decimal places; values less than 0.001 will be 
presented as <0.001. 
‘ONTA’ is the acronym of ontamalimab which will be used in output treatment 
presentation. 
12.2 
Definition of Treatment Failure 
Treatment failure is declared for those randomized into the SHP647-303 study prior to 
Protocol Amendment 2 when an endoscopic subscore that has increased by at least 
1 point over baseline in this maintenance study or a value of at least 2 and an increase in 
clinical subscore (SF plus RB score) of at least 2 points. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
Treatment failure is declared for those randomized into the SHP647-303 study under 
Protocol Amendment 2 when the 3 following conditions are met: 
• E-diary documented sustained* symptomatic worsening that includes RB 
• No other etiology (ie, infection) can be identified 
• Endoscopy confirms disease activity. 
*Sustained: for at least 1 week if the RB score has increased by ≥2 points, or at least 
2 weeks if the RB score has increased by <2 points. 
If treatment failure is not confirmed, subjects may continue with their next scheduled 
visit. 
12.3 
Definition of Visit Windows 
Assessments will be assigned to visits based upon the date the assessment took place 
regardless of the completed CRF page. Assessments will be mapped to visits as outlined 
in Table 6 to Table 9. 
Should there be more than 1 assessment mapped into a given study visit with nonmissing 
results, the assessment closest to the planned visit will be used for analysis (referred to as 
analysis visit); in case of ties between observations, the later assessment will be used. 
Study day will be calculated as follows: 
• If the assessment date is on or after the date of first dose of IP: 
Study day = assessment date – first dosing date + 1 
• If the assessment date is before the date of first dose of IP: 
Study day = assessment date – first dosing date 
Table 6: Visit Windows (Study Day Based) – PRO, Partial Mayo, Vital Sign, 
Weight, and Endoscopy Assessments 
Visit 
Planned Study Day 
Start Day of Window 
End Day of Window 
Week 4 
28 
2 
42 
Week 8 
56 
43 
70 


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Week 12 
84 
71 
98 
Week 16 
112 
99 
126 
Week 20 
140 
127 
154 
Week 24 
168 
155 
182 
Week 28 
196 
183 
210 
Week 32 
224 
211 
238 
Week 36 
252 
239 
266 
Week 40 
280 
267 
294 
Week 44 
308 
295 
322 
Week 48 
336 
323 
350 
Week 52 
364 
351 
EOT Date 
Follow-up 
EOT Date + 84 
EOT Date +1 
EOF Date 
EOT=end of treatment; PRO=patient-reported outcomes; RB=rectal bleeding; SF=stool frequency 
*Endoscopy is performed only as part of the Week 52 assessments. To accommodate the scheduling of the 
endoscopy prior to the Week 52 visit, the start day of the analysis window will be extended to >342 for this 
parameter only if there is a valid assessment of SF and RB mapped to Week 52. 
*Follow-up visit applies to vital sign and weight assessments only. 
 
Table 7: Visit Windows (Study Day Based) – ADA Assessments 
Visit 
Planned Study Day 
Start Day of Window 
End Day of Window 
Week 12 
84 
2 
126 
Week 24 
168 
127 
210 
Week 36 
252 
211 
EOT Date 
ADA=anti-drug antibody; EOT=end of treatment 
*Following the implementation of Protocol Amendment 3, ADA assessments are not performed at Week 52. 
 
Table 8: Visit Windows (Study Day Based) – 
 and ECG Assessments 
Visit 
Planned Study Day 
Start Day of Window 
End Day of Window 
Week 12 
84 
2 
126 
Week 24 
168 
127 
266 
Week 52 
364 
267 
EOT Date 
ECG=electrocardiogram; EOT=end of treatment; 
 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
 
Table 9: Visit Windows (Study Day Based) – Safety Lab,  Physical Examination, 
and Neurological Testing Assessments 
Visit 
Planned Study Day 
Start Day of Window 
End Day of Window 
Week 12 
84 
2 
126 
Week 24 
168 
127 
210 
Week 36 
252 
211 
308 
Week 52 
364 
309 
EOT Date 
Follow-up 
EOT Date + 84 
EOT Date + 1 
EOF Date 
EOF=end of follow-up; EOT=end of treatment 
 
12.4 
Derived Efficacy Endpoints 
12.4.1 Total Mayo Score 
The Mayo score is a measure of UC disease activity. The total Mayo score ranges from 0 
to 12 points and consists of the following 4 subscores, each graded from 0 to 3 with 
higher scores indicating more severe disease: 
• Stool frequency (0-3) 
• Rectal bleeding (0-3) 
• Findings on endoscopy (0-3) 
• Physician’s global assessment (0-3). 
The calculation of the total score requires SF subscore and RB subscores, reported by 
subjects in the PRO UC daily e-diary, and PGA and centrally read endoscopic subscores. 
The Mayo SF and RB subscores will be calculated based on each subject’s daily e-diary 
data recorded over the most recent 3 days (consecutive or nonconsecutive) of the last 
10 days prior to the visit excluding the following days: day of any bowel preparation, day 
of endoscopy, any days between day of bowel preparation and day of endoscopy, and the 
2 days after the day of endoscopy. The most recent 3 days’ subscores will be averaged 
and rounded to the nearest score according to standard rounding rules. Physician’s global 
assessment and centrally read endoscopic subscores will be collected at MNT baseline 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
and the Week 52 visit. The total Mayo score is the sum of the 4 subscores, and will be 
calculated at MNT baseline and at the Week 52 visit. The total Mayo score from the 
induction baseline is calculated in an identical fashion in the induction studies (SHP647-
301 and SHP647-302) and will be carried over for use in the SHP647-303 study. 
12.4.2 Composite Score 
The composite score is a regulatory authority-recommended measure derived from the 
Mayo score omitting the PGA subscore and ranges from 0 to 9 points. 
12.4.3 Mucosal Healing 
Mucosal healing is based on the endoscopic and histological assessment at the Week 52 
visit. Mucosal healing is defined by the centrally read endoscopic subscore 0 or 1 
(modified, excludes friability) and the centrally read Geboes score of ≤2. 
Mucosal healing based on endoscopic and histological assessment at the MNT baseline 
and Week 52 visit. Mucosal healing is defined by centrally read endoscopic subscore 0 or 
1 (modified, excludes friability) and 
 
, with lamina propria neutrophils, neutrophils in epithelium, and erosion or ulceration 
scores of 0. 
12.4.4 Total Sign/Symptom Score 
Patient-reported UC signs and symptoms data will be collected using a daily e-diary 
throughout the study. Subjects will be required to enter e-diary data daily. Subjects will 
enter data on UC signs and symptoms items using an electronic handheld device that will 
be provided to subjects at the start of the study. Compliance is assessed by site staff at 
each visit. The site staff will instruct the subject on the appropriate use of the e-diary, 
particularly when compliance is below 80% (eg, <8 out of 10 diary entries) when 
compared to the previous visit. 
Subjects will be asked to record the following signs and symptom data, as experienced 
over the previous 24 hours, in the e diary: 
• Stool frequency: Number of Bowel Movements (0-99) 
• Rectal bleeding severity and frequency: Rectal Bleeding Worst Experience (0-3) 
and Number of Bowel Movements with Blood (0-99) 


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• Diarrhea frequency: Number of Loose Bowel Movements (0-99) 
• Urgency frequency: Number of Bowel Movements with Urgency (0-99) 
• Abdominal pain worst severity: Worst Abdominal Pain Over the Past 24 Hours 
(0-10) 
Note: In the instrument, if the Number of Bowel Movements is entered as 0, then the rest 
of questions except Worst Abdominal Pain Over the Past 24 Hours question are skipped 
as they are further questions about the bowel movements. These skipped items will be 
considered as 0 for analysis purposes. 
Subject’s signs and symptom average scores at each scheduled visit will be calculated 
based on data recorded over the most recent 3 days (consecutive or nonconsecutive) of 
the last 10 days prior to the scheduled visit start date excluding the following days: day of 
any bowel preparation, day of endoscopy, any days between day of bowel preparation 
and day of endoscopy, and the 2 days after the day of endoscopy. Daily signs and 
symptom records will be assigned to visits based on visit window in Table 6. The 
assessment closest to the planned visit day will be used for analysis at that visit. 
Number of bowel movements and rectal bleeding worst experience will be used to 
determine the Mayo stool frequency and rectal bleeding subscores, which will be used to 
calculate the total and partial Mayo scores and the composite score. Subject’s signs and 
symptom average scores of number bowel movements with blood, number bowel 
movements with urgency, number of bowel movements and number of loose bowel 
movements will be converted to the same scale as shown in Table 10. No conversion will 
be applied for average scores of worst abdominal pain over the past 24 hours. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
Table 10 Proposed Categorized Sign/Symptom Score Conversion Scale 
Response 
Conversion (applied to each item) 
0-2 
0 
3-5 
2.5 
6-8 
5 
9-11 
7.5 
≥12 
10 
Total sign/symptom score is the average of the average scores of worst abdominal pain 
over the past 24 hours and the conversion scale values for number of bowel movements 
blood, number of bowel movements with urgency, number of bowel movements and 
number of loose bowel movements, with scale range of 0-10. The categorized and total 
score scoring systems will be confirmed after database lock according to the UC PRO 
SAP and are subject to change after the psychometric assessment has been completed. 
12.5 
Repeated or Unscheduled Assessments of Safety Parameters 
Assessments will be assigned to visits based on the date the assessment took place 
regardless of the completed CRF page. Assessments will be mapped to visits as outlined 
in Table 6 to Table 9. 
If a subject has more than 1 assessment mapped into a given study visit with non-missing 
results, the assessment closest to the planned visit will be used for analysis. However, all 
post-MNT baseline assessments will be used for PCI value determination. 
12.6 
Handling of Missing, Unused, and Spurious Data 
12.6.1 Missing Date of End of Treatment 
When the date of the end of treatment is missing for a subject, all efforts should be made 
to obtain the date from the investigator. If it is still missing after all efforts, then the last 
dose date + 28 days will be used in the calculation of treatment duration. 
12.6.2 Missing Date of Ulcerative Colitis Diagnoses 
If day of diagnosis date is missing, then the day will be imputed as 1; if both the day and 
month of diagnosis date are missing, then the day will be imputed as 1 and the month will 
be imputed as 1 (January). 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
12.6.3 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) 
The induction study (SHP647-301 or SHP647-302) imputed dates will be used for prior 
medications for those collected in induction study. 
For prior or concomitant medications collected in SHP647-303, including rescue 
medications, incomplete (ie, partially missing) start date and/or stop date will be imputed. 
When the start date and the stop date are both incomplete for a subject, impute the start 
date first. 
12.6.3.1 Incomplete Start Date 
The following rules will be applied to impute the missing numerical fields. If the stop 
date is complete and the imputed start date is after the stop date, then the start date will be 
imputed using the stop date. 
12.6.3.1.1 Missing Day and Month 
• 
If the year of the incomplete start date is the same as the year of the date of the first 
dose of IP, then the day and month of the date of the first dose of IP in the 
SHP647-303 study will be assigned to the missing fields. 
• 
If the year of the incomplete start date is before the year of the date of the first dose 
of IP in the SHP647-303 study, then December 31 will be assigned to the missing 
fields. 
• 
If the year of the incomplete start date is after the year of the date of the first dose 
of IP in the SHP647-303 study, then 01 January will be assigned to the missing 
fields. 
12.6.3.1.2 Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
12.6.3.1.3 Missing Day Only 
• 
If the month and year of the incomplete start date are the same as the month and 
year of the date of the first dose of IP, then the day of the date of the first dose of 
IP in the SHP647-303 study will be assigned to the missing day. 
• 
If either the year is before the year of the date of the first dose of IP or if both years 
are the same but the month is before the month of the date of the first dose of IP in 
the SHP647-303 study, then the last day of the month will be assigned to the 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
missing day. 
• 
If either the year is after the year of the date of the first dose of IP or if both years 
are the same but the month is after the month of the date of the first dose of IP in 
the SHP647-303 study, then the first day of the month will be assigned to the 
missing day. 
12.6.3.2 Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields. If the date of 
the last dose of IP in the SHP647-303 study is missing, then replace it with the last visit 
date. If the imputed stop date is before the start date (imputed or non-imputed start date), 
then the imputed stop date will be equal to the start date. 
12.6.3.2.1 Missing Day and Month 
• 
If the year of the incomplete stop date is the same as the year as of the date of the 
last dose of IP, then the day and month of the date of the last dose of IP in the 
SHP647-303 study will be assigned to the missing fields. 
• 
If the year of the incomplete stop date is before the year of the date of the last dose 
of IP in the SHP647-303 study, then 31 December will be assigned to the missing 
fields. 
• 
If the year of the incomplete stop date is after the year of the date of the last dose of 
IP in the SHP647-303 study, then 01 January will be assigned to the missing fields. 
12.6.3.2.2 Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
12.6.3.2.3 Missing Day Only 
• 
If the month and year of the incomplete stop date are the same as the month and 
year of the date of the last dose of IP, then the day of the date of the last dose of IP 
in the SHP647-303 study will be assigned to the missing day. 
• 
If either the year is before the year of the date of the last dose of IP or if both years 
are the same but the month is before the month of the date of the last dose of IP in 
the SHP647-303 study, then the last day of the month will be assigned to the 
missing day. 
• 
If either the year is after the year of the last dose of IP or if both years are the same 
but the month is after the month of the date of the last dose of IP in the 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
SHP647-303 study, then the first day of the month will be assigned to the missing 
day. 
12.6.4 Missing Date Information for Adverse Events 
For AEs, the default is to only impute incomplete (ie, partially missing) start dates. If 
start date is missing, no imputation will be performed. 
12.6.4.1 
Incomplete Start Date 
Follow the same rules as in Section 12.6.3.1. 
12.6.4.2 Incomplete Stop Date 
Not applicable. 
12.6.5 Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of IP, then a 
severity of “Mild” will be assigned. If the severity is missing for an AE starting on or 
after the date of the first dose of IP in the SHP647-303 study, then a severity of “Severe” 
will be assigned. The imputed values for severity assessment will be used for incidence 
summaries, while the actual values will be used in data listings. 
12.6.6 Missing Relationship to IP for Adverse Events 
If the relationship to IP is missing for an AE starting on or after the date of the first dose 
of IP in the SHP647-303 study, a causality of “Related” will be assigned. The imputed 
values for relationship to double-blind IP will be used for incidence summaries, while the 
actual values will be presented in data listings. 
12.6.7 Character Values of Clinical Laboratory Variables 
If the reported value of a clinical laboratory variable cannot be used in a statistical 
analysis due to, for example, that a character string is reported for a numerical variable, 
the appropriately determined coded value will be used in the statistical analysis. 
However, the actual values as reported in the database will be presented in data listings. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
13. 
ANALYSIS SOFTWARE 
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified environment. 
14. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
The following changes to the analysis specified in Protocol Amendment 3 dated 
17 Sep 2020 (final version 1.0 dated 10 Jul 2017, Amendment 1 dated 11 Sep 2018, 
Amendment 2 dated 11 Nov 2019) have been made. 
Changed the other secondary endpoint total sign/symptom score calculation from sum of 
daily e-diary entries to average of daily e-diary entries. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
15. 
REFERENCES 
Bretz, F., Maurer, W., Brannath, W.and Posch, M. 2009. A graphical approach to 
sequentially rejective multiple test procedures. Stat Med, 28, 586-604. 
Feagan, B. G., Rutgeerts, P., Sands, B. E., Hanauer, S., Colombel, J. F., Sandborn, W. J., 
Van Assche, G., Axler, J., Kim, H. J., Danese, S., Fox, I., Milch, C., Sankoh, S., Wyant, 
T., Xu, J.and Parikh, A. 2013. Vedolizumab as induction and maintenance therapy for 
ulcerative colitis. N Engl J Med, 369, 699-710. 
Sandborn, W. J., Su, C., Sands, B. E., D'Haens, G. R., Vermeire, S., Schreiber, S., 
Danese, S., Feagan, B. G., Reinisch, W., Niezychowski, W., Friedman, G., Lawendy, N., 
Yu, D., Woodworth, D., Mukherjee, A., Zhang, H., Healey, P.and Panes, J. 2017. 
Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med, 
376, 1723-1736. 
Yan, X. and Su, X. 2010. Stratified Wilson and Newcombe Confidence Intervals for 
Multiple Binomial Proportions. Stat Biopharm Res, 2, 329-35. 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
16. 
APPENDICES 
16.1 
Schedule of Activities Prior to Amendment 3 
 


















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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
16.3 
Geographic Regions 
Table 11 Geographic Regions 
Country 
Region 
Japan 
Asia 
Korea, Republic of 
Asia 
Bosnia and Herzegovina 
Eastern Europe 
Bulgaria 
Eastern Europe 
Croatia 
Eastern Europe 
Czech Republic 
Eastern Europe 
Estonia 
Eastern Europe 
Hungary 
Eastern Europe 
Lithuania 
Eastern Europe 
Poland 
Eastern Europe 
Romania 
Eastern Europe 
Russia 
Eastern Europe 
Serbia 
Eastern Europe 
Slovakia 
Eastern Europe 
Ukraine 
Eastern Europe 
Austria 
Western Europe 
Belgium 
Western Europe 
Germany 
Western Europe 
Greece 
Western Europe 
Ireland 
Western Europe 
Italy 
Western Europe 
Netherlands 
Western Europe 
Portugal 
Western Europe 
Spain 
Western Europe 
Switzerland 
Western Europe 
United Kingdom 
Western Europe 
Argentina 
ROW 
Australia 
ROW 
Brazil 
ROW 
Colombia 
ROW 
Israel 
ROW 
Lebanon 
ROW 
Mexico 
ROW 
New Zealand 
ROW 
South Africa 
ROW 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
Country 
Region 
Turkey 
ROW 
Canada 
North America 
United States 
North America 
ROW (Africa/Australia/Latin America/Middle East). Asia (Japan/South Korea) 
 
 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
16.4 
UC Medication History or Use Subgroup Identification 
The following UC medications/therapies/procedures are recorded on the concomitant medication 
indication specific form. 
o Immunosuppressant Experienced at Baseline 
• 
Rule 
o Yes: At least one of the listed medications is on or before the date of the first 
dose of study medication in the induction study 
o No: Otherwise 
o Immunosuppressant Use at MNT Baseline 
• 
Rule 
o Yes: At least one of the listed medications is used 6 days prior to the dose of 
study medication at the Week 12 visit in the induction study 
o No: Otherwise 
o Anti-TNF Experienced 
• 
Recorded in induction study eCRF (Ulcerative Colitis History); Experienced 
(Yes)/Naïve (No) 
o Anti-TNF Failure 
• 
Rule 
o Yes: At least one of the anti-TNF medications is on or before the date of the 
first dose of study medication in the induction study and “Inadequate 
response” or “Loss of response” was the reason for the discontinuation. 
o No: Otherwise 
o Anti-TNF Failure Times 
• 
Rule 
o Naïve: None of the anti-TNF medications is on or before the date of the first 
dose of study medications in the induction study 
o Experienced without failure: At least one of the anti-TNF medications is on 
or before the date of the first dose of study medication in the induction study 
but “Inadequate response” or “Loss of response” is NOT the reason for 
discontinuation 
o Number of failures: Count (1, 2, or 3 or more): Count the number of unique 
records on or before the date of the first dose of study medication in the 
induction study where anti-TNF medication is in the list below and 
“Inadequate response” or “Loss of response” is the reason for the 
discontinuation. 
o Glucocorticoid Use at Baseline 
• 
Rule 
o Yes: 
▪ 
At least one systemic glucocorticoids in the 6 days prior to the first 
dose of study medication in the induction study given by “oral” route 
OR 


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Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
▪ 
At least one topical glucocorticoids in the 6 days prior to the first 
dose of study medication in the induction study given by “oral” route 
o No: Otherwise 
o Glucocorticoid Use at MNT Baseline 
• 
Rule 
o Yes: 
▪ 
At least one systemic glucocorticoids in the 6 days prior to the dose 
of study medication at the Week 12 visit in the induction study given 
by “oral” route 
OR 
▪ 
At least one topical glucocorticoids in the 6 days prior to the dose of 
study medication at the Week 12 visit in the induction study given by 
“oral” route 
o No: Otherwise 
o Maximum Prior Treatment Experience 
• 
Immunosuppressant experienced: 
o Rule 
▪ 
Yes: At least one of the listed medications in or before the date of the 
first dose of study medication in the induction study 
▪ 
No: Otherwise 
• 
Biologic Failure 
o Rule 
▪ 
Yes: At least one of the listed medications on or before the date of 
first dose of study medication in the induction study and “Inadequate 
response” or “Loss of response” was the reason for the 
discontinuation. 
▪ 
No: Otherwise 
• 
 
• 
Systemic glucocorticoid experienced 
o Rule 
▪ 
Yes: least one of the systemic glucocorticoids on or before the date 
of first dose of study medication in the induction study given by 
“Oral”, “Intravenous”, or ”Intramuscular” 
▪ 
No: Otherwise 
• 
Topical glucocorticoid experienced 
o Rule 
▪ 
Yes: 
• 
At least one of the topical glucocorticoids on or before the date 
of first dose of study medication in the induction study given by 
“oral” or “rectal” route. 
OR 


Shire                                                           CONFIDENTIAL                                               Page 82 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
• 
At least one of the systemic glucocorticoids on or before the date 
of first dose of study medication in the induction study given by 
“rectal” route. 
OR  
• 
At least one of the  following medications on or before the date 
of first dose of study medication in the induction study 
regardless of route. 
o PROCTOFOAM 
o PROCTOSEDYL /03159801/" 
o STEROIDS 
o CORTICOSTEROIDS ACTING LOCALLY 
o ENTOCORT ENEMA 
o ENEMAS 
▪ 
No: Otherwise 
• 
Amino salicylates experienced 
o Rule 
• 
Yes: At least one of the listed medications on or before the date of 
first dose of study medication in the induction study 
• 
No: Otherwise 
o 5-ASA Use at MNT Baseline 
• 
Rule 
o Yes: At least one of the listed medications in the 6 days prior to the dose of 
study medication at the Week 12 visit in the induction study given by “oral” 
or “rectal” route 
o No: Otherwise 


Shire                                                           CONFIDENTIAL                                               Page 83 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
16.5 
Rescue Therapy for Ulcerative Colitis  
In order for a medication to be a rescue therapy for UC, it should be reported on the concomitant 
medication indication specific form. 
If the exposure happens in the follow-up period (beginning on the EOT date), then it would not 
satisfy the criteria, as we are concerned here only about exposure with regards to the estimand, 
which is during the treatment period. 
• 
Biologics with immunomodulatory properties 
o Any exposure after first dose 
• 
Non-biologics with immunomodulatory properties 
o Immunosuppressants 
▪ 
Rule 
• 
After first dose and up to and including Week 48: any increase 
from MNT baseline for more than 5 days 
• 
After Week 48: Any dose above MNT baseline for greater than 
1 day 
▪ 
MNT baseline 
• 
Subjects who have at least one dose in the 6 days prior to the  
dose of study medication at the Week 12 visit in the induction 
study will be considered to have a MNT baseline dose >0. The 
MNT baseline dose to be used for these subjects is the median 
nonmissing daily dose from these 6 days. Subjects without at 
least one dose in the 6 days prior to the dose at the Week 12 visit 
in the induction study will be considered to take a 0 for the dose 
for the purposes of assessing an increase from MNT baseline 
o 5-ASA 
▪ 
Rule 
• 
After first dose and up to and including Week 48: any increase 
from MNT baseline for more than 5 days 
• 
After Week 48: Any dose above MNT baseline for greater than 
1 day 
▪ 
MNT baseline 
• 
Subjects who have at least one dose in the 6 days prior to the 
dose of study medication at the Week 12 visit in the induction 
study will be considered to have a MNT baseline dose >0. The 
MNT baseline dose to be used for these subjects is the median 
nonmissing daily dose from these 6 days. Subjects without at 
least one dose in the 6 days prior to the dose at the Week 12 visit 
in the induction study will be considered to take a 0 for the dose 
for the purposes of assessing an increase from MNT baseline 
▪ 
Note 


Shire                                                           CONFIDENTIAL                                               Page 84 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
• 
Subjects cannot start the study on the combination of 
Beclometasone and mesalazine so there would be no switching. 
It would be only according to the rules. 
o Other small molecule immunodulatory active agents 
▪ 
Rule 
• 
Any exposure after first dose 
• 
Leukocyte apheresis, other apheresis, and plasma exchange 
o Rule 
▪ 
Any exposure after first dose 
• 
Systemic glucocorticoids 
o Systemic glucocorticoids given via oral or rectal routes of administration 
▪ 
Rule 
• 
After first dose and up to and including Week 48: any increase 
from MNT baseline for more than 7 days 
• 
After Week 48: Any dose above MNT baseline for greater than 
1 day 
• 
 
▪ 
Equivalency 
• 
Because of multiple types of systemic glucocorticoids that could 
be given to the same subject, we need to apply systemic 
glucocorticoid equivalency rules. Below is the table to follow. 
▪ 
MNT baseline 
• 
Subjects who have at least one dose in the 6 days prior to the 
dose of study medication at the Week 12 visit in the induction 
study will be considered to have a baseline dose >0. The MNT 
baseline dose to be used for these subjects is the median 
nonmissing daily dose from these 6 days. Subjects without at 
least one dose in the 6 days prior to the dose at the Week 12 visit 
in the induction study will be considered to take a 0 for the dose 
for the purposes of assessing an increase from MNT baseline 
o Systemic glucocorticoids given via parenteral routes of administration 
▪ 
Rule 
• 
Any exposure after first dose 
 
• 
Topical glucocorticoids 
o Budesonide 
▪ 
Rule 
• 
Subjects not taking Budesonide at MNT baseline: 


Shire                                                           CONFIDENTIAL                                               Page 85 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
o After first dose and up to and including Week 48: more 
than 9 mg/day for one day or any exposure for more than 
5 days 
o After Week 48: Any dose above MNT baseline for 
greater than 1 day 
• 
Subjects taking oral Budesonide at baseline: 
o After first dose and up to and including Week 48: more 
than 9 mg/day for one day or any increase for more than 
5 days 
o After Week 8: Any dose above MNT baseline for greater 
than 1 day 
▪ 
MNT Baseline 
• 
Subjects who have at least one dose in the 6 days prior to the 
dose of study medication at the Week 12 visit in the induction 
study will be considered to have a baseline dose >0. The MNT 
baseline dose to be used for these subjects is the median 
nonmissing daily dose from these 6 days. Subjects without at 
least one dose in the 6 days prior to the dose at the Week 12 visit 
in the induction study will be considered to take a 0 for the dose 
for the purposes of assessing an increase from MNT baseline 
o Beclomethasone 
▪ 
Rule 
• 
Subjects not taking Budesonide at MNT baseline: 
o After first dose and up to and including Week 48: more 
than 5 mg/day for one day or any exposure for more than 
5 days 
o After Week 48: Any dose above MNT baseline for 
greater than 1 day 
• 
Subjects taking oral Budesonide at MNT baseline: 
o After first dose and up to and including Week 48: more 
than 5 mg/day for one day or any increase for more than 
5 days 
o After Week 8: Any dose above MNT baseline for greater 
than 1 day 
▪ 
MNT Baseline 
• 
Subjects who have at least one dose in the 6 days prior to the 
dose of study medication at the Week 12 visit in the induction 
study will be considered to have a MNT baseline dose >0. The 
MNT baseline dose to be used for these subjects is the median 
nonmissing daily dose from these 6 days. Subjects without at 
least one dose in the 6 days prior to the dose at the Week 12 visit 


Shire                                                           CONFIDENTIAL                                               Page 86 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
in the induction study will be considered to take a 0 for the dose 
for the purposes of assessing an increase from MNT baseline 
 
 


Shire                                                           CONFIDENTIAL                                               Page 87 of 87 
Statistical Analysis Plan v 3 
Protocol Number: SHP647-303                                                                                                  23 Jun 2021 
16.6 
Treatment Groups 
Data will be presented by treatment group into 3 pages as follows: 
Page 1 (SHP647-301 or SHP647-302 Study Treatment/SHP647-303 Study Treatment) 
• Ontamalimab 25 mg/Placebo 
• Ontamalimab 25 mg/Ontamalimab 25 mg 
• Ontamalimab 75 mg/Placebo 
• Ontamalimab 75 mg/Ontamalimab 75 mg 
Page 2 (SHP647-301 or SHP647-302 Study Treatment/SHP647-303 Study Treatment) 
• Placebo/Placebo 
• Placebo/Ontamalimab 25 mg 
• Placebo/Ontamalimab 75 mg 
Page 3 (SHP647-303 Study Treatment) 
• Placebo 
• Ontamalimab 25 mg 
• Ontamalimab 75 mg 
• Ontamalimab All Doses 
• Total (for disposition, demographics, and baseline characteristics tables)