A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Examine the Efficacy and Safety of Intravenous Vedolizumab (300 mg) Infusion Treatment in Chinese Subjects With Moderately to Severely Active Crohn's Disease
Phase: PHASE3
Conditions: Crohn's Disease
Sponsor: Takeda




Title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Examine the Efficacy and Safety of Intravenous Vedolizumab (300 mg) Infusion 
Treatment in Chinese Subjects with Moderately to Severely Active Crohn’s Disease
NCT Number: NCT03234907
Protocol Approve Date: 23 April 2019
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
PROTOCOL
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Examine the Efficacy and Safety of Intravenous Vedolizumab (300 mg) Infusion
Treatment in Chinese Subjects With Moderately to Severely Active Crohn’s Disease
Vedolizumab IV Compared to Placebo in Chinese Subjects With Crohn’s Disease 
Sponsor:
Takeda Development Center Asia, Pte Ltd
21 Biopolis Road
Nucleos North Tower, Level 4
Singapore 138567
Study Number:
Vedolizumab-3034
IND Number:
Not Applicable
EudraCT Number:
Not Applicable
Compound:
Vedolizumab IV
Date:
23 April 2019
Amendment Number:
03
Amendment History:
Date
Amendment Number
Region
08 July 2015
Initial version
Asia
03 March 2017
01
Asia
21 February 2018
02
Asia
23 April 2019
03
Asia
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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
China 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)
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ssigned 
signe
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Cont
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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 and other signatories, as applicable can be 
found on the signature page.
Electronic Signatures may be found on the last page of this document.
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
dance
ance
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wing:
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a privac
priva
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 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 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)
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1.3
Protocol Amendment 03 Summary of Changes 
Rationale for Amendment 03
This document describes the changes in reference to the Protocol Incorporating Amendment 03.
The primary purpose of this amendment is to update the stratification factors and include a data 
monitoring committee. The previous protocol amendment (02) has not been implemented at any 
study site. Additional feedback from the health authority on protocol amendment 02 has been 
incorporated in protocol amendment 03. Other minor changes in procedures are proposed. Minor 
grammatical and editorial changes are included for clarification purposes only. For specific 
descriptions of text changes and where the changes are located, see Appendix G.
Changes in Amendment 03
1. Update to the stratification factors.
2. Inclusion of a data monitoring committee.
3. Addition of definition for sponsor executive committee. 
4. Inclusion of maximum sample size.
5. Update schedule of assessment table to include 1 early termination procedure for all subjects.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Coordinating Investigator.........................................................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................17
3.5
Study Definitions.....................................................................................................17
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.1.1
Crohn’s Disease .................................................................................................18
4.1.2
Vedolizumab IV.................................................................................................18
4.1.2.1 Nonclinical...................................................................................................19
4.1.2.2 Human Experience .......................................................................................19
4.2
Rationale for the Proposed Study.............................................................................21
4.2.1
Benefit:Risk Assessment....................................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................23
5.1
Objectives................................................................................................................23
5.1.1
Primary Objective ..............................................................................................23
5.1.2
Secondary Objective ..........................................................................................23
5.2
Endpoints.................................................................................................................23
5.2.1
Primary Endpoint...............................................................................................23
5.2.2
Secondary Endpoint ...........................................................................................23
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................26
6.1
Study Design ...........................................................................................................26
6.2
Justification for Study Design, Dose, and Endpoints ................................................27
6.3
Premature Termination or Suspension of Study or Investigational Site.....................28
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................28
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........29
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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................29
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............30
7.1
Inclusion Criteria .....................................................................................................30
7.2
Exclusion Criteria ....................................................................................................32
7.2.1
Gastrointestinal Exclusion Criteria.....................................................................32
7.2.2
Infectious Disease Exclusion Criteria .................................................................33
7.2.3
General Exclusion Criteria .................................................................................33
7.3
Excluded Medications and Treatments.....................................................................35
7.3.1
Permitted Medications and Treatments...............................................................35
7.3.1.1 Oral Corticosteroid Dosing and Tapering .....................................................36
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................37
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................38
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................39
8.1
Study Medication and Materials...............................................................................39
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................39
8.1.1.1 Vedolizumab IV and Placebo .......................................................................39
8.1.1.2 Other Protocol-Specified Materials...............................................................39
8.1.2
Storage...............................................................................................................40
8.1.3
Dose and Regimen .............................................................................................40
8.1.4
Overdose............................................................................................................41
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................41
8.3
Randomization Code Creation and Storage..............................................................41
8.4
Investigational Drug Blind Maintenance ..................................................................41
8.5
Unblinding Procedure..............................................................................................42
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................42
9.0
STUDY PLAN ..............................................................................................................44
9.1
Study Procedures.....................................................................................................44
9.1.1
Informed Consent Procedure..............................................................................44
9.1.2
Demographics, Medical History, and Medication History Procedure..................44
9.1.3
Physical Examination Procedure ........................................................................44
9.1.4
Weight, Height...................................................................................................44
9.1.5
Vital Sign Procedure..........................................................................................45
9.1.6
Primary Efficacy Measurement ..........................................................................45
9.1.6.1 Diary Completion and Review......................................................................45
9.1.7
Documentation of Concomitant Medications......................................................45
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9.1.8
Documentation of Concurrent Medical Conditions.............................................46
9.1.9
Procedures for Clinical Laboratory Samples.......................................................46
9.1.11 Contraception and Pregnancy Avoidance Procedure...........................................48
9.1.12 Pregnancy ..........................................................................................................49
9.1.13 ECG Procedure..................................................................................................50
9.1.15 Tuberculosis Screening ......................................................................................50
9.1.17 Stool sample ......................................................................................................50
9.1.18 PML Checklist...................................................................................................51
9.1.20 Documentation of Screen Failure .......................................................................52
9.1.21 Documentation of Randomization......................................................................52
9.2
Monitoring Subject Treatment Compliance..............................................................52
9.3
Schedule of Observations and Procedures................................................................52
9.3.1
Screening...........................................................................................................53
9.3.2
Randomization...................................................................................................53
9.3.3
Final Visit or Early Termination.........................................................................53
9.3.4
Final Safety Follow-up Visit ..............................................................................54
9.3.5
Poststudy 6-Month Long-Term Follow-up Survey .............................................54
9.3.6
Unscheduled Visits Due to Disease Exacerbation...............................................54
9.3.7
Poststudy Care ...................................................................................................54
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................55
10.1
Definitions...............................................................................................................55
10.1.1 PTEs..................................................................................................................55
10.1.2 AEs....................................................................................................................55
10.1.3 Additional Points to Consider for PTEs and AEs................................................55
10.1.4 SAEs..................................................................................................................57
10.1.5 Special Interest AEs...........................................................................................58
10.1.6 Severity of PTEs and AEs..................................................................................58
10.1.7 Causality of AEs ................................................................................................59
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10.1.8 Relationship to Study Procedures.......................................................................59
10.1.9 Start Date...........................................................................................................59
10.1.10
Stop Date .....................................................................................................59
10.1.11
Frequency ....................................................................................................59
10.1.12
Action Concerning Study Medication...........................................................59
10.1.13
Outcome.......................................................................................................60
10.2
Procedures...............................................................................................................60
10.2.1 Collection and Reporting of AEs........................................................................60
10.2.1.1
PTE and AE Collection Period ...............................................................60
10.2.1.2
PTE and AE Reporting ...........................................................................60
10.2.1.3
AE Collection Involving Medically Anticipated Clinical Events.............61
10.2.1.4
Special Interest AE Reporting.................................................................61
10.2.2 Collection and Reporting of SAEs......................................................................63
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................63
10.3
Follow-up of SAEs ..................................................................................................63
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....64
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................65
11.1
DMC .......................................................................................................................65
11.2
Adjudication Committee..........................................................................................65
11.2.1 Risk Minimization Action Plan for PML (RAMP Program) ...............................65
12.0
DATA HANDLING AND RECORD KEEPING...........................................................67
12.1
CRFs (Electronic)....................................................................................................67
12.2
Record Retention .....................................................................................................67
13.0
STATISTICAL METHODS..........................................................................................69
13.1
Statistical and Analytical Plans ................................................................................69
13.1.1 Analysis Sets......................................................................................................69
13.1.2 Analysis of Demographics and Other Baseline Characteristics...........................69
13.1.3 Efficacy Analysis...............................................................................................70
13.1.5 Safety Analysis ..................................................................................................70
13.2
Interim Analysis and Criteria for Adaptation............................................................71
13.3
Determination of Sample Size..................................................................................72
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................74
14.1
Study-Site Monitoring Visits ...................................................................................74
14.2
Protocol Deviations..................................................................................................74
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14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................74
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................75
15.1
IRB and/or IEC Approval ........................................................................................75
15.2
Subject Information, Informed Consent, and Subject Authorization .........................76
15.3
Subject Confidentiality ............................................................................................77
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................77
15.4.1 Publication and Disclosure.................................................................................77
15.4.2 Clinical Trial Registration..................................................................................78
15.4.3 Clinical Trial Results Disclosure ........................................................................78
15.5
Insurance and Compensation for Injury....................................................................78
16.0
REFERENCES..............................................................................................................79
LIST OF IN-TEXT TABLES
Table 8.a
Dose and Regimen for Induction Phase ..............................................................40
Table 8.b
Dose and Regimen for Maintenance Phase.........................................................40
Table 9.a
Clinical Laboratory Tests...................................................................................47
Table 10.a
Takeda Medically Significant AE List................................................................58
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................27
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................83
Appendix B
Responsibilities of the Investigator.....................................................................86
Appendix C
Elements of the Subject Informed Consent.........................................................88
Appendix D
Investigator Consent to Use of Personal Information..........................................91
Appendix E
CDAI.................................................................................................................92
Appendix F
Appendix G
Detailed Description of Amendments to Text.....................................................94
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Asia, Pte. Ltd.
Compound:
Vedolizumab IV
Title of Protocol: A Phase 3, Multicenter, Randomized, 
Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Examine the Efficacy and Safety of Intravenous 
Vedolizumab (300 mg) Infusion Treatment in Chinese
Subjects With Moderately to Severely Active Crohn’s 
Disease
IND No.:
Not Applicable
EudraCT No.:
Not Applicable
Study Number: Vedolizumab-3034
Phase: 3
Study Design:
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to examine the 
efficacy and safety of vedolizumab treatment in Chinese subjects with moderately to severely active Crohn’s disease 
(CD). 
Approximately 204 eligible subjects will be enrolled in the induction phase and randomized 1:2 in a double-blinded
manner to receive placebo or vedolizumab intravenous (IV) 300 mg at Week 0 (Day 1), Week 2 (Day 15), and Week 6 
(Day 43). The primary efficacy evaluation for the induction phase will be performed at Week 10.
The induction study will be conducted using an adaptive statistical design, permitting potential to increase sample size 
and/or primary endpoint change for the final induction phase analysis. One interim analysis will occur when 
approximately 144 patients are enrolled into the study and with week 10 observation or early discontinuation from the 
induction phase. At the interim analysis, enhanced clinical response and clinical remission will be tested and 
conditional power will be calculated by an independent statistical center (ISC). The data monitoring committee 
(DMC) will compare the calculated conditional power with the prespecified sample size and primary endpoint 
adaptation rules to determine the final sample size and primary endpoint for the study. The DMC will recommend to 
the sponsor executive committee the sample size and primary endpoint adaptation decisions. The sponsor will remain 
blinded to the interim results until completion of the study.
To adjust for the known confounding factors in the induction phase, subjects’ randomization assignment will be 
stratified by:

Previous failure of tumor necrosis factor-alpha (TNF-α) antagonist therapy or concomitant use of 
immunomodulators (6-mercaptopurine, azathioprine, or methotrexate).

Concomitant use of oral corticosteroids.
In the maintenance phase, subjects who received vedolizumab or placebo in the induction phase and achieved clinical 
response at Week 10 will continue to receive the same treatment as they received in the induction phase once every 8 
weeks (Q8W) starting from Week 14 (ie, Weeks 14, 22, 30, 38, 46, and 54) in a double-blinded manner. Subjects who 
received vedolizumab IV or placebo in the induction phase and did not achieve clinical response at Week 10 will
receive vedolizumab once every 4 weeks (Q4W) starting from Week 14 (ie, Weeks 14, 18, 22, 26, 30, 34, 38, 42, 46,
50, 54, and 58) in a double-blinded manner. Subjects receiving oral corticosteroids who have achieved clinical 
response at Week 10 will begin a corticosteroid tapering regimen. Ileocolonoscopy will be performed at screening, 
Week 10, and Week 60/early termination (ET). All ileocolonoscopy will be centrally read.
No more than 50% of the subjects enrolled in the trial should have previously been exposed to and failed TNF-α 
antagonist treatment.
Primary Objective: 
To assess the effect of vedolizumab IV as induction treatment in Chinese subjects with moderately to severely active 
CD at Week 10. 
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Secondary Objective: 
To assess the effect of vedolizumab IV on clinical remission in the induction phase in Chinese subjects with 
moderately to severely active CD at Week 10.
Subject Population: 
Chinese subjects aged 18 to 80 years, inclusive, with moderately to severely active CD.
Number of Subjects:
Estimated total: Approximately 204 subjects randomized
Vedolizumab IV 300 mg: 136 subjects
Placebo IV: 68 subjects
Number of Sites: 
Estimated total: Approximately 20 sites in China
Dose Level(s):
Vedolizumab 300 mg IV (dose will be administered with 
modified frequency based on subject response)
Placebo IV
Route of Administration:
IV
Duration of Treatment:
60 week treatment period
Period of Evaluation: 
This study includes a 4-week screening phase, a 
10-week induction phase, a 50-week maintenance 
phase, and an 18-week safety (ie, 5 vedolizumab 
half-lives) Follow-up phase starting from the last study 
drug dose (Week 54 or Week 58/ET). Additionally, 
subjects will be required to participate in a long-term 
follow-up 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 histopathology report.
The subject has moderately to severely active CD defined as a Crohn’s Disease Activity Index (CDAI) score of 
220-400.
The subject has CD involvement of the ileum and/or colon, at minimum.
The subject has extensive colitis or pancolitis of >8years duration limited colitis of >12 years duration must have 
documented evidence that a surveillance colonoscopy was performed within 12 months of the initial screening visit.
The subject has demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the 
following agents: Corticosteroids, immunomodulators (azathioprine or 6-mercaptopurine), TNF-α antagonists.
Main Exclusion Criteria: 
The subject has had subtotal or total colectomy.
The subject has a history of >3 small bowel resections or diagnosis of short bowel syndrome.
The subject has received any investigational or approved biologic or biosimilar agent within 60 days or 5 half-lives of 
screening (whichever is longer).
The subject has had prior exposure to approved or investigational anti-integrins including, but not limited to, 
natalizumab, efalizumab, etrolizumab, or AMG-181, or mucosal addressin cell adhesion molecule-1 antagonists, or 
rituximab.
The subject has had previous exposure to vedolizumab.
The subject has clinically significant extra-intestinal infection (eg, pneumonia, pyelonephritis) within 30 days of the 
initial screening visit, or ongoing chronic infection.
The subject has a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist at 
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screening or prior to the administration of the first dose of study drug at Week 0.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study is the proportion of subjects with enhanced clinical response (defined as ≥100-point 
decrease in the CDAI score) at Week 10.
The secondary endpoint of the study is the proportion of subjects with clinical remission (defined as CDAI score of 
≤150 points) at Week 10.
Statistical Considerations:
Cochran-Mantel-Haenszel chi-square test will be used in analyzing the proportion based primary and secondary 
endpoints in the induction phase.
Sample Size Justification:
Assuming an enhanced clinical response (CDAI-100) rate of 48% for vedolizumab and 25% for placebo at Week 10, a 
sample size of 136 subjects in the vedolizumab group and 68 subjects in the placebo group will provide 90% power at 
2-sided 0.05 level of significance.
The assumed clinical remission and enhanced clinical response rates are based on a global study of vedolizumab in 
induction and maintenance treatment of subjects with moderately to severely active CD (C13007) as well as a global 
study of vedolizumab in induction treatment of subjects with moderately to severely active CD (C13011).
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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.
3.2
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
5-ASA
5-aminosalicylate
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate transaminase
AUCss
area under the serum concentration-time curve over the dosing interval at steady-state
AVA
anti-vedolizumab antibody
Cavg,ss
average concentration over the dosing interval at steady-state
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CFDA
China Food and Drug Administration
Cmax,ss
maximum observed serum concentration at steady-state
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
CRP
C-reactive protein
Ctrough
trough serum concentration
Ctrough,ss
trough serum concentration at steady state
Ctrough, Week 10
trough serum concentration at Week 10
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
EQ-5D
Euro Quality of Life-5D
ET
early termination
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GALT
gut-associated lymphoid tissue
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
GI
gastrointestinal
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HCVAb
HCV antibody
HIV
human immunodeficiency virus
HRQOL
health-related quality of life
IAC
Independent Adjudication Committee
IBD
inflammatory bowel disease
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ICH
International Conference on Harmonisation
IEC
independent ethics committee
Ig
immunoglobin
INR
international normalized ratio
IRB
institutional review board
ISC
independent statistical center
ITT
intent-to-treat
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
IWRS
interactive web response system
JCV
John Cunningham virus
K2EDTA
potassium ethylenediaminetetraacetic acid
LFT
liver function test
LTFU
long-term follow-up
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PP
per protocol
PTE
pretreatment event
Q4W
once every 4 weeks
Q8W
once every 8 weeks
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
US
United States
VAS
visual analog scale
VCAM-1
vascular cell adhesion molecule-1
WBC
white blood cell
CCI
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WFI
water for injection
WPAI
Work Productivity and Activity Impairment
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
3.5
Study Definitions
Clinical remission
Crohn’s Disease Activity Index (CDAI) score of ≤150 points.
Clinical response
A ≥70 point decrease in CDAI score from baseline (Week 0).
Disease worsening
A ≥100-point increase in CDAI score from the Week 10 value on 2 consecutive 
visits and/or reaching a CDAI score ≥220 points.
Enhanced clinical response
≥100-point decrease in the CDAI score from baseline (Week 0).
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4.0
INTRODUCTION
4.1
Background
4.1.1
Crohn’s Disease
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 manifested by asymmetric, and transmural inflammation of the digestive tract. In contrast to 
the diffuse, superficial, continuous inflammation limited to the colon in UC, the inflammation of 
CD is focal, may be transmural, and can involve any segment of the GI tract from mouth to anus. 
The prevalence of CD is approximately 150 per 100,000 of the United States (US) population and 
approximately 125 per 100,000 of population in Western Europe [1-3] and 21.2 per 100,000 of the 
population in Japan [4]. It is estimated that CD prevalence in China is about 1.4 cases per 
100,000 person-years [5]. The prevalence may be underestimated from hospital based data. 
Although the prevalence in China is lower than in the West, these figures increase rapidly.
Compared to 1990, the nationwide ratio of patients with UC and CD to total hospitalized patients 
has increased by 2.11 times [6] in 2001 and by 2.78 times [7] in 2003, respectively. In Hong Kong, 
the incidence of CD tripled over the last 10 years [8].
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, ankylosing 
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.
4.1.2
Vedolizumab IV
Vedolizumab (also called MLN0002) is a humanized immunoglobulin (Ig) G1 mAb directed 
against the human lymphocyte integrin α4β7. The α4β7 integrin mediates lymphocyte trafficking to 
GI mucosa and gut-associated lymphoid tissue (GALT) through adhesive interaction with mucosal 
addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed on the endothelium of 
mesenteric lymph nodes and GI mucosa [9-12]. Vedolizumab binds the α4β7 integrin, antagonizing 
its adherence to MAdCAM-1 and as such, impairs the migration of gut homing leukocytes into GI 
mucosa. As a result, vedolizumab acts as a gut-selective immunomodulator [13]. Vedolizumab has 
been developed as a treatment for UC and CD, which are characterized by inflammation of the GI 
tract. 
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 US and European 
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Union, for the treatment of adult patients with moderately to severely active UC or CD who have 
had an inadequate response with, lost response to, or were intolerant to conventional therapy or a 
tumor necrosis-alpha (TNF-α) antagonist. The initial approved dosing and administration regimen 
consists of 300 mg vedolizumab IV infused intravenously, over approximately 30 minutes, at 
Weeks 0, 2, and 6, then once every 8 weeks (Q8W) thereafter.
Previously conducted clinical studies have characterized the efficacy, safety, tolerability, 
pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of 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 
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 4β1 integrin [13].
4.1.2.2
Human Experience
Single- and multiple-dose PK of vedolizumab have been studied in healthy subjects and in patients 
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 intravenous (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 IV is 
approximately 5 L.
Different intrinsic and extrinsic factors, including age, body weight, serum albumin, severity of 
disease state, prior treatment with TNF-α antagonist, coadministration with immunomodulators 
(including azathioprine, 6-mercaptopurine, methotrexate) or aminosalicylates, did not impact the 
PK of vedolizumab in subjects with UC or CD based on population PK analysis, as such, no dose 
adjustment is recommended for any of the above-mentioned covariates. Pharmacokinetics of 
vedolizumab was similar between Japanese and Western subjects.
As of 19 November 2016, more than 4200 subjects have received at least 1 dose of vedolizumab 
across all studies in the clinical development program. As of 19 November 2016, vedolizumab 
exposure has extended for ≥12 months in 1832 subjects, ≥24 months in 1379 subjects, ≥36 months 
in 1169 subjects, ≥48 months in 862 subjects, ≥60 months in 645 subjects, ≥72 months in 
308 subjects, ≥84 months in 32 subjects, and ≥96 months in 22 subjects. Based on the most recent 
drug shipment data (19 November 2016), the cumulative patient exposure to vedolizumab IV 
since its marketing approval in May 2014 is estimated to be approximately 77,382 patient-years.
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 
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Weeks 0, 2, and 6 (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 period and maintenance period. The study met 
its primary endpoint for the induction period, 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. The study did meet its primary 
endpoint for the maintenance period, 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 [14].
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 [15].
Vedolizumab has shown an acceptable safety profile based on an analysis of safety data from both 
completed and ongoing studies (see current version of Investigator’s Brochure). 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 patients), there was no consistent evidence of any dose-toxicity relationships, and 
vedolizumab was well tolerated up to doses of 10 mg/kg. The majority of the safety data is from 
3 well-controlled, phase 3 clinical studies that evaluated the safety of vedolizumab 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 assessment of safety was performed for the ongoing, 
uncontrolled extension study (Study C13008) for subjects who participated in Studies C13004, 
C13006, C13007, or C13011 as well as de novo subjects.
Vedolizumab has shown an acceptable and consistent safety profile in clinical trials. 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 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 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). 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. 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 anti-vedolizumab antibodies (AVAs) 16 weeks following the 
last dose of vedolizumab. Results from the clinical program to date do not suggest an increased 
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risk for malignancy with vedolizumab treatment. Overall, the safety profile following long-term 
treatment with vedolizumab in Study C13008 is consistent with safety in the completed studies. 
One death occurred in a vedolizumab-treated subject during Study C13006 and 5 deaths occurred 
during Study C13007, including 1 death in a placebo-treated subject. As of 19 May 2016, a total of 
27 deaths from multiple causes were reported in the vedolizumab clinical development program, 
including the ongoing long-term Study C13008. Twenty-six of the 27 subjects were randomized to 
the vedolizumab treatment group. Of these deaths, 14 occurred within 18 weeks of the last dose of 
vedolizumab in phase 3 clinical studies and 12 occurred more than 18 weeks after the last dose of 
vedolizumab was administered. The cause of the deaths varied, with the majority considered not to 
be related to vedolizumab.
Overall, vedolizumab IV was well tolerated in clinical studies.
4.2
Rationale for the Proposed Study
Current treatments have been effective for many patients with IBD 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 the treatment of 
moderately to severely active CD [16]. However, the efficacy of 5-ASAs in CD has been called
into question by a recent meta-analysis [17]. Corticosteroids are often required for patients who 
fail to respond to 5-ASAs. While highly effective for induction of remission, corticosteroids are 
not recommended for the maintenance of 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 [18]. 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 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 [19-21]. However, 
efficacy data for both infliximab and adalimumab in CD indicate only a minority of patients 
having a durable response at 1 year [22,23]. 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 [24,25]. In addition to its modest efficacy, treatment 
with TNF-α antagonists has been associated with SAEs involving hypersensitivity and infection.
Reactivations of latent tuberculosis (TB) [26] and disseminated histoplasmosis have been reported 
and, in some cases, have been fatal [27]. 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 US Food and Drug Administration (FDA) in 2008 
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for use in CD patients who are refractory to standard therapy [28]. 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 (VCAM-1), 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 [29]. The limitations of current 
therapies for IBD indicate that there is a significant need for safer and more effective therapies.
Vedolizumab is being developed to meet the unmet medical needs in CD treatment in China.
4.2.1
Benefit:Risk Assessment
The proposed study (Vedolizumab-3034) is designed to evaluate the efficacy and safety of 
vedolizumab IV as induction and maintenance therapy in Chinese subjects with moderately to 
severely active CD. The dosing and administration regimen and study population in 
Vedolizumab-3034 are consistent with the approved vedolizumab IV label globally. Overall, 
vedolizumab has been well tolerated in clinical studies. The procedures performed during the 
study are part of usual clinical practice. Taking into account the risks associated with procedures 
and the disease worsening in this population, the benefit-risk profile remains positive for 
vedolizumab in this study.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective 
!
To assess the effect of vedolizumab IV as induction treatment in Chinese subjects with 
moderately to severely active CD at Week 10. 
5.1.2
Secondary Objective
!
To assess the effect of vedolizumab IV on clinical remission in the induction phase in Chinese 
subjects with moderately to severely active CD at Week 10.
5.1.3
Additional Objectives
5.2
Endpoints
5.2.1
Primary Endpoint
!
Proportion of subjects with enhanced clinical response (defined as ≥100-point decrease in the 
CDAI score) in the induction phase at Week 10.
5.2.2
Secondary Endpoint
!
Proportion of subjects with clinical remission (defined as CDAI score of ≤150 points) in the 
induction phase at Week 10.
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5.2.3
Additional Endpoints
CCI
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!
Safety Assessments 
–
Safety assessed by: Adverse events (AEs), SAEs, adverse events of special interest 
(AESIs), vital signs, results of standard laboratory tests (clinical chemistry, hematology, 
coagulation, and urinalysis), AEs related to AVA, and results of 12-lead 
electrocardiograms (ECGs).
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
to examine the efficacy and safety of vedolizumab treatment in Chinese subjects with moderately 
to severely active CD. Moderately to severely active CD is defined as a CDAI score of 
220-450 points. No more than 50% of the subjects enrolled in the trial should have previously been 
exposed to and failed TNF-α antagonist treatment. 
This study includes a 4-week screening phase, a 10-week induction phase, a 50-week maintenance 
phase, and an 18-week safety (ie, 5 vedolizumab half-lives) follow-up phase starting from the last 
study drug dose (Week 54 or Week 58/early termination [ET]). In addition, subjects will 
participate in a long-term follow-up (LTFU) safety survey by telephone at 6 months following the 
last dose, during which information will be collected on events such as infections resulting in 
hospitalizations, pregnancy, colorectal dysplasia, cancer, CD-related surgeries, and development 
of PML.
Approximately 204 eligible subjects will be enrolled in induction phase and randomized 1:2 in a
double-blinded manner to receive placebo or vedolizumab IV 300 mg at Week 0 (Day 1), Week 2 
(Day 15), and Week 6 (Day 43). The primary efficacy evaluation for the induction phase will be 
performed at Week 10.
The induction study will be conducted using an adaptive statistical design, permitting potential to 
increase sample size and/or primary endpoint change for the final induction phase analysis. One 
interim analysis will occur when approximately 144 patients are enrolled into the study and with 
week 10 observation. At the interim analysis, enhanced clinical response and clinical remission 
will be tested and conditional power will be calculated respectively by an independent statistical 
center (ISC). The data monitoring committee (DMC) will compare the calculated conditional 
power with the prespecified sample size and primary endpoint adaptation rules to determine the 
final sample size and primary endpoint for the study. The DMC will recommend to the sponsor 
executive committee the sample size and primary endpoint adaptation decisions. The sponsor will 
remain blinded to the interim results until completion of the study.
To adjust for the known confounding factors in the induction phase, subjects’ randomization 
assignment will be stratified by:

Previous failure of TNF-α antagonist therapy or concomitant use of immunomodulators 
(6-mercaptopurine, azathioprine, or methotrexate).

Concomitant use of oral corticosteroids.
In the maintenance phase, subjects who achieved clinical response at Week 10 will continue to 
receive the same treatment as they received in the induction phase; either vedolizumab starting 
from Week 14 (ie, Weeks 14, 22, 30, 38, 46, and 54) or placebo in a double-blinded manner.
Subjects who received vedolizumab IV or placebo in the induction phase and did not achieve
clinical response at Week 10 will receive vedolizumab Q4W starting from Week 14 (ie, Weeks 14, 
18, 22, 26, 30, 34, 38, 42, 46, 50, 54, and 58) in a double-blinded manner. In order to maintain the 
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blind, all subjects will receive study drug infusions (placebo or vedolizumab 300 mg) every 4 
weeks as detailed in Section 8.1. Subjects receiving oral corticosteroids who have achieved
clinical response at Week 10 will begin a corticosteroid tapering regimen. Clinical response is 
defined as a ≥70 point reduction in CDAI from baseline (Week 0). Evaluation of efficacy for the 
maintenance phase will be performed at Week 60. Ileocolonoscopy will be performed at screening, 
Week 10, and Week 60/ET. All ileocolonoscopy will be centrally read.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design
Q4W: every 4 weeks; Q8W: every 8 weeks.
6.2
Justification for Study Design, Dose, and Endpoints
Study Design
The study design permits double-blind, placebo-controlled comparison of efficacy and safety 
parameters between the vedolizumab treatment arm and placebo arm for induction treatment in 
moderately to severely active CD. Due to the low incidence and prevalence of CD in China and 
limited study sites, this study is not statistically powered to evaluate the efficacy and safety of 
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maintenance treatment with vedolizumab IV. Descriptive analyses will be performed for 
maintenance phase efficacy.
Additional measure will be taken to collect safety parameters beyond the 60-week duration of the 
trial, where a final visit will be conducted 18 weeks after the last study dose, and additional 
information will be collected for up to 6 months after the last study dose.
Dose Selection
The strategy for dose selection in this phase 3 study is based on clinical efficacy and dose response 
in global phase 2 and phase 3 studies, suppression of AVA formation, and serum concentration of 
vedolizumab at the efficacious doses in phase 2 and 3studies (PK considerations) and maintenance 
of α4β7 receptor saturation (PD considerations). The dose of 300 mg vedolizumab IV at Weeks 0, 
2, and 6 followed by Q8W starting from Week 14 has been tested in global CD phase 3 study
(C13007). It is also the dose being used in an ongoing phase 3 CD study in Japan and the 
recommended dose of vedolizumab IV in countries where vedolizumab is commercially available.
The induction phase efficacy evaluation at Week 10 is based on the results from C13011, which 
suggested that some CD subjects require an additional dose at Week 6. Results from C13011 
showed at Week 6, 19.1% of vedolizumab-treated and 12.1% of placebo-treated subjects were in 
clinical remission (p = 0.0478) and 39.2% of vedolizumab-treated subjects and 22.7% 
placebo-treated subjects were in enhanced clinical response (p = 0.0011). A greater treatment 
effect was seen at Week 10, with 28.7% and 13.0% of subjects, respectively, achieving clinical 
remission (p < 0.002) and 47.8% and 24.2% of subjects, respectively, achieving enhanced clinical 
response. Hence, Week 10 is considered a better time point than Week 6 to evaluate the induction 
phase efficacy. 
Endpoints
The primary efficacy endpoint for the induction phase is enhanced clinical response (CDAI-100) 
at Week 10. This is generally accepted as the standard indicator of disease activity in CD subjects. 
Cochran-Mantel-Haenszel (CMH) chi-square test will be used in analyzing the proportion based 
primary and secondary endpoints in the induction phase.
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 compound, such that the risk
/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
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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 institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a 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 randomization or first dose or 
other. 
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 corroborated by a histopathology report. Cases of CD established at 
least 6 months prior to randomization 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 
randomization.
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 9.1.12 Pregnancy.
7. The subject has moderately to severely active CD as determined by a CDAI score of 220 to 400
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 phase, OR

Ileocolonoscopy with photographic documentation of a minimum of 3 nonanastomotic 
ulcerations (each >0.5 cm in diameter) or 10 aphtous ulcerations (involving a minimum of 
10 contiguous cm of intestine) consistent with CD, within 4 months prior to randomization, 
OR

Fecal calprotectin >250 µg/g during the screening phase in conjunction with computed 
tomography enterography, magnetic resonance enterography, contrast-enhanced small 
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bowel radiography, or wireless capsule endoscopy revealing CD ulcerations (aphthae not 
sufficient), within 4 months prior to screening. 
8. The subject has CD involvement of the ileum and/or colon, at a minimum.
9. The subject has extensive colitis or pancolitis of >8 years duration or limited colitis of 
>12 years duration must have documented evidence that a surveillance colonoscopy was 
performed within 12 months prior to initial screening (may be performed during screening if 
not performed in previous 12 months).
10. The subject has a family history of colorectal cancer, personal history of increased colorectal 
cancer risk, age >50 years, or other known risk factor 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: 
–
Corticosteroids.

Resistance: subjects in whom the response was inadequate after treatment of 
≥40 mg/day for ≥1 week (oral or IV), or 30 to 40 mg/day for ≥2 weeks (oral or IV).

Dependence: subjects for whom it is difficult to reduce the dosage to <10 mg/day due 
to recurrence during gradual dose reduction (oral or IV) or subjects had disease 
recurrence within 3 months after discontinuation of corticosteroids.

Intolerance: subjects who were unable to receive continuous treatment due to adverse 
reactions (eg, Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, 
insomnia, mood disturbance, infection).
–
Immunomodulators.

Refractory: the subject has signs and symptoms of persistently active disease despite a 
history of at least one 12-week regimen of azathioprine, 6-mercaptopurine, or 
injectable methotrexate, with a dose of azathioprine ≥0.75 mg/kg/day or 
6-mercaptopurine ≥0.5 mg/kg/day, or methotrexate ≥15 mg/week.

Intolerance: the subject has a history of intolerance of at least 1 immunomodulators 
(including but not limited to nausea/vomiting, abdominal pain, pancreatic, liver 
function test [LFT] abnormalities, lymphopenia, thiopurine S-methyltransferase 
genetic mutation, hair loss, infection).
–
TNF-α antagonists.

Inadequate response: subjects in whom the response was inadequate after the induction 
therapy in the dosage described in the package insert.

Loss of response: recurrence of symptoms during maintenance dosing following prior 
clinical benefit (discontinuation despite clinical benefit does not qualify).

Intolerance: subjects who were unable to receive continuous treatment due to adverse 
reactions (eg, reaction at administration, drug-induced lupus-like reaction, psoriasis, 
demyelination disease, congestive heart failure, infection).
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7.2
Exclusion Criteria
The exclusion criteria are divided into 3 categories: GI, 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 
21 days prior to the administration of the first dose of study drug.
5. The subject has had ileostomy, colostomy, known fixed symptomatic stenosis of the intestine, 
or evidence of fixed stenosis, or small bowel stenosis with prestenotic dilation.
6. Within 30 days prior to randomization, the subject has received any of the following for the 
treatment of underlying disease:

Nonbiologic therapies (eg, cyclosporine, thalidomide) or traditional Chinese medications 
other than those specifically listed in the Permitted Medications for the Treatment of CD 
section.

An approved or investigational nonbiologic therapy or traditional Chinese medications in 
an investigational protocol.
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 had previous exposure to approved or investigational anti-integrins including, 
but not limited to natalizumab, efalizumab, etrolizumab, or AMG-181, or MAdCAM-1 
antagonists, or rituximab.
9. The subject has had previous exposure to vedolizumab.
10. The subject has used topical (rectal) treatment with 5-ASA, corticosteroid 
enemas/suppositories or traditional Chinese medications for CD treatment within 2 weeks of 
the administration of the first dose of study drug.
11. The subject requires currently or is anticipated to require surgical intervention for CD during 
the study.
12. The subject has a history or evidence of adenomatous colonic polyps that have not been 
removed.
13. The subject has a history or evidence of colonic mucosal dysplasia including low or high-grade 
dysplasia, as well as indeterminate for dysplasia.
14. The subject has a suspected or confirmed diagnosis of ulcerative colitis, indeterminate colitis, 
ischemic colitis, and radiation colitis.
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7.2.2
Infectious Disease Exclusion Criteria
15. The subject has evidence of active infection during the screening period.
16. The subject has evidence of treatment for Clostridium difficile infection or other intestinal 
pathogen with 28 days prior to first dose of study drug.
17. The subject has chronic hepatitis B virus (HBV) infection* or chronic hepatitis C virus (HCV) 
infection**.
* Subjects who are positive for hepatitis B surface antigen (HBsAg) will be excluded.
For subjects who are negative for HBsAg but are positive for either surface antibodies and/or 
core antibodies, HBV DNA polymerase chain reaction will be performed and if any test result 
meets or exceeds detection sensitivity, the subject will be excluded.
** If subject is HCV antibody (HCVAb) positive, then a viral load test will be performed. If 
the viral load test is positive then the subject will be excluded.
18. The subject has active or latent tuberculosis as evidenced by the following:

A positive diagnostic TB test within 30 days prior to screening or during the screening 
period defined as:
–
Positive QuantiFERON test, OR 
–
2 successive indeterminate QuantiFERON tests, OR
–
Chest x-ray within 3 months prior to Week 0 for which the results are suspicious of 
pulmonary TB.
Note: Subjects with history of TB who have documented previously treated TB which 
was successful, with a negative QuantiFERON test, can be included in the study.
19. The subject has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
20. The subject has received any live vaccinations within 30 days prior to screening.
21. The subject has a clinically significant extra-intestinal infection (eg, pneumonia, 
pyelonephritis) within 30 days of the initial screening visit, or ongoing chronic infection.
7.2.3
General Exclusion Criteria
22. The subject has had hypersensitivity or allergies to vedolizumab or its components.
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 
enrollment 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 
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treated and that has not recurred for at least 1 year prior to randomization; 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 randomization. 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 randomization.
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 phase:
–
Hemoglobin level <8 g/dL.
–
White blood cell (WBC) count <3 × 109/L.
–
Lymphocyte count <0.5 × 109/L.
–
Platelet count <100×109/L or >1200×109/L.
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit 
of normal (ULN).
–
Alkaline phosphatase >3 × ULN.
–
Serum creatinine >2 × ULN.
29. Removed at Amendment 01.
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.
31. The subject has an active psychiatric problem that, in the opinion of investigator’s opinion, 
may interfere with compliance with study procedures.
32. The subject is unable to attend all study visits or comply with study procedures.
33. The subject is required to take excluded medications listed in Section 7.3.
34. If female, the subject is intending to become pregnant before, during, or within 18 weeks after 
participating in the study or intending to donate ova during such time period.
35. If male, the subject intends to donate sperm during the course of this study or for 18 weeks 
thereafter.
36. 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. 
37. 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.
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7.3
Excluded Medications and Treatments
The following medications are excluded from the use during the study:

Any treatments 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.)

Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
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 or 6-mercaptopurine 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.
–
Methotrexate provided that the dose has been stable for the 8 weeks immediately prior to 
first dose of study drug;
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–
Antibiotics used for the treatment of CD (ie, 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 
corticosteroids, dose reduction should be performed, as per the tapering schedule (see 
Section 7.3.1.1).

Need for rescue medication: 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. Administration of a rescue 
medication, approved or investigational, constitutes treatment failure (ie, lack of efficacy) and 
the subject should be withdrawn from the study according to Section 7.4. Rescue medications 
should not be withheld if, in the opinion of the investigator, failure to prescribe them would
compromise subject safety.
7.3.1.1
Oral Corticosteroid Dosing and Tapering 
Subjects receiving oral corticosteroids who have achieved clinical response at Week 10 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 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 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. 
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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 9.1.19.
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, see 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
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).

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 vedolizumab 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 vedolizumab 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.
2. Significant protocol deviation. The discovery postrandomization 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. Attempts to contact the subject must be documented.
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.
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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 9.1.12.
7. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject, or treatment failure during the maintenance phase, defined as disease worsening 
(defined as a ≥100-point increase in CDAI score from the Week 10 value on 2 consecutive 
visits and/or reaching a CDAI score ≥220 points), need for rescue medications (as defined in 
Section 7.3.1), or need for surgical intervention for treatment of CD.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
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 
early termination visit and long-term follow-up. 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
8.1.1.1
Vedolizumab IV and Placebo
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 (WFI). Each vial will be packaged in an appropriately labeled single vial carton. 
The placebo infusion will be 250 mL of 0.9% sodium chloride. For both active vedolizumab and 
placebo infusions, the investigational pharmacist or designee will mask the IV bags after 
preparation in order to maintain the study blind.
All infusions will be administered IV over approximately 30 minutes. Longer infusion times of up 
to 60 minutes may be used based on study observations. Subjects will be observed at the clinical 
site for approximately 2 hours after the completion of the first dose and 1 hour after the completion 
of subsequent doses 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.
8.1.1.2
Other Protocol-Specified Materials 
The following supplies will also be required for study drug administration and are to be provided 
by the clinical study site unless otherwise indicated:

Sterile WFI, 10 mL container or larger for study drug reconstitution.

250 mL 0.9% sodium chloride for injection in polyvinyl chloride IV bag(s) or 250 mL 0.9% 
sodium chloride in alternative IV bags or bottles listed in the Pharmacy Manual. 

Polyvinyl chloride infusion line or alternative infusion line listed in the Pharmacy Manual.

Alcohol swabs.

Syringes.

Needles (syringe and infusion).

Infusion pump (optional).

Needle sharps container.
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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 must be stored at 2ºC to 8ºC (36ºF to 46ºF). Store the vial or syringe in the carton 
until time of use. A daily temperature log of the drug storage area must be maintained every day. 
Any temperature excursions must be reported to Takeda; if the site refrigerator goes out of range, 
or study drug has been stored incorrectly, immediately contact the unblinded clinical research 
associate.
8.1.3
Dose and Regimen
The dose and regimen for both randomized groups is provided in Table 8.a and Table 8.b. 
Instructions for reconstitution and blinded administration will be provided in the pharmacy 
manual.
Table 8.a
Dose and Regimen for Induction Phase
Treatment Group
Dose
Treatment Description
A
Placebo IV
Weeks: 0, 2, and 6
B
Vedolizumab IV 300 mg
Weeks: 0, 2, and 6
IV: intravenous.
During the maintenance phase, subjects randomized or assigned to receive vedolizumab Q4W will 
receive a 300 mg dose of vedolizumab Q4W from Week 14 through Week 58. Subjects 
randomized or assigned to receive vedolizumab Q8W during the maintenance phase will receive a 
300 mg dose of vedolizumab beginning at Week 14 and every other visit thereafter (ie, Weeks 22, 
30, 38, 46, and 54). These subjects will receive placebo (250 mL of 0.9% sodium chloride) at the 
other study visits (ie, Weeks 18, 26, 34, 42, 50, and 58). Subjects randomized or assigned to 
placebo will receive 250 mL of 0.9% sodium chloride IV Q4W.
Table 8.b
Dose and Regimen for Maintenance Phase
Treatment Group
Dose
Treatment Description
C 
(A: Week 10 Responder)
Placebo IV
Weeks: 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, and 
58 (Q4W)
D
(A: Week 10 Nonresponder)
(B: Week 10 Nonresponder)
Vedolizumab IV 300 mg
Weeks: 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54 and 
58 (Q4W)
E
(B: Week 10 Responder)
Vedolizumab IV 300 mg 
and
Placebo IV
Weeks: 14, 22, 30, 38, 46, and 54 (Q8W)
and
Weeks: 18, 26, 34, 42, 50, and 58 (Q8W)
IV: intravenous; Q4W: every 4 weeks; Q8W: every 8 weeks.
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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 and Adverse Events.
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
The investigator or the investigator’s designee will access the interactive web response system 
(IWRS) at screening to register a subject and obtain the subject study number to identify the 
subjects throughout the study. The investigator or the investigator’s designee will utilize the IWRS 
to randomize the subject into the study. During this contact, the investigator or designee will 
provide the necessary subject-identifying information, including the subject number assigned at 
screening. If the subject is randomized to the active treatment arm the medication identification 
(ID) number of the investigational drug to be dispensed will then be provided by the IWRS by
email notification to the unblinded site pharmacist/nurse. To maintain the blind the IWRS will 
ensure the investigator or designee is unaware if a medication ID has been assigned or not. If 
sponsor-supplied drug (active vials) is lost or damaged, the site can request a replacement from 
IWRS by the unblinded site pharmacist/nurse. Refer to IWRS manual provided separately.
At subsequent drug-dispensing visits, the investigator or designee will again contact the IWRS to 
register the visits. If the subject is on the active treatment arm the medication ID number of the 
investigational drug to be dispensed will again be provided by the IWRS by email notification only 
to the unblinded site pharmacist/nurse and the investigator or designee will again be unaware if a 
medication ID has been assigned or not.
8.3
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule 
prior to the start of the study. All randomization information will be stored in a secured area, 
accessible only by authorized personnel.
8.4
Investigational Drug Blind Maintenance
The investigational drug blind will be maintained using the IWRS. All subjects and study 
personnel except for those directly involved with study drug preparation will be blinded to study 
drug assignment for the entire study.
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8.5
Unblinding Procedure
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary 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.
8.6
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 blinded investigator or blinded designee and delegated unblinded pharmacist, 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 300 
mg), the appropriate blinded or unblinded 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 unblinded pharmacist.
Upon receipt of sponsor-supplied drug, the appropriate unblinded 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, the 
unblinded pharmacist should acknowledge the receipt of the shipment. If there are any 
discrepancies between the packing list versus 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 (unblinded pharmacy file).
The unblinded pharmacist must maintain 100% accountability for all sponsor-supplied drugs
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Continuously monitoring expiration dates based on expiry dating provided on the label.

Monitoring of vedolizumab IV after receipt, during storage and subject administration to 
ensure that drug does not experience a temperature excursion outside the range specified.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the medication ID used to prepare each dose.

Verifying that all containers used are documented accurately on the log.
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
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 unblinded pharmacist must record the current inventory of all sponsor-supplied drugs 
(vedolizumab IV 300 mg) on a 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, seal, 
or signature of the person dispensing the drug. The 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 in the subject’s medical records and on the drug accountability log.
Prior to site closure or at appropriate intervals, an unblinded 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 designated 
unblinded pharmacist 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 to each subject at the 
time that informed consent is obtained; 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 date of birth, sex, 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.
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) GI system; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) nervous system; (10) lymph nodes; and (12) other. All subsequent 
physical examinations should assess clinically significant changes from the assessment prior to 
first dose examination.
9.1.4
Weight, 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. 
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9.1.5
Vital Sign Procedure
Vital signs will include body temperature, respiratory rate, blood pressure, and pulse (beats per 
minute).
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 or after the scheduled blood draw.
On dosing days, vital signs are taken predose.
9.1.6
Primary Efficacy Measurement 
Due to low incidence and prevalence of CD and limited study sites in China, this study is only 
statistically powered to detect difference of treatment arm and placebo arm in efficacy for 
induction phase. Primary efficacy endpoint of this study is enhanced clinical response (CDAI-100) 
at Week 10. Disease activity for entry into this study and for efficacy assessment throughout the 
study will be measured by the CDAI, a standard assessment tool to measure CD disease activity in 
clinical trials. CDAI includes 2 subjective items (number of liquid stools and abdominal pain), and 
6 objective items(general well-being, number of extra-intestinal complications, use of 
antidiarrheal drugs, presence of abdominal mass, hematocrit, and ideal/observed body weight 
ratio). During screening, subjects will be instructed on how to appropriately complete the diary. 
Diary entries will be reviewed by site personnel during screening and (prior to dosing, if 
applicable) at scheduled visits and at any unscheduled visit due to disease exacerbation. A 
validated electronic system will be used for collection of the patient diary. A CDAI score will be 
evaluated during screening to determine eligibility, using patient diary entries within 14 days prior 
to enrollment, and hematocrit results within 28 days prior to first dose.
9.1.6.1
Diary Completion and Review
Diary entries will be made 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 phase. 
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 based on daily 
diaries, laboratory assessments, and clinical examination. 
The CDAI score evaluated during screening will be used to determine eligibility, using subject 
diary entries within 14 days prior to Week 0 and hematocrit results within 28 days prior to Week 0.
The Week 10 total CDAI score will determine whether the subject has achieved clinical response 
at Week 10 (a ≥70 point decrease in CDAI score from baseline [Week 0]), and will determine the 
dosing frequency (Q8W or Q4W) in the maintenance phase.
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 
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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.
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, electrocardiogram 
(ECG), or physical examination abnormalities noted at 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. The maximum 
volume of blood at any single visit is approximately 23 mL, and the approximate total volume of 
blood for the study is 196 mL.
Clinical laboratory tests to be performed in this study are summarized in Table 9.a. Refer to the 
Schedule of Study Procedures in Appendix A for timing of all assessments. See Laboratory 
Manual for testing regimen.
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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 test
Hepatitis panel, including HBsAg, HBsAb, HBcAb, 
and HCVAb a
AVA
QuantiFERON for TB
Beta hCG and Urine Pregnancy hCG
(female subjects of childbearing potential)
FSH b
C. difficile
ALT: alanine aminotransferase; AST: aspartate transaminase; AVA: anti-vedolizumab antibody; CRP: C-reactive 
protein; FSH: follicle-stimulating hormone; GGT: γ-Glutamyl transferase; HBcAb: hepatitis B core antibody; 
HBsAb: hepatitis B surface antibody; hCG: human chronic gonadotropin; INR: international normalized ratio;
PT: prothrombin time; RBC: red blood cell; TB: tuberculosis; WBC: white blood cell.
a If subject is HCVAb positive, then a viral load test should be performed. If subject is negative for HBsAg but is 
positive for either surface antibodies and/or core antibodies, HBV DNA polymerase chain reaction will be performed.
b FSH level will be obtained for female subject at screening if they are postmenopausal by history (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) and not surgically sterile. The FSH result must be >40 IU/mL 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 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 (Appendix A).
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If subjects experience ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) 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).
9.1.11 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.
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 are:
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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.
All women of childbearing potential will have a serum pregnancy test during screening and 
Week 60 or ET visit. During the course of the study, regular urine hCG pregnancy tests will be 
performed only for women of childbearing potential and subjects will receive continued guidance 
with respect to the avoidance of pregnancy and sperm/ova donation as part of the study procedures 
(Appendix A). In addition to a negative serum and urine hCG pregnancy test at screening, subjects 
also must have a negative urine hCG pregnancy test prior to receiving first dose of investigational 
drug.
9.1.12 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (Vedolizumab IV, Placebo IV) should be immediately discontinued. 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, eg, after drug 
administration at Week 0 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. 
If the female subject and/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/female 
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partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable).
All pregnancies in subjects on active study drug including comparator will be followed up to final 
outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
9.1.13 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 and all other 
subject identifiers will be removed or obscured.
9.1.15 Tuberculosis Screening
All subjects will complete TB screening to determine eligibility. All subjects must complete a 
QuantiFERON test and chest x-ray during screening. Subjects will be excluded from the study if 
they have active or latent TB as defined in Section 7.2.
9.1.17 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.
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9.1.18 PML Checklist
Staff will administer the subjective PML checklist during screening to exclude subjects with
positive responses from enrolling into the study. During the course of the study, the PML 
subjective checklist will be administered on the days of physical examination prior to dosing.
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 Risk Assessment and Minimization for PML (RAMP) 
algorithm described in Section 11.2.1. The symptoms from a positive PML checklist will be 
recorded as an AE. Additional information and tools for the RAMP can be found in the Study
Manual. 
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9.1.20 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible at this visit, the investigator should complete the eCRF. 
The IWRS should be contacted as a notification of screen failure.
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.
!
Significant protocol deviation.
!
Lost to follow-up.
!
Voluntary withdrawal.
!
Study termination.
!
Other.
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.
9.1.21 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization 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).
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9.3.1
Screening 
Subjects will be screened within 28 days prior to randomization. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.19 for procedures for documenting screening failures.
Procedures to be completed at screening can be found in the Schedule of Study Procedures
(Appendix A).
9.3.2
Randomization
Randomization will take place at Week 0 (Day 1). 
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IWRS, as described in Section 8.2. 
Subjects will be instructed on when to take the first dose of investigational drug as described in 
Section 6.0. The procedure for documenting screening failures is provided in Section 9.1.19.
Eligible subjects will be enrolled in induction phase and randomized 1:2 in a double-blinded
manner to receive placebo or vedolizumab IV 300 mg at Week 0 (Day 1), Week 2 (Day 15), and 
Week 6 (Day 43). The primary efficacy evaluation for the induction phase will be performed at 
Week 10.
To adjust for the known confounding factors within treatment arms in the induction phase, 
subjects’ randomization assignment will be stratified by:

Previous failure of TNF-α antagonist therapy or concomitant use of immunomodulators 
(6-mercaptopurine, azathioprine, or methotrexate).

Concomitant use of oral corticosteroids.
In the maintenance phase, subjects who received vedolizumab or placebo in the induction phase 
and achieved clinical response at Week 10 will continue to receive the same treatment as they 
received in the induction phase Q8W starting from Week 14 (ie, Weeks 14, 22, 30, 38, 46, and 54) 
in a double-blinded manner. Subjects who received vedolizumab IV or placebo in the induction 
phase and did not achieve clinical response at Week 10 will receive vedolizumab Q4W starting 
from Week 14 (ie, Weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, and 58) in a double-blind 
manner. Subjects receiving oral corticosteroids who have achieved clinical response at Week 10 
will begin a corticosteroid tapering regimen. Clinical response is defined as a ≥70 point reduction 
in CDAI from baseline (Week 0). Evaluation of efficacy for the maintenance phase will be 
performed at Week 60. 
No more than 50% of the subjects enrolled in the trial should have previously been exposed to and 
failed TNF-α antagonist treatment. 
Randomization will be handled by the IVRS.
9.3.3
Final Visit or Early Termination
The final visit will be performed on Week 60 or at the ET visit. 
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For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
9.3.4
Final Safety Follow-up Visit
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 60 visit.
9.3.5
Poststudy 6-Month Long-Term Follow-up Survey
Upon completion of or early termination from the study, all subjects will participate in a LTFU 
safety questionnaire. The questionnaire will be administered by telephone at 6 months from the 
last dose of study drug. 
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 procedures:

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.

AVA sample collection.

Fecal calprotectin (if indicated).

C. difficile (if indicated).
There is no minimum time for repeat evaluation by unscheduled visits 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 (eg, 1 week).
9.3.7
Poststudy Care
The study medication will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies as required.
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
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.
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 versus 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 PTE(s) or as 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 
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 
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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. Leads to 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
AE: adverse event.
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 AE (serious or nonserious) 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 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 –To be used only 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.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
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 
Week 0 (Day 1) or until 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 at Week 0 (Day 1). Routine collection of AEs will continue until 18 weeks after last 
dose of study medication.
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. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
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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.
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.
10.2.1.3 AE 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 will not be collected as 
AEs. These characteristics of disease activity will be regularly captured in the CDAI. 
Exacerbations of disease activity (eg, increase in the daily amount of abdominal pain beyond the 
subject’s normal fluctuation, new signs and 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 a special 
interest AE eCRF Form or an SAE Form. The applicable Form should be completed and reported 
to the SAE reporting contact in Section 1.1 within 24 hours.
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Hypersensitivity Reactions (including infusion-related 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. 
During clinic visits, vedolizumab IV should be administered in the presence of a health care 
professional 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.
If signs or symptoms of an infusion-related 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 infusion-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 Study Manual). 
In all cases of infusion-related reaction, the medical monitor must be informed as soon as practical. 
The disposition of subjects with less severe infusion-related reactions should be discussed with the 
medical monitor.
Serious Infection 
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.
The special interest AEs have to be recorded as AEs in the eCRF. An evaluation form along with 
all other required documentation must be submitted to the sponsor.
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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 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).

Causality assessment.
The SAE form should be transmitted 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.
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.
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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 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 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
DMC
At the interim analysis, enhanced clinical response and clinical remission will be tested and 
conditional power will be calculated respectively by an independent statistical group who will 
deliver the results to the DMC. The DMC will compare the calculated conditional power with the 
prespecified sample size and primary endpoint adaptation rules to determine the final sample size 
and primary endpoint for the study. The DMC will recommend to the sponsor executive committee 
the sample size and primary endpoint adaptation decisions. The operational study team will remain 
blinded to the interim results until completion of the study.
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 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 [33,34]. 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 [35,36]. In contrast, vedolizumab binds to the α4β7 integrin only [13] 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 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 study drug, at time points as per the schedule of 
procedures, 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 next dose of 
study drug will be held 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. 
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 
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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 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
CRFs (Electronic)
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 eCRF. 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 
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. Reasons for significant corrections should additionally be included. 
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
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, 
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 
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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.
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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.
For the purpose of statistical analyses, the induction and maintenance phases will be treated as 
2 independent studies. The analysis of the induction phase will formally evaluate and provide 
conclusive evidence of the efficacy and safety of 300 mg Vedolizumab versus placebo as an 
induction therapy.
The analysis of the combined induction and maintenance phase data will be exploratory and 
descriptive in nature. 
A blinded data review will be conducted prior to unblinding of randomized 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 (FAS), also known as the ITT population, for the induction phase consists of 
all randomized subjects who received any amount of blinded study drug. Subjects in this set will 
be analyzed according to the treatment they were randomized to receive, regardless of any errors 
of dosing.
The FAS for the combined induction and maintenance phase FAS consists of all the randomized 
subjects who received any amount of maintenance phase study drug. The subjects will be analyzed 
according to the treatment they were randomized to and the Week 10 response status in order to 
characterize subjects' straight-through experience in the combined induction and maintenance 
phase.
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 per-protocol population dataset will be 
made prior to the unblinding of the study. Analyses using the per-protocol 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.
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 
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subjects, mean, SD, 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
For the induction study, 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 and 
placebo groups for the primary and secondary endpoint, closed sequential testing procedure will 
be used. The secondary endpoint will not be formally tested if the primary endpoint testing result is 
negative. Multiplicity will not be adjusted across additional endpoints.
All dichotomous efficacy endpoints will be analyzed using CMH tests for risk differences, 
stratified by:
!
Previous failure of TNF-α antagonist therapy or concomitant use of immunomodulators 
(6-mercaptopurine, azathioprine, or methotrexate). 
!
Concomitant use of oral corticosteroids.
All subjects with missing data for determination of endpoint status will be considered as a 
nonresponder in the analysis.
To evaluate the robustness of the efficacy results, sensitivity analyses will be conducted via using 
different approaches on missing data (such as last observation carried forward, etc); adjusting for 
baseline covariates via logistic regressions, etc. Further details will be provided in the SAP.
For the maintenance study, descriptive and exploratory analyses on efficacy will be conducted. 
13.1.5 Safety Analysis
Safety analysis will be performed using the Safety Analysis Set. No statistical inference will be 
made for safety analyses. Safety summary will cover both induction and maintenance phase of the 
study.
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The number and percentage of subjects with treatment-emergent adverse events (TEAEs, defined 
as any AEs newly occurring or worsening during first dose and 18 weeks after last dose of study
treatment, regardless of relationship to study drug), AESIs (ie, serious infections, 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 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 AEs overall and by severity. 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.
In addition to summarize the AE data by incidence, exposure adjusted AE rates will also be 
presented.
Long-term safety follow-up data will be summarized descriptively. The 
 infusion reactions and safety will be summarized.
13.2
Interim Analysis and Criteria for Adaptation 
A single interim analysis is planned for this study with the objective of a potential sample size 
adjustment and endpoint change. The interim analysis will be conducted after approximately the 
first 144 subjects (96 subjects in the vedolizumab arm and 48 subjects in the placebo arm) have 
been enrolled and have completed the Week 10 observation or discontinued from the induction 
phase early. 
Based on this interim analysis, the sample size may be increased if the observed treatment effect 
for enhanced clinical response is promising but not large enough to yield the likely conclusion of 
statistical significance at the end of the study using the original planned sample size; in addition, 
primary endpoint may be changed [37] if the conditional power for clinical remission is much 
better than that for enhanced clinical response. It is also possible that the entire study design 
remain unchanged as a result of the interim analysis. Due to low prevalence of CD and limited 
study sites in China, the primary endpoint in this study is partially different from the global studies. 
To lower the risk of such a change, the adaptive approach will make the China study be closer to a 
global study which used clinical remission as one of the co-primary endpoints.
The interim analysis will be conducted by an ISC and presented for review to the DMC. The 
interim results will not be shared with the sponsor. During the closed session of the DMC meeting,
the DMC will compare the conditional power for both enhanced clinical response and clinical 
remission based on the interim results with the prespecified sample size and primary endpoint 
adaptation rules and recommend to the sponsor executive committee the final adaptation decision.
This recommendation will be documented in the DMC closed meeting minutes.
The sponsor executive committee—individuals identified by Takeda who have the clinical, 
statistical, and business expertise needed to make critical decisions for Takeda, but who will not 
have any direct involvement with the study—will meet to review the recommendation. The 
sponsor executive committee will make a decision to accept or reject the DMC’s recommendation 
and will relay its decision to the DMC.
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The sponsor executive committee will inform the study team of the final total sample size only. 
That is, the study team will remain blinded to the adaptation decision of the primary endpoint until 
the study database is unlocked for the final induction study analysis.
The final induction phase efficacy and safety analysis will be performed when the induction 
treatment is completed for the enrolled number of patients as determined by the sample size 
adaptation rule in the interim analysis. If the decision is made by Takeda to conduct the efficacy 
and safety induction analyses, the analyses will be performed when the induction treatment is 
completed for last subject. Results of the induction phase will be submitted to the China Food and 
Drug Administration (CFDA). The Cui-Hung-Wang test statistic [38] for the first and second stage 
test statistics will be used for testing the primary endpoint and the conventional test statistic will 
also be calculated as a sensitivity analysis. The formal proof of strong type I error rate control due 
to the potential sample size and primary endpoint adaptation in the study design will be included in 
the SAP. 
In such a case, to protect integrity of the maintenance study, the final induction phase analysis will 
be conducted by an independent statistical team which members will not be involved in the daily 
study management activities. The final induction phase analysis results will be available to an 
unblinded team consisted of selected people from needed functions. The unblinded team will 
summarize the results and submit them to CFDA. Study team members who are not in the 
unblinded operations as well as study investigators from study sites will not have access to 
unblinded patient level data from both induction and maintenance phase until the end of the study. 
Supplemental efficacy and safety results including both the induction phase and maintenance 
phase will be analyzed at the end of the study and submitted to CFDA. The final safety follow-up 
visit will occur 18 weeks after the last study drug dose.
If the decision is made by Takeda to not conduct the efficacy and safety analyses until after the 
maintenance phase is completed, the study data will be available to the study team and the 
investigators only after the database lock at the end of the study.
13.3
Determination of Sample Size
The assumed clinical remission and enhanced clinical response rates are based on a global study of 
vedolizumab IV in induction and maintenance treatment of subjects with moderately to severely 
active CD (C13007) as well as a global study of vedolizumab in induction treatment of subjects 
with moderately to severely active CD (C13011).
The sample size calculation is based on the adaptive sample size re-assessment approach [39]. The 
study is initially powered on an optimistic assumption that the effect size will be similar to what 
was observed in study C13011 for enhanced clinical response: with assuming enhanced response 
rate of 48% for vedolizumab and 25% for placebo at Week 10, a sample size of 136 subjects in the 
vedolizumab group and 68 subjects in the placebo group will provide 90% power at 2-sided 0.05 
level of significance. 
At the interim analysis, the conditional power based on enhanced clinical response and clinical 
remission at week 10 will be calculated. If the conditional power for enhanced clinical response 
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falls in the favorable zone or if it is no less than the conditional power for clinical remission, the 
enhanced clinical response will remain as the primary endpoint. Otherwise, clinical remission will 
become the primary endpoint. Once the primary endpoint is determined, sample size will be 
re-assessed according to a prespecified adaptation rule for the selected endpoint, with a maximum 
sample size of 300 subjects (200 subjects in the vedolizumab group and 100 subjects in the placebo 
group). If the conditional power falls in the futility zone, the study will stop for futility; if it falls in 
the unfavorable zone or favorable zone, no change to sample size will be made; if it falls in the 
promising zone, sample size will be increased. 
The sample size adaptation rule is a prespecified stepwise function to avoid the back calculation 
problem because 1 sample size can correspond to either barely promising or highly promising 
interim results. Both the sample size and endpoint adaptation rule will be designed by the sponsor 
independent design statistician and approved by the sponsor head of biostatistics. Both the sponsor 
independent design statistician and sponsor head of biostatistics are not involved in the study 
conduct. 
The adaptation rules will be a separate document and will not be accessible to the sponsor study 
team until completion of the study. It will only be available to the sponsor independent design 
statistician, the sponsor head of biostatistics, the DMC, and the statistics representative in the 
sponsor executive committee (if different from the sponsor head of biostatistics).
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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
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 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 
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.
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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 
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.
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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
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9. Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking and 
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10. Salmi M, Jalkanen S. Lymphocyte homing to the gut: attraction, adhesion, and commitment. 
Immunol Rev 2005;206:100-13.
11. 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.
12. 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.
13. 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.
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14. 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.
15. 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.
16. Summers RW, Switz DM, Sessions JT, Jr., Becktel JM, Best WR, Kern F, Jr., et al. National 
Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology 1979;77(4 Pt 
2):847-69.
17. Akobeng AK, Gardener E. Oral 5-aminosalicylic acid for maintenance of medically-induced 
remission in Crohn's Disease. Cochrane Database Syst Rev 2005(1):CD003715.
18. Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD. Increased risk of lymphoma 
among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. 
Gut 2005;54(8):1121-5.
19. Remicade (infliximab) lyophilized concentrate for injection, for intravenous use. Prescribing 
Information. Horsham, PA: Janssen Biotech, Inc., Revised January 2015.
20. Humira (adalimumab) injection, for subcutaneous use. Full Prescribing Information. North 
Chicago, IL: AbbVie Inc., Revised May 2013.
21. Cimzia (certolizumab pegol) for injection, for subcutaneous use. Prescribing Information. 
Smyrna, GA: UCB, Revised October 2013.
22. 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.
23. 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.
24. 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.
25. 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 
2007;357(3):239-50.
26. 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.
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27. 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.
28. Tysabri (natalizumab) injection. Full Prescribing Information. Cambridge, MA: Biogen Idec
Inc., Revised March 2014.
29. 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 
Williams & Wilkins; 1999, p. 1775-839.
30. 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.
31. 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.
32. 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.
33. Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory 
therapies. Annu Rev Med 2010;61:35-47.
34. Steiner I, Berger JR. Update on progressive multifocal leukoencephalopathy. Curr Neurol 
Neurosci Rep 2012;12(6):680-6.
35. 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.
36. TYSABRI (natalizumab) injection. Full Prescribing Information. Cambridge, MA: Biogen 
Idec Inc., Revised June 2013.
37. Hung HM, Wang SJ, O'Neill RT. Methodological issues with adaptation of clinical trial 
design. Pharm Stat 2006;5(2):99-107.
38. Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics 1999;55(3):853-7.
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39. Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stat Med 2011;30(28):3267-84.
40. 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
Study
Procedure
Screening
Induction Phase
Maintenance Phase
At 
Complet
ion/ET
18
Weeks 
After 
Final 
Dose
Un-
Scheduled 
Visit d
Week
0 b
2
6
10
14
18
22
26
30
34
38
42
46
50
54
58
60/ ET c
Day
-28 to -1
1 b
15
43
71
99
127
155
183
211
239
267
295
323
351
379
407 421/ ET c
Time window 
(days) a
―
―
±2
±3
±3
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
VISIT
1
2 b
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18/ ET c
19
Informed consent
X
Register subject in IWRS
X
Inclusion criteria/exclusion 
criteria
X e
X
Demographic data 
X e
Medical and CD history
X
Prior CD therapies
X
Physical examination f
X e
X
X
X
X
X
X
X
X
X
X
Vital signs g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (ECG)
X e
X
X
Chest x-ray
X e
X
QuantiFERON test
X i
PML checklist h
X e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PML wallet card
X
X
Randomization
X
Study drug assignment and 
administration/register IWRS 
visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fistula assessment (if indicated) 
j
X
X
X
X
X
X
X
X
X
X
Laboratory test
Blood 
biochemistry
X i
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X i
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematocrit 
X k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X i
X
X
Urinalysis
X i
X
X
X
X
X
Serum pregnancy
test l
X i
X
X
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Protocol Incorporating Amendment 03
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Study
Procedure
Screening
Induction Phase
Maintenance Phase
At 
Complet
ion/ET
18
Weeks 
After 
Final 
Dose
Un-
Scheduled 
Visit d
Week
0 b
2
6
10
14
18
22
26
30
34
38
42
46
50
54
58
60/ ET c
Day
-28 to -1
1 b
15
43
71
99
127
155
183
211
239
267
295
323
351
379
407 421/ ET c
Time window 
(days) a
―
―
±2
±3
±3
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
VISIT
1
2 b
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18/ ET c
19
FSH m
X i
Urine pregnancy 
test l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV, HCV, HIV 
screening
X i
Fecal calprotectin 
n
X
X
X
X
X
CRP
X
X
X
X
X
C. difficile stool 
sample 
X o
X o
CDAI score p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Diary instruction 
X
r
Concomitant 
medication/concomitant 
nondrug therapy
X e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PTE/AEs t
X e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE assessment
X e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CCI
CCI
CCI
CCI
CCI
CCI
CCI
Property of Takeda: For N
X
X
a:
or N
X
da:
a:
a:
a
X e
ed
ake
mm
mmerciaiaiaia
rc
e
mmer
omm
Com
Use Only and Subject to the Applicable Terms of Use
Te
le
50
50
pli
Ap
323
35
23
35
Ap
Ap
App
Ap
±7
±7
A
he A
13
13
th
t
h
to
t t
X
ct 
bje t
ubjbjbj
S bj
X
d
a
 
y a
y a
y a
n y a
nly
On
X
X
e
Us
n-C
l Use
ial U
r Non

Vedolizumab IV
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Page 85 of 97
Protocol Incorporating Amendment 03
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AE: adverse event; AVA: anti-vedolizumab antibody; CD: Crohn’s disease; CDAI: Crohn’s Disease Activity Index; CRP: C-reactive protein; ECG: electrocardiogram; ET: early
termination; FSH: follicle-stimulating hormone; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; I
IWRS: interactive web response system; PML: progressive multifocal leukoencephalopathy; PTE: pretreatment event; SAE: serious adverse event; WPAI: Work 
Productivity and Activity Impairment. 
a The date of the first dose of study drug in the induction phase is Week 0 (Day 1). The acceptable time windows are given as the number of days away from each scheduled visit.
b All baseline (Week 0) assessments will be done predose.
c Examinations to be performed at discontinuation must be performed in subjects who prematurely withdraw from the study in the induction and maintenance phases.
d Unscheduled visit will be made due to worsening of CD, etc. Additional tests will be performed as required.
e Can be conducted between Day -28 and Day -1.
f Physical examination: Clinically significant findings will be recorded as concurrent conditions if start prior to signing the informed consent, or as PTEs if start after signing of the 
informed consent and as AEs if starts after the first dose of study drug.
g 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.
h On the days of study drug administration, procedure to be performed before administration of study drug.
i The test results should be obtained by Visit 2 (Week 0).
j Fistula assessment: The presence of a draining fistula (per the CD activity assessment) will trigger a specific fistula assessment at that visit and at each subsequent visit until Week 
60/ ET, even if the fistula has closed in the interim.
k Hematocrit will be measured at central laboratory (in addition to scheduled hematology tests) within 10 days before CDAI score evaluation. Hematocrit level from screening could 
be used for CDAI score that determine eligibility at Week 0.
l Will be performed only in women of childbearing potential.
(m) FSH level will be obtained for female subjects at screening if they are postmenopausal by history (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) and not surgically sterile. The FSH result must be 40>IU/L for the subject to be 
permitted not to use adequate contraception.
n Fecal calprotectin stool sample should be the first bowel movement on the day of collection.
o A stool sample for culture, ova and parasite evaluation, and C. difficile assay will be obtained (if indicated) at screening and at any time point during the study when a subject 
becomes symptomatic, including worsening or return of disease activity.
p CDAI score components are to be performed prior to dosing; the total 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.
q To be performed prior to dosing. 
r Performed prior to administration of study drug.
t A PTE is an event occurred before the first dose of study drug. An AE is an event occurred after the first dose of study drug.
CCI
CCI
Property of Takeda: For No
of study d
f study
cabl
CCI
CCI
n-Commercial Use Only and Subject to the Applicable Terms of Use
Te
otein; EC
otein; E
us; I
nt; SAE
nt; SAE:
s the num
the num
study in th
udy in
o signing 
ignin
vital signs
al sign
drug
drug.
gger a spe
er a sp
ests)
sts) with
w
enopausal
enopau
ation is im
tion is 
the day o
e day 
ile assay w
assay
tivity.
vity.
e total sco
total s
Non

Vedolizumab IV
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Page 86 of 97
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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 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 
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 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.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, 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.
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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. Report adverse reactions to 
the sponsor promptly. In the event of an SAE, notify the sponsor within 24 hours.
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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.
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 
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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. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. 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 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.
24. 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 
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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.
25. 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.
26. 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 
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Appendix E
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. 
CDAI: Crohn’s Disease Activity Index.
a If hematocrit subtotal <0, enter 0.
b If body weight subtotal <-10, enter -10.
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CCI
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Appendix G
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment 03 are indicated. The 
corresponding text has been revised throughout the protocol. 
Change 1: Update to the stratification factors.
The primary change occurs in Section 6.1 Study Design.
Initial 
wording:
To adjust for the known confounding factors in the Induction Phase, subjects’ 
randomization assignment will be stratified by:

Previous failure of TNF-α antagonist therapy.

Concomitant use of oral corticosteroids.
Amended or 
new wording:
To adjust for the known confounding factors in the induction phase, subjects’ 
randomization assignment will be stratified by:

Previous failure of TNF-α antagonist therapy or concomitant use of 
immunomodulators (6-mercaptopurine, azathioprine, or 
methotrexate).

Concomitant use of oral corticosteroids.
Rationale for Change:
To keep in line with previous protocol amendment 01, as all recruitment was completed for the 
study before modification of the stratification factor in protocol amendment 02.
The following section also contains this change:

Section 2.0 STUDY SUMMARY

Section 9.3.2 Randomization. 

Section 13.1.3 Efficacy Analysis
Change 2: Inclusion of a data monitoring committee.
The primary change occurs in Section 11.1 DMC:
Added text:
11.1  DMC
At the interim analysis, enhanced clinical response and clinical remission will 
be tested and conditional power will be calculated respectively by an 
independent statistical group who will deliver the results to the DMC. The 
DMC will compare the calculated conditional power with the prespecified 
sample size and primary endpoint adaptation rules to determine the final 
sample size and primary endpoint for the study. The DMC will recommend to 
the sponsor executive committee the sample size and primary endpoint 
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adaptation decisions. The operational study team will remain blinded to the 
interim results until completion of the study.
Rationale for Change:
To keep in line with previous protocol amendment 01, as the interim analysis was triggered prior 
to CDE's feedback on protocol amendment 02.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 6.1 Study Design. 

Section 13.2 Interim Analysis and Criteria for Adaptation.

Section 13.3 Determination of Sample Size.
Change 3: Addition of definition for sponsor executive committee.
The primary change occurs in Section 13.2 Interim Analysis and Criteria for Adaptation. 
Initial 
wording:
[…]
The interim analysis will be conducted by an independent statistical center (ISC). 
The interim results will not be shared with the sponsor. The independent statistician 
will compare the conditional power for both enhanced clinical response and 
clinical remission based on the interim results with the prespecified sample size and 
primary endpoint adaptation rules and recommend to the sponsor the final 
adaptation decision.
[…]
Amended or 
new wording:
[…]
The interim analysis will be conducted by an independent statistical center (ISC) 
and presented for review to the DMC. The interim results will not be shared with 
the sponsor. The independent statistician During the closed session of the DMC 
meeting, the DMC will compare the conditional power for both enhanced clinical 
response and clinical remission based on the interim results with the prespecified 
sample size and primary endpoint adaptation rules and recommend to the sponsor 
executive committee the final adaptation decision. This recommendation will be 
documented in the DMC closed meeting minutes.
The sponsor executive committee—individuals identified by Takeda who have 
the clinical, statistical, and business expertise needed to make critical 
decisions for Takeda, but who will not have any direct involvement with the 
study—will meet to review the recommendation. The sponsor executive 
committee will make a decision to accept or reject the DMC’s 
recommendation and will relay its decision to the DMC.
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The sponsor executive committee will inform the study team of the final total 
sample size only. That is, the study team will remain blinded to the adaptation 
decision of the primary endpoint until the study database is unlocked for the 
final induction study analysis.
[…]
Rationale for Change:
To provide a definition of the sponsor executive committee and its role within the study.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 6.1 Study Design. 

Section 13.3 Determination of Sample Size. 
Change 4: Inclusion of maximum sample size.
The primary change occurs in Section 13.3 Determination of Sample Size.
Initial 
wording:
[…]
At the interim analysis, the conditional power based on enhanced clinical response 
and clinical remission at week 10 will be calculated. If the conditional power for 
enhanced clinical response falls in the favorable zone or if it is no less than the 
conditional power for clinical remission, the enhanced clinical response will 
remain as the primary endpoint. Otherwise, clinical remission will become the 
primary endpoint. Once the primary endpoint is determined, sample size will be 
re-assessed according to a prespecified adaptation rule for the selected endpoint. If 
the conditional power falls in the unfavorable zone or favorable zone, no change to 
sample size will be made; if it falls in the promising zone, sample size will be 
increased.
[…]
Amended or 
new wording:
[…]
At the interim analysis, the conditional power based on enhanced clinical response 
and clinical remission at week 10 will be calculated. If the conditional power for 
enhanced clinical response falls in the favorable zone or if it is no less than the 
conditional power for clinical remission, the enhanced clinical response will 
remain as the primary endpoint. Otherwise, clinical remission will become the 
primary endpoint. Once the primary endpoint is determined, sample size will be 
re-assessed according to a prespecified adaptation rule for the selected endpoint, 
with a maximum sample size of 300 subjects (200 subjects in the vedolizumab 
group and 100 subjects in the placebo group). If the conditional power falls in
the futility zone, the study will stop for futility; if it falls in the unfavorable zone 
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or favorable zone, no change to sample size will be made; if it falls in the promising 
zone, sample size will be increased. 
[…]
Rationale for Change:
To keep in line with previous protocol amendment 01, as the interim analysis was triggered prior 
to CDE's feedback on protocol amendment 02, and the adaptation rule was developed based on 
protocol amendment 01.
Change 5: Update schedule of assessment table to include 1 early termination procedure for all 
subjects.
The primary change occurs in Appendix A
Schedule of Study Procedures. 
Initial 
wording:
(c) Examinations to be performed at discontinuation must be performed in subjects who prematurely withdraw 
from the study in the induction phase after receiving at least 1 dose.
(d) Examinations to be performed at discontinuation must be performed in subjects who prematurely withdraw 
from the study in the maintenance phase.
Amended or 
new wording:
c Examinations to be performed at discontinuation must be performed in subjects who prematurely withdraw 
from the study in the induction phase after receiving at least 1 dose.
d Examinations to be performed at discontinuation must be performed in subjects who prematurely withdraw 
from the study in the induction and maintenance phases.
Rationale for Change:
Removal of ET visit specifically for subjects in the induction phase to keep 1 ET procedure for all 
subjects regardless of study phase.
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