Conditions: Crohn's Disease Ulcerative Colitis
Keywords: Immunosuppressants Mesalamine Ulcerative Colitis Crohn's disease Gastroenteritis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 557
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of long-term treatment with ontamalimab in participants with moderate to severe Ulcerative Colitis (UC) or Crohn's disease (CD)

Detailed description:

Arms:
arm 1: Participants received 25 milligrams (mg) of ontamalimab solution for injection subcutaneously (SC), every 4 weeks (Q4W), for up to 3 years. arm 2: Participants received 25 mg of ontamalimab solution for injection SC, Q4W, and later progressed to receive 75 mg in a similar manner for up to 5.79 years. arm 3: Participants received 75 mg of ontamalimab solution for injection SC, Q4W, for up to 5.79 years. arm 4: Participants received 25 mg of ontamalimab solution for injection SC, Q4W, for up to 3 years. arm 5: Participants received 25 mg of ontamalimab solution for injection SC, Q4W, and later progressed to receive 75 mg in a similar manner for up to 5.79 years. arm 6: Participants received 75 mg of ontamalimab solution for injection SC, Q4W, for up to 5.79 years.

Interventions: intervention 1: 25 mg Ontamalimab intervention 2: 75 mg Ontamalimab
Intervention descriptions: intervention 1: Ontamalimab SC solution for injection intervention 2: Ontamalimab SC solution for injection

Protocol document:
Prot_000.pdf: 
For non-commercial use only


PROTOCOL: SHP647-304 
TITLE: 
A Phase 3 Long-term Safety Extension Study of SHP647 in Subjects with 
Moderate to Severe Ulcerative Colitis or Crohn’s Disease (AIDA) 
DRUG: 
Ontamalimab (SHP647) 
IND: 
100,222 
EUDRACT NO.: 
2017-000574-11 
SPONSOR: 
Shire Human Genetic Therapies, Inc. (“Shire”), a wholly owned subsidiary 
of Takeda Pharmaceutical Company Limited 
300 Shire Way, Lexington, MA 02421 US 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
, MD, PhD 
PROTOCOL 
HISTORY: 
Protocol Amendment 4: 21 Sep 2020 
Protocol Amendment 3: 07 Nov 2019 
Protocol Amendment 2: 17 Sep 2018 
Protocol Amendment 1: 18 Dec 2017 
Original Protocol: 13 Jul 2017 
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire. 
For non-commercial use only


For non-commercial use only


Shire 
CONFIDENTIAL 
Page 3 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Protocol Amendment Summary and Rationale: 
The main purpose of SHP647-304 Amendment 4 is to allow subjects with moderate to severe ulcerative colitis (UC) 
or Crohn’s disease (CD) to enter this study following discontinuation of the Phase 3 maintenance studies 
(SHP647-303 or SHP647-307) or those already enrolled in this study (SHP647-304) and who are responding to 
active treatment to receive ontamalimab treatment under a reduced schedule of assessments to minimize subject 
burden, as it is expected that this study will be completed in no more than 3 years (ie, by December 2023) if not 
terminated early. Certain types of pharmacodynamic assessments have been reduced, and efficacy and 
pharmacokinetic assessments have been removed. Response to ontamalimab treatment will be assessed throughout 
the study, and safety will continue to be monitored closely. 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). 
If an efficacious dose is determined based on data from the induction studies, the study is planned to become a 
single-dose study, with the dose to be chosen after the analysis of data from those studies. This study has been 
double-blind and will continue as such until the induction study results become available (ie, unblinding will not 
occur until the final analysis of the induction studies is completed and the lowest effective dose determined), as it is 
planned that subjects will receive the lowest effective dose based on the results of the induction studies. In the 
occurrence that the analysis of these results demonstrates the efficacy of at least one of the doses investigated, this 
dose will be selected to be administered open label in this study. If both doses are effective and the difference 
compared to placebo is similar, then the lowest effective dose will be selected. However, if no efficacious dose is 
found, then the study will be terminated. 
Amendment 4 removes the planned direct-entry of new subjects with UC that was added with Amendment 3 (dated 
07 Nov 2019). No subject new to the program had been enrolled directly prior to, nor since, the company decision to 
close the ontamalimab clinical development program. 
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 SHP647-304 Protocol Amendment 4 relative to the previous edition, SHP647-304 
Protocol Amendment 3, are captured below. 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 4 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 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 
Replaced electronic diary with 
memory aid throughout the 
document. 
Memory aid can be applicable for this 
type of long-term study for practical 
reasons. 
Global 
Removed direct-entry of subjects 
with UC. 
Due to the discontinuation of the 
ontamalimab clinical trial program and 
because no subjects had been enrolled 
directly prior to this decision. 
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). 
Global 
Updated the term ‘MAdCAM’ to 
‘MAdCAM-1’ throughout the 
document. 
As per the latest version of the 
ontamalimab Investigator’s Brochure, 
Edition 9.0. 
Study Synopsis, Number of Subjects 
(total and for each treatment arm) 
Revised total sample size 
projection. 
Due to the early discontinuation of the 
induction (SHP647-301, SHP647-302, 
SHP647-305, and SHP647-306) and 
maintenance (SHP647-303 and 
SHP647-307) studies and the removal 
of the criteria for direct-entry of 
subjects with UC in 
Study SHP647-304. 
Study Synopsis, Site(s) and 
Region(s) 
Section 3.3, Sites and Regions 
Updated the number of sites and 
the countries in which the study 
will be conducted. 
To reflect the changes due to 
discontinuation of the induction and 
maintenance studies. 
Study Synopsis, Objectives 
Section 2.2, Study Objectives 
Added a secondary objective to 
evaluate the maintenance of 
response to long-term treatment 
with ontamalimab as measured by 
the clinical composite score (for 
subjects with UC) or CDAI score 
(for subjects with CD) and 
biomarkers, with or without 
endoscopy. 
The study drug will be available for 
those who have been benefiting from 
it. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 5 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Rationale 
Section 2.1, Rationale for the Study 
Added text to report the 
discontinuation of the ontamalimab 
Phase 3 clinical development 
program and the intention to 
continue this long-term safety 
extension study, which is expected 
to be completed in no more than 
3 years (ie, by December 2023) if 
not terminated early, to provide 
active treatment to subjects already 
enrolled who are responding to 
treatment and to subjects entering 
who have responded to active 
treatment. 
In 2019, Takeda formally acquired 
Shire, the sponsor of this study. On 
29 May 2020, Takeda announced the 
closure of the ontamalimab Phase 3 
clinical development program, which 
included induction and maintenance 
studies for subjects with moderate to 
severe inflammatory bowel disease 
(IBD) who had failed at least 1 prior 
treatment. Per the announcement, the 
induction and maintenance studies will 
be closed earlier than originally 
planned. In recognition that this could 
potentially cause hardships for 
subjects who were benefiting from this 
investigational treatment, this 
long-term safety extension study, 
which is expected to be completed in 
no more than 3 years (ie, by 
December 2023), may continue to 
provide active treatment to subjects 
already enrolled who are responding to 
treatment and to subjects entering 
from a maintenance study who have 
responded to treatment (ie, in the 
induction or maintenance studies and 
who meet the entry criteria). However, 
if the results of the induction or 
maintenance studies show that 
ontamalimab does not have evidence 
of efficacy over placebo, this study 
will be terminated. 
Study Synopsis, Rationale 
Study Synopsis, Methodology 
Section 2.1, Rationale for the Study 
Section 3.1, Study Design 
Section 6.1.1, Blinding the 
Treatment Assignment 
Section 6.2.4, Unblinding the 
Treatment Assignment 
Added text to describe the 
unblinding of the study following 
the completion of the final analysis 
of the induction studies. 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 6 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Methodology 
Section 3.1, Study Design and 
Flowchart 
Addition of details about Direct to 
Patient [DTP] program/provision 
for home administration of 
investigational product. 
Added text that no additional 
subjects from the induction studies 
will be enrolled in 
Study SHP647-304. 
 
Revised the criteria for enrollment 
from maintenance studies 
SHP647-303 and SHP647-307 into 
Study SHP647-304. 
 
 
Removed pharmacokinetic and 
health outcome assessments. 
 
Updated randomization details. 
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 reflect that the induction studies 
will no longer have active subjects due 
to the discontinuation of the program. 
To enable the subjects to continue 
active treatment who had ever 
responded to active treatment in the 
Phase 3 clinical development program. 
 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 7 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Methodology 
Section 3.1, Study Design and 
Flowchart 
Updated the duration for the entry 
of subject data from 10 days (for 
subjects with UC) and 14 days (for 
subjects with CD) before each 
specified visit (using diaries) to 
7 days (for all subjects) before 
each specified visit (using memory 
aids). 
Updated language to specify that 
endoscopy is optional and that, if 
performed, it is recommended that 
the Mayo endoscopic subscore be 
recorded (for subjects with UC) 
and that the SES-CD is recorded 
(for subjects with CD). 
Added text that at every third visit, 
the subject will be assessed for 
ongoing benefit (treatment 
response) using the clinical 
composite score or composite 
score (for subjects with UC) and 
CDAI score (for subjects with 
CD). Biomarkers (C-reactive 
protein and fecal calprotectin) will 
be assessed every 3 months or in 
case there is a necessity to confirm 
the loss of clinical treatment 
response. 
Revised patient-reported CD sign 
and symptoms data (rectal bleeding 
frequency, rectal urgency 
frequency, vomiting frequency, 
nausea severity, incontinence 
frequency, total stool frequency) to 
‘general well-being’. 
The term ‘potential treatment 
failure’ has been replaced by the 
term ‘loss of response’. 
Added criteria for the loss of 
response and included clinical 
composite score (for subjects with 
UC) and CDAI score (for subjects 
with CD) for the evaluation of loss 
of response. 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
 
To determine if the subject is 
receiving benefit from active 
treatment. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 8 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Rationale 
Study Synopsis, Methodology 
Study Synopsis, Maximum duration 
of subject involvement in the study 
Section 3.1, Study Design and 
Flowchart 
Section 3.2, Duration and Study 
Completion Definition 
Updated the subject’s maximum 
duration of study participation 
from approximately 7 years to no 
more than 3 years (ie, a subject’s 
participation is not planned to 
extend beyond 2023). 
To more accurately reflect the 
expected maximum duration of study 
participation. 
Study Synopsis, Maximum duration 
of subject involvement in the study 
Section 3.2, Duration and Study 
Completion Definition 
Updated the time of study 
completion from approximately 
7 years to no more than 3 years 
(ie, a subject’s participation is not 
expected to extend beyond 2023). 
To more accurately reflect the 
expected duration of the study based 
on changes to study plans. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4, Study Population 
Revised inclusion criterion 3 
describing the milestones that 
subjects who rollover from 
maintenance studies to 
Study SHP647-304 must meet. 
Reduced inclusion/exclusion 
criteria for subjects with CD. 
To align with the change in study 
design and as per the early 
discontinuation of induction and 
maintenance studies and the removal 
of criteria for direct-entry of subjects 
with UC. 
Study Synopsis, Endpoints and 
statistical analysis 
Section 9.7, Study Population 
Reduced analysis sets. 
Due to the early discontinuation of the 
study and limited sample size, 
previously planned analyses will no 
longer be conducted. 
Study Synopsis, Safety Endpoints 
Study Synopsis, Secondary 
Endpoints 
Section 9.8.1.1, Secondary 
Endpoints (Subjects with UC) 
Section 9.8.2.1, Secondary 
Endpoints (Subjects with CD) 
Section 9.9, Safety Analyses 
Updated endpoints to reflect the 
inclusion of maintenance 
discontinuation rollover subjects. 
 
Removed secondary and 
exploratory endpoints and 
assessments that are no longer 
applicable under Amendment 4. 
To align with the change in study 
entry criteria. 
 
 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 9 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Table 1, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
UC) 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
UC) 
Table 3, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
CD) 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
CD) 
Updated the visit window for all 
study procedures (including safety 
follow-up) from ±7 days to 
±10 days. 
 
Specified that laboratory 
assessments will be performed by 
the central laboratory and 12-lead 
electrocardiogram will be read by 
the local reader. 
 
 
Added treatment response 
assessment. 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
 
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 determine if subjects are receiving 
benefit from active treatment. 
Table 1, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
UC), footnote “f” 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
UC), footnote “e” 
Table 3, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
CD), footnote “f” 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
CD), footnote “e” 
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 – 
Treatment Year 1 (Subjects with 
UC), footnote “g” 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
UC), footnote “f” 
Table 3, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
CD), footnote “g” 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
CD), footnote “f” 
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. 
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Shire 
CONFIDENTIAL 
Page 10 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Table 1, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
UC), footnote “h” 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
UC), footnote “g” 
Table 3, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
CD), footnote “h” 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
CD), footnote “g” 
Added footnote to specify that 
subjects performing home 
administrations consecutively for 
3 months will need to perform liver 
function testing per 
FDA requirement, which may be 
done locally if it is not possible to 
collect samples at the central 
laboratory. 
To comply with the FDA 
requirements. 
Table 1, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
UC), footnote “m” 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
UC), footnote “k” 
Table 3, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
CD), footnote “m” 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
CD), footnote “k” 
Section 7.3.2.1, Endoscopy 
Section 7.3.3.1, Colonoscopy 
Updated language to specify that 
endoscopy (flexible sigmoidoscopy 
or colonoscopy for subjects with 
UC)/colonoscopy (for subjects 
with CD) is optional; that, if 
performed, the results are to be 
recorded; and that if more than 
2 endoscopies/colonoscopies are 
needed in a year, the subject 
should be discontinued. 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
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Shire 
CONFIDENTIAL 
Page 11 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Table 1, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
UC), footnote “p” 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
UC), footnote “n” 
Table 3, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
CD), footnote “p” 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
CD), footnote “n” 
Added footnote to report the 
assessment of treatment response 
and also to clarify that it is 
applicable only after the 
implementation of Amendment 4. 
To align with the change in study 
design as per the early discontinuation 
of induction and maintenance studies. 
Table 1, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
UC), footnote “q” 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
UC), footnote “o” 
Table 3, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
CD), footnote “q” 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
CD), footnote “o” 
Section 7.3.2.2, Mayo Score 
Section 7.3.2.3, Ulcerative Colitis 
Memory Aid 
Section 7.3.3.3, Crohn’s Disease 
Activity Index 
Section 7.3.3.4, Crohn’s Disease 
Memory Aid 
Updated the duration for the entry 
of subject data from 10 days (for 
subjects with UC) before each 
specified visit and 14 days (for 
subjects with CD) before each 
specified visit (using diaries) to 
7 days (for all subjects) before 
each specified visit (using memory 
aids). 
To adopt for memory aid data 
collection. 
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Shire 
CONFIDENTIAL 
Page 12 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Table 1, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
UC), footnote “t” 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
UC), footnote “q” 
Table 3, Schedule of Assessments – 
Treatment Year 1 (Subjects with 
CD), footnote “t” 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
CD), footnote “q” 
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. 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
UC) 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through Year 3 
and End of Study (Subjects with 
CD) 
Revised tables to reflect duration 
of treatment. 
Added note on study participation 
extending beyond Year 3. 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
Section 2.2, Study Objectives 
Removed the secondary and 
exploratory objectives that are no 
longer applicable under 
Amendment 4. 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
Section 3.1, Study Design and Flow 
Chart 
Added study design flow chart for 
subjects enrolling under 
Amendment 4 (Figure 1). 
To show the change in study design 
and treatment allocation of subjects 
entering from the discontinued 
maintenance studies. 
Section 3.2, Duration and Study 
Completion Definition 
Section 7.2, Study Schedule 
Updated subject’s expected 
maximum study duration and 
overall study duration to no more 
than 3 years. 
Added text on allowing EOT and 
12-week safety follow-up visits to 
be conducted at subject’s home 
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 reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
 
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. 
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Shire 
CONFIDENTIAL 
Page 13 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Methodology 
Section 4.4.1, Loss of Response 
Added the steps to be performed if 
the response criteria are not 
satisfied. 
To facilitate correct clinical judgment. 
Section 4.4.2, Subject Withdrawal 
Criteria 
Removed information around 
treatment failure assessment and 
stopping criteria. 
 
Added text regarding subject 
withdrawal from the study due to 
personal concerns related to 
COVID-19 (or other similar 
pandemic). 
An even stricter criterion (treatment 
response/loss of treatment response) 
will guide study drug and study 
discontinuation. 
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. 
Section 4.4.3, Reason for 
Withdrawal 
Replaced the term ‘treatment 
failure’ with ‘loss of response’. 
 
Added text regarding subject 
withdrawal from the study due to 
personal concerns related to 
COVID-19 (or other similar 
pandemic). 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
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.. 
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). 
Updated details on permitted 
glucocorticoid use and prior 
treatments. 
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 6.2.2, Allocation of Subjects 
to Treatment 
Added text to specify dose 
allocation in subjects who 
withdrew from 
Studies SHP647-303 or 
SHP647-307. 
To provide the dose allocation for the 
maintenance discontinuation rollover 
subjects with the change in study entry 
criteria. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 14 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
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 6.3.2, Packaging 
Updated the packaging of 
pre-filled syringe from tray to 
foam insert. 
To accurately describe study drug 
packaging. 
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. 
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. 
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Shire 
CONFIDENTIAL 
Page 15 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 7.1, Changes to Study 
Procedures Due to a Pandemic 
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. 
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, Study Schedule 
Updated details regarding the study 
baseline visit. 
 
Updated the window for the safety 
follow-up visit to ±10 days from 
±7 days for subjects with UC 
(Section 7.2.1.3) and subjects with 
CD (Section 7.2.2.3). 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
Section 7.3.2, Treatment Response 
Assessments – Subjects with 
Ulcerative Colitis 
Added note that Mayo composite 
score will be computed only if an 
endoscopy is performed. 
Reduced signs and symptoms to be 
collected from subjects. 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
Section 7.3.3.4, Crohn’s Disease 
Memory Aid 
Added information to be collected 
from subjects with the option of a 
memory aid. 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
Section 7.3.4.3, Targeted 
Neurological Assessment 
Added text on the assessment of 
potential PML following 
unblinding of the study. 
Added figure on post-unblinding 
process for quarterly neurological 
assessments. 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
Section 7.3.4.6, 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. 
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CONFIDENTIAL 
Page 16 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 7.3.4.8, Electrocardiogram 
Changed the ECG reading from 
central to local. 
Added details on performance of 
ECG in case of COVID-19-related 
or other pandemic-related issues. 
To comply with study procedures as 
per the protocol due 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 7.3.4.11, Colonoscopy in 
Subjects at Elevated Risk of 
Colorectal Cancer 
Added language to specify that 
colonoscopy is not required by the 
protocol. 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
Section 7.3.5, Others 
Removed the sections on 
health-related quality-of-life 
assessments and healthcare 
resource utilization assessments. 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
Section 7.3.5.1, Pharmacodynamic 
Assessments 
Section 7.3.6, Volume of Blood to 
be Drawn from Each Subject 
Removed laboratory assessments 
for serum soluble MAdCAM-1 and 
blood β7+ T cells. 
Removed antidrug antibody and 
neutralizing antibody sampling. 
Updated volume of blood to be 
drawn. 
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 analysis 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 interim 
analyses and the use of a 
hypersensitivity adjudication 
committee. 
To reflect the discontinuation of 
ontamalimab Phase 3 clinical 
development program. 
Section 9.6, Sample Size 
Calculation and Power 
Considerations 
Added text to report the 
discontinuation of the ontamalimab 
Phase 3 clinical development 
program. 
Updated sample size projection for 
the enrollment of subjects from 
induction and maintenance studies 
and removal of planned projection 
of direct-entry of subjects with UC. 
Revised projections due to plan of 
early discontinuation of induction and 
maintenance studies and the removal 
of criteria for direct-entry of subjects 
with UC. 
Section 9.8, Efficacy Analyses 
Removed the efficacy endpoints 
that are no longer applicable after 
the implementation of 
Amendment 4. 
To minimize the subject burden due to 
discontinuation of ontamalimab 
Phase 3 clinical development program. 
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CONFIDENTIAL 
Page 17 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
4 
Amendment Date 
21 Sep 2020 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 9.10, Other Analyses 
Removed the section on PK and 
PD analyses. 
As there will be no PK or PD analyses 
due to 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. 
Appendices 
Added Summary of Changes of 
Protocol Amendment 3. 
Removed scales and assessments 
no longer applicable under 
Amendment 4. 
Removed Appendix 5, 
Determination of Failure or 
Intolerance to Prior Treatment for 
Ulcerative Colitis. 
Administrative change. 
See Appendix 1 for protocol history, including all amendments. 
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CONFIDENTIAL 
Page 18 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 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 
+1 484 595 8155 (Global) 
Email 
drugsafety@shire.com 
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 +1 888 483 7729; Wilmington +1 800 201 8725 
PPD 24 Hour Safety Hotline Fax: RTP +1 888 529 3580 or +1 919 654 3836; 
Wilmington +1 888 488 9697 or +1 919 654 3849 
Latin America: 
PPD 24 Hour Safety Hotline: +55 11 4504 4801 
PPD 24 Hour Safety Hotline Fax: +55 11 3958 0983 
Europe, the Middle East, and Africa; and Asia-Pacific: 
PPD 24 Hour Safety Hotline: +44 1223 374 240 
PPD 24 Hour Safety Hotline Fax: +44 1223 374 102 
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CONFIDENTIAL 
Page 19 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 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 below: 
ctmcomplaint@takeda.com 
Telephone number (provided for reference if needed): 
1 800 828 2088 
Shire, Lexington, MA (USA) 
For instructions on reporting AEs related to product complaints, see Section 8.2.2. 
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Page 20 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS VERSION ........................................................3 
EMERGENCY CONTACT INFORMATION ..............................................................................18 
PRODUCT QUALITY COMPLAINTS........................................................................................19 
TABLE OF CONTENTS ...............................................................................................................20 
LIST OF TABLES .........................................................................................................................25 
LIST OF FIGURES .......................................................................................................................25 
LIST OF APPENDICES ................................................................................................................25 
ABBREVIATIONS .......................................................................................................................26 
STUDY SYNOPSIS ......................................................................................................................28 
STUDY SCHEDULES ..................................................................................................................37 
1. 
BACKGROUND INFORMATION .......................................................................................51 
1.1 
Indication and Current Treatment Options ...............................................................51 
1.1.1 Ulcerative Colitis ...................................................................................................51 
1.1.2 Crohn’s Disease .....................................................................................................51 
1.2 
Product Background and Clinical Information ........................................................52 
1.3 
Benefit/Risk Assessment ..........................................................................................53 
2. 
STUDY OBJECTIVES AND PURPOSE ..............................................................................55 
2.1 
Rationale for the Study .............................................................................................55 
2.2 
Study Objectives ......................................................................................................57 
2.2.1 Primary Objective ..................................................................................................57 
2.2.2 Secondary Objectives – Subjects with Ulcerative Colitis ......................................57 
2.2.3 Secondary Objectives – Subjects with Crohn’s Disease ........................................57 
3. 
STUDY DESIGN ...................................................................................................................58 
3.1 
Study Design and Flow Chart ..................................................................................58 
3.2 
Duration and Study Completion Definition .............................................................62 
3.3 
Sites and Regions .....................................................................................................62 
4. 
STUDY POPULATION .........................................................................................................63 
4.1 
Eligibility Criteria – Subjects with Ulcerative Colitis .............................................63 
4.1.1 Inclusion Criteria ...................................................................................................63 
4.1.2 Exclusion Criteria ..................................................................................................64 
4.2 
Eligibility Criteria – Subjects with Crohn’s Disease ...............................................65 
4.2.1 Inclusion Criteria ...................................................................................................65 
4.2.2 Exclusion Criteria ..................................................................................................66 
4.3 
Reproductive Potential .............................................................................................67 
4.3.1 Contraceptive Methods for Female Study Subjects ...............................................68 
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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
4.3.2 Contraceptive Methods for Male Study Subjects ..................................................70 
4.4 
Withdrawal of Subjects ............................................................................................70 
4.4.1 Loss of Response ...................................................................................................71 
4.4.2 Subject Withdrawal Criteria ..................................................................................72 
4.4.3 Reasons for Withdrawal .........................................................................................72 
4.4.4 Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................73 
5. 
PRIOR AND CONCOMITANT TREATMENT ...................................................................74 
5.1 
Prior and Concomitant Treatment – Subjects with Ulcerative Colitis .....................74 
5.1.1 Prior Treatment ......................................................................................................74 
5.1.2 Concomitant Treatment .........................................................................................74 
5.1.2.1 
Permitted Treatment ...............................................................................74 
5.1.2.2 
Prohibited Treatment ..............................................................................75 
5.2 
Prior and Concomitant Treatment – Subjects with Crohn’s Disease .......................76 
5.2.1 Prior Treatment ......................................................................................................76 
5.2.2 Concomitant Treatment .........................................................................................76 
5.2.2.1 
Permitted Treatment ...............................................................................76 
5.2.2.2 
Prohibited Treatment ..............................................................................78 
5.3 
COVID-19 ................................................................................................................79 
6. 
INVESTIGATIONAL PRODUCT ........................................................................................80 
6.1 
Identity of Investigational Product ...........................................................................80 
6.1.1 Blinding the Treatment Assignment ......................................................................80 
6.2 
Administration of Investigational Product(s) ...........................................................80 
6.2.1 Interactive Response Technology for Investigational Product Management ........80 
6.2.2 Allocation of Subjects to Treatment ......................................................................81 
6.2.3 Dosing ....................................................................................................................82 
6.2.4 Unblinding the Treatment Assignment ..................................................................83 
6.3 
Labeling, Packaging, Storage, and Handling ...........................................................84 
6.3.1 Labeling .................................................................................................................84 
6.3.2 Packaging ...............................................................................................................85 
6.3.3 Storage ...................................................................................................................85 
6.3.4 Special Handling ....................................................................................................86 
6.4 
Drug Accountability .................................................................................................86 
6.5 
Subject Compliance ..................................................................................................87 
7. 
STUDY PROCEDURES ........................................................................................................88 
7.1 
Changes to Study Procedures Due to a Pandemic ....................................................88 
7.2 
Study Schedule .........................................................................................................89 
7.2.1 Subjects with Ulcerative Colitis .............................................................................90 
7.2.1.1 
Baseline Visit (Week 0/Day 1) ...............................................................90 
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7.2.1.2 
Treatment Period ....................................................................................90 
7.2.1.3 
Follow-up Period ....................................................................................91 
7.2.2 Subjects with Crohn’s Disease...............................................................................91 
7.2.2.1 
Baseline Visit (Week 0/Day 1) ...............................................................91 
7.2.2.2 
Treatment Period ....................................................................................92 
7.2.2.3 
Follow-up Period ....................................................................................93 
7.2.3 Additional Care of Subjects After the Study .........................................................93 
7.3 
Study Evaluations and Procedures ...........................................................................93 
7.3.1 Demographic and Other Baseline Characteristics .................................................94 
7.3.2 Treatment Response Assessments – Subjects with Ulcerative Colitis ..................94 
7.3.2.1 
Endoscopy ..............................................................................................94 
7.3.2.2 
Mayo Score ............................................................................................94 
7.3.2.3 
Ulcerative Colitis Memory Aid ..............................................................96 
7.3.3 Treatment Response Assessments – Subjects with Crohn’s Disease ....................96 
7.3.3.1 
Colonoscopy ...........................................................................................96 
7.3.3.2 
Simple Endoscopic Activity Score for Crohn’s Disease ........................97 
7.3.3.3 
Crohn’s Disease Activity Index .............................................................98 
7.3.3.4 
Crohn’s Disease Memory Aid ................................................................98 
7.3.4 Safety .....................................................................................................................99 
7.3.4.1 
Medical and Medication History ............................................................99 
7.3.4.2 
Physical Examination (Including Weight) .............................................99 
7.3.4.3 
Targeted Neurological Assessment ......................................................100 
7.3.4.4 
Adverse Event Collection .....................................................................102 
7.3.4.5 
Vital Signs ............................................................................................103 
7.3.4.6 
Clinical Laboratory Evaluations ...........................................................103 
7.3.4.7 
Pregnancy Test and Follicle-stimulating Hormone Test ......................105 
7.3.4.8 
Electrocardiogram ................................................................................106 
7.3.4.9 
Monitoring for Type I and Type III Immune Reactions ......................106 
7.3.4.10 
Evaluation of Increased Gastrointestinal Symptoms ...........................107 
7.3.4.11 
Colonoscopy in Subjects at Elevated Risk of Colorectal Cancer .........107 
7.3.5 Others ...................................................................................................................108 
7.3.5.1 
Pharmacodynamic Assessments ...........................................................108 
7.3.6 Volume of Blood to Be Drawn from Each Subject – All Subjects ......................108 
8. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ..................................110 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events .....................................................................................................................110 
8.1.1 Severity Categorization ........................................................................................110 
8.1.2 Relationship Categorization .................................................................................111 
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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
8.1.3 Adverse Events of Special Interest ......................................................................112 
8.1.3.1 
Hypersensitivity ...................................................................................112 
8.1.4 Outcome Categorization ......................................................................................114 
8.1.5 Symptoms of the Disease Under Study ...............................................................114 
8.1.6 Clinical Laboratory and Other Safety Evaluations ..............................................114 
8.1.7 Pregnancy .............................................................................................................115 
8.1.8 Abuse, Misuse, Overdose, and Medication Error ................................................116 
8.1.9 Unexpected Adverse Event ..................................................................................117 
8.1.10 Suspected Unexpected Serious Adverse Reaction ...............................................117 
8.2 
Serious Adverse Event Procedures ........................................................................117 
8.2.1 Reference Safety Information ..............................................................................117 
8.2.2 Reporting Procedures ...........................................................................................117 
8.2.3 Serious Adverse Event Definition .......................................................................118 
8.2.4 Serious Adverse Event Collection Time Frame ...................................................119 
8.2.5 Serious Adverse Event Onset and Resolution Dates ...........................................119 
8.2.6 Fatal Outcome ......................................................................................................119 
8.2.7 Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting..............................................................................................................120 
8.2.8 Safety Monitoring for Potential Cases of Drug-induced Liver Injury .................120 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS .............................................123 
9.1 
Data Collection .......................................................................................................123 
9.2 
Clinical Data Management .....................................................................................123 
9.3 
Data Handling Considerations ...............................................................................123 
9.4 
Statistical Analysis Process ....................................................................................124 
9.5 
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee ....125 
9.6 
Sample Size Calculation and Power Considerations ..............................................125 
9.7 
Study Population ....................................................................................................126 
9.8 
Efficacy Analyses ...................................................................................................126 
9.8.1 Treatment Response Analyses – Subjects with Ulcerative Colitis ......................126 
9.8.1.1 
Secondary Endpoints ............................................................................126 
9.8.2 Treatment Response Analyses – Subjects with Crohn’s Disease ........................127 
9.8.2.1 
Secondary Endpoints ............................................................................127 
9.9 
Safety Analyses ......................................................................................................127 
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .........................................129 
10.1 
Sponsor’s Responsibilities .....................................................................................129 
10.1.1 Good Clinical Practice Compliance .....................................................................129 
10.1.2 Indemnity/Liability and Insurance .......................................................................130 
10.1.3 Public Posting of Study Information ....................................................................130 
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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees .........................................130 
10.1.5 Study Suspension, Termination, and Completion................................................130 
10.2 
Investigator’s Responsibilities ...............................................................................131 
10.2.1 Good Clinical Practice Compliance .....................................................................131 
10.2.2 Protocol Adherence and Investigator Agreement ................................................131 
10.2.3 Documentation and Retention of Records ...........................................................132 
10.2.3.1 
Case Report Forms ...............................................................................132 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study 
Documents ............................................................................................132 
10.2.3.3 
Audit/Inspection ...................................................................................133 
10.2.3.4 
Financial Disclosure .............................................................................133 
10.3 
Ethical Considerations ............................................................................................134 
10.3.1 Informed Consent.................................................................................................134 
10.3.2 Institutional Review Board or Ethics Committee ................................................134 
10.4 
Privacy and Confidentiality ....................................................................................135 
10.5 
Study Results/Publication Policy ...........................................................................136 
11. REFERENCES .....................................................................................................................138 
 
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Page 25 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments – Treatment Year 1 (Subjects with UC) ...............37 
Table 2 
Schedule of Assessments – Treatment Year 2 Through Year 3 and End 
of Study (Subjects with UC) ..........................................................................41 
Table 3 
Schedule of Assessments – Treatment Year 1 (Subjects with CD) ...............44 
Table 4 
Schedule of Assessments – Treatment Year 2 Through Year 3 and End 
of Study (Subjects with CD) ..........................................................................48 
Table 5 
Glucocorticoid Tapering – Subjects with Ulcerative Colitis .........................75 
Table 6 
Glucocorticoid Tapering – Subjects with Crohn’s Disease ...........................77 
Table 7 
Quarterly Neurological Assessments ..........................................................100 
Table 8 
Volume of Blood to Be Drawn from Each Subject – Treatment Year 1 
(All Subjects) ...............................................................................................108 
Table 9 
Volume of Blood to Be Drawn from Each Subject – Treatment Year 2 
Through Year 3 (All Subjects) ....................................................................109 
Table 10 
Clinical Criteria for Diagnosing Anaphylaxis (Type 1 
Hypersensitivity) .........................................................................................113 
Table 11 
Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin .......................................................................................................121 
 
LIST OF FIGURES 
Figure 1 
Study Design Flow Chart for Subjects who Enter SHP647-304 Under 
Amendment 4 ................................................................................................61 
Figure 2 
Flow Diagram for Quarterly Neurological Assessments .............................101 
Figure 3 
Post-unblinding Flow Diagram for Quarterly Neurological 
Assessments .................................................................................................102 
Figure 4 
Potential Immunogenicity of Therapeutic Monoclonal Antibodies ............112 
LIST OF APPENDICES 
Appendix 1 
Protocol History ...........................................................................................140 
Appendix 2 
Scales and Assessments ...............................................................................199 
Appendix 3 
Glucocorticoid Equivalent Doses ................................................................207 
Appendix 4 
Guidance for Diagnosis and Treatment of Increased Gastrointestinal 
Symptoms ....................................................................................................208 
 
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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
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 
CDAI 
Crohn’s Disease Activity Index 
CNS 
central nervous system 
CRA 
clinical research associate 
CRO 
contract research organization 
CRP 
C-reactive protein 
DMC 
data monitoring committee 
EC 
ethics committee 
ECCO 
European Crohn’s and Colitis Organisation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EOT 
end of treatment 
ET 
early termination 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 
hsCRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
ICH 
International Council for Harmonisation 
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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
IgG2κ 
immunoglobulin G2 kappa 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
MAdCAM-1 
mucosal addressin cell adhesion molecule-1 
MTX 
methotrexate 
NAb 
neutralizing antibody 
PFS 
prefilled syringe 
PGA 
physician global assessment 
PK 
pharmacokinetic(s) 
PML 
progressive multifocal leukoencephalopathy 
RB 
rectal bleeding 
RSI 
reference safety information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SES-CD 
Simple Endoscopic Score for Crohn’s Disease 
SMT 
Safety Management Team 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TB 
Mycobacterium tuberculosis 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
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STUDY SYNOPSIS 
Protocol number: SHP647-304 
Drug: Ontamalimab (SHP647) 
Title of the study: A Phase 3 Long-term Safety Extension Study of SHP647 in Subjects with Moderate to Severe 
Ulcerative Colitis or Crohn’s Disease (AIDA) 
Number of subjects (total and for each treatment arm): 
A maximum of 451 subjects are projected for enrollment in this study. 
Investigator(s): Multicenter study 
Site(s) and Region(s): 
This study will be conducted in approximately 225 sites in approximately 33 countries. 
Study period (planned): 
2018 – 2023 
Clinical phase: 
3 
Objectives: 
Primary: To evaluate the safety and tolerability of long-term treatment with ontamalimab in subjects with moderate 
to severe ulcerative colitis (UC) or Crohn’s disease (CD). 
Secondary - Subjects with Ulcerative Colitis: 
• 
To evaluate the maintenance of response to long-term treatment with ontamalimab as measured by clinical 
composite score and biomarkers, with or without endoscopy. 
Secondary - Subjects with Crohn’s Disease: 
• 
To evaluate the maintenance of response to long-term treatment with ontamalimab as measured by Crohn’s 
Disease Activity Index (CDAI) score and biomarkers, with or without endoscopy. 
Rationale: In 2019, Takeda formally acquired Shire, the sponsor of this study. On 29 May 2020, Takeda announced 
the closure of the ontamalimab Phase 3 clinical development program, which included induction and maintenance 
studies for subjects with moderate to severe inflammatory bowel disease who had failed at least 1 prior treatment. 
Per the announcement, the induction and maintenance studies will be closed earlier than originally planned. In 
recognition that this could potentially cause hardships for subjects who were benefiting from this investigational 
treatment (ie, fulfilling treatment response criteria as defined in Section 9.8.1.1 and Section 9.8.2.1), this long-term 
safety extension study, which is expected to be completed in no more than 3 years (ie, by December 2023), may 
continue to provide active treatment to subjects already enrolled who are responding to treatment and to subjects 
entering from a maintenance study who have responded to treatment (ie, in the induction or maintenance studies and 
who meet the entry criteria). However, if the results of the induction or maintenance studies show that ontamalimab 
does not have evidence of efficacy over placebo, this study will be terminated. 
Originally, this extension study was designed to evaluate the safety and efficacy of long-term treatment with 
ontamalimab in subjects with moderate to severe UC or CD who: (1) completed one of the 4 multicenter, 
randomized, double-blind, placebo-controlled, parallel-group studies evaluating ontamalimab as an induction 
therapy (SHP647-301, SHP647-302, SHP647-305, or SHP647-306) and did not meet the response criteria (clinical 
and/or endoscopic response/remission as appropriate) required for entry into a maintenance study (SHP647-303 or 
SHP647-307), or (2) were treatment failures (as defined in the respective protocols) and/or completers in one of the 
2 multicenter, double-blind, randomized, placebo-controlled, parallel-group studies evaluating ontamalimab as 
maintenance therapy (SHP647-303 or SHP647-307). This study has been double-blind and will continue as such 
until the induction study results become available (ie, unblinding will not occur until the final analysis of the 
induction studies is completed and the lowest effective dose determined), as it is planned that subjects will receive 
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the lowest effective dose based on the results of the induction studies. It is expected that the analysis of these results 
will demonstrate the efficacy of at least one of the doses and allow for the selection of a single dose, at which time 
this study will be open label. If both doses are effective and the difference compared to placebo is similar, then the 
lowest effective dose will be selected. However, if the results of the induction or maintenance studies show that 
ontamalimab does not have evidence of efficacy over placebo, this study will be terminated. 
Subjects in the induction studies SHP647-301 or SHP647-302: 
• 
As of September 2020, no subjects remain in the induction studies who would be eligible to participate in 
this study (SHP647-304); therefore, no additional subjects from the induction studies will enter this study 
under Amendment 4. 
Subjects in the maintenance studies SHP647-303 or SHP647-307: 
• 
Subjects who received and responded to active treatment in either or both of the induction or maintenance 
studies may be eligible to enter this study. 
• 
Subjects who have not received ontamalimab yet (ie, received placebo in both the induction and 
maintenance studies) will not be eligible to enter this study. 
• 
Subjects eligible to enter this study will be assessed for treatment response criteria according to the revised 
study schedule in Study SHP647-304. 
Subjects currently in Study SHP647-304 (ie, enrolled prior to Amendment 4) will be assessed for treatment response 
as follows: 
• 
Subjects who have already entered Study SHP647-304 may continue and will be assessed for treatment 
response according to the revised study schedule. If they show response to ontamalimab treatment, they 
may continue further in this study. 
• 
If the results of the induction or maintenance studies show that ontamalimab does not have evidence of 
efficacy over placebo, this study will be terminated. 
All subjects will be evaluated periodically and in case of clinical worsening at an unscheduled visit during the study 
for treatment response. If a subject shows response to ontamalimab treatment, he or she may continue in this study 
either until he or she shows a loss of treatment response (ie, no longer meets response criteria) or elects to seek 
another treatment option, or until the end of the study. 
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. 
Methodology: 
This is a Phase 3 multicenter extension study designed to evaluate the long-term safety of ontamalimab in subjects 
with moderate to severe UC or CD. The study has enrolled subjects from 6 separate Phase 3 studies to 
date: 4 multicenter, randomized, double-blind, placebo-controlled, parallel-group studies evaluating ontamalimab as 
an induction therapy in subjects with moderate to severe UC (SHP647-301 and SHP647-302) or CD (SHP647-305 
and SHP647-306); and 2 multicenter, double-blind, randomized, placebo-controlled, parallel-group studies 
evaluating ontamalimab as maintenance therapy in subjects with moderate to severe UC (SHP647-303) or CD 
(SHP647-307). As the induction and maintenance studies will be closed earlier than planned, the study will enroll 
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subjects with moderate to severe UC and CD from the 2 maintenance studies (at the time of their closure) who have 
responded to active treatment. As the 4 induction studies do not have any subjects eligible for rollover to the 
SHP647-304 study, no additional subjects will enter from those studies. 
This study is planned to become a single-dose study, with the dose to be determined after the analysis of data from 
the induction studies. This study has been double-blind and will continue as such until the induction study results 
become available (ie, unblinding will not occur until the final analysis of the induction studies is completed and the 
lowest effective dose determined), as it is planned that subjects will receive the lowest effective dose based on the 
results of the induction studies. It is expected that the analysis of these results will demonstrate the efficacy of at 
least one of the doses and allow for the selection of a single dose, at which time this study will be open label. If both 
doses are effective and the difference compared to placebo is similar, then the lowest effective dose will be selected. 
However, if the results of the induction or maintenance studies show that ontamalimab does not have evidence of 
efficacy over placebo, this study will be terminated. 
All subjects will receive active drug in this study. Eligible subjects entering Study SHP647-304 will be assigned to 
continue their present dose of ontamalimab (if currently receiving active drug) or to return to the dose of active drug 
associated with previous response (if on placebo). Ongoing subjects in this study will remain on the dose to which 
they have been previously assigned. Once the final dose has been determined, all subjects will continue on that dose 
only. 
Subjects will come to the investigational site every 4 weeks (unless unable to participate on site due to the ongoing 
COVID-19 pandemic [or other similar pandemic], in which case they may qualify for the “Direct to Patient” [DTP] 
program) for investigational product administration and appropriate assessments. 
The eligibility of a subject for this study will be assessed from study data collected at the following time points: 
• 
For subjects with UC, the Week 12 visit of the induction study (SHP647-301 or SHP647-302) OR the Week 52 
or Early Termination (ET) visit of the maintenance study (SHP647-303), which are considered and recorded as 
the baseline visit for this extension study (with the exception of the treatment response evaluation, for which 
baseline of the induction study will be used as baseline of this extension study). No additional subjects from the 
induction studies will be enrolling into Study SHP647-304. Subjects from the maintenance study (SHP647-303) 
will have the opportunity to enroll into this study at the time of the approval of Amendment 4 if they have 
benefited from active treatment in the induction or maintenance study. 
• 
For subjects with CD, the Week 16 visit of the induction study (SHP647-305 or SHP647-306), OR the ET or 
Week 52 visit of the maintenance study (SHP647-307), which will be considered and recorded as the baseline 
visit for this extension study (with the exception of the treatment response evaluation, for which baseline of the 
induction study will be used as baseline of this extension study), with an additional window of 1 week for 
subjects whose treatment failure status is still under evaluation at the time of the Week 52 visit of the 
maintenance study. No additional subjects from the induction studies will be enrolling into Study SHP647-304. 
Subjects from the maintenance study (SHP647-307) will have the opportunity to enroll into this study at the 
time of the approval of Amendment 4 if they have benefited from active treatment in the induction or 
maintenance study. 
Subjects enrolled in this study will receive treatment every 4 weeks, in the form of SC injections using PFSs. 
Subjects will undergo treatment response and safety assessments. 
At every third visit, subjects with UC will be assessed for ongoing benefit (treatment response) using the clinical 
composite score or composite score. To facilitate data collection and reliability, subjects will have the option to use 
a memory aid. Endoscopies are not required, but if performed (eg, for routine surveillance), it is recommended that 
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the Mayo endoscopic subscore be recorded by the endoscopist for assessment. The total Mayo score will be 
calculated only when endoscopy data are available. 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 
physician global assessment (PGA) subscore. The clinical composite score is a measure consisting of rectal bleeding 
(RB) plus stool frequency without the endoscopic and PGA subscore. The data for Mayo scores and composite score 
will be collected from subjects, who have the option of using a memory aid, for 7 days before each specified visit as 
in the schedules of assessments. Biomarkers (C-reactive protein [CRP] and fecal calprotectin) will be assessed every 
3 months or in case there is a necessity to confirm the loss of clinical treatment response. 
At every third visit, subjects with CD will be assessed for ongoing benefit (treatment response) using the 
CDAI score (treatment response defined as CDAI-100). Data on CDAI components (abdominal pain severity, very 
soft stool/liquid stool frequency, general well-being) will be collected from the subjects by the investigators. To 
facilitate data collection and reliability, subjects will have the option to use a memory aid. Endoscopies are not 
required, but if performed (eg, for routine surveillance), it is recommended that the Simple Endoscopic Score for 
Crohn’s Disease (SES-CD) be recorded by the endoscopist for assessment. The CDAI is a composite measure with 
8 components. Five components will be captured at the visits, and 3 components (abdominal pain severity, very soft 
stool/liquid stool frequency, and general well-being) will be collected from subjects, who have the option of using a 
memory aid, for 7 days before each specified visit as in the schedules of assessments. Biomarkers (CRP and fecal 
calprotectin) will be assessed every 3 months or in case there is a necessity to confirm the loss of clinical treatment 
response. 
Treatment response will be assessed at every third visit for all subjects to allow monitoring of clinical benefit 
derived and evaluation of loss of response throughout the study. At these assessment visits, subjects’ response will 
be evaluated and compared to the value of clinical composite score (for subjects with UC) or CDAI (for subjects 
with CD) determined at entry into the induction studies. As long as response criteria are satisfied, subjects may 
remain in the study. If there is a concern regarding loss of response between scheduled assessment visits, 
assessments may be performed at any scheduled or, if necessary, unscheduled visit to evaluate response. To ensure 
that placebo-treated subjects from a feeder study (SHP647-301, SHP647-302, SHP647-303, SHP647-305, 
SHP647-306, or SHP647-307) have sufficient exposure to active drug to permit assessment of treatment response, 
treatment response will be assessed according to the revised study schedule. Subjects may discontinue participation 
at any time, for any reason. If response to investigational product is lost, based on clinical criteria, or if there is an 
unexplained clinical exacerbation or unacceptably low level of clinical response the investigator may assess 
biomarkers and perform other investigations to exclude other potential causes like Clostridium difficile infection or 
an appropriate ad-hoc endoscopy to determine whether the loss of response is confirmed or not at an unscheduled 
visit. The totality of available data will be used to determine ongoing response status and subjects whose loss of 
response is confirmed. 
If clinical response criteria are no longer satisfied and alternative explanations for clinical worsening (eg, infection) 
can be excluded, the subject will be discontinued. If necessary for assessment in the opinion of the investigator 
(eg, borderline treatment response results), the following evaluations may be considered: 
1) 
Have subject return in 2 to 4 weeks for repeat assessment if loss of response criteria is still met: 
a) 
Perform endoscopy to determine if there is an objective benefit despite clinical 
symptoms; if the composite of clinical and endoscopic data meets response criteria, continue the 
study. 
1. Endoscopic response criterion for UC is Mayo endoscopic subscore decreased by 
≥1 point as compared to the baseline value recorded upon entry into the induction studies. 
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2. Endoscopic response criterion for CD is SES-CD improved by >25% as compared to the 
baseline value recorded upon entry into the induction studies. 
b) 
Biomarkers may be used to determine overall response criteria at the discretion of the 
investigator; serum CRP < upper limit of normal or fecal calprotectin <250 µg/g is considered 
indicative of clinical benefit. 
Upon termination from the study, subjects must return for a safety visit 12 weeks after the last dose of 
investigational product. 
Subjects who have experienced loss of response should be withdrawn from active treatment once other possible 
etiologies have been ruled out and appropriate clinical evaluation has been performed as suggested above. While 
these response criteria are offered as general guidance to the investigator, there may be additional criteria that 
warrant withdrawal from active treatment and the ultimate decision of withdrawal from active treatment is left to the 
investigator based on the assessment of disease activity, subject’s clinical benefit and tolerance of the investigational 
product. 
For subjects who are tolerating investigational product and receiving clinical benefit in the judgment of the 
investigator (ie, fulfilling treatment response criteria as defined in Section 9.8.1.1 and Section 9.8.2.1), study 
participation may continue until the subject withdraws from the study, or the investigator or sponsor decide to 
withdraw the subject (eg, in the interest of subject safety), or the sponsor decides to close the study, or the program 
is stopped completely. A subject’s maximum duration of participation in this study under the current amendment is 
expected to be no more than 3 years (ie, a subject’s participation is not planned to extend beyond 2023), subject to 
local or country requirements. Subjects will enter a 12-week safety follow-up period following the last dose of 
investigational product. 
Inclusion and exclusion criteria: 
Inclusion Criteria – Subjects with UC: 
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 been enrolled previously in Study SHP647-301 or SHP647-302 and are in the treatment 
period of Study SHP647-303, completed the ET or Week 52 visit in the maintenance study SHP647-303, had 
responded to ontamalimab treatment (in the induction and/or maintenance studies), and meet one of the 
following criteria: 
o 
Subjects are on placebo at the maintenance study ET or Week 52 visit: they received ontamalimab 
in the induction studies and fulfilled the maintenance study response entry criteria, OR 
o 
Subjects have received ontamalimab at the maintenance study ET or Week 52 visit: 
 
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, 
compared to the baseline value for induction studies, AND/OR 
 
Composite score that has decreased by ≥30% and ≥3 points compared to the baseline 
value for induction studies. 
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4. Subjects receiving any treatment(s) for UC described in Section 5.2.1 are eligible provided they have been on a 
stable dose for the designated period of time. 
Exclusion Criteria – Subjects with UC: 
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 Study SHP647-301, 
SHP647-302, or SHP647-303. 
2. Subjects who permanently discontinued investigational product because of an adverse event (AE), regardless 
of relatedness to investigational product, in Study SHP647-301, SHP647-302, or SHP647-303. 
3. Subjects who are likely to require major surgery for UC. 
4. Subjects are females who became pregnant during Study SHP647-301, SHP647-302, or SHP647-303, females 
who are lactating, females who are planning to become pregnant during the study period, or males or females 
of childbearing potential not agreeing to continue using appropriate contraception methods (ie, highly effective 
methods for female and medically appropriate methods for male study subjects) through the conclusion of 
study participation. 
5. Subjects who do not agree to postpone donation of any organ or tissue, including male subjects who are 
planning to bank or donate sperm and female subjects who are planning to harvest or donate eggs, for the 
duration of the study and through 16 weeks after last dose of investigational product. 
6. Subjects who, in the opinion of the investigator or the sponsor, will be uncooperative or unable to comply with 
study procedures. 
7. Subjects who have 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 [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 
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 
Study SHP647-301 or SHP647-302 and who have been advised to require treatment for latent or active 
disease, but 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 other investigational studies (other than SHP647-301, SHP647-302, or 
SHP647-303) or plan to participate in other investigational studies during long-term extension study 
SHP647-304. 
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Inclusion Criteria – Subjects with CD: 
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 been enrolled previously in Study SHP647-305 or SHP647-306 and are in the treatment 
period of Study SHP647-307, completed the ET or Week 52 visit in maintenance study SHP647-307, had 
responded to ontamalimab treatment (in the induction and/or maintenance studies), and meet one of the 
following criteria: 
o 
Subjects are on placebo at the maintenance study ET or Week 52 visit: they received ontamalimab 
in the induction study and fulfilled the maintenance study response criteria, OR 
o 
Subjects have received ontamalimab at the maintenance study ET or Week 52 visit: 
• 
CDAI score that has decreased by ≥100 points at the end of treatment visit compared to 
the baseline value for induction studies, AND/OR 
• 
SES-CD that has decreased by ≥25% compared to the baseline value for induction studies. 
4. Subjects receiving any treatment(s) for CD described in Section 5.3.1 are eligible provided they have been on a 
stable dose for the designated period of time. 
Exclusion Criteria – Subjects with CD: 
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 Study SHP647-305, 
SHP647-306, or SHP647-307. 
2. Subjects who permanently discontinued investigational product because of an AE, regardless of relatedness to 
investigational product, in Study SHP647-305, SHP647-306, or SHP647-307. 
3. Subjects who are likely to require major surgery for CD or developed acute severe complications of CD (with 
or without fulfilling the treatment failure criteria in the maintenance study) that required immediate 
intervention (eg, need for immediate biologic treatment with proven effect) and/or CDAI score >450. 
4. Subjects are females who became pregnant during Study SHP647-305, SHP647-306, or SHP647-307, females 
who are lactating, females who are planning to become pregnant during the study period, or males or females 
of childbearing potential not agreeing to continue using appropriate contraception methods (ie, highly effective 
methods for female and medically appropriate methods for male study subjects) through the conclusion of 
study participation. 
5. Subjects who do not agree to postpone donation of any organ or tissue, including male subjects who are 
planning to bank or donate sperm and female subjects who are planning to harvest or donate eggs, for the 
duration of the study and through 16 weeks after last dose of investigational product. 
6. Subjects who, in the opinion of the investigator or the sponsor, will be uncooperative or unable to comply with 
study procedures. 
7. Subjects who have 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 
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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. 
10. Subjects with known exposure to TB since testing at screening in Study SHP647-305 or SHP647-306, and who 
have been advised to require treatment for latent or active disease, but who are without a generally accepted 
course of treatment. 
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 other investigational studies (other than SHP647-305, SHP647-306, or 
SHP647-307) or plan to participate in other investigational studies during long-term extension study 
SHP647-304. 
Maximum duration of subject involvement in the study: 
For subjects who are tolerating investigational product and receiving clinical benefit in the judgment of the 
investigator (ie, fulfilling treatment response criteria as defined in Section 9.8.1.1 and Section 9.8.2.1), study 
participation may continue until the subject withdraws from the study, or the investigator or sponsor decide to 
withdraw the subject (eg, in the interest of subject safety), or the sponsor decides to close the study, or the program 
is stopped completely. Subjects will enter a 12-week safety follow-up period following the last dose of 
investigational product. A subject’s maximum duration of participation in this study under the current amendment is 
expected to be no more than 3 years (ie, a subject’s participation is not planned to extend beyond 2023), subject to 
local or country requirements. It is expected that the study will be completed in no more than 3 years (ie, by 
December 2023). 
Endpoints and statistical analysis: 
Analysis Sets: 
The full analysis set (FAS) will consist of all subjects in the randomized set who receive at least 1 dose of 
investigational product in the SHP647-304 study. 
The safety set will consist of all subjects who receive at least 1 dose of investigational product in the SHP647-304 
study. 
Primary Endpoint: The primary endpoint is the assessment of safety as measured by: incidence and severity of 
AEs; incidence and nature of serious infections; and actual values and change from baseline, as well as incidence of 
abnormalities, in laboratory tests, ECGs, and vital signs. 
Safety Endpoints: 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. Summaries will be presented by indication separately and also overall. Summaries may be presented by 
the status at entry into this study (eg, induction nonresponder, maintenance ontamalimab completer, maintenance 
discontinuation rollovers, etc.). 
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Treatment-emergent AEs (TEAEs) are defined as AEs with start dates or worsening dates at the time of or following 
the first exposure to investigational product in the SHP647-304 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/listed. Adverse events 
of special interest will be summarized by treatment group. 
Clinical laboratory tests, vital signs, and ECG findings will be summarized by indication, treatment group, and visit. 
Potentially clinically important findings will also be summarized or listed. 
Secondary Endpoints – Subjects with Ulcerative Colitis: 
The secondary endpoint is as follows: 
• 
Treatment response over time, with response defined as 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 , and/or composite score that has decreased by ≥30% and ≥3 points compared to the baseline value 
for induction studies. 
Secondary Endpoints – Subjects with Crohn’s Disease: 
The secondary endpoint is as follows: 
• 
Treatment response over time, with response defined as CDAI score that has decreased by ≥100 points 
compared to the baseline value for induction studies and/or SES-CD that has decreased by ≥25% compared 
to the baseline value for induction studies. 
All analyses will be performed using the FAS. 
Secondary endpoints will be summarized by treatment group using descriptive statistics at each assessment visit. 
Summaries may be presented by the status at entry into the study (eg, induction nonresponder, maintenance 
ontamalimab completer, maintenance early discontinuation rollovers, etc.). Statistical summaries will include 
number of subjects and percentages, and 95% confidence intervals. 
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STUDY SCHEDULES 
Table 1 
Schedule of Assessments – Treatment Year 1 (Subjects with UC) 
Study Procedure 
Baselinea 
Treatment – Year 1 
W0/ 
Day 1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit Window 
None 
±10 days 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessmentb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
IDT or MNT 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examinationd 
IDT or MNT 
 
 
 
 
 
X 
 
 
 
 
 
 
Targeted physical examinationd 
IDT or MNT 
 
 
 
 
 
 
 
 
 
 
 
X 
Targeted neurological assessmente,f 
IDT or MNT 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signs 
IDT or MNT 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Weight 
IDT or MNT 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
12-lead ECG (local) 
IDT or MNT 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Laboratory (Central)g 
Hematology 
IDT or MNT 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Serum chemistryh 
IDT or MNT 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Urinalysis 
IDT or MNT 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Urine β-hCGi 
IDT or MNT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSHj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Contraception checkk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stool sample for fecal calprotectin 
IDT or MNT 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum CRPl 
IDT or MNT 
 
 
 
 
 
X 
 
 
 
 
 
X 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 38 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Table 1 
Schedule of Assessments – Treatment Year 1 (Subjects with UC) 
Study Procedure 
Baselinea 
Treatment – Year 1 
W0/ 
Day 1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit Window 
None 
±10 days 
Endoscopic Procedure 
OPTIONAL endoscopy (flexible 
sigmoidoscopy or colonoscopy)m 
IDT or MNT 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
UC Assessmentsn 
OPTIONAL Total Mayo scoreo 
IDT or MNT 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Partial Mayo score 
IDT or MNT 
 
 
 
 
 
X 
 
 
 
 
 
X 
Treatment response assessmentp,q 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Treatment Procedures 
Administration of ontamalimabr,s,t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypersensitivity monitoringu 
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 
Concomitant medication and procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense stool collection kit for stool 
samplev 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 39 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Table 1 
Schedule of Assessments – Treatment Year 1 (Subjects with UC) 
Study Procedure 
Baselinea 
Treatment – Year 1 
W0/ 
Day 1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit Window 
None 
±10 days 
β-hCG=beta-human chorionic gonadotropin; CLIA=Clinical Laboratory Improvement Amendments; CRP=C-reactive protein; DTP=Direct-To-Patient; ECG=electrocardiogram; 
ET=early termination; FDA=Food and Drug Administration; FSH=follicle-stimulating hormone; GI=gastrointestinal; IDT=induction study (SHP647-301 or SHP647-302); 
LFT=liver function testing; MNT=maintenance study SHP647-303; O=optional; UC=ulcerative colitis; W=Week. 
a Baseline = Week 0 (Day 1). For subjects previously enrolled in induction study SHP647-301 or SHP647-302, the baseline visit is the Week 12 study visit (with the exception of 
treatment response assessment). For subjects entering from maintenance study SHP647-303, the baseline visit is the Week 52 visit (for subjects who completed the study) or the 
ET visit (for subjects who withdrew early), with the exception of treatment response assessment. 
b Eligibility will be assessed after the consent form is signed and after procedures are completed at Visit 6, Part 2 in Study SHP647-301 or SHP647-302, or at Visit 14, Part 2 or 
the ET or Week 52 visit in Study SHP647-303. 
c Medical history from Studies SHP647-301, SHP647-302, and SHP647-303 will be used as the baseline medical history data for Study SHP647-304. 
d Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; 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, eyes, abdomen, and examination of body systems where there are symptom complaints by the subject. 
e Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, speech, 
verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of progressive multifocal leukoencephalopathy 
should be excluded. See Section 7.3.4.3 for further details. 
f In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application). 
g 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. 
h 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. 
i The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory. 
j For confirmation of postmenopausal status in women 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 or maintenance study SHP647-303. 
k Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential; see Section 4.3. 
l Samples must be collected before administration of investigational product. 
m Flexible sigmoidoscopy or colonoscopy (if preferred). Endoscopy is optional for treatment response evaluation after the implementation of Amendment 4; if performed (eg, due 
to routine cancer surveillance required by GI guidelines or due to local clinical practice), the results should be recorded. If more than 2 endoscopies/colonoscopies are needed in 
a year, the subject should be discontinued. 
n Mayo score will be based on subject self-report, with the assistance of a memory aid. 
o The total Mayo score will be calculated based on the locally read endoscopic subscore (if endoscopy is performed). The total Mayo score will be calculated only when 
endoscopy data are available. 
p Measured by clinical composite score and biomarkers, with or without endoscopy. Applicable only after the implementation of Amendment 4. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 40 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Table 1 
Schedule of Assessments – Treatment Year 1 (Subjects with UC) 
Study Procedure 
Baselinea 
Treatment – Year 1 
W0/ 
Day 1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit Window 
None 
±10 days 
q Subjects will have the option to fill in a memory aid to collect data at least 7 days before each specified visit. See Section 7.3.2.3 for further details. 
r Interactive response technology will be used for dispensation of study treatment. 
s Investigational product is to be administered after all other visit assessments have been performed. 
t 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). 
u 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. 
v Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one 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 SHP647-304 baseline. 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 41 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Table 2 
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with UC) 
Study Procedure 
Treatment – Year 2 Through Year 3 
 
Follow-up 
W52/ 
W100 
W56/ 
W104 
W60/ 
W108 
W64/ 
W112 
W68/ 
W116 
W72/ 
W120 
W76/ 
W124 
W80/ 
W128 
W84/ 
W132 
W88/ 
W136 
W92/ 
W140 
W96a/ 
W144 
EOT 
Visit 
12 Weeks 
Post-EOTb 
Visit Number 
14/ 
26 
15/ 
27 
16/ 
28 
17/ 
29 
18/ 
30 
19/ 
31 
20/ 
32 
21/ 
33 
22/ 
34 
23/ 
35 
24/ 
36 
25/ 
37 
 
 
Visit Window 
±10 days 
 
 
Complete physical 
examinationc 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Targeted physical 
examinationc 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Targeted neurological 
assessmentd,e 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Vital signs 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Weight 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
12-lead ECG (local) 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Laboratory (Central)f 
Hematology 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Serum chemistryg 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Urinalysis 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Urine β-hCGh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception checki 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stool sample for fecal 
calprotectin 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Serum CRPj 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Endoscopic Procedure 
OPTIONAL 
endoscopy (flexible 
sigmoidoscopy or 
colonoscopy)k 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 42 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Table 2 
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with UC) 
Study Procedure 
Treatment – Year 2 Through Year 3 
 
Follow-up 
W52/ 
W100 
W56/ 
W104 
W60/ 
W108 
W64/ 
W112 
W68/ 
W116 
W72/ 
W120 
W76/ 
W124 
W80/ 
W128 
W84/ 
W132 
W88/ 
W136 
W92/ 
W140 
W96a/ 
W144 
EOT 
Visit 
12 Weeks 
Post-EOTb 
Visit Number 
14/ 
26 
15/ 
27 
16/ 
28 
17/ 
29 
18/ 
30 
19/ 
31 
20/ 
32 
21/ 
33 
22/ 
34 
23/ 
35 
24/ 
36 
25/ 
37 
 
 
Visit Window 
±10 days 
 
 
UC Assessmentsl 
OPTIONAL Total 
Mayo scorem 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Treatment response 
assessmentn,o 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Partial Mayo score 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Treatment Procedures 
Administration of 
ontamalimabp,q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hypersensitivity 
monitoringr 
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 
Concomitant 
medication and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense stool 
collection kit for stool 
samples 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
β-hCG=beta-human chorionic gonadotropin; CLIA=Clinical Laboratory Improvement Amendments; CRP=C-reactive protein; DTP=Direct-To-Patient; 
ECG=electrocardiogram; EOT=end of treatment; FDA=Food and Drug Administration; GI=gastrointestinal; LFT=liver function testing; O=optional; UC=ulcerative 
colitis; W=Week. 
a 
After Treatment Year 1, assessments will be repeated on the subsequent year rotation from Week 52. 
b 
Subjects will enter a 12-week safety follow-up period, with a visit at the study site at 12 weeks following the EOT visit. 
c 
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; 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, eyes, abdomen, and examination of body systems where there are symptom complaints by the subject. 
d 
Subject will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar 
function, speech, verbal comprehension, cognition/behavior. See Section 7.3.4.3 for further details. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 43 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Table 2 
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with UC) 
Study Procedure 
Treatment – Year 2 Through Year 3 
 
Follow-up 
W52/ 
W100 
W56/ 
W104 
W60/ 
W108 
W64/ 
W112 
W68/ 
W116 
W72/ 
W120 
W76/ 
W124 
W80/ 
W128 
W84/ 
W132 
W88/ 
W136 
W92/ 
W140 
W96a/ 
W144 
EOT 
Visit 
12 Weeks 
Post-EOTb 
Visit Number 
14/ 
26 
15/ 
27 
16/ 
28 
17/ 
29 
18/ 
30 
19/ 
31 
20/ 
32 
21/ 
33 
22/ 
34 
23/ 
35 
24/ 
36 
25/ 
37 
 
 
Visit Window 
±10 days 
 
 
e 
In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application). 
f 
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. 
g 
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. 
h 
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory. 
i 
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential; see 
Section 4.3. 
j 
Samples must be collected before administration of investigational product. 
k 
Flexible sigmoidoscopy or colonoscopy (if preferred). Endoscopy is optional for treatment response evaluation after the implementation of Amendment 4; if 
performed (eg, due to routine cancer surveillance required by GI guidelines or due to local clinical practice), the results should be recorded. If more than 
2 endoscopies/colonoscopies are needed in a year, the subject should be discontinued. 
l 
Mayo score will be based on subject self-report, with the assistance of a memory aid. 
m 
The total Mayo score will be calculated based on the locally read endoscopic subscore (if endoscopy is performed). The total Mayo score will be calculated only 
when endoscopy data are available. 
n 
Measured by clinical composite score and biomarkers, with or without endoscopy. Applicable only after the implementation of Amendment 4. 
o 
Subjects will have the option to fill in a memory aid to collect data at least 7 days before each specified visit. See Section 7.3.2.3 for further details. 
p 
Investigational product is to be administered after all other visit assessments have been performed. 
q 
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). 
r 
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. 
s 
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one at which testing will be done. 
Note: For subjects whose study participation extends beyond Year 3 (ie, subjects already enrolled in this study prior to the implementation of Amendment 4), 
assessments will be repeated on the subsequent year rotation beginning with Week 100. 
See Section 7.3 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 44 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Table 3 
Schedule of Assessments – Treatment Year 1 (Subjects with CD) 
Study Procedure 
Baselinea 
Treatment – Year 1 
W0/ 
Day 1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit Window 
None 
±10 days 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessmentb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyc 
IDT or MNT 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examinationd 
IDT or MNT 
 
 
 
 
 
X 
 
 
 
 
 
 
Targeted physical examinationd 
IDT or MNT 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Targeted neurological assessmente,f 
IDT or MNT 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signs 
IDT or MNT 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Weight 
IDT or MNT 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
12-lead ECG (local) 
IDT or MNT 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Laboratory (Central)g 
Hematology 
IDT or MNT 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Serum chemistryh 
IDT or MNT 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Urinalysis 
IDT or MNT 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Urine β-hCGi 
IDT or MNT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSHj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Contraception checkk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stool sample for fecal calprotectin 
IDT or MNT 
 
 
 
 
 
X 
 
 
 
 
 
X 
Serum CRPl 
IDT or MNT 
 
 
 
 
 
X 
 
 
 
 
 
X 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 45 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Table 3 
Schedule of Assessments – Treatment Year 1 (Subjects with CD) 
Study Procedure 
Baselinea 
Treatment – Year 1 
W0/ 
Day 1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit Window 
None 
±10 days 
Endoscopic Procedure 
OPTIONAL colonoscopym 
IDT or MNT 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
CD Assessmentsn 
OPTIONAL SES-CDo 
IDT or MNT 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
CDAI 
IDT or MNT 
 
 
 
 
 
X 
 
 
 
 
 
X 
Treatment response assessmentp,q 
IDT 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Treatment Procedures 
Administration of ontamalimabr,s,t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypersensitivity monitoringu 
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 
Concomitant medication and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense stool collection kit for stool 
samplev 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 46 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Table 3 
Schedule of Assessments – Treatment Year 1 (Subjects with CD) 
Study Procedure 
Baselinea 
Treatment – Year 1 
W0/ 
Day 1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit Window 
None 
±10 days 
β-hCG=beta-human chorionic gonadotropin; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; CLIA=Clinical Laboratory Improvement Amendments; 
CRP=C-reactive protein; DTP=Direct-To-Patient; ECG=electrocardiogram; ET=early termination; FSH=follicle-stimulating hormone; GI=gastrointestinal; IDT=induction study 
(SHP647-305 or SHP647-306); LFT=liver function testing; MNT=maintenance study SHP647-307; O=optional; SES-CD=Simple Endoscopic Score for Crohn’s Disease; 
W=Week. 
a 
Baseline = Week 0 (Day 1). For subjects previously enrolled in induction study SHP647-305 or SHP647-306, the baseline visit is the Week 16 study visit (with the exception 
of treatment response assessment). For subjects entering from maintenance study SHP647-307, the baseline visit is the Week 52 visit (for subjects who completed the study) 
or the ET visit (for subjects who withdrew early), with the exception of treatment response assessment. 
If results for confirmation of treatment failure are pending at the time of the end of study visit in Study SHP647-307, sites will have 1 additional week to confirm final status 
of the subject (treatment failure or not) before enrolling the subject in Study SHP647-304. 
b 
Eligibility will be assessed after the consent form is signed and after procedures are completed at Visit 7, Part 2 in Study SHP647-305 or SHP647-306, or at Visit 14, Part 2 or 
the ET or Week 52 visit in Study SHP647-307. 
c 
Medical history from Studies SHP647-305, SHP647-306, and SHP647-307 will be used as the baseline medical history data for Study SHP647-304. 
d 
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; breast (optional); 
abdomen; external genitalia (optional); extremities; neurologic function; back; and lymph nodes. Targeted physical examination includes the review of the following body 
systems: skin and mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, eyes, abdomen, and examination of body systems where there 
are symptom complaints by the subject. 
e 
Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, speech, 
verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of progressive multifocal leukoencephalopathy 
should be excluded. See Section 7.3.4.3 for further details. 
f 
In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application). 
g 
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. 
h 
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. 
i 
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory. 
j 
For confirmation of postmenopausal status in women who have had 12 consecutive months of spontaneous amenorrhea and are ≥51 years of age. This does not need to be 
performed if postmenopausal status was confirmed by FSH in induction study SHP647-305 or SHP647-306 or maintenance study SHP647-307. 
k 
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential; see Section 4.3. 
l 
Samples must be collected before administration of investigational product. 
m 
Colonoscopy is optional for treatment response evaluation after the implementation of Amendment 4; if performed (eg, due to routine cancer surveillance required by 
GI guidelines or due to local clinical practice), the results should be recorded. If more than 2 colonoscopies are needed in a year, the subject should be discontinued. 
n 
CDAI score will be calculated based on data reported by the subject, with the assistance of a memory aid, as well as data obtained at the site visit. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 47 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Table 3 
Schedule of Assessments – Treatment Year 1 (Subjects with CD) 
Study Procedure 
Baselinea 
Treatment – Year 1 
W0/ 
Day 1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Visit Window 
None 
±10 days 
o 
Endoscopies are not required, but if performed, it is recommended that the SES-CD be recorded by the endoscopist for assessment. SES-CD total score will be calculated 
based on the locally read endoscopic subscores for each of the segments investigated. 
p 
Measured by CDAI score and biomarkers, with or without endoscopy. Applicable only after the implementation of Amendment 4. 
q 
Subjects will have the option to fill in a memory aid to collect data at least 7 days before each specified visit. See Section 7.3.3.4 for further details. 
r 
Interactive response technology will be used for dispensation of study treatment. 
s 
Investigational product is to be administered after all other visit assessments have been performed. 
t 
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). 
u 
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. 
v 
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one 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 SHP647-304 baseline. 
 
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Table 4 
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with CD) 
Study Procedure 
Treatment – Year 2 Through Year 3 
 
Follow-
up 
W52/ 
W100 
W56/ 
W104 
W60/ 
W108 
W64/ 
W112 
W68/ 
W116 
W72/ 
W120 
W76/ 
W124 
W80/ 
W128 
W84/ 
W132 
W88/ 
W136 
W92/ 
W140 
W96a/ 
W144 
EOT 
Visit 
12 Weeks 
Post-
EOTb 
Visit Number 
14/ 
26 
15/ 
27 
16/ 
28 
17/ 
29 
18/ 
30 
19/ 
31 
20/ 
32 
21/ 
33 
22/ 
34 
23/ 
35 
24/ 
36 
25/ 
37 
 
 
Visit Window 
±10 days 
 
 
Complete physical 
examinationc 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Targeted physical 
examinationc 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Targeted neurological 
assessmentd,e 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Vital signs 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Weight 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
12-lead ECG (local) 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Laboratory (Central)f 
Hematology 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Serum chemistryg 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Urinalysis 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Urine β-hCGh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception checki 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stool sample for fecal 
calprotectin 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Serum CRPj 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Endoscopic Procedure 
OPTIONAL colonoscopyk 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
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Table 4 
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with CD) 
Study Procedure 
Treatment – Year 2 Through Year 3 
 
Follow-
up 
W52/ 
W100 
W56/ 
W104 
W60/ 
W108 
W64/ 
W112 
W68/ 
W116 
W72/ 
W120 
W76/ 
W124 
W80/ 
W128 
W84/ 
W132 
W88/ 
W136 
W92/ 
W140 
W96a/ 
W144 
EOT 
Visit 
12 Weeks 
Post-
EOTb 
Visit Number 
14/ 
26 
15/ 
27 
16/ 
28 
17/ 
29 
18/ 
30 
19/ 
31 
20/ 
32 
21/ 
33 
22/ 
34 
23/ 
35 
24/ 
36 
25/ 
37 
 
 
Visit Window 
±10 days 
 
 
CD Assessmentsl 
OPTIONAL SES-CDm 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
CDAI 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Treatment response 
assessmentn,o 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Treatment Procedures 
Administration of 
ontamalimabp,q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hypersensitivity monitoringr 
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 
Concomitant medication and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense stool collection kit 
for stool samples 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
β-hCG=beta-human chorionic gonadotropin; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; CLIA=Clinical Laboratory Improvement Amendments; 
CRP=C-reactive protein; DTP=Direct-To-Patient; ECG=electrocardiogram; EOT=end of treatment; FDA=Food and Drug Administration; GI=gastrointestinal; LFT=liver 
function testing; O=optional; SES-CD=Simple Endoscopic Score for Crohn’s Disease; W=Week. 
a 
After Treatment Year 1, assessments will be repeated on the subsequent year rotation from Week 52. 
b 
Subjects will enter a 12-week safety follow-up period, with a visit at the study site at 12 weeks following the EOT visit. 
c 
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; breast 
(optional); abdomen, external genitalia (optional); extremities; neurologic function, back, and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin and mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, eyes, abdomen, and examination of 
body systems where there are symptom complaints by the subject. 
d 
Subject will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, cognition/behavior. See Section 7.3.4.3 for further details. 
e 
In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application). 
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Table 4 
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with CD) 
Study Procedure 
Treatment – Year 2 Through Year 3 
 
Follow-
up 
W52/ 
W100 
W56/ 
W104 
W60/ 
W108 
W64/ 
W112 
W68/ 
W116 
W72/ 
W120 
W76/ 
W124 
W80/ 
W128 
W84/ 
W132 
W88/ 
W136 
W92/ 
W140 
W96a/ 
W144 
EOT 
Visit 
12 Weeks 
Post-
EOTb 
Visit Number 
14/ 
26 
15/ 
27 
16/ 
28 
17/ 
29 
18/ 
30 
19/ 
31 
20/ 
32 
21/ 
33 
22/ 
34 
23/ 
35 
24/ 
36 
25/ 
37 
 
 
Visit Window 
±10 days 
 
 
f 
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. 
g 
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. 
h 
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory. 
i 
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential; see Section 4.3. 
j 
Samples must be collected before administration of investigational product. 
k 
Colonoscopy is optional for treatment response evaluation after the implementation of Amendment 4; if performed (eg, due to routine cancer surveillance required by 
GI guidelines or due to local clinical practice), the results should be recorded. If more than 2 colonoscopies are needed in a year, the subject should be discontinued. 
l 
CDAI score will be calculated based on data reported by the subject, with the assistance of a memory aid, as well as data obtained at the site visit. 
m 
Endoscopies are not required, but if performed, it is recommended that the SES-CD be recorded by the endoscopist for assessment. SES-CD total score will be 
calculated based on the locally read endoscopic subscores for each of the segments investigated. 
n 
Measured by CDAI and biomarkers, with or without endoscopy. Applicable only after the implementation of Amendment 4. 
o 
Subjects will have the option to fill in a memory aid to collect data at least 7 days before each specified visit. See Section 7.3.3.4 for further details. 
p 
Investigational product is to be administered after all other visit assessments have been performed. 
q 
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). 
r 
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. 
s 
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one at which testing will be done. 
Note: For subjects whose study participation extends beyond Year 3 (ie, subjects already enrolled in this study prior to the implementation of Amendment 4), assessments 
will be repeated on the subsequent year rotation beginning with Week 100. 
See Section 7.3 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline. 
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1. 
BACKGROUND INFORMATION 
1.1 
Indication and Current Treatment Options 
1.1.1 
Ulcerative Colitis 
Ulcerative colitis (UC) is a chronic, relapsing disease marked by ulceration and inflammation of 
the colonic mucosa and submucosa. Initially it usually involves the rectum but may extend 
proximally to involve a portion of, or the entirety of, the colon. In the early stages, hemorrhagic 
and erythematous tissue is observed, progressing to mucosal ulceration with purulent exudates in 
severe cases. The ulceration pattern is continuous and may extend the entire length of the colon. 
Perforation of the bowel wall causing ileus and peritonitis can occur with transmural extension of 
the ulceration. Bloody diarrhea with or without mucus and lower abdominal pain with periods of 
remission and exacerbation are the most common symptoms. 
The incidence of UC is estimated to be up to 24.3 cases per 100,000 persons per year in Europe 
and up to 19.2 cases per 100,000 persons per year in North America. No clear difference in 
incidence has been observed between men and women. Although UC can occur at any age, peak 
incidence has been observed in the second to fourth decades of life (Molodecky et al., 2012). 
Ulcerative colitis is a lifelong condition with a serious effect on the quality of life. Current 
treatment primarily consists of symptomatic management with dietary modifications and opiates 
(loperamide), as well as disease modifying agents such as 5-aminosalicylic acid (5-ASA), 
systemic glucocorticoids, immunosuppressive agents (azathioprine [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. 
1.1.2 
Crohn’s Disease 
Crohn’s disease (CD) is a chronic, relapsing disease marked by granulomatous inflammation of 
the gastrointestinal (GI) tract. Although the terminal ileum and right colon are the most 
commonly involved sites, CD can affect any part of the GI tract, from the mouth to the perianal 
region. Inflammation is typically transmural (full-thickness), segmental, and discontinuous, and 
symptoms are predominantly determined by the part of bowel or organ involved. Patients 
typically present with symptoms including abdominal pain, diarrhea, rectal bleeding (RB), which 
may be persistent and lead to anemia, and weight loss due to pain on eating and malabsorption. 
As the disease progresses, extraintestinal manifestations and associated conditions can develop, 
including bowel obstruction, fistulas, and stenosis, as well as painful skin ulcerations, eye pain, 
and arthritis. 
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The incidence of CD is estimated to be up to 12.7 cases per 100,000 persons per year in Europe 
and up to 20.2 cases per 100,000 persons per year in North America. No clear difference in 
incidence has been observed between men and women. Although CD can occur at any age, peak 
incidence has been observed in the second to fourth decades of life, with a second modest rise in 
incidence in the latter decades of life (Molodecky et al., 2012). 
Crohn’s disease is a lifelong condition with a serious effect on quality of life. The traditional 
approach to therapy of CD has been the step-up approach usually represented as a pyramid 
where, progressing from mild to severe disease, therapeutic choices proceed step by step from 
less potent drugs at the base of the pyramid to more potent but also more toxic drugs at the top. 
Current treatment primarily consists of symptomatic management with dietary modifications, 
5-ASA, opiates (loperamide), systemic glucocorticoids, immunosuppressive agents (AZA/6-MP, 
methotrexate [MTX]), and biologic therapy with anti-TNF agents or anti-integrin agents. Despite 
recent advances, there is still an unmet need for a safe, effective, and durable pharmacological 
treatment that will induce and maintain remission. 
1.2 
Product Background and Clinical Information 
The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal sites of the 
GI tract is influenced by the endothelial expression of mucosal addressin cell adhesion 
molecule-1 (MAdCAM-1). MAdCAM-1 is a member of the immunoglobulin super family of 
cell adhesion molecules and is mostly expressed on the cell surface of high endothelial venules 
of organized intestinal lymphoid tissue such as Peyer’s patches and mesenteric lymph nodes 
(Briskin et al., 1997; Shyjan et al., 1996; Liaskou et al., 2011). MAdCAM-1 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-1, and expression of this ligand on populations of CD4+ and CD8+ T cells, as well as 
on subsets of B cells, distinguishes them as unique gut homing lymphocytes. 
Ontamalimab (previously known as PF-00547659 and SHP647) is a fully human 
immunoglobulin G2 kappa (IgG2κ) monoclonal antibody that binds to human MAdCAM-1 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-1-expressing sites in the high endothelial venules of the GI tract. 
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1.3 
Benefit/Risk Assessment 
Ontamalimab has been evaluated in Phase 1 and Phase 2 clinical studies in subjects with UC and 
CD. In UC study A7281009, induction with ontamalimab at doses of 7.5 mg, 22.5 mg, or 75 mg 
every 4 weeks resulted in statistically significantly higher proportions of subjects in remission at 
Week 12 based on total Mayo score (both local and central read) when compared with placebo 
treatment. In CD study A7281006, induction with ontamalimab did not meet the primary 
endpoint; no statistically significant differences were observed between the active treatment arms 
and the placebo arm in Crohn’s Disease Activity Index [CDAI]-70 response rate at Week 8 or 
Week 12. Post hoc analyses suggested evidence of drug effect in subjects with more 
inflammation at baseline, as indicated by higher serum concentrations of C-reactive protein 
(CRP) or Simple Endoscopic Score for CD (SES-CD). 
In UC 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. 
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 
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GI disorders SOC followed by the infections and infestations SOC. The most common 
all-causality TEAE was headache, followed by abdominal pain, nasopharyngitis, UC (worsening 
and progression of underlying disease), and nausea, all with similar incidence between 
placebo- and drug-treated subjects. 
The long-term, open-label safety studies (Studies A7281007 and A7281010) were not 
placebo-controlled, but permitted exposure to the investigational product at doses of 75 mg or 
225 mg every 4 weeks for 18 and 36 months, respectively. In Study A7281007, the most 
common all-causality TEAE was CD (worsening or progression), arthralgia, nasopharyngitis, 
and abdominal pain. In Study A7281010, the most common all-causality TEAEs were 
UC (worsening or progression), arthralgia, and nasopharyngitis. 
Ontamalimab appears to be generally well tolerated, with the majority of TEAEs distributed at 
similar frequencies among treatment arms with only peripheral edema, gastroenteritis, and 
arthralgia more frequently reported in ontamalimab- than placebo-treated subjects in the pooled 
induction studies. In the placebo-controlled induction studies, nasopharyngitis was not reported 
more frequently in ontamalimab- than placebo-treated subjects, but occurred at relatively high 
frequency during long-term safety studies. Ontamalimab does not appear to be associated with 
impaired central nervous system (CNS) immune surveillance. No case of progressive multifocal 
leukoencephalopathy (PML) or myocarditis has been reported. Ontamalimab, in doses of 7.5 mg, 
22.5 mg, and 75 mg, appears to increase the rate of remission in subjects with UC, and may have 
an effect in patients with CD who have greater evidence of inflammation based on biomarker or 
endoscopic data. 
Always refer to the latest version of the ontamalimab Investigator’s Brochure (IB) for the overall 
benefit/risk assessment and the most accurate and current information regarding the 
pharmacokinetics (PK), efficacy, and safety of ontamalimab. 
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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the Study 
Ontamalimab, a fully human IgG2κ antihuman MAdCAM-1 monoclonal antibody, was under 
development for the treatment of UC and CD. Ontamalimab prevents the binding of 
α4β7+ lymphocytes to MAdCAM-1-expressing sites with high affinity and selectivity. Principal 
sites of the MAdCAM-1 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; Pullen et al., 2009). 
Although selective targeting of the MAdCAM-1 receptors is a novel approach, the basic 
interference of lymphocyte homing by preventing the binding of these α4β7+ lymphocytes to the 
MAdCAM-1 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-1 receptor by selectively binding to 
MAdCAM-1 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. 
In 2019, Takeda formally acquired Shire, the sponsor of this study. On 29 May 2020, Takeda 
announced the closure of the ontamalimab Phase 3 clinical development program, which 
included induction and maintenance studies for subjects with moderate to severe inflammatory 
bowel disease (IBD) who had failed at least 1 prior treatment. Per the announcement, the 
induction and maintenance studies will be closed earlier than originally planned. In recognition 
that this could potentially cause hardships for subjects who were benefiting from this 
investigational treatment (ie, fulfilling treatment response criteria as defined in Section 9.8.1.1 
and Section 9.8.2.1), this long-term safety extension study, which is expected to be completed in 
no more than 3 years (ie, by December 2023), may continue to provide active treatment to 
subjects already enrolled who are responding to treatment and to subjects entering from a 
maintenance study who have responded to active treatment (ie, in the induction or maintenance 
studies and who meet the entry criteria). However, if the results of the induction or maintenance 
studies show that ontamalimab does not have evidence of efficacy over placebo, this study will 
be terminated. 
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Originally, this extension study was designed to evaluate the safety and efficacy of long-term 
treatment with ontamalimab in subjects with moderate to severe UC or CD who: (1) completed 
one of the 4 multicenter, randomized, double-blind, placebo-controlled, parallel-group studies 
evaluating ontamalimab as an induction therapy (SHP647-301, SHP647-302, SHP647-305, or 
SHP647-306) and did not meet the response criteria (clinical and/or endoscopic 
response/remission as appropriate) required for entry into a maintenance study (SHP647-303 or 
SHP647-307), or (2) were treatment failures (as defined in the respective protocols) and/or 
completers in one of the 2 multicenter, double-blind, randomized, placebo-controlled, 
parallel-group study evaluating ontamalimab as maintenance therapy (SHP647-303 or 
SHP647-307). This study has been double-blind and will continue as such until the induction 
study results become available (ie, unblinding will not occur until the final analysis of the 
induction studies is completed and the lowest effective dose determined), as it is planned that 
subjects will receive the lowest effective dose based on the results of the induction studies. It is 
expected that the analysis of these results will demonstrate the efficacy of at least one of the 
doses and allow for the selection of a single dose, at which time this study will be open label. If 
both doses are effective and the difference compared to placebo is similar, then the lowest 
effective dose will be selected. However, if the results of the induction or maintenance studies 
show that ontamalimab does not have evidence of efficacy over placebo, this study will be 
terminated. 
Subjects in the induction studies SHP647-301 or SHP647-302: 
• As of September 2020, no subjects remain in the induction studies who would be 
eligible to participate in this study (SHP647-304); therefore, no additional subjects 
from the induction studies will enter this study under Amendment 4. 
Subjects in the maintenance studies SHP647-303 or SHP647-307: 
• Subjects who received and responded to active treatment in either or both of the 
induction or maintenance studies may be eligible to enter this study. 
• Subjects who have not received ontamalimab yet (ie, received placebo in both the 
induction and maintenance studies) will not be eligible to enter this study. 
• Subjects eligible to enter this study will be assessed for treatment response criteria 
according to the revised study schedule in Study SHP647-304. 
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Subjects currently in Study SHP647-304 (ie, enrolled prior to Amendment 4) will be assessed for 
treatment response as follows: 
• Subjects who have already entered Study SHP647-304 may continue and will be 
assessed for treatment response according to the revised study schedule. If they show 
response to ontamalimab treatment, they may continue further in this study. 
• If the results of the induction or maintenance studies show that ontamalimab does not 
have evidence of efficacy over placebo, this study will be terminated. 
All subjects will be evaluated periodically and in case of clinical worsening at an unscheduled 
visit during the study for treatment response. If a subject shows response to ontamalimab 
treatment, he or she may continue in this study either until he or she shows a loss of treatment 
response (ie, no longer meets response criteria) or elects to seek another treatment option, or 
until the end of the study. 
2.2 
Study Objectives 
2.2.1 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of long-term 
treatment with ontamalimab in subjects with moderate to severe UC or CD. 
2.2.2 
Secondary Objectives – Subjects with Ulcerative Colitis 
• To evaluate the maintenance of response to long-term treatment with ontamalimab as 
measured by clinical composite score and biomarkers, with or without endoscopy. 
2.2.3 
Secondary Objectives – Subjects with Crohn’s Disease 
• To evaluate the maintenance of response to long-term treatment with ontamalimab as 
measured by CDAI score and biomarkers, with or without endoscopy. 
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3. 
STUDY DESIGN 
3.1 
Study Design and Flow Chart 
This is a Phase 3 multicenter extension study designed to evaluate the long-term safety of 
ontamalimab in subjects with moderate to severe UC or CD. The study has enrolled subjects 
from 6 separate Phase 3 studies to date: 4 multicenter, randomized, double-blind, 
placebo-controlled, parallel-group studies evaluating ontamalimab as an induction therapy in 
subjects with moderate to severe UC (SHP647-301 and SHP647-302) or CD (SHP647-305 and 
SHP647-306); and 2 multicenter, double-blind, randomized, placebo-controlled, parallel-group 
studies evaluating ontamalimab as maintenance therapy in subjects with moderate to severe UC 
(SHP647-303) or CD (SHP647-307). As the induction and maintenance studies will be closed 
earlier than planned, the study will enroll subjects with moderate to severe UC and CD from the 
2 maintenance studies (at the time of their closure) who have responded to active treatment. As 
the 4 induction studies do not have any subjects eligible for rollover to the SHP647-304 study as 
of September 2020, no additional subjects will enter from those studies. 
This study is planned to become a single-dose study, with the dose to be determined after the 
analysis of data from the induction studies. This study has been double-blind and will continue as 
such until the induction study results become available (ie, unblinding will not occur until the 
final analysis of the induction studies is completed and the lowest effective dose determined), as 
it is planned that subjects will receive the lowest effective dose based on the results of the 
induction studies. It is expected that the analysis of these results will demonstrate the efficacy of 
at least one of the doses and allow for the selection of a single dose, at which time this study will 
be open label. If both doses are effective and the difference compared to placebo is similar, then 
the lowest effective dose will be selected. However, if the results of the induction or maintenance 
studies show that ontamalimab does not have evidence of efficacy over placebo, this study will 
be terminated. 
All subjects will receive active drug in this study. Eligible subjects entering Study SHP647-304 
from the discontinued SHP647-303 and SHP647-307 studies will be assigned to continue their 
present dose of ontamalimab (if currently receiving active drug) or to return to the dose of active 
drug associated with previous response (if on placebo). Ongoing subjects in this study will 
remain on the dose to which they have been previously assigned. Once the final dose has been 
determined, all subjects will continue on that dose only. 
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Subjects will come to the investigational site every 4 weeks (unless unable to participate on 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), in which case they may qualify for the “Direct to Patient” [DTP] program) for 
investigational product administration and appropriate assessments. 
The eligibility of a subject for this study will be assessed from study data collected at the 
following time points: 
• For subjects with UC, the Week 12 visit of the induction study (SHP647-301 or 
SHP647-302) OR the Week 52 or Early Termination (ET) visit of the maintenance 
study (SHP647-303), which are considered and recorded as the baseline visit for this 
extension study (with the exception of the treatment response evaluation, for which 
baseline of the induction study will be used as baseline of this extension study). No 
additional subjects from the induction studies will be enrolling into 
Study SHP647-304. Subjects from the maintenance study (SHP647-303) will have 
the opportunity to enroll into this study at the time of the approval of Amendment 4 if 
they have benefited from active treatment in the induction or maintenance study. 
• For subjects with CD, the Week 16 visit of the induction study (SHP647-305 or 
SHP647-306), OR the ET or Week 52 visit of the maintenance study (SHP647-307), 
which will be considered and recorded as the baseline visit for this extension study 
(with the exception of the treatment response evaluation, for which baseline of the 
induction study will be used as baseline of this extension study), with an additional 
window of 1 week for subjects whose treatment failure status is still under evaluation 
at the time of the Week 52 visit of the maintenance study. No additional subjects from 
the induction studies will be enrolling into Study SHP647-304. Subjects from the 
maintenance study (SHP647-307) will have the opportunity to enroll into this study at 
the time of the approval of Amendment 4 if they have benefited from active treatment 
in the induction or maintenance study. 
Subjects enrolled in this study will receive treatment every 4 weeks, in the form of subcutaneous 
(SC) injections using prefilled syringes (PFSs). Subjects will undergo treatment response and 
safety assessments as outlined in the Schedules of Assessments. Assessments for Year 1 are 
provided in Table 1 (for subjects with UC) and Table 3 (for subjects with CD). Assessments for 
Year 2 through end of study, are provided in Table 2 (for subjects with UC) and Table 4 (for 
subjects with CD). 
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At every third visit, subjects with UC will be assessed for ongoing benefit (treatment response) 
using the clinical composite score or composite score. To facilitate data collection and reliability, 
subjects will have the option to use a memory aid. Endoscopies are not required, but if performed 
(eg, for routine surveillance), it is recommended that the Mayo endoscopic subscore be recorded 
by the endoscopist for assessment. The total Mayo score will be calculated only when endoscopy 
data are available. 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 physical global assessment (PGA) subscore. The clinical composite score is a measure 
consisting of RB plus stool frequency without the endoscopic and PGA subscore. The data for 
Mayo scores and composite score will be collected from subjects, who have the option of using a 
memory aid, for 7 days before each specified visit as in the schedules of assessments. 
Biomarkers (C-reactive protein and fecal calprotectin) will be assessed every 3 months or in case 
there is a necessity to confirm the loss of clinical treatment response. 
At every third visit, subjects with CD will be assessed for ongoing benefit (treatment response) 
using the CDAI score (treatment response defined as CDAI-100). Data on CDAI components 
(abdominal pain severity, very soft stool/liquid stool frequency, general well-being) will be 
collected from the subjects by the investigators. To facilitate data collection and reliability, 
subjects will have the option to use a memory aid. Endoscopies are not required, but if performed 
(eg, for routine surveillance), it is recommended that the SES-CD be recorded by the endoscopist 
for assessment. The CDAI is a composite measure with 8 components. Five components will be 
captured at the visits, and 3 components (abdominal pain severity, very soft stool/liquid stool 
frequency, and general well-being) will be collected from subjects, who have the option of using 
a memory aid, for 7 days before each specified visit as in the schedules of assessments. 
Biomarkers (C-reactive protein and fecal calprotectin) will be assessed every 3 months or in case 
there is a necessity to confirm the loss of clinical treatment response. 
Treatment response will be assessed at every third visit for all subjects to allow monitoring of 
clinical benefit derived and evaluation of loss of response throughout the study. At these 
assessment visits, subjects’ response will be evaluated and compared to the value of clinical 
composite score (for subjects with UC) or CDAI (for subjects with CD) determined at entry into 
the induction studies. As long as response criteria are satisfied, subjects may remain in the study. 
If there is a concern regarding loss of response between scheduled assessment visits, assessments 
may be performed at any scheduled or, if necessary, unscheduled visit to evaluate response. To 
ensure that placebo-treated subjects from a feeder study (SHP647-301, SHP647-302, 
SHP647-303, SHP647-305, SHP647-306, or SHP647-307) have sufficient exposure to active 
drug to permit assessment of treatment response, treatment response will be assessed according 
to the revised study schedule. Subjects may discontinue participation at any time, for any reason. 
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If response to investigational product is lost, based on clinical criteria, or if there is an 
unexplained clinical exacerbation or unacceptably low level of clinical response the investigator 
may assess biomarkers and perform other investigations to exclude other potential causes like 
Clostridium difficile infection or an appropriate ad-hoc endoscopy to determine whether the loss 
of response is confirmed or not at an unscheduled visit. The totality of available data will be used 
to determine ongoing response status and subjects whose loss of response is confirmed (see 
Section 4.4.1 for further details). 
The overall study design is shown in Figure 1. 
Figure 1 
Study Design Flow Chart for Subjects who Enter SHP647-304 Under 
Amendment 4 
 
EOT=end of treatment; SC=subcutaneous; wks=weeks. 
a 
Prior to unblinding. Subjects enrolling after unblinding will continue on their selected dose. 
b 
Determined by active dose received in maintenance or induction study. 
Maintenance studies are SHP647-303 and SHP647-307. 
Induction studies are SHP647-301, SHP647-302, SHP647-305, and SHP647-306. 
 
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3.2 
Duration and Study Completion Definition 
For subjects who are tolerating investigational product and receiving clinical benefit in the 
judgment of the investigator (ie, fulfilling treatment response criteria as defined in 
Section 9.8.1.1 and Section 9.8.2.1), study participation may continue until the subject withdraws 
from the study, or the investigator or sponsor decide to withdraw the subject (eg, in the interest 
of subject safety), or the sponsor decides to close the study, or the program is stopped 
completely. A subject’s maximum duration of participation in this study under the current 
amendment is expected to be no more than 3 years (ie, a subject’s participation is not planned to 
extend beyond 2023), subject to local or country requirements. Subjects will enter a 12-week 
safety follow-up period following the last dose of investigational product. Both the end of 
treatment (EOT) 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 visits may also be conducted at a subject’s home, provided a qualified site staff 
member performs these evaluations following DTP guidance. It is expected that the study will be 
completed in no more than 3 years (ie, by December 2023). 
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 225 sites in approximately 33 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 
Eligibility Criteria – Subjects with Ulcerative Colitis 
4.1.1 
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 been enrolled previously in Study SHP647-301 or SHP647-302 and are 
in the treatment period of Study SHP647-303, completed the ET or Week 52 visit in 
maintenance study SHP647-303, had responded to ontamalimab treatment (in the induction 
and/or maintenance studies), and meet one of the following criteria: 
• Subjects are on placebo at the maintenance study ET or Week 52 visit: they received 
ontamalimab in the induction studies and fulfilled the maintenance study response 
criteria, OR 
• Subjects have received ontamalimab at the maintenance study ET or Week 52 visit: 
 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, compared to the baseline value for induction studies, and/or 
 Composite score that has decreased by ≥30% and ≥3 points compared to 
the baseline value for induction studies. 
4. Subjects receiving any treatment(s) for UC described in Section 5.1.2.1 are eligible provided 
they have been on a stable dose for the designated period of time. 
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4.1.2 
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 
Study SHP647-301, SHP647-302, or SHP647-303. 
2. Subjects who permanently discontinued investigational product because of an AE, regardless 
of relatedness to investigational product, in Study SHP647-301, SHP647-302, or 
SHP647-303. 
3. Subjects who are likely to require major surgery for UC. 
4. Subjects are females who became pregnant during Study SHP647-301, SHP647-302, or 
SHP647-303, females who are lactating, females who are planning to become pregnant 
during the study period, or males or females of childbearing potential not agreeing to 
continue using appropriate contraception methods (ie, highly effective methods for female 
and medically appropriate methods for male study subjects) through the conclusion of study 
participation (see Section 4.3). 
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 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. 
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10. Subjects with known exposure to Mycobacterium tuberculosis (TB) since testing at screening 
in Study SHP647-301 or SHP647-302 and who have been advised to require treatment for 
latent or active disease, but 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 other investigational studies (other than SHP647-301, 
SHP647-302, or SHP647-303) or plan to participate in other investigational studies during 
long-term extension study SHP647-304. 
4.2 
Eligibility Criteria – Subjects with Crohn’s Disease 
4.2.1 
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 been enrolled previously in Study SHP647-305 or SHP647-306 and are 
in the treatment period of Study SHP647-307, completed the ET or Week 52 visit in 
maintenance study SHP647-307, had responded to ontamalimab treatment (in the induction 
and/or maintenance studies), and meet one of the following criteria: 
• Subjects are on placebo at the maintenance study ET or Week 52 visit: they received 
ontamalimab in the induction study and fulfilled the maintenance study response 
criteria, OR 
• Subjects have received ontamalimab at the maintenance study ET or Week 52 visit: 
 CDAI score that has decreased by ≥100 points at EOT visit compared to 
the baseline value for induction studies, and/or 
 SES-CD that has decreased by ≥25% compared to the baseline value for 
induction studies. 
4. Subjects receiving any treatment(s) for CD described in Section 5.2.2.1 are eligible provided 
they have been on a stable dose for the designated period of time. 
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4.2.2 
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 
Study SHP647-305, SHP647-306, or SHP647-307. 
2. Subjects who permanently discontinued investigational product because of an AE, regardless 
of relatedness to investigational product, in Study SHP647-305, SHP647-306, or 
SHP647-307. 
3. Subjects who are likely to require major surgery for CD, or developed acute severe 
complications of CD (with or without fulfilling the treatment failure criteria in the 
maintenance study) that required immediate intervention (eg, need for immediate biologic 
treatment with proven effect) and/or CDAI score >450. 
4. Subjects are females who became pregnant during Study SHP647-305, SHP647-306, or 
SHP647-307, females who are lactating, females who are planning to become pregnant 
during the study period, or males or females of childbearing potential not agreeing to 
continue 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 4.3). 
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. 
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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. 
10. Subjects with known exposure to TB since testing at screening in Study SHP647-305 or 
SHP647-306, and who have been advised to require treatment for latent or active disease, but 
who are without a generally accepted course of treatment. 
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 other investigational studies (other than SHP647-305, 
SHP647-306, or SHP647-307) or plan to participate in other investigational studies during 
long-term extension study SHP647-304. 
4.3 
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 once every 4 weeks), maternal exposure (AUC) in 
cynomolgus monkeys within a similar duration at 30 and 60 mg/kg once every 10 days is 
approximately 77 times and 172 times the clinical exposure, respectively. 
To minimize the risk of unintentional exposure of the embryo or fetus in the clinical study, all 
sexually active male and female subjects who, in the opinion of the investigator, are biologically 
capable of having children and with their partners are at risk of pregnancy, must agree to use an 
appropriate form of contraception (ie, highly effective methods for female and medically 
appropriate methods for male study subjects), in accordance with the package 
instructions/leaflet, for the duration of the active treatment period and for at least 16 weeks after 
the last dose of investigational product. 
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True abstinence is considered to be a highly effective contraception (ie, a method that results in a 
failure rate of <1% per year) when it is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
declaration of abstinence for the duration of exposure to investigational product, and withdrawal 
are not appropriate methods of contraception. 
During the induction studies (SHP647-301, SHP647-302, SHP647-305, and SHP647-306) or 
maintenance studies (SHP647-303 and SHP647-307), the investigator or designee in consultation 
with the subject will confirm the subject’s childbearing potential status. For subjects of 
childbearing potential, it must be confirmed and documented that the subject has selected the 
most appropriate method of contraception (ie, highly effective methods for female and medically 
appropriate methods for male study subjects) from the permitted list of contraception methods. 
Subjects must affirm the consistent and correct use of at least one of these selected methods. 
Regular contraception check discussions will take place at the time points specified in Table 1 
and Table 2 (for subjects with UC), Table 3 and Table 4 (for subjects with CD) (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. 
4.3.1 
Contraceptive Methods for Female Study Subjects 
For subjects entering from a maintenance study, at baseline in this study, the childbearing 
potential of subjects must be re-established and documented if the subject’s status has changed 
since the induction studies (SHP647-301, SHP647-302, SHP647-305, or SHP647-306) or 
maintenance studies (SHP647-303 or SHP647-307) (see Section 7.3.4.7). 
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 one of the following categories: 
• Postmenopausal (12 consecutive months of spontaneous amenorrhea and ≥51 years of 
age); postmenopausal status should be confirmed by follicle-stimulating hormone 
(FSH) testing. 
• Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization or has medically confirmed ovarian failure. 
• Females of childbearing potential with a negative pregnancy test result at 
Study SHP647-304 baseline. 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 Study SHP647-304 baseline 
• 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 4.3). 
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4.3.2 
Contraceptive Methods for Male Study Subjects 
Contraception is required for all sexually active male subjects, who with their female sexual 
partners, must agree to use one of the following appropriate methods of contraception throughout 
the study period and for 16 weeks following the last dose of investigational product. 
Appropriate methods of contraception for male subjects are: 
• Male condom with spermicide; however, if spermicide is not available in the country, 
additional contraception (ie, one of those listed below) must be used in addition to a 
male condom 
• Male sterilization with documented absence of sperm in the postvasectomy ejaculate. 
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 4.3.1 OR an 
acceptable method of contraception (failure rate of >1% per year) 
 Female condom with spermicide (use by female sexual partner); however, if 
spermicide is not available in the country, additional contraception (ie, one of 
those listed below) must be used in addition to a female condom 
 Intrauterine device with spermicide 
 Contraceptive sponge with spermicide 
 Intravaginal system (eg, vaginal ring with spermicide, a diaphragm with 
spermicide, or a cervical cap with spermicide). 
4.4 
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 the 
EOT visit are to be performed. All subjects who discontinue investigational product should also 
undergo the protocol-specified 12-week follow-up period. In the event that subjects are unable to 
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attend in person for the follow-up visit, 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. 
4.4.1 Loss of Response 
If response to investigational product is lost, based on clinical criteria, or if there is an 
unexplained clinical exacerbation or unacceptably low level of clinical response, the investigator 
may assess biomarkers and perform other investigations to exclude other potential causes like 
C. difficile infection or an appropriate ad-hoc endoscopy to determine whether the loss of 
response is confirmed or not at an unscheduled visit. The totality of available data will be used to 
determine ongoing response status and subjects whose loss of response is confirmed. 
If clinical response criteria are no longer satisfied and alternative explanations for clinical 
worsening (eg, infection) can be excluded, the subject will be discontinued. If necessary for 
assessment in the opinion of the investigator (eg, borderline treatment response results), the 
following evaluations may be considered: 
1. Have subject return in 2 to 4 weeks for repeat assessment if loss of response criteria is still 
met: 
a) 
Perform endoscopy to determine if there is an objective benefit despite clinical 
symptoms; if the composite of clinical and endoscopic data meets response criteria, 
continue the study. 
1. Endoscopic response criterion for UC is Mayo endoscopic subscore 
decreased by ≥1 point as compared to the baseline value recorded upon 
entry into the induction studies. 
2. Endoscopic response criterion for CD is SES-CD improved by >25% as 
compared to the baseline value recorded upon entry into the induction 
studies. 
b) 
Biomarkers may be used to determine overall response criteria at the discretion of 
the investigator; serum CRP < upper limit of normal (ULN) or fecal calprotectin 
<250 µg/g is considered indicative of clinical benefit. 
Upon termination from the study, subjects must return for a safety visit 12 weeks after the last 
dose of investigational product. 
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Subjects who have experienced loss of response should be withdrawn from active treatment once 
other possible etiologies have been ruled out and appropriate clinical evaluation has been 
performed as suggested above. While these response criteria are offered as general guidance to 
the investigator, there may be additional criteria that warrant withdrawal from active treatment, 
and the ultimate decision of withdrawal from active treatment is left to the investigator based on 
the assessment of disease activity, the subject’s clinical benefit, and tolerance of the 
investigational product. 
4.4.2 
Subject Withdrawal Criteria 
Additional reasons a subject may be withdrawn from active treatment include but are not limited 
to: AEs, SAEs, pregnancy, protocol deviations, and failure to return for visits. 
A subject should be withdrawn from study treatment if the subject undergoes surgery for UC or 
CD. 
Subjects who withdraw from active 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 electronic case report form (eCRF). 
If a subject withdraws from the study, and also withdraws consent for disclosure of future 
information, 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. 
4.4.3 
Reasons for Withdrawal 
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and source document. 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. 
Other reasons for discontinuation may include but are not limited to: 
• Adverse event (AE) 
• Protocol deviation 
• Withdrawal by subject 
• Lost to follow-up 
• Loss of response 
• Other (if “other” is selected, the investigator must specify the reason) 
• Death 
• Physician decision 
• Pregnancy 
• Screen failure 
• Site terminated by sponsor 
• Study terminated by sponsor. 
4.4.4 
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point before the last scheduled contact (office visit or telephone contact). At least 
one of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgement of receipt request) asking that 
they return to the site for final safety evaluations. 
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5. 
PRIOR AND CONCOMITANT TREATMENT 
5.1 
Prior and Concomitant Treatment – Subjects with Ulcerative Colitis 
5.1.1 
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. It is expected that prior treatment will have been 
recorded during the induction study. 
5.1.2 
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product in this study and the end of the safety follow-up period, inclusive. 
Additional safety assessments may be required, according to concomitant therapy safety 
recommendations. 
5.1.2.1 
Permitted Treatment 
Any permitted treatment may be initiated or discontinued as clinically appropriate. The 
following treatments for UC are permitted as concomitant medication: 
• 5-ASA (mesalamine) and sulfasalazine 
• Immunosuppressants (AZA, 6-MP, MTX) 
• Concomitant oral glucocorticoids; however, tapering should start once subject 
achieves adequate treatment response and should be guided by investigator clinical 
judgment. The recommended tapering scheme, based on European Crohn’s and 
Colitis Organisation (ECCO) guidelines, is shown in Table 5. 
Note: If a new course of oral glucocorticoid treatment (for IBD) is required, the subject should 
be discontinued from the study. 
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Table 5 
Glucocorticoid Tapering – Subjects with Ulcerative Colitis 
 
First Taper 
Subsequent Taper 
Timing 
Prospectively define glucocorticoid-dependent 
subjects (ie, ECCOa) 
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 
• If daily dose is >5 mg: 
Taper by 2.5 mg/day each week 
• When daily dose is ≤5 mg: 
Taper by 1 mg/day each week 
Action if unable to taper 
Return to SHP647-304 baseline dose 
 
ECCO=European Crohn’s and Colitis Organisation. 
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). 
Medicinal marijuana (cannabis) under a physician’s prescription, obtained from a licensed 
pharmacy or provider may be used. 
Routine nonlive vaccinations are allowed during the study. 
Dietary and herbal supplements and probiotics are allowed in the study and should be recorded 
as concomitant medications. 
Use of nicotine-containing preparations should be recorded as concomitant medication. 
5.1.2.2 
Prohibited Treatment 
The following common treatments are excluded medications for this study. As the subjects are 
transferred from Study SHP647-301, SHP647-302, or SHP647-303, during which these 
treatments were also prohibited, no washout period is applicable. 
• Anti-integrin or antiadhesion molecule treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab) 
• Anti-TNF treatment and other biologics with immunomodulatory properties including 
biosimilars 
• Live (attenuated) vaccines 
• Any investigational product other than ontamalimab 
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• Nonbiologics with immunomodulatory properties (except for AZA, 6-MP, and MTX, 
which are permitted) 
• Leukocyte apheresis or selective lymphocyte, monocyte, or granulocyte apheresis or 
plasma exchange. 
Treatments not listed in this section may be considered allowable; see Section 5.1.2.1 for further 
details. 
No new nonpharmacological therapies that might affect bowel habit or GI function should be 
started during the study. 
Subjects who enter the 12-week safety follow-up period will no longer need to abstain from the 
medications that were prohibited during the treatment period. Other UC treatments will be 
allowed. Biologics or nonbiologic immunosuppressants should not be initiated without prior 
discussion with the sponsor study physician or designee, due to the long half-life of 
ontamalimab. 
5.2 
Prior and Concomitant Treatment – Subjects with Crohn’s Disease 
5.2.1 
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. It is expected that prior treatment will have been 
recorded during the induction study. 
5.2.2 
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product in this study and the end of the safety follow-up period, inclusive. 
Additional safety monitoring may be required, according to concomitant therapy safety 
recommendations. 
5.2.2.1 
Permitted Treatment 
The following treatments for CD are permitted as concomitant medication: 
• Oral 5-ASA (mesalamine) and sulfasalazine 
• Immunosuppressants (AZA, 6-MP, MTX) 
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• Concomitant oral glucocorticoids; however, tapering should start once subject 
achieves adequate treatment response and should be guided by investigator clinical 
judgment. The recommended tapering scheme, based on ECCO guidelines, is shown 
in Table 6. Parenteral and rectally used glucocorticoids are permitted per discretion of 
the investigator. 
Note: If a new course of oral glucocorticoid treatment (for IBD) is required, the subject should 
be discontinued from the study.  
Table 6 
Glucocorticoid Tapering – Subjects with Crohn’s Disease 
 
First Taper 
Subsequent Taper 
Timing 
Prospectively define 
glucocorticoid-dependent subjects 
(ie, ECCOa) 
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 is >5 mg: 
Taper by 2.5 mg/day each week 
• When daily dose is ≤5 mg: 
Taper by 1 mg/day each week 
Action if unable to taper 
Return to SHP647-304 baseline dose 
 
ECCO=European Crohn’s and Colitis Organisation. 
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). 
Antidiarrheal opiate drugs such as IMODIUM® (loperamide), LOMOTIL® (diphenoxylate 
hydrochloride and atropine sulfate), tincture of opium, and codeine will be recorded. 
Medicinal marijuana (cannabis) under a physician’s prescription, obtained from a licensed 
pharmacy or provider may be used. 
Routine nonlive vaccinations are allowed during the study. 
Dietary and herbal supplements and probiotics are allowed in the study and should be recorded 
as concomitant medications. 
Use of nicotine-containing preparations should be recorded as concomitant medication. 
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5.2.2.2 
Prohibited Treatment 
The following common treatments are excluded medications for this study. As the subjects are 
transferred from Study SHP647-305, SHP647-306, or SHP647-307, during which these 
treatments were also prohibited, no washout period is applicable. 
• Off-label usage of immunosuppressants used in transplantation or other 
non-established therapies for CD (eg, mycophenolate mofetil, cyclosporine, 
rapamycin, thalidomide, tofacitinib, or tacrolimus) 
• Rectally administered 5-ASA 
• Bismuth subsalicylate products 
• Anti-TNF treatment and other biologics with immunomodulatory properties, 
including biosimilars 
• Anti-integrin or antiadhesion molecule treatment (eg, natalizumab, vedolizumab, 
efalizumab, etrolizumab) 
• Nonbiologics with immunomodulatory properties (except for AZA, 6-MP, and MTX, 
which are permitted) 
• Lymphocytes apheresis or selective monocyte granulocytes apheresis 
• Live (attenuated) vaccines 
• Fecal microbiota transplantation 
• Any investigational product other than ontamalimab. 
Treatments not listed in this section may be considered allowable; see Section 5.2.2.1 for further 
details. 
No new nonpharmacological therapies that might affect bowel habit or GI function should be 
started during the study. 
Parenteral nutrition is not permitted at any time during the study. 
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Subjects who enter the 12-week safety follow-up period will no longer need to abstain from the 
medications that were prohibited during the treatment period. Other CD treatments will be 
allowed. Biologics or nonbiologic immunosuppressants should not be initiated without prior 
discussion with the sponsor study physician or designee, due to the long half-life of 
ontamalimab. 
5.3 
COVID-19 
In cases in which the subject is known to have been infected with the COVID-19 virus but does 
not have the disease, he or she should be actively moved to lower doses of prednisone 
(<20 mg/day) or transition to budesonide when feasible. Thiopurines and MTX should be 
temporarily withheld. The study drug should have dosing delayed for 2 weeks while the subject 
is monitored for the development of COVID-19. 
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6. 
INVESTIGATIONAL PRODUCT 
6.1 
Identity of Investigational Product 
The test product is ontamalimab, which will be provided as a sterile aqueous buffered solution 
for SC administration in a glass PFS with a fixed needle. Each PFS contains 1 mL of 
ontamalimab solution for injection at an appropriate concentration to provide the intended dose 
of drug (25 mg or 75 mg). Additional information is provided in the current ontamalimab IB. 
6.1.1 
Blinding the Treatment Assignment 
The fill volume for all syringes will be the same. 
This study has been double-blind, as the purpose of the blinding was to maintain the blind in 
maintenance study SHP647-303 for UC subjects and SHP647-307 for CD subjects while these 
studies are ongoing. Due to the early discontinuation of the program, this study is planned to 
become unblinded after the completion of the analysis for the induction studies (SHP647-301, 
SHP647-302, SHP647-305, and SHP647-306) and prior to the completion of the SHP647-303 
and SHP647-307 studies. Until the induction study results become available, this study will 
continue to be blinded (ie, unblinding will not occur until the final analysis of the induction 
studies is completed), as it is planned that subjects will receive the lowest effective dose based 
on the results of the induction studies. It is expected that the analysis of these results will 
demonstrate the efficacy of at least one of the doses and allow for the selection of a single dose, 
at which time this study will be open label. If both doses are effective and the difference 
compared to placebo is similar, then the lowest effective dose will be selected. If neither dose is 
deemed efficacious, this study will be terminated. 
As the treatment assignment is planned to be unblinded after the completion of the analysis for 
the induction studies (SHP647-301, SHP647-302, SHP647-305, and SHP647-306) and prior to 
the completion of the SHP647-303 and SHP647-307 studies, these two studies will be considered 
unblinded, and the date of study unblinding will be recorded. 
6.2 
Administration of Investigational Product(s) 
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, investigational product supply dispensation and management, inventory 
management and supply ordering, and investigational product expiration tracking and 
management. Please refer to the Study Manual for additional details regarding the IRT system. 
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6.2.2 
Allocation of Subjects to Treatment 
Originally, subjects were to be randomized to treatment in this study. Under Amendment 4 of the 
protocol, randomization will not be performed, as the aim of the study is to provide subjects with 
the ontamalimab dose associated with their treatment response. 
Following the confirmation of eligibility, subjects will be allocated to receive either 25 mg or 
75 mg of ontamalimab SC every 4 weeks depending on which dose they had responded to in a 
prior study. 
Eligible subjects who withdrew from Study SHP647-303 or SHP647-307 due to the early 
discontinuation of these studies, who received active treatment and showed treatment response at 
the EOT visit, will receive the dose of ontamalimab (that resulted in treatment response) in the 
previous maintenance study every 4 weeks. Eligible subjects currently receiving placebo in 
maintenance study SHP647-303 or SHP647-307 will receive the same dose of ontamalimab that 
they received in the previous induction study every 4 weeks. 
Subject numbers are assigned to all subjects as they consent to take part in the study. The subject 
numbers will be different than the numbers assigned in SHP647-301, SHP647-302, SHP647-303, 
SHP647-305, SHP647-306, and SHP647-307 for subjects who enter from these studies. The 
randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. 
If during the study, either the 25 mg or 75 mg dose of ontamalimab is determined to be the 
efficacious dose, based on emergent data from the induction studies, subjects may have their 
treatment assignment switched to that dose, and the study would continue as an open-label study 
at that dose level, unless neither dose is efficacious, in which case this study will be terminated. 
To preserve blinding, all subjects will receive a randomization number, including those subjects 
who completed a maintenance study (SHP647-303 or SHP647-307) and are to receive the same 
ontamalimab dose in this study. 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, until the time of unblinding. In these cases, the same investigational 
product packing identification number may not be assigned to more than 1 subject. 
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6.2.3 
Dosing 
Investigational product (ontamalimab) will be administered subcutaneously every 4 weeks for 
the duration of the treatment period. 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. The 
injection site should be rotated. If there are clinical reasons why the drug cannot be administered 
in the thigh, the drug may be administered in the deltoid area or abdomen with appropriate 
documentation. 
As some subjects may enter this study having received placebo and not active treatment in the 
induction (SHP647-301, SHP647-302, SHP647-305, or SHP647-306) or maintenance 
(SHP647-303 or SHP647-307) study, after the first administration of investigational product, the 
subject must be observed by a member of the study staff for at least 30 minutes (the total 
duration should be determined at the discretion of the investigator). For subsequent 
administrations, observation of the subject is at the discretion of the investigator. Injection site 
and allergic reaction monitoring should be completed by a member of the study staff. 
Principal investigators are responsible for ensuring that all study and nonstudy personnel 
identified to administer investigational product are qualified, with documented training and 
delegation of responsibilities prior to their first investigational product administration visit at 
subjects’ homes. 
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. 
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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 results 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 remain in the study. 
Dosing delays up to 8 weeks (2 doses) are allowed, and the subjects are allowed to miss a 
maximum of 2 doses due to COVID-related or other pandemic-related issues (see Section 5.3). 
Sites must receive Shire approvals for each subject meeting the missed/delayed dosing criteria. 
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational product is dispensed by qualified staff members. During the COVID-19 public 
health emergency (or other similar pandemic), alternative investigational product delivery to 
study participants may be necessary to avoid unnecessary subject visits to sites while providing 
needed investigational product. Additional investigational product may be dispensed during a 
scheduled study visit or investigational product may be shipped directly from investigational 
sites to participants’ residences by a contracted logistics provider or distributor (DTP shipment) 
in compliance with national laws or temporary national emergency measures and sponsor 
processes. 
6.2.4 
Unblinding the Treatment Assignment 
This study has been double-blind and will continue as such until the induction study results 
become available (ie, unblinding will not occur until the final analysis of the induction studies is 
completed and the lowest effective dose determined), as it is planned that subjects will receive 
the lowest effective dose based on the results of the induction studies. 
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Prior to the time of unblinding, 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. 
Note: This is applicable only until the time of unblinding. 
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. 
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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 labelled carton. 
Changes to sponsor-supplied packaging before dosing may not occur without full agreement in 
advance by the sponsor. 
6.3.3 
Storage 
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or delegated member of the study team. The pharmacist or delegated 
team member will enter the unique subject identifier on the investigational product labels as they 
are distributed. 
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. In case of a DTP situation, the 
investigational product can be shipped to subject’s home; please refer to DTP guidance for 
further details. 
The investigator is responsible for ensuring that the temperature is monitored throughout the 
duration of the study and that records are maintained; the temperature should be monitored 
continuously by using either an in-house system, a mechanical recording device such as a 
calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording. The sponsor must be notified immediately upon discovery of any excursion from the 
established range. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the investigational 
product and will provide supportive documentation as necessary. Under no circumstances should 
the product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor. 
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room. 
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6.3.4 
Special Handling 
The investigational product should be protected from light and should not be frozen. Do not 
shake. In case of a DTP situation, the safety of the investigational product will be managed; it 
will be transported via a secured courier or study site personnel with temperature monitoring and 
tracking. Please refer to DTP guidance for further details. 
6.4 
Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section. 
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form. 
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying his/her treatment assignment. All administered 
investigational product will be documented in the subject’s source document and/or other 
investigational product record. In case of a DTP situation, the investigational product 
administration will be documented in the drug administration visit report form (if nonstudy 
personnel administer the investigational product) and in the drug administration log (in case of 
self-administration by the subjects/caregivers/parents). 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
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. 
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With the written agreement of the sponsor, at the end of the study all unused stock may be 
destroyed at the site or a local facility. In this case, destruction records identifying what was 
destroyed, when and how, must be obtained with copies provided to the sponsor. Destruction of 
investigational products must be in accordance with local, state, and national laws. 
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction. 
6.5 
Subject Compliance 
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, bottles, vials, 
and 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) that require 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, Table 2, Table 3, and Table 4 for details on subject visits 
that must be done with the subject present at the investigative site and visits that may 
be conducted at the clinic or by home healthcare visits to extend flexibility to patients 
during the COVID-19 public health emergency (or other similar pandemic). Home 
healthcare visits will be documented in the study records and eCRF. 
• Allowance of more flexibility around scheduling of study visits and/or allowing some 
assessments to be conducted remotely (See Table 1, Table 2, Table 3, and Table 4). 
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• 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, or at a local laboratory if 
necessary. 
• Missed clinic visits or subject withdrawals due to COVID-19 (or other similar 
pandemic) must be recorded on the eCRF (See Section 4.4.3, 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 
schedules of assessments (Table 1 and Table 2 for subjects with UC and Table 3 and Table 4 for 
subjects with CD), in order to conduct evaluations or assessments required to protect the 
well-being of the subject. 
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7.2.1 
Subjects with Ulcerative Colitis 
7.2.1.1 
Baseline Visit (Week 0/Day 1) 
For subjects entering into Study SHP647-304 from maintenance study SHP647-303 and who 
completed the 52-week treatment period, procedures performed (with the exception of the 
treatment response evaluation) at the Week 52 visit will be used as the baseline visit 
(Week 0/Day 1) assessments for this extension study. For subjects entering from maintenance 
study SHP647-303 and who completed participation prior to Week 52, procedures performed 
(with the exception of the treatment response evaluation) at the ET visit will be used as the 
baseline visit (Week 0/Day 1) assessments for this extension study. The assessments and 
procedures performed during the baseline visit are specified in Table 1. 
For subjects entering into Study SHP647-304 from a maintenance study, baseline of the 
induction study will be used as the baseline visit (Week 0/Day 1) for treatment response 
evaluation for this extension study. 
The assessments and procedures performed during the baseline visit are specified in Table 1. 
A screen failure is a subject who has given informed consent or assent, as applicable (and whose 
parents or legally authorized representatives have given informed consent, as applicable), failed 
to meet the inclusion criteria and/or met at least one of the exclusion criteria, and has not been 
administered investigational product. 
For eligible subjects, all relevant study information (with the exception of the treatment response 
evaluation) recorded for Week 12 of the induction study or Week 52 or ET of the maintenance 
study will be used as the baseline visit data for this extension study. 
After eligibility has been confirmed and all baseline procedures and assessments have been 
completed, each subject will be assigned to 1 of the 2 treatment groups as described in 
Section 6.2.2 and the first dose of investigational product will be administered. 
7.2.1.2 
Treatment Period 
During the treatment period in this extension study, subjects will attend study visits every 
4 weeks (Weeks 4, 8, 12, 16, etc.). Assessments and procedures to be performed at each visit are 
specified in Table 1. 
Assessments and procedures to be performed at each visit beginning in Treatment Year 2 
(Week 52) are specified in Table 2. 
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For subjects who are tolerating investigational product and receiving clinical benefit in the 
judgment of the investigator, study participation may continue until the subject withdraws from 
the study, or the investigator or sponsor decide to withdraw the subject (eg, in the interest of 
subject safety), or the sponsor decides to close the study, or the program is stopped completely. 
Once study treatment has ended, ie, for any of the reasons described in Section 4.4, subjects will 
attend the EOT visit, at which assessments and procedures will be performed as shown in 
Table 2. The EOT visit is preferred to be an on-site visit; 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, this visit may also 
be conducted at a subject’s home, provided a qualified site staff member performs these 
evaluations following DTP guidance. After completion of the EOT visit, subjects will enter the 
safety follow-up period. 
7.2.1.3 
Follow-up Period 
The safety follow-up period for this protocol is 12 weeks from the EOT visit for each subject. 
During the follow-up period, there will be a visit at the study site at 12 weeks (±10 days) 
post-EOT. The 12-week safety follow-up visit is preferred to be an on-site visit; 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, this 
visit may also be conducted at a subject’s home, provided a qualified site staff member performs 
these evaluations following DTP guidance. 
The assessments and procedures specified in Table 2 will be performed, including querying for 
SAEs, AEs, and concomitant treatments. All AEs and SAEs that are not resolved at the time of 
this visit will be followed to closure (see Section 8.1). 
7.2.2 
Subjects with Crohn’s Disease 
7.2.2.1 
Baseline Visit (Week 0/Day 1) 
For subjects entering into Study SHP647-304 from maintenance study SHP647-307 and who 
completed the 52-week treatment period, procedures performed (with the exception of the 
treatment response evaluation) at the Week 52 visit will be the baseline visit (Week 0/Day 1) 
assessments for this extension study. For subjects entering from maintenance study SHP647-307 
and who completed participation prior to Week 52, procedures performed (with the exception of 
the treatment response evaluation) at the ET visit will be the baseline visit (Week 0/Day 1) 
assessments for this extension study. 
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For subjects entering into Study SHP647-304 from a maintenance study, baseline of the 
induction study will be used as the baseline visit (Week 0/Day 1) for treatment response 
evaluation for this extension study. 
The assessments and procedures performed during the baseline visit are specified in Table 3. 
A screen failure is a subject who has given informed consent or assent, as applicable (and whose 
parents or legally authorized representatives have given informed consent, as applicable), failed 
to meet the inclusion criteria and/or met at least one of the exclusion criteria, and has not been 
administered investigational product. 
For eligible subjects, all relevant study information (with the exception of the treatment response 
evaluation) recorded for Week 16 of the induction study or Week 52 or ET of the maintenance 
study will be used as the baseline visit data for this extension study. 
After eligibility has been confirmed and all baseline procedures and assessments have been 
completed, each subject will be assigned 1 of the 2 treatment groups as described in 
Section 6.2.2 and the first dose of investigational product will be administered. 
7.2.2.2 
Treatment Period 
During the treatment period in this extension study, subjects will attend study visits every 
4 weeks (Weeks 4, 8, 12, 16, etc.). Assessments and procedures to be performed at each visit are 
specified in Table 3. 
Assessments and procedures to be performed at each visit beginning in Treatment Year 2 
(Week 52) are specified in Table 4. 
For subjects who are tolerating investigational product and receiving clinical benefit in the 
judgment of the investigator, study participation may continue until the subject withdraws from 
the study, or the investigator or sponsor decide to withdraw the subject (eg, in the interest of 
subject safety), or the sponsor decides to close the study, or the program is stopped completely. 
Once study treatment has ended, ie, for any of the reasons described in Section 4.4, subjects will 
attend the EOT visit, at which assessments and procedures will be performed as shown in 
Table 4. The EOT visit is preferred to be an on-site visit; 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, this visit may also 
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be conducted at a subject’s home, provided a qualified site staff member performs these 
evaluations following DTP guidance. After completion of the EOT visit, subjects will enter the 
safety follow-up period. 
7.2.2.3 
Follow-up Period 
The safety follow-up period for this protocol is 12 weeks from the EOT visit for each subject. 
During the follow-up period, there will be a visit at the study site at 12 weeks (±10 days) 
post-EOT. The 12-week safety follow-up visit is preferred to be an on-site visit; 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, this 
visit may also be conducted at a subject’s home, provided a qualified site staff member performs 
these evaluations following DTP guidance. 
The assessments and procedures specified in Table 4 (for subjects with CD) will be performed, 
including querying for SAEs, AEs, and concomitant treatments. All AEs and SAEs that are not 
resolved at the time of this visit will be followed to closure (see Section 8.1). 
7.2.3 
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: 
• Vital signs and ECG 
• Laboratory sample collection 
• Endoscopy, if performed (see Sections 7.3.2.1 and 7.3.3.1) 
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• Investigational product administration. 
Notes: 
• Blood and tissue samples may be stored for up to the duration allowed by local 
regulations but for no longer than 25 years. 
• Endoscopy is optional after the implementation of Amendment 4; if performed, the 
results should be recorded. 
7.3.1 
Demographic and Other Baseline Characteristics 
For subjects entering this extension study SHP647-304 from a maintenance study, all relevant 
demographic and baseline characteristics recorded for the induction study (SHP647-301, 
SHP647-302, SHP647-305, or SHP647-306) or maintenance study (SHP647-303 or 
SHP647-307) will be used as the baseline characteristics for this study. 
7.3.2 
Treatment Response Assessments – Subjects with Ulcerative Colitis 
7.3.2.1 
Endoscopy 
Endoscopy is optional after the implementation of Amendment 4; if performed, the results 
should be recorded using the Mayo endoscopic subscore. Endoscopy may be performed at the 
time points specified in Table 1 and Table 2 and is to consist of either flexible sigmoidoscopy or 
colonoscopy (if preferred) for subjects with UC or colonoscopy (if preferred) for subjects with 
CD. If more than 2 endoscopies/colonoscopies are needed in a year, the subject should be 
discontinued. 
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) or maintenance study (SHP647-303). 
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. Endoscopy results will be 
reviewed by a local reader. 
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 and Table 2. 
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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): 
• Bowel movement frequency (0-3) 
• Rectal bleeding (0-3) 
• Findings of flexible sigmoidoscopy or 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. Note: After the implementation of Amendment 4, 
endoscopy is optional, and the composite score will be computed only if an endoscopy is 
performed. 
The clinical composite score is a measure consisting of RB plus stool frequency without 
endoscopic and PGA subscore. 
Subjects will be instructed to maintain a daily memory aid for the 7 days prior to each visit. In 
the memory aid, subjects will record the total number of bowel movements and the worst RB 
experienced each day (see Section 7.3.2.3). At the scheduled visit, the investigator will ask the 
subject to report the daily stool count and RB score and enter the data into the eCRF to calculate 
the clinical composite (and if appropriate, composite) score for that visit. 
The Mayo stool frequency and RB subscores will be calculated based on each subject’s data over 
the most recent 3 days (consecutive or nonconsecutive) prior to the visit, excluding the following 
days: day of any bowel preparation, day of endoscopy, any days between day of bowel 
preparation and day of endoscopy, and the 2 days after the day of endoscopy. 
The mucosal appearance during the sigmoidoscopic portion of the endoscopic examination (if 
performed) 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 the 
operator or study site investigator using video recorded during the procedure. Locally read 
endoscopic subscores, if performed, will be used for treatment response analyses. 
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The PGA acknowledges the 3 other criteria: the patient’s recollection of abdominal discomfort 
and general sense of well-being and other observations (such as physical findings and the 
patient’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 
Ulcerative Colitis Memory Aid 
Subjects will be asked to report the following signs and symptom data, as experienced over the 
previous 24 hours, with the assistance of a memory aid, which they may use for the 7 days prior 
to each scheduled visit: 
• Stool frequency 
• Rectal bleeding severity 
The memory aid guidelines for subjects with UC are presented in Appendix 2. 
7.3.3 
Treatment Response Assessments – Subjects with Crohn’s Disease 
7.3.3.1 
Colonoscopy 
Colonoscopy is optional after the implementation of Amendment 4; if performed, the results 
should be recorded using the SES-CD. Colonoscopy may be performed at the time points 
specified in Table 3 and Table 4. If more than 2 colonoscopies are needed in a year, the subject 
should be discontinued. 
Bowel preparation regimens typically incorporate dietary modifications along with oral 
cathartics. Typically, the standard dose of a bowel preparation is split between the day before 
and the morning of the procedure. In this study, bowel preparation and colonoscopy are to be 
conducted as per local routine; however, sodium phosphate based preparations should be 
avoided, as such regimens can produce mucosal changes that mimic IBD. 
A complete colonoscopy that includes the visualization of rectum, the sigmoid colon, the left 
colon, the transverse colon, the right colon, the ileocecal valve, and the terminal ileum should be 
performed. Incomplete endoscopy caused by but not limited to a complication during endoscopy, 
interruption of the endoscopy for any reasons cannot be accepted as complete colonoscopy with 
the exception of impassable stenosis or other CD-related complications as cause of failure to 
complete the colonoscopy procedure. 
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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 (SHP647-305 or SHP647-306). The colonoscopy report and 
any photographs and/or video recordings taken during the procedure per local custom should be 
filed in the subject’s medical record. Colonoscopy results will be reviewed by a local reader. 
7.3.3.2 
Simple Endoscopic Activity Score for Crohn’s Disease 
Colonoscopy, if performed, will be evaluated by the SES-CD scoring system at the time points 
specified in Table 3 and Table 4. 
The SES-CD will be calculated using the subscores of each of the segments investigated and 
read by the local endoscopist at each of the visits when colonoscopy is performed. The baseline 
score will be based on the colonoscopy that was performed prior to the start time of the first dose 
of this study. If not taken in this study, the score for the baseline (Week 0/Day 1) visit will be 
based on the last colonoscopy performed in the study from which the subject is entering. 
The SES-CD is a simple scoring system based on 4 endoscopic variables (presence and size of 
ulcers, proportion of surface covered by ulcers, proportion of affected surface, and presence and 
severity of stenosis [narrowing]) measured in the same 5 ileocolonic segments as the CD index 
of severity. Overall, values on the SES-CD range from 0 to 56, with higher values indicating 
more severe disease. The 4 endoscopic variables are scored from 0 to 3 in each bowel segment 
(ileum, right/transverse/left colon, and rectum): 
• Presence and size of ulcers (none = score 0; diameter 0.1–0.5 cm = score 1;  
0.5–2 cm = score 2; diameter >2 cm = score 3) 
• Extent of ulcerated surface (none = 0; <10% =1; 10%–30% = 2; >30% = 3); extent of 
affected surface (none = 0; <50% = 1; 50%–75% = 2; >75% = 3) 
• Presence and type of narrowings (none = 0; single, can be passed = 1; multiple, can 
be passed = 2; cannot be passed = 3). 
The maximum stenosis score in a segment distal to another evaluable segment cannot exceed 2, 
so that the stenosis scores cannot exceed a total of 11 (Reinisch et al., 2017). 
The SES-CD is presented in Appendix 2. 
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7.3.3.3 
Crohn’s Disease Activity Index 
The CDAI is a composite measure with 8 components; 3 components (abdominal pain severity, 
very soft stool/liquid stool frequency, and general well-being) will be self-reported by the 
subject, as described in Section 7.3.3.4, and 5 components will be recorded at the time points 
specified in Table 3 and Table 4. 
The CDAI scores at visits specified in Table 3 and Table 4 will be calculated using the 
following: 
• Components 1 to 3 from subject-reported data collected for 7 days before the visit 
(see Section 7.3.3.4) and 
• Components 4 to 8 (weight, medical and physical examination, use of diarrhea 
treatment, and hematocrit value) collected at the visit. 
Change in CDAI has been used as a primary endpoint in multiple pivotal trials in the 
CD indication. The algorithm for calculating the CDAI score was first published by William 
Best and colleagues (Best et al., 1976). 
The CDAI is presented in Appendix 2. 
7.3.3.4 
Crohn’s Disease Memory Aid 
Subjects will be asked to recall clinical data for the CDAI score. They may use a memory aid to 
record for the 7 days prior to each scheduled visit: 
• Number of very soft or liquid bowel movements (as shown by Bristol Stool Form 
Scale type 6/7) 
• Level of abdominal pain (using the parameters as described in CDAI) 
• Sense of general well-being (using the parameters as described in CDAI) 
The investigator will record this information in the eCRF and use it to calculate the CDAI score 
for that visit. 
The memory aid guidelines for subjects with CD are presented in Appendix 2. 
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7.3.4 
Safety 
7.3.4.1 
Medical and Medication History 
For subjects entering from an induction or maintenance study, medical history, including UC or 
CD history, cardiac history, and smoking history, and prior medications will be collected at the 
screening visit of Study SHP647-301, SHP647-302, SHP647-305, or SHP647-306. 
Concomitant medications and procedures will be documented throughout the SHP647-304 study 
at the time points specified in Table 1 and Table 2 (for subjects with UC) and in Table 3 and 
Table 4 (for subjects with CD). 
7.3.4.2 
Physical Examination (Including Weight) 
Complete and targeted physical examinations and weight assessments will be performed at the 
times specified in Table 1 and Table 2 (for subjects with UC) and in Table 3 and Table 4 (for 
subjects with CD). Complete physical examination includes the review of the following body 
systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; 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, eyes, abdomen, and examination of body systems where there are symptom 
complaints by the subject. For subjects with CD, targeted physical examination includes review 
of the skin and mucosa, specifically perianal for fistula and oral cavity for stomatitis as part of 
the CDAI assessment. 
Weight will be measured at the time points specified in Table 1 and Table 2 (for subjects with 
UC), and Table 3 and Table 4 (for subjects with CD). 
The complete physical examination performed at Week 12 of induction study SHP647-301 or 
SHP647-302, at Week 16 of induction study SHP647-305 or SHP647-306, or at the ET or 
Week 52 visit of maintenance study SHP647-303 or SHP647-307, will be the baseline 
(Week 0/Day 1) examination of Study SHP647-304. Abnormalities identified during this visit 
will be documented. Any changes from the baseline visit (Week 0/Day 1) in physical 
examination findings that are deemed clinically significant in the opinion of the investigator are 
to be recorded as an AE. 
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7.3.4.3 
Targeted Neurological Assessment 
Targeted neurological assessments to monitor for the development of signs and/or symptoms of 
PML will be performed at the time points specified in Table 1 and Table 2 (for subjects with 
UC), and Table 3 and Table 4 (for subjects with CD). 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. 
A step-wise approach for the proposed neurological assessment plan is provided in Table 7. 
Table 7 
Quarterly Neurological Assessments 
Domain 
Step 1: Interim Neurologic History 
and Targeted Neurological 
Examination 
Step 2: If Abnormal Response 
Vision 
Diplopia or visual/visual field loss 
Perform visual field assessment 
Motor 
Major motor weakness (eg, legs, arms) 
Test leg strength (hopping, foot tapping), 
finger tapping, pronator drift, and bilateral 
muscle strength 
Tactile sensation 
Paresthesia, anesthesia in any domain 
(peripheral, central) 
Pinprick test 
Coordination/Cerebellar 
Clumsiness, difficulty with walking, 
writing, or fine motor skills, etc. 
Finger-nose, heel-shin, heel-toe walk, 
writing sample, draw a clock 
Speech 
Dysarthria, expressive aphasia 
Naming objects, repeat multipart phrase, 
observe for dysarthria or aphasia 
Verbal comprehension 
Agnosia, receptive aphasia 
Test to follow routine commands, 
eg, close eyes, touch finger to ear 
Cognition/Behavior 
New onset of difficulties with memory or 
thinking, important changes in behavior 
Recall 3 objects over 1 minute, serial 7 s, 
proverbs; changes in activities of daily 
living over prior 6 months 
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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 2. Any concerns from the DMC will be promptly 
communicated to the sponsor, investigator, and treating neurologist. 
After the study is unblinded, assessment of potential PML will be conducted by independent 
physicians with PML expertise. If they conclude that a diagnosis of PML is likely, there will be 
an urgent meeting of the Safety Management Team (SMT) to review the data and make a 
recommendation regarding continuation of the study. Any concerns from the independent experts 
or the SMT will be promptly communicated to the investigator and treating neurologist. 
Figure 2 
Flow Diagram for Quarterly Neurological Assessments 
 
DMC=data monitoring committee; IND=investigational new drug; neuro=neurological; PML=progressive multifocal 
leukoencephalopathy. 
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After the study has been unblinded, the flow diagram will be modified as shown in Figure 3. 
Figure 3 
Post-unblinding Flow Diagram for Quarterly Neurological Assessments 
 
IND=investigational new drug; neuro=neurological; PML=progressive multifocal leukoencephalopathy; SMT=Safety 
Management Team. 
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. 
7.3.4.4 
Adverse Event Collection 
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent and/or assent is signed until the end 
of the defined follow-up period (See Section 8, Adverse and Serious Adverse Events 
Assessment). 
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7.3.4.5 
Vital Signs 
Vital signs will be measured at the time points specified in Table 1 and Table 2 (for subjects with 
UC), and Table 3 and Table 4 (for subjects with CD). 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 collection of blood samples for laboratory assessments, where applicable. 
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 (Week 0/Day 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. 
7.3.4.6 
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, which are 
unexpected or not explained by the subject’s clinical condition, may, at the discretion of the 
investigator or sponsor, be repeated as soon as possible until confirmed, explained, or resolved. 
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The following clinical laboratory assessments will be performed at the time points specified in 
Table 1 and Table 2 (for subjects with UC) and in Table 3 and Table 4 (for subjects with CD): 
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 the 
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. 
7.3.4.7 
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 and Table 2 (for subjects 
with UC) and Table 3 and Table 4 (for subjects with CD), 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, SHP647-302, 
SHP647-305, SHP647-306, or maintenance study SHP647-303 or SHP647-307. 
If a female subject’s status has changed to postmenopausal since the induction study 
(SHP647-301, SHP647-302, SHP647-305, SHP647-306) or maintenance study (SHP647-303 or 
SHP647-307), the childbearing potential of the subject must be re-established and documented 
(FSH confirmation test) at baseline of SHP647-304. Once FSH results are received, and if 
postmenopausal status is uncertain, the routine pregnancy testing will continue as planned for the 
remainder of the study. If postmenopausal status is confirmed, routine pregnancy testing is no 
longer required. 
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7.3.4.8 
Electrocardiogram 
A 12-lead ECG will be recorded at the time points specified in Table 1 and Table 2 (for subjects 
with UC) and Table 3 and Table 4 (for subjects with CD). When timing of measurements 
coincide, ECGs should be performed before collection of blood samples for laboratory 
assessments. 
A local 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 local reader, the investigator, in consultation with the appointed sponsor or 
contract research organization (CRO) medical monitor, will reconfirm subject eligibility to 
continue. 
If it is not possible to perform an ECG due to a COVID-19-related or other pandemic-related 
issue, the investigator is to ensure that an ECG is performed at the next possible visit (scheduled 
or unscheduled). 
7.3.4.9 
Monitoring for Type I and Type III Immune Reactions 
Subjects will be educated on the signs and symptoms of hypersensitivity reactions and how to 
respond to them. In addition, subjects will be instructed to report hypersensitivity AEs to the 
investigator at the time of occurrence, and to seek immediate medical care if hypersensitivity 
develops. At each visit, the subject will be queried for AEs of special interest (AESIs) related to 
hypersensitivity. 
Subjects will be also instructed to report AEs such as serum sickness, vasculitis, Arthus reaction, 
and severe injection related reactions to the investigator, and to seek immediate medical care if 
these events are severe in intensity. 
Subjects who experience a hypersensitivity reaction or severe or serious injection-related 
reaction (eg, shortness of breath, wheezing, stridor, angioedema, life-threatening change in vital 
signs) should discontinue investigational product. 
For 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), the investigator will decide on treatment 
discontinuation. 
Further details of hypersensitivity reactions as AESIs are provided in Section 8.1.3.1. 
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7.3.4.10 
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 5 (for subjects with UC), and Table 6 for subjects with CD). 
Subjects should be assessed for possible treatment failure. 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 4.4.2 should be followed. 
In each case, the appropriate AE (eg, infection, exacerbation) should be recorded in the subject’s 
source document. 
7.3.4.11 
Colonoscopy in Subjects at Elevated Risk of Colorectal Cancer 
Subjects at risk for colorectal cancer who undergo annual endoscopy may undergo a 
colonoscopy with all annual surveillance procedures followed (eg, excision of adenomatous 
polyps with pathology report included in source documents). This is not required by the protocol, 
but if performed, the results should be recorded. Subjects at high risk for colorectal cancer are 
those who meet either of the following criteria: 
• Subjects with extensive colitis for ≥8 years or disease limited to left side of colon 
(ie, distal to splenic flexure) for ≥10 years before screening, regardless of age 
• Subjects ≥50 years of age at the time of signing of the informed consent form. 
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7.3.5 
Others 
7.3.5.1 
Pharmacodynamic Assessments 
Predose blood and stool samples will be collected at the time points specified in Table 1 and 
Table 2 (for subjects with UC), and Table 3 and Table 4 (for subjects with CD) for each of the 
following biomarkers: 
• Serum CRP 
• Stool fecal calprotectin 
Stool samples will be analyzed for fecal calprotectin at the time points indicated in Table 1 and 
Table 2 (for subjects with UC), Table 3 and Table 4 (for subjects with CD). 
Details of sample collection, handling, shipment, and analysis will be provided in the laboratory 
manual. In case of a DTP situation, samples can be collected at subject’s home or nearby clinic; 
please refer to DTP guidance for further details. 
7.3.6 
Volume of Blood to Be Drawn from Each Subject – All Subjects 
For subjects entering from an induction or maintenance study, the volume of blood to be drawn 
from each subject is summarized in Table 8 for Treatment Year 1 and Table 9 for Treatment 
Year 2 through Year 3. 
Table 8 
Volume of Blood to Be Drawn from Each Subject – Treatment Year 1 (All 
Subjects) 
Assessment 
Sample Volume (mL) 
Number of 
Samples 
Total Volume (mL) 
Hematology 
2 
5 
10 
Serum chemistry 
4 
5 
20 
FSH 
2 
1 
2 
Blood samples for biomarkers 
 
Serum CRP 
2 
2 
4 
Total mL 
36 
CRP=C-reactive protein; FSH=follicle-stimulating hormone. 
 
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Table 9 
Volume of Blood to Be Drawn from Each Subject – Treatment Year 2 Through 
Year 3 (All Subjects) 
Assessment 
Sample Volume (mL) 
Number of 
Samples 
Total Volume (mL) 
Hematology 
2 
4 
8 
Serum chemistry 
4 
2 
8 
Blood samples for biomarkers 
 
Serum CRP 
2 
2 
4 
Total mL 
20 
CRP=C-reactive protein. 
For subjects entering from a maintenance study, during this study (after the implementation of 
Amendment 4) it is expected that approximately 36 mL of blood will be drawn from each subject 
in the first year of study participation and approximately 20 mL of blood in each year thereafter. 
Additionally, it is expected that an approximate total of 30 mL of blood will be drawn from each 
subject at the EOT visit and the safety follow-up visit at 12 weeks following the last dose of 
investigational product. 
Note: 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. 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 is signed until the defined follow-up 
period stated in Sections 7.2.1.3 and 7.2.2.3. 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 Studies SHP647-301, SHP647-302, SHP647-303, SHP647-305, SHP647-306, or 
SHP647-307 will be captured as part of the SHP647-304 baseline medical history, while ongoing 
AEs from Studies SHP647-301, SHP647-302, SHP647-303, SHP647-305, SHP647-306, or 
SHP647-307 will be captured as AEs in Study SHP647-304. 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. 
 
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8.1.3 
Adverse Events of Special Interest 
Adverse events of special interest will be captured and monitored during this study. Investigators 
will report all AESIs to the sponsor, regardless of causality, using the same timelines as 
described for SAE reporting (see Section 8.2.2). The following describe the AESIs and the 
criteria for reporting AESIs. 
8.1.3.1 
Hypersensitivity 
Potential hypersensitivity, serum sickness, vasculitis, and Arthus reactions to ontamalimab will 
be regarded as AESIs. These events must be reported on Shire “Clinical Study SAE and 
Nonserious AE as Required by the Protocol Form” and within the time frame mandated for 
SAEs (see Section 8.2.2). 
It is well known that the administration of foreign proteins can cause immune responses 
including hypersensitivity reactions such as anaphylaxis and serum sickness. Other immune 
responses to foreign proteins include the development of ADAs and neutralizing antibodies 
(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 
 
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Ontamalimab is a fully human antibody of the immunoglobulin G2 subclass. In Phase 1 and 
Phase 2 clinical trials of ontamalimab, in which over 700 subjects were treated for up to 3 years, 
there has been no case of anaphylaxis. There have been 2 reported cases of drug hypersensitivity: 
serum sickness attributed to concomitant administration of penicillin; and a reaction 
characterized by dyspnea, facial erythema, and chest pain with onset 2 days after administration 
of the fifth dose of ontamalimab. The latter event mimicked a reaction that the subject had 
previously experienced after 4 doses of infliximab. In addition, low titer activity has been 
observed in ADA assays, including pretreatment samples and placebo-treated subjects, and no 
subject has had a 2-fold or greater increase in ADA titer. Analysis of PK and clinical parameters 
has shown no difference between subjects whose ADA assays results are positive as compared 
with those whose are negative. 
Nonetheless the possibility of a hypersensitivity reaction occurring after drug exposure cannot be 
fully ruled out. The reactions of concern are Type I (anaphylaxis) and Type III (immune 
complex) reactions. The clinical presentation of anaphylactic reactions is described in Table 10. 
Table 10 Clinical Criteria for Diagnosing Anaphylaxis (Type 1 Hypersensitivity) 
Anaphylaxis is highly likely when below criterion and at least any one of the following criteria a and b are 
fulfilled: 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, 
generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST 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 blood pressure 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 
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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. 
8.1.4 
Outcome Categorization 
The outcome of AEs must be recorded during the course of the study in the eCRF. Outcomes are 
as follows: 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved With Sequelae 
• Recovering/Resolving 
• Unknown. 
8.1.5 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the 
treatment response 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 EOT with the investigational product, and the range of variation of the respective 
parameter within its reference range, must be taken into consideration. 
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If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or 
ECG values which were not present at the pretreatment value observed closest to the start of 
study treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values. 
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE. 
8.1.7 
Pregnancy 
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Sections 7.2.1.3 and 7.2.2.3. 
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to Shire Global Pharmacovigilance using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum. 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 
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Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine β-hCG 
test or ultrasound result will determine the pregnancy onset date. 
8.1.8 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category. 
• Abuse – Persistent or sporadic intentional intake of investigational product when 
used for a nonmedical purpose (eg, to alter one’s state of consciousness or get high) 
in a manner that may be detrimental to the individual and/or society 
• Misuse – Intentional use of investigational product other than as directed or indicated 
at any dose (Note: this includes a situation where the investigational product is not 
used as directed at the dose prescribed by the protocol) 
• Overdose – Intentional or unintentional administration of investigational product at a 
dosing 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 e-mail 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 one 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 
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that do not result in inpatient hospitalization; or the development of drug dependency 
or drug abuse. 
8.2.4 
Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Sections 7.2.1.3 and 7.2.2.3 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 11 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 11 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 an induction study 
(SHP647-301, SHP647-302, SHP647-305 
or SHP647-306) or maintenance study 
(SHP647-303 or SHP647-307) 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 an induction study 
(SHP647-301, SHP647-302, SHP647-305 
or SHP647-306) or maintenance study 
(SHP647-303 or SHP647-307) with 
HBcAb with or without HBsAb, would 
need evaluation with HBV DNA to rule 
out HBV reactivation.c 
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Table 11 Safety Monitoring Rules for Treatment-emergent Elevated ALT and/or 
Bilirubin 
Treatment-emergent ALT 
Treatment-
emergent total 
bilirubin 
Treatment-
emergent 
symptoms 
Action 
Normal baseline: 
ALT ≥3× ULN 
Elevated baselinea: 
ALT ≥2× baseline 
or 
≥300 U/L (whichever occurs first) 
TBL≥2mg/dL 
increased over 
baseline 
or 
Patients with Gilbert’s 
syndrome of 
hemolysis: Doubling 
of baseline direct 
bilirubin 
None 
Interrupt investigational 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 an induction study 
(SHP647-301, SHP647-302, SHP647-305 
or SHP647-306) or maintenance study 
(SHP647-303 or SHP647-307) with 
HBcAb with or without HBsAb, would 
need evaluation with HBV DNA to rule 
out HBV reactivation.c 
Normal baseline: 
ALT ≥5× ULN 
Elevated baselinea: 
ALT ≥2× baseline 
or 
≥300 U/L (whichever occurs first) 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
or 
Immunologic 
symptoms Rash 
Eosinophilia >5% 
Interrupt investigational 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 an induction study 
(SHP647-301, SHP647-302, SHP647-305 
or SHP647-306) or maintenance study 
(SHP647-303 or SHP647-307) 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 
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 treatment response 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 27513, US). 
Unless otherwise specified, summary tabulations will be presented by indication and treatment 
group. All data listings will be sorted by indication, treatment group, site, and subject number, 
and will include the subject’s age, sex, and race. Summaries will be presented by indication 
separately and also overall. Summaries may be presented by the status at entry into this study 
(eg, induction nonresponder, maintenance ontamalimab completer, maintenance discontinuation 
rollovers, etc.). 
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. 
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9.5 
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee 
An external DMC will be established to review the overall safety of the study subjects on an 
ongoing basis. 
Until the time of unblinding, the DMC will be responsible for the ongoing monitoring of safety 
of subjects enrolled in the study according to the DMC charter. Recommendations made by the 
DMC to alter the conduct of the study or to amend the protocol will be forwarded to Shire for 
review and for a final decision. Shire or its designee will notify investigative sites and regulatory 
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. 
See Section 7.3.4.3 for details on the handling of suspected PML cases in this study. 
9.6 
Sample Size Calculation and Power Considerations 
A maximum of 451 subjects are projected to enroll into this study. No formal sample size 
estimation was performed on this study. 
On 29 May 2020, Takeda announced the closure of the ontamalimab Phase 3 clinical 
development program, which included induction and maintenance studies for subjects with 
moderate to severe IBD who had failed at least 1 prior treatment. With this closure, the induction 
and maintenance studies were discontinued before full enrollment, and the planned direct-entry 
of 800 subjects with UC that was added with Amendment 3 was not initiated. The previously 
projected sample size of 3384 subjects will not be attained. 
As of 04 Sep 2020, there were 334 subjects that were enrolled in this SHP647-304 study. With 
117 subjects active in the ongoing SHP647 induction and maintenance studies, up to a maximum 
of 451 subjects may be enrolled into this study. 
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9.7 
Study Population 
The full analysis set (FAS) will consist of all subjects in the randomized set who receive at least 
1 dose of investigational product in the SHP647-304 study. 
The safety set will consist of all subjects who receive at least 1 dose of investigational product in 
the SHP647-304 study. 
9.8 
Efficacy Analyses 
Efficacy will not be formally evaluated in this study. Treatment response analyses are described 
below. 
9.8.1 
Treatment Response Analyses – Subjects with Ulcerative Colitis 
Treatment response analyses will be performed using the FAS. 
9.8.1.1 
Secondary Endpoints 
The secondary endpoint is as follows: 
• Treatment response over time, with response defined as 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, and/or composite score that has 
decreased by ≥30% and ≥3 points compared to the baseline value for induction 
studies. 
Secondary endpoints will be summarized by treatment group using descriptive statistics at each 
assessment visit. Summaries may be presented by the status at entry into the study (eg, induction 
nonresponder, maintenance ontamalimab completer, maintenance discontinuation rollovers, etc.). 
Statistical summaries will include number of subjects and percentages, and 95% confidence 
intervals. 
The detailed analyses will be described in the SAP. 
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9.8.2 
Treatment Response Analyses – Subjects with Crohn’s Disease 
Treatment response analyses will be performed using the FAS. 
9.8.2.1 
Secondary Endpoints 
The secondary endpoint is as follows: 
• Treatment response over time, with response defined as CDAI score that has 
decreased by ≥100 points compared to the baseline value for induction studies and/or 
SES-CD that has decreased by ≥25% compared to the baseline value for induction 
studies. 
Secondary endpoints will be summarized by treatment group using descriptive statistics at each 
assessment visit. Summaries may be presented by the status at entry into the study (eg, induction 
nonresponder, maintenance ontamalimab completer, maintenance discontinuation rollovers, etc.). 
Statistical summaries will include number of subjects and percentages, and 95% confidence 
intervals. 
The detailed analyses will be described in the SAP. 
9.9 
Safety Analyses 
The primary endpoint is the assessment of safety as measured by: incidence and severity of AEs; 
incidence and nature of serious infections; and actual values and change from baseline, as well as 
incidence of abnormalities, in laboratory tests, ECGs, and vital signs. 
All safety analyses will be performed using the safety set. Subjects will be analyzed according to 
the treatment they actually received. Summaries will be presented by indication separately and 
also overall. Summaries may be presented by the status at entry into this study (eg, induction 
nonresponder, maintenance ontamalimab completer, maintenance early discontinuation rollovers, 
etc.). 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. 
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Treatment-emergent AEs are defined as AEs with start dates or worsening dates at the time of or 
following the first exposure to investigational product in the SHP647-304 study. The number of 
events, incidence, and percentage of TEAEs will be calculated overall, by system organ class, by 
preferred term, by indication, 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/listed. Adverse events of special 
interest will be summarized by treatment group. 
Clinical laboratory tests, vital signs, and ECG findings will be summarized by indication, 
treatment group, and visit. Potentially clinically important findings will also be summarized or 
listed. 
Further details of safety analyses will be described in the SAP. 
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10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate. 
10.1 
Sponsor’s Responsibilities 
10.1.1 
Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) 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. 
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10.1.2 
Indemnity/Liability and Insurance 
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines. 
The sponsor ensures that suitable clinical study insurance coverage is in place before the start of 
the study. An insurance certificate is supplied to the CRO and investigator as necessary. 
10.1.3 
Public Posting of Study Information 
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information. 
10.1.4 
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees 
The sponsor will upload the clinical study report to the EudraCT database and will also provide a 
summary of the clinical study report 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 representative will make an end-of-study declaration to the relevant 
competent authority as required by Article 10 (c) of Directive 2001/20/EC. 
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10.2 
Investigator’s Responsibilities 
10.2.1 
Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements 
and guidelines. 
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site before commitment to participate in this study. The investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators 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, 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 co-investigators 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 
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the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations. 
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement. 
10.2.3 
Documentation and Retention of Records 
10.2.3.1 
Case Report Forms 
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded in eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. The eCRFs must be completed 
by the investigator or designee as stated in the site delegation log. 
All data in the eCRF will have a separate source (eg, paper or electronic patient-reported 
outcome); 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: 
subject’s medical file, subject 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. 
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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. 
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 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). 
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10.3 
Ethical Considerations 
10.3.1 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to 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 
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 prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to 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. 
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Before implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. 
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents. 
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs. 
10.4 
Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor or designee. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market ontamalimab; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
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). 
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The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities. 
10.5 
Study Results/Publication Policy 
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(eg, Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2-4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a noncommercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy. 
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish before release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications. 
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form. 
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days before 
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submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application. 
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented. 
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications. 
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11. REFERENCES 
Best, W. R., Becktel, J. M. and Singleton, J. W. 1979. Rederived values of the eight coefficients 
of the Crohn's Disease Activity Index (CDAI). Gastroenterology, 77, 843-6. 
Best, W. R., Becktel, J. M., Singleton, J. W. and Kern, F. 1976. Development of a Crohn's 
disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology, 
70, 439-44. 
Briskin, M., Winsor-Hines, D., Shyjan, A., Cochran, N., Bloom, S., Wilson, J., McEvoy, L. M., 
Butcher, E. C., Kassam, N., Mackay, C. R., Newman, W. and Ringler, D. J. 1997. Human 
mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract 
and associated lymphoid tissue. Am J Pathol, 151, 97-110. 
Chalasani, N. and Regev, A. 2016. Drug-Induced Liver Injury in Patients With Preexisting 
Chronic Liver Disease in Drug Development: How to Identify and Manage? 
Gastroenterology, 151, 1046-1051. 
Dignass, A., Eliakim, R., Magro, F., Maaser, C., Chowers, Y., Geboes, K., Mantzaris, G., 
Reinisch, W., Colombel, J.-F., Vermeire, S., Travis, S. and Lindsay, J. 2012. Second 
European evidence-based consensus on the diagnosis and management of ulcerative 
colitis Part 1: Definitions and diagnosis. Journal of Crohn’s and Colitis, 6, 965-990. 
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. 
Isabwe, G. A. C., Garcia Neuer, M., de Las Vecillas Sanchez, L., Lynch, D. M., Marquis, K., and 
Castells, M. 2018. Hypersensitivity reactions to therapeutic monoclonal antibodies: 
Phenotypes and endotypes. J Allergy Clin Immunol, 142, 159-170 e2. 
Khanna, S., Shin, A. and Kelly, C. 2017. Management of Clostridium difficile Infection in 
Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates 
Committee of the AGA Institute. Clin Gastroenterol Hepatol, 15, 166-74. 
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. 
Loftus, E. V., Jr., Colombel, J. F., Feagan, B. G., Vermeire, S., Sandborn, W. J., Sands, B. E., 
Danese, S., D'Haens, G. R., Kaser, A., Panaccione, R., Rubin, D. T., Shafran, I., 
McAuliffe, M., Kaviya, A., Sankoh, S., Mody, R., Abhyankar, B. and Smyth, M. 2017. 
Long-term Efficacy of Vedolizumab for Ulcerative Colitis. J Crohns Colitis, 11, 
400-411. 
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. 
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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. 
Pullen, N., Molloy, E., Carter, D., Syntin, P., Clemo, F., Finco-Kent, D., Reagan, W., Zhao, S., 
Kawabata, T. and Sreckovic, S. 2009. Pharmacological characterization of PF-00547659, 
an anti-human MAdCAM monoclonal antibody. Br J Pharmacol, 157, 281-93. 
Reinisch, W., Colombel, J.-F., D’Haens, G., Sandborn, W. J., Rutgeerts, P., Geboes, K., 
Petersson, J., Eichner, S., Zhou, Q., Robinson, A. M., Read, H. A. and Thakkar, R. 2017. 
Characterisation of Mucosal Healing with Adalimumab Treatment in Patients with 
Moderately to Severely Active Crohn’s Disease: Results from the EXTEND Trial. 
Journal of Crohn’s and Colitis, 11, 425-434. 
Sampson, H. A., Munoz-Furlong, A., Campbell, R. L., Adkinson, N. F., Jr., Bock, S. A., 
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. 
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., Loftus, E. V., Colombel, J.-F., Feagan, B. G., Sandborn, W. J., Sands, B. E., 
Danese, S., D'Haens, G. R., Kaser, A., Panaccione, R., Rubin, D. T., Shafran, I., 
McAuliffe, M., Kaviya, A., Sankoh, S., Mody, R., Abhyankar, B. and Smyth, M. 2017. 
Long-term Efficacy of Vedolizumab for Crohn's Disease. Journal of Crohn’s and Colitis, 
11, 412-424. 
Warrington, R., Silviu-Dan, F. and Wong, T. 2018. Drug allergy. Allergy, Asthma & Clinical 
Immunology, 14, 1-11. 
 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
07 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) 
Updated total sample size 
projected for the enrollment in the 
study. 
To reflect changes in sample size in 
the SHP647-301, SHP647-302, and 
SHP647-303 studies and revised 
projections for the number of subjects 
who may rollover from those studies, 
and to reflect targeted sample size for 
direct-entry UC subjects who may 
enter directly based on the completed 
A7281010 study and assessment of the 
literature. 
Study Synopsis, Rationale 
Section 2.1, Rationale for the Study 
Added language to describe 
UC subjects who would be 
entering directly. 
To specify inclusion of UC subjects 
who had not previously participated in 
an induction (SHP647-301 or 
SHP647-302) or maintenance 
(SHP647-303) study. 
Study Synopsis, Methodology 
Section 3.1, Study Design and 
Flowchart 
Section 6.2.2, Allocation of Subjects 
to Treatment 
Revised language to reflect 
inclusion of direct-entry 
UC subjects. 
Updated Figure 1, Study Design 
Flow Chart to include direct-entry 
UC subjects. 
To reflect inclusion of UC subjects 
entering directly. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
07 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Methodology 
Section 3.1, Study Design and 
Flowchart 
Table 1, Schedule of Assessments – 
Treatment Year 1 (UC Subjects, 
Entering from Study SHP647-301, 
SHP647-302, or SHP647-303), 
footnote “m” 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through End of 
Study (UC Subjects, Entering from 
Study SHP647-301, SHP647-302, or 
SHP647-303), footnote “k” 
Table 3, Schedule of Assessments – 
Treatment Year 1 (CD Subjects, 
Entering from Study SHP647-305, 
Study SHP647-306, or Study 
SHP647-307), footnote “l” 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through End of 
Study (CD Subjects, Entering from 
Study SHP647-305, Study SHP647 
306, or Study SHP647 307), 
footnote “j” 
Updated language to clarify that 
the e-diary will be available daily 
throughout the study. 
To provide additional clarity around 
the collection of e-diary data. 
Study Synopsis, Methodology 
Section 3.1, Study Design and 
Flowchart 
Section 4.4.2.1, Treatment Failure 
Assessment and Stopping Criteria 
Added treatment failure language 
for direct-entry UC subjects. 
To reflect inclusion of UC subjects 
entering directly. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.1.2, Exclusion Criteria 
Section 4.2.2, Exclusion Criteria 
Added the term ‘highly effective 
methods for female and medically 
appropriate methods for male study 
subjects’ in the parentheses after 
the term ‘appropriate contraception 
methods’. 
For UC and CD subjects entering 
from an induction or maintenance 
study, added to exclusion criterion 
number 4 that females who are 
lactating also are excluded. 
To clarify what is meant by 
appropriate contraception methods. 
 
 
 
To clarify that females who are 
lactating are excluded. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
07 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.2, Eligibility Criteria – 
Direct-entry Subjects with 
Ulcerative Colitis 
Added inclusion and exclusion 
criteria for UC subjects entering 
directly. 
To reflect inclusion of UC subjects 
entering directly. 
Study Synopsis, Endpoints and 
statistical analysis 
Section 9.4, Statistical Analysis 
Process 
Section 9.8.1, Efficacy Analyses – 
Subjects with Ulcerative Colitis 
Updated efficacy endpoints to 
reflect inclusion of direct-entry 
UC subjects. 
To reflect inclusion of direct-entry 
UC subjects. 
Study Synopsis, Analysis Sets 
Section 9.7, Study Population 
Updated PD analysis set definition 
to include the word ‘evaluable’ in 
the definition: ‘The 
pharmacodynamics (PD) analysis 
set will consist of all subjects who 
receive at least 1 dose of 
investigational product in study 
SHP647-304 and have at least 
1 evaluable postdose PD value.’  
To clarify that PD values must be 
evaluable, and for consistency with the 
PK analysis set. 
Study Synopsis, Safety Endpoints 
Section 9.9, Safety Analyses 
Updated safety endpoints to reflect 
inclusion of direct-entry 
UC subjects. 
Added that adverse events of 
special interest will be summarized 
by treatment group. 
To reflect inclusion of direct-entry 
UC subjects. 
To include analysis of adverse events 
of special interest. 
Table 1, Schedule of Assessments – 
Treatment Year 1 (UC Subjects, 
Entering from Study SHP647-301, 
SHP647-302, or SHP647-303) 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through End of 
Study (UC Subjects, Entering from 
Study SHP647-301, SHP647-302, or 
SHP647-303) 
Table 3, Schedule of Assessments – 
Treatment Year 1 (CD Subjects, 
Entering from Study SHP647-305, 
SHP647-306, or SHP647-307) 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through End of 
Study (CD Subjects, Entering from 
Study SHP647-305, SHP647-306, or 
SHP647-307) 
Added visit numbers to the 
Schedules of Assessments. 
For clarity regarding visit numbers. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
07 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Table 1, Schedule of Assessments – 
Treatment Year 1 (UC Subjects, 
Entering from Study SHP647-301, 
SHP647-302, or SHP647-303), 
footnote “j” 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through End of 
Study (UC Subjects, Entering from 
Study SHP647-301, SHP647-302, or 
SHP647-303), footnote “g” 
Section 7.2.2.1, Endoscopy 
Section 7.2.4.12, Colonoscopy in 
Subjects at Elevated Risk of 
Colorectal Cancer 
Added language to specify subjects 
at risk for colorectal cancer must 
undergo annual colonoscopy with 
appropriate surveillance 
procedures followed. 
To specify surveillance of subjects at 
elevated risk of colorectal cancer. 
Table 1, Schedule of Assessments – 
Treatment Year 1 (UC Subjects, 
Entering from Study SHP647-301, 
SHP647-302, or SHP647-303), 
footnote “q” 
Table 2, Schedule of Assessments – 
Treatment Year 2 Through End of 
Study (UC Subjects, Entering from 
Study SHP647-301, SHP647-302, or 
SHP647-303), footnote “n” 
Table 3, Schedule of Assessments – 
Treatment Year 1 (CD Subjects, 
Entering from Study SHP647-305, 
SHP647-306, or SHP647-307), 
footnote “p” 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through End of 
Study (CD Subjects, Entering from 
Study SHP647-305, SHP647-306, or 
SHP647-307), footnote “m” 
Section 7.2.4.10, Monitoring for 
Hypersensitivity 
Added new row in Tables 1, 2, 5, 
and 6, new subsection to 
Section 7.2.5, and language to 
describe 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. 
Table 3, Schedule of Assessments – 
Treatment Year 1 (UC Subjects, 
Direct Entry) 
Table 4, Schedule of Assessments – 
Treatment Year 2 Through End of 
Study (UC Subjects, Direct Entry) 
Added new Schedules of 
Assessments tables for 
UC subjects entering directly. 
To provide detailed procedures for 
UC subjects entering the study 
directly. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
07 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 4.3, Reproductive Potential 
Updated text to reflect results of an 
enhanced pre- and postnatal 
development (ePPND) toxicity 
study in nonhuman primates. 
Added language to describe 
UC subjects who would be 
entering directly. 
 
 
 
 
 
 
 
 
Added the term ‘highly effective 
methods for female and medically 
appropriate methods for male study 
subjects’ in parentheses after the 
terms ‘appropriate form of 
contraception’ and ‘appropriate 
method of contraception’. 
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. 
Added to reflect inclusion of UC 
subjects who had not previously 
participated in an induction 
(SHP647-301 or SHP647-302) or 
maintenance (SHP647-303) study. 
To clarify what is meant by 
appropriate contraception methods. 
Section 4.3.1, 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 4.4.2, Subject Withdrawal 
Criteria 
The term ‘major protocol 
deviations’ has been changed to 
‘protocol deviations’. 
For consistency with Section 4.4.3 
(Reasons for Withdrawal). 
Section 5.1.2.1, Permitted Treatment 
Added the statement “any 
permitted treatment may be 
initiated or discontinued as 
clinically appropriate.” 
To clarify that during the study any 
permitted treatment may be initiated or 
discontinued as clinically appropriate. 
Table 5, Glucocorticoid Tapering – 
Subjects with Ulcerative Colitis 
Table 6, Glucocorticoid Tapering – 
Subjects with Crohn’s Disease 
Changed to column heading from 
‘Second Taper’ to ‘Subsequent 
Taper’. 
To clarify that, as this is long-term 
study, there may be more than two 
tapers of glucocorticoid dosing. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
07 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 5.2, Prior and Concomitant 
Treatment – Direct-entry Subjects 
with Ulcerative Colitis 
Added new subsection to describe 
prior and concomitant treatment 
for UC subjects entering directly. 
To reflect inclusion of UC subjects 
entering directly. 
Section 7.1.2, Direct-entry Subjects 
with Ulcerative Colitis 
Added new subsection to describe 
study schedule for UC subjects 
entering directly. 
To reflect inclusion of UC subjects 
entering directly. 
Section 7.2.1, Demographic and 
Other Baseline Characteristics 
Appendix 2, Scales and 
Assessments 
Added text to describe assessment 
of demographics/baseline 
characteristics for UC subjects 
entering directly. 
Added stool frequency screening 
questions to Appendix 2. 
To reflect inclusion of UC subjects 
entering directly. 
Section 7.2.3, Efficacy Assessments 
– Direct-entry Subjects with 
Ulcerative Colitis 
Added new subsection to describe 
efficacy assessments for 
UC subjects entering directly. 
To reflect inclusion of UC subjects 
entering directly. 
Section 7.2.4, Safety 
Section 7.2.5, Others 
Updated the text in the subsections 
to describe inclusion of 
UC subjects entering directly. 
To reflect inclusion of UC subjects 
entering directly. 
Table 7, Quarterly Neurological 
Assessments 
Column heading changed from 
‘targeted neurological history’ to 
‘interim neurologic history and 
targeted neurologic examination’. 
To align with language of newly 
proposed electronic case report form. 
Section 7.2.4.6, Clinical Laboratory 
Evaluations 
Section 7.2.4.11, Evaluation of 
Increased Gastrointestinal 
Symptoms 
Added text to describe evaluation 
of increased gastrointestinal 
symptoms. 
To clarify that infectious etiology must 
be evaluated when a subject 
experiences an increase in 
gastrointestinal symptoms. 
Section 7.2.5.7, Additional Clinical 
Laboratory Assessments – 
Direct-entry Subjects with 
Ulcerative Colitis 
Added new subsection to describe 
additional clinical laboratory 
assessments as part of screening, 
for UC subjects entering directly. 
To reflect inclusion of UC subjects 
entering directly. 
Section 7.2.5.10, Chest X-ray 
(Direct-entry Subjects with 
Ulcerative Colitis Only) 
Added new subsection to describe 
screening chest x-ray to be 
performed for UC subjects entering 
directly. 
To reflect inclusion of UC subjects 
entering directly. 
Section 7.2.5.12, Anti-vedolizumab 
Antibodies (Only for Direct-entry 
UC Subjects with Ulcerative Colitis 
Previously Treated with 
Vedolizumab) 
Added new subsection to describe 
collection of a blood sample for 
measurement of anti-vedolizumab 
antibodies, for UC subjects 
entering directly who had received 
prior vedolizumab treatment. 
To reflect inclusion of a baseline 
anti-vedolizumab antibody 
measurement for UC subjects entering 
directly who had received prior 
vedolizumab treatment. 
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Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
07 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 7.2.6, Volume of Blood to 
Be Drawn from Each Subject – UC 
and CD Subjects 
Decreased serum chemistry sample 
volume from 6 mL to 4 mL. 
To correct the sample volume needed 
for the serum chemistry test. 
Section 7.2.6, Volume of Blood to 
Be Drawn from Each Subject – UC 
and CD Subjects 
Increased pharmacokinetic sample 
volume from 3 mL to 5 mL. 
To correct the sample volume needed 
for the pharmacokinetic assessment. 
Section 7.2.8, Volume of Blood to 
Be Drawn from Each Subject – UC 
Subjects Entering Directly 
Added new subsection to provide 
blood volumes for UC subjects 
entering directly. 
To reflect inclusion of UC subjects 
entering directly. 
Section 8.1, Definition of Adverse 
Events, Period of Observation, 
Recording of Adverse Events 
Table 11, Safety Monitoring Rules 
for Treatment-emergent Elevated 
ALT and/or Bilirubin 
Updated the text to describe 
inclusion of UC subjects entering 
directly. 
To reflect inclusion of UC subjects 
entering directly. 
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 an 
external hypersensitivity 
adjudication committee will be 
established to review data from 
subjects who experience a 
suspected Type I or Type III 
hypersensitivity reaction. 
To address FDA recommendation to 
evaluate the risk of hypersensitivity 
reactions in the Phase 3 studies and aid 
in the collection of relevant safety 
data. 
Section 9.6, Sample Size 
Calculation and Power 
Considerations 
Updated sample size projections 
for UC subjects entering from an 
induction or maintenance study. 
Added targeted sample size for 
UC subjects entering directly. 
To reflect changes in sample size in 
the SHP647-301, SHP647-302, and 
SHP647-303 studies and revised 
projections for the number of subjects 
who may rollover from those studies, 
and to provide targeted sample size for 
direct-entry UC subjects who may 
enter directly based on the completed 
A7281010 study and assessment of the 
literature. 
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Page 148 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
07 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 9.8.1.2, Exploratory 
Efficacy Endpoints 
For the endpoint “Change from 
induction study (SHP647-301 or 
SHP647-302) baseline, or 
Study SHP647-304 baseline for 
direct-entry subjects, in abdominal 
pain, diarrhea and urgency item 
scores, absolute stool frequency, 
absolute rectal bleeding, and total 
sign/symptom score based on 
subject daily e-diary entries (sum 
of rectal bleeding, stool frequency, 
abdominal pain, diarrhea, and 
urgency) over time”, revised the 
final part of the text in parentheses 
to read “(average of rectal 
bleeding, stool frequency, 
abdominal pain, diarrhea, and 
urgency)”. 
To correctly describe the scoring of 
patient-reported UC sign and symptom 
data. 
Section 9.8.2.2, Exploratory 
Efficacy Endpoints 
For the endpoint “Change from 
induction study (SHP647-305 or 
SHP647-306) baseline in 
abdominal pain, very soft 
stool/liquid stool frequency (as 
shown by type 6/7 on BSFS), total 
stool frequency, rectal urgency, 
rectal bleeding, nausea, vomiting, 
and incontinence, and total 
sign/symptom score based on 
subject daily e-diary entries 
(average of rectal bleeding, stool 
frequency, abdominal pain, very 
soft stool/liquid stool, and rectal 
urgency) over time”, revised the 
final part of the text in parentheses 
to read “(average of rectal 
bleeding, stool frequency, 
abdominal pain, very soft 
stool/liquid stool, and rectal 
urgency)”. 
For the endpoint, “Subject TSQM 
total scores and 4 domain scores 
over time”, deleted reference to 
“total scores”. 
To correctly describe the scoring of 
patient-reported CD sign and symptom 
data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
To correctly describe scoring for the 
Treatment Satisfaction Questionnaire 
for Medication (TSQM). 
Section 9.10.1, Pharmacodynamic 
Analyses 
Added that biomarker endpoints 
will be summarized by indication 
along with treatment group and 
visit. 
Added for clarity. 
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Page 149 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3 
Amendment Date 
07 Nov 2019 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 10.1.5, Study Suspension, 
Termination, and Completion 
To clarify that the end-of-study 
declaration may be made by the 
sponsor or alternatively its 
representatives. 
Added for clarity. 
Appendix 1, Protocol History 
Added Summary of Changes for 
Amendment 2 relative to 
Amendment 1, and for 
Amendment 1 relative to original 
protocol. 
For completeness, such that the 
Protocol History section includes the 
summary of changes made with all 
prior global amendments to this 
protocol. 
Appendix 5, Determination of 
Failure or Intolerance to Prior 
Treatment for Ulcerative Colitis 
Added new appendix section, 
“Determination of failure or 
intolerance to prior treatment for 
ulcerative colitis” to provide 
guidance as related to inclusion 
criterion #5 in which subjects 
meeting these criteria on prior 
conventional treatments 
(eg, sulfasalazine, mesalamine, 
glucocorticoids, 
immunosuppressants, or anti-TNF) 
may be eligible for this study. 
To provide granularity regarding the 
eligibility of direct-entry UC subjects 
who demonstrated inadequate 
response, loss of response, or 
intolerance on conventional treatment. 
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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Page 150 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
14 Sep 2018 
Global/Region/Country/Site Specific 
Global 
Protocol Amendment Summary and Rationale: 
The main purpose of SHP647-304 Amendment 2 is to further clarify the rationale for the study design with regard to 
subjects who would enter following participation in one of the maintenance studies (SHP647-303 or SHP647-307) 
and have been classified as nonresponsive to treatment and met the protocol-specified definition of treatment failure. 
This amendment clarifies how subjects will be monitored for safety and clinical benefit, and for assessment of 
potential treatment failure and criteria for withdrawal of treatment in this long-term extension study. The 
amendment also describes the potential benefit for subjects, including for those who previously had been classified 
as nonresponsive to active treatment. Additionally, this amendment elevates efficacy endpoints based on clinical 
remission and endoscopic outcomes from “exploratory” to “secondary” to emphasize that assessment of efficacy and 
monitoring of clinical benefit is an important aspect of the study. The significant changes in SHP647-304 Protocol 
Amendment 2 relative to the previous edition, SHP647-304 Protocol Amendment 1, are captured below. 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
14 Sep 2018 
Global/Region/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 fax number for serious 
adverse event reporting. 
To provide updated and correct 
information. 
Study Synopsis, Methodology  
Section 3.1, Study design and 
flowchart 
Added language to clarify that 
efficacy data will be collected to 
monitor clinical benefit, and to 
provide information on treatment 
failure assessment as also outlined 
in Section 4.1.1, Treatment Failure 
Assessment and Stopping Criteria. 
To emphasize and further describe that 
subjects will be monitored for clinical 
benefit and for assessment of potential 
treatment failure. 
Study Synopsis, Methodology 
Study Synopsis, Maximum duration 
of subject involvement in the study 
Section 3.1, Study Design and 
Flowchart 
Section 3.2, Duration and Study 
Completion Definition 
Added text to clarify that a 
subject’s maximum duration of 
treatment is expected to be 7 years, 
subject to local or country 
requirements, and removed the 
phrase “or until SHP647 becomes 
available commercially, whichever 
occurs earlier.” 
To provide clarity regarding the 
maximum duration of study 
participation. 
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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
14 Sep 2018 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Study Synopsis, Exclusion Criteria – 
Subjects with CD 
Section 4.2.2, Exclusion Criteria 
(Subjects with Crohn’s Disease) 
Revised exclusion criterion #3 (for 
subjects with CD) to add that 
subjects who developed acute 
severe complications of CD that 
required immediate intervention 
and/or CDAI score >450 are 
excluded. 
To further define the criterion related 
to disease severity for subjects with 
CD. 
Study Synopsis, Inclusion and 
exclusion criteria 
Section 4.1.2, Exclusion Criteria 
(Subjects with Ulcerative Colitis) 
Section 4.2.2, Exclusion Criteria 
(Subjects with Crohn’s Disease) 
Updated exclusion criterion #5 (for 
subjects with UC and subjects with 
CD) to indicate the exclusion of 
subjects who do not agree to 
postpone donation of any organ or 
tissue, including male subjects are 
planning to bank or donate sperm 
and female subjects who are 
planning to harvest or donate eggs, 
for the duration of the study and 
for 16 weeks after last dose of 
investigational product. 
To specify the exclusion of subjects 
who do not agree to postpone donation 
of any organ or tissue, including sperm 
banking or donation for male subjects 
and egg donation or harvest for female 
subjects, are excluded. 
Study Synopsis, Objectives 
Section 2.2.2, Secondary Objectives 
– Subjects with Ulcerative Colitis 
Section 2.2.3, Secondary Objectives 
– Subjects with Crohn’s Disease 
Moved efficacy objectives related 
to clinical remission and 
endoscopic outcomes, from 
“exploratory” to “secondary.” 
To emphasize that this study will 
evaluate efficacy as well as safety. 
Study Synopsis, Endpoints and 
statistical analyses 
Section 9.8.1, Efficacy Analyses – 
Subjects with Ulcerative Colitis 
Section 9.8.2, Efficacy Analyses – 
Subjects with Crohn’s Disease 
Moved efficacy endpoints based on 
clinical remission and endoscopic 
outcomes, from “exploratory” to 
“secondary.” 
To emphasize that this study will 
evaluate efficacy as well as safety. 
Schedule of Assessments 
Table 8 Volume of Blood to Be 
Drawn from Each Subject – 
Treatment Year 1 
Added PK and ADA sample 
collection at 2 additional time 
points, Week 4 and Week 12. 
To obtain additional PK and ADA 
measurements earlier in the study to 
identify immunogenicity status, 
particularly for those subjects entering 
the study who are naïve to active 
treatment or who would be restarting 
active treatment after receiving 
placebo in the maintenance study. 
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Page 152 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
14 Sep 2018 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 1.3, Benefit/Risk 
Assessment 
Added new section describing 
benefit and risk of SHP647 
treatment. 
To provide a summary of benefit and 
risk information for SHP647. 
Section 2.1, Rationale for the Study 
Added language to clarify the 
rationale for the study design, ie to 
offer access to active treatment to 
subjects who may have benefited 
from treatment at the end of a 
maintenance study, to subjects who 
had received placebo or an 
insufficient duration of active 
treatment in an induction study, or 
who may have met treatment 
failure criteria in a maintenance 
study. 
Added text to emphasize that 
efficacy data will be collected 
regularly for all subjects, to allow 
for monitoring of clinical benefit 
and evaluation of potential 
treatment failure. 
Added a statement (from 
Section 6.1.1, Blinding the 
Treatment Assignment) to explain 
the reason for the double-blind 
study design. 
Added text (from Section 6.2.2, 
Allocation of Subjects to 
Treatment) to describe the 
treatment allocation for entering 
subjects. 
Added reference citation (Pullen et 
al, 2009) to the first paragraph 
where the SHP647 molecule is 
described. 
To improve clarity of the study 
rationale. 
Section 4.4.1, Subject Withdrawal 
Criteria 
Added pregnancy as a reason that a 
subject may be withdrawn from 
study treatment. 
Removed initiation of a new 
therapy for UC or CD as a reason 
that a subject should be withdrawn 
from study treatment. 
For clarity and consistency with 
language in Section 8.1.6. 
To reflect that a new therapy may be 
permitted as described in Section 5.2.1 
and Section 5.3.1. 
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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
14 Sep 2018 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
Section 4.4.1.1, Treatment Failure 
Assessment and Stopping Criteria 
Added language that subjects will 
be assessed regularly for efficacy 
to monitor clinical benefit and for 
evaluation of potential treatment 
failure. 
To improve clarity regarding 
assessment of potential treatment 
failure and criteria for withdrawal 
from study treatment. 
Section 5.2, Concomitant Treatment 
– Subjects with Ulcerative Colitis 
Section 5.3, Concomitant Treatment 
– Subjects with Crohn’s Disease 
Added a statement that additional 
safety assessments may be 
necessary for concomitant 
treatments, in accordance with the 
safety recommendations for the 
treatments. This change was made 
with SHP647-304 Protocol 
Administrative Change Memo #3, 
dated 22 Mar 2018. 
To provide correct 
information/guidance. 
Section 5.2.1, Permitted Treatment 
(Subjects with Ulcerative Colitis) 
Revised language to clarify 
tapering of glucocorticoids. 
Removed requirement for a stable 
dose of medicinal marijuana to be 
maintained during the study. 
Added that dietary and herbal 
supplements and probiotics should 
be recorded as concomitant 
medications. 
To provide correct information and for 
consistency of language provided for 
UC and CD. 
Section 5.2.2, Prohibited Treatment 
(Subjects with Ulcerative Colitis) 
Section 5.3.2, Prohibited Treatment 
(Subjects with Crohn’s Disease) 
Revised language to clarify 
tapering of glucocorticoids. 
Added text to clarify the 
prohibition of anti-TNF treatment 
or other biologics including 
biosimilars or nonbiologic agents 
with immunomodulatory 
properties, except for azathioprine 
[AZA], 6-mercaptopurine [6-MP], 
and methotrexate, which are 
permitted. 
Added text to clarify the 
prohibition of leukocyte apheresis 
or selective lymphocyte, 
monocyte, or granulocyte apheresis 
or plasma exchange. 
Added text to specify that subjects 
who enter the 16-week safety 
follow-up period will no longer 
need to abstain from the 
medications that were prohibited 
during the treatment period and 
To provide correct information, and 
for consistency of language for the UC 
and CD indications and alignment 
with the induction and maintenance 
study protocols. 
To clarify that once subjects enter the 
16-week safety follow-up period, 
medications that were prohibited 
during the treatment period, including 
other treatments for UC or CD, will be 
allowed. 
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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
14 Sep 2018 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
that other treatments for UC or CD 
will be allowed. Biologics or 
nonbiologic immunosuppressants 
should not be initiated without 
prior discussion with the sponsor 
study physician or designee due to 
the long half-life of SHP647. 
Section 5.3.1, Permitted Treatment 
(Subjects with Crohn’s Disease) 
Revised language to clarify 
tapering of glucocorticoids. 
Removed requirement for 
antidiarrheal opiate drugs, 
medicinal marijuana, and dietary 
and herbal supplements to be at a 
stable dose at study entry and 
maintained at a stable dose during 
the study. 
Removed parenteral or rectal 
glucocorticoids from the list of 
prohibited medications. 
To provide correct information and for 
alignment of permitted medications 
across UC and CD, where applicable. 
Section 7.2, Study Procedures 
Added language to specify that the 
duration of blood and tissue 
sample storage is dependent on 
local regulations. 
To clarify that local regulations should 
be considered for duration of blood 
and tissue sample storage. 
Section 7.2.4.6, Clinical Laboratory 
Evaluations 
Added information on laboratory 
testing for C. difficile infection, 
including diagnostic algorithms. 
To provide appropriate guidance 
regarding laboratory testing for 
C. difficile infection. 
Section 7.2.5.2, Pharmacodynamic 
Assessments 
Revised text to clarify the stool 
sample collection and assessment. 
To improve clarity in the description 
of stool sample collection and 
assessment. 
Section 8.2.8, Safety Monitoring 
Rules 
Added new section describing 
safety monitoring and stopping 
algorithms for elevated hepatic 
blood tests. 
To provide appropriate guidance on 
patients who have been enrolled with 
elevated liver function test values or 
who experience and increase in liver 
function test(s) during the study. 
Section 9.9, Safety Analyses 
Added text to clarify that the 
primary endpoint is assessment of 
safety. 
To improve clarity and for alignment 
with language in the study synopsis. 
Section 10, Sponsor’s and 
Investigator’s Responsibilities 
Added a statement that compliance 
with the noted regulations and 
guidelines also constitutes 
compliance with the ethical 
principles described in the 
Declaration of Helsinki. 
To clarify that the study is conducted 
in accordance with the ethical 
principles in the Declaration of 
Helsinki. 
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Page 155 
Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
2 
Amendment Date 
14 Sep 2018 
Global/Region/Country/Site Specific 
Global 
Section(s) Affected by Change 
Description of Change 
Rationale 
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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21 Sep 2020 
 
APPENDIX 2 
SCALES AND ASSESSMENTS 
The following scales/assessments will be used in the study after the implementation of 
Amendment 4 and are provided in this appendix. 
For subjects with UC: 
• Mayo scoring system 
For subjects with CD: 
• Simple Endoscopic Score for Crohn’s Disease (SES-CD) 
• Crohn’s Disease Activity Index (CDAI) 
For all subjects: 
• Memory aid 
 
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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. 
Source: Schroeder et al., 1987 
a 
Each subject serves as his or her own control to establish the degree of abnormality of the stool frequency. 
b 
The daily bleeding score represents the most severe bleeding of the day. 
c 
Findings on endoscopy scoring represents the modified endoscopy subscore (value of 1 does not include 
friability). 
Note: Data will be collected to calculate the total Mayo score using both the modified endoscopy subscore and 
traditional endoscopy subscore (value of 1 including mild friability) as a sensitivity analysis and to estimate the 
impact of the modification on the endoscopic subscore. 
d 
The physician’s global assessment acknowledges the three other criteria, the subject’s daily recollection of 
abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and the 
subject’s performance status. 
 
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Crohn’s Disease Activity Index (CDAI) 
Crohn’s Disease Activity Index (CDAI)
CDAI 
Score
X 1
Body weight (1-weight/standard weight) X 100                                   
(add or subtract according to sign)
8
X 6
Hematocrit [Males: 47-Hct (%), Females: 42-Hct (%)]
7
X 10
Abdominal mass (0 = no, 2 = questionable, 5 = definite)
6
X 30
Use of diphenoxylate or loperamide for diarrhea (0 = no, 1 = yes)
5
X 20
Number of listed complications [arthritis or arthralgia, iritis or uveitis, 
erythema nodosum or pyoderma gangrenosum or aphthous
stomatitis, anal fissure or  fistula or abscess, other fistula, fever     
over 37.8oC (100oF)]
4
X 7
General well-being (0 = generally well, 1 = slightly under par,             
2 = poor, 3 = very poor, 4 = terrible)
3
X 5
Abdominal pain (0 = none, 1 = mild, 2 = moderate, 3 = severe)
2
X 2
No. of liquid or soft stools (each day for 7 days)
1
Total
Multiplier
Variable Description
Variable 
No.
 
CDAI=Crohn’s Disease Activity Index; ePRO=electronic patient-reported outcome; Hct=hematocrit. 
Note: Variable 5: covers taking medication for symptomatic relief from diarrhoea, eg bulking agents, opiate, etc. 
Variable 7: Absolute deviation of hematocrit is the difference in hematocrit from standard. A male subject with a hematocrit of 
40% has an absolute deviation of 7. Each percentage deviation has a value of 6 points. If hematocrit subtotal is <0, enter 0;  
Variable 8: is based on Metropolitan Life Tables (these are programmed into the ePRO device. 
 
Percent deviation from standard weight is (1 - weight/standard weight) × 100; therefore, positive percent deviation represents 
weight loss, which adds points to the CDAI. Percentage deviation from standard weight = 1 point for each percent deviation. If 
body weight subtotal is less than minus 10, enter -10. 
CDAI Interpretation: 
• 
0-149 points: Asymptomatic remission (Note: subjects requiring steroids to remain asymptomatic are not 
considered to be in remission but are referred to as being “steroid dependent”). 
• 
150-220 points: Mild to moderate active CD. 
• 
221-450 points: Moderate to severe active CD. 
• 
>451 points: Severely active to fulminant disease. 
CDAI online estimator: http://www.ibdjohn.com/cdai/ 
Sources: Best et al., 1976; Best et al., 1979. 
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Memory Aid 
Subject Reference Guide on “Memory Aid” Collection and Use 
As you have noted in your consent, instead of a daily electronic diary, you may use a memory 
aid at each visit to track your clinical signs and symptoms for discussion with your study staff to 
assess your treatment response. 
The memory aid can be in any form suitable to you and will not be collected by the study staff. 
This will assist you to verbally discuss the information about your daily disease activity for the 
week prior to your scheduled visit with your study staff. They will record it into your medical 
records/charts. 
These written instructions will guide you on the needed information to be provided to your study 
doctor. For subjects with ulcerative colitis, the information recorded will consist of daily stool 
count and rectal bleeding as characterized by the Mayo subscore. For subjects with Crohn’s 
disease, the information recorded will consist of the number of soft or loose stools, the level of 
abdominal pain, and sense of general well-being to calculate the CDAI (Crohn’s Disease 
Activity Index) score. 
 
“Memory Aid” Guidelines for Subjects with Ulcerative Colitis 
Every day for the week (7 days) before each visit, you may use the memory aid to help you 
record the number of bowel movements you had that day and the WORST degree of blood you 
observed in your stool. 
For the number of bowel movements: Every time you go to the toilet and pass liquid or solid 
material (blood, diarrhea, stool) will count as a bowel movement. You can write down the 
number of bowel movements you had that day. The day begins at 1 minute after midnight 
(12:01 AM) and ends at midnight (12:00 AM). 
For blood in the stool: At the end of the day, think about the most blood you saw in any bowel 
movement and write down the number from the table below: 
Observation 
Number to Record 
No blood seen 
0 
Streaks of blood with stool less than half of the time 
1 
Obvious blood (more than just streaks) or streaks of blood with stool most of 
the time 
2 
Blood alone passes 
3 
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You may have a separate entry each day for both number of stool and blood in stool; reporting in 
this manner helps you track your symptoms to discuss with your study staff at your next visit. 
Example 1 
October 21, 2020 
Number of bowel movements: 
Number you had (for example, 3) 
Blood in stool: 
 
 
If “streaks of blood less than half of the time”, write 1 
 
October 22, 2020 
Number of bowel movements: 
5 
Blood in stool: 
 
 
If “no blood seen”, write 0 
 
Example 2 
Date 
Bowel Movements 
Blood 
October 21, 2020 
3 
1 
October 22, 2020 
5 
0 
 
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21 Sep 2020 
 
Example 1 
October 21, 2020 
Number of very soft/liquid bowel movements: 
Number you had (for example, 3) 
Abdominal pain: 
 
 
 
 
Mild 
General well-being:  
 
 
 
Slightly below par 
 
October 22, 2020 
Number of very soft/liquid bowel movements: 
1 
Abdominal pain: 
 
 
 
 
Mild 
General well-being:  
 
 
 
Generally well 
 
Example 2 
Date 
Very Soft/Liquid 
Bowel Movements 
Abdominal Pain 
General Well-being 
October 21, 2020 
3 
Mild 
Slightly below par 
October 22, 2020 
1 
Mild 
Generally well 
 
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Page 207 
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APPENDIX 3 
GLUCOCORTICOID EQUIVALENT DOSES 
Glucocorticoid 
Equivalent Dose (mg) 
Short Acting: 
 
Cortisone 
25 
Hydrocortisone 
20 
Intermediate Acting: 
 
Methylprednisolone 
4 
Prednisolone 
5 
Prednisone 
5 
Triamcinolone 
4 
Long Acting: 
 
Betamethasone 
0.6 
Dexamethasone 
0.75 
Reference: Lacy et al., 2001-2002. 
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APPENDIX 4 
GUIDANCE FOR DIAGNOSIS AND TREATMENT OF INCREASED 
GASTROINTESTINAL SYMPTOMS 
If, for any reason, the central laboratory is not available, the preferred diagnostic algorithm is to 
use the Alere Quik Chek card test (Figure A1). 
Figure A1: 
Algorithm for C. difficile Diagnosis Using the Quick Check Card Test 
 
If the Alere Quik Chek card test is not available, then a diagnosis may be established by 
following either of the algorithms shown in Figure A2 (using 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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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
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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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Figure A4: 
Alternative 3 for C. difficile Testing Using Local Laboratory When No Alere 
Quick Chek Card Test is Available 
 
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Ontamalimab 
SHP647-304 Protocol Amendment 4 
 
21 Sep 2020 
 
Treatment 
When medically reasonable, treatment decisions should be deferred until an etiology has been 
determined. When this is not feasible, management of symptoms should be dictated by the 
clinical situation. If management requires a prohibited treatment (eg, intravenous 
glucocorticoids for induction or maintenance studies), the subject should be withdrawn 
from treatment. 
If treatment has been deferred, once an etiology is determined (eg, C. difficile, disease 
exacerbation, Campylobacter), appropriate treatment should be promptly implemented without 
waiting for a scheduled visit. If the etiology is determined to be C. difficile, treatment guidelines 
conforming to the current IDSA recommendations for C. difficile infection (McDonald et al., 
2018) or the recent expert review on C. difficile infection in IBD (Khanna et al., 2017) should be 
consulted. 
If C. difficile infection was identified, clinical improvement should be noted within about 5 days 
after the start of treatment. If improvement does not occur, the etiology is most likely an 
IBD flare secondary to C. difficile, and treatment failure assessment should proceed per the 
protocol. Another possible explanation is primary failure of C. difficile therapy, which is 
unlikely. 
If an infectious etiology other than C. difficile is identified, it should be managed as appropriate, 
with reference to current clinical guidelines (Shane et al., 2017). 
If any infectious etiology is determined, the site should contact the medical monitor to make him 
or her aware of the diagnosis and to discuss treatment and ongoing study participation. 
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SAP_001.pdf: 
For non-commercial use only


STATISTICAL ANALYSIS PLAN
SHP647
PHASE 3
A Phase 3 Long-term Safety Extension Study of SHP647 in Subjects with Moderate to 
Severe Ulcerative Colitis or Crohn’s Disease (AIDA)
PROTOCOL IDENTIFIER: SHP647-304
Study Sponsor(s):
Shire Human Genetic Therapies, Inc. (“Shire”), a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited
300 Shire Way, Lexington, MA 02421 US
Author:
, MS
    
, Statistics and Quantitative Sciences
Protocol:
V1 (13JUL2017)
Amendment 1 (18DEC2017)
Amendment 2 (17SEP2018)
Amendment 3 (07NOV2019)
     Amendment 4 (21SEP2020)
SAP Version #:
      2.0
SAP Date:
06 Sep 2022
Status:
Final
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Statistical Analysis Plan v2.0
06 Sep 2022
REVISION HISTORY
Version 
Issue Date
Summary of Changes
1.0
25FEB2021
Final Document
2.0
06Sept2022
Corrected secondary endpoint for response of ulcerative 
colitis participants from “or a sub-score for RB ≥1” to 
“or a sub-score for RB ≤1”. 
Added Section 10.2 of conducting sensitivity analyses 
to assess the impact of the Russian – Ukraine Crisis.
Added method to calculate the exact unconditional 
confidence limits for treatment difference if the number 
of responders or non-responders in either treatment 
group is too small (i.e., ≤5)
Section 7.1.1.1 updated and removed texts related to 
Hypersensitivity Adjudication Committee per Protocol 
Amendment 4.
Edited text in Section 5.2 to be consistent with the 
actual data.
Updated Section 12.2 and added analysis visit window 
for the visits after Week 144.
Edited text in Section 5.7, Section 7, and Section 7.5 to 
be consistent with Protocol Amendment 4. 
Edited text in Section 12.3 to further clarify the efficacy 
endpoint derivation before and after Protocol 
Amendment 4. 
Added Section 6.3 and Section 7.6.4 to clarify the data 
before Protocol Amendment 4 will be listed. 
Added Section 10.3 for possible sensitivity analysis of 
efficacy endpoints if any significant investigator 
noncompliance occurs. 
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TABLE OF CONTENTS
REVISION HISTORY.....................................................................................................................2
TABLE OF CONTENTS.................................................................................................................3
LIST OF TABLES...........................................................................................................................7
LIST OF FIGURES .........................................................................................................................8
ABBREVIATIONS .........................................................................................................................9
1.
INTRODUCTION..................................................................................................................10
2.
OBJECTIVES AND ENDPOINTS........................................................................................11
2.1
Objectives.................................................................................................................11
2.1.1
Primary Objective..................................................................................................11
2.1.2
Secondary Objectives – Subjects with Ulcerative Colitis......................................11
2.1.3
Secondary Objectives – Subjects with Crohn’s Disease........................................11
2.2
Endpoints..................................................................................................................11
2.2.1
Primary Endpoint...................................................................................................11
2.2.2
Secondary Endpoints – Subjects with Ulcerative Colitis ......................................11
2.2.3
Secondary Endpoints – Subjects with Crohn’s Disease ........................................11
3.
STUDY DESIGN ...................................................................................................................12
3.1
General Description..................................................................................................12
3.2
Randomization .........................................................................................................15
3.3
Blinding....................................................................................................................16
3.4
Sample Size and Power Considerations...................................................................17
4.
STATISTICAL ANALYSIS SETS........................................................................................18
4.1
Screened Set .............................................................................................................18
4.2
Randomized Set........................................................................................................18
4.3
Safety Set..................................................................................................................18
4.4
Full Analysis Set ......................................................................................................18
5.
STUDY SUBJECTS...............................................................................................................19
5.1
Disposition of Subjects.............................................................................................19
5.2
Demographic and Other Baseline Characteristics....................................................19
5.3
Smoking History ......................................................................................................23
5.4
Medical History........................................................................................................23
5.5
Prior Medications .....................................................................................................24
5.6
Concomitant Medications ........................................................................................24
5.7
Exposure to Investigational Product ........................................................................25
5.8
Measurements of Treatment Compliance.................................................................25
5.9
Protocol Deviations..................................................................................................25
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6.
TREATMENT RESPONSE ANALYSES .............................................................................26
6.1
Treatment Response Analyses – Subjects with Ulcerative Colitis ..........................26
6.1.1
Secondary Endpoints .............................................................................................26
6.2
Treatment Response Analyses – Subjects with Crohn’s Disease ............................26
6.2.1
Secondary Endpoints .............................................................................................26
6.3
Other Efficacy Data..................................................................................................27
7.
SAFETY ANALYSIS ............................................................................................................28
7.1
Adverse Events.........................................................................................................28
7.1.1
Adverse Events of Special Interest and Other Potential Risks ..............................29
7.1.1.1
Hypersensitivity .....................................................................................29
7.2
Clinical Laboratory Data..........................................................................................29
7.3
Pregnancy Test and Follicle-stimulating Hormone Test..........................................32
7.4
Vital Signs................................................................................................................32
7.5
Electrocardiogram (ECG).........................................................................................33
7.6
Other Safety Data.....................................................................................................34
7.6.1
Targeted Neurological Assessment........................................................................34
7.6.2
Contraception Check..............................................................................................34
7.6.3
Physical Examination.............................................................................................34
7.6.4
Other Safety Data Prior to Protocol Amendment 4 ...............................................34
8.
PHARMACOKINETIC ANALYSIS.....................................................................................35
8.1
Drug Concentration..................................................................................................35
8.2
Handling Below Limit of Quantitation (BLQ) Values.............................................35
8.3
Pharmacokinetic Parameters ....................................................................................35
8.4
Statistical Analysis of Pharmacokinetic Data ..........................................................35
9.
PHARMACODYNAMIC ANALYSIS..................................................................................36
9.1
Pharmacodynamic Data............................................................................................36
10. OTHER ANALYSES .............................................................................................................37
10.1
Coronavirus Pandemic .............................................................................................37
10.2
Russia – Ukraine Crisis............................................................................................37
10.3
Significant Investigator Noncompliance..................................................................38
11. INTERIM ANALYSIS/DATA MONITORING (REVIEW) COMMITTEE........................39
12. DATA HANDLING CONVENTIONS..................................................................................40
12.1
General Data Reporting Conventions ......................................................................40
12.2
Definition of Visit Windows....................................................................................40
12.3
Treatment Response Assessments............................................................................43
12.3.1 Subjects with UC ...................................................................................................43
12.3.1.1
Mayo Score ............................................................................................43
12.3.1.2
UC Subject Reporting of Symptoms......................................................44
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12.3.2 Subjects with CD ...................................................................................................44
12.3.2.1
SES-CD..................................................................................................44
12.3.2.2
CDAI......................................................................................................45
12.3.2.3
CD Subject Reporting of Symptoms......................................................45
12.4
Repeated or Unscheduled Assessments of Safety Parameters.................................46
12.5
Handling of Missing, Unused, and Spurious Data...................................................46
12.5.1 Missing Date of End of Treatment.........................................................................46
12.5.2 Missing Date of CD or UC Diagnoses...................................................................46
12.5.3 Missing Date Information for Prior or Concomitant Medications.........................46
12.5.3.1
Incomplete Start Date.............................................................................46
12.5.3.2
Incomplete Stop Date.............................................................................47
12.5.4 Missing Date Information for Adverse Events......................................................48
12.5.4.1
Incomplete Start Date.............................................................................48
12.5.4.2
Incomplete Stop Date.............................................................................48
12.5.5 Missing Severity Assessment for Adverse Events.................................................48
12.5.6 Missing Relationship to Investigational Product for Adverse Events ...................48
12.5.7 Character Values of Clinical Laboratory Variables...............................................48
13. ANALYSIS SOFTWARE......................................................................................................50
14. CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ..................................................51
15. REFERENCES .......................................................................................................................52
16. APPENDICES ........................................................................................................................53
16.1
Schedule of Assessments – Treatment Year 1 (Subjects with UC) .........................53
16.2
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of 
Study (Subjects with UC).........................................................................................56
16.3
Schedule of Assessments – Treatment Year 1 (Subjects with CD) .........................59
16.4
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of 
Study (Subjects with CD).........................................................................................62
16.5
Schedule of Assessments Under Amendment 3 – Treatment Year 1 (UC 
Subjects, Entering from Study SHP647-301, SHP647-302, or SHP647-303).........65
16.6
Schedule of Assessments Under Amendment 3 – Treatment Year 2 Through 
End of Study (UC Subjects, Entering from Study SHP647-301, SHP647-302, 
or SHP647-303)........................................................................................................69
16.7
Schedule of Assessments Under Amendment 3 – Treatment Year 1 (UC 
Subjects, Direct Entry) .............................................................................................73
16.8
Schedule of Assessments Under Amendment 3 – Treatment Year 2 Through 
End of Study (UC Subjects, Direct Entry) ...............................................................78
16.9
Schedule of Assessments Under Amendment 3 – Treatment Year 1 (CD 
Subjects, Entering from Study SHP647-305, Study SHP647-306, or Study 
SHP647-307)............................................................................................................82
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16.10
Schedule of Assessments Under Amendment 3 – Treatment Year 2 Through 
End of Study (CD Subjects, Entering from Study SHP647 305, SHP647-306, 
or SHP647-307)........................................................................................................86
16.11
Geographic Regions .................................................................................................90
16.12
Treatment Groups.....................................................................................................92
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LIST OF TABLES
Table 1
Criteria for Potentially Clinically Important Laboratory Tests .....................31
Table 2
Criteria for Potentially Clinically Important Vital Signs ..............................32
Table 3
Criteria for Potentially Clinically Important ECG Values ............................34
Table 4
Analysis Visit Windows (Study Day Based) – Vital Signs and Safety 
Lab (Chemistry and Urinalysis) (Subjects with UC/CD) and Weight 
(Subjects with UC) ........................................................................................41
Table 5
Analysis Visit Windows (Study Day Based) –Safety Lab 
(Hematology) (Subjects with UC/CD) and Weight (Subjects with CD).......41
Table 6
Analysis Visit Windows (Study Day Based) – Neurological 
Assessments and Treatment Response Assessments (Subjects with 
UC/CD), Partial Mayo Score (Subjects with UC), CDAI Score 
(Subjects with CD), Safety Lab (Stool Sample for Fecal Calprotectin, 
Serum CRP) (Subjects with UC/CD) ............................................................42
Table 7
Analysis Visit Windows (Study Day Based) – ECG Assessments 
(Subjects with UC/CD)..................................................................................43
Table 8
Schedule of Assessments – Treatment Year 1 (Subjects with UC)...............53
Table 9
Schedule of Assessments – Treatment Year 2 Through Year 3 and End 
of Study (Subjects with UC)..........................................................................56
Table 10
Schedule of Assessments – Treatment Year 1 (Subjects with CD)...............59
Table 11
Schedule of Assessments – Treatment Year 2 Through Year 3 and End 
of Study (Subjects with CD)..........................................................................62
Table 12
Schedule of Assessments – Treatment Year 1 (UC Subjects, Entering 
from Study SHP647-301, SHP647-302, or SHP647-303) ............................65
Table 13
Schedule of Assessments – Treatment Year 2 Through End of Study 
(UC Subjects, Entering from Study SHP647-301, SHP647-302, or 
SHP647-303).................................................................................................69
Table 14
Schedule of Assessments – Treatment Year 1 (UC Subjects, Direct 
Entry).............................................................................................................73
Table 15
Schedule of Assessments – Treatment Year 2 Through End of Study 
(UC Subjects, Direct Entry) ..........................................................................78
Table 16
Schedule of Assessments – Treatment Year 1 (CD Subjects, Entering 
from Study SHP647-305, Study SHP647-306, or Study SHP647-307)........82
Table 17
Schedule of Assessments – Treatment Year 2 Through End of Study 
(CD Subjects, Entering from Study SHP647-305, SHP647-306, or 
SHP647-307).................................................................................................86
Table 18
Geographic Regions ......................................................................................90
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LIST OF FIGURES
Figure 1
Study Design Flow Chart for Subjects who Enter SHP647-304 Under 
Amendment 4 ................................................................................................15
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ABBREVIATIONS
5-ASA
5-aminosalicylic acid
AE 
adverse event
BMI
body mass index
CD 
Crohn’s disease
CDAI 
Crohn’s Disease Activity Index
CRF
case report form
CRP 
C-reactive protein
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
EOF
end of follow-up
EOT
end of treatment
ET
early termination
FAS 
full analysis set
HEOR
Health Economics and Outcomes Research
IBD 
inflammatory bowel disease
IP
investigational product
IRT 
interactive response technology
LTS
long-term safety
MedDRA
Medical Dictionary for Regulatory Activities
MNT
maintenance study
PCI
potentially clinically important
PD
pharmacodynamic(s)
PGA 
physician global assessment
PML
progressive multifocal leukoencephalopathy
PRO
patient-reported outcome
RB 
rectal bleeding
SAE 
serious adverse event
SAP 
statistical analysis plan
SC
subcutaneous
SES-CD 
Simple Endoscopic Score for Crohn’s Disease
SF
stool frequency
SOC 
system organ class
TEAE 
treatment-emergent adverse event
TNF 
tumor necrosis factor
UC 
ulcerative colitis
WHO
World Health Organization
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1.
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of safety, Health Economics and Outcomes Research (HEOR), and pharmacodynamic 
(PD) data as described in the final study protocol amendment 4 dated 21 Sep 2020 (original 
protocol dated 13 Jul 2017). Specifications for tables, figures, and listings are contained in a 
separate document. The analysis plans for PD 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.
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2.
OBJECTIVES AND ENDPOINTS
2.1
Objectives
2.1.1
Primary Objective
The primary objective of the study is to evaluate the safety and tolerability of long-term 
treatment with ontamalimab in subjects with moderate to severe UC or CD.
2.1.2
Secondary Objectives – Subjects with Ulcerative Colitis

To evaluate the maintenance of response to long-term treatment with ontamalimab as 
measured by clinical composite score and biomarkers, with or without endoscopy.
2.1.3
Secondary Objectives – Subjects with Crohn’s Disease

To evaluate the maintenance of response to long-term treatment with ontamalimab as 
measured by Crohn’s Disease Activity Index (CDAI) score and biomarkers, with or 
without endoscopy.
2.2
Endpoints
2.2.1
Primary Endpoint
The primary endpoint is the assessment of safety as measured by: incidence and severity of 
adverse events (AEs); incidence and nature of serious infections; and actual values and change 
from baseline, as well as incidence of abnormalities, in laboratory tests, electrocardiograms 
(ECGs), and vital signs. All safety analyses will be performed using the Safety Set. Subjects will 
be analyzed according to the treatment they actually receive. Adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Summaries will be presented by 
indication separately. Summaries may be presented by the status at entry into this study (eg, 
induction nonresponder, maintenance ontamalimab completer, maintenance discontinuation 
rollover, etc.).
2.2.2
Secondary Endpoints – Subjects with Ulcerative Colitis
Treatment response over time, with response defined as clinical composite score that has 
decreased by ≥2 points and ≥30%, with an accompanying decrease in the subscore for rectal 
bleeding (RB) ≥1 point or a subscore for RB ≤1, and/or composite score that has decreased by 
≥30% and ≥3 points compared to the baseline value for the induction studies.
2.2.3
Secondary Endpoints – Subjects with Crohn’s Disease 
Treatment response over time, with response defined as CDAI score that has decreased by 
≥100 points compared to the baseline value for the induction studies and/or Simple Endoscopic 
Score for Crohn’s Disease (SES-CD) that has decreased by ≥25% compared to the baseline value 
for the induction studies.
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3.
STUDY DESIGN
3.1
General Description
This is a Phase 3 multicenter extension study designed to evaluate the long-term safety of 
ontamalimab in subjects with moderate to severe UC or CD. The study has enrolled subjects 
from 6 separate Phase 3 studies to date: 4 multicenter, randomized, double-blind, 
placebo-controlled, parallel-group studies evaluating ontamalimab as an induction therapy in 
subjects with moderate to severe UC (SHP647-301 and SHP647-302) or CD (SHP647-305 and 
SHP647-306); and 2 multicenter, double-blind, randomized, placebo-controlled, parallel-group 
studies evaluating ontamalimab as maintenance therapy in subjects with moderate to severe UC 
(SHP647-303) or CD (SHP647-307). As the induction and maintenance studies will be closed 
earlier than planned, the study will enroll subjects with moderate to severe UC and CD from the 
2 maintenance studies (at the time of their closure) who have responded to active treatment. As 
the 4 induction studies do not have any subjects eligible for rollover to the SHP647-304 study as 
of September 2020, no additional subjects will enter from those studies.
This study is planned to become a single-dose study, with the dose to be determined after the 
analysis of data from the induction studies. This study has been double-blind and will continue as 
such until the induction study results become available (ie, unblinding will not occur until the 
final analysis of the induction studies is completed and the lowest effective dose determined), as 
it is planned that subjects will receive the lowest effective dose based on the results of the 
induction studies. It is expected that the analysis of these results will demonstrate the efficacy of 
at least one of the doses and allow for the selection of a single dose, at which time this study will 
be open-label. If both doses are effective and the difference compared to placebo is similar, then 
the lowest effective dose will be selected. However, if the results of the induction or maintenance 
studies show that ontamalimab does not have evidence of efficacy over placebo, this study will 
be terminated.
All subjects will receive active drug in this study. Eligible subjects entering Study SHP647-304 
from the discontinued SHP647-303 and SHP647-307 studies will be assigned to continue their 
present dose of ontamalimab (if currently receiving active drug) or to return to the dose of active 
drug associated with previous response (if on placebo). Ongoing subjects in this study will 
remain on the dose to which they have been previously assigned. Once the final dose has been 
determined, all subjects will continue on that dose only.
Subjects will come to the investigational site every 4 weeks (unless unable to participate on 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), in which case they may qualify for the “Direct to Patient” program for investigational 
product (IP) administration and appropriate assessments.
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The eligibility of a subject for this study will be assessed from study data collected at the 
following time points:

For subjects with UC, the Week 12 visit of the induction study (SHP647-301 or 
SHP647-302) OR the Week 52 or Early Termination (ET) visit of the maintenance study 
(SHP647-303), which are considered and recorded as the baseline visit for this extension 
study (with the exception of the treatment response evaluation, for which baseline of the 
induction study will be used as baseline of this extension study). No additional subjects 
from the induction studies will be enrolling into Study SHP647-304. Subjects from the 
maintenance study (SHP647-303) will have the opportunity to enroll into this study at the 
time of the approval of Amendment 4 if they have benefited from active treatment in the 
induction or maintenance study. 

For subjects with CD, the Week 16 visit of the induction study (SHP647-305 or 
SHP647-306) OR the ET or Week 52 visit of the maintenance study (SHP647-307), 
which will be considered and recorded as the baseline visit for this extension study (with 
the exception of the treatment response evaluation, for which baseline of the induction 
study will be used as baseline of this extension study), with an additional window of 
1 week for subjects whose treatment failure status is still under evaluation at the time of 
the Week 52 visit of the maintenance study. No additional subjects from the induction 
studies will be enrolling into Study SHP647-304. Subjects from the maintenance study 
(SHP647-307) will have the opportunity to enroll into this study at the time of the 
approval of Amendment 4 if they have benefited from active treatment in the induction or 
maintenance study.
Subjects enrolled in this study will receive treatment every 4 weeks, in the form of subcutaneous 
(SC) injections using prefilled syringes. Subjects will undergo treatment response and safety 
assessments as outlined in the Schedules of Assessments. Assessments for Year 1 are provided in 
Table 8 (for subjects with UC) and Table 10 (for subjects with CD). Assessments for Year 2 
through the end of the study are provided in Table 9 (for subjects with UC) and Table 11 (for 
subjects with CD).
At every third visit, subjects with UC will be assessed for ongoing benefit (treatment response) 
using the clinical composite score or composite score. To facilitate data collection and reliability, 
subjects will have the option to use a memory aid. Endoscopies are not required, but if performed 
(eg, for routine surveillance), it is recommended that the Mayo endoscopic subscore be recorded 
by the endoscopist for assessment. The total Mayo score will be calculated only when endoscopy 
data are available. The partial Mayo score consists of the Mayo score without the endoscopic sub 
scores. The composite score is a recommended measure consisting of the Mayo score without the 
physical global assessment (PGA) subscore. The clinical composite score is a measure consisting 
of RB plus stool frequency (SF) without the endoscopic and PGA subscore. The data for Mayo 
scores and composite score will be collected from subjects, who have the option of using a 
memory aid, for 7 days before each specified visit as in the schedules of assessments. 
Biomarkers (C-reactive protein [CRP] and fecal calprotectin) will be assessed every 3 months or 
in case there is a necessity to confirm the loss of clinical treatment response.
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At every third visit, subjects with CD will be assessed for ongoing benefit (treatment response) 
using the CDAI score (treatment response defined as CDAI-100). Data on CDAI components 
(abdominal pain severity, very soft stool/liquid stool frequency, general well-being) will be 
collected from the subjects by the investigators. To facilitate data collection and reliability, 
subjects will have the option to use a memory aid. Endoscopies are not required, but if performed 
(eg, for routine surveillance), it is recommended that the SES-CD be recorded by the endoscopist 
for assessment. The CDAI is a composite measure with 8 components. Five components will be 
captured at the visits, and 3 components (abdominal pain severity, very soft stool/liquid stool 
frequency, and general well-being) will be collected from subjects, who have the option of using 
a memory aid, for 7 days before each specified visit as in the schedules of assessments. 
Biomarkers (CRP and fecal calprotectin) will be assessed every 3 months or in case there is a 
necessity to confirm the loss of clinical treatment response.
Treatment response will be assessed at every third visit for all subjects to allow monitoring of 
clinical benefit derived and evaluation of loss of response throughout the study. At these 
assessment visits, subjects’ response will be evaluated and compared to the value of clinical 
composite score (for subjects with UC) or CDAI (for subjects with CD) determined at entry into 
the induction studies. As long as response criteria are satisfied, subjects may remain in the study. 
If there is a concern regarding loss of response between scheduled assessment visits, assessments 
may be performed at any scheduled or, if necessary, unscheduled visit to evaluate response. To 
ensure that placebo-treated subjects from a feeder study (SHP647-301, SHP647-302, 
SHP647-303, SHP647-305, SHP647-306, or SHP647-307) have sufficient exposure to active 
drug to permit assessment of treatment response, treatment response will be assessed according 
to the revised study schedule. Subjects may discontinue participation at any time, for any reason.
If response to IP is lost, based on clinical criteria, or if there is an unexplained clinical 
exacerbation or unacceptably low level of clinical response, the investigator may assess 
biomarkers and perform other investigations to exclude other potential causes like Clostridium 
difficile infection or an appropriate ad-hoc endoscopy to determine whether the loss of response 
is confirmed or not at an unscheduled visit. The totality of available data will be used to 
determine ongoing response status and subjects whose loss of response is confirmed.
The overall study design is shown in Figure 1.
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Figure 1
Study Design Flow Chart for Subjects who Enter SHP647-304 Under
Amendment 4
EOT=end of treatment; SC=subcutaneous; wks=weeks.
a
Prior to unblinding. Subjects enrolling after unblinding will continue on their selected dose.
b
Determined by active dose received in maintenance or induction study.
Maintenance studies are SHP647-303 and SHP647-307.
Induction studies are SHP647-301, SHP647-302, SHP647-305, and SHP647-306. 
3.2
Randomization
Originally, subjects were to be randomized to treatment in this study. Under Amendment 4 of the 
protocol, randomization will not be performed, as the aim of the study is to provide subjects with 
the ontamalimab dose associated with their treatment response.
Following the confirmation of eligibility, subjects will be allocated to receive either 25 mg or 
75 mg of ontamalimab SC every 4 weeks depending on which dose they had responded to in a 
prior study.
Eligible subjects who withdrew from Study SHP647-303 or SHP647-307 due to the early 
discontinuation of these studies, who received active treatment and showed treatment response at 
the end of treatment (EOT) visit, will receive the dose of ontamalimab (that resulted in treatment 
response) in the previous maintenance study every 4 weeks. Eligible subjects currently receiving 
placebo in maintenance study SHP647-303 or SHP647-307 will receive the same dose of 
ontamalimab that they received in the previous induction study every 4 weeks.
Subject numbers are assigned to all subjects as they consent to take part in the study. The subject 
numbers will be different than the numbers assigned in SHP647-301, SHP647-302, SHP647-303, 
SHP647-305, SHP647-306, and SHP647-307 for subjects who enter from these studies. The 
randomization number represents a unique number corresponding to IP allocated to the subject, 
once eligibility has been determined.
If during the study, either the 25 mg or 75 mg dose of ontamalimab is determined to be the 
efficacious dose, based on emergent data from the induction studies, subjects may have their 
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treatment assignment switched to that dose, and the study would continue as an open-label study 
at that dose level, unless neither dose is efficacious, in which case this study will be terminated.
To preserve blinding, all subjects will receive a randomization number, including those subjects 
who completed a maintenance study (SHP647-303 or SHP647-307) and are to receive the same 
ontamalimab dose in this study. Individual subject treatment is automatically assigned by the 
interactive response technology (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, until the time of unblinding. In these cases, the same IP packing 
identification number may not be assigned to more than 1 subject.
3.3
Blinding 
This is a long-term safety (LTS) extension study. All IP (ontamalimab 25 mg or ontamalimab 
75 mg) will appear identical to protect the study blind.
Data that may potentially unblind the treatment assignment (ie, 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.
This study has been double-blind and will continue as such until the induction study results 
become available (ie, unblinding will not occur until the final analysis of the induction studies is 
completed and the lowest effective dose determined), as it is planned that subjects will receive 
the lowest effective dose based on the results of the induction studies.
The induction studies have now been analyzed and the results show that both the 25 and the 
75mg dose have been well tolerated but only the 75mg dose showed significant efficacy in the 
primary endpoint (and all the key secondary endpoints) of the pooled analysis of the UC 
induction studies (SHP647-301 and SHP647-302). Therefore, subjects who are starting or 
continuing to take part in SHP647-304 based on Protocol Amendment 4 will receive the 75mg 
dose in an open label manner for the rest of the study.
Prior to the time of unblinding, 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 
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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.
Note: This is applicable only until the time of unblinding.
3.4
Sample Size and Power Considerations
A maximum of 568 subjects are projected to enroll into this study. No formal sample size 
estimation was performed on this study.
On 29 May 2020, Takeda announced the closure of the ontamalimab Phase 3 clinical 
development program, which included induction and maintenance studies for subjects with 
moderate to severe inflammatory bowel disease (IBD) who had failed at least 1 prior treatment. 
With this closure, the induction and maintenance studies were discontinued before full 
enrollment, and the planned direct entry of 800 subjects with UC that was added with 
Amendment 3 was not initiated. The previously projected sample size of 3384 subjects will not 
be attained.
As of 04 Sep 2020, there were 334 subjects that were enrolled in this SHP647-304 study. With 
117 subjects active in the ongoing SHP647 induction and maintenance studies, up to a maximum 
of 568 subjects may be enrolled into this study.
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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 SHP647-304 study.
4.2
Randomized Set
The Randomized Set will consist of all subjects in the Screened Set for whom a SHP647-304 
randomization number has been assigned.
4.3
Safety Set  
The Safety Set will consist of all subjects who receive at least 1 dose of IP in the SHP647-304 
study.
4.4
Full Analysis Set
The Full Analysis Set (FAS) will consist of all subjects in the randomized set who receive at 
least 1 dose of IP in the SHP647-304 study.
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5.
STUDY SUBJECTS
5.1
Disposition of Subjects
The number of screened subjects and the number of screen failures will be presented in the 
overall column. The number of subjects included in each analysis set (i.e., Randomized, Safety, 
and FAS) will be summarized by treatment group as listed in Appendix 16.12. The percentage, 
based on the number of subjects in the Safety Set, will be presented for the FAS. The study 
analysis set classifications of each subject will be listed for the Screened Set. Subjects excluded 
from the efficacy analysis will be listed for the Randomized Set.
The number and percentage of subjects who completed and prematurely discontinued the study 
will be presented by treatment group as listed in Appendix 16.12 for the Safety Set. Reasons for 
premature discontinuation from the study are recorded on the study completion page of the 
electronic case report form (eCRF). All subjects who prematurely discontinued from the study 
will be listed for the Safety Set.  
In addition, the 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 16.12 for the Safety Set and FAS. All demographic and 
baseline characteristics will be listed for the Safety Set.
Subject’s age is from the induction studies (SHP647-301, SHP647-302, SHP647-305, or 
SHP647-306), 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]) (refer to 
Appendix 16.11), 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).
There are 3 baselines, defined as the last assessment prior to the first administration of IP in (1) 
the induction studies (SHP647-301, SHP647-302, SHP647-305, or SHP647-306); (2) 
maintenance studies (SHP647-303 or SHP647-307); and (3) this LTS extension study 
(SHP647-304), respectively, unless otherwise specified. The baseline value for a characteristic is 
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the baseline value of the induction studies. For subjects with UC, the maintenance (MNT) 
baseline is the value collected at the Week 12 visit of the induction studies (SHP647-301 and 
SHP647-302). For subjects with CD, the MNT baseline is the value collected at the Week 16 
visit of the induction studies (SHP647-305 and SHP647-306). The LTS baseline is the value 
collected at the Week 12 visit of the UC induction study or Week 16 of the CD induction study 
or the Week 52 or ET visit of the maintenance study (SHP647-303 or SHP647-307). The 
following baseline characteristics will be summarized: 
For subjects with UC: 

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)
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 at Baseline (<6, 6 to <9, and ≥9),

Total Mayo Severity and Total Mayo Severity Category at MNT Baseline (<6, 6 to <9, 
and ≥9),

Total Mayo Severity and Total Mayo Severity Category at LTS Baseline (<6, 6 to <9, 
and ≥9),

Stool Frequency Score at Baseline (0, 1, 2, and 3),

Stool Frequency Score at MNT Baseline (0, 1, 2, and 3),

Stool Frequency Score at LTS Baseline (0, 1, 2, and 3),

Rectal Bleeding Score at Baseline (0, 1, 2, and 3),

Rectal Bleeding Score at MNT Baseline (0, 1, 2, and 3),

Rectal Bleeding Score at LTS Baseline (0, 1, 2, and 3),

Status at Entry into LTS Study (Induction Nonresponder, Maintenance Ontamalimab 
Completer, Maintenance Discontinuation Rollover).
The following UC medication history/use will be summarized:

Immunosuppressant Experienced at LTS Baseline (Yes, No),

Anti-tumor Necrosis Factor (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),
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
Anti-TNF Experienced (Experienced vs. Naïve) (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),

Glucocorticoid Use at MNT Baseline (Yes, No) (actual status),

Glucocorticoid Use at LTS Baseline (Yes, No) (actual status),

Immunosuppressant Use at LTS Baseline (Yes, No),

Glucocorticoid Use at LTS baseline AND Immunosuppressant Use at LTS Baseline 
(Both Glucocorticoid and Immunosuppressant Use, Only Glucocorticoid Use, Only 
Immunosuppressant Use, Neither Glucocorticoid nor Immunosuppressant Use),

Glucocorticoid Use at LTS Baseline (Systemic or Topical, Systemic Only, Topical Only, 
None),

Systemic Glucocorticoid Dose at LTS Baseline,

Systemic Glucocorticoid Dose at LTS Baseline Category (≤10, >10),

5-aminosalicylic acid (5-ASA) Use at LTS Baseline (Yes, No).
The following outcomes from the induction study will be summarized:

Actual Treatment Received in the Induction Study (Placebo, Ontamalimab 25 mg, 
Ontamalimab 75 mg).
The following outcomes from the maintenance study will be summarized:

Actual Treatment Received in the MNT Study (Placebo, Ontamalimab 25 mg, 
Ontamalimab 75 mg),

MNT Treatment Failure Status (Completed without Treatment Failure, Treatment 
Failure),

Stool Frequency Subscore with at least a 1-point Change from Induction Study 
(SHP647-301 or SHP647-302) (Yes, No),

Rectal Bleeding Subscore (0, 1, 2, 3).
For subjects with CD:

Weight, 

Height, 

BMI, 
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
CD Disease Duration (years) and CD Disease Duration Category (<1 year,
≥1 to <3 years, ≥3 to <7 years, and ≥7 years)
Note: CD disease duration is defined as the number of years from the date of 
CD diagnosis to the date of informed consent in the induction study (SHP647-305 or 
SHP647-306),

CD Disease Location (Small Intestine alone, Colon and/or Rectum alone, Ileo-colitis, 
Perianal, and Other),

CDAI Score at Baseline,

CDAI Score at MNT Baseline,

CDAI Score at LTS Baseline,

SES-CD at Baseline (≥17 and <17) (actual status),

SES-CD at MNT Baseline (≥17 and <17),

SES-CD at LTS Baseline (≥17 and <17),

Status at Entry into LTS Study (Induction Nonresponder, Maintenance Ontamalimab 
Completer, Maintenance Discontinuation Rollover).
The following CD medication history/use will be summarized where “randomization status” 
refers to SHP647-304 randomization stratification and “actual status” refers to the actual 
information collected in the case report form (CRF) at LTS baseline: 

Anti-TNF Experienced (Naïve and Experienced) (actual status),

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),

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),

Glucocorticoid Use at MNT Baseline (Yes, No) (actual status), 

Glucocorticoid Use at LTS Baseline (Yes, No) (actual status), 

Glucocorticoid Use at LTS Baseline (Systemic and Topical, Systemic Only, Topical 
Only, None),

Systemic Glucocorticoid Dose at LTS Baseline,

Systemic Glucocorticoid Dose at LTS Baseline Category (≤10 mg, >10 mg),

Immunosuppressant Experienced at LTS Baseline (Yes, No),
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
Immunosuppressant Use at LTS Baseline (Yes, No),

Glucocorticoid Use at LTS Baseline AND Immunosuppressant Use at LTS Baseline 
(Both Glucocorticoid and Immunosuppressant Use, Only Glucocorticoid Use, Only 
Immunosuppressant Use, Neither Glucocorticoid nor Immunosuppressant Use),

5-ASA Use at LTS Baseline (Yes, No).
The following outcomes from the induction study will be summarized: 
Actual Treatment Received in Induction Study (Placebo, Ontamalimab 25 mg, 
Ontamalimab 75 mg).
The following outcomes from the maintenance study will be summarized: 

Actual Treatment Received in MNT Study (Placebo, Ontamalimab 25 mg, Ontamalimab 
75 mg),

MNT Treatment Failure Status (Completed without Treatment Failure, Treatment 
Failure),

Clinical Remission at LTS Baseline (Yes, No),

Enhanced Endoscopic Response at LTS Baseline as measured by a decrease in SES-CD 
of at least 50% from induction study (SHP647-305 or SHP647-306) baseline (Yes, No).
5.3
Smoking History
Smoking history will be recorded in the eCRF at the Screening Visit (Visit 1) in the induction 
studies (SHP647-301 or SHP647-302 and SHP647-305 or SHP647-306) and will be summarized 
by treatment group as listed in Appendix 16.12. 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 of the 
induction studies (SHP647-301 or SHP647-302 and SHP647-305 or SHP647-306).
5.4
Medical History
Medical history will be collected at the Screening Visit (Visit 1) in the induction studies 
(SHP647-301, SHP647-302, SHP647-305, or SHP647-306) or maintenance studies (SHP647-
303 or SHP647-307) and this extension study (SHP647-304) and will be listed for the Safety Set.
Medical history will be coded using MedDRA Version 19.1 2016 or newer. Induction study and 
maintenance study medical history will be summarized by the number and percentage of subjects 
for each treatment group as listed in Appendix 16.12, system organ class (SOC), and preferred 
term.
Cardiovascular history will be collected at the Screening Visit (Visit 1) in the induction studies 
(SHP647-301 or SHP647-302 and SHP647-305 or SHP647-306) and will be summarized by 
treatment group as listed in Appendix 16.12 for the Safety Set. Cardiovascular history will be 
listed for the Safety Set.
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Ulcerative colitis 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.
Crohn’s disease history will be collected at the Screening Visit (Visit 1) in the induction study 
(SHP647-305 or SHP647-306) and will be listed for the Safety Set.
5.5
Prior Medications 
Prior medications will be coded using the World Health Organization (WHO) Drug Dictionary 
dated 01 December 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 SHP647-304 study, and which is ongoing at the date of the baseline visit in the 
SHP647-304 study. Incomplete medication dates will be imputed as described in Section 12.5.3. 
Prior treatment includes any treatment (including but not limited to herbal remedies and 
vitamins) that is ongoing at the time of the baseline visit in the SHP647-304 study. This should 
include concomitant medications in the induction or maintenance studies that are ongoing at the 
baseline visit of the SHP647-304 study.
All prior medications, medical/surgical procedures, and therapies will be listed for the Safety Set.
5.6
Concomitant 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 date of the 
first dose of IP in the SHP647-304 study and continuing after the first dose of IP in the 
SHP647-304 study, or with a start date between the dates of the first dose of IP in the 
SHP647-304 study and EOT date, inclusive. Medication that starts after the first dose of 
SHP647-304 IP will be collected in the SHP647-304 database and will be considered as 
concomitant medication in SHP647-304. Incomplete medication dates will be imputed as 
described in Section 12.5.3. Any medication with a start date between the dates of the first dose 
of IP and EOT date in SHP647-304, inclusive, or with a start date after the EOT date 
(post-treatment) in SHP647-304 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 16.12, 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 occurring during the 
SHP647-304 study will be listed for the Safety Set.
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5.7
Exposure to Investigational Product
Investigational product (ontamalimab or placebo) will be administered SC every 4 weeks. 
Exposure to IP in the SHP647-304 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 group as listed in Appendix 16.12. The administration records by visit 
will be listed for the Safety Set.
Exposure to IP in the SHP647-304 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 SHP647-304 study to the date of the last dose of IP taken in the SHP647-304 study + 
29 days. Subject years of exposure is calculated as (date of last dose of IP in the SHP647-304 
study – date of first dose of IP in the SHP647-304 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 by treatment group as listed in Appendix 16.12.
5.8
Measurements of Treatment Compliance 
Compliance for the treatment period is defined as the total number of SC injections administered 
from the start of treatment in the SHP647-304 study until EOT in the SHP647-304 study divided 
by the number of injections expected to be taken during that time period, times 100. Percentage 
compliance will be summarized by treatment group as listed in Appendix 16.12. Compliance will 
be listed for the Safety Set.
5.9
Protocol Deviations
Protocol deviations will be recorded by Pharmaceutical Product Development (PPD) separately 
from the clinical database. PPD/Shire will classify significant and nonsignificant protocol 
deviations per the agreed protocol deviation management plan. The Shire study team will review 
the protocol deviations and their classifications 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 16.12 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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6.
TREATMENT RESPONSE ANALYSES
Treatment response analyses will be performed using the FAS.
6.1
Treatment Response Analyses – Subjects with Ulcerative Colitis 
6.1.1
Secondary Endpoints 
The secondary endpoint is as follows:

Treatment response over time, with response defined as 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, and/or composite score that has decreased by 
≥30% and ≥3 points compared to the baseline value for induction studies.
The clinical composite score is a measure consisting of RB plus stool frequency without 
endoscopic and PGA subscore.
Secondary endpoints will be summarized by planned treatment group as listed in Appendix 16.12
using descriptive statistics at each assessment visit.
For each treatment group listed in Appendix 16.12 and for each visit, the treatment response rate, 
including number of subjects, the proportion of all subjects in the treatment group, and 
corresponding Wilson Score (Yan and Su, 2010) 95% confidence intervals, will be presented. 
In the event that the number of responders or non-responders in either treatment group is too 
small (i.e., ≤5), exact unconditional confidence limits for treatment difference 
(Chan and Zhang, 1999) will be performed instead. Subjects with missing data to determine 
endpoint status will be considered as undesired treatment outcome (i.e, non-responders).
An overlay plot of the proportions for these same treatment groups across study visits will also 
be generated. 
6.2
Treatment Response Analyses – Subjects with Crohn’s Disease
6.2.1
Secondary Endpoints 
The secondary endpoint is as follows: 

Treatment response over time, with response defined as CDAI score that has decreased 
by ≥100 points compared to the baseline value for induction studies and/or SES-CD that 
has decreased by ≥25% compared to the baseline value for induction studies.
Secondary endpoints will be summarized by planned treatment group as listed in Appendix 16.12
using descriptive statistics at each assessment visit.
For each treatment group listed in Appendix 16.12 and for each visit, the treatment response rate, 
including number of subjects, the proportion of all subjects in the treatment group, and 
corresponding Wilson Score (Yan and Su, 2010) 95% confidence intervals, will be presented. 
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In the event that the number of responders or non-responders in either treatment group is too 
small (i.e., ≤5), exact unconditional confidence limits for treatment difference 
(Chan and Zhang, 1999) will be performed instead. Subjects with missing data to determine 
endpoint status will be considered as undesired treatment outcome (ie, non-responders).
An overlay plot of the proportions for these same treatment groups across study visits will also 
be generated.
6.3
Other Efficacy Data 
Inpatient hospitalizations and emergency room visits will be listed for the Full Analysis Set.
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7.
SAFETY ANALYSIS 
All safety analyses will be performed using the Safety Set. Safety variables include AEs, clinical 
laboratory variables, vital signs, and ECG variables. For each safety variable, the last value 
collected before the first dose of IP will be used as baseline for all analyses of that safety 
variable. For subjects with UC, the Week 12 visit of the induction study (SHP647-301 or 
SHP647-302) or the Week 52 or ET visit of the maintenance study (SHP647-303) will be 
considered and recorded as the baseline visit for this extension study (with the exception of the 
treatment response evaluation, for which baseline of the induction study will be used as baseline 
of this extension study). For subjects with CD, the Week 16 visit of the induction study 
(SHP647-305 or SHP647-306) or the Week 52 or ET visit of the maintenance study 
(SHP647-307) will be considered and recorded as the baseline visit for this extension study (with 
the exception of the treatment response evaluation, for which baseline of the induction study will 
be used as baseline of this extension study), with an additional window of 1 week for subjects 
whose treatment failure status is still under evaluation at the time of the Week 52 visit of the 
maintenance study.
Last Observed Value on Treatment will be defined as the last valid assessment obtained after 
baseline and whilst on IP. 
All safety analyses will be conducted according to the treatment the subject actually received. 
Summaries will be presented by indication separately. 
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 or worsening dates at the 
time of or following the first exposure to investigational product in the SHP647-304 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 study discontinuation, TEAEs leading to study 
medication discontinuation, and TEAEs leading to death.
The number of events, incidence, and percentage of subjects reporting TEAEs in each treatment 
group will be summarized by treatment group as listed in Appendix 16.12; 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 1 AE occurs with the same preferred term for the same subject, then the subject will 
be counted only once for that preferred term using the most severe and most related occurrence 
for the summarization by severity and by relationship to IP.
The most common TEAEs (incidence ≥2% in any treatment group) will be summarized by 
preferred term in descending order of frequency by treatment group as listed in Appendix 16.12. 
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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 listed in 
Appendix 16.12. Adverse events leading to withdrawal, SAEs, and deaths will be similarly 
summarized or listed. 
7.1.1
Adverse Events of Special Interest and Other Potential Risks
There is 1 identified important potential risk of progressive multifocal leukoencephalopathy 
(PML). 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 16.12. 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. Reported hypersensitivity 
events, adjudicated hypersensitivity events, and study drug recommendations will be 
summarized by treatment group as listed in Appendix 16.12.
The number of hypersensitivity reactions and percentage of subjects with hypersensitivity 
reactions as adjudicated will be summarized by treatment group as listed in Appendix 16.12; and 
by SOC, preferred term, and hypersensitivity type. Reported hypersensitivity events and 
adjudicated hypersensitivity events will be listed for the Safety Set.
7.2
Clinical Laboratory Data
Descriptive statistics for clinical laboratory values (in conventional units), the LTS baseline, and 
changes from the induction studies (SHP647-301, SHP647-302, SHP647-305, or SHP647-306) 
baseline at each assessment time point for quantitative variables will be presented by treatment 
group as listed in Appendix 16.12 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 16.12 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
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Hematology

hemoglobin 

hematocrit 

mean corpuscular hemoglobin

mean corpuscular hemoglobin 
concentration

mean corpuscular volume

erythrocyte (red blood cell) count

leukocyte (white blood cell) count

neutrophils

lymphocytes

monocytes

eosinophils

basophils

platelet count
Urinalysis

glucose

protein

specific gravity

pH

nitrite

bilirubin

ketones

hemoglobin

urobilinogen

leukocyte esterase
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 1. The number and percentage of subjects with post-LTS 
baseline PCI values will be tabulated by treatment group as listed in Appendix 16.12. The 
percentages will be calculated relative to the number of subjects with at least 1 post-LTS 
baseline assessment. The numerator is the total number of subjects with at least 1 post-LTS 
baseline PCI value. A supportive listing of subjects with post-LTS baseline PCI values will be 
provided including the subject number, induction study baseline, and post-LTS baseline values.
Figures will be presented for hematology and chemistry to show the changes in laboratory 
parameters over time. Data will be presented as box-and-whisker plots by treatment group as 
listed in Appendix 16.12 at each visit, with 1 laboratory parameter per page. 
Shifts from the induction studies (SHP647-301, SHP647-302, SHP647-305, or SHP647-306) 
baseline category to each visit will be presented for each treatment group and ontamalimab all 
doses as listed in Appendix 16.12 for hematology, chemistry, and urinalysis. For hematology and 
chemistry, shifts will be categorized as Low, Normal, or High. For urinalysis, shifts will be 
categorized as Abnormal or Normal. 
All laboratory data will be listed for the Safety Set.
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Table 1
Criteria for Potentially Clinically Important Laboratory Tests
Parameter
Age 
Range
Sex
Outlier Criteriaa
Low
High
pH
All
NA
NA
Specific gravity
All
NA
NA
Urobilinogen
All
NA
NA
DILI=drug-induced liver injury; 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 studies 
(SHP647-301, SHP647-302, SHP647-305, or SHP647-306) baseline at each postbaseline visit 
and at the end of the study will be presented by treatment group as listed in Appendix 16.12.
For pulse rate, a post-LTS value is considered as a PCI value if it meets both criteria for 
observed value and change from induction studies (SHP647-301, SHP647-302, SHP647-305, or 
SHP647-306) baseline. For systolic/diastolic blood pressure, a post-LTS baseline value is 
considered as a PCI value if it meets criteria for observed value or change from induction studies 
(SHP647-301, SHP647-302, SHP647-305, or SHP647-306) baseline. For weight and BMI, a 
post-LTS baseline value is considered as a PCI value if it meets criteria for change from 
induction studies (SHP647-301, SHP647-302, SHP647-305, or SHP647-306) baseline. The PCI 
criteria are listed in Table 2. The number and percentage of subjects with PCI post-LTS baseline 
values will be tabulated by treatment group as listed in Appendix 16.12. The percentages will be 
calculated relative to the number of subjects with available induction studies (SHP647-301, 
SHP647-302, SHP647-305, or SHP647-306) baseline values and at least 1 post-LTS baseline 
assessment. The numerator is the total number of subjects with at least 1 PCI post-LTS baseline 
vital sign value. A supportive listing of subjects with post-LTS baseline PCI values will be 
provided including the subject number, site, and induction studies (SHP647-301, SHP647-302, 
SHP647-305, or SHP647-306) baseline and post-LTS baseline values.  
All vital signs data will be listed for the Safety Set.
Table 2
Criteria for Potentially Clinically Important Vital Signs
Vital Sign Parameter
Flag
Criteriaa
Observed Value
Change from Baseline
Systolic blood pressure
(mmHg)
High
180
Increase of 20
Low
90
Decrease of 20
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Table 2
Criteria for Potentially Clinically Important Vital Signs
Vital Sign Parameter
Flag
Criteriaa
Observed Value
Change from Baseline
Diastolic blood pressure 
(mmHg)
High
105
Increase of 15
Low
50
Decrease of 15
Pulse rate
(beats per minute)
High
120
Increase of 15
Low
50
Decrease of 15
Weight (kg)
High
-
Increase of 7%
Low
-
Decrease of 7%
BMI (kg/m2)
High
-
Increase of 10%
Low
<18
Decrease of 10%
Temperature (◦C)
NA
NA
a For pulse rate, a post-baseline value is considered as a PCI value if its meets both criteria for observed value and change 
from baseline. For systolic/diastolic blood pressure, a post-baseline value is considered as a PCI value if it meets criteria for 
observed value or change from baseline. For weight and BMI, a post-baseline value is considered as a PCI value if it meets 
criteria for change from baseline.
7.5
Electrocardiogram (ECG)
A central ECG reader will be used for data collected prior to Protocol Amendment 4. A local 
ECG reader will be used for data collected after Protocol Amendment 4. 
Descriptive statistics for ECG variables (eg, heart rate, PR interval, QRS interval, QT interval, 
and QTc interval using both Bazett and Fridericia corrections) and their changes from induction 
studies (SHP647-301, SHP647-302, SHP647-305, or SHP647-306) baseline at each assessment 
time point will be presented by treatment group as listed in Appendix 16.12. 
Electrocardiogram interpretation will be summarized by visit. A shift table from induction 
studies (SHP647-301, SHP647-302, SHP647-305, or SHP647-306) baseline to each visit for 
ECG interpretation results will be presented by treatment group as listed in Appendix 16.12.
Electrocardiogram variable values will be considered PCI if they meet or exceed the upper limit 
values listed in Table 3. The number and percentage of subjects with available induction studies 
(SHP647-301, SHP647-302, SHP647-305, or SHP647-306) baseline values and post-LTS 
baseline PCI values will be tabulated by treatment group as listed in Appendix 16.12. The 
percentages will be calculated relative to the number of subjects with available baseline values 
and at least 1 post-LTS baseline assessment. The numerator is the total number of subjects with 
at least 1 post-LTS baseline PCI value. 
Listings of ECG data including the central reader’s assessment and investigator’s interpretation 
by individual subject will be produced. Separate listings will be produced for subjects with ECG 
results meeting PCI criteria. Data from unscheduled visits will be listed but not summarized. 
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Table 3
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 consultation evaluation results with 
unexplained abnormal neurological findings will be summarized at screening and at each visit 
and by treatment group as listed in Appendix 16.12. The number and percentage of subjects with 
a 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 16.12. 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 16.12. The neurological evaluation and 
consultation results will be listed for the Safety Set.
7.6.2
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.
7.6.3
Physical Examination
Complete and targeted physical examinations will be performed at the time points specified in 
Table 8, Table 9, Table 10, and Table 11. Physical examination results will be listed for the 
Safety Set.
7.6.4
Other Safety Data Prior to Protocol Amendment 4
All other safety assessments removed by Protocol Amendment 4 will be listed for the Safety Set.
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8.
PHARMACOKINETIC ANALYSIS
8.1
Drug Concentration
Serum concentration data collected prior to Amendment 4 (as shown in Table 12, Table 13, 
Table 14, Table 15, Table 16, and Table 17) will be listed by subject in the Safety Set.
8.2
Handling Below Limit of Quantitation (BLQ) Values
The lower limit of quantification for ontamalimab is 10 ng/mL. Plasma concentrations below the 
limit of quantification (BLQ) will be presented as BLQ in the listing.
8.3
Pharmacokinetic Parameters
Not applicable.
8.4
Statistical Analysis of Pharmacokinetic Data
Not applicable.
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9.
PHARMACODYNAMIC ANALYSIS
9.1
Pharmacodynamic Data
Actual values of biomarkers including fecal calprotectin and serum CRP at each sample 
collection will be listed by subject in the Safety Set.
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10.
OTHER ANALYSES
10.1
Coronavirus Pandemic
The coronavirus (COVID-19) pandemic of 2019-20 particularly poses risks to the safety of 
subjects enrolled in clinical trials and the availability and interpretability of data from those 
trials. COVID-19 impacts on individual subjects collected on COVID-19 CRF pages will be 
listed for the Randomized Set. Protocol deviations related to COVID-19 will be listed for the 
Randomized Set. The study disruptions related to COVID-19 will be listed for the Safety Set.
10.2
Russia – Ukraine Crisis
Russia’s recent invasion of Ukraine was initiated on 24 February 2022. Due to the ongoing 
Russia-Ukraine crisis, it is estimated that 17 active sites and potentially 38 subjects in Study 
SHP647-304 may be affected by the crisis. The crisis may cause both the loss of data, due to 
discontinuation of patients from the study, missed treatment, missed visits, or missed 
assessments within a visit, and the inflation of adverse events because of the diminished quality 
of treatment.
Additional analysis may be performed to evaluate the impact of Russia-Ukraine crisis on the 
efficacy and safety of all participating subjects focusing on primary and secondary endpoints, 
including but not limited to the following:

Data listing of Protocol deviations related to Russia-Ukraine crisis 

Data listing of all subjects potentially affected by Russia-Ukraine crisis, including subject 
ID, site number, treatment arm, country, enrollment date, discontinuation date/reason
For the primary endpoints, a sensitivity analysis using the Safety Set may be conducted for 
adverse events by excluding AEs with an onset date on or after 24 February 2022 for the subjects 
from the potentially affected Russia-Ukraine sites for both UC and CD subjects:

Overall Treatment-Emergent Adverse Events (TEAEs) by Treatment Group (Safety Set)

Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and 
Treatment Group (Safety Set)
For the secondary efficacy endpoints, a sensitivity analysis using Full Analysis Set may be 
performed by using the same approach as mentioned in Section 6.1.1 and Section 6.2.1 but 
excluding subjects who were actively enrolled and on treatment during the conflict period 
beginning 24 February 2022 from the potentially affected Russia-Ukraine sites for both UC and 
CD subjects:

Summary of Treatment Response Based on Clinical Composite Score by Treatment 
Group (SHP647-304 Ulcerative Colitis) (Full Analysis Set)

Summary of Treatment Response Based on CDAI Score by Treatment Group 
(SHP647-304 Crohn’s Disease) (Full Analysis Set)
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10.3
Significant Investigator Noncompliance
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 
efficacy endpoints by using the same approach but excluding all subjects from the noncompliant 
site(s).
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11.
INTERIM ANALYSIS/DATA MONITORING (REVIEW) COMMITTEE 
A data monitoring committee (DMC) was set up to review 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.
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12.
DATA HANDLING CONVENTIONS
12.1
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, standard deviation, minimum, and maximum. For the summary statistics of all 
numerical variables, unless otherwise specified, minimum and maximum will be displayed to the 
same level of precision as reported. Mean and median will be displayed to 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 4 decimal places; values less than 0.0001 will be 
presented as <0.0001. 
12.2
Definition of Visit Windows 
Assessments will be assigned to visits based upon the date on which the assessment took place 
regardless of the completed CRF page. Assessments will be mapped to visits as outlined in 
Table 4, Table 5, Table 6, and Table 7. Any other mapping of day of assessment to the planned 
study day of a visit will use the study day midpoint between planned study days as the dividing 
line between visits. The ‘End of Treatment’ (EOT) will be assigned to visit based on the date of 
assessment. The EOT date is unique for each subject and uses the date recorded on the study 
completion CRF page.   
Should there be more than 1 assessment mapped into a given study visit with non-missing 
results, the assessment closest to the planned visit will be used for analysis (referred to as 
analysis visit); in case of ties between observations, the later assessment will be used.  
Study day will be calculated as follows: 

If the assessment date is on or after the date of first dose of IP: 
Study day = assessment date – first dosing date + 1

If the assessment date is before the date of first dose of IP:
Study day = assessment date – first dosing date
The possibility exists, that subjects who were enrolled before SHP647-304 protocol 
amendment 4 was implemented could participate in study treatment of SHP647-304 for more 
than 144 weeks. When on treatment visits beyond 144 weeks occur in the study, data those 
results will be assigned to visit windows and presented in the same manner as other on treatment 
visits prior to the Week 144 visit.
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Table 4
Analysis Visit Windows (Study Day Based) – Vital Signs and Safety Lab 
(Chemistry and Urinalysis) (Subjects with UC/CD) and Weight (Subjects with 
UC)
Visit
Planned Study Day
Start Day of Window
End Day of Window
Week 4
28
2
56
Week 12
84
57
126
Week 24
168
127
210
Week 36
252
211
294
Week 48
336
295
420
Week 72
504
421
588
Week 96
672
589
756
Week 120
840
757
924
Week 144
1008
925
1092
…
…
…
…
Follow-up[a]
EOT date + 84
EOT date + 1
EOF date
CD=Crohn’s disease; EOF=end of follow-up; EOT=end of treatment; UC=ulcerative colitis
Note: For subjects whose study participation extends beyond Year 3 (ie, subjects already enrolled in this study 
prior to the implementation of Amendment 4), assessments will be repeated on the subsequent year rotation 
beginning with Week 100.
[a] Weight is not calculated at the follow-up visit
Table 5
Analysis Visit Windows (Study Day Based) –Safety Lab (Hematology) 
(Subjects with UC/CD) and Weight (Subjects with CD)
Visit
Planned Study Day
Start Day of Window
End Day of Window
Week 4
28
2
56
Week 12
84
57
126
Week 24
168
127
210
Week 36
252
211
294
Week 48
336
295
378
Week 60
420
379
462
Week 72
504
463
546
Week 84
588
547
630
Week 96
672
631
714
Week 108
756
715
798
Week 120
840
799
882
Week 132
924
883
966
Week 144
1008
967
1050
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Table 5
Analysis Visit Windows (Study Day Based) –Safety Lab (Hematology) 
(Subjects with UC/CD) and Weight (Subjects with CD)
Visit
Planned Study Day
Start Day of Window
End Day of Window
…
…
…
…
Follow-up
EOT date + 84
EOT date + 1
EOF date
CD=Crohn’s disease; EOF=end of follow-up; EOT=end of treatment; UC=ulcerative colitis
Note: For subjects whose study participation extends beyond Year 3 (ie, subjects already enrolled in this study 
prior to the implementation of Amendment 4), assessments will be repeated on the subsequent year rotation 
beginning with Week 100.
Table 6
Analysis Visit Windows (Study Day Based) – Neurological Assessments and 
Treatment Response Assessments (Subjects with UC/CD), Partial Mayo Score 
(Subjects with UC), CDAI Score (Subjects with CD), Safety Lab (Stool 
Sample for Fecal Calprotectin, Serum CRP) (Subjects with UC/CD)
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
294
Week 48
336
295
378
Week 60
420
379
462
Week 72
504
463
546
Week 84
588
547
630
Week 96
672
631
714
Week 108
756
715
798
Week 120
840
799
882
Week 132
924
883
966
Week 144
1008
967
1050
…
…
…
…
Follow-up[a]
EOT date + 84
EOT date + 1
EOF date
CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; EOF=end of follow-up; EOT=end of treatment; 
UC=ulcerative colitis
Note: For subjects whose study participation extends beyond Year 3 (ie, subjects already enrolled in this study 
prior to the implementation of Amendment 4), assessments will be repeated on the subsequent year rotation 
beginning with Week 100. 
[a] Treatment Response Assessments, Partial Mayo Score, CDAI scores, Weight, and Safety Lab (Stool Sample 
for Fecal Calprotectin, Serum CRP) are not calculated at the follow-up visit
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Table 7
Analysis Visit Windows (Study Day Based) – ECG Assessments (Subjects 
with UC/CD)
Visit
Planned Study Day
Start Day of Window
End Day of Window
Week 12
84
2
126
Week 24
168
127
252
Week 48
336
253
504
Week 96
672
505
840
Week 144
1008
841
1176
…
…
…
…
CD=Crohn’s disease; ECG=electrocardiogram; EOT=end of treatment; UC=ulcerative colitis
Note: For subjects whose study participation extends beyond Year 3 (ie, subjects already enrolled in this study 
prior to the implementation of Amendment 4), assessments will be repeated on the subsequent year rotation 
beginning with Week 100.
12.3
Treatment Response Assessments
12.3.1
Subjects with UC
12.3.1.1
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 8, Table 9, and Section 14.
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:

Bowel movement frequency (0-3)

Rectal bleeding (0-3)

Findings of flexible sigmoidoscopy or endoscopy (0-3)

Physician global assessment (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. Note: Endoscopy is optional based on Protocol 
Amendment 4, and the composite score will be computed only if an endoscopy is performed.
The clinical composite score is a measure consisting of RB plus SF without endoscopic and PGA 
subscore. Subjects will be instructed to maintain a daily memory aid for the 7 days prior to each 
visit. In the memory aid, subjects will record the total number of bowel movements and the worst 
RB experienced each day (see Section 12.3.1.2). At the scheduled visit, the investigator will ask 
the subject to report the daily stool count and RB score and enter the data into the eCRF to 
calculate the clinical composite (and if appropriate, composite) score for that visit.
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The Mayo SF and RB subscores will be calculated based on each subject’s data over the most 
recent 3 days (consecutive or nonconsecutive) prior to the visit, excluding the following days: 
day of any bowel preparation, day of endoscopy, any days between day of bowel preparation and 
day of endoscopy, and the 2 days after the day of endoscopy. For the data that was collected 
prior to Protocol Amendment 4, the most recent 3 days is selected from the last 10 days prior to 
the scheduled visit start date. The most recent 3 days’ subscores will be averaged and rounded to 
the nearest score according to standard rounding rules.
The mucosal appearance during the sigmoidoscopic portion of the endoscopic examination (if 
performed) will be assessed for the Mayo endoscopic subscore based on the scoring system 
provided in the protocol. The endoscopic appearance will be read by the operator or study site 
investigator using video recorded during the procedure. Locally read endoscopic subscores, if 
performed, will be used for treatment response 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 subscore must be 
determined 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.
The Mayo score data will be listed for the FAS.
12.3.1.2
UC Subject Reporting of Symptoms
Subjects will be asked to report the following signs and symptom data, as experienced over the 
previous 24 hours and for the 7 days prior to each scheduled visit:

Stool frequency

Rectal bleeding severity.
The UC subject reporting of symptoms data will be listed for the FAS.
12.3.2
Subjects with CD
12.3.2.1
SES-CD
The SES-CD will be calculated using the subscores of each of the segments investigated and 
read by the local endoscopist at each of the visits during which colonoscopy is performed. The 
baseline score will be based on the colonoscopy that was performed prior to the start time of the 
first dose of this study. If not taken in this study, the score for the baseline (Week 0/Day 1) visit 
will be based on the last colonoscopy performed in the study from which the subject is entering.
The SES-CD is a simple scoring system based on 4 endoscopic variables (presence and size of 
ulcers, proportion of surface covered by ulcers, proportion of affected surface, and presence and 
severity of stenosis [narrowing]) measured in the same 5 ileocolonic segments as the CD index 
of severity. Overall, values on the SES-CD range from 0 to 56, with higher values indicating 
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more severe disease. The 4 endoscopic variables are scored from 0 to 3 in each bowel segment 
(ileum, right/transverse/left colon, and rectum):

Presence and size of ulcers (none = score 0; diameter 0.1–0.5 cm = score 1; 
0.5–2 cm = score 2; diameter >2 cm = score 3)

Extent of ulcerated surface (none = 0; <10% =1; 10%–30% = 2; >30% = 3); extent of 
affected surface (none = 0; <50% = 1; 50%–75% = 2; >75% = 3)

Presence and type of narrowings (none = 0; single, can be passed = 1; multiple, can be 
passed = 2; cannot be passed = 3).
The maximum stenosis score in a segment distal to another evaluable segment cannot exceed 2, 
so the stenosis scores cannot exceed a total of 11 (Reinisch et al., 2017).
The SES-CD data will be listed for the FAS.
12.3.2.2
CDAI
The CDAI is a composite measure with 8 components: 3 components (abdominal pain severity, 
very soft stool/liquid SF, and general well-being) will be self-reported by the subject, as 
described in Section 12.3.2.3, and 5 components (weight, medical and physical examination, use 
of diarrhea treatment, and hematocrit value) will be recorded at the time points specified in 
Table 10, Table 11, and Section 14.
The CDAI scores will be calculated using the following: 

Components 1 to 3 from subject-reported data collected for 7 days before the visit
and

Components 4 to 8 collected at the visit.
For the data (components 1 to 3) collected prior to Protocol Amendment 4, the most recent 
7 days is selected from the last 10 days prior to the scheduled visit start date. If fewer than 7 days 
are available, the components scores 1 to 3 will be calculated on all available most recent 6 or 
5 days. If fewer than 5 days are available, the components scores 1 to 3 will be treated as 
missing.
Change in CDAI has been used as a primary endpoint in multiple pivotal trials in the 
CD indication. The algorithm for calculating the CDAI score was first published by William 
Best and colleagues (Best et al., 1976).
The CDAI data will be listed for the FAS.
12.3.2.3
CD Subject Reporting of Symptoms
Subjects will be asked to recall clinical data for CDAI score for the 7 days prior to each 
scheduled visit:

Number of very soft or liquid bowel movements (as shown by Bristol Stool Form Scale 
type 6/7)
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
Level of abdominal pain (using the parameters as described in CDAI)

Sense of general well-being (using the parameters as described in CDAI)
The CD subject reporting of symptoms data will be listed for the FAS.
The investigator will record this information in the eCRF and use it to calculate the CDAI score 
for that visit.
12.4
Repeated or Unscheduled Assessments of Safety Parameters 
Assessments will be assigned to visits based on the date on which the assessment took place 
regardless of the completed CRF page. Assessments will be mapped to visits as outlined in 
Table 4, Table 5, Table 6, and Table 7.
If a subject has 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. However, all post-LTS 
baseline assessments will be used for PCI value determination. 
12.5
Handling of Missing, Unused, and Spurious Data 
12.5.1
Missing Date of End of Treatment
When the date of EOT is missing for a subject, all efforts should be made to obtain the date from 
the investigator. If it is still missing after all efforts, then the last dose date + 28 days will be used 
in the calculation of treatment duration.
12.5.2
Missing Date of CD or UC Diagnoses
If day of diagnosis date is missing, then the day will be imputed as 1; if both the day and month 
of diagnosis date are missing, then the day will be imputed as 1 and the month will be imputed as 
1 (January).
12.5.3
Missing Date Information for Prior or Concomitant Medications 
The induction studies (SHP647-301, SHP647-302, SHP647-305, or SHP647-306) or 
maintenance studies (SHP647-303 or SHP647-307) imputed dates will be used for prior 
medications for those collected in the induction studies or maintenance studies.
For concomitant medications collected in the SHP647-304 study, 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, the start date will be imputed first.
12.5.3.1
Incomplete Start Date 
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date.
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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 SHP647-304 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 SHP647-304 study, then 31 December 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 SHP647-304 study, then 01 January will be assigned to the missing fields.
Missing Month Only

The day will be treated as missing, and both month and day will be replaced according to 
the above procedure.
Missing Day Only

If the month and year of the incomplete start date are the same as the month and year of 
the date of the first dose of IP in the SHP647-304 study, then the day of the date of the 
first dose of IP in the SHP647-304 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 in the SHP647-304 
study 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 SHP647-304 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 date of the first dose of IP in the SHP647-304 
study 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 SHP647-304 study, then the first day of the month will be assigned to 
the missing day.
12.5.3.2
Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of IP in the SHP647-304 study is missing, then it will be replaced with the last visit date. If 
the imputed stop date is before the start date (imputed or non-imputed start date), then the 
imputed stop date will be equal to the start date.
Missing Day and Month

If the year of the incomplete stop date is the same as the year of the date of the last dose 
of IP in the SHP647-304 study, then the day and month of the date of the last dose of IP 
in the SHP647-304 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 SHP647-304 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 SHP647-304 study, then 01 January will be assigned to the missing fields.
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Missing Month Only

The day will be treated as missing, and both month and day will be replaced according to 
the above procedure.
Missing Day Only

If the month and year of the incomplete stop date are the same as the month and year of 
the date of the last dose of IP in the SHP647-304 study, then the day of the date of the 
last dose of IP in the SHP647-304 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 in the SHP647-304 
study 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 SHP647-304 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 in the SHP647-304 study 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 
SHP647-304 study, then the first day of the month will be assigned to the missing day.
12.5.4
Missing Date Information for Adverse Events 
For AEs, the default is to impute only incomplete (ie, partially missing) start dates. If start date is 
missing, no imputation will be performed.
12.5.4.1
Incomplete Start Date 
The same rules as in Section 12.5.3.1 will be followed.
12.5.4.2
Incomplete Stop Date 
Not applicable.
12.5.5
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of 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 SHP647-304 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 presented in data listings.
12.5.6
Missing Relationship to Investigational Product 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 SHP647-304 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.
12.5.7
Character Values of Clinical Laboratory Variables
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, a character string being reported for a numerical variable, the appropriately 
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determined coded value will be used in the statistical analysis. However, the actual values as 
reported in the database will be presented in data listings.
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13.
ANALYSIS SOFTWARE 
Statistical analyses will be performed using Version 9.4 (or newer) of SASon a suitably 
qualified environment.  
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14.
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL
The following changes to the analysis specified in Protocol Amendment 4 dated 21 Sep 2020 
(final version 1.0 dated 13 Jul 2017, Amendment 1 dated 18 Dec 2017, Amendment 2 dated 
17 Sep 2018, Amendment 3 dated 07 Nov 2019) have been made.
1. Secondary endpoints and safety analysis summaries will not be presented by the status at 
entry into this study (e.g., induction nonresponder, maintenance ontamalimab completer, 
maintenance discontinuation rollover, etc.).
2. Summaries will be presented by indication separately but not overall.
3. Efficacy components of partial Mayo score for UC subjects and CDAI score for CD 
subjects will be summarized every 12 weeks during treatment as part of the treatment 
response assessment mentioned in the text of Protocol Amendment 4 in addition to every 
24 weeks as mentioned in Section 16, Schedule of Assessments.
4. The items mentioned in the “SHP647-304 Protocol Administrative Change / Clarification 
Memo” dated 01 February 2021 were incorporated into the text of this document and will 
be implemented as stated in the memo in the summarization of the results of this 
SHP647-304 study.
5. Secondary endpoint for response of ulcerative colitis participants was changed from “or a 
subscore for RB ≥1” to “or a subscore for RB ≤ 1”. 
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15.
REFERENCES
Best, W. R., Becktel, J. M., Singleton, J. W. and Kern, F. 1976. Development of a Crohn's 
disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology, 
70, 439-44.
Chan I. and Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
proportions. Biometrics. 1999; 55(4) 1202-1209. 
Reinisch, W., Colombel, J.-F., D’Haens, G., Sandborn, W. J., Rutgeerts, P., Geboes, K., 
Petersson, J., Eichner, S., Zhou, Q., Robinson, A. M., Read, H. A. and Thakkar, R. 2017. 
Characterisation of Mucosal Healing with Adalimumab Treatment in Patients with 
Moderately to Severely Active Crohn’s Disease: Results from the EXTEND Trial. 
Journal of Crohn’s and Colitis, 11, 425-434.
Yan, X., and Su, X. G. (2010). “Stratified Wilson and Newcombe Confidence Intervals for 
Multiple Binomial Proportions.” Statistics in Biopharmaceutical Research 2:329–335.
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16.
APPENDICES 
16.1
Schedule of Assessments – Treatment Year 1 (Subjects with UC)
Table 8
Schedule of Assessments – Treatment Year 1 (Subjects with UC)
Study Procedure
Baselinea
Treatment – Year 1
W0/
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±10 days
Informed consent/assent
X
Eligibility assessmentb
X
Medical historyc
IDT or MNT
Complete physical examinationd
IDT or MNT
X
Targeted physical examinationd
IDT or MNT
X
Targeted neurological assessmente,f
IDT or MNT
X
X
X
X
Vital signs
IDT or MNT
X
X
X
X
X
Weight
IDT or MNT
X
X
X
X
X
12-lead ECG (local)
IDT or MNT
X
X
X
Laboratory (Central)g
Hematology
IDT or MNT
X
X
X
X
X
Serum chemistryh
IDT or MNT
X
X
X
X
X
Urinalysis
IDT or MNT
X
X
X
X
X
Urine β-hCGi
IDT or MNT
X
X
X
X
X
X
X
X
X
X
X
X
FSHj
X
Contraception checkk
X
X
X
X
X
X
X
X
X
X
X
X
Stool sample for fecal calprotectin
IDT or MNT
X
X
Serum CRPl
IDT or MNT
X
X
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Table 8
Schedule of Assessments – Treatment Year 1 (Subjects with UC)
Study Procedure
Baselinea
Treatment – Year 1
W0/
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±10 days
Endoscopic Procedure
OPTIONAL endoscopy (flexible 
sigmoidoscopy or colonoscopy)m
IDT or MNT
O
O
O
O
O
O
O
O
O
O
O
O
UC Assessmentsn
OPTIONAL Total Mayo scoreo
IDT or MNT
O
O
O
O
O
O
O
O
O
O
O
O
Partial Mayo score
IDT or MNT
X
X
Treatment response assessmentp,q
IDT
X
X
X
X
Treatment Procedures
Administration of ontamalimabr,s,t
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypersensitivity monitoringu
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
Concomitant medication and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool collection kit for stool 
samplev
X
X
β-hCG=beta-human chorionic gonadotropin; CLIA=Clinical Laboratory Improvement Amendments; CRP=C-reactive protein; DTP=Direct-To-Patient; 
ECG=electrocardiogram; ET=early termination; FDA=Food and Drug Administration; FSH=follicle-stimulating hormone; GI=gastrointestinal; IDT=induction study (SHP647-
301 or SHP647-302); LFT=liver function testing; MNT=maintenance study SHP647-303; O=optional; UC=ulcerative colitis; W=Week.
a Baseline = Week 0 (Day 1). For subjects previously enrolled in induction study SHP647-301 or SHP647-302, the baseline visit is the Week 12 study visit (with the exception 
of treatment response assessment). For subjects entering from maintenance study SHP647-303, the baseline visit is the Week 52 visit (for subjects who completed the study) 
or the ET visit (for subjects who withdrew early), with the exception of treatment response assessment.
b Eligibility will be assessed after the consent form is signed and after procedures are completed at Visit 6, Part 2 in Study SHP647-301 or SHP647-302, or at Visit 14, Part 2 
or the ET or Week 52 visit in Study SHP647-303.
c Medical history from Studies SHP647-301, SHP647-302, and SHP647-303 will be used as the baseline medical history data for Study SHP647-304.
d Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; 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, eyes, abdomen, and examination of body systems where there are symptom complaints by the subject.
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Table 8
Schedule of Assessments – Treatment Year 1 (Subjects with UC)
Study Procedure
Baselinea
Treatment – Year 1
W0/
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±10 days
e Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of progressive multifocal 
leukoencephalopathy should be excluded. See Section 7.6.1 of Protocol Amendment 4 for further details.
f In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application).
g 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.
h 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.
i
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
j
For confirmation of postmenopausal status in women 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 or maintenance study SHP647-303.
k Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential; see Section 4.3 of 
Protocol Amendment 4.
l
Samples must be collected before administration of investigational product.
m Flexible sigmoidoscopy or colonoscopy (if preferred). Endoscopy is optional for treatment response evaluation after the implementation of Amendment 4; if performed 
(eg, due to routine cancer surveillance required by GI guidelines or due to local clinical practice), the results should be recorded. If more than 2 endoscopies/colonoscopies 
are needed in a year, the subject should be discontinued.
n Mayo score will be based on subject self-report, with the assistance of a memory aid.
o The total Mayo score will be calculated based on the locally read endoscopic subscore (if endoscopy is performed). The total Mayo score will be calculated only when 
endoscopy data are available.
p Measured by clinical composite score and biomarkers, with or without endoscopy. Applicable only after the implementation of Amendment 4.
q Subjects will have the option to fill in a memory aid to collect data at least 7 days before each specified visit. See Section 7.3.2.3 of Protocol Amendment 4 for further details.
r Interactive response technology will be used for dispensation of study treatment.
s Investigational product is to be administered after all other visit assessments have been performed.
t
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).
u 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.
v Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one at which testing will be done.
Note: See Section 7.3 of Protocol Amendment 4 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline.
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16.2
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with UC)
Table 9
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with UC)
Study Procedure
Treatment – Year 2 Through Year 3
Follow-up
W52/
W100
W56/
W104
W60/
W108
W64/
W112
W68/
W116
W72/
W120
W76/
W124
W80/
W128
W84/
W132
W88/
W136
W92/
W140
W96a/
W144
EOT
Visit
12 Weeks
Post-EOTb
Visit Number
14/
26
15/
27
16/
28
17/
29
18/
30
19/
31
20/
32
21/
33
22/
34
23/
35
24/
36
25/
37
Visit Window
±10 days
Complete physical 
examinationc
X
X
Targeted physical 
examinationc
X
Targeted neurological 
assessmentd,e
X
X
X
X
X
X
Vital signs
X
X
X
X
Weight
X
X
X
12-lead ECG (local)
X
X
Laboratory (Central)f
Hematology
X
X
X
X
X
X
Serum chemistryg
X
X
X
X
Urinalysis
X
X
X
X
Urine β-hCGh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception checki
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Stool sample for fecal 
calprotectin
X
X
Serum CRPj
X
X
Endoscopic Procedure
OPTIONAL 
endoscopy (flexible 
sigmoidoscopy or 
colonoscopy)k
O
O
O
O
O
O
O
O
O
O
O
O
O
O
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Table 9
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with UC)
Study Procedure
Treatment – Year 2 Through Year 3
Follow-up
W52/
W100
W56/
W104
W60/
W108
W64/
W112
W68/
W116
W72/
W120
W76/
W124
W80/
W128
W84/
W132
W88/
W136
W92/
W140
W96a/
W144
EOT
Visit
12 Weeks
Post-EOTb
Visit Number
14/
26
15/
27
16/
28
17/
29
18/
30
19/
31
20/
32
21/
33
22/
34
23/
35
24/
36
25/
37
Visit Window
±10 days
UC Assessmentsl
OPTIONAL Total 
Mayo scorem
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Treatment response 
assessmentn,o
X
X
X
X
X
X
Partial Mayo score
X
X
X
Treatment Procedures
Administration of 
ontamalimabp,q
X
X
X
X
X
X
X
X
X
X
X
X
Hypersensitivity 
monitoringr
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
Concomitant 
medication and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool 
collection kit for stool 
samples
X
X
β-hCG=beta-human chorionic gonadotropin; CLIA=Clinical Laboratory Improvement Amendments; CRP=C-reactive protein; DTP=Direct-To-Patient; 
ECG=electrocardiogram; EOT=end of treatment; FDA=Food and Drug Administration; GI=gastrointestinal; LFT=liver function testing; O=optional; UC=ulcerative colitis; 
W=Week.
a
After Treatment Year 1, assessments will be repeated on the subsequent year rotation from Week 52.
b
Subjects will enter a 12-week safety follow-up period, with a visit at the study site at 12 weeks following the EOT visit.
c
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; 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, eyes, abdomen, and examination of body systems where there are symptom complaints by the subject.
d
Subject will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, cognition/behavior. See Section 7.6.1 of Protocol Amendment 4 for further details.
e
In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application).
For non-commercial use only


Shire
CONFIDENTIAL
Page 58
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 9
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with UC)
Study Procedure
Treatment – Year 2 Through Year 3
Follow-up
W52/
W100
W56/
W104
W60/
W108
W64/
W112
W68/
W116
W72/
W120
W76/
W124
W80/
W128
W84/
W132
W88/
W136
W92/
W140
W96a/
W144
EOT
Visit
12 Weeks
Post-EOTb
Visit Number
14/
26
15/
27
16/
28
17/
29
18/
30
19/
31
20/
32
21/
33
22/
34
23/
35
24/
36
25/
37
Visit Window
±10 days
f
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.
g
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.
h
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
i
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential; see Section 4.3 of 
Protocol Amendment 4.
j
Samples must be collected before administration of investigational product.
k
Flexible sigmoidoscopy or colonoscopy (if preferred). Endoscopy is optional for treatment response evaluation after the implementation of Amendment 4; if performed 
(eg, due to routine cancer surveillance required by GI guidelines or due to local clinical practice), the results should be recorded. If more than 2 endoscopies/colonoscopies 
are needed in a year, the subject should be discontinued.
l
Mayo score will be based on subject self-report, with the assistance of a memory aid.
m
The total Mayo score will be calculated based on the locally read endoscopic subscore (if endoscopy is performed). The total Mayo score will be calculated only when 
endoscopy data are available.
n
Measured by clinical composite score and biomarkers, with or without endoscopy. Applicable only after the implementation of Amendment 4.
o
Subjects will have the option to fill in a memory aid to collect data at least 7 days before each specified visit. See Section 7.3.2.3 of Protocol Amendment 4 for further 
details.
p
Investigational product is to be administered after all other visit assessments have been performed.
q
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).
r
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.
s
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one at which testing will be done.
Note: For subjects whose study participation extends beyond Year 3 (ie, subjects already enrolled in this study prior to the implementation of Amendment 4), assessments will 
be repeated on the subsequent year rotation beginning with Week 100.
See Section 7.3 of Protocol Amendment 4 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline.
For non-commercial use only


Shire
CONFIDENTIAL
Page 59
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
16.3
Schedule of Assessments – Treatment Year 1 (Subjects with CD)
Table 10
Schedule of Assessments – Treatment Year 1 (Subjects with CD)
Study Procedure
Baselinea
Treatment – Year 1
W0/
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±10 days
Informed consent/assent
X
Eligibility assessmentb
X
Medical historyc
IDT or MNT
Complete physical examinationd
IDT or MNT
X
Targeted physical examinationd
IDT or MNT
X
X
X
Targeted neurological assessmente,f
IDT or MNT
X
X
X
X
Vital signs
IDT or MNT
X
X
X
X
X
Weight
IDT or MNT
X
X
X
X
X
12-lead ECG (local)
IDT or MNT
X
X
X
Laboratory (Central)g
Hematology
IDT or MNT
X
X
X
X
X
Serum chemistryh
IDT or MNT
X
X
X
X
X
Urinalysis
IDT or MNT
X
X
X
X
X
Urine β-hCGi
IDT or MNT
X
X
X
X
X
X
X
X
X
X
X
X
FSHj
X
Contraception checkk
X
X
X
X
X
X
X
X
X
X
X
X
Stool sample for fecal calprotectin
IDT or MNT
X
X
Serum CRPl
IDT or MNT
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 60
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 10
Schedule of Assessments – Treatment Year 1 (Subjects with CD)
Study Procedure
Baselinea
Treatment – Year 1
W0/
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±10 days
Endoscopic Procedure
OPTIONAL colonoscopym
IDT or MNT
O
O
O
O
O
O
O
O
O
O
O
O
CD Assessmentsn
OPTIONAL SES-CDo
IDT or MNT
O
O
O
O
O
O
O
O
O
O
O
O
CDAI
IDT or MNT
X
X
Treatment response assessmentp,q
IDT
X
X
X
X
Treatment Procedures
Administration of ontamalimabr,s,t
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypersensitivity monitoringu
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
Concomitant medication and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool collection kit for stool 
samplev
X
X
β-hCG=beta-human chorionic gonadotropin; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; CLIA=Clinical Laboratory Improvement Amendments; 
CRP=C-reactive protein; DTP=Direct-To-Patient; ECG=electrocardiogram; ET=early termination; FSH=follicle-stimulating hormone; GI=gastrointestinal; IDT=induction 
study (SHP647-305 or SHP647-306); LFT=liver function testing; MNT=maintenance study SHP647-307; O=optional; SES-CD=Simple Endoscopic Score for Crohn’s Disease; 
W=Week.
a
Baseline = Week 0 (Day 1). For subjects previously enrolled in induction study SHP647-305 or SHP647-306, the baseline visit is the Week 16 study visit (with the 
exception of treatment response assessment). For subjects entering from maintenance study SHP647-307, the baseline visit is the Week 52 visit (for subjects who 
completed the study) or the ET visit (for subjects who withdrew early), with the exception of treatment response assessment.
If results for confirmation of treatment failure are pending at the time of the end of study visit in Study SHP647-307, sites will have 1 additional week to confirm final 
status of the subject (treatment failure or not) before enrolling the subject in Study SHP647-304.
b
Eligibility will be assessed after the consent form is signed and after procedures are completed at Visit 7, Part 2 in Study SHP647-305 or SHP647-306, or at Visit 14, Part 
2 or the ET or Week 52 visit in Study SHP647-307.
c
Medical history from Studies SHP647-305, SHP647-306, and SHP647-307 will be used as the baseline medical history data for Study SHP647-304.
d
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; breast 
(optional); abdomen; external genitalia (optional); extremities; neurologic function; back; and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin and mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, eyes, abdomen, and examination of body 
systems where there are symptom complaints by the subject.
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 10
Schedule of Assessments – Treatment Year 1 (Subjects with CD)
Study Procedure
Baselinea
Treatment – Year 1
W0/
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±10 days
e
Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of progressive multifocal 
leukoencephalopathy should be excluded. See Section 7.6.1 of Protocol Amendment 4 for further details.
f
In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application).
g
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.
h
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.
i
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
j
For confirmation of postmenopausal status in women who have had 12 consecutive months of spontaneous amenorrhea and are 51 years of age. This does not need to be 
performed if postmenopausal status was confirmed by FSH in induction study SHP647-305 or SHP647-306 or maintenance study SHP647-307.
k
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential; see Section 4.3 of 
Protocol Amendment 4.
l
Samples must be collected before administration of investigational product.
m
Colonoscopy is optional for treatment response evaluation after the implementation of Amendment 4; if performed (eg, due to routine cancer surveillance required by 
GI guidelines or due to local clinical practice), the results should be recorded. If more than 2 colonoscopies are needed in a year, the subject should be discontinued.
n
CDAI score will be calculated based on data reported by the subject, with the assistance of a memory aid, as well as data obtained at the site visit.
o
Endoscopies are not required, but if performed, it is recommended that the SES-CD be recorded by the endoscopist for assessment. SES-CD total score will be calculated 
based on the locally read endoscopic subscores for each of the segments investigated.
p
Measured by CDAI score and biomarkers, with or without endoscopy. Applicable only after the implementation of Amendment 4.
q
Subjects will have the option to fill in a memory aid to collect data at least 7 days before each specified visit. See Section 7.3.3.4 of Protocol Amendment 4 for further 
details.
r
Interactive response technology will be used for dispensation of study treatment.
s
Investigational product is to be administered after all other visit assessments have been performed.
t
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).
u
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.
v
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one at which testing will be done.
Note: See Section 7.3 of  Protocol Amendment 4 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline.
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
16.4
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with CD)
Table 11
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with CD)
Study Procedure
Treatment – Year 2 Through Year 3
Follow-
up
W52/
W100
W56/
W104
W60/
W108
W64/
W112
W68/
W116
W72/
W120
W76/
W124
W80/
W128
W84/
W132
W88/
W136
W92/
W140
W96a/
W144
EOT
Visit
12 Weeks 
Post-
EOTb
Visit Number
14/
26
15/
27
16/
28
17/
29
18/
30
19/
31
20/
32
21/
33
22/
34
23/
35
24/
36
25/
37
Visit Window
±10 days
Complete physical 
examinationc
X
X
Targeted physical 
examinationc
X
X
X
X
Targeted neurological 
assessmentd,e
X
X
X
X
X
X
Vital signs
X
X
X
X
Weight
X
X
X
12-lead ECG (local)
X
X
Laboratory (Central)f
Hematology
X
X
X
X
X
X
Serum chemistryg
X
X
X
X
Urinalysis
X
X
X
X
Urine β-hCGh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception checki
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Stool sample for fecal 
calprotectin
X
X
Serum CRPj
X
X
Endoscopic Procedure
OPTIONAL colonoscopyk
O
O
O
O
O
O
O
O
O
O
O
O
O
O
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 11
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with CD)
Study Procedure
Treatment – Year 2 Through Year 3
Follow-
up
W52/
W100
W56/
W104
W60/
W108
W64/
W112
W68/
W116
W72/
W120
W76/
W124
W80/
W128
W84/
W132
W88/
W136
W92/
W140
W96a/
W144
EOT
Visit
12 Weeks 
Post-
EOTb
Visit Number
14/
26
15/
27
16/
28
17/
29
18/
30
19/
31
20/
32
21/
33
22/
34
23/
35
24/
36
25/
37
Visit Window
±10 days
CD Assessmentsl
OPTIONAL SES-CDm
O
O
O
O
O
O
O
O
O
O
O
O
O
O
CDAI
X
X
X
Treatment response 
assessmentn,o
X
X
X
X
X
Treatment Procedures
Administration of 
ontamalimabp,q
X
X
X
X
X
X
X
X
X
X
X
X
Hypersensitivity monitoringr
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
Concomitant medication and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool collection kit 
for stool samples
X
X
β-hCG=beta-human chorionic gonadotropin; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; CLIA=Clinical Laboratory Improvement Amendments; 
CRP=C-reactive protein; DTP=Direct-To-Patient; ECG=electrocardiogram; EOT=end of treatment; FDA=Food and Drug Administration; GI=gastrointestinal; LFT=liver 
function testing; O=optional; SES-CD=Simple Endoscopic Score for Crohn’s Disease; W=Week.
a
After Treatment Year 1, assessments will be repeated on the subsequent year rotation from Week 52.
b
Subjects will enter a 12-week safety follow-up period, with a visit at the study site at 12 weeks following the EOT visit.
c
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; breast
(optional); abdomen, external genitalia (optional); extremities; neurologic function, back, and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin and mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, eyes, abdomen, and examination of body 
systems where there are symptom complaints by the subject.
d
Subject will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, cognition/behavior. See Section 7.6.1 of Protocol Amendment 4 for further details.
e
In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application).
f
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 11
Schedule of Assessments – Treatment Year 2 Through Year 3 and End of Study (Subjects with CD)
Study Procedure
Treatment – Year 2 Through Year 3
Follow-
up
W52/
W100
W56/
W104
W60/
W108
W64/
W112
W68/
W116
W72/
W120
W76/
W124
W80/
W128
W84/
W132
W88/
W136
W92/
W140
W96a/
W144
EOT
Visit
12 Weeks 
Post-
EOTb
Visit Number
14/
26
15/
27
16/
28
17/
29
18/
30
19/
31
20/
32
21/
33
22/
34
23/
35
24/
36
25/
37
Visit Window
±10 days
g
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.
h
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
i
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential; see Section 4.3 of 
Protocol Amendment 4.
j
Samples must be collected before administration of investigational product.
k
Colonoscopy is optional for treatment response evaluation after the implementation of Amendment 4; if performed (eg, due to routine cancer surveillance required by GI 
guidelines or due to local clinical practice), the results should be recorded. If more than 2 colonoscopies are needed in a year, the subject should be discontinued.
l
CDAI score will be calculated based on data reported by the subject, with the assistance of a memory aid, as well as data obtained at the site visit.
m
Endoscopies are not required, but if performed, it is recommended that the SES-CD be recorded by the endoscopist for assessment. SES-CD total score will be calculated 
based on the locally read endoscopic subscores for each of the segments investigated.
n
Measured by CDAI and biomarkers, with or without endoscopy. Applicable only after the implementation of Amendment 4.
o
Subjects will have the option to fill in a memory aid to collect data at least 7 days before each specified visit. See Section 7.3.3.4 of Protocol Amendment 4 for further 
details.
p
Investigational product is to be administered after all other visit assessments have been performed.
q
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).
r
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.
s
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one at which testing will be done.
Note: For subjects whose study participation extends beyond Year 3 (ie, subjects already enrolled in this study prior to the implementation of Amendment 4), assessments will 
be repeated on the subsequent year rotation beginning with Week 100.
See Section 7.3 of Protocol Amendment 4 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline.
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
16.5
Schedule of Assessments Under Amendment 3 – Treatment Year 1 (UC Subjects, Entering from Study SHP647-301, 
SHP647-302, or SHP647-303)
Table 12
Schedule of Assessments – Treatment Year 1 (UC Subjects, Entering from Study SHP647-301, SHP647-302, or 
SHP647-303)
Study Procedure
Baselinea
Treatment – Year 1
W0/
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±10 days
Informed consent/assent
X
Eligibility assessmentb
X
Medical historyc
IDT or MNT
Complete physical examinationd
IDT or MNT
X
Targeted physical examinationd
IDT or MNT
X
Targeted neurological assessmente,f
IDT or MNT
X
X
X
X
Vital signs
IDT or MNT
X
X
X
X
X
Weight
IDT or MNT
X
X
X
X
X
12-lead ECG (local)
IDT or MNT
X
X
X
Laboratory (Central)g
Hematology
IDT or MNT
X
X
X
X
X
Serum chemistryh
IDT or MNT
X
X
X
X
X
Urinalysis
IDT or MNT
X
X
X
X
X
Urine β-Hcgi
IDT or MNT
X
X
X
X
X
X
X
X
X
X
X
X
FSHj
X
Contraception checkk
X
X
X
X
X
X
X
X
X
X
X
X
Stool sample for fecal calprotectin
IDT or MNT
X
X
Serum CRPl
IDT or MNT
X
X
Serum soluble MAdCAMi
IDT or MNT
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 12
Schedule of Assessments – Treatment Year 1 (UC Subjects, Entering from Study SHP647-301, SHP647-302, or 
SHP647-303)
Study Procedure
Baselinea
Treatment – Year 1
W0/
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±10 days
Blood 7+ T cellsi
IDT or MNT
X
X
Pharmacokinetic samplingi
IDT or MNT
X
X
X
X
ADA and NAb samplingi
IDT or MNT
X
X
X
X
Endoscopic Procedure
Endoscopy (flexible sigmoidoscopy or 
colonoscopy)j
IDT or MNT
X
UC Assessmentsk
Total Mayo score
IDT or MNT
Xl
Partial Mayo score
IDT or MNT
X
X
X
PRO-UC daily e-diary data instruction
X
PRO-UC daily e-diary datam
IDT or MNT
X
X
X
X
Health Assessmentsn
IBDQ
IDT or MNT
X
X
EQ-5D-5L
IDT or MNT
X
X
Hospitalizations, inpatient days, ED visits 
(HRUA)
IDT or MNT
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-UC
IDT or MNT
X
X
SF-36-v.2, acute
IDT or MNT
X
X
TSQM
IDT or MNT
X
X
Treatment Procedures
Randomizationo
X
Administration of ontamalimabo,p
X
X
X
X
X
X
X
X
X
X
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 67
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 12
Schedule of Assessments – Treatment Year 1 (UC Subjects, Entering from Study SHP647-301, SHP647-302, or 
SHP647-303)
Study Procedure
Baselinea
Treatment – Year 1
W0/
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±10 days
Hypersensitivity monitoring q
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
Concomitant medication and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool collection kit for stool 
samplev
X
X
β-Hcg=beta-human chorionic gonadotropin; CLIA=Clinical Laboratory Improvement Amendments; CRP=C-reactive protein; DTP=Direct-To-Patient; 
ECG=electrocardiogram; ET=early termination; FDA=Food and Drug Administration; FSH=follicle-stimulating hormone; GI=gastrointestinal; IDT=induction study (SHP647-
301 or SHP647-302); LFT=liver function testing; MNT=maintenance study SHP647-303; O=optional; UC=ulcerative colitis; W=Week.
a
Baseline = Week 0 (Day 1). For subjects previously enrolled in induction study SHP647-301 or SHP647-302, the baseline visit is the Week 12 study visit (with the 
exception of treatment response assessment). For subjects entering from maintenance study SHP647-303, the baseline visit is the Week 52 visit (for subjects who 
completed the study) or the ET visit (for subjects who withdrew early), with the exception of treatment response assessment.
b Eligibility will be assessed after the consent form is signed and after procedures are completed at Visit 6, Part 2 in Study SHP647-301 or SHP647-302, or at Visit 14, Part 2 
or the ET or Week 52 visit in Study SHP647-303.
c Medical history from Studies SHP647-301, SHP647-302, and SHP647-303 will be used as the baseline medical history data for Study SHP647-304.
d Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; 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, eyes, abdomen, and examination of body systems where there are symptom complaints by the subject.
e Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of progressive multifocal 
leukoencephalopathy should be excluded.
f In case of a DTP situation, to be performed by remote visits via virtual communications (eg, TeleHealth application).
g 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.
h 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.
i
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
j
For confirmation of postmenopausal status in women 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 or maintenance study SHP647-303.
k Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential; see Section 4.3 of 
Protocol Amendment 4.
l
Samples must be collected before administration of investigational product.
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 12
Schedule of Assessments – Treatment Year 1 (UC Subjects, Entering from Study SHP647-301, SHP647-302, or 
SHP647-303)
Study Procedure
Baselinea
Treatment – Year 1
W0/
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±10 days
m Flexible sigmoidoscopy or colonoscopy (if preferred). Endoscopy is optional for treatment response evaluation after the implementation of Amendment 4; if performed 
(eg, due to routine cancer surveillance required by GI guidelines or due to local clinical practice), the results should be recorded. If more than 2 endoscopies/colonoscopies 
are needed in a year, the subject should be discontinued.
n Mayo score will be based on subject self-report, with the assistance of a memory aid.
o The total Mayo score will be calculated based on the locally read endoscopic subscore (if endoscopy is performed). The total Mayo score will be calculated only when 
endoscopy data are available.
p Measured by clinical composite score and biomarkers, with or without endoscopy. Applicable only after the implementation of Amendment 4.
q Subjects will have the option to fill in a memory aid to collect data at least 7 days before each specified visit.
r Interactive response technology will be used for dispensation of study treatment.
s Investigational product is to be administered after all other visit assessments have been performed.
t
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).
u 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.
v Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one at which testing will be done.
Note: See Section 7.3 of Protocol Amendment 3 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline.
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
16.6
Schedule of Assessments Under Amendment 3 – Treatment Year 2 Through End of Study (UC Subjects, Entering from 
Study SHP647-301, SHP647-302, or SHP647-303)
Table 13
Schedule of Assessments – Treatment Year 2 Through End of Study (UC Subjects, Entering from 
Study SHP647-301, SHP647-302, or SHP647-303)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96p
EOT
8 W 
post-
EOTq
16 W 
post-
EOTq
Visit Number
14
15
16
17
18
19
20
21
22
23
24
25
Visit Window
±7 days
Complete physical 
examinationa
X
X
Targeted physical 
examinationa
X
Targeted neurological 
assessmentb
X
X
X
X
X
X
Vital signs
X
X
X
X
Weight
X
X
X
12-Lead ECG
X
X
Laboratory
Hematology
X
X
X
X
X
X
Serum chemistry
X
X
X
X
Urinalysis
X
X
X
X
Urine β–hCGc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception checkd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Stool sample for fecal 
calprotectin
X
X
X
Serum CRPe
X
X
X
Serum soluble 
MAdCAMe
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 70
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 13
Schedule of Assessments – Treatment Year 2 Through End of Study (UC Subjects, Entering from 
Study SHP647-301, SHP647-302, or SHP647-303)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96p
EOT
8 W 
post-
EOTq
16 W 
post-
EOTq
Visit Number
14
15
16
17
18
19
20
21
22
23
24
25
Visit Window
±7 days
Blood 7+ T cellse
X
X
X
Pharmacokinetic 
samplinge
Xf
Xf
ADA and NAb 
samplinge
Xf
Xf
X
Endoscopic Procedure
Endoscopy (flexible 
sigmoidoscopy or 
colonoscopy)g
X
Xh
UC Assessmentsi
Total Mayo score
Xj
Xj
Partial Mayo score
X
X
X
PRO-UC daily e-diary 
datak
X
X
X
X
X
Health Assessmentsl
IBDQ
X
X
X
EQ-5D-5L
X
X
X
Hospitalizations, 
inpatient days, ED visits 
(HRUA)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-UC
X
X
X
SF-36-v.2, acute
X
X
X
TSQM
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 71
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 13
Schedule of Assessments – Treatment Year 2 Through End of Study (UC Subjects, Entering from 
Study SHP647-301, SHP647-302, or SHP647-303)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96p
EOT
8 W 
post-
EOTq
16 W 
post-
EOTq
Visit Number
14
15
16
17
18
19
20
21
22
23
24
25
Visit Window
±7 days
Treatment Procedures
Administration of 
ontamalimabm
X
X
X
X
X
X
X
X
X
X
X
X
Hypersensitivity 
monitoring n
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
Concomitant 
medication and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool 
collection kit for stool 
sampleo
X
X
ADA=antidrug antibody; β-hCG=beta-human chorionic gonadotropin; CRP=C-reactive protein; ECG=electrocardiogram; ED=emergency department; e-diary=electronic diary; 
EOT=end of treatment; EQ-5D-5L=European Quality of Life 5 Dimensions, 5 Levels questionnaire; HRUA=Healthcare Resource Utilization Assessment; IBDQ=Inflammatory 
Bowel Disease Questionnaire; MAdCAM=mucosal addressin cell adhesion molecule; NAb=neutralizing antibody; PRO=patient-reported outcome; SF-36=Short Form-36 
Health Survey; TSQM=Treatment Satisfaction Questionnaire for Medication; UC=ulcerative colitis; W=week; WPAI-UC=Work Productivity and Activity Impairment 
Questionnaire – Ulcerative Colitis
a
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; eyes; breast 
(optional); abdomen; external genitalia (optional); extremities; neurologic function; back; and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin, heart, lungs, eyes, abdomen, and examination of body systems where there are symptom complaints by the subject.
b
Subject will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, cognition/behavior. 
c
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
d
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential.
e
Samples must be collected before administration of investigational product.
f
Samples are to be collected in Year 2 only (ie, at Weeks 72 and 96) and not in subsequent years.
g
Flexible sigmoidoscopy or colonoscopy (if preferred). At Week 96 and annually, subjects at risk for colorectal cancer must undergo a colonoscopy (for cancer surveillance, 
including removal of adenomatous polyps with histopathology assessment).
h
Endoscopy is to be done at the EOT visit unless performed for any reason within 12 weeks before the EOT visit.
i
Mayo and PRO-UC assessments will be based on subject daily e-diary entries.
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Shire
CONFIDENTIAL
Page 72
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 13
Schedule of Assessments – Treatment Year 2 Through End of Study (UC Subjects, Entering from 
Study SHP647-301, SHP647-302, or SHP647-303)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96p
EOT
8 W 
post-
EOTq
16 W 
post-
EOTq
Visit Number
14
15
16
17
18
19
20
21
22
23
24
25
Visit Window
±7 days
j
The total Mayo score will be calculated based on the locally read endoscopic subscore.
k
PRO-UC daily e-diary will be available daily throughout the study. Subjects will be required to enter e-diary data at least 10 days before each specified visit. Compliance is 
assessed by site staff at each specified 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.
l
All health outcome/patient-reported questionnaires should be completed before completing any other visit assessments.
m
Investigational product is to be administered after all other visit assessments have been performed.
n
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.
o
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one where testing will be done.
p
After Treatment Year 1, assessments will be repeated on the subsequent year rotation from Week 52.
q
Subjects will enter a 16-week safety follow-up period, with visits at 8 weeks and 16 weeks following the EOT visit. The 8-week visit post-EOT will routinely be conducted 
by telephone; however, as an exception the visit can be performed as a study site visit if preferred. The 16-week visit post-EOT will take place at the study site.
Note: See Section 7.3 of Protocol Amendment 3 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline.
For non-commercial use only


Shire
CONFIDENTIAL
Page 73
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
16.7
Schedule of Assessments Under Amendment 3 – Treatment Year 1 (UC Subjects, Direct Entry)
Table 14
Schedule of Assessments – Treatment Year 1 (UC Subjects, Direct Entry)
Study Procedure
Screeninga
Baseline
Treatment – Year 1
W -6 to -1
W 0/
Day 1
W 4
W 8
W 12
W 
16
W 
20
W 
24
W 
28
W 
32
W 
36
W 
40
W 
44
W 
48
Visit Number
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
-42 to 0
±7 days
Informed consent/assent
X
Eligibility assessment
X
X
Demographics and medical 
historyb
X
Complete physical examinationc
X
X
Targeted physical examinationc
X
X
Targeted neurological assessmentd
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
12-Lead ECGe
X
X
X
X
X
Chest x-rayf
X
Laboratory
Hematology
Xg
X
X
X
X
X
X
Serum chemistry
Xg
X
X
X
X
X
X
Urinalysis
Xg
X
X
X
X
X
X
Stool microbiologyh
Xg
HBsAg, HBcAb, HCVAbi
Xg
HIV testing per local regulationj
X
FSHk
Xg
Serum β–hCGl
Xg
Urine β–hCGl
X
X
X
X
X
X
X
X
X
X
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 74
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 14
Schedule of Assessments – Treatment Year 1 (UC Subjects, Direct Entry)
Study Procedure
Screeninga
Baseline
Treatment – Year 1
W -6 to -1
W 0/
Day 1
W 4
W 8
W 12
W 
16
W 
20
W 
24
W 
28
W 
32
W 
36
W 
40
W 
44
W 
48
Visit Number
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
-42 to 0
±7 days
Contraception checkm
X
X
X
X
X
X
X
X
X
X
X
X
X
TB test (PPD or 
QuantiFERON-TB Gold Plus)n
Xh
JCV antibody banked sampleo
X
Stool sample for fecal calprotectin
X
X
X
Serum CRPp
X
X
X
Serum soluble MAdCAMp
X
X
X
Blood 7+ T cellsp
X
X
X
Pharmacokinetic samplingp
X
X
X
X
X
ADA and NAb samplingp
X
X
X
X
X
Anti-vedolizumab antibody 
sampling p(only for subjects 
previously treated with 
vedolizumab)
X
Endoscopic Procedure
Endoscopy 
(flexible 
sigmoidoscopy or 
colonoscopy)q
Centrally 
read
Xq
Locally 
read
Xq
X
X
UC Assessments
Total Mayo score
Xr
Xr
Partial Mayo score
X
X
X
X
X
Remission stool frequency and 
pre-UC stool frequency
X
PRO-UC daily e-diary data 
instruction
X
X
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Shire
CONFIDENTIAL
Page 75
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 14
Schedule of Assessments – Treatment Year 1 (UC Subjects, Direct Entry)
Study Procedure
Screeninga
Baseline
Treatment – Year 1
W -6 to -1
W 0/
Day 1
W 4
W 8
W 12
W 
16
W 
20
W 
24
W 
28
W 
32
W 
36
W 
40
W 
44
W 
48
Visit Number
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
-42 to 0
±7 days
PRO-UC daily e-diary datas
X
X
X
X
X
X
X
X
Health Assessmentst
IBDQ
X
X
X
EQ-5D-5L
X
X
X
Hospitalizations, inpatient days, 
ED visits (HRUA)
X
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-UC
X
X
X
SF-36-v.2, acute
X
X
X
TSQM
X
X
X
Treatment Procedures
Randomizationu
X
Administration of ontamalimab u,v
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypersensitivity monitoring w
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
Concomitant medication and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool collection kit for 
stool samplex
X
X
X
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Shire
CONFIDENTIAL
Page 76
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 14
Schedule of Assessments – Treatment Year 1 (UC Subjects, Direct Entry)
Study Procedure
Screeninga
Baseline
Treatment – Year 1
W -6 to -1
W 0/
Day 1
W 4
W 8
W 12
W 
16
W 
20
W 
24
W 
28
W 
32
W 
36
W 
40
W 
44
W 
48
Visit Number
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
-42 to 0
±7 days
ADA=antidrug antibody; β-hCG=beta-human chorionic gonadotropin; CRP=C-reactive protein; ECG=electrocardiogram; ED=emergency department; e-diary=electronic diary; 
EQ-5D-5L=European Quality of Life 5 Dimensions, 5 Levels questionnaire; FSH=follicle-stimulating hormone; HBcAb=hepatitis B core antibody; HBsAg=hepatitis B surface 
antigen; HBV=hepatitis B virus; HCVAb=hepatitis C virus antibody; HIV=human immunodeficiency virus; HRUA=Healthcare Resource Utilization Assessment; 
IBDQ=Inflammatory Bowel Disease Questionnaire; JCV=John Cunningham virus; MAdCAM=mucosal addressin cell adhesion molecule; NAb=neutralizing antibody; 
PGA=physician global assessment; PPD=purified protein derivative; PRO=patient-reported outcome; SF-36=Short Form-36 Health Survey; TB=tuberculosis; 
TSQM=Treatment Satisfaction Questionnaire for Medication; UC=ulcerative colitis; W=week; WPAI-UC=Work Productivity and Activity Impairment Questionnaire –
Ulcerative Colitis
a
At least 2 visits will be necessary to complete the screening procedures, including endoscopy.
b
Medical history will include UC history, cardiac history, and smoking history.
c
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; eyes; breast 
(optional); abdomen; external genitalia (optional); extremities; neurologic function; back; and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin, heart, lungs, eyes, abdomen, and examination of body systems where there are symptom complaints by the subject.
d
Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of progressive multifocal 
leukoencephalopathy should be excluded.
e
Vital signs (including blood pressure, pulse, respiratory rate, and temperature) and 12-lead ECG should be performed before collection of blood samples for laboratory 
assessments and before endoscopic procedure.
f
A chest x-ray performed up to 12 weeks before screening may be used if available; the official reading must be located in the subject’s source documentation.
g
Screening laboratory test results, if considered by the investigator to be transient and inconsistent with the subject’s clinical condition, may be repeated once during the 
screening period for confirmation. Results of repeated tests must be reviewed for eligibility prior to the screening endoscopy procedure.
h
Diagnosis of Clostridium difficile infection should be made using the central laboratory. If for any reason the central laboratory is not available, see Appendix 4 of Protocol 
Amendment 3 for guidance regarding alternate diagnostic algorithms. When a subject experiences an increase in gastrointestinal symptoms, which could be an 
exacerbation of disease, an infectious etiology must be evaluated including testing for C. difficile as described in Appendix 4 of Protocol Amendment 3.
i
Subjects who test negative for HBsAg but positive for HBcAb without HBV DNA may be considered eligible. For subjects who test positive for HBcAb and negative for 
HBsAg, a blood sample should be taken for HBV DNA. Blood for HBV DNA reflex testing is collected for required subjects only. If HBV DNA is positive, these subjects 
will not be eligible.
j
Documentation of a negative HIV test result within 6 months prior to screening will be accepted.
k
For confirmation of postmenopausal status in women who have had 12 consecutive months of spontaneous amenorrhea and are 51 years of age.
l
For females of childbearing potential who are not surgically sterile, do not have confirmed ovarian failure, or do not meet the definition of postmenopausal as described in 
Section 4.4.1 and Section 7.2.5.8 of Protocol Amendment 3. The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
m
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential; see Section 4.4 of 
Protocol Amendment 3.
n
A documented negative PPD test within 12 weeks before screening visit is acceptable. Interferon gamma release assay official reading and method or test must be located 
in the source documentation (see Section 7.2.5.7 of Protocol Amendment 3).
o
A serum sample will be collected and banked. It may be analyzed if a subject shows neurologic symptoms suggestive of progressive multifocal leukoencephalopathy.
For non-commercial use only


Shire
CONFIDENTIAL
Page 77
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 14
Schedule of Assessments – Treatment Year 1 (UC Subjects, Direct Entry)
Study Procedure
Screeninga
Baseline
Treatment – Year 1
W -6 to -1
W 0/
Day 1
W 4
W 8
W 12
W 
16
W 
20
W 
24
W 
28
W 
32
W 
36
W 
40
W 
44
W 
48
Visit Number
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
-42 to 0
±7 days
p
The sample must be collected before administration of investigational product.
q
Flexible sigmoidoscopy or colonoscopy (if preferred) at screening must be performed on all subjects after the majority of other eligibility criteria (eg, laboratory values) are 
met. Endoscopy must be performed during the screening period within 10 days before baseline (Visit 1), preferably within 5 to 7 days before the baseline visit, to obtain 
the centrally read endoscopic subscore. The screening endoscopy will be both centrally and locally read. All subsequent endoscopy results will be read only by local 
reader. Subjects at risk of colorectal cancer, as defined in exclusion criterion 5, must have a colonoscopy performed at screening, unless the subject has had a surveillance 
colonoscopy performed within 1 year prior to screening, and any adenomatous polyps found at that examination have been excised. Colonoscopy report and pathology 
report (if biopsies are obtained) from the colonoscopy performed during screening or in the prior year confirming no evidence of dysplasia and colon cancer must be 
available in the source documents. At Week 48, subjects at risk for colorectal cancer must undergo a colonoscopy (for cancer surveillance, including removal of 
adenomatous polyps with histopathology assessment).
r
Mayo score will be based on subject daily e-diary entries. The Mayo score at baseline will be calculated based on the stool frequency subscore and rectal bleeding 
subscore, reported by subjects in the PRO-UC daily e-diary and PGA obtained at baseline and using the centrally and locally read endoscopic subscores for the endoscopy 
performed during the screening period. The centrally read endoscopic subscore will be used for eligibility determination and locally read endoscopic subscore will be used 
for baseline efficacy assessment. At all other visits requiring endoscopy, the Mayo score will be calculated based on the stool frequency subscore and rectal bleeding 
subscore reported by subjects in the PRO-UC daily e diary and PGA and the locally read endoscopic subscore.
s
PRO-UC daily e-diary will be available daily throughout the study. Subjects will be required to enter e-diary data daily through Week 12; thereafter, subjects will be 
required to enter e-diary data for at least 10 days before each specified visit. 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. Compliance will be 
calculated based upon required e-diary data entry as indicated above.
t
All health outcome/patient-reported questionnaires should be completed before completing any other visit assessments.
u
Interactive response technology will be used for randomization and dispensation of study treatment.
v
Investigational product is to be administered after all other visit assessments have been performed.
w
Beginning at Visit 1, 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.
x
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one where testing will be done.
Note: See Section 7.2 of Protocol Amendment 3 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline.
For non-commercial use only


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CONFIDENTIAL
Page 78
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
16.8
Schedule of Assessments Under Amendment 3 – Treatment Year 2 Through End of Study (UC Subjects, Direct Entry)
Table 15
Schedule of Assessments – Treatment Year 2 Through End of Study (UC Subjects, Direct Entry)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96p
EOT
8 W 
post-
EOTq
16 W 
post-
EOTq
Visit Number
15
16
17
18
19
20
21
22
23
24
25
26
Visit Window
±7 days
Complete physical 
examinationa
X
X
Targeted physical 
examinationa
X
Targeted neurological 
assessmentb
X
X
X
X
X
X
Vital signs
X
X
X
X
Weight
X
X
X
12-Lead ECG
X
X
Laboratory
Hematology
X
X
X
X
X
X
Serum chemistry
X
X
X
X
Urinalysis
X
X
X
X
Urine β–hCGc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception checkd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Stool sample for fecal 
calprotectin
X
X
X
Serum CRPe
X
X
X
Serum soluble 
MAdCAMe
X
X
X
Blood 7+ T cellse
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 79
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 15
Schedule of Assessments – Treatment Year 2 Through End of Study (UC Subjects, Direct Entry)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96p
EOT
8 W 
post-
EOTq
16 W 
post-
EOTq
Visit Number
15
16
17
18
19
20
21
22
23
24
25
26
Visit Window
±7 days
Pharmacokinetic 
samplinge
Xf
Xf
ADA and NAb 
samplinge
Xf
Xf
X
Endoscopic Procedure
Locally read endoscopy 
(flexible sigmoidoscopy 
or colonoscopy)g
X
Xh
UC Assessmentsi
Total Mayo score
Xj
Xj
Partial Mayo score
X
X
X
PRO-UC daily e-diary 
datak
X
X
X
X
X
Health Assessmentsl
IBDQ
X
X
X
EQ-5D-5L
X
X
X
Hospitalizations, 
inpatient days, ED visits 
(HRUA)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-UC
X
X
X
SF-36-v.2, acute
X
X
X
TSQM
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 80
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 15
Schedule of Assessments – Treatment Year 2 Through End of Study (UC Subjects, Direct Entry)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96p
EOT
8 W 
post-
EOTq
16 W 
post-
EOTq
Visit Number
15
16
17
18
19
20
21
22
23
24
25
26
Visit Window
±7 days
Treatment Procedures
Administration of 
SHP647m
X
X
X
X
X
X
X
X
X
X
X
X
Hypersensitivity 
monitoringn
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
Concomitant medication 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool 
collection kit for stool 
sampleo
X
X
ADA=antidrug antibody; β-hCG=beta-human chorionic gonadotropin; CRP=C-reactive protein; ECG=electrocardiogram; ED=emergency department; e-diary=electronic diary; 
EOT=end of treatment; EQ-5D-5L=European Quality of Life 5 Dimensions, 5 Levels questionnaire; HRUA=Healthcare Resource Utilization Assessment; IBDQ=Inflammatory 
Bowel Disease Questionnaire; MAdCAM=mucosal addressin cell adhesion molecule; NAb=neutralizing antibody; PRO=patient-reported outcome; SF-36=Short Form-36 
Health Survey; TSQM=Treatment Satisfaction Questionnaire for Medication; UC=ulcerative colitis; W=week; WPAI-UC=Work Productivity and Activity Impairment 
Questionnaire – Ulcerative Colitis
a
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; eyes; breast 
(optional); abdomen; external genitalia (optional); extremities; neurologic function; back; and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin, heart, lungs, eyes, abdomen, and examination of body systems where there are symptom complaints by the subject.
b
Subject will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, cognition/behavior. 
c
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
d
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential.
e
Samples must be collected before administration of investigational product.
f
Samples are to be collected in Year 2 only (ie, at Weeks 72 and 96) and not in subsequent years.
g
Flexible sigmoidoscopy or colonoscopy (if preferred). At Week 96 and annually, subjects at risk for colorectal cancer must undergo a colonoscopy (for cancer surveillance, 
including removal of adenomatous polyps with histopathology assessment).
h
Endoscopy is to be done at the EOT visit unless performed for any reason within 12 weeks before the EOT visit.
i
Mayo and PRO-UC assessments will be based on subject daily e-diary entries.
j
The total Mayo score will be calculated based on the locally read endoscopic subscore.
For non-commercial use only


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CONFIDENTIAL
Page 81
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 15
Schedule of Assessments – Treatment Year 2 Through End of Study (UC Subjects, Direct Entry)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96p
EOT
8 W 
post-
EOTq
16 W 
post-
EOTq
Visit Number
15
16
17
18
19
20
21
22
23
24
25
26
Visit Window
±7 days
k
PRO-UC daily e-diary will be available daily throughout the study. Subjects will be required to enter e-diary data at least 10 days before each specified visit. Compliance is 
assessed by site staff at each specified 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.
l
All health outcome/patient-reported questionnaires should be completed before completing any other visit assessments.
m
Investigational product is to be administered after all other visit assessments have been performed.
n
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. 
o
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one where testing will be done.
p
After Treatment Year 1, assessments will be repeated on the subsequent year rotation from Week 52.
q
Subjects will enter a 16-week safety follow-up period, with visits at 8 weeks and 16 weeks following the EOT visit. The 8-week visit post-EOT will routinely be conducted 
by telephone; however, as an exception the visit can be performed as a study site visit if preferred. The 16-week visit post-EOT will take place at the study site.
Note: See Section 7.2 of Protocol Amendment 3 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline.
For non-commercial use only


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CONFIDENTIAL
Page 82
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
16.9
Schedule of Assessments Under Amendment 3 – Treatment Year 1 (CD Subjects, Entering from Study SHP647-305, 
Study SHP647-306, or Study SHP647-307)
Table 16
Schedule of Assessments – Treatment Year 1 (CD Subjects, Entering from Study SHP647-305, Study SHP647-
306, or Study SHP647-307)
Study Procedure
Baselinea
Treatment – Year 1
W 0/
Day 1
W 4
W 8
W 12
W 16
W 20
W 24
W 28
W 32
W 36
W 40
W 44
W 48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±7 days
Informed consent/assent
X
Eligibility assessmentb
X
Medical historyc
IDT or MNT
Complete physical 
examinationd
IDT or MNT
X
Targeted physical 
examinationd
IDT or MNT
X
X
X
Targeted neurological 
assessmente
IDT or MNT
X
X
X
X
Vital signs
IDT or MNT
X
X
X
X
X
Weight
IDT or MNT
X
X
X
X
X
12-Lead ECG
IDT or MNT
X
X
X
Laboratory
Hematology
IDT or MNT
X
X
X
X
X
Serum chemistry
IDT or MNT
X
X
X
X
X
Urinalysis
IDT or MNT
X
X
X
X
X
Urine β–hCGf
IDT or MNT
X
X
X
X
X
X
X
X
X
X
X
X
FSHg
X
Contraception checkh
X
X
X
X
X
X
X
X
X
X
X
X
Stool sample for fecal 
calprotectin
IDT or MNT
X
X
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CONFIDENTIAL
Page 83
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 16
Schedule of Assessments – Treatment Year 1 (CD Subjects, Entering from Study SHP647-305, Study SHP647-
306, or Study SHP647-307)
Study Procedure
Baselinea
Treatment – Year 1
W 0/
Day 1
W 4
W 8
W 12
W 16
W 20
W 24
W 28
W 32
W 36
W 40
W 44
W 48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±7 days
Serum CRPi
IDT or MNT
X
X
Serum soluble MAdCAMi
IDT or MNT
X
X
Blood 7+ T cellsi
IDT or MNT
X
X
Pharmacokinetic samplingi
IDT or MNT
X
X
X
X
ADA and NAb samplingi
IDT or MNT
X
X
X
X
CD Assessmentsj Including 
Endoscopic Procedure
Colonoscopy
IDT or MNT
X
SES-CD
IDT or MNT
X
CDAI
IDT or MNT
X
X
X
Xk
PRO-CD daily e-diary data 
instruction
X
PRO-CD daily e-diary datal
IDT or MNT
X
X
X
X
Health Assessmentsm
IBDQ
IDT or MNT
X
X
EQ-5D-5L
IDT or MNT
X
X
Hospitalizations, inpatient 
days, ED visits (HRUA)
IDT or MNT
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-CD
IDT or MNT
X
X
SF-36-v.2, acute
IDT or MNT
X
X
TSQM
IDT or MNT
X
X
For non-commercial use only


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CONFIDENTIAL
Page 84
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 16
Schedule of Assessments – Treatment Year 1 (CD Subjects, Entering from Study SHP647-305, Study SHP647-
306, or Study SHP647-307)
Study Procedure
Baselinea
Treatment – Year 1
W 0/
Day 1
W 4
W 8
W 12
W 16
W 20
W 24
W 28
W 32
W 36
W 40
W 44
W 48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±7 days
Treatment Procedures
Randomizationn
X
Administration of 
ontamalimabn,o
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypersensitivity monitoringp
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
Concomitant medication and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool collection kit
for stool sampleq
X
X
ADA=antidrug antibody; β-hCG=beta-human chorionic gonadotropin; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; CRP=C-reactive protein; 
ECG=electrocardiogram; ED=emergency department; e-diary=electronic diary; EQ-5D-5L=European Quality of Life 5 Dimensions, 5 Levels questionnaire; ET=early 
termination; FSH=follicle-stimulating hormone; HRUA=Healthcare Resource Utilization Assessment; IBDQ=Inflammatory Bowel Disease Questionnaire; IDT=induction 
study (SHP647-305 or SHP647-306); MAdCAM=mucosal addressin cell adhesion molecule; MNT=Maintenance Study SHP647-307; NAb=neutralizing antibody; 
PRO=patient-reported outcome; SES-CD=Simple Endoscopic Score for Crohn’s Disease; SF-36=Short Form-36 Health Survey; TSQM=Treatment Satisfaction Questionnaire 
for Medication; W=week; WPAI-CD=Work Productivity and Activity Impairment Questionnaire – Crohn’s Disease.
a
Baseline = Week 0 (Day 1). For subjects previously enrolled in induction study SHP647-305 or SHP647-306, the baseline visit is the Week 16 study visit. For subjects 
entering from maintenance study SHP647-307, the baseline visit is the Week 52 visit (for subjects who completed the study) or the ET visit (for subjects who withdrew 
early).
If results for confirmation of treatment failure are pending at the time of the end of study visit in study SHP647-307, sites will have 1 additional week to confirm final 
status of the subject (treatment failure or not) before enrolling the subject to study SHP647-304.
b
Eligibility will be assessed after the consent form is signed and after procedures are completed at Visit 7, Part 2 in study SHP647-305 or SHP647-306, or at Visit 14, Part 2 
or the ET visit in study SHP647-307.
c
Medical history from studies SHP647-305, SHP647-306 and SHP647-307 will be used as the baseline medical history data for study SHP647-304.
d
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; eyes; breast 
(optional); abdomen; external genitalia (optional); extremities; neurologic function; back; and lymph nodes. Targeted physical examination includes the review of the 
following body systems: skin and mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, eyes, abdomen, and examination of body 
systems where there are symptom complaints by the subject. 
e
Subjects will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, and cognition/behavior. Subjects with any unexplained positive item at screening that is suggestive of progressive multifocal 
leukoencephalopathy should be excluded.
For non-commercial use only


Shire
CONFIDENTIAL
Page 85
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 16
Schedule of Assessments – Treatment Year 1 (CD Subjects, Entering from Study SHP647-305, Study SHP647-
306, or Study SHP647-307)
Study Procedure
Baselinea
Treatment – Year 1
W 0/
Day 1
W 4
W 8
W 12
W 16
W 20
W 24
W 28
W 32
W 36
W 40
W 44
W 48
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window
None
±7 days
f
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
g
For confirmation of postmenopausal status in women who have had 12 consecutive months of spontaneous amenorrhea and are 51 years of age. This does not need to be 
performed if postmenopausal status was confirmed by FSH in induction study SHP647-305 or SHP647-306 or maintenance study SHP647-307.
h
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential.
i
Samples must be collected before administration of investigational product.
j
PRO assessments will be based on subject daily e-diary entries. CDAI score will be calculated based on data collected in the subject diary as well as data obtained at the 
site visit.
k
SES-CD total score will be calculated based on the locally read endoscopic subscores for each of the segments investigated.
l
PRO-CD daily e-diary will be available daily throughout the study, Subjects will be required to enter e-diary data at least 14 days before each specified visit. Compliance 
is assessed by site staff at each specified visit. The site staff will instruct the subject on the appropriate use of the e-diary, particularly when compliance is below 80% (eg, 
<12 out of 14 diary entries) when compared with the previous visit.
m
All health outcome/patient-reported questionnaires should be completed before completing any other visit assessments.
n
Interactive response technology will be used for randomization and dispensation of study treatment.
o
Investigational product is to be administered after all other visit assessments have been performed.
p
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.
q
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one where testing will be done.
Note: See Section 7.2 of Protocol Amendment 3 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline.
For non-commercial use only


Shire
CONFIDENTIAL
Page 86
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
16.10 Schedule of Assessments Under Amendment 3 – Treatment Year 2 Through End of Study (CD Subjects, Entering 
from Study SHP647 305, SHP647-306, or SHP647-307)
Table 17
Schedule of Assessments – Treatment Year 2 Through End of Study (CD Subjects, Entering from 
Study SHP647-305, SHP647-306, or SHP647-307)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96o
EOT
8 W 
post-
EOTp
16 W 
post-
EOTp
Visit Number
14
15
16
17
18
19
20
21
22
23
24
25
Visit Window
±7 days
Complete physical 
examinationa
X
X
Targeted physical 
examinationa
X
X
X
X
Targeted neurological 
assessmentb
X
X
X
X
X
X
Vital signs
X
X
X
X
Weight
X
X
X
12-Lead ECG
X
X
Laboratory
Hematology
X
X
X
X
X
X
Serum chemistry
X
X
X
X
Urinalysis
X
X
X
X
Urine β–hCGc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception checkd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Stool sample for fecal 
calprotectin
X
X
X
Serum CRPe
X
X
X
Serum soluble 
MAdCAMe
X
X
X
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CONFIDENTIAL
Page 87
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 17
Schedule of Assessments – Treatment Year 2 Through End of Study (CD Subjects, Entering from 
Study SHP647-305, SHP647-306, or SHP647-307)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96o
EOT
8 W 
post-
EOTp
16 W 
post-
EOTp
Visit Number
14
15
16
17
18
19
20
21
22
23
24
25
Visit Window
±7 days
Blood 7+ T cellse
X
X
X
Pharmacokinetic 
samplinge
Xf
Xf
ADA and NAb 
samplinge
Xf
Xf
X
CD Assessmentsg 
Including Endoscopic 
Procedure
Colonoscopy
X
Xh
SES-CD
Xi
Xi
CDAI
X
X
X
X
X
PRO-CD daily e-diary 
dataj
X
X
X
X
X
Health Assessmentsk
IBDQ
X
X
X
EQ-5D-5L
X
X
X
Hospitalizations, 
inpatient days, ED
visits (HRUA)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-CD
X
X
X
SF-36-v.2, acute
X
X
X
TSQM
X
X
X
Treatment 
Procedures
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Shire
CONFIDENTIAL
Page 88
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 17
Schedule of Assessments – Treatment Year 2 Through End of Study (CD Subjects, Entering from 
Study SHP647-305, SHP647-306, or SHP647-307)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96o
EOT
8 W 
post-
EOTp
16 W 
post-
EOTp
Visit Number
14
15
16
17
18
19
20
21
22
23
24
25
Visit Window
±7 days
Administration of 
ontamalimabl
X
X
X
X
X
X
X
X
X
X
X
X
Hypersensitivity 
monitoring m
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
Concomitant 
medication and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool 
collection kit for stool 
samplen
X
X
ADA=antidrug antibody; β-hCG=beta-human chorionic gonadotropin; CD=Crohn’s disease; CDAI=Crohn’s Disease Activity Index; CRP=C-reactive protein; 
ECG=electrocardiogram; ED=emergency department; e-diary=electronic diary; EOT=end of treatment; EQ-5D-5L=European Quality of Life 5 Dimensions, 5 Levels 
questionnaire; HRUA=Healthcare Resource Utilization Assessment; IBDQ=Inflammatory Bowel Disease Questionnaire; MAdCAM=mucosal addressin cell adhesion 
molecule; NAb=neutralizing antibody; PRO=patient-reported outcome; SES-CD=Simple Endoscopic Score for Crohn’s Disease; SF-36=Short Form-36 Health Survey; 
TSQM=Treatment Satisfaction Questionnaire for Medication; W=week; WPAI-CD=Work Productivity and Activity Impairment Questionnaire – Crohn’s Disease.
a
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; eyes; 
breast (optional); abdomen, external genitalia (optional); extremities; neurologic function, back, and lymph nodes. Targeted physical examination includes the review 
of the following body systems: skin and mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, eyes, abdomen, and 
examination of body systems where there are symptom complaints by the subject.
b
Subject will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, cognition/behavior.
c
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
d
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential.
e
Samples must be collected before administration of investigational product.
f
Samples are to be collected in Year 2 only (ie, at Weeks 72 and 96) and not in subsequent years.
g
PRO assessments will be based on subject daily e-diary entries. CDAI score will be calculated based on data collected on patient diary as well as data obtained at the 
site visit.
h
Complete physical examination includes the review of the following body systems: general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; eyes; 
For non-commercial use only


Shire
CONFIDENTIAL
Page 89
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 17
Schedule of Assessments – Treatment Year 2 Through End of Study (CD Subjects, Entering from 
Study SHP647-305, SHP647-306, or SHP647-307)
Study Procedure
Treatment – Subsequent Years
Follow-up
W 52
W 56
W 60
W 64
W 68
W 72
W 76
W 80
W 84
W 88
W 92
W 96o
EOT
8 W 
post-
EOTp
16 W 
post-
EOTp
Visit Number
14
15
16
17
18
19
20
21
22
23
24
25
Visit Window
±7 days
breast (optional); abdomen, external genitalia (optional); extremities; neurologic function, back, and lymph nodes. Targeted physical examination includes the review 
of the following body systems: skin and mucosa (specifically including perianal for fistula and oral cavity for stomatitis), heart, lungs, eyes, abdomen, and 
examination of body systems where there are symptom complaints by the subject.
i
Subject will be evaluated to reveal any potential abnormalities in the following neurologic domains: vision, motor, tactile sensation, coordination/cerebellar function, 
speech, verbal comprehension, cognition/behavior.
j
The urine pregnancy test will be performed at the site using test kits supplied by the central laboratory.
k
Contraception check should be made for female subjects of childbearing potential and male subjects who are with a partner of childbearing potential.
l
Samples must be collected before administration of investigational product.
m
Samples are to be collected in Year 2 only (ie, at Weeks 72 and 96) and not in subsequent years.
n
PRO assessments will be based on subject daily e-diary entries. CDAI score will be calculated based on data collected on patient diary as well as data obtained at the 
site visit.
o
Colonoscopy is to be done at the EOT visit unless performed for any reason within 12 weeks before the EOT visit.
p
SES-CD total score will be calculated based on the locally read endoscopic subscores for each of the segments investigated.
q
PRO-CD daily e-diary will be available daily throughout the study. Subjects will be required to enter e-diary data at least 14 days before each specified visit. 
Compliance is assessed by site staff at each specified visit. The site staff will instruct the subject on the appropriate use of the e-diary, particularly when compliance is 
below 80% (eg, <12 out of 14 diary entries) when compared with the previous visit.
r
All health outcome/patient-reported questionnaires should be completed before completing any other visit assessments.
s
Investigational product is to be administered after all other visit assessments have been performed.
t
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.
u
Stool sample collection kit will be dispensed to the subject to take home at the visit prior to the one where testing will be done.
v
After Treatment Year 1, assessments will be repeated on the subsequent year rotation from Week 52.
w
Subjects will enter a 16-week safety follow-up period, with visits at 8 weeks and 16 weeks following the EOT visit. The 8-week visit post-EOT will routinely be 
conducted by telephone; however, as an exception the visit can be performed as a study site visit if preferred. The 16-week visit post-EOT will take place at the study 
site.
Note: See Section 7.2 of Protocol Amendment 3 for the order in which assessments should be performed. Timing of visits is relative to SHP647-304 baseline.
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CONFIDENTIAL
Page 90
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
16.11 Geographic Regions  
Table 18
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
France
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
Lebanon
ROW
Israel
ROW
Mexico
ROW
New Zealand
ROW
South Africa
ROW
Turkey
ROW
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Page 91
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
Table 18
Geographic Regions
Country
Region
Canada
North America
United States
North America
ROW (Africa/Australia/Latin America/Middle East); Asia (Japan/South Korea)
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Page 92
Protocol Number: SHP647-304
Statistical Analysis Plan v2.0
06 Sep 2022
16.12 Treatment Groups
Data will be presented by SHP647-304 treatment group as follows:

Ontamalimab 25 mg (subjects who enrolled and terminated prior to SHP647-304 
Amendment 4)

Ontamalimab 25 mg then 75 mg (subjects who were enrolled prior to SHP647-304 
Amendment 4 and received 25 mg)

Ontamalimab 75 mg (subjects who received 75 mg prior to Amendment 4 or enrolled 
under SHP647-304 Amendment 4)

All doses*
                                                
* Treatment groups with * will not be shown in the secondary endpoint’s summary tables.
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