Clinical trial NCT02611817
Conditions: Crohn's Disease
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2016-01-04; Completion date: 2019-08-06
Enrollment: 644 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effect of vedolizumab subcutaneous (vedolizumab SC) as maintenance treatment in participants with moderately to severely active CD who achieved clinical response following administration of vedolizumab intravenous (vedolizumab IV) induction therapy.

Detailed description:
The drug being tested in this study is called vedolizumab SC. Vedolizumab SC is being tested to treat people who have moderate to severely active CD. This study will look at clinical remission, as well as enhanced clinical response and corticosteroid-free remission in participants with CD who receive vedolizumab SC maintenance therapy after having achieved a clinical response to vedolizumab IV induction therapy.

The study will enroll approximately 824 participants. All participants will enter a 6 week Induction Phase where they will be administered open-label vedolizumab IV 300 mg via IV infusion at Week 0 (Day 1) and Week 2 (Day 15), and will then be assessed for a clinical response at Week 6. Participants who achieve a clinical response at Week 6 will be randomly assigned to one of the two treatment groups:

* Vedolizumab SC 108 mg Maintenance Arm
* Placebo SC Maintenance Arm

Participants who do not achieve a clinical response will not be randomized into the Maintenance Period, and instead will receive a third infusion of vedolizumab IV 300 mg at Week 6.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is up to 71 weeks. Participants will make multiple visits to the clinic, plus a final visit 18 weeks after last dose of study drug for a follow-up assessment. Participants will also participate in a long-term safety follow-up, by phone, at 6 months after the last dose of study drug.

Arms: arm 1: Open-label Induction: vedolizumab IV 300 milligram (mg), infusion at Week 0 (Day 1) and Week 2 (Day 15)

Double-blind Maintenance: vedolizumab SC 108 mg injection once every 2 weeks (Q2W) starting at Week 6 up to Week 50 arm 2: Open-label Induction: vedolizumab IV 300 mg, infusion at Week 0 (Day 1) and Week 2 (Day 15)

Double-blind Maintenance: matching placebo to vedolizumab SC injection Q2W starting at Week 6 up to Week 50
Interventions: intervention 1: Vedolizumab SC 108 mg intervention 2: Placebo intervention 3: Vedolizumab IV 300 mg
Intervention descriptions: intervention 1: Vedolizumab SC Injection. intervention 2: Vedolizumab placebo-matching SC injection. intervention 3: Vedolizumab IV Injection.

Protocol documents:
Prot_000.pdf: 



Title:  Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Vedolizumab Subcutaneous as Maintenance Therapy in Subjects With Moderately to 
Severely Active Crohn’s Disease Who Achieved Clinical Response Following Open-Label 
Vedolizumab Intravenous Therapy
NCT Number: NCT02611817
Protocol Approve Date: 24 August 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Vedolizumab Subcutaneous as Maintenance Therapy in Subjects With Moderately to 
Severely Active Crohn’s Disease Who Achieved Clinical Response Following Open-Label 
Vedolizumab Intravenous Therapy
Efficacy and Safety of Vedolizumab SC as Maintenance Therapy in Crohn’s Disease
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway, Deerfield, IL 60015
Takeda Development Centre Europe, Ltd.
61 Aldwych, London, WC2B 4AE
United Kingdom
Takeda Development Center Asia, Pte. Ltd.
Biopolis Road, Nucleos North Tower Level 4
Singapore, 138567
Takeda Pharmaceutical Company Limited, 
1-1, Doshomachi 4-Chome, Chuo-ku Osaka 540-8645, Japan
Study Number:
MLN0002SC-3031
IND Number:
118980
EudraCT Number:
2015-000481-58
Compound:
Vedolizumab SC
Date:
24 August 2017
Amendment Number:
06
Amendment History: 
Date
Amendment Number
Amendment Type
Region
26 February 2015
Initial Protocol
Not applicable
Global
12 October 2015
01
Substantial
Global
10 February 2016
02
Substantial
Global
12 May 2016
03
Substantial
Global
28 July 2016
04
Substantial
Global
28 September 2016
05
Substantial
Japan
24 August 2017
06
Substantial
Global
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1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts
A separate contact information list will be provided to each site.
TDC sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Americas, Europe, Asia and Japan 
TDC Contact 
Serious adverse event and pregnancy reporting
Medical Monitor
(medical advice on protocol and compound)
Responsible Medical Officer 
(carries overall responsibility for the 
conduct of the study)
Property of Takeda: For non-commercial
ialal
 the applicable Terms of Use
ssigned 
signed
nt guide
t guid
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he 
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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer can be found on the signature page.
Electronic Signatures may be found on the last page of this document.
bject to the applicable Terms of Use
da
dance
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wing:
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure or
package insert as applicable, and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the life, 
dignity, integrity, confidentiality of personal information, rights, safety, privacy, and well-being of 
study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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1.3
Protocol Amendment 06 Summary of Changes
Rationale for Amendment No. 06
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 06. 
The primary reason for this amendment is to include a pre-Week 14 visit and to clarify the
Week 14 procedures for subjects who enroll and do not enroll into the open-label extension (OLE) 
study (MLN0002SC-3030). Minor grammatical, editorial, and formatting changes are included for 
clarification purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix H. 
Changes in Amendment 06
1. Clarification of the Sponsor address in Japan.
2. Administrative change to the Responsible Medical Officer and Approvers.
3. Inclusion of an additional secondary objective and endpoint, and exploratory endpoint.
4. Clarification to the Final Visit/Early Termination procedures for subjects who complete (OLE 
Enroller/Nonenroller) at Week 14 (Induction Phase), and subjects who complete (Week 52) or 
discontinue from the Maintenance Phase.
5. Clarification to the study design schematic.
6. Study design updated to clarify that all endoscopies will be centrally read.
7. Clarification to Inclusion Criterion #11.
8. Clarification to Exclusion Criterion #5.
9. Clarification to Exclusion Criterion #15.
10. Clarification to Exclusion Criterion #20.
11. Clarification to the period for excluded medications and treatments.
12. Clarification to Section 9.1.5 Vital Signs Procedure.
13. Clarification to Section 9.1.6.1 Diary Completion and Review.
14. ECG procedure updated.
15. Addition of a Pre–Week 14 visit for Week 6 nonresponders.
16. Update to Appendix A Schedule of Study Procedures for Crohn’s disease–related events.
17. Update to Appendix B Responsibilities of the Investigator.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 06 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Principal Investigator/Coordinating Investigator ......................................................15
3.3
List of Abbreviations ...............................................................................................16
3.4
Corporate Identification...........................................................................................18
3.5
Study Definitions.....................................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.1.1
Diseases and Current Treatments .......................................................................19
4.1.2
Vedolizumab......................................................................................................20
4.1.2.1 Nonclinical...................................................................................................21
4.1.2.2 Clinical Experience With Vedolizumab IV...................................................22
4.1.2.3 Clinical Experience With Vedolizumab SC ..................................................24
4.2
Rationale for the Proposed Study.............................................................................26
4.3
Benefit:Risk Assessment..........................................................................................27
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................28
5.1
Objectives................................................................................................................28
5.1.1
Primary Objective(s)..........................................................................................28
5.1.2
Secondary Objectives.........................................................................................28
5.1.3
Exploratory Objectives.......................................................................................28
5.2
Endpoints.................................................................................................................29
5.2.1
Primary Endpoints .............................................................................................29
5.2.2
Secondary Endpoints..........................................................................................29
5.2.3
PRO Endpoints ..................................................................................................29
5.2.4
Exploratory Endpoints .......................................................................................30
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................32
6.1
Study Design ...........................................................................................................32
6.2
Justification for Study Design, Dose, and Endpoints ................................................36
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6.3
Premature Termination or Suspension of Study or Investigational Site.....................38
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................38
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........38
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................38
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............40
7.1
Inclusion Criteria .....................................................................................................40
7.2
Exclusion Criteria ....................................................................................................42
7.2.1
Gastrointestinal Exclusion Criteria.....................................................................42
7.2.2
Infectious Disease Exclusion Criteria.................................................................43
7.2.3
General Exclusion Criteria .................................................................................44
7.3
Excluded Medications and Treatments.....................................................................45
7.3.1
Permitted Medications and Treatments...............................................................46
7.3.1.1 Oral Corticosteroid Dosing and Tapering .....................................................47
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................47
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................49
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................50
8.1
Study Medication and Materials...............................................................................50
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................50
8.1.1.1 Vedolizumab for Injection, for Intravenous Use (Vedolizumab IV)..............50
8.1.1.2 Vedolizumab Injection, for Subcutaneous Use (Vedolizumab SC)................50
8.1.1.3 Sponsor-Supplied Drug ................................................................................51
8.1.1.4 Other Protocol-Specified Materials...............................................................51
8.1.2
Storage...............................................................................................................51
8.1.3
Dose and Regimen .............................................................................................51
8.1.4
Overdose............................................................................................................52
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................52
8.3
Randomization Code Creation and Storage..............................................................53
8.4
Investigational Drug Blind Maintenance and Unblinding .........................................53
8.5
Accountability and Destruction of Sponsor-Supplied Drugs.....................................54
9.0
STUDY PLAN ..............................................................................................................56
9.1
Study Procedures.....................................................................................................56
9.1.1
Informed Consent Procedure..............................................................................56
9.1.1.1
............................................56
9.1.1.2
...........................................56
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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9.1.2
Demographics, Medical History, and Medication History Procedure..................56
9.1.3
Physical Examination Procedure ........................................................................57
9.1.4
Weight and Height .............................................................................................57
9.1.5
Vital Sign Procedure..........................................................................................57
9.1.6
Primary Efficacy Measurement ..........................................................................57
9.1.6.1 Diary Completion and Review......................................................................57
9.1.7
Documentation of Concomitant Medications......................................................58
9.1.8
Documentation of Concurrent Medical Conditions.............................................58
9.1.9
Procedures for Clinical Laboratory Samples.......................................................58
9.1.10 Contraception and Pregnancy Avoidance Procedure...........................................60
9.1.11 Pregnancy ..........................................................................................................61
9.1.12 ECG Procedure..................................................................................................62
9.1.13
...................................................................62
9.1.14 Pharmacokinetic Sample Collection...................................................................62
9.1.15
................................................................62
9.1.16 Tuberculosis Screening ......................................................................................63
9.1.17 Fecal Calprotectin Sample Collection.................................................................64
9.1.18 Stool Sample......................................................................................................64
9.1.19 PML Checklist...................................................................................................64
9.1.20 Patient Reported Outcomes Instruments.............................................................64
9.1.20.1
Inflammatory Bowel Disease Questionnaire ...........................................64
9.1.20.2
EQ-5D Questionnaire .............................................................................64
9.1.20.3
Work Productivity and Activity Impairment-CD.....................................65
9.1.21
................................................................................65
9.1.22 Documentation of Screen Failure .......................................................................65
9.1.23 Documentation of Study Entrance......................................................................66
9.2
Monitoring Subject Treatment Compliance..............................................................66
9.3
Schedule of Observations and Procedures................................................................66
9.3.1
Screening...........................................................................................................66
9.3.2
Enrollment/Randomization.................................................................................66
9.3.2.1 Nonresponders .............................................................................................67
9.3.3
Final Visit or ET ................................................................................................67
9.3.4
Final Safety Follow-up Visit ..............................................................................68
9.3.5
Post Study 6-month Long-Term Follow-Up Survey ...........................................68
9.3.6
Unscheduled Visits Due to Disease Exacerbation...............................................68
Property of Takeda: For n
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9.3.7
Poststudy Care ...................................................................................................69
9.4
Biological Sample Retention and Destruction ..........................................................69
10.0
PRETREATMENT EVENTS (PTE) ADVERSE EVENTS (AE) AND PRODUCT 
COMPLAINTS (PC).....................................................................................................70
10.1
Definitions...............................................................................................................70
10.1.1 PTEs..................................................................................................................70
10.1.2 AEs....................................................................................................................70
10.1.3 Additional Points to Consider for PTEs and AEs................................................70
10.1.4 SAEs..................................................................................................................72
10.1.5 Special Interest AEs...........................................................................................73
10.1.6 Severity of PTEs and AEs..................................................................................73
10.1.7 Causality of AEs ................................................................................................74
10.1.8 Relationship to Study Procedures.......................................................................74
10.1.9 Start Date...........................................................................................................74
10.1.10
Stop Date .....................................................................................................74
10.1.11
Frequency ....................................................................................................74
10.1.12
Action Concerning Study Medication...........................................................74
10.1.13
Outcome.......................................................................................................75
10.1.14
Product Complaints......................................................................................75
10.2
Procedures...............................................................................................................75
10.2.1 Collection and Reporting of AEs........................................................................75
10.2.1.1
PTE and AE Collection Period ...............................................................75
10.2.1.2
PTE and AE Reporting ...........................................................................76
10.2.1.3
Adverse Event Collection Involving Medically Anticipated Clinical 
Events ..........................................................................................................77
10.2.1.4
Special Interest AE Reporting.................................................................77
10.2.2 Collection and Reporting of SAEs......................................................................78
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................79
10.3
Follow-up of SAEs ..................................................................................................79
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....79
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................81
11.1
Data Safety Monitoring Board .................................................................................81
11.2
Adjudication Committee..........................................................................................81
11.2.1 Risk Minimization Action Plan for PML (RAMP Program) ...............................81
12.0
DATA HANDLING AND RECORD KEEPING...........................................................83
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12.1
Electronic CRFs.......................................................................................................83
12.2
Record Retention .....................................................................................................83
13.0
STATISTICAL METHODS..........................................................................................85
13.1
Statistical and Analytical Plans ................................................................................85
13.1.1 Analysis Sets......................................................................................................85
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................85
13.1.3 Efficacy Analysis...............................................................................................85
13.1.4 Resource Utilization and PRO............................................................................86
13.1.5 Pharmacokinetic Analysis ..................................................................................86
13.1.6 Other Analysis ...................................................................................................86
13.1.7 Safety Analysis ..................................................................................................87
13.2
Interim Analysis and Criteria for Early Termination ................................................87
13.3
Determination of Sample Size..................................................................................88
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................89
14.1
Study-Site Monitoring Visits ...................................................................................89
14.2
Protocol Deviations..................................................................................................89
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................90
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................91
15.1
IRB and/or IEC Approval ........................................................................................91
15.2
Subject Information, Informed Consent, and Subject Authorization .........................92
15.3
Subject Confidentiality ............................................................................................93
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................93
15.4.1 Publication and Disclosure.................................................................................93
15.4.2 Clinical Trial Registration..................................................................................94
15.4.3 Clinical Trial Results Disclosure ........................................................................94
15.5
Insurance and Compensation for Injury....................................................................94
16.0
REFERENCES..............................................................................................................95
LIST OF IN-TEXT TABLES
Table 4.a
Efficacy of Vedolizumab IV in Subjects With CD During the Induction Phase 
(Week 6, C13007)..............................................................................................22
Table 4.b
Efficacy of Vedolizumab IV in Subjects With CD During the Maintenance 
Phase (Week 52, C13007)..................................................................................23
Table 7.a
Eligibility for Study MLN0002SC-3030 Based on Reason for Withdrawal.........49
Table 8.a
Dose and Regimen .............................................................................................51
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Table 9.a
Clinical Laboratory Tests...................................................................................59
Table 10.a
Takeda Medically Significant AE List................................................................73
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................35
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures: Screening, Induction and Nonresponders ...........99
Appendix B
Responsibilities of the Investigator...................................................................106
Appendix C
Elements of the Subject Informed Consent.......................................................108
Appendix D
Investigator Consent to Use of Personal Information........................................111
Appendix E
....................112
Appendix F
Crohn’s Disease Activity Index (CDAI)...........................................................113
Appendix G
................................................114
Appendix H
Detailed Description of Amendments to Text...................................................115
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc. 
Takeda Development Centre Europe, Ltd. 
Takeda Development Center Asia, Pte. Ltd.
Takeda Pharmaceutical Company, Ltd.
Compound:
Vedolizumab SC
Title of Protocol: A Phase 3 Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
Vedolizumab Subcutaneous as Maintenance Therapy in Subjects With 
Moderately to Severely Active Crohn’s Disease Who Achieved Clinical 
Response Following Open-Label Vedolizumab Intravenous Therapy
IND No.:
118980
EudraCT No.:
2015-000481-58
Study Number: MLN0002SC-3031
Phase: 3
Study Design:
This is a pivotal, phase 3, multicenter, multinational, randomized, double-blind, placebo-controlled trial designed to 
evaluate the efficacy and safety of maintenance treatment with vedolizumab subcutaneous (vedolizumab SC) in adult 
subjects with moderately to severely active Crohn’s Disease (CD) who achieved a clinical response at Week 6 with 
open-label therapy with 300 mg vedolizumab intravenous (vedolizumab IV) at Weeks 0 and 2. 
Subjects that are either tumor necrosis factor-alpha (TNF-α) antagonist naïve or with TNF-α antagonist failure will be 
included, ensuring approximately 50% of subjects with TNF-α antagonist failure are enrolled. Subjects with previous 
use of TNF-α antagonist but not failed will be included ensuring that no more than 10% of such subjects are enrolled.
Primary Objectives:
To assess the effect of vedolizumab SC maintenance treatment on clinical remission at Week 52 in subjects with 
moderately to severely active CD who achieved clinical response at Week 6 following administration of vedolizumab 
IV at Weeks 0 and 2. 
Secondary Objectives: 
!
To assess the effect of vedolizumab SC maintenance treatment on enhanced clinical response at Week 52 in 
subjects who achieved clinical response at Week 6 following administration of vedolizumab IV at Weeks 0 and 2.
!
To assess the effect of vedolizumab SC maintenance treatment on corticosteroid-free remission at Week 52 in 
subjects who achieved clinical response at Week 6 following administration of vedolizumab IV at Weeks 0 and 2.
!
To assess the effect of vedolizumab SC maintenance treatment on clinical remission at Week 52 in subjects who 
are naïve to TNF-α antagonist exposure and achieved clinical response at Week 6 following administration of 
vedolizumab IV at Weeks 0 and 2.
Select Exploratory Objectives:
!
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Subject Population: Adult subjects with CD, aged 18 to 80 years inclusive.
Number of Subjects: 
Approximately 824 subjects enrolled to enable approximately 387 subjects 
to be randomized for maintenance treatment.
Number of Sites: 
Approximately 240 sites globally
Dose Level(s):
Vedolizumab SC, 108 mg.
Vedolizumab IV, 300 mg.
Routes of Administration:
Subcutaneous
Intravenous
Duration of Treatment:
52-week treatment period
Period of Evaluation:
The study includes a 4-week (28-day)
Screening Period, a 6-week open-label 
vedolizumab IV Induction Phase, and a 
46-week randomized, double-blind, 
placebo-controlled Maintenance Phase 
with vedolizumab SC with a final visit 
at Week 52. 
Subjects who do not participate in the 
open-label extension (OLE) study will 
be required to participate in a Final 
Safety Visit 18-weeks after the last 
study drug dose and a long-term 
follow-up (LTFU) safety survey by 
telephone, 6 months after the last dose 
of study drug.
Main Criteria for Inclusion:
The subject has a diagnosis of CD established at least 3 months prior to screening, by clinical and endoscopic evidence 
and corroborated by a histopathology report. 
The subject has moderately to severely active CD.
The subject has CD involvement of the ileum and/or colon, at a minimum.
The subject has demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the 
following agents: immunomodulators, corticosteroids, or TNF-α antagonists.
Main Criteria for Exclusion:
The subject has had extensive colonic resection, subtotal or total colectomy.
The subject has a history of >3 small bowel resections or diagnosis of short bowel syndrome.
The subject has any evidence of an active infection during Screening. 
The subject has a positive progressive multifocal leukoencephalopathy (PML) subjective checklist at Screening (or at 
Week 0 before the administration of study drug). 
The subject has received any investigational or approved biologic or biosimilar within 60 days or 5 half-lives, of 
screening, whichever is longer. 
The subject has had prior exposure to vedolizumab. The subject has had prior exposure to natalizumab, efalizumab, 
etrolizumab, AMG-181, anti- mucosal addressin cell adhesion molecule-1(MAdCAM-1) antibodies, or rituximab.
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Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is the proportion of subjects with clinical remission, defined as CDAI score ≤150, 
at Week 52.
Secondary endpoints for this study are:
!
Proportion of subjects with enhanced clinical response, defined as a ≥100 point decrease in CDAI score from 
Baseline (Week 0), at Week 52.
!
Proportion of subjects with corticosteroid-free remission, defined as subjects using oral corticosteroids at 
Baseline (Week 0) who have discontinued oral corticosteroids and are in clinical remission at Week 52.
!
Proportion of TNF-α antagonist naïve subjects who achieved clinical remission, defined as CDAI score ≤150, at 
Week 52.
Select exploratory endpoints for this study:
Statistical Considerations:
All statistical testing will be performed at 2-sided 0.05 level of significance. To control the overall Type I error rate for 
the primary and secondary endpoints, the statistical inference for the first secondary endpoint of enhanced clinical 
response will only be performed if the primary endpoint is statistically significant. The second secondary endpoint of 
corticosteroid-free clinical remission will only be tested if the first secondary endpoint is statistically significant. 
All dichotomous efficacy endpoints will be analyzed using Cochran-Mantel-Haenszel tests for risk differences, 
stratified by randomization stratum. All subjects with missing data for determination of endpoint status will be 
considered as a nonresponder in the analysis. 
Sample Size Justification: 
Assuming a clinical remission rate of 38% for vedolizumab and 22% for placebo at Week 52, a sample size of 
258 subjects in the vedolizumab SC group and 129 subjects in the placebo group will provide 90% power at 2-sided 
0.05 level of significance. To ensure a randomized sample size of 387 subjects, assuming 47% of the subjects entering 
induction will achieve clinical response at Week 6, approximately 824 subjects will need to be enrolled into the study.
Property of Takeda: For non-commercia
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
The study is being funded by Takeda. Payments for the conduct of the study that will be made to 
study sites (and, if applicable, investigators and/or other study staff) will be specified in the 
Clinical Study Site Agreement(s). All investigators and subinvestigators must declare potential
conflicts of interests to the sponsor. The sponsor will provide a financial disclosure form that must 
be signed by each investigator and subinvestigator before the study starts at their study site; in 
addition, any potential conflicts of interests that are not covered by this financial disclosure form 
should be disclosed separately to the sponsor prior to the start of the study at their site.
All institutional affiliations of the investigator and subinvestigator should be declared on their 
curriculum vitae, which must be provided to sponsor before the start of the study.
3.2
Principal Investigator/Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
Term
Definition
5-ASA
5-aminosalicylate
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
Cmax
maximum observed serum concentration
CNS
central nervous system
CRP
C-reactive protein
Ctrough
trough serum concentration levels 
DSMB
Data Safety Monitoring Board
ECG
electrocardiogram
ECL
electrochemiluminescence
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EPX
E-Pro eXchange
EQ-5D
Euro Quality of Life-5D
ET
Early Termination
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal(ly)
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCP
healthcare provider
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRQOL
health-related quality of life 
IAC
Independent Adjudication Committee
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBDQ
inflammatory bowel disease questionnaire
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
IM
intramuscular(ly)
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
bent assay
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IBD
IBD
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Term
Definition
INR
international normalized ratio
IRB
institutional review board
ITT
intent-to-treat
IV
intravenous(ly)
IWRS
interactive web response system
JCV
John Cunningham virus
LFT
liver function test
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
NSAID
nonsteroidal anti-inflammatory drug
OLE
open-label extension
PC
product complaint
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PP
per protocol
PRO
patient-reported outcome
PTE
pretreatment event
PVC
polyvinyl chloride
Q2W
once every 2 weeks
Q4W
once every 4 weeks
Q8W
once every 8 weeks
QOL
quality of life
RAMP
Risk Assessment and Management Program for PML
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TEAE
treatment-emergent adverse event
TNF-α
tumor necrosis factor- alpha
UC
ulcerative colitis
ULN
upper limit of normal
VAS
visual analog scale
VCAM-1
vascular cell adhesion molecule-1
WBC
white blood cell
Property of Takeda: 
on-commercial use only and subject to the applicable Terms of Use
lopathy
pathy
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weeks
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Assess
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NF-α
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3.4
Corporate Identification
TPC
Takeda Pharmaceutical Company Limited
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TPC, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TPC, TDC Asia, TDC Europe and/or TDC Americas, as applicable
3.5
Study Definitions
Term
Definition
Clinical remission by 
A Crohn’s Disease Activity Index (CDAI) score ≤150.
Corticosteroid-free 
remission
Subjects using oral corticosteroids at Baseline (Week 0) who have discontinued oral 
corticosteroids and are in clinical remission at Week 52.
Disease worsening
A ≥100 point increase in CDAI score from the Week 6 value on 2 consecutive visits and a
minimum CDAI score of 220 points.
Durable clinical 
remission
Clinical remission at Week 6 and Week 52.
Enhanced clinical 
response
A ≥100 point decrease in CDAI score from Baseline (Week 0).
Treatment failure
Defined as disease worsening, need for rescue medications (as defined in Section 7.3.1), or 
need for surgical intervention for treatment of Crohn’s Disease.
Property of Takeda: For non-commercial use on
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4.0
INTRODUCTION
4.1
Background
4.1.1
Diseases and Current Treatments 
Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder of the 
gastrointestinal (GI) tract that includes 2 entities, namely ulcerative colitis (UC) and Crohn’s 
disease (CD). 
CD is a relapsing, remitting inflammatory disease that may involve any portion of the length of the 
GI tract from mouth to anus in a transmural fashion from mucosa to serosa. The prevalence of CD 
is approximately 150/100,000 of the US population and approximately 125/100,000 of population 
in Western Europe [1-3] and 21.2/100,000 of the population in Japan [4]. The characteristic 
pathology involves a chronic inflammatory infiltrate consisting of neutrophils and macrophages. 
Hallmarks of CD include granulomatous inflammation and aphthous ulceration.
Clinical manifestations of CD include diarrhea, as well as abdominal pain, fecal urgency, and 
incontinence. Systemic features such as fever, weight loss, malaise, and fatigue are indicators of 
more extensive disease. Extra-intestinal manifestations such as uveitis, arthritis, ankylosis 
spondylitis, or primary sclerosing cholangitis may also be seen in conjunction with IBD. The 
diagnosis of CD is usually made by histopathologic examination of endoscopic mucosal biopsy 
specimens obtained on ileocolonoscopy.
Because in CD, clinical manifestations are not necessarily correlated with endoscopic and 
radiographic findings of disease activity [5], and as further evidence has emerged on the predictive 
potential of endoscopic improvement on long term clinical outcomes [6-8] endoscopic 
assessments have been incorporated in clinical studies for therapeutic outcomes evaluation. 
Currently, limited endoscopic data in CD patients exists and are inconsistent due to lack of a 
validated definition of endoscopic mucosal healing, guidelines for scoring mucosal lesions and for 
the appropriate timing of assessment, as well as of cutoff values for disease severity and response 
to therapy [9,10]. 
 
 
 
 
Current treatments have been effective for many patients with CD but have numerous limitations 
for patients with moderately to severely active disease. The National Cooperative Crohn’s Disease 
Study demonstrated a role for sulfasalazine (a 5-aminosalicylate [5-ASA]) in moderately to 
severely active CD [11]. However, the efficacy of 5-ASAs in CD has been called into question by 
a recent meta-analysis [12].
Corticosteroids are often required for the patients who fail to respond to 5-ASAs. While highly 
effective for induction of remission, corticosteroids are not recommended for the maintenance of 
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remission in CD due to significant undesirable side effects, including osteoporosis, glucose 
intolerance, and increased risk of infection. 
Immunomodulatory agents, including 6-mercaptopurine and azathioprine, have a role in 
maintenance of remission of moderately to severely active CD. Their relatively slow onset of 
action precludes their use during flares of disease, and the use of these agents has been reported to 
potentially increase the risk of lymphoma in patients with IBD [13].
Methotrexate has a role in the management of refractory CD; however, it also demonstrates a 
number of dose-limiting toxicities. Antibiotics have marginal efficacy in maintenance of remission 
in CD.
Biologic agents, including monoclonal antibodies (mAbs) against tumor necrosis factor-alpha
(TNF-α), such as infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (Cimzia), 
have proven useful for both induction and maintenance of clinical response and clinical remission 
in CD [14-16]. However, efficacy data for both infliximab and adalimumab in CD indicate only a 
minority of patients having a durable response at 1 year [17,18]. Certolizumab pegol as 
maintenance therapy was studied only up to 26 weeks, and achieves the same modest results in the 
general moderately to severely active CD population with more substantial outcomes in the 
subgroup of patients with baseline C-reactive protein (CRP) ≥10 mg/L [19,20]. In addition to its 
modest efficacy, treatment with TNF-α antagonists has been associated with serious adverse 
events (SAEs) involving hypersensitivity and infection. Reactivations of latent tuberculosis (TB) 
[21] and disseminated histoplasmosis have been reported and, in some cases, have been fatal [22]. 
A new class of therapy, the integrin inhibitors, has shown promising results to date. Integrin 
antagonists target and disrupt the leukocyte adhesion and trafficking systems, thereby reducing 
inflammation. Natalizumab (Tysabri), a pan-α4 (α4β7 and α4β1) integrin antagonist was approved 
by the Food and Drug Administration (FDA) in 2008 for use in CD patients who are refractory to 
standard therapy [23]. However, due to the antagonizing effect of natalizumab on α4β1, which 
mediates T-cell migration into the central nervous system (CNS), bone marrow, and skin via 
adhesion to its ligand, vascular cell adhesion molecule-1 (VCAM1), natalizumab therapy has been 
associated with increased risk of John Cunningham virus (JCV) reactivation and subsequent 
development of progressive multifocal leukoencephalopathy (PML). As a result, natalizumab is 
cautiously prescribed for the treatment of CD. 
Surgical removal of highly diseased, strictured, or stenotic segments of bowel in CD is not 
curative. Relapse occurs in a majority of patients with CD who undergo segmental resections, and 
the need for additional surgery is the rule rather than the exception [24]. The limitations of current 
therapies for IBD indicate that there is a significant need for safer and more effective therapies.
4.1.2
Vedolizumab
Vedolizumab (also known as MLN0002) is a novel recombinant humanized mAb composed of 
2 light chains of the subclass and 2 immunoglobulin G1 heavy chains. Vedolizumab binds 
specifically to the human lymphocyte integrin 47. The α4β7integrin mediates lymphocyte 
trafficking to GI mucosa and gut-associated lymphoid tissue through adhesive interaction with 
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mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed on the 
endothelium of mesenteric lymph nodes and GI mucosa [25-28]. As a result, vedolizumab impairs 
the migration of gut-homing leukocytes into GI mucosa [29] and acts as a gut-selective 
immunomodulator.
Vedolizumab IV (also known as ENTYVIO; KYNTELES; Vedolizumab for Injection, for 
Intravenous Use; Vedolizumab Powder for Concentrate for Solution for Infusion; or MLN0002 
IV) has been granted marketing approval in several regions, including the United States and 
European Union. Vedolizumab IV is approved for the treatment of adult patients with moderately 
to severely active UC and CD, who have failed conventional treatment, such as 
immunomodulators, corticosteroids, or TNF-α antagonists. The approved dosing and 
administration regimen is 300 mg vedolizumab IV infused intravenously at Weeks 0 and 2, then 
once every 8 weeks (Q8W) thereafter, beginning at Week 6.
Vedolizumab subcutaneous (SC) (also known as Vedolizumab Injection, for Subcutaneous Use; 
Vedolizumab Solution for Injection in Pre-filled Syringe; or MLN0002 SC) is a new liquid 
presentation that has been developed for SC administration. 
 
 
 
 
 
Therefore, the nonclinical and clinical information from studies 
with vedolizumab IV are considered relevant.
As of 19 May 2015 (data lock point), more than 3600 subjects have received at least 1 dose of 
vedolizumab across all studies in the clinical development program. Phase 3 placebo-controlled 
studies enrolled 2427 subjects with UC or CD, of whom 1434 subjects were administered 300 mg 
of vedolizumab IV for induction followed by once every 4 weeks (Q4W) or Q8W for up to a total 
of 52 weeks and 488 subjects were administered 300 mg vedolizumab for induction only [30-32]. 
As of 19 May 2015, vedolizumab exposure has extended for ≥12 months in 1667 subjects, 
≥24 months in 1306 subjects, ≥36 months in 935 subjects, ≥48 months in 676 subjects, 
≥60 months in 267 subjects, and ≥72 months in 26 subjects. Based on the most recent drug 
shipment data (19 November 2015), the cumulative patient exposure to vedolizumab since its 
marketing approval in May 2014 is estimated to be approximately 25,831 patient-years.
Previously conducted clinical studies have characterized the efficacy, safety, tolerability, 
pharmacokinetic (PK), pharmacodynamic, and immunogenicity of vedolizumab in healthy 
subjects and subjects with UC or CD. Please refer to the current edition of the Investigator’s 
Brochure (IB) for the most recent data for vedolizumab.
4.1.2.1
Nonclinical
Nonclinical in vitro and in vivo studies have been conducted with vedolizumab and its murine 
homologue, Act-1. Act-1 has demonstrated clinical and histomorphologic evidence of efficacy in 
an animal model of IBD (cotton-top tamarins). Extensive nonclinical evaluations of the 
Property of Takeda: For non-commercial use 
 subject to the applicable Terms of Use
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cardiovascular, acute, local, subchronic, chronic, immunologic, and reproductive toxicity of 
vedolizumab in pharmacologically responsive species (New Zealand white rabbits and 
cynomolgus monkeys) have been conducted and support its clinical development. Nonclinical 
studies also show that vedolizumab does not antagonize 41 integrin [29].
A single-dose local tolerance study was conducted to determine the local irritancy potential of 
vedolizumab SC when administered by SC injection to rabbits. Macroscopic and histological 
examinations of the injection sites indicated no findings of concern with the vehicle or formulated 
vedolizumab SC. 
4.1.2.2
Clinical Experience With Vedolizumab IV
Single- and multiple-dose PK of vedolizumab have been studied in healthy subjects and in subjects 
with moderately to severely active UC or CD and similar PK was observed. Vedolizumab exhibits 
target-mediated drug disposition; hence, its elimination is characterized by linear and nonlinear 
processes. Following IV infusion, vedolizumab serum concentrations generally fell in a 
biexponential fashion until approximately 1 to 10 µg/mL, with a linear total body clearance of 
approximately 0.157 L/day and a serum half-life of around 25 days. Thereafter, the serum 
concentrations fell in a nonlinear fashion. The volume of distribution for vedolizumab is 
approximately 5 L.
In subjects with moderately to severely active CD (Study C13007), including subjects who had 
failed treatment with 1 or more therapies including TNF-α antagonists, vedolizumab IV 300 mg at 
Weeks 0 and 2 (induction) followed by 300 mg either once every 4 weeks (Q4W) or Q8W from 
Week 6 through Week 52 (maintenance) demonstrated statistically significant differences in 
efficacy compared to placebo for both the induction phase and maintenance phase. The study met 
its primary endpoint for the induction phase, clinical remission at Week 6, but did not meet the 
second primary endpoint of enhanced clinical response (CDAI-100) at Week 6 in the overall 
population although the treatment difference favored vedolizumab (Table 4.a). The study did meet 
its primary endpoint for the maintenance phase, clinical remission at Week 52, as well as important 
secondary endpoints, including enhanced clinical response at Week 52 and corticosteroid-free 
clinical remission at Week 52 (Table 4.b) [31]. 
Table 4.a
Efficacy of Vedolizumab IV in Subjects With CD During the Induction Phase 
(Week 6, C13007)
Endpoint
PBO
N=148
VDZ
N=220
Difference
p-value
Primary endpoint
Clinical remission (%)
6.8
14.5
7.8
0.0206
Enhanced clinical response
25.7
31.4
5.7
0.2322
Source: C13007 Clinical Study Report.
PBO=placebo, VDZ=vedolizumab.
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Table 4.b
Efficacy of Vedolizumab IV in Subjects With CD During the Maintenance 
Phase (Week 52, C13007)
Endpoint
PBO
N=153
VDZ
Q8W
N=154
VDZ
Q4W
N=154
Difference
Q8W vs PBO
Q4W vs PBO
p-value
Primary endpoint
Clinical remission (%)
21.56
39.0
36.4
17.4
14.7
0.0007
0.0042
Secondary endpoint
Enhanced clinical 
response at Week 52 
(%) (a)
30.1
43.5
45.5
13.4
15.3
0.0132
0.0053
Corticosteroid-free 
clinical remission at 
Week 52(%) (b)
15.9
31.7
28.8
15.9
12.9
0.0154
0.0450
Source: C13007 Clinical Study Report.
PBO=placebo, VDZ=vedolizumab.
(a) Enhanced clinical response is defined as a ≥100-point reduction in CDAI score from Baseline.
(b) Corticosteroid-free clinical remission is defined as subjects using oral corticosteroids at Baseline who had 
discontinued corticosteroids and were in clinical remission at Week 52.
In Study C13011, vedolizumab IV (300 mg at Weeks 0, 2, and 6) was administered to subjects 
with moderately or severely active CD who had failed conventional therapies, including TNF-α 
antagonists. The primary endpoint of clinical remission at Week 6 in the TNF-α antagonist failure 
intent-to-treat (ITT) population was not met; however, a treatment difference was observed at 
Week 10 in this population. Similar treatment differences favoring vedolizumab IV were also 
demonstrated for the overall population and in the subgroup of subjects who were TNF-α 
antagonist naïve [32].
Vedolizumab has shown an acceptable safety profile based on an analysis of safety data from both 
completed and ongoing studies (see current version of IB). In phase 1 and 2 clinical trials 
(7 completed phase 1 studies in healthy subjects and 8 completed phase 1b/2 studies in UC or CD 
subjects), there was no consistent evidence of any dose-toxicity relationships, and vedolizumab 
was well-tolerated. The majority of the safety data is from 3 well-controlled, phase 3 clinical 
studies that evaluated the safety of vedolizumab IV for up to 12 months in subjects with UC 
(Study C13006 [52 weeks]) or CD (Studies C13007 [52 weeks] and C13011 [10 weeks]). In 
addition, an interim safety assessment is available for an ongoing long-term open-label extension 
(OLE) study (C13008), in which subjects are administered vedolizumab IV Q4W.
In the pivotal phase 3 studies (C13006 and C13007), the most common (≥5% and at a higher
incidence than placebo) adverse reactions in subjects administered vedolizumab IV were nausea, 
nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, fatigue, headache, and 
cough. Most serious adverse events (SAEs) have been related to exacerbations or complications of 
the underlying UC or CD. For those infections that were reported more frequently in 
vedolizumab-treated subjects, the sites of these infections correlated with the known tissue 
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distribution of MAdCAM-1 binding sites. Anal abscess, abdominal abscess, and gastroenteritis 
were the most frequently reported serious infections. Extraintestinal infections (bronchitis, 
pneumonia, urinary tract infection, sepsis) occurred at low frequency (<1%). A total of 4% of 
vedolizumab-treated subjects and 3% of placebo-treated subjects experienced an infusion-related 
reaction. In Studies C13006 and C13007, 10% of subjects were positive for antivedolizumab 
antibodies 16 weeks following the last dose of vedolizumab. Results from the clinical program to 
date do not suggest an increased risk for malignancy with vedolizumab treatment. Overall, the 
safety profile following long-term treatment with vedolizumab IV in Study C13008 is consistent 
with safety in the completed studies. 
Concomitant use of corticosteroids and/or conventional immunomodulators did not appear to be 
associated with any increased rate of infections based on the comparative rates of infections in the 
phase 3 trials among subjects who had and had not received these medications. 
One death occurred in a vedolizumab-treated subjects during Study C13006, and 5 deaths 
occurred during Study C13007, including 1 death in a placebo-treated subject. As of 19 May 2015, 
a total of 26 deaths from multiple causes were reported in the vedolizumab clinical development 
program, including the ongoing long-term Study C13008. Twenty-five of the 26 subjects were 
randomized to the vedolizumab treatment group. Of these deaths, 14 occurred within 18 weeks of 
the last dose of study drug in phase 3 clinical studies, and 11 occurred more than 18 weeks after the 
last dose of vedolizumab was administered. The causes of death varied and detailed information 
can be found in the current edition of the IB. 
Overall, vedolizumab was well tolerated in clinical studies.
4.1.2.3
Clinical Experience With Vedolizumab SC
The feasibility of administering the vedolizumab IV formulation by alternative dosing routes SC 
or intramuscular (IM) injection was explored in an open-label, single dose, parallel-group 
bioavailability study (C13010) in healthy male subjects. In this study, 42 subjects were enrolled 
and 14 subjects each received a single dose of 180 mg vedolizumab IV as IV infusion (over 
30 minutes), SC injections (2 × 1.5 mL × 60 mg/mL), or IM injections (2 × 1.5 mL × 60 mg/mL). 
Following SC administration, absorption of vedolizumab was gradual, achieving maximum 
concentration at 7 days post-injection (time to reach maximum serum concentration). The 
maximum observed serum concentration (Cmax) following SC injection was approximately 1/3 of 
the Cmax following 30 minute IV infusion. There was no difference in the terminal elimination 
profile of the SC cohort compared to the IV cohort, indicating that the elimination of vedolizumab 
is not absorption rate-limited. The absolute bioavailability of vedolizumab was approximately 
75% for SC administration. Vedolizumab was well tolerated when administered at a dose of 
180 mg by SC injection. Five of the 14 subjects (36%) in the IV infusion cohort and 3 of the 
14 subjects (21%) in the SC cohort experienced a drug-related AE (assessed by the investigator). 
Most AEs were mild or moderate in severity. Three of the 14 subjects (21%) in the IV infusion 
cohort and 2 of the 14 subjects (14%) in the SC cohort in this study were anti-vedolizumab 
antibody (AVA) positive using the originally developed AVA assay that was used in the phase 3 
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Vedolizumab SC
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studies with vedolizumab IV. While all 3 AVA positive subjects in the IV infusion cohort had 
neutralizing AVA, no neutralizing AVA was observed in the SC cohort.
The bioavailability and PK of vedolizumab following a single SC injection of vedolizumab SC at 
3 dose levels (54, 108, and 160 mg) relative to a single IV infusion of vedolizumab IV 300 mg was 
examined in a phase 1, open-label study (MLN0002SC-101). Forty-eight (24 Japanese and 
24 non-Japanese) healthy, adult male and female subjects were randomized. A total of 12 subjects 
received a single dose of vedolizumab IV 300 mg and 36 subjects received a single dose of 
vedolizumab SC at 54, 108, or 160 mg (12 subjects per dose group).
The bioavailability following a single SC injection of vedolizumab SC was 75.1%, independent of 
the vedolizumab SC dose evaluated (54, 108, or 160 mg). Vedolizumab reached maximum serum 
concentrations around 1 week after a single SC injection. Vedolizumab was eliminated by both 
linear and nonlinear pathways following SC injection, with more rapid elimination with 
decreasing dose/concentration. Compared with non-Japanese subjects, Japanese subjects generally 
showed similar or slightly higher exposure; however, ethnicity did not have an impact on clearance 
or central volume of distribution based on the population PK analysis, likely due to the fact that 
weight was included as a covariate for various population PK parameters. Simulations further 
confirmed that vedolizumab SC at 108 mg every 2 weeks (Q2W) is expected to provide lower 
trough concentrations at steady state than vedolizumab IV 300 mg Q4W and similar steady-state 
exposures (average serum concentration at steady state) as the approved vedolizumab IV 300 mg 
Q8W maintenance regimen.
An electrochemiluminescence (ECL) assay has been developed to determine serum titers of AVA. 
This assay has improved drug tolerance as compared with the prior enzyme-linked immunosorbent 
assay (ELISA) method used in the vedolizumab clinical development program and, as a result, is 
more sensitive. Both assays were used in Study MLN0002SC-101; the ECL assay data were used 
in the analysis of PK and safety.
Overall, 75.0% (36/48) of subjects had treatment-emergent adverse events (TEAEs), and the 
percentage of subjects with a TEAE was identical in subjects who received vedolizumab SC 
compared with subjects who received vedolizumab IV. All TEAEs were considered by the 
investigator to be mild or moderate in intensity; no TEAEs of severe intensity were reported. The 
percentage of subjects with mild or moderate TEAEs was similar between subjects who received 
vedolizumab SC and vedolizumab IV; the percentages were also similar across the dose groups. 
No subjects had clinical laboratory test results, vital signs, or electrocardiogram (ECG) results that 
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Vedolizumab SC
Study No. MLN0002SC-3031
Page 26 of 126
Protocol Incorporating Amendment No. 06
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were reported as AEs. Two subjects had elevated bilirubin levels that met the predefined markedly 
abnormal value criteria; however, no subject had abnormal liver function test (LFT) results 
involving aspartate aminotransferase (AST) or alanine aminotransferase (ALT).
Two AEs of special interest were reported: 1 subject in the vedolizumab SC 108 mg group 
experienced erythema at the injection site on the left thigh, and 1 subject in the vedolizumab SC 
160 mg group experienced an injection site reaction. Both events occurred on Day 1 and were 
observed at the 30 minute postdose observation time point (a protocol-defined time point). In each 
case, the event resolved at the 1.5 hour postdose observation time point and was considered by the 
investigator to be mild in intensity and related to study drug. Both subjects recovered without any 
sequelae.
 
 
No SAEs, severe AEs, or deaths were reported in Study MLN0002SC-101. The observed AEs are 
consistent with the overall safety profile of vedolizumab.
4.2
Rationale for the Proposed Study
As IV infusion may not be convenient as long-term therapy for some patients, vedolizumab SC has 
been developed to enable injection by patients or their caregivers. 
This phase 3 study is designed to evaluate the efficacy, safety, PK, and immunogenicity of 
multiple injections of the new presentation, vedolizumab SC, as maintenance therapy in subjects 
with CD. 
 
Therefore, all nonclinical and 
clinical information from studies with vedolizumab IV is considered relevant. 
The vedolizumab exposure-efficacy relationship has been demonstrated in UC subjects in the 
phase 3 vedolizumab IV study (C13006), where higher serum vedolizumab concentrations were 
associated with higher efficacy (Source: Population PK Efficacy Report 2013). Although the 
exposure-efficacy relationship demonstrated in UC subjects was not as clear in CD subjects 
participating in the vedolizumab IV phase 3 studies, the vedolizumab SC dosing regimen selection 
is applicable to CD subjects based on the following important considerations:
!
Vedolizumab targets the same mechanism of action in both the UC and CD indications. 
!
Vedolizumab IV was effective in inducing and maintaining remission in subjects with 
moderately to severely active UC or CD who had failed conventional and/or TNF-α antagonist 
therapy. 
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!
No differences in PK, safety, or immunogenicity between the UC or CD subjects were 
observed in the vedolizumab IV phase 3 studies.
The proposed vedolizumab SC maintenance dosing regimen (108 mg Q2W) was selected to 
provide lower steady-state trough concentrations than the vedolizumab IV Q4W dosing regimen 
and similar Cavg steady-state exposures to that from the approved vedolizumab IV Q8W dosing 
regimen, and the safety and efficacy of the vedolizumab SC presentation are expected to be similar 
to those of vedolizumab IV, outside of expected local administration site events, such as 
injection-site reactions.
4.3
Benefit:Risk Assessment
The proposed study (MLN0002SC-3031) is designed to evaluate the efficacy and safety of 
vedolizumab SC as maintenance therapy in subjects with moderately to severely active CD who 
achieved clinical response following open-label vedolizumab IV therapy. Because IV infusion 
may not be convenient as long-term therapy, vedolizumab SC has been developed to ultimately 
enable injection by patients or their caregivers.
 
 
. Therefore, the 
nonclinical and clinical information from studies with vedolizumab IV are considered relevant.
The study population in Study MLN0002SC-3031 is consistent with the approved vedolizumab IV 
label. The proposed vedolizumab SC maintenance dosing regimen (108 mg Q2W) was selected to 
provide similar steady-state exposure to that from the approved vedolizumab IV dosing regimen 
(300 mg Q8W). It is expected that similar steady-state exposure to vedolizumab will result in 
similar maintenance efficacy, independent of the dosing route or presentation. In addition, safety 
of the vedolizumab SC presentation is expected to be similar to that of vedolizumab IV due to 
similar exposure, outside of expected local administration site events, such as injection-site 
reactions.
 
The observed AEs with 
vedolizumab SC are consistent with the vedolizumab IV safety profile. 
Overall, vedolizumab has been well tolerated in clinical studies, including a phase 1 study of 
vedolizumab SC, and has a positive benefit-risk profile in the treatment of CD.
Property of Takeda: For 
mmercial use only 
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective(s)
!
To assess the effect of vedolizumab SC maintenance treatment on clinical remission at 
Week 52 in subjects with moderately to severely active CD who achieved clinical response at 
Week 6 following administration of vedolizumab IV at Weeks 0 and 2.
5.1.2
Secondary Objectives
!
To determine the effect of vedolizumab SC maintenance treatment on enhanced clinical 
response at Week 52 in subjects who achieved clinical response at Week 6 following 
administration of vedolizumab IV at Weeks 0 and 2.
!
To determine the effect of vedolizumab SC maintenance treatment on corticosteroid-free 
remission at Week 52 in subjects who achieved clinical response at Week 6 following 
administration of vedolizumab IV at Weeks 0 and 2.
!
To assess the effect of vedolizumab SC maintenance treatment on clinical remission at 
Week 52 in subjects who are naïve to TNF-α antagonist exposure, and achieved clinical 
response at Week 6 following administration of vedolizumab IV at Weeks 0 and 2.
5.1.3
Exploratory Objectives
Propert
use only and subject to the applicable Terms of Use
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5.2
Endpoints
5.2.1
Primary Endpoints
!
Proportion of subjects with clinical remission, defined as CDAI score ≤150, at Week 52.
5.2.2
Secondary Endpoints
!
Proportion of subjects with enhanced clinical response, defined as a ≥100 point decrease in 
CDAI score from Baseline (Week 0), at Week 52.
!
Proportion of subjects with corticosteroid-free remission, defined as subjects using oral 
corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in 
clinical remission at Week 52.
!
Proportion of TNF-α antagonist naïve subjects who achieved clinical remission, defined as 
CDAI score ≤150, at Week 52.
5.2.3
PRO Endpoints
!
Changes in inflammatory bowel disease questionnaire (IBDQ) total score and subscores, from 
Baseline (Week 0) to Week 52 and from Week 6 to Week 52.
!
Changes in Euro Quality of Life-5D (EQ-5D) utility scores and EQ-5D visual analog scale 
(VAS) score from Baseline (Week 0) to Week 52 and from Week 6 to Week 52.
!
 
Property of Takeda: For non-commercial use only and subject t
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5.2.4
Exploratory Endpoints
f Use
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a pivotal, phase 3, multicenter, multinational, randomized, double-blind, 
placebo-controlled trial, designed to evaluate the efficacy and safety of maintenance treatment 
with vedolizumab SC in adult subjects with moderately to severely active CD who achieved a 
clinical response at Week 6 with open-label therapy with 300 mg vedolizumab IV at Weeks 0 and 
2. 
Moderately to severely active CD is defined as described in Inclusion Criteria (Section 7.1).
Subjects who are either TNF-α antagonist naïve or with TNF-α antagonist failure will be included 
ensuring approximately 50% of subjects with TNF-α antagonist failure are enrolled. Subjects with 
previous use of TNF-α antagonist but not failed will be included ensuring that no more than 10% 
of such subjects are enrolled.
The study includes a 4-week (28-day) Screening Period, a 6-week open-label vedolizumab IV 
Induction Phase, and a 46-week randomized, double-blind, placebo-controlled Maintenance Phase 
with vedolizumab SC with final visit at Week 52. 
Eligible subjects will be enrolled into the Induction Phase at Week 0, will receive open-label 
infusions of vedolizumab IV 300 mg at Weeks 0 and 2, and will be assessed for clinical response 
by CDAI (defined as a ≥70 point decrease in CDAI score from Baseline [Week 0]) at Week 6, as 
follows:

Subjects who achieve a clinical response at Week 6 will be randomized into the Maintenance 
Phase. Upon completion of the Week 52 assessment or upon early discontinuation due to 
treatment failure (ie, disease worsening after Week 6 or need for rescue medications after 
Week 14) these subjects will be eligible to enter the OLE study (Table 7.a).

Subjects who do not achieve a clinical response at Week 6 will not be randomized in to the 
Maintenance Phase, and instead will receive a third infusion of vedolizumab IV 300 mg at 
Week 6. Subjects who achieve a clinical response at Week 14 (by CDAI) will be eligible to 
enroll in the OLE study. Subjects who respond but choose not to enroll in the OLE study and 
subjects who do not achieve clinical response at Week 14 will be discontinued. 
Subjects who achieve a clinical response at Week 6 will be randomized at a 2:1 ratio to receive 
blinded injections of vedolizumab SC 108 mg or placebo SC Q2W, beginning at Week 6 through 
Week 50. 
Randomization will be stratified by:

Concomitant use of oral corticosteroids.

Clinical remission status at Week 6.

Previous TNF-α antagonist failure/exposed or concomitant immunomodulator (azathioprine, 
6-mercaptopurine, or methotrexate) use.
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At Week 6, subjects receiving oral corticosteroids who achieved a clinical response and are 
randomized into the Maintenance Phase will begin a corticosteroid tapering regimen.
After receiving training from the health care provider (HCP; investigator or designee) on the 
proper SC injection technique and how to manage hypersensitivity reactions potentially associated 
with the injection, subjects or their caregivers will inject vedolizumab SC or placebo SC under the 
supervision of the HCP during at least the Week 6 and 8 clinic visits to ensure proper injection 
technique prior to home dosing. In addition, injection during clinic visits will allow for direct 
observation of any potential hypersensitivity or injection site reactions associated with SC 
injection and timely intervention by the HCP. Subjects and caregivers may attend the clinic at 
Weeks 10 and 12 if further training is required. Subjects or their caregivers will also administer SC 
injections during the scheduled clinic visits at Weeks 14, 22, 30, 38, 46, and 50 under the 
supervision of the HCP to allow continued observation of injection technique and AEs; all other 
scheduled SC injections should occur outside of the clinic. HCPs will have appropriate monitoring 
and treatment for hypersensitivity reactions available for use following administration of study 
drug. Subjects who experience a severe hypersensitivity reaction associated with study drug 
administration will be discontinued from the study (see Section 7.4). 
Subjects and their caregivers will be instructed to inject SC doses into the thigh, abdomen, or upper 
arm, and to rotate the injection sites. Subjects and their caregivers will be instructed that the upper 
arm is to be used only when the caregiver administers the SC injection. Details on the training 
protocol and injection technique will be included in the appropriate Study Manual. For all dosing 
occurring outside of the clinic, subjects will receive a phone call from study staff within 24 hours 
prior to every injection for these scheduled doses to administer the PML subjective checklist and 
enquire about general health status and experience with prior injection. In accordance with the 
Risk Assessment and Management Plan for PML (RAMP), any positive PML subjective finding 
must be evaluated via the physician administered PML objective checklist prior to the subject 
receiving the respective dose (refer to RAMP Site Staff Brochure). Subjects will also receive a 
phone call from their HCP within 12 hours after the home injection at Weeks 10 and 12 to enquire 
about health status and experience with injection unless they attended the clinic on these days. AEs 
reported by the subject will be handled in accordance with Section 10.0 of the protocol.
Subjects who do not participate in the OLE study or are discontinued from the study before Week
6, will enter the Follow-Up Period and complete a final on-study safety assessment at 18 weeks (ie, 
5 vedolizumab half-lives) after the last study drug dose. 
Additionally, subjects who do not participate in the OLE study or a discontinued before Week 6
will be required to participate in a long-term follow-up (LTFU) safety survey by telephone, 6 
months after the last dose of study drug.
 
 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Property of Takeda: For non-commercial use on
Figur
Figu
 Use
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Vedolizumab SC
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Figure 6.a
Schematic of Study Design
WEEK 6 RESPONDERS
Screening
Period
Induction 
Phase
Maintenance 
Phase
Follow-up 
Period
Additional
Follow-up
LTFU Safety 
Survey by 
Telephone (b)
(6 months 
after the last dose 
of study drug)
Final Safety 
Visit (b) 
(18 weeks after 
the last dose of 
study drug)
OL 
Vedolizumab IV 
300 mg
Responder:
Vedolizumab SC 
108 mg Q2W
or
Placebo SC Q2W
End-of-Study 
(a)/
ET procedures
R
OLE Study 
MLN0002SC-
3030 (c)
Days
Wk
Wk Wk
Wk
Wk
Wk
-28 to -1
0
6
7
51
52
68
Visit: 1
2
5
6
14
15
16
WEEK 6 NONRESPONDERS
Follow-up 
Period
Additional
Follow-up
Responder at 
Wk 14
OLE Enroller
(d)
OLE Study 
MLN0002SC-
3030 (c)
Nonresponder at Wk 6:
Vedolizumab IV 
300 mg
OLE 
nonenroller (d)
Nonresponder at 
Wk 14:
OLE Nonenroller 
(d)
Discontinued
Final Safety Visit 
(b) 
(18 weeks after the 
last dose of study 
drug)
LTFU Safety 
Survey by 
Telephone (b)
(6 months 
after the last dose 
of study drug)
Days
Wk
Wk
Wk
-28 to -1
0
6
14
Visit: 1
2
5
Figure 6.a footnotes on next page.
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Vedolizumab SC
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OL=open-label, R=randomization.
(a) Maintenance Period: Subjects who ET (Table 7.a) may consent to participate in the OLE study 
(MLN0002SC-3030) and may enter the OLE study and begin OLE study dosing after End-of-Study Visit procedures 
have been completed.
(b) For subjects who do not enroll into the OLE study (MLN0002SC-3030) (including early terminators before 
Week 6 in the Maintenance Phase) 
(c) First visit of OLE Study MLN0002SC-3030 is within 4 weeks after last dose of study drug for Week 52 
completers/ET or 1 week of Week 14 for Week 14 responders.
(d) Week 14 responders and nonresponders (OLE enroller/nonenroller) will complete the procedures as per the 
Schedule of Assessments (Appendix A).
6.2
Justification for Study Design, Dose, and Endpoints
This phase 3 study is designed to evaluate the efficacy, safety, PK, and immunogenicity of 
multiple injections of the new presentation, vedolizumab SC, as maintenance therapy in subjects 
with CD. The proposed vedolizumab SC maintenance dosing regimen (108 mg Q2W) was 
selected to provide similar exposure to that from the approved IV vedolizumab dosing regimen 
(300 mg Q8W). Therefore, the safety and efficacy of the vedolizumab SC presentation are 
expected to be similar to those of vedolizumab IV, outside of expected local administration site 
events, such as injection-site reactions. 
The study design allows for independent assessments of vedolizumab SC efficacy as maintenance 
therapy in subjects who responded to vedolizumab IV by comparing the active therapy to the 
placebo group during the Maintenance Phase. It also permits double-blind, placebo-controlled 
comparisons of safety parameters during the Maintenance Phase. Additional measures will be 
taken to collect safety parameters beyond the 52-week duration of the trial, where a Final Safety
Follow-up Visit will be conducted 18 weeks (>5 half-lives) after the subject’s final dose of study 
drug if they do not enroll in the OLE, and additional safety information will be collected by 
telephone using a LTFU survey at 6 months after the last study drug dose (for both SC and IV 
dosing). 
The entry criteria ensure that subjects who are appropriate for treatment with biologic agents, as 
assessed by severity of disease and failure of 1 or more standard therapies (ie, corticosteroids, 
immunomodulators, or TNF-α antagonists), will be enrolled into the study. Entry criteria will also 
exclude subjects who might not benefit from drug or who might be at risk for treatment toxicities. 
Additional measures to ensure the safety of enrolled subjects include protocol mandated criteria 
for withdrawal from the study of subjects who experience worsening of disease or require rescue 
medication (ie, any new medication or any increase in dose of a baseline medication required to 
treat new or unresolved CD symptoms, other than antidiarrheals for control of chronic diarrhea). 
Thus, subjects who may be treated with placebo (inactive treatment) between Weeks 6 and 52 will 
be withdrawn from the study if they experience treatment failure (ie, disease worsening after 
Week 6, need for rescue medications after Week 14), but may be eligible to enroll in the OLE 
study.
At Week 6, subjects receiving oral corticosteroids who achieve clinical response must begin a 
corticosteroid tapering regimen as described in Section 7.3.1.1. Subjects are allowed to continue 
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Protocol Incorporating Amendment No. 06
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background therapy such as 5-ASAs or immunomodulators, as indicated in the Permitted 
Medications and Treatments in Section 7.3.1.
The primary efficacy endpoint of this study is clinical remission, defined as a CDAI score 
≤150 points, at Week 52. To further characterize the clinical efficacy and safety of vedolizumab 
SC, secondary and additional endpoints include enhanced clinical response at Week 52, 
corticosteroid-free remission at Week 52, and durable clinical remission.
Disease activity for entry into this study and for efficacy assessments throughout the study will be 
measured by the CDAI, a standard assessment tool to measure CD disease activity in clinical trials 
[36], 
. CDAI includes 3 subjective items 
(number of liquid stools, abdominal pain and general wellbeing), and 5 objective items (number of 
extraintestinal complications, use of antidiarrheal drugs, presence of abdominal mass, hematocrit, 
and ideal/observed body weight ratio).
 
 
Exposure-efficacy analyses were conducted using either observed or population model predicted 
vedolizumab concentrations from the phase 3 vedolizumab IV studies. In both the quartile analysis 
using the Ctrough and the logistic regression analysis using the population PK model predicted Cav
(Cav=AUCτ/τ), there was an apparent exposure-efficacy relationship in subjects with UC for both
the Induction and Maintenance Phases, where higher vedolizumab concentrations were associated 
with higher efficacy. Although the exposure-efficacy relationship demonstrated in UC subjects 
was not as clear in CD subjects participating in the vedolizumab IV phase 3 studies, the 
vedolizumab SC dosing regimen selection is applicable to CD subjects based on the following 
important considerations:
!
Vedolizumab targets the same mechanism of action in both the UC and CD indications. 
!
Vedolizumab IV was effective in inducing and maintaining remission in subjects with 
moderately to severely active UC or CD who had failed conventional and/or TNF-α antagonist 
therapy. 
!
No differences in PK, safety or immunogenicity between the UC or CD subjects were observed 
in the vedolizumab IV phase 3 studies. 
Based on the exposure-efficacy relationship for vedolizumab IV, the vedolizumab SC dosing 
regimen was selected to provide lower trough concentrations than the vedolizumab IV Q4W 
regimen and similar exposure to that from the approved vedolizumab IV Q8W regimen (300 mg 
vedolizumab IV at Weeks 0 and 2, followed by 300 mg Q8W starting from Week 6) during the 
Maintenance Phase. It is expected that similar exposure to vedolizumab will result in similar 
efficacy and safety during maintenance, independent of the dosing route or formulation.
In addition to efficacy and safety evaluations, the multiple dose PK and immunogenicity of 
vedolizumab SC in subjects during the Maintenance Phase will be evaluated in this study. Given 
the long half-life of vedolizumab (approximately 25 days), blood samples will be collected up to 
18 weeks (>5 half-lives) after the last dose to assess the PK of vedolizumab IV followed by 
vedolizumab SC.
Property of Takeda: For non-commercial use only and subjec
he applicable Terms of Use
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During the Maintenance Phase of this study, vedolizumab SC or placebo SC injections will be 
administered by the subjects or their caregivers both at clinic visits (Weeks 6, 8, 14, 22, 30, 38, 46,
and 50 under HCP supervision) and outside of the clinic. HCPs will train the subjects (and their 
caregivers) on the adequate technique to prepare and inject study drug during at least at the Week 6 
and 8 clinic visits, and will also provide instructions on adequate storage of vedolizumab SC, 
disposal of used prefilled syringe and needles, hypersensitivity reaction management, and contact 
information for any questions on vedolizumab SC use. Details on the training protocol and 
injection technique will be included in the appropriate Study Manual. 
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.
!
New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.
!
The Data Monitoring Committee recommends the study should be suspended or terminated. 
!
Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an IRB/independent ethics committee (IEC) or regulatory authority 
elects to terminate or suspend the study or the participation of an investigational site, a 
Property of Takeda: For non-commercial use only
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study-specific procedure for early termination or suspension will be provided by the sponsor; the 
procedure will be followed by applicable investigational sites during the course of termination or 
study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to first dose. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures.
3. The subject has a diagnosis of CD established at least 3 months prior to screening by clinical 
and endoscopic evidence, and corroborated by a histopathology report. Cases of CD 
established at least 6 months prior to screening for which a histopathology report is not 
available will be considered based on the weight of evidence supporting the diagnosis and 
excluding other potential diagnoses, and must be discussed with the sponsor on a case-by-case 
basis prior to entry. 
4. The subject is male or female and aged 18 to 80 years, inclusive.
5. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use adequate contraception* from signing of informed consent throughout 
the duration of the study and for 18 weeks after last dose. 
6. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 18 weeks after last dose. 
*Definitions and acceptable methods of contraception are defined in Section 9.1.10
Contraception and Pregnancy Avoidance Procedure and reporting responsibilities are 
defined in Section 9.1.11 Pregnancy.
7. The subject has moderately to severely active CD as determined by a CDAI score of 220 to 
450 within 7 days prior to the first dose of study drug and 1 of the following:

CRP level >2.87 mg/L during the Screening Period OR

Ileocolonoscopy with photographic documentation of a minimum of 3 nonanastomotic 
ulcerations (each >0.5 cm in diameter) or 10 aphthous ulcerations (involving a minimum of 
10 contiguous cm of intestine) consistent with CD, within 4 months prior to Screening OR

Fecal calprotectin >250 mcg/g stool during the screening period in conjunction with
computed tomography enterography, magnetic resonance enterography, contrast-enhanced 
small bowel radiography, or wireless capsule endoscopy revealing CD ulcerations 
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(aphthae not sufficient), within 4 months prior to screening. (Subjects with evidence of 
fixed stenosis or small bowel stenosis with prestenotic dilatation should not be included). 
8. The subject has CD involvement of the ileum and/or colon, at a minimum.
9. Subjects with extensive colitis or pancolitis of >8 years duration or left-sided colitis >12 years 
duration must have documented evidence that a surveillance colonoscopy was performed 
within 12 months of the initial Screening Visit (if not performed in previous 12 months, must 
be performed during Screening).
10. Subjects with a family history of colorectal cancer, personal history of increased colorectal 
cancer risk, age >50 years, or other known risk factors must be up-to-date on colorectal cancer 
surveillance (may be performed during Screening).
11. The subject has demonstrated an inadequate response to, loss of response to, or intolerance of 
at least 1 of the following agents as defined below:

Immunomodulators:
i.
The subject has signs and symptoms of persistently active disease despite a history of at 
least one 12-week regimen of oral azathioprine (≥1.5 mg/kg) or 6-mercaptopurine 
(≥0.75 mg/kg), or, at least one 8-week regimen of oral azathioprine (≥50 mg) or 
6-mercaptopurine (≥30 mg) (Japan only) OR
ii.
The subject has signs and symptoms of persistently active disease despite a history of at 
least one 16-week regimen of methotrexate of 25 mg/week OR
iii.
The subject has a history of intolerance of at least 1 immunomodulator (including, but 
not limited to nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, 
lymphopenia, thiopurine S-methyltransferase genetic mutation, infection).

Corticosteroids
i.
The subject has signs and symptoms of persistently active disease despite a history of a 
least one 4-week induction regimen that included at dose equivalent to prednisone 
≥30 mg daily orally for 2 weeks or intravenously for 1 week, OR
ii.
The subject has had 2 failed attempts to taper corticosteroids to below a dose equivalent 
to prednisone 10 mg daily orally on 2 separate occasions. In Japan, at least 1 failed 
attempt to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily 
orally or intravenously, OR
iii.
The subject has a history of intolerance of corticosteroids (including, but not limited to, 
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and 
infection).
iv.
The subject had a relapse within 3 months of stopping steroids.
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
TNF-α antagonists:
i.
The subject has signs and symptoms of persistently active disease despite a history of at 
least 1 induction with:

Infliximab: At least 4-week regimen of 5 mg/kg, 2 doses at 2 weeks apart, OR

Adalimumab: At least 80 mg on Day 1 and 40 mg on Day 15, OR

Certolizumab pegol: At least 400 mg SC at Weeks 0, 2, and 4, OR
ii.
The subject has recurrence of symptoms during scheduled maintenance dosing 
following prior clinical benefit OR
iii.
The subject has a history of intolerance of at least 1 TNF-α antagonist (including, but 
not limited to infusion-related reaction, demyelination, congestive heart failure, 
infection).
7.2
Exclusion Criteria
The exclusion criteria are divided into 3 categories: gastrointestinal, infectious disease, and 
general. Any subject who meets any of the following criteria will not qualify for entry into the 
study: 
7.2.1
Gastrointestinal Exclusion Criteria
1. The subject has evidence of abdominal abscess at the initial Screening Visit.
2. The subject has had extensive colonic resection, subtotal or total colectomy.
3. The subject has a history of >3 small bowel resections or diagnosis of short bowel syndrome.
4. The subject has received tube feeding, defined formula diets, or parenteral alimentation within 
28 days prior to the administration of the first dose of study drug.
5. The subject has ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
6. The subject has received any of the investigational or approved non-biologic therapies 
(eg, cyclosporine, tacrolimus, thalidomide, methotrexate, or tofacitinib except for those 
specifically listed in the protocol Section 7.3.1 Permitted Medications for the Treatment of 
CD) for the treatment of underlying disease within 30 days or 5 half-lives of screening 
(whichever is longer).
7. The subject has received any investigational or approved biologic or biosimilar agent within 
60 days or 5 half-lives of screening (whichever is longer). 
8. The subject has used topical (rectal) treatment with 5-ASA or corticosteroid 
enemas/suppositories within 2 weeks of the administration of the first dose of study drug.
9. The subject currently requires or is anticipated to require surgical intervention for CD during 
the study.
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10. The subject has a history or evidence of adenomatous colonic polyps that have not been 
removed.
11. The subject has a history or evidence of colonic mucosal dysplasia.
12. The subject has a suspected or confirmed diagnosis of ulcerative colitis, indeterminate colitis, 
ischemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic 
colitis.
7.2.2
Infectious Disease Exclusion Criteria
13. The subject has evidence of an active infection during the Screening Period.
14. The subject has evidence of, or treatment for, C. difficile infection or other intestinal pathogen 
with 28 days prior to first dose of study drug.
15. The subject has chronic hepatitis B virus (HBV) infection* or chronic hepatitis C virus (HCV) 
infection.
* HBV immune subjects (ie, being hepatitis B surface antigen [HBsAg] negative and hepatitis 
B surface antibody [HBsAb] positive) may, however, be included.
16. The subject has active or latent TB as evidenced by the following:
i.
A positive diagnostic TB test within 30 days prior to screening or during the screening 
period, defined as:
1. A positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests, 
(or, A positive T-SPOT TB test [Japan only]), 
OR,
2. A tuberculin skin test reaction ≥5 mm.
Note: if subjects have received BCG vaccine then a QuantiFERON TB Gold test 
should be performed instead of the tuberculin skin text
OR
ii.
Chest X-ray within 3 months prior to Week 0 which is suspicious for pulmonary TB, 
and a positive or 2 successive indeterminate QuantiFERON tests (or, A positive 
T-SPOT TB test [Japan only]) within 30 days prior to Screening or during the 
Screening Period.
Note: subjects with documented previously treated TB with a negative QuantiFERON 
test can be included in the study.
17. The subject has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
18. The subject has received any live vaccinations within 30 days prior to screening.
19. The subject has clinically significant infection (eg, pneumonia, pyelonephritis) within 30 days 
prior to screening, or ongoing chronic infection.
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7.2.3
General Exclusion Criteria 
20. The subject has had previous exposure to approved or investigational anti-integrin antibodies
(eg, natalizumab, efalizumab, etrolizumab, AMG 181), anti-MAdCAM-1 antibodies or 
rituximab.
21. The subject has had previous exposure to vedolizumab.
22. The subject has had hypersensitivity or allergies to any of the vedolizumab excipients.
23. The subject has any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, 
genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other 
medical disorder that, in the opinion of the investigator, would confound the study results or 
compromise subject safety.
24. The subject has had any surgical procedure requiring general anesthesia within 30 days prior to 
screening or is planning to undergo major surgery during the study period.
25. The subject has any history of malignancy, except for the following: (a) adequately-treated 
nonmetastatic basal cell skin cancer; (b) squamous cell skin cancer that has been adequately 
treated and that has not recurred for at least 1 year prior to screening; and (c) history of cervical 
carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years 
prior to screening. Subjects with remote history of malignancy (eg, >10 years since completion 
of curative therapy without recurrence) will be considered based on the nature of the 
malignancy and the therapy received and must be discussed with the sponsor on a case-by-case 
basis prior to screening.
26. The subject has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, or neurodegenerative disease.
27. The subject has a positive PML subjective symptom checklist at Screening (or prior to the 
administration of the first dose of study drug at Week 0).
28. The subject has any of the following laboratory abnormalities during the Screening Period:
i.
Hemoglobin level <8 g/dL.
ii.
White blood cell (WBC) count <3 × 109/L.
iii.
Lymphocyte count <0.5 × 109/L.
iv.
Platelet count <100 × 109/L or >1200 × 109/L.
v.
ALT or AST >3 × the upper limit of normal (ULN).
vi.
Alkaline phosphatase >3 × ULN.
vii.
Serum creatinine >2 × ULN.
29. Removed in Amendment 03. 
30. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 1 year prior to screening. 
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31. The subject has an active psychiatric problem that, in the investigator’s opinion, may interfere 
with compliance with study procedures.
32. The subject or caregiver is unable to attend all the study visits or comply with study 
procedures.
33. The subject is required to take excluded medications listed in Section 7.3.
34. The subject is unwilling or unable to self-inject, or does not have a caregiver (defined as a legal 
adult) to inject the study medication.
35. Female subjects who are lactating or have a positive serum pregnancy test during the 
Screening Period or a positive urine pregnancy test at Week 0, prior to study drug 
administration.
36. If female, the subject is intending to become pregnant before, during, or within 18 weeks after 
participating in this study; or intending to donate ova during such time period. 
37. If male, the subject intends to donate sperm during the course of this study or for 18 weeks 
thereafter. 
38. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress. 
7.3
Excluded Medications and Treatments
The following medications are excluded from use during the study (from informed consent to 
Week 68): 

Any treatment for CD other than those listed in Section 7.3.1 (either approved or 
investigational).

All live vaccines from 30 days prior to screening to at least 6 months after the last dose of study 
drug.

Either approved or investigational biological agents for the treatment of non-IBD conditions, 
other than localized injections (eg, intra-ocular injections for wet macular degeneration).

Chronic nonsteroidal anti-inflammatory drug (NSAID) use. (Note: occasional use of NSAIDs 
and acetaminophen for headache, arthritis, myalgias, menstrual cramps, etc. and daily use of 
baby or low-dose [81-162.5 mg] aspirin for cardiovascular prophylaxis are permitted.)

Leukocytapheresis (white blood apheresis) or granulocytapheresis (Japan only).

Enteral nutrients (>900 kcal/day) (Japan only).

Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
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7.3.1
Permitted Medications and Treatments 

The subject may be receiving a therapeutic dose of the following drugs: 
–
Oral 5-ASA compounds provided that the dose has been stable for the 2 weeks 
immediately prior to first dose of study drug. The dose of these medications should remain 
stable throughout the study.
–
Oral corticosteroid therapy (prednisone at a stable dose ≤30 mg/day, budesonide at a stable 
dose ≤9 mg/day, or equivalent steroid) provided that the dose has been stable for the 4 
weeks immediately prior to first dose of study drug if corticosteroids have just been 
initiated, or for the 2 weeks immediately prior to first dose of study drug if corticosteroids 
are being tapered. Corticosteroid doses should remain stable until the subject meets the 
criteria for initiating a corticosteroid tapering regimen (see Section 7.3.1.1).
–
Probiotics (eg, Culturelle, Saccharomyces boulardii) provided that the dose has been stable 
for the 2 weeks immediately prior to first dose of study drug. The dose for these 
medications should remain stable throughout the study.
–
Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic 
diarrhea. Stable doses are encouraged.
–
Azathioprine, 6-mercaptopurine, or methotrexate provided that the dose has been stable for 
the 8 weeks immediately prior to first dose of study drug. Dose(s) should remain stable 
unless the medication is discontinued due to a toxicity related to the medication. Even if the 
toxicity resolved, azathioprine, 6-mercaptopurine, or methotrexate will not be restarted.
–
Antibiotics used for the treatment of CD (eg, ciprofloxacin, metronidazole) provided that 
the dose has been stable for the 2 weeks immediately prior to first dose of study drug. The
dose of these medications should remain stable throughout the study.

For immunosuppressives, oral 5-ASAs, probiotics and antibiotics for CD, dose reduction or 
discontinuation will be allowed per label only due to adverse reactions. For oral corticosteroid, 
as per the tapering schedule (see Section 7.3.1.1).

Enteral nutrients (≤900 kcal/day), stable for at least 3 weeks prior to enrollment. The dosage 
may be modified after Week 6; however it should preferably remain the stable dose and not 
exceed the initial dosage (Japan only).

Need for rescue medication: In this study, any new medication or any increase in dose of a 
baseline medication required to treat new or unresolved CD symptoms (other than 
antidiarrheals for control of chronic diarrhea) is considered a rescue medication. An increase in 
corticosteroid dose back to baseline for subjects undergoing corticosteroid tapering within the 
guidelines presented in Section 7.3.1.1 is not considered rescue medication. Administration of 
rescue medications, approved or investigational, constitutes treatment failure. Rescue 
medications should not be withheld if, in the opinion of the investigator, failure to prescribe 
them would compromise subject safety.
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7.3.1.1
Oral Corticosteroid Dosing and Tapering 
At Week 6, subjects receiving oral corticosteroids who achieved clinical response will begin a 
corticosteroid tapering regimen. The tapering schedule is as follows: 

For prednisone at doses >10 mg/day (or equivalent), the dose should be reduced at a rate of 
5 mg/week until a 10 mg/day dose is reached. 

For prednisone at doses ≤10 mg/day (or equivalent) or once a 10 mg/day dose (or equivalent) is 
achieved by tapering, the dose should be reduced at a rate of 2.5 mg/week until 
discontinuation.

For budesonide, the dose should be tapered at a rate of 3 mg every 3 weeks.
For subjects who cannot tolerate the corticosteroid taper without recurrence of clinical symptoms, 
corticosteroids may be increased up to the original dose at the start of induction therapy (should 
not exceed baseline dose). In such cases, the tapering regimen above must be reinitiated within 
2 weeks. Subjects who require consistent higher doses should be withdrawn from the study 
according to Section 7.4.
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence, such premedication 
is unlikely to be necessary or beneficial. At the discretion of the investigator, however, subjects 
may be administered premedication prior to any study drug administration. Corticosteroids, if 
given as a premedication, should be limited to the day of administration. 
7.4
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the electronic case report form (eCRF) using the following 
categories. For screen failure subjects, refer to Section 9.1.22.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.

LFT Abnormalities.
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, Section 9.1.9), if the following circumstances occur at any time 
during study medication treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
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–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
2. Significant protocol deviation. The discovery after the first dose of study medication that the 
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Three attempts to contact the subject must be documented (ie, 2 attempts 
by phone and 1 attempt by registered letter).
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE or lack of efficacy should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.11.
7. Lack of efficacy. The subject should be discontinued from the study if the following criteria 
apply:

Treatment failure during the Maintenance Phase, defined as disease worsening (as defined 
in Section 3.5), need for rescue medications (as defined in Section 7.3.1), or need for 
surgical intervention for treatment of CD.
8. Leukopenia or Lymphopenia: WBC and lymphocyte counts will be monitored for all subjects. 
Azathioprine, 6-mercaptopurine, or methotrexate, if applicable, should be discontinued and the 
dose of study drug held for an absolute lymphocyte count <0.5 × 109/L at any point in the study. 
The absolute lymphocyte count must be repeated at appropriate intervals as determined by the 
investigator. The next dose of study drug can be administered only if the absolute lymphocyte 
count is ≥0.5 × 109/L. If the absolute lymphocyte count remains <0.5 × 109/L, study drug should 
be discontinued and the subject withdrawn from the study.
9. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
Subjects who discontinue due to lack of efficacy are permitted to enroll in the OLE study 
(MLN0002SC-3030) according to the criteria in Table 7.a.
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Table 7.a
Eligibility for Study MLN0002SC-3030 Based on Reason for Withdrawal 
Reason for Withdrawal
Time Point
Prior to Week 6
Weeks 6-14
Beyond Week 14
Disease worsening (a)
Not applicable
Eligible
Eligible
Requires rescue medication, but does not meet 
criteria for disease worsening
Not applicable
Not eligible
Eligible
AE related to study drug leading to discontinuation 
of study drug
Not eligible
Not eligible
Not eligible
Requires surgical intervention for CD
Not eligible
Not eligible
Not eligible
(a) See Section 3.5 for study definitions.
7.5
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.4. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the ET 
Visit (if applicable), Final Safety Visit, and LTFU. Discontinued or withdrawn subjects will not be 
replaced.
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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to all or any of the drugs defined below: 
8.1.1.1
Vedolizumab for Injection, for Intravenous Use (Vedolizumab IV)
The study sites will be supplied by the sponsor with the following medication in an open-label 
manner: vedolizumab IV 300 mg/vial, for single use, in 20 mL vials. The study medication will be 
provided in a glass vial as a lyophilized solid formulation for reconstitution using sterile water for 
injection. Each vial will be packaged in an appropriately labeled single vial carton. 
Each carton will have a single-panel or multilingual booklet label that will contain, but will not be 
limited to the following: sponsor’s name and address, protocol number, packaging job/lot number, 
name and strength of the product, medication identification number, subject information, caution 
statement, directions for use, and storage conditions.
There is no placebo IV for this study.
Additional reference information and administration instructions can be found in the Pharmacy 
Manual. 
8.1.1.2
Vedolizumab Injection, for Subcutaneous Use (Vedolizumab SC)
The study sites will be supplied with the following medication in a blinded manner: vedolizumab 
SC 108 mg/0.68 mL or placebo in a pre-filled syringe. The study medication is a liquid 
presentation provided in pre-filled syringe with backstop and plunger rod assembled together. 
Each syringe will be packaged in folding box or carton.
The subcutaneous placebo is a liquid solution supplied at 0.68 mL in pre-filled syringes for SC 
injection with similar formulation composition as the vedolizumab SC solution, and administered 
via SC injection.
Each carton will have a single-panel or multilingual booklet label that will contain, but will not be 
limited to the following: sponsor’s name and address, protocol number, packaging job/lot number, 
name and strength of the product, medication identification number, subject information, caution 
statement, directions for use, and storage conditions.
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8.1.1.3
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following:

Vedolizumab for Injection, for Intravenous Use (vedolizumab IV).

Vedolizumab Injection, for Subcutaneous Use (vedolizumab SC)/vedolizumab SC placebo.
8.1.1.4
Other Protocol-Specified Materials
The following supplies will also be required for study drug administration and are to be provided 
by the clinical study center unless otherwise indicated:

Bottled sterile water for injection (for study drug reconstitution).

250 mL 0.9% sodium chloride for injection in polyvinyl chloride (PVC) IV bag(s) or 250 mL 
0.9% sodium chloride in alternative IV bags or bottles listed in the Pharmacy Manual. (100 mL 
in Japan).

PVC infusion line or alternative infusion line listed in the Pharmacy Manual.

Alcohol swabs.

Needle sharps container (provided by sponsor).
8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug must be stored under the 
conditions specified on the label, and remain in the original container until dispensed. 
Vedolizumab IV and vedolizumab SC must be stored at 2ºC to 8ºC (36ºF to 46ºF). A daily 
temperature log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
The dose and dosing regimen for all subjects is provided in Table 8.a.
Table 8.a
Dose and Regimen 
Treatment Group
Dose
Treatment Description
All Subjects 
Vedolizumab IV 300 mg 
Open-label
Weeks 0 and 2
A (Week 6 
Nonresponders)
Vedolizumab IV 300 mg 
Open-label
Week 6
B
Vedolizumab SC 108 mg
Blinded
Weeks 6-50 (Q2W)
C
Vedolizumab SC Placebo
Blinded
Weeks 6-50 (Q2W)
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8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0, Pretreatment 
Events, Adverse Events (AEs), and Product Complaints (PC).
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically. 
8.2
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned to receive treatment according to the schedule allocated to each study 
site.
The investigator or investigator’s designee will access the interactive web response system 
(IWRS) at screening to register a subject and obtain a subject identification number to identify the 
subject throughout the study. The investigator or the investigator’s designee will use the IWRS to 
enroll the subject into the study. The medication identification (ID) number of the investigational 
drug to be dispensed will then be provided by the IWRS as well as at subsequent visits. If
sponsor-supplied drug is lost or damaged, the site can request a replacement from IWRS. Refer to 
the appropriate study manual provided separately for additional information. 
For IV infusion, subjects will receive a 300 mg dose of vedolizumab IV infusion over 
approximately 30 minutes. Longer infusion times of up to 60 minutes may be used based on study 
observations. Vedolizumab IV should be administered by a HCP prepared to manage 
hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and 
medical support measures should be available for immediate use. Subjects should be observed for 
2 hours following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion in 
a room where appropriate treatment for infusion-related reactions is available. The subject should 
be considered clinically stable by the investigator or designee prior to discharge.
For SC injection, the recommended sites are the abdomen (except for the 2-inch area around the 
navel), the outer area of the upper arms, or the front of the thighs. The arm injection site should be 
used only by caregivers administering the injection. The injection site should be changed for 
consecutive injections. Each new injection should be given at least 1 inch from a site used before.
During clinic visits, SC injections should be administered by the subject (or caregiver) under the 
supervision of a HCP prepared to manage hypersensitivity reactions including anaphylaxis, if they 
occur. Appropriate monitoring and medical support measures should be available for immediate 
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use. Subjects should be observed during the administration and for 1 hour following completion of 
the administration.
Study medication storage, disposal and directions for use for the subject self-injections will be 
described in information provided to the subject.
For further dispensing information, please refer to the pharmacy and/or appropriate study manual.
8.3
Randomization Code Creation and Storage
After receiving open-label infusions of vedolizumab IV 300 mg at Weeks 0 and 2, subjects will be 
assessed for clinical response (defined as a ≥70 point decrease in CDAI score from Baseline 
[Week 0]) at Week 6). Subjects with clinical response at Week 6 will be randomized at a 2:1 ratio 
to receive blinded injections of vedolizumab SC 108 mg or placebo SC Q2W, beginning at Week 6 
through Week 50.
Randomization will be stratified by:

Concomitant use of oral corticosteroids.

Clinical remission status at Week 6.

Previous TNF-α antagonist failure/exposed or concomitant immunomodulator (azathioprine, 
6-mercaptopurine, or methotrexate) use.
Randomization personnel of the sponsor or designee will generate the randomization schedule 
prior to the start of the study. An IWRS system will be used for subject randomization. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.4
Investigational Drug Blind Maintenance and Unblinding
The investigational drug blind will be maintained using the IWRS. In addition, in order to maintain 
the blind, all study site personnel will be blinded to the treatment assignments for the duration of 
the study.
The investigational drug blind may be broken by the investigator if information concerning the 
investigational drug is essential for the medical treatment of the subject. The medical monitor must 
be informed of the unblinding at the earliest possible opportunity. In nonurgent cases, the medical 
monitor must be contacted before the subject is unblinded.
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the IWRS. The sponsor must be notified as soon as possible if the investigational drug 
blind is broken. The date, time, and reason the blind is broken must be recorded in the source 
documents and eCRF as appropriate.
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8.5
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee and delegated pharmacy staff, must ensure that the sponsor-supplied 
drug is used in accordance with the protocol and is dispensed only to subjects enrolled in the study. 
To document appropriate use of sponsor-supplied drug, [vedolizumab IV vials and vedolizumab 
SC/placebo SC pre-filled syringes], the appropriate person must maintain respective records of all 
sponsor-supplied drug delivery to the site, site inventory, dispensation, and use, by each subject, 
and return to the sponsor or designee.
Records of the subject number, the date study drug was dispensed, and the study drug/cohort 
assignment will be maintained by the pharmacist.
Upon receipt of sponsor-supplied drug, the appropriate pharmacist must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, they should 
acknowledge the receipt of the shipment (by signing the bottom half of the packing list and faxing 
per instructions provided on the form/ or by recording in IWRS). If there are any discrepancies 
between the packing list and the actual product received, Takeda must be contacted to resolve the 
issue. The packing list should be filed in the investigator’s essential document file (pharmacy file).
The pharmacist must maintain 100% accountability for all sponsor-supplied drugs received and 
dispensed. Proper drug accountability includes, but is not limited to:

Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the (drug lot/medication ID/job number) used to prepare 
each dose.

Verifying that all containers used/assigned are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The pharmacist must record the current inventory of all sponsor-supplied drugs on a 
sponsor-approved drug accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, description 
of sponsor-supplied drugs, date and amount dispensed including initials, date and amount returned 
to the site by the subject, and the initials, seal, or signature of the person dispensing the drug. The 
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log should include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned by IWRS to each subject
at the time of screening; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include age or date of birth (depending on local 
regulations), sex, Hispanic ethnicity (as applicable, United States only), race as described by the 
subject and smoking status of the subject at screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.8).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 30 days prior to signing of informed consent.
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9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of investigational 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; 
(7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; (11) other. All 
subsequent physical examinations should assess clinically significant changes from the assessment 
prior to first dose examination.
9.1.4
Weight and Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters without decimal places and for 
weight it is kilograms (kg) with 1 decimal place. 
9.1.5
Vital Sign Procedure
Vital signs will include body temperature, respiratory rate, blood pressure (sitting), and pulse 
(bpm). On dosing days, vital signs are taken predose. 
9.1.6
Primary Efficacy Measurement
Primary efficacy assessments during the Maintenance Phase will be based on CDAI scores. 
During screening, subjects will be instructed on how to appropriately complete the diary. The 
symptoms of CD must be recorded throughout the study, including the Screening Period. A 
validated electronic system will be used for collection of the patient diary.
On all dosing visits CDAI components are to be performed prior to dosing; the total CDAI score 
will be calculated once results are available for all components.
9.1.6.1
Diary Completion and Review
Diary entries will be made daily by subjects from screening to end of study, and will be used for 
CDAI calculation. At screening, subjects will be instructed on how to appropriately complete the 
daily diary. The symptoms of CD must be recorded throughout the study, including the Screening 
Period. Diary entries will be made daily by the subject through a validated electronic system. At 
each visit, including during screening, the CDAI score must be calculated prior to dosing by the 
, accessed by the investigator or designee based on daily diaries, 
laboratory assessments, and clinical examination and recorded in the subject’s source documents. 
The CDAI score evaluated during screening will be used to determine eligibility, using subject 
diary entries within 10 days prior to Week 0. At a minimum, 7 days of diary data from the last 
10 days prior to Week 0 will be required for the calculation of the score. Subjects will be required 
to complete diary entries for at least 14 days prior to Week 0. 
 
 
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The Week 6 total CDAI score will be used to determine whether the subject has achieved clinical 
response at Week 6 (a ≥70-point decrease in CDAI score from baseline [Week 0]), and will 
determine eligibility for randomization in the Maintenance Phase.
Entries should be reviewed and monitored by the study staff (see the appropriate Study Manual). 
9.1.7
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. Medications used 
specifically for premedication purposes will be collected separately in the eCRF.
9.1.8
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at screening or baseline examination. The condition (ie, 
diagnosis) should be described.
9.1.9
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures at the time 
points specified in the schedule of events. The maximum volume of blood at any single visit is 
approximately 24 mL, and the approximate total volume of blood for the study is 260 mL. Details 
of these procedures and required safety monitoring will be given in the laboratory manual.
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Clinical laboratory tests to be performed in this study are summarized in Table 9.a. Refer to the 
Schedule of Events in Appendix A for timing of all assessments. See Laboratory Manual for 
testing regimen.
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis 
RBC
WBC w/ differential 
Hemoglobin
Hematocrit
Platelets
PT/INR
ALT
Albumin
Alkaline phosphatase
Amylase
Lipase
AST 
Total and direct bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Calcium
Chloride
Bicarbonate
Magnesium
Phosphorus 
Uric Acid 
Glucose 
Bilirubin
Blood 
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein 
Specific Gravity 
Microscopic (to be 
obtained in the event of 
positive leukocyte esterase 
or blood, will include 
WBCs, RBCs, and cast[s])
Other:
HIV
Hepatitis panel, including HBsAg, HBsAb, and 
anti-HCV (a)
CRP
Fecal Calprotectin
QuantiFERON for TB
PK
Beta hCG and Urine Pregnancy hCG
(female subjects of childbearing potential)
FSH (b)
C. difficile
CRP= C-reactive Protein, FSH=follicle-stimulating hormone, GGT= γ-Glutamyl transferase, hCG=human chorionic 
gonadotropin, HBsAb=antibody to hepatitis B surface antigen, PT=prothrombin time, RBC=red blood cells.
(a) HBV immune subjects (ie, being HBsAg negative and HBsAb positive) may, however, be included.
(b) FSH level will be obtained for female subjects at Screening if they are postmenopausal by history (ie, last regular 
menstrual cycle >1 years) and not surgically sterile. The FSH result must be >40 IU/L for the subject to be permitted 
not to use adequate contraception.
Central laboratories will perform laboratory tests for hematology, serum chemistries, and 
urinalysis as well as specialty testing outlined above. The results of safety laboratory tests will be 
returned to the investigator, who is responsible for reviewing and filing these results. Refer to the 
schedule of events for timing of all assessments.
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If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests should be performed 
within a maximum of 7 days and preferably within 48-72 hours after the abnormality was noted.
(Please refer to Section 7.4 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in 
conjunction with total bilirubin >2 ×ULN.)
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements).
9.1.10 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study medication, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period.
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with an FSH >40 IU/L or at least 5 years since last 
regular menses, confirmed before any study medication is implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
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An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are included, the only 
acceptable methods of contraception will be:
Barrier methods (each time the 
subject has intercourse):
Intrauterine devices 
(IUDs):
Hormonal contraceptives:

Male condom PLUS spermicide.

Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide.

Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide.

Copper T PLUS condom 
or spermicide.

Progesterone T PLUS 
condom or spermicide.

Implants.

Hormone shot/injection.

Combined pill.

Minipill.

Patch.

Vaginal ring PLUS male 
condom and spermicide.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study.
During the course of the study, subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures (Appendix A). 
All female subjects of child bearing potential will have a serum pregnancy test during screening 
and at Week 52 (or ET Visit) and Week 68 (or Final Safety Visit). A urine pregnancy test will be 
completed for all females of child bearing potential on a 4-weekly basis prior to administration of 
study drug.
9.1.11 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued and returned to the study site. In 
addition, any pregnancies in the partner of a male subject during the study or for 18 weeks after the 
last dose, should also be recorded following authorization from the subject’s partner.
If the pregnancy occurs during administration of active study medication or within 18 weeks of the 
last dose of active study medication, the pregnancy should be reported immediately, using a 
pregnancy notification form, to the contact listed in Section 1.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator.
Subjects randomized to placebo need not be followed.
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If the female subject, or female partner of a male subject, agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject was 
participating in a clinical study at the time the subject/female partner of the subject became 
pregnant and provide details of treatment the subject received.
All pregnancies in subjects on active study drug will be followed up to final outcome, using the 
pregnancy form. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted.
9.1.12 ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. 
Any findings from ECGs collected after study drug administration at Week 0 will be captured as 
AEs if, in the opinion of the investigator, there has been a clinically significant change from 
baseline.
Subjects will be supine and will have rested for 5 or more minutes before any ECG is recorded. 
Tracings will include subject number and initials and the date and time of recording.
9.1.13
 
 
 
 
 
.
9.1.14
 
 
 
 
9.1.15
 
 
 
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9.1.16 Tuberculosis Screening 
All subjects will complete TB screening to determine eligibility. Subjects will be excluded from 
the study if they have active or latent TB, regardless of treatment history, as defined in 
Section 7.2.2.
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9.1.17
9.1.18 Stool Sample
A stool sample will be obtained for culture, ova and parasite evaluation, and C. difficile assay. A 
sample will be collected and cultured during screening and at any point in the study when a subject 
becomes symptomatic, including worsening or return of disease activity.
9.1.19 PML Checklist 
Staff will administer the subjective PML checklist during screening to exclude subjects with 
positive responses from enrolling into the study. The PML subjective checklist will be 
administered in person prior to dosing at visits occurring in the clinic. The PML subjective 
checklist will be administered over the phone prior to dosing when the subject is self-injecting 
outside of the clinic. 
Any subjects reporting signs or symptoms of PML will be told to withhold the respective dosing 
and will undergo physician administered objective testing and may be referred to a neurologist for 
a full evaluation, as described in the RAMP Algorithm referenced in Section 11.2.1. The 
symptoms from a positive PML checklist will be recorded as an AE in the eCRF. Additional 
information and tools for the RAMP can be found in the appropriate Study Manual. 
9.1.20 Patient Reported Outcomes Instruments 
Subjects will complete the IBDQ and EQ-5D health related quality-of-life (HRQOL) 
questionnaires at the time points specified in the schedule of events. 
 
.
9.1.20.1 Inflammatory Bowel Disease Questionnaire
The IBDQ is a valid and reliable [37] instrument used to assess quality of life (QOL) in adult 
subjects with IBD. It includes 32 questions on 4 domains of HRQOL: Bowel Systems (10 items), 
Emotional Function (12 items), Social Function (5 items), and Systemic Function (5 items). 
Subjects are asked to recall symptoms and QOL from the last 2 weeks and rate each item on a 
7-point Likert scale (higher scores equate to higher QOL). A total IBDQ score is calculated by 
summing the scores from each domain; the total IBDQ score ranges from 32 to 224.
9.1.20.2 EQ-5D Questionnaire
The EQ-5D questionnaire, developed by the ‘EuroQol Research Foundation’ is a simple, valid, 
and reliable [38] instrument used to measure general health-related QOL in subjects and includes 5
domain items - mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
Subjects choose the level of health problems they currently have on each item as “None”, 
“Moderate”, or “Extreme” and are scored a 1, 2, or 3, respectively. A composite EQ-5D score can 
Property of Takeda: For non-c
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be calculated from the individual scores to assess overall HRQOL. The EQ-5D VAS score is a 
self-assigned rating of overall health using a 20 cm visual, vertical scale, with a score of 0 as the 
worst and 100 as best possible health. The EQ-5D total score and EQ-5D VAS score have been 
shown in many studies to be valid and reliable instruments for measuring HRQOL in patients with 
GI diseases.
9.1.20.3
 
 
 
 
 
 
 
 
 
9.1.21
9.1.22 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible during screening, the investigator should contact the IWRS 
as a notification of screen failure and complete the Screen Failure eCRF.
The primary reason for screen failure is recorded in the eCRF using the following categories:
!
PTE/AE.
!
Did not meet inclusion criteria or did meet exclusion criteria.
Property of Takeda:
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
Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal <specify reason>.

Study termination.

Other <specify reason>.
Subject numbers assigned to subjects who fail screening should not be reused. Re-screening of 
subjects will be assessed by the Medical Monitor on a case by case basis.
9.1.23 Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria at Week 0 are 
eligible for enrolment into the Induction Phase.
At Week 6 subjects will be assessed for eligibility for randomization into the Maintenance Phase.
If the subject is found to be not eligible for the study, the Investigator should record the primary 
reason for failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
If a subject is persistently noncompliant with the study medication, it may be appropriate to 
withdraw the subject from the study. All subjects should be reinstructed about the dosing 
requirement during study contacts. The authorized study personnel conducting the re-education 
must document the process in the subject source records.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening 
Subjects will be screened within 28 days prior to enrollment. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.22 for procedures for documenting screening failures.
Procedures to be completed at screening can be found in the schedule of events (Appendix A). 
9.3.2
Enrollment/Randomization 
Enrollment will take place at Week 0. If the subject has satisfied all of the inclusion criteria and 
none of the exclusion criteria, the subject should be enrolled using the IWRS. Subjects will be 
instructed on when the first dose of investigational drug will be given as described in Section 6.1. 
The procedure for documenting screening failures is provided in Section 9.1.22.
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Eligible subjects will receive open-label infusions of vedolizumab IV 300 mg at Weeks 0 and 2, 
and will be assessed for clinical response (defined as a ≥70 point decrease in CDAI score from 
baseline [Week 0] at Week 6). Subjects with clinical response at Week 6 will be randomized at a 
2:1 ratio to receive blinded injections of vedolizumab SC 108 mg or placebo SC Q2W, beginning 
at Week 6 through Week 50.
Randomization will be stratified by:

Concomitant use of oral corticosteroids.

Clinical remission status at Week 6. 

Previous TNF-α antagonist failure/exposed or concomitant immunomodulator (azathioprine, 
6-mercaptopurine, or methotrexate) use.
9.3.2.1
Nonresponders
Subjects who are nonresponders at Week 6 and hence are not randomized into the Maintenance 
Period of the study will receive a third vedolizumab IV infusion at Week 6. Subjects who achieve 
a clinical response (by CDAI score) at Week 14 are eligible to enroll in the OLE study. Subjects 
who respond at Week 14 but do not enroll into the OLE study, and subjects who do not respond at 
Week 14 will be discontinued.
9.3.3
Final Visit or ET
The Final Visit will be performed on Week 52 or at ET for all subjects who enter the Maintenance 
Phase.
For all subjects receiving study medication in the Maintenance Phase, the investigator must 
complete the End of Study eCRF page.
Subjects who complete the study will be offered entry into the OLE study after completion of the 
Week 52/ET assessment. Week 0 of the OLE study should occur within 4 weeks of the last dose of 
study drug for Week 52 completers/ET.
Subjects at Week 14 who are responders and are eligible to participate in the OLE will not 
complete an ET visit but complete procedures as per the Schedule of Study Procedures (Appendix 
A). For Week 14 responders, subjects should receive their first OLE vedolizumab SC dose as close 
to Week 14 as possible (preferably within Week 14 ±3 days). If this window is too challenging for 
the sites, dosing within week 14 ±7 days is acceptable from a PK perspective (ie, maintaining 
trough concentration at or above 10 µg/mL).
Subjects who are discontinued due to disease worsening (after Week 6) during the Maintenance 
Period will be offered entry into the OLE study.
From Week 14 onwards, subjects in the Maintenance Phase who are withdrawn from the study due 
to need for rescue medications, despite not meeting the criteria for disease worsening, will be 
offered entry into the OLE study. Rescue medications are defined as any new medication or any 
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increase in dose of a baseline medication required to treat new or unresolved CD symptoms (other 
than antidiarrheals for control of chronic diarrhea).
Subjects who are discontinued due to AEs related to study drug that lead to discontinuation or 
require a surgical intervention for their CD will not be eligible to enroll into the OLE study.
9.3.4
Final Safety Follow-up Visit
For those subjects not entering the OLE study or are discontinued, a Final Safety Follow-up Visit 
will be performed 18 weeks after the last dose of study drug. Assessments will be completed per 
the schedule of events Week 68 Visit. 
9.3.5
Post Study 6-month Long-Term Follow-Up Survey
Upon completion of (including OLE nonenrollers from Week 14) or ET from the study, all 
subjects not entering the OLE study will be required to participate by telephone in a LTFU safety 
survey 6 months after the last dose of study drug (from the last dose received). 
9.3.6
Unscheduled Visits Due to Disease Exacerbation 
Subjects who are seen by the investigator or site staff at a time point not required by the protocol 
(ie, unscheduled visit) due to disease exacerbation will undergo the following: 
!
Physical examination. 
!
Vital signs assessment. 
!
Diary review. 
!
Collection of concomitant medications and procedures.
!
Collection of AEs and SAEs.
!
Clinical chemistry and hematology, as indicated.
!
Partial or complete CDAI. 
!
PK sample collection
!
 
!
Stool sample for fecal calprotectin, if indicated.
!
C. difficile, if indicated.
There is no minimum time for repeat evaluation by unscheduled visit in order to determine if a
subject meets the criteria for disease worsening. In general, however, enough time should be 
provided for clinically meaningful change to occur. 
Property of Take
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9.3.7
Poststudy Care
Following study end, subjects who meet the relevant eligibility criteria will be provided an 
opportunity to continue receiving study drug by participating in the OLE study
MLN0002SC-3030. Otherwise, study drug will not be available upon completion of the subject’s 
participation in the study and the subject should be returned to the care of a physician and standard 
therapies as required.
9.4
Biological Sample Retention and Destruction
In this study, specimens will be collected as described. The samples will be sent to a central 
laboratory that processes the samples and serves as a secure storage facility. The sponsor and 
researchers working with the sponsor will have access to the samples collected and any test results. 
All samples collected during the study will be stored securely with limited access and the sponsor 
will require anyone who works with the samples to agree to hold the research information and any 
results in confidence.
Samples will be stored for no longer than 15 years after completion of the study. No samples will 
be stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification from Takeda. 
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
 
 
.
Property of Takeda: For non-comm rcial use only and subject to the applicable Terms of Use
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10.0
PRETREATMENT EVENTS (PTE) ADVERSE EVENTS (AE) AND PRODUCT 
COMPLAINTS (PC)
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
In addition, drug-device AEs related to quality or malfunction will be collected.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
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investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” 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 that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
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
Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Special Interest AEs
A Special Interest Adverse Event (serious or non-serious) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by 
the investigator to Takeda may be appropriate. Such events may require further investigation in 
order to characterize and understand them and would be described in protocols and instructions 
provided for investigators as to how and when they should be reported to Takeda. Refer to 
Section 10.2.1.4 for information for special interest AE reporting.
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
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10.1.7 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is a 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship should 
be assessed as Not Related. 
10.1.9 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.10
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.11
Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.12
Action Concerning Study Medication 

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE eg, 
the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE.

Dose Interrupted – the dose was interrupted due to the particular AE.
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10.1.13
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death. 

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.1.14
Product Complaints
A PC is a verbal, written, or electronic expression that implies dissatisfaction regarding the 
identity, strength, purity, quality, or stability of a drug product and/or device (eg, prefilled 
syringe).
An investigator who is made aware of or identifies a potential PC should immediately report the 
event to Takeda in accordance with the contact list provided to the site. Whenever possible, the 
associated product should be maintained in accordance with the instructions pending further 
guidance from a Takeda representative. Refer to the appropriate study manual provided separately 
for additional information (depending on local regulations).
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Start of AE collection: AEs must be collected from start of study medication administration. 
End of AE collection: AEs must be collected for 18 weeks following the last dose of study 
medication. 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication or until 
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screen failure. For subjects who discontinue prior to study medication administration, PTEs are 
collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication (enrollment). Routine collection of AEs will continue until 18 weeks after last dose.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date (and time, if deemed directly related to the study drug administration).
3. Severity.
4. Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related) (not completed for PTEs).
5. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
6. Action concerning study medication (not applicable for PTEs).
7. Outcome of event.
8. Seriousness.
Several patient-reported outcomes measures will be used in this study (eg, IBDQ, EQ5D, 
). They will not be used as a primary means to collect AEs. However, should the 
investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up, if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied.
Property o
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10.2.1.3 Adverse Event Collection Involving Medically Anticipated Clinical Events 
CD is associated with certain characteristic signs and symptoms, including diarrhea and abdominal 
pain, that may be present at baseline and persist or fluctuate based on the individual subject’s 
disease history during the course of the study. These signs and symptoms are considered medically 
anticipated clinical events for the condition under study and will not be collected as AEs. These 
characteristics of disease activity will be regularly captured in the CDAI score and will be 
reviewed by the Data Safety Monitoring Board (DSMB).
Exacerbations of disease activity (eg, increase in the daily amount of abdominal pain beyond the 
subject’s normal fluctuation, new signs or symptoms of CD) will be collected as AEs and reported 
according to regulatory reporting requirements. 
Extra-intestinal manifestations of the subject’s disease (eg, arthralgia, arthritis, uveitis) that 
develop or worsen during the study are considered AEs. 
10.2.1.4 Special Interest AE Reporting
If this special interest AE, which occurs during the treatment period or the follow-up period, is 
considered to be clinically significant based on the criteria below, it should be recorded in the special 
interest AE eCRF or an SAE Form. The applicable form should be completed and reported to the 
SAE reporting contact in Section 1.1 within 24 hours.
Hypersensitivity Reactions (Including Injection Site Reactions).
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence such premedications 
are unlikely to be necessary or beneficial. At the discretion of the investigator, however, subjects 
may be administered premedication prior to any study drug administration. Corticosteroids, if given 
as a premedication, should be limited to the day of administration. 
Vedolizumab IV should be administered by a HCP prepared to manage hypersensitivity reactions 
including anaphylaxis, if they occur. Appropriate monitoring and medical support measure should 
be available for immediate use. Subjects should be observed for 2 hours following the first 2 
infusions, at a minimum, and 1 hour after each subsequent infusion.
During clinic visits, subjects should be observed during the SC administration and for 1 hour 
following completion of the administration. Vedolizumab SC should be administered by the subject 
or caregiver in the presence of a HCP prepared to manage hypersensitivity reactions including 
anaphylaxis, if they occur. Appropriate monitoring and medical support measure should be available 
for immediate use. 
Subjects and caregivers will be instructed to report the development of rash, hives, pruritus, flushing, 
urticaria, injections site pain, redness and/or swelling, etc. that may represent an 
administration-related reaction (ie, injection-site reaction or infusion-related reaction) to study 
medication. Subjects will be asked to report administration-related AEs to the sites immediately as 
they are experienced or after having received appropriate medical care. Appropriate treatment and 
follow-up will be determined by the investigator. If signs or symptoms of an administration-related 
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reaction are observed during the administration of study medication, it should be immediately 
discontinued and the subject treated as medically appropriate. In the case of a mild reaction, study 
drug administration may be reinitiated (with appropriate premedication and investigator 
supervision) at the discretion of the investigator. Subjects with a severe or serious 
administration-related reaction (eg, shortness of breath, wheezing, stridor, angioedema, 
life-threatening change in vital signs, severe injection site reactions) must be withdrawn from the 
study (see the appropriate Study Manual). 
In all cases of administration-related reaction, the medical monitor must be informed as soon as 
practical. The disposition of subjects with less severe administration-related reactions should be 
discussed with the medical monitor.
Serious Infections 
Subjects will be monitored for signs and symptoms of infection and for lymphopenia during the 
study. Subjects with signs and symptoms suggestive of infections, including GI infections, will be 
treated as clinically indicated. Interventions may include antibiotic treatment, if appropriate and/or 
discontinuation of concomitant immunomodulators. Blood, sputum, urine, and/or stool cultures 
should be obtained as appropriate for the detection and diagnosis of infection. Withholding or 
terminating study drug administration may be considered as described in Section 7.4.
Malignancy 
All cases of malignancies that are detected during the study will be reported as AEs. Local medical 
practices for the management of malignances will apply. Subjects with history of malignancy 
(except for specific cancers) or at high risk for malignancy will be excluded from the study per the 
exclusion criteria. 
Other 
Other special interest AEs include liver injury and PML, which are discussed in Sections 10.2.3
and 11.2.1 respectively.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE eCRF or Form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s)
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
Causality assessment.
The SAE eCRF should be completed within 24 hours of first onset or notification of the event. 
However, as a back-up, if required, the SAE Form should be completed and reported to Takeda 
Pharmacovigilance or designee within 24 hours to the attention of the contact listed in Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
*Note: For Japanese sites, the investigator should report the detailed paper SAE report provided by 
sponsor or by the institution without delay after notification of initial information. Additional 
detailed follow-up data surrounding the serious adverse event that becomes available following 
the initial report should be communicated through the same channels as outlined above. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.9 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE Form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
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event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as expedited report within 7 days for fatal and life-threatening events and 
15 days for other serious events, unless otherwise required by national regulations. The sponsor 
will also prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of an investigational medicinal product or that would be sufficient 
to consider changes in the investigational medicinal products administration or in the overall 
conduct of the trial. The investigational site also will forward a copy of all expedited reports to his 
or her IRB or IEC in accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
11.1
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) independent from the sponsor will be established to 
review unblinded safety data from this study on a regular basis and to make appropriate 
recommendations regarding the safe conduct of the study. 
A detailed charter will outline the activities and scope of the DSMB (eg, type of data reviewed, 
frequency of meetings and location of meetings). 
11.2
Adjudication Committee 
A PML Independent Adjudication Committee (IAC) will be implemented for this study. The PML 
IAC will consist of a panel of leading PML experts, including a neurologist, neuroradiologist, and 
a virologist. 
11.2.1 Risk Minimization Action Plan for PML (RAMP Program)
Natalizumab (TYSABRI), another integrin receptor antagonist, has been associated with 
progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection 
of the CNS. PML is caused by the JCV and typically only occurs in patients who are 
immunocompromised [40,41]. Natalizumab is a pan-α4 integrin antagonist that binds to both the 
α4β1 and α4β7 integrins and inhibits cellular adhesion to VCAM-1 and MAdCAM-1 [42,43]. In 
contrast, vedolizumab binds to the α4β7 integrin only [29] and inhibits adhesion to MAdCAM-1, 
but not VCAM-1. Although no cases of PML have been reported in clinical trials with 
vedolizumab to date, a risk of PML cannot be ruled out.
To address the theoretical risk of the development of PML in subjects treated with vedolizumab, 
the sponsor, with input from renowned PML experts, has developed a Risk Minimization Action 
Plan for PML, the RAMP. The complete description of the RAMP program, including materials 
and instructions for its implementation and monitoring, is included in the appropriate Study 
Manual. 
The RAMP is focused on early clinical detection and management of that specific safety risk, 
including the discontinuation of study drug, if applicable. Subjects are assessed for signs and 
symptoms of PML prior to the administration of each dose of study drug using a PML subjective 
symptom checklist. Subjects with a positive PML subjective symptom checklist at any time after 
enrollment in a vedolizumab clinical study will be evaluated according to a prespecified algorithm 
(the PML Case Evaluation Algorithm). The respective dose of study drug will be withheld until the 
evaluation is complete and results are available. Subsequent doses of study will be administered 
only if the possibility of PML is definitively excluded, as described in the RAMP algorithm. An 
IAC has been stabled as part of the RAMP program to review new neurological signs and 
symptoms potentially consistent with PML, and will provide input regarding subject evaluation 
and management as defined in the IAC charter. 
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To ensure success of the RAMP program, site personnel will be trained to recognize the features of 
PML, and subjects will be trained to report specific neurological signs and symptoms without 
delay. Educational materials for teaching site personnel and subjects about PML and the RAMP 
procedures will be distributed to all sites and are included in the appropriate Study Manual. Formal 
teaching and training will be performed for site personnel prior to the start of the study. Subjects 
will receive training and educational materials prior to receiving treatment. The informed consent 
form will contain specific information on the hypothetical risk of PML. Any documented case of 
PML will be reported as an SAE, regardless of whether hospitalization occurs.
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12.0
DATA HANDLING AND RECORD KEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
Drug Dictionary.
12.1
Electronic CRFs
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRFs. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
1. The following procedure is applied for the countries except for Japan.
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
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International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
2. The following procedure is applied for Japanese site only.
The investigator and the head of the institution agree to keep the records stipulated in Section 12.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as thermal 
sensitive paper, source worksheets, all original signed and dated informed consent forms, subject 
authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Any source documentation printed on degradable thermal sensitive paper should be 
photocopied by the site and filed with the original in the subject’s chart to ensure long term 
legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator and the head of the 
institution to retain essential documents specified in ICH E6 (Section 8) until at least 2 years after 
the last approval of a marketing application for a specified drug indication being investigated or, if 
an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and/or the head of the 
institution and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock and 
unblinding of subjects’ treatment assignments. This document will provide further details 
regarding the definition of analysis variables and analysis methodology to address all study 
objectives.
A blinded data review meeting will be conducted prior to unblinding of subjects’ treatment 
assignment and database lock. This review will assess the accuracy and completeness of the study 
database, subject evaluability, and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
The Full Analysis Set will include all randomized subjects who receive at least 1 dose of study 
drug. Subjects in this set will be analyzed according to the treatment they were randomized to 
receive.
The per protocol (PP) population is a subset of the ITT population. The PP population consists of 
all subjects who do not violate the terms of the protocol in a way that would impact the study 
output significantly. All decisions to exclude subjects for the PP population dataset will be made 
prior to the unblinding of the study. Analyses using the PP population may be provided as a 
sensitivity analysis.
The Safety Analysis Set will include all subjects who receive at least 1 dose of study drug. Subjects 
in this set will be analyzed according to the treatment they actually received.
The PK evaluable population is defined as all subjects who receive at least 1 dose of study drug 
and have sufficient blood sampling to allow for PK evaluation.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Baseline and demographic information will be listed and summarized by treatment group and 
overall. For continuous variables, the summary will consist of descriptive statistics (number of 
subjects, mean, standard deviation, minimum, median, and maximum). For categorical variables, 
the summary will consist of number and percentage of subjects in each category.
Medical history and concurrent medical conditions will be summarized by system organ class and 
preferred term. Medication history and concomitant medications will be summarized by preferred 
term.
13.1.3 Efficacy Analysis
All statistical testing will be performed at 2-sided 0.05 level of significance. To control the overall 
Type I error rate for the primary and secondary endpoints, the statistical inference for the first 
secondary endpoint of enhanced clinical response will only be performed if the primary endpoint, 
proportion of subjects with clinical remission at Week 52, is statistically significant. The second 
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secondary endpoint of corticosteroid-free clinical remission will only be tested if the first 
secondary endpoint is statistically significant. All dichotomous efficacy endpoints will be 
analyzed using Cochran-Mantel-Haenszel tests for risk differences, stratified by randomization 
stratum. All subjects with missing data for determination of endpoint status will be considered as a 
nonresponder in the analysis. Multiplicity will not be adjusted across additional endpoints. 
13.1.4 Resource Utilization and PRO
All statistical testing will be performed at 2-sided 0.05 level of significance. To control the overall 
Type I error rate for the comparison between vedolizumab SC and placebo groups, a hierarchy 
approach will be applied to the PRO endpoints if the primary endpoint is significant. 
The order of testing of PRO endpoints in Section 5.2.3 will be finalized in the SAP before database 
lock. 
Changes from Baseline to Week 52 in IBDQ, EQ-5D scores and 
 components will be 
analyzed in an Analysis of Covariance model with treatment as a factor and baseline score as a 
covariate. Changes from Week 6 to Week 52 will be analyzed in a similar fashion.
13.1.5
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13.1.7 Safety Analysis
Safety analysis will be performed using the Safety Analysis Set. No statistical inference will be 
made for safety analyses.
The number and percentage of subjects with TEAEs (defined as any AEs, regardless of 
relationship to study drug), AESIs (ie, serious infections, including opportunistic infection such as 
PML, malignancies, liver injury, infusion reactions, injection site reactions), and SAEs which 
occur on or after the first dose date and up to 18 weeks after the last dose date of the study drug in 
subjects who do not enroll in OLE study or up to the first dose of the OLE study in those who do, 
will be summarized by MedDRA System Organ Class, High Level Term, and Preferred Term 
overall, by severity, and by relationship to study drug for each treatment group. Separate 
summaries will also be generated for treatment-related adverse events overall and by severity. In 
addition to incident rates, exposure adjusted AE rates will be summarized as well.
Change from baseline in clinical laboratory tests and vital signs will be summarized by treatment 
group. Subjects with markedly abnormal values for laboratory tests and vital signs will be 
tabulated.
Additional summaries of TEAEs will be provided that only include TEAEs that occur in the 
Maintenance Phase between the Week 6 dose and 18 weeks after the last dose date of the study 
drug, or up to the first dose of the OLE study, whichever comes first.
Data from the LTFU survey will be summarized descriptively.
The shift in ECG interpretation from Baseline will be summarized by treatment group. Physical 
examination findings and PML checklist data will be presented in data listings.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
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13.3
Determination of Sample Size
Assuming a clinical remission rate of 38% for vedolizumab and 22% for placebo at Week 52, a 
sample size of 258 subjects in the vedolizumab group and 129 subjects in the placebo group will 
provide 90% power at 2-sided 0.05 level of significance. To ensure a randomized sample size of 
387 subjects, assuming 47% of the subjects entering induction will achieve clinical response at 
Week 6, approximately 824 subjects will need to be enrolled into the study.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. 
Significant protocol deviations will be entered into the eCRF, which is reviewed by the study 
sponsor or designee.
The procedure below applies to Japanese sites only.
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the 
investigator should notify the sponsor and the head of the study site of the deviation or change as 
well as its reason in a written form, and then retain a copy of the written form. When necessary, the 
investigator may consult and agree with the sponsor on a protocol amendment. If the protocol 
amendment is appropriate, the amendment proposal should be submitted to the head of the study 
site as soon as possible and an approval from IRB should be obtained. The investigator should 
document all protocol deviations.
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14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug and notify site once the sponsor 
has confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor 
has received permission from competent authority to begin the trial. Until the site receives 
notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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CCI


Vedolizumab SC
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Protocol Incorporating Amendment No. 06
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investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
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review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
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Shivananda S, Lennard-Jones J, Logan R, Fear N, Price A, Carpenter L, et al. Incidence of 
inflammatory bowel disease across Europe: is there a difference between north and south? 
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Trallori G, Palli D, Saieva C, Bardazzi G, Bonanomi AG, d'Albasio G, et al. A 
population-based study of inflammatory bowel disease in Florence over 15 years (1978-92). 
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Asakura K, Nishiwaki Y, Inoue N, Hibi T, Watanabe M, Takebayashi T. Prevalence of 
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Kakkar A, Wasan SK, Farraye FA. Targeting mucosal healing in Crohn's disease. 
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Froslie KF, Jahnsen J, Moum BA, Vatn MH. Mucosal healing in inflammatory bowel 
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Ferrante M, Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, et al. 
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Daperno M, D'Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development 
and validation of a new, simplified endoscopic activity score for Crohn's disease: the 
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Mazzuoli S, Guglielmi FW, Antonelli E, Salemme M, Bassotti G, Villanacci V. Definition 
and evaluation of mucosal healing in clinical practice. Dig Liver Dis 2013;45(12):969-77.
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Akobeng AK, Gardener E. Oral 5-aminosalicylic acid for maintenance of medically-induced 
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Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD. Increased risk of lymphoma 
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Remicade (infliximab) 100 mg powder for concentrate for solution for infusion. Summary of 
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Humira (adalimumab) injection, for subcutaneous use. Full Prescribing Information. North 
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Cimzia (certolizumab pegol) for injection, for subcutaneous use. Prescribing Information. 
Smyrna, GA: UCB, Revised October 2013.
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Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. 
Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 
2002;359(9317):1541-9.
18.
Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. 
Adalimumab for maintenance of clinical response and remission in patients with Crohn's 
disease: the CHARM trial. Gastroenterology 2007;132(1):52-65.
19.
Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. 
Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med 2007;357(3):228-38.
20.
Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OO, Hanauer SB, McColm J, et al. 
Maintenance therapy with certolizumab pegol for Crohn's disease. New Engl J Med 
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21.
Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. 
Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N 
Engl J Med 2001;345(15):1098-104.
22.
Colombel JF, Loftus EV, Jr., Tremaine WJ, Egan LJ, Harmsen WS, Schleck CD, et al. The 
safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 
500 patients. Gastroenterology 2004;126(1):19-31.
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Tysabri (natalizumab) injection. Full Prescribing Information. Cambridge, MA: Biogen Idec 
Inc., Revised March 2014.
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Stenson WF. Inflammatory Bowel Disease. In: Yamada T, Alpers DH, Laine L, Owyang C, 
Powell DW, editors. Textbook of Gastroenterology. 3rd ed. Philadelphia, PA: Lippincott 
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25.
Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking and 
regional immunity. Adv Immunol 1999;72:209-53.
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Salmi M, Jalkanen S. Lymphocyte homing to the gut: attraction, adhesion, and commitment. 
Immunol Rev 2005;206:100-13.
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Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, et al. Human 
mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and 
associated lymphoid tissue. Am J Pathol 1997;151(1):97-110.
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Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. Expression 
and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. 
Immuno 1994;153(2):517-28.
29.
Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and 
selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in 
development for inflammatory bowel diseases. J Pharmacol Exp Ther 2009;330(3):864-75.
30.
Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. 
Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 
2013;369(8):699-710.
31.
Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. 
Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 
2013;369(8):711-21.
32.
Sands B, Feagan B, Rutgeerts P, Colombel J-F, Sandborn W, Sy R, et al. Vedolizumab 
induction therapy for patients with Crohn's disease and prior anti-tumour necrosis factor 
antagonist failure: a randomised, placebo-controlled, double-blind, multicentre trial. Journal 
of Crohn's and Colitis 2013;7(Suppl. 1):Pages S5–S6. 8th Congress of the European Crohn's 
and Colitis Organisation.
33.
Schellekens H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol 
Dial Transplant 2005;20 Suppl 6:vi3-9.
34.
Porter S. Human immune response to recombinant human proteins. J Pharm Sci 
2001;90(1):1-11.
35.
Sipponen T, Karkkainen P, Savilahti E, Kolho KL, Nuutinen H, Turunen U, et al. Correlation 
of faecal calprotectin and lactoferrin with an endoscopic score for Crohn's disease and 
histological findings. Aliment Pharmacol Ther 2008;28(10):1221-9.
36.
Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn's disease activity 
index. National Cooperative Crohn's Disease Study. Gastroenterology 1976;70(3):439-44.
37.
Irvine EJ. Development and subsequent refinement of the inflammatory bowel disease 
questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel 
disease. J Pediatr Gastroenterol Nutr 1999;28(4):S23-7.
38.
Konig HH, Ulshofer A, Gregor M, von Tirpitz C, Reinshagen M, Adler G, et al. Validation 
of the EuroQol questionnaire in patients with inflammatory bowel disease. Eur J 
Gastroenterol Hepatol 2002;14(11):1205-15.
39.
Reilly MC, Gerlier L, Brabant Y, Brown M. Validity, reliability, and responsiveness of the 
work productivity and activity impairment questionnaire in Crohn's disease. Clin Ther 
2008;30(2):393-404.
40.
Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory 
therapies. Annu Rev Med 2010;61:35-47.
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41.
Steiner I, Berger JR. Update on progressive multifocal leukoencephalopathy. Curr Neurol 
Neurosci Rep 2012;12(6):680-6.
42.
Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. 
Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med 
2005;353(18):1912-25.
43.
TYSABRI (natalizumab) injection. Full Prescribing Information. Cambridge, MA: Biogen 
Idec Inc., Revised June 2013.
44.
Vitali R, Stronati L, Negroni A, Di Nardo G, Pierdomenico M, del Giudice E, et al. Fecal 
HMGB1 is a novel marker of intestinal mucosal inflammation in pediatric inflammatory 
bowel disease. Am J Gastroenterol 2011;106(11):2029-40.
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Appendix A
Schedule of Study Procedures: Screening, Induction and Nonresponders 
Study Procedure
Screening
Induction
Open Label Treatment 
Period
Induction 
Observation
Week 6 Nonresponders
Open Label Treatment Period
Days -28 to 
-1
Week 0 (a)
Day 1
Week 2
Day 15
(±2 days)
Week 6a (b)
Day 43
(-5 days)
Week 6b (b)
Day 43
(+3 days)
Week 6b
Day 43
(+3 days)
Pre-Week 14
Day 92
(+4 days)
Week 14 (t)
Day 99
(±3 days)
OLE Nonenroller
OLE Enroller
Clinic Visit Number
1
2
3
4
5
NR5
PW14
NR6
NR6
Informed consent
X
Demographics
X
Tobacco use
X
Medical and CD history
X
Prior therapies for CD
X
Physical examination (c)
X
X
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
PML checklist (e)
X
X
X
X
X
X
X
PML wallet card
X
Diary instruction
X
Diary review (f)
X
X
X
X
X
X
Concomitant medications and 
procedures (g)
X
X
X
X
X
X
X
12-lead ECG
X
TB screening (i)
X
Vedolizumab IV OL Dosing (j) 
X
X
X
Footnotes are on last table page.
Property of Takeda: 
n-commercial use only 
subject to the applicable Terms of Use
le
ppl
app
Week 
Week 
he ap
Open L
Open 
pli
t to t
t to
6b
ct t
ay 43
43
bject
+3 days)
+3 days)
o the
o he
o th
ubje
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NR
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y
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e o
e o
e o
us
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er
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X
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-c
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age.
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Appendix A
Schedule of Study Procedures: Screening, Induction and Nonresponders (continued)
Study Procedure
Screening
Induction
Open Label Treatment 
Period
Induction 
Observation
Week 6 Nonresponders
Open Label Treatment Period
Days -28 to 
-1
Week 0 (a)
Day 1
Week 2
Day 15
(±2 days)
Week 6a (b)
Day 43
(-5 days)
Week 6b (b)
Day 43
(+3 days)
Week 6b
Day 43
(+3 days)
Pre-Week 14
Day 92
(+4 days)
Week 14 (t)
Day 99
(±3 days)
OLE Nonenroller
OLE Enroller
Clinic Visit Number
1
2
3
4
5
NR5
PW14
NR6
NR6
Randomization
X
Assess eligibility for OLE
X
CDAI (k)
X (k)
X
X (k)
X(k)
X (k)
X (k)
PRO (IBDQ; EQ-5D)
X
X
X
X
PTE/AE assessment (l)
X
X
X
X
X
X
X
X
SAE assessment (m)
X
X
X
X
X
X
X
X
Sample collection for:
Serum pregnancy test
X
X
Urine pregnancy test (n)
X
X
X
X
X
X
HBV, HCV, HIV screen
X
FSH (o)
X
Clinical chemistry
X
X
X
X
X
X
Hematology
X (k)
X
X
X (k)
X
X
X (k)
Coagulation
X
Urinalysis
X
X
X
X
X
PK assessment (p)
X
X
X
X
X
Fecal calprotectin (q)
X
X
X
X
CRP
X
X
X
X
X
C. difficile stool sample (r)
X
Property of
eda:
non-commercial use o
nd subject to the applicable Terms of Use
le
ued)
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pplic
app
Week 6
Week 
e ap
Open La
Open La
lic
t
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t to
43
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days)
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o the 
o th
P
o 
e
o th
o
bjec
NR5
NR5
ec
ubje
bje
d sub
d
)
d s
d s
d
X
d
nd
X
o
e o
se
us
al
rc
rc
rc
rc
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X
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X
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X
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Protocol Incorporating Amendment No. 06
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Study Procedure
Screening
Induction
Open Label Treatment 
Period
Induction 
Observation
Week 6 Nonresponders
Open Label Treatment Period
Days -28 to 
-1
Week 0 (a)
Day 1
Week 2
Day 15
(±2 days)
Week 6a (b)
Day 43
(-5 days)
Week 6b (b)
Day 43
(+3 days)
Week 6b
Day 43
(+3 days)
Pre-Week 14
Day 92
(+4 days)
Week 14 (t)
Day 99
(±3 days)
OLE Nonenroller
OLE Enroller
Clinic Visit Number
1
2
3
4
5
NR5
PW14
NR6
NR6
Footnotes are on last table page.
Footnotes: 
Day=day after the first dose. 
HBV=hepatitis B virus, HCV=hepatitis C virus, NR=non-responders, OL=open-label, PML=progressive multifocal 
leukoencephalopathy, 
.
(a) All Baseline (Week 0) assessments will be done pre-dose.
(b) Week 6a visit should be performed between Day 38 and 43 (inclusive) and Week 6b visit should be performed between Days 43 and 46 (inclusive). The Week 6a and 6b visits 
should not be performed on the same day.
(c) Physical examination: Clinically significant findings will be recorded as concurrent conditions if they started prior to signing the informed consent, or as PTEs if they started after 
signing the informed consent and as AEs if they started after the first dose of study drug.
(d) Vital signs: Height (cm) and weight (kg; without shoes) will be measured during screening. Weight and vital signs will also be measured on dosing days prior to dosing
(e) PML checklist: will be administered prior to each dosing event. The PML subjective checklist will be administered in person at dosing occurring in the clinic during scheduled 
visits. The PML subjective checklist will be administered over the phone when the subject is injecting outside of the clinic.
(f) Diary review: will be administered prior to each dosing event either in person at dosing occurring in the clinic during scheduled visits or over the phone when the subject is 
injecting outside of the clinic.
(g) Concomitant medications and procedures: Monitoring of concomitant medications and concomitant procedures will begin at signing of the informed consent.
(h)
 
(i) TB screening: To be performed prior to dosing.
(j) Week 0 and 2 dosing will be done with vedolizumab IV; from randomization at Week 6B onwards dosing will be done with vedolizumab SC. WK6 Nonresponders (NR) will 
receive a 3rd infusion with open-label vedolizumab IV and be assessed for response at WK14. Responders at Week 14 will be eligible for the OLE study, Week 14 Responders that do 
not enter the OLE study and Nonresponders at Week 14 will complete Visit NR6 and discontinue from the study.
(k) CDAI: CDAI score components are to be performed prior to dosing; the total CDAI score will be calculated once results are available for all components. Hematocrit level from 
central laboratory results will be used for calculation of the CDAI score. 
The components of the CDAI score to determine eligibility at Week 0 must be available within 7 days prior to receiving the first dose of study drug (at a minimum, 7 days of diary data 
from the last 10 days prior to Week 0 will be required for the calculation of the score and the hematocrit level from Screening. Subjects will be required to complete diary entries for 
at least 14 days prior to Week 0). For Randomization at Week 6b, the sample taken for the hematocrit at Week 6a will be used to calculate the CDAI score. For Week 14, the sample 
taken for hematocrit at pre-Week 14 will be used to calculate the CDAI score.
(l) PTEs will be captured immediately following the signing of the informed consent at Screening, up until the first dose of study drug. Collection of AEs, to include concomitant 
le
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plica
ek 6 Non
k 6 No
pplic
n Label T
Label 
ab
t
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)
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Pre
Pre-W
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patitis C vi
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isitit should
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when th
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Week 14
Week 14
e performe
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calculatio
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will be
For Rand
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eek 14 wil
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mmediatel
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Protocol Incorporating Amendment No. 06
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medications, will begin following first dose of study drug and will continue through Week 68/Final Safety Visit. To be performed in person at dosing occurring in the clinic during 
scheduled visit. To be performed over the phone at dosing occurring outside of the clinic. 
(m) Collection of all SAEs will begin once the informed consent is signed and will continue through Week 68/ Final Safety Visit. To be performed in person at dosing occurring in the 
clinic during scheduled visit. 
(n) A urine pregnancy test will be completed for all female subjects of child bearing potential on a 4-weekly basis prior to administration of study drug.
(o) Follicle-stimulating hormone (FSH) level will be obtained for female subjects at Screening if they are postmenopausal by history (ie, last regular menstrual cycle >1 years) and not 
surgically sterile. The FSH result must be >40 IU/L for the subject to be permitted not to use adequate contraception.
(p) All PK
 samples will be obtained at predose (within 30 minutes prior to dosing).
(q) Fecal calprotectin stool sample should be collected from the first bowel movement on the day of collection.
(r) A stool sample for culture, ova and parasite evaluation, and C. difficile assay will be obtained at Screening and at any time point during the study when a subject becomes 
symptomatic, including worsening or return of disease activity. 
(s)
 
(t) For OLE enrollers, subjects should receive their first OLE vedolizumab SC dose as close to Week 14 of MLN0002SC-3031 as possible (preferably within Week 14 ±3 days). If this 
window is too challenging for the sites, dosing within week 14 ±7 days is acceptable from a PK perspective (ie, maintaining trough concentration at or above 10 μg/mL).
Property of Takeda: For non-commercial use only and
k 
d
ect to the applicable Terms of Use
le
rson at dos
on at d
o be perfor
be perf
dministrati
nistrat
by history 
by histo
and d at any
at a
14 of ML
4 o
K perspecti
perspec
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Protocol Incorporating Amendment No. 06
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Appendix A
Schedule of Study Procedures (Maintenance Phase)
Study Procedures
Maintenance Phase (a)
Final Safety 
Follow-up
Visit (b)
Unscheduled 
Visit (c)
46-Week Double Blind, Randomized Treatment Period 
(Week 7 must occur +7 days after Randomization)
Wk 7 Wk 8
Wk 
10, 12 
(d)
Wk 
14
Wk 
16, 
18, 20 
(d)
Wk 
22
Wk 
24, 
26, 28 
(d)
Wk 
30
Wk 
32, 
34, 36 
(d)
Wk 
38
Wk 
40, 
42, 44 
(d)
Wk 
46
Wk 
48 (d)
Wk 
50
Wk 
51
Wk 
52/ET
(s)
Wk 68
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 7 
days
± 1 week
Clinic Visit Number
6
7
8
9
10
11
12
13
14
15
16
Physical examination (e)
X
X
X
X
X
X
X
X
X
Vital signs (f)
X
X
X
X
X
X
X
X
X
X
X
X
PML checklist (g)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PML wallet card
X
Diary review 
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing - Blinded SC
X
X
X
X
X
X
X
X
X
X
X
X
X
CDAI (h)
X
X
X
X
X
X
X (i)
X
PRO (IBDQ; EQ-5D)
X
X
12-lead ECG
X
X
PTE/AE assessment (k)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE assessment (l)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.
Property of Takeda: Fo
mercial use only and subject to the applicable Terms of Use
le
lic
pp
k k 
46
Wk 
Wk
48 
4
he
ct t
th
days
ays
± 3
± 3
day
da
ec
ubj c
su
d u
X
d
nd
X
an
ly
n
X
X
lylyly
on
e
X
e
X
us
er al
X
X
er
er
erc
er
X
me
o
X
Fo
a:
o
X
X
a:
a:
a:
eda:
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Page 104 of 126
Protocol Incorporating Amendment No. 06
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Appendix A
Schedule of Study Procedures (Maintenance Phase) (continued)
Study Procedures
Maintenance Phase (a)
Final Safety 
Follow-up 
Visit (b)
Unscheduled
Visit (c)
46-week Double Blind, Randomized, Treatment Period
(Week 7 must occur +7 days after Randomization)
Wk 7 Wk 8
Wk 
10, 12 
(d)
Wk 
14
Wk 
16, 
18, 20 
(d)
Wk 
22
Wk 
24, 
26, 28 
(d)
Wk 
30
Wk 
32, 
34, 36 
(d)
Wk 
38
Wk 
40, 
42, 44 
(d)
Wk 
46
Wk 
48 (d)
Wk 
50
Wk 
51
Wk 
52/ET
(s)
Wk 68
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 7 
days
± 1 week
Clinic Visit Number
6
7
8
9
10
11
12
13
14
15
16
Sample collection for:
Serum pregnancy test
X
X
Urine pregnancy test (m)
wk10
X
wk 18
X
wk 26
X
wk 34
X
wk 42
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X (r)
Hematology
X
X
X
X
X
X
X (i)
X
X (r)
Coagulation
X
X
Urinalysis
X
PK assessment (n)
X
X
X
X
X
X
X
X
X
X
X
X
Fecal calprotectin (o)
X
X
CRP
X
X
C difficile stool sample (p)
X (p)
Footnotes are on last table page.
Property of Takeda: For
n-co
rcial use only and subject to the applicable Terms of Use
le
lic
pp
Wk k 
46
46
Wk
W
48
he
he
he
t t
he
3 3
days
ays
± 3
±
da
d
ec
bj
su
d
an
y
wk 34
k 34
ly
o y
on
e o
X
e
us
lal
X
ci
r
o
-c
n
r
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Footnotes: 
Day=day after the first dose in Induction Period. 
 HBV=hepatitis B virus, HCV=hepatitis C virus, PML=progressive multifocal 
leukoencephalopathy
(a) Maintenance period: There should be a minimum of 7 days between 2 consecutive doses.
(b) Subjects discontinued from the study for any reason during the Maintenance Phase will complete the ET Visit, the Final Safety Visit and LTFU. These subjects are not enrolling 
in the OLE study.
(c) Subjects seen at an unscheduled visit for disease exacerbation or SAE will complete the Unscheduled Visit assessments.
(d) Nonclinic visits. Subject will inject once the site has confirmed the subject can inject via the pre-dose phone call.
(e) Physical examination: Clinically significant findings will be recorded as AEs if they start after the first dose of study drug.
(f) Vital signs: Weight and vital signs will also be measured on dosing days prior to dosing.
(g) PML checklist: will be administered prior to each dosing event. The PML subjective checklist will be administered in person at dosing occurring in the clinic during scheduled 
visits. The PML subjective checklist will be administered over the phone when the subject is injecting outside of the clinic.
(h) CDAI score components are to be performed prior to dosing; the total CDAI score will be calculated once results are available for all components. 
(i) Hematocrit level from central laboratory results will be used for calculation of the CDAI score.
(j)
 
(k) Collection of AEs, to include concomitant medications, will begin following first dose of study drug and will continue through Week 68/Final Safety Visit. To be performed in 
person at dosing occurring in the clinic during scheduled visit. To be performed over the phone at dosing occurring outside of the clinic. 
(l) Collection of all SAEs will continue from Week 7 through Week 68/Final Safety Visit. To be performed in person at dosing occurring in the clinic during scheduled visit. To be 
performed over the phone at dosing occurring outside of the clinic.
(m) A urine pregnancy test will be completed for all female subjects of child bearing potential on a 4-weekly basis prior to administration of study drug.
(n) PK samples at Weeks 7, 51 and 52 can be collected at any time during the visit. All other PK 
 samples will be obtained at predose (within 30 minutes prior to dosing). The 
(o) Fecal calprotectin stool sample should be the first bowel movement on the day of collection.
(p) A stool sample for culture, ova and parasite evaluation, and C. difficile assay will be obtained (if indicated) at any time point during the study when a subject becomes 
symptomatic, including worsening or return of disease activity.
(q)
 
(r) If indicated.
(s) Subjects randomized in the Maintenance Phase who complete the study or ET after Week 6 for disease worsening or after Week 14 who require rescue medication will be offered 
entry into the OLE study after completion of the Week 52/ET assessments. Week 0 of the OLE study should occur no more than 4 weeks after the last dose of study drug for 
completers/ET. 
Property of Takeda: For non-
er
use only 
 subject to the applicable Terms of Use
le
, PML=pr
PML=p
Safety Vis
ety Vi
ments.
nts.
l.
of study dr
study d
dministere
dminist
utside of th
ide of 
ted once r
d once
e of study d
of stu
he phone a
phone a
Visit. To 
it. T
earing pot
aring p
e visit. All 
A
nt on the d
on
difficile
ficile as
ho comple
o com
Week 52
Week 52/E
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Page 106 of 126
Protocol Incorporating Amendment No. 06
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the 
applicable local laws and regulations. The responsibilities imposed on Investigators from 
the FDA are summarized in the “Statement of Investigator” (Form FDA 1572) which must 
be completed and signed before the Investigator may participate in this study. 
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
study related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study related duties and functions, and 
should implement procedures to ensure the integrity of the study related duties and 
functions performed and any data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard 
panel) screening assessments are NOT performed on potential subjects, prior to the 
receipt of written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are 
informed of these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that 
conform to 21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory 
requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research 
activity and all anticipated risks to subjects. Make at least yearly reports on the progress 
of the study to the IRB/IEC, and issue a final report within 3 months of study 
completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and 
local regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and 
document the date of consent in the subject’s medical chart. Valid informed consent is 
the most current version approved by the IRB/IEC. Each informed consent form should 
contain a subject authorization section that describes the uses and disclosures of a 
subject’s personal information (including personal health information) that will take 
place in connection with the study. If an informed consent form does not include such a 
subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
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Protocol Incorporating Amendment No. 06
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10. Prepare and maintain adequate case histories of all persons entered into the study, 
including (e)CRFs, hospital records, laboratory results, etc, and maintain these data for 
a minimum of 2 years following notification by the sponsor that all investigations have 
been discontinued or that the regulatory authority has approved the marketing 
application. The investigator should contact and receive written approval from the 
sponsor before disposing of any such documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified 
essential documents.
12. Maintain current records of the receipt, administration, and disposition of 
sponsor-supplied drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the 
sponsor within 24 hours.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to 
each treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, 
when applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be 
expected from the research. When there is no intended clinical benefit to the subject, 
the subject should be made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the 
subject will be maintained, and a note of the possibility that regulatory agencies, 
auditor(s), IRB/IEC, and the monitor may inspect the records. By signing a written 
informed consent form, the subject or the subject’s legally acceptable representative is 
authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if 
injury occurs and, if so, what they consist of or where further information may be 
obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the 
research (investigator), subject’s rights, and IRB/IEC and whom to contact in the event 
of a research-related injury to the subject.
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Protocol Incorporating Amendment No. 06
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19. A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the subject otherwise is entitled, and that the subject 
may discontinue participation at any time without penalty or loss of benefits to which 
the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and 
procedures for orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to 
the subject’s willingness to continue participation in the study.
22. A statement that results of 
analysis will not be disclosed to an 
individual, unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the 
study may be terminated.
24. A written subject authorization (either contained within the informed consent form or 
provided as a separate document) describing to the subject the contemplated and 
permissible uses and disclosures of the subject’s personal information (including 
personal health information) for purposes of conducting the study. The subject 
authorization must contain the following statements regarding the uses and disclosures 
of the subject’s personal information:
a) that personal information (including personal health information) may be 
processed by or transferred to other parties in other countries for clinical research 
and safety reporting purposes, including, without limitation, to the following: 
(1) Takeda, its affiliates, and licensing partners; (2) business partners assisting 
Takeda, its affiliates, and licensing partners; (3) regulatory agencies and other 
health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may 
be processed and transferred to countries that do not have data protection laws that 
offer subjects the same level of protection as the data protection laws within this 
country; however, Takeda will make every effort to keep your personal information 
confidential, and your name will not be disclosed outside the clinic unless required 
by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of 
the safety and effectiveness of the study medication(s), studying other therapies for 
patients, developing a better understanding of disease, and improving the efficiency 
of future clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal 
information (including personal health information) upon withdrawal from the 
will be
will be
relevant
eleva
sclos
sclosed 
e
bject’s p
ect’s 
n the in
the in
subject 
ubjec
s persona
person
conducti
onduc
tatement
atemen
uding per
ding p
o other p
 othe
oses, inc
es, in
s, and lic
, and l
s, and lic
and l
; and (4)
and (4
that pers
hat p
sed and t
d and
ubjects th
ubjects 
ntry; how
y; ho
onfident
nfide
by 
by law
law
c)c) th
t
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Protocol Incorporating Amendment No. 06
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study to the extent that the restricted use or disclosure of such information may 
impact the scientific integrity of the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female 
subjects) who are sexually active must use adequate contraception (as defined in the 
informed consent) from Screening throughout the duration of the study. Regular 
pregnancy tests will be performed throughout the study for all female subjects of 
childbearing potential. If a subject is found to be pregnant during study, study 
medication will be discontinued and the investigator will offer the subject the choice to 
receive unblinded treatment information.
26. Male subjects must use adequate contraception (as defined in the informed consent) 
from Screening throughout the duration of the study. If the partner or wife of the 
subject is found to be pregnant during the study, the investigator will offer the subject 
the choice to receive unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her 
name, address, and other personally identifiable information. In addition, investigator’s 
personal information may be transferred to other parties located in countries throughout the 
world (eg, the United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda 
and these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications 
to regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications 
to regulatory agencies relating to other medications used in other clinical studies that 
may contain the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly 
accessible clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have 
data protection laws that offer the same level of protection as data protection laws in 
investigator’s own country.
Investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.
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Appendix F
Crohn’s Disease Activity Index (CDAI)
Category
Count
Initial 
Total
Multiplication 
Factor
Total
Number of liquid or very 
soft stools
7-day total number of liquid or very 
soft stools (reported on the 7 days 
immediately prior to the study visit)
2
Abdominal pain
7-day total of daily abdominal pain 
scores on a 3-point scale: 0 = none, 
1=mild, 2=moderate, 3=severe 
(reported on the 7 days immediately 
prior to the study visit)
5
General well being
7-day total of daily general well-being 
scores on a 4-point scale: 0=generally 
well, 1=slightly under par, 2=poor, 
3=very poor, 4=terrible (reported on 
the 7 days immediately prior to the 
study visit)
7
Extra-intestinal 
manifestations of Crohn’s 
Disease 
Total number of checked boxes (check 
all that apply):
Arthritis/arthralgia
Iritis/uveitis
Erythema nodosum/pyoderma 
gangrenosum/aphthous stomatitis
Anal fissure, fistula, or abscess
Other fistula
Fever over 37.8°C during past 
week
20
Lomotil/Imodium/opiates 
for diarrhea
Yes = 1
No = 0
30
Abdominal mass
None = 0
Questionable = 2
Definite = 5
10
Hematocrit (%) (a)
Males: subtract value from 47
Females: subtract value from 42
6
Body Weight (b)
(1 – (Body weight/
Standard Weight)) 100 
1
Final Score
Add totals:
Source: Adapted from: Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s disease 
activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70 (3):439-44.
(a) If hematocrit subtotal <0, enter 0.
(b) If body weight subtotal <-10, enter -10.
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Appendix H
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 06 are 
indicated. The corresponding text has been revised throughout the protocol. 
Change 1: Clarification of the Sponsor address in Japan.
The primary change occurs on Page 1: 
Initial 
wording:
Takeda Development Center Japan, 
Takeda Pharmaceutical Company Limited, 
1-1, Doshomachi 4-Chome, Chuo-ku Osaka 540-8645, Japan
Amended 
or new 
wording:
Takeda Development Center Japan, 
Takeda Pharmaceutical Company Limited, 
1-1, Doshomachi 4-Chome, Chuo-ku Osaka 540-8645, Japan
Rationale for Change:
Administrative change to the Sponsor address in Japan. 
Section 3.4 Corporate Identification also contains this change. 
Change 2: Administrative change to the Responsible Medical Officer and Approvers.
The primary change occurs in Section 1.1 Contacts and Section 1.2 Approval:
Initial 
wording:
Amended 
or new 
wording:
Initial 
wording:
Amended 
or new 
wording:
Initial 
wording:
Property of Take
mended 
mende
or new
or new
word
wo
ke
ng:g:
ke
y
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Vedolizumab SC
Study No. MLN0002SC-3031
Page 116 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Amended 
or new 
wording:
Rationale for Change:
Administrative change to study personnel.
Change 3: Inclusion of an additional secondary objective and endpoint, and exploratory 
endpoint.
The primary change occurs in Sections 5.1.2 Secondary Objectives, 5.2.2 Secondary 
Endpoints and 5.2.4 Exploratory Endpoints: 
Added 
text:
!
To assess the effect of vedolizumab SC maintenance treatment on 
clinical remission at Week 52, in subjects who are naïve to TNF-α 
antagonist exposure and achieved clinical response at Week 6 
following administration of vedolizumab IV at Weeks 0 and 2.
Added 
text:
!
Proportion of TNF-α antagonist naïve subjects who achieved clinical 
remission, defined as CDAI score ≤150, at Week 52.
Added 
text:
Rationale for Change:
Inclusion of an additional secondary objective and associated endpoints to assess the effect
of vedolizumab SC treatment in subjects with no prior TNF-α antagonist exposure, TNF-α 
exposure, and TNF-α failure. 
Section 2.0 STUDY SUMMARY also contains this change. 
Change 4: Clarification to the Final Visit/Early Termination procedures for subjects who 
complete (OLE Enroller/Nonenroller) at Week 14 (Induction Phase), and subjects who 
complete (Week 52) or discontinue from the Maintenance Phase.
The primary change occurs in Section 6.1 Study Design and Appendix A Schedule of 
Study Procedures: Screening, Induction and Nonresponders:
Property of Takeda
primary
rimary c
y
udy
udy Proc
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da: For non-commercia
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Vedolizumab SC
Study No. MLN0002SC-3031
Page 117 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Initial 
wording:

Subjects who achieve a clinical response at Week 6 will be randomized 
into the Maintenance Phase. Upon completion of the Week 52 assessment 
or upon early discontinuation due to treatment failure (ie, disease worsening 
or need for rescue medications) these subjects will be eligible to enter the 
OLE study. 

Subjects who do not achieve a clinical response at Week 6 will not be 
randomized in to the Maintenance Phase, and instead will receive a third 
infusion of vedolizumab IV 300 mg at Week 6. Subjects who achieve a 
clinical response at Week 14 (by CDAI) will be eligible to enroll in the OLE 
study, while subjects who do not achieve clinical response will be 
discontinued. 
…
Subjects who do not participate in the OLE trial or are discontinued, will enter 
the Follow-Up Period and complete a final on-study safety assessment at 
18 weeks (ie, 5 vedolizumab half-lives) from the last study drug dose (Week 50 
or early termination [ET]). 
Additionally, subjects who do not participate in the OLE trial will be required to 
participate in a long-term follow-up (LTFU) safety survey by telephone, 6 
months after the last dose of study drug.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Vedolizumab SC
Study No. MLN0002SC-3031
Page 118 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Amended 
or new 
wording:

Subjects who achieve a clinical response at Week 6 will be randomized 
into the Maintenance Phase. Upon completion of the Week 52 assessment 
or upon early discontinuation due to treatment failure (ie, disease worsening 
after Week 6 or need for rescue medications after Week 14) these subjects 
will be eligible to enter the OLE study (Table 7.a). 

Subjects who do not achieve a clinical response at Week 6 will not be 
randomized in to the Maintenance Phase, and instead will receive a third 
infusion of vedolizumab IV 300 mg at Week 6. Subjects who achieve a 
clinical response at Week 14 (by partial Mayo score) will be eligible to 
enroll in the OLE study. Subjects who respond but choose not to enroll 
in the OLE study and, while subjects who do not achieve clinical response 
at Week 14will be discontinued. 
…
Subjects who do not participate in the OLE trialstudy or are discontinued from 
the study before Week 6, will enter the Follow-Up Period and complete a final 
on-study safety assessment at 18 weeks (ie, 5 vedolizumab half-lives) from the 
last study drug dose (Week 50 or early termination [ET]).
Additionally, subjects who do not participate in the OLE trial study or have 
discontinued before Week 6 will be required to participate in a long-term 
follow-up (LTFU) safety survey by telephone, 6 months after the last dose of 
study drug.
Appendix A Schedule of Study Procedures: Screening, Induction and Nonresponders:
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Vedolizumab SC
Study No. MLN0002SC-3031
Page 119 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Description 
of change:
Column labelled Week 14, Day 99 (±3 days) split into 2 columns labelled OLE 
nonenroller and OLE enroller:
!
Footnote (t) added:
o
(t) For OLE enrollers, subjects should receive their first 
OLE vedolizumab SC dose as close to Week 14 of 
MLN0002SC-3031 as possible (preferably within Week 14 
±3 days). If this window is too challenging for the sites, 
dosing within week 14 ±7 days is acceptable from a PK 
perspective (ie, maintaining trough concentration at or 
above 10 μg/mL).
!
OLE nonenroller column:
o
X included in rows Physical examination, Vital signs, PML 
checklist, Diary review, Concomitant medications and 
procedures,
 CDAI, PTE/AE 
assessment, SAE assessment, Urine pregnancy test, PK 
assessment 
!
OLE enroller column:
o
X included in rows Physical examination, Vital signs, PML 
checklist, Diary review, Concomitant medications and 
procedures, Fistula Assessment (if indicated), Assess eligibility 
for OLE, CDAI, PRO (IBDQ; EQ-5D), 
, PTE/AE 
assessment, SAE assessment, and Urine pregnancy test.
Rationale for Change:
Clarification to the Final Visit/Early Termination procedures for subjects who complete 
(OLE Enroller/Nonenroller) at Week 14 in the Induction Phase, and subjects who complete 
(Week 52) or ET from the Maintenance Phase.
The following sections also contain this change:
!
Figure 6.a Schematic of Study Design.
!
Section 7.5 Procedures for Discontinuation or Withdrawal of a Subject.
!
Section 9.3.2.1 Nonresponders.
!
Section 9.3.3 Final Visit or ET.
!
Section 9.3.4 Final Safety Follow-up Visit.
Property of Takeda: For 
g sect
g sectioi
urere 6.a
6.a Sc
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Section
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ites,
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CDAI
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Vedolizumab SC
Study No. MLN0002SC-3031
Page 120 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Change 5: Clarification to the study design schematic.
The primary change occurs in Figure 6.a Schematic of Study Design:
Initial 
wording:
(c) Visit 1 of Extension Study MLN0002SC-3030 is within 1 week of 
completing Week 52 (Visit 15) procedures. Subjects not randomized into the 
Maintenance Phase (Week 6 Nonresponders) and respond at Week 14 on 
vedolizumab IV 300 mg are also eligible for entry into the Extension Study.
Amended 
or new 
wording:
(c) Visit 1First visit of Extension OLE Study MLN0002SC-3030 is within 14
weeks after last dose of study drug for Week 52 completers/ET or 1 week 
of Week 14 for Week 14 responders of completing Week 52 (Visit 15) 
procedures. Maintenance Phase (Week 6 Nonresponders) and respond at Week 
14 on vedolizumab IV 300 mg are also eligible for entry into the Extension 
Study.
Rationale for Change:
Clarification to the timing of the first visit of OLE Study MLN0002SC-3030.
Change 6: Study design updated to clarify that all endoscopies will be centrally read.
The primary change occurs in Section 6.1 Study Design:
Initial 
wording:
 
 
 
 
Prope
se only
dy
ly and subject to the applicable Terms of Use
tudy
udy.
s within
withi
ET or 1 
T or 1 
2 (Visit 
2 (Visit
he
and resp
nd res
th
y into th
y into 
to
lic
dy MLN0
MLN
y
bje
endosco
ndos
nd
Desig
Desi
y
ly
e o
CCI
CCI


Vedolizumab SC
Study No. MLN0002SC-3031
Page 121 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Rationale for Change:
Study design updated to clarify that all endoscopies will be centrally read.
The following sections also contain this change:
!
!
Appendix A Schedule of Study Procedures: Screening, Induction and Nonresponders
Change 7: Clarification to Inclusion Criterion #11.
The primary change occurs in Section 7.1 Inclusion Criteria:
Initial 
wording:
!
Corticosteroids
i.
The subject has signs and symptoms of persistently active disease 
despite a history of a least one 4-week induction regimen that 
included at dose equivalent to prednisone ≥30 mg daily orally for 2 
weeks or intravenously for 1 week, OR
ii.
The subject has had two failed attempts to taper corticosteroids to 
below a dose equivalent to prednisone 10 mg daily orally on 2 
separate occasions. In Japan, at least 1 failed attempt to taper 
corticosteroids to below a dose equivalent to prednisone 10 mg daily 
orally or intravenously, OR
iii.
The subject has a history of intolerance of corticosteroids 
(including, but not limited to, Cushing’s syndrome, 
osteopenia/osteoporosis, hyperglycemia, insomnia, and infection).
Amended 
or new 
wording:
!
Corticosteroids
i.
The subject has signs and symptoms of persistently active disease 
despite a history of a least one 4-week induction regimen that 
included at dose equivalent to prednisone ≥30 mg daily orally for 2 
weeks or intravenously for 1 week, OR
ii.
The subject has had 2 failed attempts to taper corticosteroids to 
below a dose equivalent to prednisone 10 mg daily orally on 2 
separate occasions. In Japan, at least 1 failed attempt to taper 
corticosteroids to below a dose equivalent to prednisone 10 mg daily 
orally or intravenously, OR
iii.
The subject has a history of intolerance of corticosteroids 
(including, but not limited to, Cushing’s syndrome, 
osteopenia/osteoporosis, hyperglycemia, insomnia, and infection).
iv.
The subject had a relapse within 3 months of stopping steroids.
Property of Takeda: For non-comm
teroi
eroids
d
The subj
The sub
despi
des
inc
i
ii
mercial use only and subject to the applicable Terms of Use
onders
nders
ica
pp
sistent
istentlyl
duct
ductioion
sone 
ne ≥30
≥3
, OR
OR
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attemp
predniso
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CCI


Vedolizumab SC
Study No. MLN0002SC-3031
Page 122 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Rationale for Change:
Clarification to the inclusion criterion to include subjects who have relapsed within 
3 months of stopping steroids according to the current European Crohn’s and Colitis 
Organization guidelines.
Change 8: Clarification to Exclusion Criterion #5.
The primary change occurs in Section 7.2.1 Gastrointestinal Exclusion Criteria:
Initial 
wording:
5. The subject has had ileostomy, colostomy, or known fixed symptomatic 
stenosis of the intestine.
Amended 
or new 
wording:
5. The subject has had ileostomy, colostomy, or known fixed symptomatic 
stenosis of the intestine.
Rationale for Change:
Subjects with past medical history but no current ileostomy, colostomy, or known fixed 
symptomatic stenosis of the intestine are allowed into the study.
Change 9: Clarification to Exclusion Criterion #15.
The primary change occurs in Section 7.2.3 General Exclusion Criteria:
Initial 
wording:
15. The subject has chronic hepatitis B virus (HBV) infection* or chronic 
hepatitis C virus (HCV) infection.
* HBV immune subjects (ie, being hepatitis B surface antigen [HBsAg] 
negative and hepatitis B antibody positive) may, however, be included.
Amended 
or new 
wording:
15. The subject has chronic hepatitis B virus (HBV) infection* or chronic 
hepatitis C virus (HCV) infection.
* HBV immune subjects (ie, being hepatitis B surface antigen [HBsAg] 
negative and hepatitis B surface antibody [HBsAb] positive) may, 
however, be included.
Rationale for Change:
Clarification to Exclusion criterion text.
Change 10: Clarification to Exclusion Criterion #20.
The primary change occurs in Section 7.2.3 General Exclusion Criteria:
Initial 
wording:
20. The subject has had previous exposure to approved or investigational 
anti-integrins (eg, natalizumab, efalizumab, etrolizumab, AMG 181), 
anti-MAdCAM-1 antibodies, or rituximab.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Vedolizumab SC
Study No. MLN0002SC-3031
Page 123 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Amended 
or new 
wording:
20. The subject has had previous exposure to approved or investigational 
anti-integrins antibodies (eg, natalizumab, efalizumab, etrolizumab, AMG 
181), anti-MAdCAM-1 antibodies, or rituximab.
Rationale for Change:
Clarification to Exclusion criterion text.
Change 11: Clarification to the period for excluded medications and treatments.
The primary change occurs in Section 7.3 Excluded Medications and Treatments:
Initial 
wording:
The following medications are excluded from use during the study: 
Amended 
or new 
wording:
The following medications are excluded from use during the study (from 
informed consent to Week 68): 
Rationale for Change:
Inclusion to text to outline the specific period for excluded medications and treatments.
Change 12: Clarification to Section 9.1.5 Vital Signs Procedure.
The primary change occurs in Section 9.1.5 Vital Sign Procedure:
Deleted 
text:
When vital signs are scheduled at the same time as blood draws, the blood draw 
will take priority and vital signs will be obtained within 0.5 hour before the 
scheduled blood draw. 
Rationale for Change:
There is no time restriction between the timing of the vital sign measurements and blood 
draws during the same visit.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Vedolizumab SC
Study No. MLN0002SC-3031
Page 124 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Change 13: Clarification to Section 9.1.6.1 Diary Completion and Review.
The primary change occurs in Section 9.1.6.1 Diary Completion and Review:
Initial 
wording:
Diary entries will be made daily by subjects from screening to end of study, and 
will be used for CDAI calculation. At screening, subjects will be instructed on 
how to appropriately complete the daily diary. The symptoms of CD must be 
recorded throughout the study, including the Screening Period. Diary entries 
will be made daily by the subject through a validated electronic system. At each 
visit, including during screening, the CDAI score must be calculated prior to 
dosing by the investigator or designee based on daily diaries, laboratory 
assessments, and clinical examination and recorded in the subject’s source 
documents. 
The CDAI score evaluated during screening will be used to determine 
eligibility, using subject diary entries within 14 days prior to Week 0. 
 
Amended 
or new 
wording:
Diary entries will be made daily by subjects from screening to end of study, and 
will be used for CDAI calculation. At screening, subjects will be instructed on 
how to appropriately complete the daily diary. The symptoms of CD must be 
recorded throughout the study, including the Screening Period. Diary entries 
will be made daily by the subject through a validated electronic system. At each 
visit, including during screening, the CDAI score must be calculated prior to 
dosing by the 
, accessed by the investigator or 
designee based on daily diaries, laboratory assessments, and clinical 
examination and recorded in the subject’s source documents. 
The CDAI score evaluated during screening will be used to determine 
eligibility, using subject diary entries within 1014 days prior to Week 0. At a 
minimum, 7 days of diary data from the last 10 days prior to Week 0 will 
be required for the calculation of the score. Subjects will be required to 
complete diary entries for at least 14 days prior to Week 0. 
 
 
 
Property of Takeda: For non-co
rcial use on
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on. At s
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Vedolizumab SC
Study No. MLN0002SC-3031
Page 125 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Rationale for Change:
Clarification to text that the CDAI score is automatically calculated by the EPX system and 
not manually calculated by the investigator. Clarification to the number of days of diary 
data that is required for the CDAI calculation at Screening.
Appendix A Schedule of Study Procedures: Screening, Induction and Nonresponders also 
contains this change. 
Change 14: ECG procedure updated.
The primary change occurs in Section 9.1.12 ECG Procedure:
Initial 
wording:
Subjects will be supine and will have rested for 5 or more minutes before any 
ECG is recorded. Tracings will include subject number and initials and the date 
and time of recording and all other subject identifiers will be removed or 
obscured.
Amended 
or new 
wording:
Subjects will be supine and will have rested for 5 or more minutes before any 
ECG is recorded. Tracings will include subject number and initials and the date 
and time of recording and all other subject identifiers will be removed or 
obscured.
Rationale for Change:
ECG tracings are source documentation and will not be seen by the sponsor.
Change 15: Addition of a Pre–Week 14 visit for Week 6 nonresponders.
The primary change occurs in Appendix A Schedule of Study Procedures: Screening, 
Induction and Nonresponders:
Description 
of change:
Additional column labelled Pre-Week 14, Day 92 (+4 days)
!
X included for Serum pregnancy test, Clinical chemistry, 
Hematology, Urinalysis, PK assessment, 
Fecal 
Calprotectin and CRP.
Rationale for Change:
Additional visit so that the safety laboratory samples can be taken so that the results are 
current and available for the Week 14 visit for Week 6 nonresponders. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
lso 
so 
ica
app
minutes
minute
and init
and in i
 will be
will b
he
for 5 or m
or 5 or
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al 
Append
Appen
ers:
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colum
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X inc
X in
He
H
co
ale for C
le for
ditioional
nal
current a
current
a:
a:
a:
of 
CCI


Vedolizumab SC
Study No. MLN0002SC-3031
Page 126 of 126
Protocol Incorporating Amendment No. 06
24 August 2017
Change 16: Update to Appendix A Schedule of Study Procedures for Crohn’s 
disease–related events.
The primary change occurs in Appendix A Schedule of Study Procedures: Screening, 
Induction and Nonresponders:
Description 
of change:
Row labelled CD-related events removed.
Rationale for Change:
CD-related events removed from the Induction Phase and Maintenance Phase schedules as 
these are recorded as AEs, SAEs, or concomitant procedures in the eCRF. 
Change 17: Update to Appendix B Responsibilities of the Investigator.
The primary change occurs in Section Appendix B Responsibilities of the Investigator: 
Added 
text:
3. If the investigator/institution retains the services of any individual or 
party to perform study related duties and functions, the 
investigator/institution should ensure that this individual or party is 
qualified to perform those study related duties and functions, and 
should implement procedures to ensure the integrity of the study 
related duties and functions performed and any data generated.
Rationale for Change:
Update to the Responsibilities of the Investigator in line with Section 4.2.6 of the Guideline 
for Good Clinical Practice E6 (R2), which was revised on 01 December 2016.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title:  Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of Vedolizumab Subcutaneous as Maintenance Therapy in Subjects With Moderately 
to Severely Active Crohn’s Disease Who Achieved Clinical Response Following Open-Label 
Vedolizumab Intravenous Therapy
NCT Number: NCT02611817
SAP Approve Date: 24 June 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: MLN0002SC-3031
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of Vedolizumab Subcutaneous as Maintenance Therapy in Subjects With 
Moderately to Severely Active Crohn’s Disease Who Achieved Clinical Response Following 
Open-Label Vedolizumab Intravenous Therapy
PHASE 3
Version: Amendment 01
Date: 24 June 2019
Prepared by:
Based on:
Protocol Version: Amendment 06
Protocol Date: 24 August 2017
Original SAP Date: 20 July 2018
Prope
 of Takeda: For non
ial use only and subject to the applicable Terms of Use
Evaluat
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Statistical Analysis Plan Amendment 01
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1.1
APPROVAL SIGNATURES
Electronic signatures can be found on the last page of this document.
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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
APPROVAL SIGNATURES.....................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................6
4.1
Primary Objectives ....................................................................................................6
4.2
Secondary Objectives.................................................................................................6
4.3
Exploratory Objectives ..............................................................................................6
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoint.......................................................................................................9
5.2
Secondary Endpoints .................................................................................................9
5.3
Patient Reported Outcome (PRO) Endpoints..............................................................9
5.4
Exploratory Endpoints ...............................................................................................9
5.5
Safety Assessments..................................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Considerations............................................................................................13
7.1.1
Study Terms and Definitions..............................................................................13
7.1.2
Definition of Study Days and Visit Window ......................................................13
7.1.3
Convention for Calculations of CDAI Scores.....................................................15
7.1.4
Convention for Missing Efficacy Data ...............................................................16
7.2
Analysis Sets ...........................................................................................................17
7.2.1
Full Analysis Set (FAS) .....................................................................................17
7.2.2
Intent-To-Treat Set (ITT)...................................................................................17
7.2.3
Per-Protocol Set (PPS).......................................................................................17
7.2.4
Safety Analysis Set (SAF)..................................................................................17
7.2.5
Pharmacokinetic Set...........................................................................................18
7.3
Disposition of Subjects ............................................................................................18
7.4
Demographic and Baseline Characteristics...............................................................18
7.5
Medical History and Concurrent Medical Conditions...............................................19
7.6
Medication History and Concomitant Medications and Procedures ..........................19
7.7
Study Drug Exposure and Compliance.....................................................................20
7.8
Efficacy Analysis.....................................................................................................20
7.8.1
Primary Efficacy Endpoint.................................................................................20
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7.8.2
Secondary Efficacy Endpoints............................................................................21
7.8.3
Multiplicity Adjustment .....................................................................................22
7.8.4
Patient Reported Outcomes (PROs) Endpoints...................................................22
7.8.5
Exploratory Efficacy Endpoints .........................................................................23
7.8.6
Subgroup Analysis.............................................................................................24
7.8.7
Additional Analysis and Sensitivity Analysis .....................................................25
7.9
Pharmacokinetic Analysis........................................................................................26
7.10
Other Outcomes.......................................................................................................26
7.10.1 Immunogenicity Endpoints ................................................................................26
7.10.2
.......................................................................................26
7.10.3
..........................................................................28
7.11
Safety Analysis........................................................................................................28
7.11.1 Adverse Events ..................................................................................................28
7.11.2 Clinical Laboratory Evaluations .........................................................................30
7.11.3 Vital Signs .........................................................................................................30
7.11.4 12-Lead ECGs ...................................................................................................30
7.11.5 Other Observations Related to Safety.................................................................30
7.12
Interim Analysis ......................................................................................................30
7.13
Changes in the Statistical Analysis Plan...................................................................31
8.0
REFERENCES..............................................................................................................35
LIST OF IN-TEXT TABLES
Table 7.a
Visit Windows (Induction Phase for Non-responders at Week 6) .......................14
Table 7.b
Visit Windows (Randomized Subjects) ..............................................................15
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................36
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs......................................37
Appendix C
CDAI Scoring System for the Assessment of Crohn’s Disease Activity..............38
Appendix D
Geographic Regions...........................................................................................39
Appendix E
AEs of Special Interest.......................................................................................40
Appendix F
Prior Therapies...................................................................................................41
Appendix G
Patient Reported Outcomes ................................................................................42
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3.0
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
AESI
adverse event of special interest
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CMH
Cochran-Mantel-Haenszel
CRF
Case Report Form
Ctrough
trough serum concentration 
ECG
Electrocardiogram
EQ-5D
Euro Quality of Life-5D
FAS
full analysis set
HLT
high level term
IBDQ
Inflammatory Bowel Disease Questionnaire
IV
intravenous(ly)
KM
Kaplan-Meier
LTFU
long-term follow-up
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
OLE
open-label extension
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PRO
patient-reported outcome
PT
preferred term
Q2W
once every 2 weeks
Q8W
once every 8 weeks
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous(ly)
SI
Systeme International
TEAE
treatment-emergent adverse event
TNF-α
tumor necrosis factor-alpha
ULN
upper limit of normal
VAS
visual analog scale
WHODRUG
World Health Organization Drug Dictionary
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4.0
OBJECTIVES
4.1
Primary Objectives
!
To assess the effect of vedolizumab subcutaneous (SC) maintenance treatment on clinical 
remission at Week 52 in subjects with moderately to severely active Crohn’s disease (CD)
who achieved clinical response at Week 6 following administration of vedolizumab 
intravenous (IV) at Weeks 0 and 2.
4.2
Secondary Objectives
!
To determine the effect of vedolizumab SC maintenance treatment on enhanced clinical 
response at Week 52 in subjects who achieved clinical response at Week 6 following 
administration of vedolizumab IV at Weeks 0 and 2.
!
To determine the effect of vedolizumab SC maintenance treatment on corticosteroid-free 
remission at Week 52 in subjects who achieved clinical response at Week 6 following 
administration of vedolizumab IV at Weeks 0 and 2.
!
To assess the effect of vedolizumab SC maintenance treatment on clinical remission at Week 
52 in subjects who are naïve to TNF-α antagonist exposure, and achieved clinical response at 
Week 6 following administration of vedolizumab IV at Weeks 0 and 2.
4.3
Exploratory Objectives
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 only and subject to the applicable Terms of Use
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4.4
Study Design
This is a pivotal, phase 3, multicenter, multinational, randomized, double-blind, 
placebo-controlled trial, designed to evaluate the efficacy and safety of maintenance treatment 
with vedolizumab SC in adult subjects with moderately to severely active CD who achieved a 
clinical response at Week 6 with open-label therapy with 300 mg vedolizumab IV at Weeks 0 
and 2. 
Moderately to severely active CD is defined as described in Inclusion Criteria in protocol Section 
7.1. Subjects who are either tumor necrosis factor-alpha (TNF-α) antagonist naïve or with TNF-α 
antagonist failure will be included ensuring approximately 50% of subjects with TNF-α 
antagonist failure are enrolled. Subjects with previous use of TNF-α antagonist but not failed will 
be included ensuring that no more than 10% of such subjects are enrolled.
The study includes a 4-week (28-day) Screening Period, a 6-week open-label vedolizumab IV 
Induction Phase, and a 46-week randomized, double-blind, placebo-controlled Maintenance 
Phase with vedolizumab SC with final visit at Week 52. 
Eligible subjects, will be enrolled into the Induction Phase at Week 0, will receive open-label 
infusions of vedolizumab IV 300 mg at Weeks 0 and 2, and will be assessed for clinical response 
by CDAI (defined as a ≥70 point decrease in CDAI score from Baseline [Week 0]) at Week 6: 
!
Subjects who achieve a clinical response at Week 6 will be randomized into the Maintenance 
Phase. Upon completion of the Week 52 assessment or upon early discontinuation due to 
treatment failure (ie, disease worsening after Week 6 or need for rescue medications after 
Week 14) these subjects will be eligible to enter the MLN0002SC-3030 open-label extension 
(OLE) study with vedolizumab SC.
!
Subjects who do not achieve a clinical response at Week 6 will not be randomized in to the 
Maintenance Phase, and instead will receive a third infusion of vedolizumab IV 300 mg at 
Week 6. Subjects who achieve a clinical response at Week 14 (by CDAI) will be eligible to 
enroll in the OLE study. Subjects who respond but choose not to enroll in the OLE study and 
subjects who do not achieve clinical response at Week 14 will be discontinued.
Property of Takeda: For non-commercial use only and subject to th
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Subjects who achieve a clinical response at Week 6 will be randomized at a 2:1 ratio to receive 
blinded injections of vedolizumab SC 108 mg or placebo SC once every 2 weeks (Q2W), 
beginning at Week 6 through Week 50.
Randomization will be stratified by:
!
Concomitant use of oral corticosteroids.
!
Clinical remission status at Week 6.
!
Previous TNF-α antagonist failure/exposed or concomitant immunomodulator (azathioprine, 
6-mercaptopurine, or methotrexate) use.
At Week 6, subjects receiving oral corticosteroids who achieved a clinical response and are 
randomized into the Maintenance Phase will begin a corticosteroid tapering regimen.
Subjects who do not participate in the OLE study or are discontinued from the study before 
Week 6, will enter the Follow-Up Period and complete a final on-site safety assessment at 
18 weeks (ie, 5 vedolizumab half-lives) from the last study drug dose. 
Additionally, subjects who do not participate in the OLE study or a discontinued before Week 6
will be required to participate in a long-term follow-up (LTFU) safety survey by telephone, 6 
months after the last dose of study drug.
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Statistical Analysis Plan Amendment 01
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
!
Proportion of subjects with clinical remission, defined as CDAI score ≤150, at Week 52.
5.2
Secondary Endpoints
!
Proportion of subjects with enhanced clinical response, defined as a ≥100 point decrease in 
CDAI score from Baseline (Week 0), at Week 52.
!
Proportion of subjects with corticosteroid-free remission, defined as subjects using oral 
corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in 
clinical remission at Week 52.
!
Proportion of TNF-α antagonist naïve subjects who achieved clinical remission, defined as 
CDAI score ≤150, at Week 52.
5.3
Patient Reported Outcome (PRO) Endpoints
!
Changes in inflammatory bowel disease questionnaire (IBDQ) total score and subscores,
from Baseline (Week 0) to Week 52 and from Week 6 to Week 52.
!
Changes in Euro Quality of Life-5D (EQ-5D) utility scores and EQ-5D visual analog scale
(VAS) score from Baseline (Week 0) to Week 52 and from Week 6 to Week 52.
5.4
Exploratory Endpoints
Other Efficacy Endpoints:
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Prop
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5.5
Safety Assessments
Safety will be assessed by adverse events (AEs), adverse events of special interest (AESIs) 
(including serious infections including opportunistic infection such as progressive multifocal 
leukoencephalopathy (PML), liver injury, malignancies, infusion-related or injection site 
reactions or systemic reactions and hypersensitivity), serious adverse events (SAEs), vital signs, 
results of standard laboratory tests (clinical chemistry, hematology, coagulation, urinalysis), and 
results of 12-lead electrocardiograms (ECGs).
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Statistical Analysis Plan Amendment 01
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6.0
DETERMINATION OF SAMPLE SIZE
Assuming a clinical remission rate of 38% for vedolizumab SC and 22% for placebo at Week 52, 
a sample size of 258 subjects in the vedolizumab SC group and 129 subjects in the placebo group 
will provide 90% power at 2-sided 0.05 level of significance. To ensure a randomized sample 
size of 387 subjects, assuming 47% of the subjects entering induction will achieve clinical 
response at Week 6, approximately 824 subjects will need to be enrolled into the study.
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Considerations
Statistical analysis will be performed using the SAS System, Version 9.2 or higher.
All study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings. Continuous data will be summarized using number of subjects with non-missing values, 
mean, standard deviation, median, minimum, and maximum. Categorical data will be 
summarized using the number and percentage of subjects for each category where appropriate.
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.05 significance level unless otherwise stated.
7.1.1
Study Terms and Definitions 
Term
Definition
Clinical remission by 
CDAI
A CDAI score ≤150. 
Clinical response
A ≥70 point decrease in CDAI score from Baseline (Week 0).
Corticosteroid-free 
remission
Subjects using oral corticosteroids at Baseline (Week 0) who have discontinued oral 
corticosteroids and are in clinical remission at Week 52.
Disease worsening
A ≥100 point increase in CDAI score from the Week 6 value on 2 consecutive visits and 
a minimum CDAI score of 220 points.
Durable clinical 
remission
Clinical remission at Week 6 and Week 52.
Enhanced clinical 
response
A ≥100 point decrease in CDAI score from Baseline (Week 0).
Treatment failure
Defined as disease worsening, need for rescue medications (as defined in Section 7.3.1 of 
the protocol), or need for surgical intervention for treatment of Crohn’s Disease.
7.1.2
Definition of Study Days and Visit Window
Study day will be calculated relative to the date of the first dose of study drug (IV infusion) in 
the study. The study day prior to the first dose of study drug will be calculated as: 
Date of assessment/event – date of first dose of study drug.
The study day on or after the first dose of study drug will be calculated as: 
Date of assessment/event – date of first dose of study drug +1.
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Statistical Analysis Plan Amendment 01
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Baseline is defined as the last non-missing measurement prior to or on the date of the first dose 
of study drug (Study Day 1). The visit windows for the postbaseline visits are defined in 
Table 7.a and Table 7.b. If a subject has more than 1 non-missing measurement in the same visit 
window, the measurement closest to the target day will be used. If 2 measurements in the same 
window are of equal distance to the target day, the measurement that occurs later will be used. If 
2 or more measurements occur on the same day, the average value will be used, unless specified 
otherwise.
Table 7.a
Visit Windows (Induction Phase for Non-responders at Week 6)
Visit
Scheduled 
Day
Safety Labs Vital Signs
Urinalysis
IBDQ, EQ-5D, 
CRP
CDAI
Baseline
Day 1
∀1
∀1
∀1
∀1
∀1
∀1
Week 2
Day 14
2-28
2-28
NA
NA
NA
2-28
Week 6
Day 42
29-70
29-70
2-70
2-70
NA
29-70
Week 14a
Day 98
71-133
71-133
71-133
71-133
NA
71-133b
Week 24c
Day 168
≥134
≥134
NA
NA
NA
NA
a Week 14 will end on Day 133 or the day prior to the first dosing of the extension study (for patients entering the 
extension study), whichever comes first. 
b Week 14 for CDAI score will end on Day 133 or the day of the first dosing of the extension study (for patients 
entering the extension study), whichever comes first.
c Safety follow up visit. Only for subjects who do not enter the Extension Study MLN0002SC-3030 (including early 
terminators and Week 14 non-responders).
For the purpose of diary compliance calculation and derivation of diary-based endpoints, the last 
visit day of study will not be included since the subject is not expected to have completed the 
diary entries for that day by the Final Visit. 
AEs that start more than 126 days after the last dose of study drug will be listed, but excluded 
from the summaries and analyses. 
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Table 7.b
Visit Windows (Randomized Subjects)
Visit
Scheduled 
Day
Safety Labs Vital Signs Urinalysis
ECG
IBDQ, EQ-
5D,
CRP
Endoscopy,
Histology
CDAI
Baseline
Day 1
∀1
∀1
∀1
∀1
∀1
∀1
∀1
Week 2
Day 14
2-28
2-28
NA
NA
NA
NA
2-28
Week 6
Day 42
29-70
29-70
2-70
NA
2-70
NA
29-70
Week 14
Day 98
71-126
71-126
NA
NA
NA
NA
71-126
Week 22
Day 154
127-182
127-182
NA
NA
NA
NA
127-182
Week 30
Day 210
183-238
183-238
NA
NA
71-238
NA
183-238
Week 38
Day 266
239-294
239-294
NA
NA
NA
NA
239-294
Week 46
Day 322
295-336
295-336
NA
NA
NA
NA
295-336
Week 50
Day 350
337-357
337-357
NA
NA
NA
NA
337-357
Week 52
Day 364
358-420
358-420
≥71
≥2
≥239
≥2
≥358
Week 68a
Day 476
≥ 421
≥ 421
NA
NA
NA
NA
NA
a Safety follow up visit. Only for subjects who do not enter the Extension Study MLN0002SC-3030.
7.1.3
Convention for Calculations of CDAI Scores
The CDAI score is a weighted sum of 8 components. Subscores should be integers. The scoring
details including multiplication factors are in Appendix C.
CDAI scores will be derived at each scheduled visit utilizing the most recent available patient 
reported eDiary components, physician reported outcomes components and body weight 
(collected via SitePRO device), and Lab (hematocrit) in following steps:
1. Identify the completion date of the physician reported CDAI components, and set it as the 
CDAI calculation date.
2. Calculate the 3 eDiary subscores (liquid/soft stool frequency, abdominal pain and general 
wellbeing) as follows:
a) Select the diary data from 10 days prior to the CDAI calculation date identified in (1).
b) Merge in endoscopy dates and set diary data one day prior, on the day and one day after 
the endoscopy to missing.
c) Take 7 most recent days of diary data. If there are multiple entries on the same day for 
the eDiary items, use the worst result of the day for calculation.
d) If less than 4 days of diary data is non-missing, then a subscore cannot be calculated. 
Otherwise:
i.
If 4, 5 or 6 days of diary is non-missing, the subscore is calculated as the (average 
of non-missing diary×7), multiplying by the factor appropriate for the given 
subscore and rounding to the nearest integer.
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Statistical Analysis Plan Amendment 01
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ii.
If 7 or more days of diary is non-missing, the subscore is calculated as the sum of 
the most recent 7 days of non-missing diary, and multiplying by the factor 
appropriate for the given subscore.
3. Calculate Extra-intestinal manifestations of Crohn’s Disease Subscore, usage of 
Lomotil/Imodium/opiates for diarrhea and abdominal mass according to Appendix C.
4. Calculate Hematocrit subscore as follows: 
a) Identify the Hematocrit (%) results using the visit window defined in Section 7.1.2.
Select the value closest to the CDAI calculation date in (1). If two hematocrits are of 
equal distance to, but on either side of, the CDAI calculation date, select the later 
measurement. If two hematocrits occur on the same date, take the average.
b) If week 52 hematocrit is missing, week 50 value will be used if available. 
c) Subtract from 47 for males and from 42 for females, multiply by a factor of 6 and round
to the nearest integer. If the hematocrit subscore is <0, set it to 0.
5. Calculate Body Weight subscore as follows: 
a) Identify the body weight result reported on the CDAI calculation date.
b) Identify the standard weight based on subject’s gender and baseline height (cm) as 
follows:
i.
Standard weight for men in kilogram = (height in cm/100)2×22.1.
ii.
Standard weight for women in kilogram = (height in cm/100)2×20.8.
c) Calculate the subscore as maximum of [(1 – (Body weight/Standard Weight)) ×100, -10] 
and round to the nearest integer.
6. Calculate total score as the weighted sum of the 8 subscores only if none of the subscores are 
missing. Otherwise, the total score is set to be missing for the visit.
7.1.4
Convention for Missing Efficacy Data

Missing data for dichotomous (ie, proportion-based) endpoints will be handled using the non-
responder imputation method, ie, any subject with missing information for determination of 
endpoint status will be considered as a non-responder in the analysis. Sensitivity analysis will
be conducted to assess the impact of dropouts for different missing mechanisms using a 
hybrid approach where discontinuation due to AE or lack of efficacy will be imputed as 
non-responder (under MNAR) and other discontinuation/missing will be imputed using 
multiple imputation (under MAR) for primary and all secondary efficacy endpoints.

Missing data for continuous endpoints will be imputed using last available post-baseline 
observation carried forward (LOCF) method. For subjects without any non-missing 
post-baseline measurement, the missing data will be imputed using baseline observation 
carried forward method. Other missing data imputation method may be explored.
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7.2
Analysis Sets
7.2.1
Full Analysis Set (FAS)
The Full Analysis Set (FAS) will include all randomized subjects who receive at least 1 dose of 
study drug. Subjects who only receive induction IV therapy and not randomized into the 
maintenance phase will not be included in the FAS. Subjects in this set will be analyzed 
according to the treatment they were randomized to receive. The FAS will be used for all the 
efficacy analysis with the following exceptions: 
!
corticosteroid-free remission, will be based on a subset of the FAS subjects with baseline 
concomitant oral corticosteroid use.
!
proportion of TNF-α antagonist naïve subjects who achieved clinical remission, will be based 
on a subset of the FAS subjects who are TNF-α antagonist naïve.
!
!
!
7.2.2
Intent-To-Treat Set (ITT)
The intent-to-treat (ITT) population will include all randomized subjects. Subjects in this set will 
be analyzed according to the treatment they were randomized to receive. Analyses of primary 
and secondary efficacy endpoints will be performed in the ITT population as an additional 
analysis.
7.2.3
Per-Protocol Set (PPS)
The per-protocol (PP) population is a subset of the FAS. The PP population consists of all 
subjects who do not violate the terms of the protocol in a way that would impact the study output 
significantly. All decisions to exclude subjects for the PP population dataset will be made prior 
to the unblinding of the study. Analyses of primary and secondary efficacy endpoints will be 
performed using the PP population as a sensitivity analysis, if more than 5% of the total subjects 
in the FAS are excluded from the PPS.
7.2.4
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) will include all subjects who receive at least 1 dose of study SC
(placebo or vedolizumab) drug. Subjects in this set will be analyzed according to the treatment 
they actually received. SAF-I will include all subjects who receive at least 1 induction dose, and 
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were not dosed in the maintenance phase. SAF-C will include all subjects who receive at least 1 
dose of vedolizumab IV.
7.2.5
Pharmacokinetic Set
The PK evaluable population is defined as all subjects who receive at least 1 dose of study drug 
(placebo or vedolizumab) and have sufficient blood sampling to allow for PK evaluation.
7.3
Disposition of Subjects
A subject disposition summary will be provided. Subjects’ study completion data, including 
reasons for premature termination, will be provided in listings and also summarized.
Significant protocol deviations captured on the electronic case report form will be summarized.
A summary of screening failures will also be provided.
7.4
Demographic and Baseline Characteristics
Demographic and baseline characteristics variables will be summarized for the SAF-C. If the 
actual treatment of any patient is different from the randomized treatment, the demographic 
variables will also be summarized for the FAS.
For continuous variables (age, weight, height, and body mass index [BMI]), summary statistics 
will be generated. BMI (in kg/m2) will be calculated using the subject’s baseline height and 
weight measurements and summarized.
For categorical variables, the number and percentage of subjects in each category will be 
presented.
The following CD-related disease characteristics will be summarized for subjects: 
!
Duration of CD (<1 year, ≥1 to <3 years, ≥3 to <7 years, ≥7 years).
!
Subjects without prior corticosteroids or immunomodulators.
!
Subjects with only prior corticosteroids.
!
Subjects with only prior immunomodulators.
!
Subjects with prior corticosteroids and immunomodulators.
!
Subjects without baseline concomitant corticosteroids or immunomodulators.
!
Subjects with only baseline concomitant corticosteroids.
!
Subjects with only baseline concomitant immunomodulators.
!
Subjects with baseline concomitant corticosteroids and immunomodulators.
Property of Takeda: For non-commercial use only and subject to the
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
Subjects with prior TNF-α antagonist use (Naïve, exposed but not failure, failure).

Subjects with prior immunomodulator and prior TNF-α antagonist failure.

Worst prior treatment failure (subjects with prior TNF-α anatomist failure, subjects with prior 
immunomodulator failure, subjects with prior corticosteroid failure).

Baseline disease activity (moderate [CDAI≤330], severe [CDAI>330]).

Baseline CRP (≤2.87 mg/L, >2.87 mg/L to ≤5 mg/L, >5 mg/L to ≤10 mg/L, >10 mg/L).

Baseline fecal calprotectin (≤250 µg/g, >250 to ≤500 µg/g, >500 µg/g).

History of prior surgery for CD.

Disease localization (ileum only, colon only, ilocolonic, other).

History of fistulizing disease.

Fistula status at Baseline (draining, all closed, none).

Extraintestinal manifestations.
7.5
Medical History and Concurrent Medical Conditions
Medical history and concurrent medical conditions will be presented in a data listing and will be 
summarized for the SAF.
7.6
Medication History and Concomitant Medications and Procedures
All medication history and concomitant medications will be coded by therapeutic classification, 
subclassification, and preferred medication name using the World Health Organization Drug 
Dictionary (WHODrug). A concomitant medication is defined as a medication that is ongoing as 
of Study Day 1, ends on or after Study Day 1, or starts on or after Study Day 1 and no more than 
126 days after the last dose of study drug.
The number and percentage of subjects taking each concomitant medication during the induction 
phase and maintenance phase will be summarized for the SAF. Additional summaries for SAF-I 
during the induction phase will be provided. A subject with 1 or more concomitant medications 
within the same level of the WHODrug classification will be counted only once in that level.
WHODrug preferred term and therapeutic classification will be used for summary:

Medication history that the study subjects stopped taking within 30 days prior to the 
Screening Visit.

Concomitant medications that started and stopped prior to Baseline.

Concomitant medications that started prior to and were ongoing at Baseline.

Concomitant medications that started after Baseline.

Concomitant medications that were ongoing at baseline and those that started after Baseline.
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In addition, concomitant IBD medication during maintenance phase will be summarized by 
preferred term.
Concomitant procedures will not be coded, but will be presented in listings for each subject.
7.7
Study Drug Exposure and Compliance
Overall study drug compliance (%) will be determined as (total count of complete injections 
taken / total number of injections expected during study treatment) 100%. 
For IV infusion during induction period, a subject must receive at least 75% of the infusion in 
order for it to be considered complete for each dose.
The total number of days on study drug (exposure) will be calculated as date of last dose of study 
drug - date of first dose of study drug + 127 days. Any gaps in dosing will be ignored when 
calculating the total. If last dose date is missing, then 127 days will be imputed as treatment 
period. Summary statistics for the total number of days on study drug and overall compliance
will be generated for the SAF. 
The number and percentage of subjects with overall study drug compliance of <80%, 80 to 
<90%, and 90% will also be summarized for the SAF. Subjects with unreturned study drug will 
be assumed to have injected Q2W of study drug for each 2 weeks of exposure for the calculation
of overall compliance. Subjects with overall compliance 100% will be set to 100% in the 
analysis.
In addition, diary compliance will be determined as the percentage of days during treatment with 
a diary entry and will be summarized based on FAS:
Diary Compliance = 
(Number of days with diary entries collected during treatment period)/(Number of days
with diary entries expected during treatment period) × 100%
7.8
Efficacy Analysis
Unless otherwise stated, the FAS will be used for the summary of the efficacy endpoints. All
statistical testing will be performed at 2-sided significance level of 0.05. 
7.8.1
Primary Efficacy Endpoint
The primary endpoint is proportion of subjects with clinical remission, defined as CDAI score 
≤150, at Week 52.
The null and alternative hypotheses for the primary efficacy endpoint, clinical remission at 
Week 52, are: 
H0: Clinical Remission Vedolizumab SC at Week 52 = Clinical Remission Placebo at Week 52
versus
HA: Clinical Remission Vedolizumab SC at Week 52 ≠Clinical Remission Placebo at Week 52
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Clinical remission at Week 52 will be analyzed in the FAS using Cochran-Mantel-Haenszel 
(CMH) tests stratified by randomization stratification factors according to: 

Concomitant use of oral corticosteroids.

Clinical remission status at Week 6.

Previous TNF-α antagonists failure/exposure or concomitant immunomodulator 
(azathioprine, 6-mercaptopurine, or methotrexate) use.
Descriptive statistics will be presented by treatment group. Count, percentage and associated 
95% CI using the Clopper-Pearson method will be provided for each treatment group. The 
p-value and point estimate of treatment difference based on the CMH method adjusted for 
stratification factors along with 95% confidence interval will be presented. If the number of 
remitters or non-remitters in either of treatment arm is too small (i.e., ≤5), the exact method 
(ie, Fisher’s Exact test and exact unconditional confidence limits) will be performed instead. All 
subjects with missing data for determination of clinical remission status at Week 52 will be 
considered as non-remitters in the analysis.
7.8.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

Proportion of subjects with enhanced clinical response, defined as a ≥100 point decrease in 
CDAI score from Baseline (Week 0), at Week 52.

Proportion of subjects with corticosteroid-free remission, defined as subjects using oral 
corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in 
clinical remission at Week 52.

Proportion of TNF-α antagonist naïve subjects who achieved clinical remission, defined as 
CDAI score ≤150, at Week 52.
Enhanced clinical response at Week 52 will be analyzed for the FAS subjects. 
Corticosteroid-free remission at Week 52 will be analyzed in a subset of the FAS subjects with 
baseline concomitant oral corticosteroid use (consider both prednisone equivalent and 
budesonide equivalent). Proportion of TNF-α antagonist naïve subjects who achieved clinical 
remission will be analyzed in a subset of the FAS subjects who are TNF-α antagonist naïve.
All secondary endpoints will be analyzed using CMH tests for treatment differences, stratified by 
randomization stratification factors (except for corticosteroid-free remission where concomitant 
use of oral corticosteroid stratification factor will not be considered). The descriptive statistics 
will be presented for each of the secondary endpoints in a similar way to the primary endpoint. 
All subjects with missing data for determination of status of secondary efficacy endpoints at 
Week 52 will be considered as non-responders/non-remitters in the analysis.
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The null and alternative hypotheses for the first secondary efficacy endpoint, enhanced clinical 
response at Week 52, are: 
H0: Enhanced Clinical Response Vedolizumab SC at Week 52 = Enhanced Clinical Response 
Placebo at Week 52
versus
HA: Enhanced Clinical Response Vedolizumab SC at Week 52 ≠Enhanced Clinical Response 
Placebo at Week 52
The null and alternative hypotheses for the second secondary efficacy endpoint, 
corticosteroid-free remission at Week 52, are: 
H0: Corticosteroid-free Remission Vedolizumab SC at Week 52 = Corticosteroid-free Remission
Placebo at Week 52
versus
HA: Corticosteroid-free Remission Vedolizumab SC at Week 52 ≠ Corticosteroid-free Remission
Placebo at Week 52
The null and alternative hypotheses for the third secondary efficacy endpoint, Clinical Remission 
at Week 52 among TNF-α antagonist naïve subjects, are: 
H0: Clinical Remission Vedolizumab SC at Week 52 among TNF-α antagonist naïve subjects = 
Clinical Remission Placebo at Week 52 among TNF-α antagonist naïve subjects
versus
HA: Clinical Remission Vedolizumab SC at Week 52 among TNF-α antagonist naïve subjects ≠
Clinical Remission Placebo at Week 52 among TNF-α antagonist naïve subjects
7.8.3
Multiplicity Adjustment
To control the overall Type I error rate for the comparison between vedolizumab SC and placebo 
groups for the primary and secondary endpoints, a hierarchical approach will be applied to the 
statistical testing of the primary and secondary endpoints. The statistical inference for the first 
secondary endpoint of enhanced clinical response at Week 52 will only be performed if the 
primary endpoint, proportion of subjects with clinical remission at Week 52, is statistically 
significant (p <0.05). The second secondary endpoint of corticosteroid-free clinical remission at 
Week 52 will only be tested if the first secondary endpoint is statistically significant (p <0.05). 
The third secondary endpoint of clinical remission at Week 52 among TNF-α antagonist naïve 
subjects will only be tested if the second secondary endpoint is statistically significant (p <0.05).
Multiplicity will not be adjusted across additional endpoints.
7.8.4
Patient Reported Outcomes (PROs) Endpoints
Changes from Baseline to Week 52 in IBDQ, EQ-5D scores,
components will be 
analyzed using an analysis of covariance (ANCOVA) model with treatment as a factor and 
baseline score as a covariate. Changes from Week 6 to Week 52 will be analyzed in a similar 
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fashion. Missing data will be handled as described in Section 7.1.4. No multiplicity adjustments 
will be performed for PRO endpoints. Nominal p-value will be presented.
The scoring details of these PROs are included in Appendix G.
7.8.5
Exploratory Efficacy Endpoints
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7.8.6
Subgroup Analysis
Exploratory analyses will be performed on the primary and all secondary endpoints to 
summarize the treatment effects across subpopulations. The treatment effect in proportions in 
Vedolizumab SC and placebo and associated 95% confidence interval using Clopper-Pearson 
method will be provided for each subgroup. Point estimate of the absolute treatment difference 
between Vedolizumab SC and placebo based on crude estimate and associated 95% confidence 
interval (using normal approximation method) will be presented. If the number of events is too 
small (ie, ≤5), the exact method will be performed instead. The results will be tabulated and the 
corresponding forest plots for the subgroup analyses will be presented as well.
For subgroup analysis by prior use of TNF-α antagonist only, nominal p-value will be obtained 
by the CMH test stratifying by randomization stratification factors, or Fisher’s exact test in the 
event of small number of responders/remitters or non-responders/non-remitters (ie, ≤5).
If the value of the baseline grouping variable cannot be determined, the subject will be excluded 
from the corresponding subgroup analysis. If the number of subjects in any subgroup is less than 
10, that subgroup will not be presented. 
Subpopulations will be defined by the following baseline characteristics. 
!
Age (<35, ≥35 to <65, ≥65 years).
!
Gender.
!
Race (Asian, Black or African American, White, Other).
!
Duration of CD (<1 year, ≥1 to <3 years, ≥3 to <7 years, ≥7 years).
!
Geographic region (Appendix D).
!
Baseline disease activity (moderate [CDAI≤330], severe [CDAI>330]).
!
Baseline fecal calprotectin (≤250 μg/g, >250 to ≤500 μg/g, >500 μg/g).
!
Baseline CRP (≤5 mg/L, >5 mg/L to ≤10 mg/L, >10 mg/L).
!
Baseline fistula status (draining, all closed, none).
!
Disease localization (ileum only, colon only, ilocolonic, other).
!
Clinical remission status at Week 6.
Property of Takeda: For non-commercial use only and subject to the app
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!
Prior TNF-α antagonist therapy (naïve, exposed but not failure, failure. Failure will be further 
categorized by type of failure – Inadequate response, Loss of response, Intolerance). 
!
Prior immunomodulator and TNF-α antagonist failure (Y/N).
!
Prior corticosteroids failure (Y/N).
!
Prior immunomodulator failure (Y/N).
!
Baseline concomitant therapies: corticosteroids and immunomodulators (Concomitant 
corticosteroids only, concomitant immunomodulators only, concomitant corticosteroids and 
immunomodulators, no concomitant corticosteroids or immunomodulators).
!
Worst prior treatment failure (subjects with prior TNF-α antagonist failure, subjects with 
prior immunomodulator failure but not TNF-α antagonist failure, subjects with prior 
corticosteroid failure but not TNF-α antagonist or immunomodulator failure).
7.8.7
Additional Analysis and Sensitivity Analysis
Analyses using the ITT population will be provided as an additional analysis for primary 
endpoint and all secondary endpoints.
Analyses using the PPS population may be provided as a sensitivity analysis for primary 
endpoint and all secondary endpoints.
In addition, if any clinical site has detected or reported significant noncompliance with 
regulatory requirements during the course of study, additional sensitivity analysis will be 
conducted for the primary efficacy endpoint in the FAS excluding all subjects from that 
particular site.
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Additional Analysis for Induction Phase Data
The proportion of subjects with clinical response at Week 6 or Week 14 in subjects who 
completed Week 6 or Week 14 of the induction phase will be tabulated based on SAF-C.
7.9
Pharmacokinetic Analysis
7.10
Other Outcomes
7.10.1 Immunogenicity Endpoints
7.10.2
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7.10.3
7.11
Safety Analysis
All safety analyses will be performed using the SAF unless otherwise specified. Data will be 
summarized by treatment group. No statistical inference will be made for safety analyses.
7.11.1 Adverse Events
All AEs will be coded using the Medical Dictionary for Regulatory Agencies (MedDRA). 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts or worsens on 
or after Study Day 1 (defined as day first dosed), and no more than 18 weeks/126 days after the 
last dose of study drug and the day prior to the first dose of the extension study (for patients 
entering the OLE study). All TEAEs will be listed by subject number and MedDRA coding. A 
listing of all unique coded terms will also be provided.
The number and percentage of subjects with TEAEs will be summarized in several different 
tables; in addition, exposure-adjusted AE rates will be summarized.
!
An overview TEAE table in SAF-C.
!
All TEAEs by system organ class (SOC), high level term (HLT), and preferred term (PT).
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
Adverse events of special interested (AESIs) (ie, serious infections including opportunistic 
infection such as PML, malignancies, liver injury, infusion reactions, injection site reactions
and hypersensitivity).

Treatment-related TEAEs by SOC, HLT, and PT.

Serious TEAEs by SOC, HLT, and PT in SAF-C (subject and event level).

Most frequent TEAEs by SOC, HLT and PT (sorted by frequency of HLT occurring in 5% 
of subjects). 

Most frequent treatment-related TEAEs by SOC, HLT and PT (sorted by frequency of HLT 
occurring in 2% of subjects). 

Severity of all TEAEs by SOC and PT (mild, moderate, or severe).

Severity of treatment-related TEAEs by SOC and PT (mild, moderate, or severe).

Relationship to study drug for all TEAEs by SOC and PT (not related, related).

Exposure-adjusted TEAEs and serious TEAEs by SOC, HLT, and PT.

Exposure-adjusted treatment-emergent infections and serious treatment-emergent infections 
by SOC, HLT and PT.

Subject mapping of TEAEs by SOC, HLT, and PT.
A subject with 2 or more AEs within the same level of the MedDRA term will be counted only 
once in that level using the most extreme incident (most severe for the severity tables and related 
for the relationship to study drug tables). 
The exposure-adjusted incidence rate is defined as the number of subjects with AEs divided by 
the total exposure-time of the subjects in the respective treatment group. The exposure-time is 
defined as follows:

For subjects do not enroll in the OLE study: (date of last dose – date of first dose + 1) + 126.

For subjects enroll in the OLE study: (date of first dose in the OLE study – date of first dose 
in MLN0002SC-3031).
Additional summaries of TEAEs will be provided that only include TEAEs that occur in the 
Maintenance Phase between the Week 6 dose and 18 weeks/126 days after the last dose date of 
the study drug, or up to the first dose of the open-label extension study, whichever comes first.
Additionally, treatment-emergent SAEs, deaths, and TEAEs resulting in premature 
discontinuation from study drug will be listed and summarized by SOC, HLT, and PT. The most 
frequent treatment-emergent non-serious AEs will also be summarized by SOC, HLT, and PT in 
SAF-C (subject and event level).
A pretreatment event (PTE) will be defined as an AE that starts before Study Day 1. A list of 
pretreatment AEs by subject number and MedDRA coding will be presented separately. 
Pretreatment AEs will be summarized by SOC and PT.
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7.11.2 Clinical Laboratory Evaluations
Clinical laboratory variables will be summarized by treatment groups using descriptive statistics 
for baseline, postbaseline, and change from baseline to postbaseline values.
Individual results for clinical hematology and chemistry laboratory tests that are within the 
predefined “markedly abnormal laboratory value (MAV) criteria” (Appendix A) will be 
summarized in tables. All clinical laboratory data will be presented in data listings.
Elevated hepatic parameters will be summarized.
Summaries and listings of laboratory data will be presented in System International (SI) and 
conventional units. MAV tables and listings will be presented in the unit specified in the MAV 
criteria in Appendix A.
7.11.3 Vital Signs
Vital signs will be summarized by treatment using descriptive statistics for Baseline, 
postbaseline, and change from Baseline to postbaseline values. 
Individual vital signs which meet predefined criteria for abnormal changes from Baseline of vital 
signs (Appendix B) will be summarized in tables. All vital sign data will be presented in data
listings.
7.11.4 12-Lead ECGs
ECG results will be interpreted using 1 of the following categories: within normal limits, 
abnormal but not clinically significant, or abnormal and clinically significant. The shift in ECG 
interpretation from Baseline will be summarized by treatment group. 
All ECG data will be presented in a data listing.
7.11.5 Other Observations Related to Safety
Physical examination results will be presented in a data listing and will not be summarized. PML 
checklist data will be presented in data listings.
Data from the long-term follow-up (LTFU) survey will be summarized descriptively.
7.12
Interim Analysis
No interim analysis is planned. 
As pre-specified in the original SAP and prior to this SAP amendment, blinded safety update was 
conducted to support the BLA/MAA filing for Ulcerative Colitis. The blinded safety update 
included subject disposition, demographic summary, AEs, AESIs, SAEs, markedly abnormal 
values for lab, markedly abnormal values for vital signs, and markedly abnormal values for 
ECG. The blinded safety data were summarized and presented in “Total” column only to 
maintain the blinding of the study.
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7.13
Changes in the Statistical Analysis Plan
Changes from Protocol:
!
No multiplicity adjustments will be performed for PRO endpoints. Nominal p-value will be 
presented. 
Rationale for Change: PRO endpoints are exploratory.
!
!
For time-to-event endpoints, the KM estimates of Week 46 event-free rates will be presented, 
instead of Week 48.
Rationale for Change: Week 46 from randomization is equivalent to Week 52 from Week 0, 
a primary time point for efficacy assessment. 
Summary of changes from the previous version of the SAP 
Changes made in this amendment (Amendment 01) to the previous SAP version dated 
20JUL2018 are summarized in this section. Substantive changes are described in the table below. 
In addition, several editorial changes were made in sections where improvement to clarity, 
transparency, completeness, flow or corrections to typographical errors was considered 
necessary. Not all of these editorial changes are described below. 
Section
Description of Change
Rationale for Change
4.4 Study Design
Clarification to the Final Visit/Early Termination 
procedures for subjects who complete (OLE 
Enroller/Non-enroller) at Week 14 (Induction 
Phase), and subjects who complete (Week 52) or 
discontinue from the Maintenance Phase. 
To be consistent with Protocol 
Amendment 06 dated 24AUG2017.
5.4 Exploratory 
Endpoints
!
!
Add “enhanced” to clinical response-related 
exploratory endpoints. 
!
Correct typographical error.
!
Clarity on the definitions of several 
exploratory endpoints.
7.1.2 Definition 
of Study Days 
and Visit 
Window
!
If 2 or more measurements occur on the 
same day, use the average value instead of 
the last value (original SAP), unless specified 
otherwise. 
!
!
To account for scenarios when 
multiple measurements occur on the 
same day and a tie on the time/date of 
measurement cannot be broken.
!
Correct typographical error.
!
Visit window convention updated to 
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Section
Description of Change
Rationale for Change
add endpoints previously not 
included.
!
Clarity on week 14 window for CDAI 
score for week 6 non-responders. 
7.1.3 Convention 
for Calculations 
of CDAI Scores
New section added with details on the CDAI 
score calculation.
For clarity and completeness on the CDAI 
score.
7.1.4 Convention 
for Missing 
Efficacy Data
Clarified that sensitivity analysis by hybrid model
approach will be conducted for primary and all 
secondary efficacy endpoints, NOT in subgroup 
analysis by prior anti-TNF status.
Sensitivity analysis is not needed for a 
subgroup analyses.
7.2 Analysis Set
!
7.2.1 FAS: Clarified exploratory endpoints 
that will be analyzed based on a subset of 
FAS.
!
7.2.2 ITT: ITT population added.
!
7.2.3 PPS: Clarified analysis of primary and 
secondary endpoints will be performed based 
on PPS if more than 5% of the total subjects 
in the FAS are excluded.
!
7.2.4 SAF: For SAF-I, the definition changed 
from “subjects who receive at least 1 
induction dose, and were not randomized to 
maintenance phase” to “were not dosed in 
the maintenance phase”.
!
!
For completeness and clarity on 
exploratory analyses and subset 
definitions.
!
!
SAF-I definition updated to account 
for subjects randomized but not dosed 
in the maintenance phase.
7.4 Demographic 
and Baseline 
Characteristics
!
Added prior corticosteroids and/or 
immunomodulators use categories for the 
summary of CD-related disease 
characteristics.
!
Added categories for Fistula status at 
Baseline: draining, all closed, none.
Added new categories and specified fistula 
status levels for better presentation of CD-
related disease characteristics data.
7.6 Medication 
History and 
Concomitant 
Medications and 
Procedures
The following sentence added:
In addition, concomitant IBD medication during 
maintenance phase will be summarized by 
preferred term
Summary of concomitant IBD medication 
added for clarity on concomitant 
medication data.
7.7 Study Drug 
Exposure and 
Compliance
Specified diary compliance will be summarized 
based on FAS. 
Diary data include patient reported 
outcome CDAI components which are 
efficacy-related; therefore, it is more 
appropriate to summarize based on FAS.
7.8.1 Primary 
Efficacy 
Endpoint
Removed the following sentence from SAP: 
The absolute treatment difference based on crude 
estimates with 95% CI using the normal 
approximation method will be displayed as well.
Point estimate of treatment difference and 
its 95% CI based on CMH method will be 
presented as described in original SAP, 
which will be consistent with the p-value 
reported from CMH test. Crude estimate 
and its 95% CI are not informative and 
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MLN0002SC-3031
Page 33 of 42
Statistical Analysis Plan Amendment 01
24 June 2019
Section
Description of Change
Rationale for Change
hence removed.
7.8.2 Secondary 
Efficacy 
Endpoints
!
For corticosteroid-free remission, added 
detail that both prednisone equivalent and 
budesonide equivalent will be considered.
!
Specified that the stratification factor related 
to the concomitant use of oral corticosteroids 
will not be used in the analysis of 
corticosteroid-free remission.
!
Added null and alternative hypotheses for the 
third secondary efficacy endpoint.
!
Clarity on the analysis of the second 
secondary efficacy endpoint. 
!
For completeness. Hypotheses for the 
third secondary efficacy endpoint was 
not specified in original SAP. 
7.8.3 Multiplicity 
Adjustment
New section.
For clarity on multiplicity adjustments for 
the primary and secondary efficacy 
endpoints.
7.8.4 Patient
Reported 
Outcomes 
(PROs) 
Endpoints
Added the following sentences:
No multiplicity adjustments will be performed for 
PRO endpoints. Nominal p-value will be 
presented.
The scoring details of these PROs are included in 
Appendix G.
To clarify that the PRO endpoints are not 
part of the multiplicity adjustment and add 
cross-reference to Appendix G for 
completeness.
7.8.5 
Exploratory 
Efficacy 
Endpoints
Added details on endpoint derivation and analysis 
methods details for exploratory endpoints 
For completeness and clarity.
7.8.6 Subgroup 
Analysis
New section.
For clarity and completeness on the 
subpopulations to be studied for the 
primary and secondary efficacy endpoints 
and associated statistical methods.
7.8.7 Additional 
Analysis and 
Sensitivity 
Analysis
!
Added ITT analysis.
!
!
Added sensitivity analysis excluding sites 
with major compliance issue.
!
!
Added additional analysis for induction 
phase data.
For completeness. The additional ITT 
analysis and sensitivity analysis were 
considered necessary to evaluate 
robustness of the results to the 
assumptions made in the related primary 
analyses.
7.10 Other 
Outcomes
!
!
!
7.11 Safety 
!
Clarified the definition of TEAE as an AE 
!
Updated TEAE definition to prevent 
Property of Ta
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MLN0002SC-3031
Page 34 of 42
Statistical Analysis Plan Amendment 01
24 June 2019
Section
Description of Change
Rationale for Change
Analysis
that starts or worsens on or after Study Day 1 
(defined as day first dosed), and no more 
than 18 weeks/126 days after the last dose of 
study drug and the day prior to the first 
dose of the extension study (for patients 
entering the OLE study). 

Added derivation details for exposure-
adjusted event rate.

Specified both subject and event level 
summary are required for the tabulation of 
serious TEAEs and most frequent non-
serious TEAEs. 
double counting. For subjects who 
enrolled in the SC-3030 study, AEs 
onset post OLE dosing are considered 
treatment-emergent in SC-3030, not 
in SC-3031. 

For clarity on the exposure-time 
calculation for exposure-adjusted AE 
summaries.

Updates to certain AE summary for 
result disclosure requirement.
8.0 References
References added.
For completeness.
Appendix D 
Geographic 
Regions

Separated East Asia and Africa/Australia as 
two regions. 

Added Ukraine and included under Eastern 
Europe region.
For better categorization of geographic 
regions.
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MLN0002SC-3031
Page 35 of 42
Statistical Analysis Plan Amendment 01
24 June 2019
8.0
REFERENCES
1. Khanna R, Zou G, D'Haens G, Feagan BG, Sandborn WJ, Vandervoort MK, et al. (2015). A 
retrospective analysis: the development of patient reported outcome measures for the 
assessment of Crohn's disease activity. Aliment Pharmacol Ther 2015;41(1):77-86.
2. Ratitch, B.R., Lipkovich, I. and O’Kelly, M. (2013). Combining Analysis Results from 
Multiply Imputed Categorical Data. PharmaSUG Proceedings 2013 - Paper SP03. 
https://www.pharmasug.org/proceedings/2013/SP/PharmaSUG-2013-SP03.pdf.
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MLN0002SC-3031
Page 36 of 42
Statistical Analysis Plan Amendment 01
24 June 2019
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
Hemoglobin
<0.8 × LLN
>1.2 × ULN
Hematocrit
<0.8 × LLN
>1.2 × ULN
RBC count 
<0.8 × LLN 
>1.2 × ULN
WBC count 
<2.0 ×103/L
>1.5 × ULN
Platelet count
<70 ×103/L
>600 × 103/L
RBC=red blood cell, WBC=white blood cell. LLN=lower limit of normal, ULN=upper limit of normal.
Chemistry—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
ALT
--
>3 ×ULN
AST
--
>3 × ULN
GGT
--
>3 × ULN
Alkaline phosphatase
--
>3 × ULN
Total bilirubin
--
>2.0 mg/dL
Albumin
<2.5 g/dL
--
Total protein
<0.8 × LLN
>1.2 × ULN
Creatinine
--
>2.0 mg/dL
Sodium
<130 mEq/L
>150 mEq/L
Potassium
<3.0 mEq/L
>6.0 mEq/L
Bicarbonate
<8.0 mmol/L
--
Chloride
<75 mmol/L
>126 mmol/L
Calcium
<1.50 mmol/L
>3.25 mmol/L
Glucose
≤2.8 mmol/L
≥20 mmol/L
Phosphorous
<0.52 mmol/L
>2.10 mmol/L
CPK
--
>5 × ULN
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, CPK=creatine 
phosphokinase, LLN=lower limit of normal, ULN=upper limit of normal.
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MLN0002SC-3031
Page 37 of 42
Statistical Analysis Plan Amendment 01
24 June 2019
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Criterion Value
Change Relative to Baseline
Pulse
120 beats/min
50 beats/min
Systolic blood pressure
180 mm Hg
85 mm Hg
Diastolic blood pressure
110 mm Hg
50 mm Hg
Body temperature
<35.6°C
>37.7°C
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MLN0002SC-3031
Page 38 of 42
Statistical Analysis Plan Amendment 01
24 June 2019
Appendix C
CDAI Scoring System for the Assessment of Crohn’s Disease Activity
Category
Count
Initial 
Total
Multiplication 
Factor
Total
Number of liquid or very 
soft stools
7-day total number of liquid or very soft 
stools (reported on the 7 days 
immediately prior to the study visit)
2
Abdominal pain
7-day total of daily abdominal pain 
scores on a 3-point scale: 0=none, 
1=mild, 2=moderate, 3=severe (reported 
on the 7 days immediately prior to the 
study visit)
5
General well being
7-day total of daily general well-being 
scores on a 4-point scale: 0=generally 
well, 1=slightly under par, 2=poor, 
3=very poor, 4=terrible (reported on the 
7 days immediately prior to the study 
visit)
7
Extra-intestinal 
manifestations of Crohn’s 
Disease 
Total number of checked boxes (check 
all that apply):
Arthritis/arthralgia
Iritis/uveitis
Erythema nodosum/pyoderma 
gangrenosum/aphthous stomatitis
Anal fissure, fistula, or abscess
Other fistula
Fever over 37.8°C during past week
20
Lomotil/Imodium/opiates 
for diarrhea
Yes = 1
No = 0
30
Abdominal mass
None = 0
Questionable = 2
Definite = 5
10
Hematocrit (%)a
Males: subtract value from 47
Females: subtract value from 42
6
Body Weightb
(1 – (Body weight/
Standard Weight)) 100 
1
Final Score
Add totals:
a If hematocrit subtotal <0, enter 0.
b If body weight subtotal <-10, enter -10.
Adapted from: Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s 
disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 
1976;70(3):439-44.
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MLN0002SC-3031
Page 39 of 42
Statistical Analysis Plan Amendment 01
24 June 2019
Appendix D
Geographic Regions
Region
Countries
North America
Canada
United States
South America
Argentina
Brazil
Mexico
Western/ Northern Europe
Belgium
Italy
Sweden
Denmark
Lithuania
Spain
Germany
Netherlands
United Kingdom
Central Europe
Czech Republic
Romania
Hungary
Serbia
Poland
Slovak Republic
Eastern Europe
Bosnia and Herzegovina
Estonia
Turkey
Bulgaria 
Israel
Ukraine
Croatia 
Russia
East Asia
Japan
Republic of Korea
Taiwan
Africa / Australia
Australia
South Africa
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MLN0002SC-3031
Page 40 of 42
Statistical Analysis Plan Amendment 01
24 June 2019
Appendix E
AEs of Special Interest
Events
MedDRA Terms or definitions
Malignancies
SOC: NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS)
Infections
SOC: INFECTIONS AND INFESTATIONS
Infusion Related Reactions
Analysis for these AEs will occur on two levels:

Investigator defined Infusion Related Reactions (as indicated on the AE CRF).

All AEs that occur on or one calendar day after the infusion date.
Injection site reaction
Injection Site Reaction (HLT)
Hypersensitivity Reactions
Anaphylactic/anaphylactoid shock conditions SMQ (broad).
Angioedema SMQ (broad).
Hypersensitivity SMQ (broad).
PML
Human polyomavirus infection PT
JC virus infection PT
Leukoencephalopathy PT
Progressive multifocal leukoencephalopathy PT
JC virus CSF test positive PT
Polyomavirus test positive PT
JC polyomavirus test positive PT
Liver injury
Cholestasis and jaundice of hepatic origin SMQ (broad) 
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions SMQ 
(broad)
Hepatitis, non-infectious SMQ (broad) 
Liver related investigations, signs and symptoms SMQ (narrow) 
Liver infections SMQ (broad)
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MLN0002SC-3031
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Statistical Analysis Plan Amendment 01
24 June 2019
Appendix F
Prior Therapies
Systemic Corticosteroids
Immunomodulators
TNF Antagonist
CRF label
Systemic Corticosteroids
Azathioprine
Infliximab
Budesonide
6-Merrcaptopurine
Adalimumab
Methotrexate
Certolizumab
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MLN0002SC-3031
Page 42 of 42
Statistical Analysis Plan Amendment 01
24 June 2019
Appendix G
Patient Reported Outcomes
IBDQ, EQ-5D 
Variable
Sub-score
Calculation
IBDQ
IBDQ Bowel symptoms score
Sum of (Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, Q29), 
Ranging from 10 to 70, 10 questions
IBDQ Emotional function score
Sum of (Q3, Q7, Q11, Q15, Q19, Q21, Q23, Q25, Q27, Q30, Q31, 
Q32), Ranging from 12 to 84, 12 questions
IBDQ Social function score
Sum of (Q4, Q8, Q12, Q16, Q28), Ranging from 5 to 35, 5 
questions
IBDQ Systemic symptoms score
Sum of (Q2, Q6, Q10, Q14, Q18), Ranging from 5 to 35, 5 
questions
Note
For each component score above, if 50% or less of the component score is missing at a visit, the MEAN 
of the remaining component score will be imputed as the value for the missing component score. If more 
than 50% of the component score is missing for the item, the imputed value will be set to missing.
IBDQ score
Sum of (bowel, emotion, social, system)
Note
If any of the component score is missing at a visit, the imputed value will be set to missing.
EQ-5D
EQ5D Mobility component score
Ranging from 1 to 3
EQ5D self-care component score
Ranging from 1 to 3
EQ5D usual activities component 
score
Ranging from 1 to 3
EQ5D Pain/discomfort component 
score
Ranging from 1 to 3
EQ5D anxiety/depression component 
score
Ranging from 1 to 3
Note
If 2 or less out of 5 of the components are missing at a visit, the MEAN of the remaining component 
score will be imputed as the value for the missing component score. If 3 or more components are missing, 
the imputed value will be set to missing.
Property of Ta
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