Clinical trial NCT02425111
Conditions: Crohn's Disease
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2015-03-30; Completion date: 2018-02-21
Enrollment: 101 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate endoscopic remission at Week 26 as assessed by ileocolonoscopy.

Detailed description:
The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat people who have Crohn's disease. This study will look at mucosal healing in people who take vedolizumab.

The study will enroll approximately 100 patients and will be conducted in 2 Parts. Part A will consist of a 26-week treatment period and all participants will receive vedolizumab 300 mg intravenously (IV) on Day 1 and at Weeks 2, 6, 14 and 22. Part B will consist of a 26-week extension treatment period and all participants will receive vedolizumab 300 mg IV at Weeks 30, 38, and 46.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 70 weeks for Parts A, B and 18-Week Follow-up combined. Participants will make multiple visits to the clinic. All participants included in the study will also have a 6 month safety follow-up telephone call following his/her last dose of study drug.

Arms: arm 1: Part A: Vedolizumab 300 mg, intravenously (IV), once on Day 1 and Weeks 2, 6, 14 and 22, followed by Part B: Vedolizumab 300 mg, intravenously (IV), once at Weeks 30, 38, and 46.
Interventions: intervention 1: Vedolizumab
Intervention descriptions: intervention 1: Vedolizumab intravenous injection

Protocol documents:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: An Open-Label Phase 3b Study to Assess Mucosal Healing in Subjects With Moderately to 
Severely Active Crohn’s Disease Treated With Vedolizumab IV
NCT Number: NCT02425111
Protocol Approve Date: 28 November 2016
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


1.0 TITLE PAGE
PROTOCOL
An Open-Label Phase 3b Study to Assess Mucosal Healing in Subjects With Moderately to 
Severely Active Crohn’s Disease Treated With Vedolizumab IV
Effect of Vedolizumab IV on Mucosal Healing in Crohn’s Disease
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway, Deerfield, IL 60015
Takeda Development Centre Europe, Ltd.
61 Aldwych, London, WC2B 4AE
United Kingdom
Study Number:
MLN0002-3028
IND Number:
009125
EudraCT Number:
2014-003509-13
Compound:
Vedolizumab IV
Date:
28 November 2016
Amendment Number:
05
Amendment History: 
Date
Amendment Number
Amendment Type 
Region
15 December 2014
Initial Protocol
Not applicable
Global
23 January 2015
01
Substantial
Global
01 September 2015
02
Non-substantial
France
09 December 2015
03
Non-substantial
Italy
28 April 2016
04
Substantial
Global
28 November 2016
05
Substantial
Czech Republic, Hungary, Italy and Poland
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts 
A separate contact information list will be provided to each site.
TDC sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Americas and Europe 
TDC Contact 
Serious adverse event and pregnancy reporting Americas: 
Fax: 
Emai
Europe/ROW:
Medical Monitor
(medical advice on protocol and compound)
Responsible Medical Officer 
(carries overall responsibility for the conduct o
the study)
PPD
PPD
PPD


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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.
Date
Date
PPD
PPD


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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert 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, State/Provence)
Location of Facility (Country)


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1.3
Protocol Amendment No. 05 Summary of Changes 
Rationale for Amendment No. 05
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 05.
The primary purpose of this amendment is to update the protocol to allow subjects in participating 
countries to transition into an Extended Access Program (XAP). Minor grammatical and editorial 
changes are included for clarification purposes only. Full details on changes of text are given in 
Appendix H.
Changes in Amendment No. 05
1. Allow all subjects (who complete Part B) in countries where vedolizumab is either not 
commercially available or is not reimbursed, continued access to vedolizumab by transition 
into an Extended Access Program (XAP), Vedolizumab-4013. 
2. Remove the requirement for subjects who transition into the XAP study to attend the 18-week 
Safety Follow-up Visit in the MLN0002-3028 study. The safety of these subjects will be 
monitored as part of the XAP study.
3. Remove the requirement for subjects who transition into the XAP study to participate in the 
6-month long-term follow-up safety questionnaire in the MLN0002-3028 study. The safety of 
these subjects will be monitored as part of the XAP study.
4. Amend the adverse event, serious adverse event, and concomitant medication reporting 
instructions for subjects who transition into the XAP study, such that the MLN0002-3028 
collection period ends at the time the subject is consented into the XAP.
5. Administrative change to the Responsible Medical Officer.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment No. 05 Summary of Changes ...................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Principal Investigator/Coordinating Investigator ......................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................17
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.1.1
Diseases and Current Treatments .......................................................................18
4.1.2
Vedolizumab IV.................................................................................................19
4.2
Rationale for the Proposed Study.............................................................................21
4.3
Risk:Benefit Assessment..........................................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................23
5.1
Objectives................................................................................................................23
5.1.1
Primary Objective ..............................................................................................23
5.1.2
Secondary Objectives.........................................................................................23
5.1.3
Additional Objectives.........................................................................................23
5.2
Endpoints.................................................................................................................24
5.2.1
Primary Endpoints .............................................................................................24
5.2.2
Secondary Endpoints..........................................................................................24
5.2.3
Additional Endpoints .........................................................................................25
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................28
6.1
Study Design ...........................................................................................................28
6.2
Justification for Study Design, Dose, and Endpoints ................................................29
6.3
Premature Termination or Suspension of Study or Investigational Site.....................30
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................30
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........30
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................30
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............31


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7.1
Inclusion Criteria .....................................................................................................31
7.2
Exclusion Criteria ....................................................................................................32
7.3
Excluded Medications and Treatments.....................................................................35
7.3.1
Permitted Medications and Treatments...............................................................35
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................36
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................37
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................38
8.1
Study Medication and Materials...............................................................................38
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................38
8.1.2
Storage...............................................................................................................38
8.1.3
Dose and Regimen .............................................................................................38
8.1.4
Overdose............................................................................................................39
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................39
8.3
Accountability and Destruction of Sponsor-Supplied Drugs.....................................39
9.0
STUDY PLAN ..............................................................................................................41
9.1
Study Procedures.....................................................................................................41
9.1.1
Informed Consent Procedure..............................................................................41
9.1.2
Demographics, Medical History, and Medication History Procedure..................41
9.1.3
Physical Examination Procedure ........................................................................41
9.1.4
Weight, Height...................................................................................................42
9.1.5
Vital Sign Procedure..........................................................................................42
9.1.6
Efficacy Measurements......................................................................................42
9.1.7
Documentation of Concomitant Medications......................................................43
9.1.8
Documentation of Concurrent Medical Conditions.............................................43
9.1.9
Procedures for Clinical Laboratory Samples.......................................................43
9.1.10 Contraception and Pregnancy Avoidance Procedure...........................................45
9.1.11 Pregnancy ..........................................................................................................46
9.1.12 ECG Procedure..................................................................................................46
9.1.13 Immunogenicity Sample Collection ...................................................................46
9.1.14 Pharmacogenomic Sample Collection ................................................................47
9.1.15 Tuberculosis Screening ......................................................................................48
9.1.16 PML Checklist...................................................................................................48
9.1.17 Crohn’s Disease Activity Index..........................................................................48
9.1.18 Diary Completion and Review ...........................................................................48
9.1.19 Patient Reported Outcome Measures..................................................................48


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9.1.20 Documentation of Screen Failure .......................................................................49
9.1.21 Documentation of Study Entrance......................................................................50
9.2
Monitoring Subject Treatment Compliance..............................................................50
9.3
Schedule of Observations and Procedures................................................................50
9.3.1
Screening...........................................................................................................50
9.3.2
Enrollment .........................................................................................................50
9.3.3
Final Visit or Early Termination.........................................................................50
9.3.4
Postdose 18-Week Safety Follow-up..................................................................51
9.3.5
Poststudy Long-term Follow-up.........................................................................51
9.3.6
Poststudy Care ...................................................................................................51
9.3.7
Unscheduled Visits Due to Disease Exacerbation...............................................51
9.4
Biological Sample Retention and Destruction ..........................................................52
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................54
10.1
Definitions...............................................................................................................54
10.1.1 PTEs..................................................................................................................54
10.1.2 AEs....................................................................................................................54
10.1.3 Additional Points to Consider for PTEs and AEs................................................54
10.1.4 SAEs..................................................................................................................56
10.1.5 Special Interest AEs...........................................................................................57
10.1.6 Severity of PTEs and AEs..................................................................................57
10.1.7 Causality of AEs ................................................................................................58
10.1.8 Relationship to Study Procedures.......................................................................58
10.1.9 Start Date...........................................................................................................58
10.1.10
Stop Date......................................................................................................58
10.1.11
Frequency.....................................................................................................58
10.1.12
Action Concerning Study Medication ...........................................................58
10.1.13
Outcome .......................................................................................................59
10.2
Procedures...............................................................................................................59
10.2.1 Collection and Reporting of AEs........................................................................59
10.2.2 Collection and Reporting of SAEs......................................................................62
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.....63
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................64
11.1
Adjudication Committee..........................................................................................64


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11.1.1 Risk Minimization Action Plan for PML (RAMP Program) ...............................64
12.0
DATA HANDLING AND RECORDKEEPING............................................................65
12.1
CRFs (Electronic)....................................................................................................65
12.2
Record Retention .....................................................................................................65
13.0
STATISTICAL METHODS..........................................................................................67
13.1
Statistical and Analytical Plans ................................................................................67
13.1.1 Analysis Sets......................................................................................................67
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................67
13.1.3 Efficacy Analysis...............................................................................................68
13.1.4 Pharmacogenomic Analysis ...............................................................................68
13.1.5 Other Analysis ...................................................................................................68
13.1.6 Safety Analysis ..................................................................................................68
13.2
Interim Analysis and Criteria for Early Termination ................................................69
13.3
Determination of Sample Size..................................................................................69
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................70
14.1
Study-Site Monitoring Visits ...................................................................................70
14.2
Protocol Deviations..................................................................................................70
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................70
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................71
15.1
IRB and/or IEC Approval ........................................................................................71
15.2
Subject Information, Informed Consent, and Subject Authorization .........................72
15.3
Subject Confidentiality ............................................................................................73
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................73
15.4.1 Publication and Disclosure.................................................................................73
15.4.2 Clinical Trial Registration..................................................................................74
15.4.3 Clinical Trial Results Disclosure ........................................................................74
15.5
Insurance and Compensation for Injury....................................................................74
16.0
REFERENCES..............................................................................................................75
LIST OF IN-TEXT TABLES
Table 8.a
Dose and Regimen .............................................................................................39
Table 9.a
Clinical Laboratory Tests...................................................................................44
Table 10.a
Takeda Medically Significant AE List................................................................57


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LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design: For Subjects on 26 Weeks of Treatment .................29
Figure 6.b
Schematic of Study Design: For Subjects on 52 Weeks of Treatment .................29
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................78
Appendix B
Responsibilities of the Investigator.....................................................................81
Appendix C
Elements of the Subject Informed Consent.........................................................83
Appendix D
Investigator Consent to Use of Personal Information..........................................86
Appendix E
Crohn’s Disease Activity Index (CDAI).............................................................87
Appendix F
Simple Endoscopic Score for Crohn’s Disease (SES-CD) ..................................88
Appendix G
Collection, Storage, and Shipment of Pharmacogenomic Samples......................89
Appendix H
Detailed Description of Amendments to Text.....................................................90


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc. 
Takeda Development Centre Europe, Ltd. 
Compound:
Vedolizumab IV 
Title of Protocol: An Open-Label Phase 3b Study to Assess 
Mucosal Healing in Subjects With Moderately to Severely 
Active Crohn’s Disease Treated With Vedolizumab IV
IND No.: 9,125
EudraCT No.:
2014-003509-13
Study Number: MLN0002-3028
Phase: 3b
Study Design:
This is a phase 3b single-arm, open-label multicenter study to evaluate the efficacy and safety of vedolizumab 300 mg 
intravenous (IV) infusion over a 26 week-treatment period using ileocolonoscopy in subjects with moderately to 
severely active Crohn’s Disease (CD) (Part A) followed by a 26 week-treatment extension period (Part B). 
Approximately 100 subjects who have failed treatment with corticosteroids, immunomodulator, and/or biologics will 
be enrolled. Subjects who are tumor necrosis factor- alpha (TNF-α) antagonist naïve as well as those who are TNF-α 
antagonist failures will be included, such that approximately 50% of enrolled subjects are TNF-α antagonist naïve. A 
magnetic resonance enterography (MREn) substudy will be conducted at selected centers to assess bowel wall 
activity.
Primary Objectives:
To evaluate endoscopic remission at Week 26 as assessed by ileocolonoscopy.
Secondary Objectives:
Part A

To examine the relationship among endoscopic, imaging, histological, and clinical assessments of CD.

To evaluate endoscopic remission at Week 14.

To evaluate endoscopic response at Weeks 14 and 26.

To evaluate clinical response assessed by Crohn’s Disease Activity Index (CDAI) at Weeks 10 and 26.

To evaluate clinical remission assessed by CDAI at Weeks 10 and 26.
Part B

To examine the relationship among endoscopic, imaging, histological, and clinical assessments of CD.

To evaluate endoscopic remission at Week 52.

To evaluate endoscopic response at Week 52.

To evaluate clinical response assessed by Crohn’s Disease Activity Index (CDAI) at Week 52.

To evaluate clinical remission assessed by CDAI at Weeks 52

To evaluate durable endoscopic remission at Week 52 in subjects with endoscopic remission at Week 26.
Subject Population: Adult subjects aged 18-80 years inclusive, with CD 
Number of Subjects:
Approximately 100 subjects
Number of Sites: 
Approximately 75 sites in North America and Europe
Dose Level(s):
Vedolizumab IV 300 mg 
Route of Administration:
Intravenous 


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Duration of Treatment:
Total 52-week treatment period:
Part A: 26-week treatment period
Part B: 26-week treatment extension period
Period of Evaluation:
The study includes a 4-week screening period, a 
52-week treatment period split into 2 parts, and an 
18-week follow-up period following last dose. The 
duration of the study will be approximately 70 weeks. 
Subjects who do not transition to the Extended Access 
Program (XAP), Vedolizumab-4013 will participate in 
a 6-month safety follow-up phone survey after last 
dose. Subjects who transition into the XAP study are 
not required to participate in the 18-week follow-up 
period or the 6-month safety follow-up phone survey. 
The safety of these subjects will be monitored as part 
of the XAP study.
Main Criteria for Inclusion:
Subjects who have had a diagnosis of moderately to severely active CD for at least 3 months prior to enrollment, with 
a CDAI of 220-450 during the screening period, a simple endoscopic score for CD (SES-CD) score of ≥7 and 
presence of at least one mucosal ulceration documented by recorded ileocolonoscopy at Screening assessed by the 
central reader. 
Subjects who have CD involvement of the ileum and/or colon that can be assessed by ileocolonoscopy. 
Subjects who have demonstrated an inadequate response to, loss of response to, or intolerance of corticosteroids, 
immunomodulators and/or TNF-α antagonists.
Main Criteria for Exclusion:
Subjects who have any evidence of an active infection during Screening. 
Subjects who have a positive progressive multifocal leukoencephalopathy (PML) subjective checklist during 
Screening and before the administration of study drug on Day 1. 
Subjects who have received any biologics within 60 days of enrollment. 
Subjects who have had prior exposure to vedolizumab, natalizumab, efalizumab, or rituximab. 
Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is the proportion of subjects achieving endoscopic remission, defined as SES-CD 
score of ≤4 at Week 26. 
Secondary endpoints for Part A are:

Proportion of subjects achieving complete mucosal healing (defined as absence of ulceration) at Week 26.

Proportion of subjects achieving endoscopic remission at Week 14. 

Proportion of subjects with endoscopic response (defined as SES-CD reduction by ≥50%) at Week 14.

Proportion of subjects with endoscopic response (defined as SES-CD reduction by ≥50%) at Week 26.

Proportion of subjects achieving clinical response (CDAI decrease from Baseline ≥100 points) at Week 10.

Proportion of subjects achieving clinical response (CDAI decrease from Baseline ≥100 points) at Week 26.

Proportion of subjects achieving clinical remission (CDAI ≤150 points) at Week 10.

Proportion of subjects achieving clinical remission (CDAI ≤150 points) at Week 26.
Secondary endpoints for Part B are:

Proportion of subjects achieving complete mucosal healing (defined as absence of ulceration) at Week 52.

Proportion of subjects achieving endoscopic remission at Week 52. 

Proportion of subjects with endoscopic response (defined as SES-CD reduction by ≥50%) at Week 52.

Proportion of subjects achieving clinical response (CDAI decrease from Baseline ≥100 points) at Week 52.

Proportion of subjects achieving clinical remission (CDAI ≤150 points) at Week 52.

Proportion of subjects with durable clinical remission, defined as clinical remission at Week 26 and Week 52.


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Statistical Considerations:
All proportion-based efficacy endpoints will be summarized by presenting the point estimate and 95% confidence 
intervals for the proportion. All subjects with missing data for determination of endpoint status will be considered as a 
non-responder in the analysis. 
All change from baseline efficacy endpoints will be summarized descriptively by time point. 
Three interim analyses will be conducted for final efficacy at Weeks 14, 26, and 52, and for safety.
Sample Size Justification:
A sample size of 100 subjects will be sufficient to provide a 95% confidence interval based on normal approximation 
for the primary endpoint (endoscopic remission rate at Week 26) that extends no more than 10% in each direction from 
the estimated rate. 


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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 for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.


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3.3
List of Abbreviations 
5-ASA
5-aminosalicylate
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate transaminase
AVA
anti-vedolizumab antibody; also called HAHA
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CRP
C-reactive protein
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate (renal system)
EMA
European Medicines Agency
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
GI
gastrointestinal(ly)
HAHA
human antihuman antibody
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRQOL
health-related quality of life 
IAC
Independent Adjudication Committee
IBD
inflammatory bowel disease
IBDQ
inflammatory bowel disease questionnaire
ICD
implantable cardioverter defibrillators
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
Ig
immunoglobin
INR
international normalized ratio
IRB
institutional review board
ITT
intent-to-treat
IV
intravenous(ly)


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IVRS
interactive voice response system
IWRS
LTFU
interactive web response system
long-term follow-up
LFT
liver function test
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MaRIA
Magnetic Resonance Index of Activity
MedDRA
Medical Dictionary for Regulatory Activities
MR
magnetic resonance 
MREn
magnetic resonance enterography
PD
pharmacodynamic(s)
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PTE
pretreatment event
Q4W
once every 4 weeks
Q8W
once every 8 weeks
QOL
quality of life
RAMP
Risk Assessment and Management Program for PML
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SES-CD
simple endoscopic score for Crohn’s Disease
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TEAE
treatment-emergent adverse event
TPMT
thiopurine S-methyltransferase 
TNF-α
tumor necrosis factor- alpha
UC
ulcerative colitis
ULN
upper limit of normal
US
United States 
VAS
visual analog scale
WBC
white blood cell
WHO
World Health Organization
WPAI
Work Productivity and Activity Impairment
XAP
Extended Access Program


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3.4
Corporate Identification 
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Europe and/or TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
4.1.1
Diseases and Current Treatments 
Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder of the 
gastrointestinal (GI) tract that includes 2 entities, namely ulcerative colitis (UC) and Crohn’s 
disease (CD). 
CD is 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 150/100,000 of the US population and approximately 
125/100,000 of population in Western Europe [2-4]. The characteristic pathology involves a 
chronic inflammatory infiltrate consisting of neutrophils and macrophages. Hallmarks of CD 
include granulomatous inflammation and aphthous ulceration.
Clinical manifestations of CD include diarrhea, as well as abdominal pain, fecal urgency, and 
incontinence. Systemic features such as fever, weight loss, malaise, and fatigue are indicators of 
more extensive disease. Extra-intestinal manifestations such as uveitis, arthritis, ankylosis 
spondylitis, or primary sclerosing cholangitis may also be seen in conjunction with IBD. The 
diagnosis of CD is usually made by the clinical presentation and key features of the history, 
physical examination, in combination with laboratory studies.
Current treatments have been effective for many patients with IBD but have numerous limitations 
for patients with moderately to severely active disease. Mild to moderately active CD has 
commonly been treated with oral 5-aminosalicylates (5-ASAs); despite their use in the past, the 
benefit is debatable [5,6]. Corticosteroids are often required for the one-third of 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 because they carry 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 [7]. Other severe adverse events 
include cytopenias, hepatitis, and infection. Methotrexate, while ineffective in UC, 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.
Monoclonal antibodies (mAbs) directed against tumor necrosis factor alpha (TNF-α) have been 
approved for treatment of UC and CD in the United States and European Union, including 
infliximab (Remicade), administered by IV infusion, and adalimumab (Humira) or certolizumab 
(Cimzia) administered by subcutaneous (SC) injection [8-10]. These agents have substantially 
improved the care of patients with CD by inducing and maintaining remission and decreasing the 


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need for hospitalization, surgeries, and other complications. Although TNF-α antagonists 
represent an important addition to the pharmacologic armamentarium for CD, they are effective in 
only a subset of patients, with roughly two-thirds of patients in controlled trials not in remission at 
the end of the first year of therapy [11,12]. In addition, controlled studies have demonstrated that, 
after failure of 1 TNF-α antagonist, a patient’s response to a second TNF-α antagonist is 
substantially lower [13]. The TNF-α antagonists are also associated with a number of serious 
safety concerns based on their suppression of systemic immunity, including reactivation of 
tuberculosis (TB); various bacterial, viral, fungal, and opportunistic infections; and malignancies 
such as hepatosplenic T-cell lymphoma [8,9]. 
Although not authorized in the European Union, another biological therapy, natalizumab 
(TYSABRI®), has been approved in the United States for induction and maintenance of remission 
in patients with moderately to severely active CD. Natalizumab blocks the α4 integrin, a cell 
surface marker on peripheral circulating lymphocytes and thereby inhibits both α4β1 and α4β7 
integrins. However, due to the increased risk of developing the rare but often fatal 
neurodegenerative disorder, progressive multifocal leukoencephalopathy (PML), which is a 
mechanism-based side effect, natalizumab is cautiously prescribed for treatment of CD [14].
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 [15]. The limitations of current 
therapies for IBD indicate that there is a significant need for safer and more effective therapies.
4.1.2
Vedolizumab IV
Vedolizumab (also called MLN0002) is a humanized immunoglobulin (Ig) G1 mAb directed 
against the human lymphocyte integrin α4β7. The α4β7integrin 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 [16-19]. 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 
[20]. Vedolizumab has been developed as a treatment for ulcerative colitis (UC) and Crohn’s 
disease (CD), which are characterized by inflammation of the gastrointestinal (GI) tract. 
Vedolizumab IV (Entyvio™) is a lyophilized powder which after appropriate reconstitution and 
dilution is intended for intravenous (IV) infusion that has been granted marketing approval in 
several regions, including the United States (US), European Union (EU), and Australia. 
Vedolizumab IV is approved for the treatment of adult patients with moderately to severely active 
UC or CD who have failed conventional treatment, (eg, immunomodulators, corticosteroids, or 
tumor necrosis factor-alpha (TNF-α) antagonists). The approved dosing and administration 
regimen consists of 300 mg vedolizumab IV infused intravenously, over approximately 
30 minutes, at Weeks 0 and 2, then once every 8 weeks (Q8W) thereafter, beginning at Week 6. 


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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 [20].
4.1.2.2
Human Experience
To date, more than 3400 subjects have received at least 1 dose of vedolizumab across all studies in 
the clinical development program (see current version of Investigator’s Brochure [IB]). Phase 3 
placebo-controlled studies enrolled 2427 subjects with UC or CD, of whom 1434 subjects were 
administered 300 mg of vedolizumab for induction followed by once every 4 weeks (Q4W) or 
Q8W for up to a total of 52 weeks and 488 subjects were administered 300 mg vedolizumab for 
induction only [21-23]. As of 20 July 2014, vedolizumab exposure has extended for ≥12 months in 
1667 subjects, ≥24 months in 1119 subjects, ≥36 months in 793 subjects, and ≥48 months in 
374 subjects.
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 300 mg 
infusion at Week 0 and Week 2 (induction) followed by either Q4W or Q8W from Week 6 through 
Week 52 (maintenance) demonstrated statistically significant differences in efficacy compared to 
placebo for both the induction phase and maintenance phase. The study met its primary endpoint 
for the induction phase, clinical remission at Week 6 but did not meet the second primary endpoint 
of enhanced clinical response (CDAI-100) at Week 6 in the overall population although the 
treatment difference favored vedolizumab. The study did meet its primary endpoint for the 
maintenance phase, clinical remission at Week 52, as well as important secondary endpoints, 
including enhanced clinical response at Week 52 and corticosteroid-free clinical remission at 
Week 52 [22].
In Study C13011, vedolizumab (300 mg infusion 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 were also 
demonstrated for the overall population and in the subgroup of subjects who were TNF-α 
antagonist naïve [23].


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Vedolizumab has shown an acceptable safety profile based on an analysis of safety data from both 
completed and ongoing studies (see current version of IB). In phase 1 and 2 clinical trials
(7 completed phase 1 studies in healthy subjects and 8 completed phase 1b/2 studies in UC or CD 
patients), there was no consistent evidence of any dose-toxicity relationships, and vedolizumab 
was well-tolerated. The majority of the safety data is from 3 well-controlled, phase 3 clinical 
studies that evaluated the safety of vedolizumab 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).
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 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). A total of 4% of vedolizumab-treated subjects and 3% of 
placebo-treated subjects experienced an infusion-related reaction. In C13006 and C13007, 10% of 
subjects were positive for antivedolizumab antibodies 16 weeks following the last dose of 
vedolizumab. Results from the clinical program to date do not suggest an increased risk for 
malignancy with vedolizumab treatment. Overall, the safety profile following long-term treatment 
with vedolizumab in C13008 is consistent with safety in the completed studies. 
Concomitant use of corticosteroids and/or conventional immunomodulators did not appear to be 
associated with any increased rate of infections based on the comparative rates of infections in the 
phase 3 trials among subjects who had and had not received these medications. 
As of 20 July 2014, a total of 14 on-study deaths (including 1 in a placebo-treated subject) were 
reported in the vedolizumab clinical development program, including the ongoing open-label 
long-term extension study C13008. The causes of death varied and detailed information can be 
found in the current version of the IB. 
Overall, vedolizumab was well tolerated in clinical studies.
4.2
Rationale for the Proposed Study
The current study is designed to further explore the effects of vedolizumab on mucosal healing as 
assessed by traditional colonoscopy, histology, and transmural bowel wall activity, via a substudy 
using magnetic resonance enterography (MREn).
Colonoscopy is used to evaluate CD disease extension and activity. Endoscopy has some 
drawbacks, including invasiveness, procedure discomfort, risk of bowel perforation, and relatively 
poor patient acceptance. The goals of imaging in CD include determination of anatomical location 


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and severity of disease, identification of complications such as fibrostenotics or penetrating 
disease, assessment of response to therapy, and identification of extraintestinal complication of the 
disease [28]. Because CD is thought to be a transmural disease, cross sectional imaging techniques 
such as magnetic resonance (MR) enterography and CT enterography are superior to 
ileocolonoscopy in their ability to assess the full thickness of the intestinal wall and disease 
processes extending deeper than the mucosa [29]. The search for techniques that allow disease 
extension and inflammation assessment with a minimally invasive approach has led to the study of 
MR in CD. MR enterography (MREn) is characterized by multi-parametric excellent soft tissue 
characterization and lack of ionizing radiation. The MREn activity index has been cited by authors 
and endorsed by European Crohn’s and Colitis Organisation as beneficial for assessment of 
healing of inflammatory lesions [1].
Histological evidence of mucosal healing has been shown with sustained reduction in the 
expression of inflammatory markers [11]. The present study will examine histology markers of 
inflammation related to mucosal disease. 
The current goals of CD treatment include: steroid-free sustained clinical remission; induction and 
maintenance of endoscopic mucosal healing; potential induction and maintenance of radiological 
healing; prevention of surgery; maintenance of normal GI function; and prevention of disability. 
To achieve these goals, the therapeutic regimen should be able to treat the underlying 
inflammation and heal the bowel.
Pharmacogenomic analysis may be conducted to evaluate the contribution of genetic variance on 
drug response, for example, its efficacy and safety. Participation of study subjects in 
pharmacogenomic sample collection is optional. As pharmacogenomics is an evolving science, 
currently many genes and their function are not yet fully understood. Future data may suggest a 
role of some of these genes in drug response and disease, which may lead to additional 
hypothesis-generating exploratory research on stored samples.
4.3
Risk:Benefit Assessment
The proposed Study MLN0002-3028 is designed to evaluate the efficacy and safety of 
vedolizumab IV in subjects with moderately to severely active CD. The dosing and administration 
regimen and study population in Study MLN0002-3028 are consistent with the approved 
vedolizumab IV label. 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 evaluate endoscopic remission at Week 26 as assessed by ileocolonoscopy. 
5.1.2
Secondary Objectives
Part A

To examine the relationship among endoscopic, imaging, histological, and clinical 
assessments of CD.

To evaluate endoscopic remission at Week 14.

To evaluate endoscopic response at Weeks 14 and 26.

To evaluate clinical response assessed by Crohn’s Disease Activity Index (CDAI) at Weeks 10 
and 26.

To evaluate clinical remission assessed by CDAI at Weeks 10 and 26.
Part B

To examine the relationship among endoscopic, imaging, histological, and clinical 
assessments of CD.

To evaluate endoscopic remission at Week 52.

To evaluate endoscopic response at Week 52.

To evaluate clinical response assessed by CDAI at Week 52.

To evaluate clinical remission assessed by CDAI at Week 52.

To evaluate durable endoscopic remission at Week 52 in patients with endoscopic remission at 
Week 26.
5.1.3
Additional Objectives 
Part A

To evaluate changes in transmural bowel wall activity and other measures of bowel wall 
inflammation using MREn at Week 26.

To assess histological response at Week 26.

To evaluate C-reactive protein (CRP) at Weeks 10 and 26.

To evaluate fecal calprotectin at Weeks 14 and 26.


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
To evaluate immunogenicity of vedolizumab. 

To evaluate health-related quality of life (as assessed by inflammatory bowel disease 
questionnaire [IBDQ] and Euro Quality of Life-5D [EQ-5D]) at Weeks 14 and 26.

To explore the relationship between endoscopic remission and health-related quality of life 
(QOL). 

To evaluate impact on loss of work productivity and activity impairment assessed by Work 
Productivity and Activity Impairment (WPAI):CD at Weeks 14 and 26.
Part B

To evaluate changes in transmural bowel wall activity and other measures of bowel wall 
inflammation using MREn at Week 52.

To assess histological response at Week 52.

To evaluate CRP at Weeks 38 and 52. 

To evaluate fecal calprotectin at Weeks 38 and 52.

To evaluate immunogenicity of vedolizumab. 

To evaluate clinical response assessed by CDAI at Weeks 38 and 46.

To evaluate clinical remission assessed by CDAI at Weeks 38 and 46.

To evaluate health-related quality of life (IBDQ and EQ-5D) at Weeks 38 and 52.

To explore the relationship between endoscopic remission and health-related QOL. 

To evaluate impact on loss of work productivity and activity impairment assessed by 
WPAI:CD at Week 52.
5.2
Endpoints
5.2.1
Primary Endpoints 
The primary endpoint is the proportion of subjects achieving endoscopic remission, defined as a 
simple endoscopic score for Crohn’s Disease (SES-CD) score of ≤4 at Week 26. 
5.2.2
Secondary Endpoints 
The secondary endpoints for Part A are:

Proportion of subjects achieving complete mucosal healing (defined as absence of ulceration) 
at Week 26.

Proportion of subjects achieving endoscopic remission at Week 14. 


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
Proportion of subjects with endoscopic response (defined as SES-CD reduction by ≥50%) at 
Week 14. 

Proportion of subjects with endoscopic response (defined as SES-CD reduction by ≥50%) at 
Week 26. 

Proportion of subjects achieving clinical response (CDAI decrease from Baseline of 
≥100 points) at Week 10. 

Proportion of subjects achieving clinical response (CDAI decrease from Baseline of 
≥100 points) at Week 26. 

Proportion of subjects achieving clinical remission (CDAI ≤150) at Week 10. 

Proportion of subjects achieving clinical remission (CDAI ≤150) at Week 26. 
The secondary endpoints for Part B are:

Proportion of subjects achieving complete mucosal healing (defined as absence of ulceration) 
at Week 52.

Proportion of subjects achieving endoscopic remission at Week 52. 

Proportion of subjects with endoscopic response (defined as SES-CD reduction by ≥50%) at 
Week 52. 

Proportion of subjects achieving clinical response (CDAI decrease from Baseline of 
≥100 points) at Week 52. 

Proportion of subjects achieving clinical remission (CDAI ≤150) at Week 52. 

Proportion of subjects with durable clinical remission, defined as clinical remission at 
Week 26 and Week 52.
5.2.3
Additional Endpoints 
The additional endpoints for Part A are: 

Change from Baseline to Week 26 in individual MREn parameters (including wall thickening, 
relative contrast enhancement, presence of ulcerations, presence of edema) for each 
ileocolonic segment and for more proximal bowel segments, if evaluable.

Proportion of subjects achieving Magnetic Resonance Index of Activity (MaRIA) score <7 at 
Week 26 globally and on a per segment basis. 

Proportion of subjects with 25% and 75% reduction of SES-CD at Weeks 14 and 26. 

Proportion of subjects with no granulocytes present in bowel biopsy at Week 26.

Proportion of subjects with a change in histology at Week 26. 


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
Proportion of subjects with elevated CRP at Baseline who achieve normalization of CRP at 
Weeks 10 and 26. 

Change from Baseline to Weeks 14 and 26 in fecal calprotectin.

Proportion of subjects positive for anti-vedolizumab antibody (AVA; also called human 
antihuman antibody [HAHA]) at Baseline, Week 26, and at the Postdose 18-week Safety
Follow-up Visit. 

Proportion of subjects with positive neutralizing AVA at Baseline, Week 26, and at the 
Postdose 18-week Safety Follow-up Visit. 

Change from Baseline to Weeks 14 and 26 in the IBDQ total and subscale scores. 

Change from Baseline to Weeks 14 and 26 in the EQ-5D utility score and visual analog scale 
(VAS) score. 

Change from Baseline to Weeks 14 and 26 in percent work time missed due to CD. 

Change from Baseline to Weeks 14 and 26 in percent impairment while working due to CD. 

Change from Baseline to Weeks 14 and 26 in percent overall work impairment due to CD. 

Change from Baseline to Weeks 14 and 26 in percent activity impairment due to CD. 

AEs, SAEs, vital signs, and laboratory tests. 
The additional endpoints for Part B are: 

Change from Baseline to Week 52 in individual MREn parameters (including wall thickening, 
relative contrast enhancement, presence of ulcerations, presence of edema) for each 
ileocolonic segment and for more proximal bowel segments, if evaluable.

Proportion of subjects achieving MaRIA score <7 at Week 52 globally and on a per segment 
basis. 

Proportion of subjects with 25% and 75% reduction of SES-CD at Week 52. 

Proportion of subjects with no granulocytes present in bowel biopsy at Week 52.

Proportion of subjects with a change in histology at Week 52. 

Proportion of subjects with elevated CRP at Baseline who achieve normalization of CRP at 
Weeks 38 and 52. 

Change from Baseline to Weeks 38 and 52 in fecal calprotectin.

Proportion of subjects positive for AVA at Week 52 and at the Postdose 18-week Safety 
Follow-up Visit (for subjects not transitioning into the Extended Access Program [XAP]
study). 


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
Proportion of subjects with positive neutralizing AVA at Week 52, at the Postdose 18-week 
Safety Follow-up Visit (for subjects not transitioning into the XAP study). 

Proportion of subjects achieving clinical response (CDAI decrease from Baseline of 
≥100 points) at Weeks 38 and 46. 

Proportion of subjects achieving clinical remission (CDAI ≤150) at Week 38 and 46. 

Change from Baseline to Weeks 38 and 52 in the IBDQ total and subscale scores. 

Change from Baseline to Weeks 38 and 52 in the EQ-5D utility score and VAS score. 

Change from Baseline to Week 52 in percent work time missed due to CD. 

Change from Baseline to Week 52 in percent impairment while working due to CD. 

Change from Baseline to Week 52 in percent overall work impairment due to CD. 

Change from Baseline to Week 52 in percent activity impairment due to CD. 

AEs, SAEs, vital signs, and laboratory tests.


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 3b single-arm, open-label multicenter study to evaluate the efficacy and safety of 
vedolizumab 300 mg IV infusion over a 26-week treatment period using ileocolonoscopy for the 
assessment in subjects with moderately to severely active CD (Part A) followed by a 26 
week-treatment extension period (Part B). Biopsies will be collected for histological assessments 
per the schedule of events for all subjects. The study will be conducted at sites in North America 
and Europe. The 26-week treatment extension (Part B) is included as part of Protocol Amendment 
No. 04 (dated 27 April 2016), ongoing subjects at the time of the amendment will have the option 
to either stop treatment at Week 26 (Part A) or continue treatment into Part B. Subjects who enrol 
into the study after Protocol Amendment No. 04 will be treated directly for 52 weeks (Part A and 
B).
Approximately 100 subjects with moderately to severely active CD who have failed treatment with 
corticosteroids, immunosuppressants, and/or biologics will be enrolled. Subjects who are TNF-α 
antagonist naïve as well as those who are TNF-α antagonist failures will be included, such that 
approximately 50% of enrolled subjects are TNF-α antagonist naïve. 
The study consists of a 4-week screening period, a 26-week treatment period (Part A), followed by 
a 26-week extension treatment period (Part B from Week 30 to 52 with last dose at Week 46), and 
an 18-week follow-up period following the last dose. The duration of the study will be 
approximately 44 weeks for subjects completing Part A, and 70 weeks for subjects completing 
Part B. All subjects included in the study will also have a 6-month safety follow-up telephone call 
following the last dose. End of trial will be the date of the last visit of the last subject at the 
Postdose 18-week Safety Follow-up visit. The Postdose 18-week Safety Follow-up visit is 
described in Section 9.3.4.
Subjects who consent to Part B will have the option to voluntarily enroll into an XAP study after 
the Final Visit or Week 52 of MLN0002-3028. Subjects who transition into the XAP study will not 
take part in the 18-week follow-up period or the 6-month safety follow-up telephone call following 
their last dose in MLN0002-3028. The end of trial will be the Week 52 visit for these subjects and 
the duration of the study will be approximately 56 weeks.
Subjects that meet all the inclusion criteria and none of the exclusion criteria will be dosed on site 
with vedolizumab 300 mg IV. Subjects will visit the site for dosing at Day 1, Weeks 2, 6, 14, and 
22 for Part A, and at Weeks 30, 38, and 46 for Part B. Ileocolonoscopy will be performed at the 
Screening, Weeks 14, 26 (Part A), and 52 (Part B) or early termination (ET) visits. Biopsies will be 
taken during the Screening, Weeks 26 (Part A), and 52 (Part B) or ET visit. All ileocolonoscopies 
will be evaluated by a central reader. 
An MREn substudy will be conducted at selected qualified centers using a standardized MR 
acquisition and procedure to assess bowel wall activity. Only subjects from the pre-selected sites 
will be included in this study; these subjects will undergo an MREn assessment at the Screening,


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Weeks 26 (Part A), and 52 (Part B) or ET visit, unless they have contraindications to the 
procedure. All MREn results will be evaluated by an independent central reader. 
Figure 6.a
Schematic of Study Design: For Subjects on 26 Weeks of Treatment
Days 
-28 to -1
Day 1
Part A
Weeks 2, 6, 10, 
14, 22, 26
Week 26
Postdose 18-week 
Safety Follow-up 
Visit
6-month Telephone 
Follow-up
Screening
1st dose
300 mg IV
300 mg IV
(all visits except 
Week 10 and 26)
Final Visit / Early 
Termination Visit
Figure 6.b
Schematic of Study Design: For Subjects on 52 Weeks of Treatment
Days 
-28 to -1
Day 1
Part A
Weeks 2, 6, 10, 
14, 22, 26
Part B
Weeks 30, 38, 
46
Week 52
Postdose 
18-week Safety 
Follow-up Visit
(a)
6-month 
Telephone 
Follow-up (a)
Screening
1st dose
300 mg IV
300 mg IV
(all visits 
except 
Week 10 and 
26)
300 mg IV
Final Visit / Early 
Termination Visit
(a) Not applicable for subjects who transition into the XAP study.
6.2
Justification for Study Design, Dose, and Endpoints
CD is a chronic inflammatory disorder of the GI tract. CD can impact any part of the digestive tract 
and symptoms commonly include abdominal pain, diarrhea, rectal bleeding, weight loss, and 
fever. The exact cause remains unknown. The aim of current CD treatments is to induce and 
maintain remission, or achieve extended periods of remission.
Treatment options include corticosteroids, antimetabolites (6-mercaptopurine, azathioprine, or 
methotrexate), and TNF-α antagonists. In 2013, results from the phase 3, randomized controlled 
C13007 trial demonstrated the efficacy of vedolizumab in inducing remission at Week 6 in adult 
subjects with moderately to severely active CD [22]. Results from the maintenance study C13007 
showed that vedolizumab maintained remission in the broad population with CD and in those who 
had failed treatment with TNF-α antagonists.
The objective of this study is to assess endoscopic remission at Week 26 after treatment with open 
label vedolizumab using ileocolonoscopy and histology as well as an assessment of CD activity in 
the bowel wall in a substudy using MREn. The study has been extended to 52 weeks to gather 
long-term mucosal healing data with vedolizumab. The study has the potential to guide the 
understanding of mucosal healing in CD subjects and the effect of vedolizumab. Subjects that meet 
the eligibility criteria will receive open-label vedolizumab 300 mg IV.


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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 one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objective or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an 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 first dose. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject 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 moderately to severely active CD at least 3 months prior to 
enrollment, with a CDAI score of 220-450 during the Screening Period, a SES-CD score of ≥7 
and presence of at least one mucosal ulceration documented by recorded ileocolonoscopy at 
Screening assessed by the central reader.
4. The subject has CD with involvement of the ileum and/or colon that can be assessed by 
ileocolonoscopy. 
5. The subject is male or female and aged 18 to 80 years, inclusive.
6. 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. 
7. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 18 weeks after last dose. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.10 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.11 Pregnancy.
8. The subject has demonstrated an inadequate response to, loss of response to, or intolerance of 
at least 1 of the following agents as defined below: 

Immunomodulators:
i.
The subject has signs and symptoms of persistently active disease despite a history 
of at least one 12-week regimen of oral azathioprine (≥1.5 mg/kg) or 
6-mercaptopurine (≥0.75 mg/kg), OR
ii. The subject has a history of intolerance (including but not limited to 
nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, 
lymphopenia, thiopurine S-methyltransferase non wild type [where wild type is 
defined as TPMT*1/*1], infection) to at least 1 immunomodulator.


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
TNF-antagonists:
i.
The subject has signs and symptoms of persistently active disease despite a history 
of at least 1 induction with:
a) Infliximab: 4-week regimen of 5 mg/kg, 2 doses at 2 weeks apart, OR
b) Adalimumab: 2-week regimen of 160 mg on Day 1 and 80 mg on Day 15, OR
c) Certolizumab: 4-week regimen of 400 mg initially at Weeks 0, 2, 4 OR
ii. The subject has recurrence of symptoms during maintenance dosing following 
prior clinical benefit (discontinuation despite clinical benefit does not qualify), OR
iii. The subject has a history of intolerance of infliximab, adalimumab, or 
certolizumab, including but not limited to, infusion-related reaction, 
demyelination, congestive heart failure, or infection.

Corticosteroids
i.
Signs and symptoms of persistently active disease despite a history of at least one 
4-week induction regimen that included a dose equivalent to prednisone 30 mg 
daily orally for 2 weeks or IV for 1 week, OR 
ii. Signs and symptoms of persistently active disease despite treatment with 
budesonide 9 mg daily or 6 mg daily for maintenance, OR
iii. At least one failed attempt to taper corticosteroids to below a dose equivalent to 
prednisone 10 mg daily orally, OR
iv. History of intolerance to corticosteroids (including, but not limited to, Cushing’s 
syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and infection).
9. The subject may be receiving a stable therapeutic dose of conventional therapies for CD as 
defined by protocol Section 7.3.1 (excluding other biologic agents 60 days before enrollment).
10. Subjects with a family history of colorectal cancer, personal history of increased colorectal 
cancer risk, age >50 years, or other known risk factors must be up-to-date on colorectal cancer 
surveillance (may be performed during Screening).
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received a diagnosis of ulcerative colitis or indeterminate colitis.
2. The subject has clinical evidence of abdominal abscess.
3. The subject has a history of >3 small bowel resections or diagnosis of short bowel syndrome. 
4. The subject has extensive colonic resection, ie, subtotal or total colectomy with <15 cm colon 
remaining.


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5. The subject has ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
6. The subject has a history or evidence of adenomatous colonic polyps that have not been 
removed. 
7. The subject has a history or evidence of colonic mucosal dysplasia. 
8. The subject has intolerance or contraindication to undergo ileocolonoscopy.
9. The subject has active or latent tuberculosis, regardless of treatment history, as evidenced by 
any of the following:
a) History of TB.
b) A diagnostic TB test performed during screening that is positive, as defined by:
i.
A positive QuantiFERON® test or 2 successive indeterminate QuantiFERON tests OR
ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in patients receiving the equivalent of 
>15 mg/day prednisone).
10. The subject has chronic hepatitis B (HBV) or hepatitis C (HCV) infection.
11. The subject has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
12. The subject has evidence of active C. difficile infection or is having treatment for C. difficile
infection or other intestinal pathogens during Screening.
13. The subject has evidence of an active infection during Screening.
14. The subject currently requires or has a planned surgical intervention for CD during the study.
15. The subject has received any investigational compound within 60 days of enrollment. 
16. The subject has received any biologics within 60 days of enrollment.
17. The subject has received any live vaccinations within 30 days prior to enrollment.
18. The subject has conditions which, in the opinion of the investigator, may interfere with the 
subject’s ability to comply with the study procedures.
19. 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.
20. The subject has a history of hypersensitivity or allergies to vedolizumab or its components.
21. The subject has had prior exposure to vedolizumab, natalizumab, efalizumab, or rituximab.
22. The subject had a surgical procedure requiring general anesthesia within 30 days prior to 
screening or is planning to undergo major surgery during the study period.


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23. The subject has a history of malignancy, except for the following: adequately-treated 
nonmetastatic basal cell skin cancer; squamous cell skin cancer that has been adequately 
treated and that has not recurred for at least 1 year prior to Screening; and history of cervical 
carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years 
prior to screening. Subjects with a 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 enrollment.
24. The subject has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, or neurodegenerative disease.
25. The subject has a positive PML subjective symptom checklist during Screening or prior to the 
administration of study drug on Day 1.
26. The subject has any of the following laboratory abnormalities during the Screening Period:
i.
Hemoglobin level <8 g/dL.
ii.
White blood cell (WBC) count <3 x 109/L.
iii.
Lymphocyte count <0.5 x 109/L.
iv.
Platelet count <100 x 109/L or >1200 x 109/L.
v.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x the upper 
limit of normal (ULN).
vi.
Alkaline phosphatase >3 x ULN.
vii.
Serum creatinine >2 x ULN.
27. 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 enrollment. 
28. The subject has an active psychiatric problem that, in the investigator’s opinion, may interfere 
with compliance with study procedures.
29. The subject is unable to attend all the study visits or comply with study procedures.
30. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 18 weeks after participating in this study; or intending to donate ova during such time 
period. 
31. If male, the subject intends to donate sperm during the course of this study or for 18 weeks 
thereafter. 
32. 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. 


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33. Subjects who are at sites participating in the MREn substudy may not participate if they have 
intolerance or contraindication to the procedure or if any of the following exclusions apply:
a) The subject has certain implanted medical devices, such as pacemakers or implantable 
cardioverter defibrillators (ICDs), or ferromagnetic metallic foreign bodies, such as 
shrapnel or certain tattoos. 
b) The subject has allergy to gadolinium-based MR IV contrast agents. 
c) The subject has known claustrophobia.
d) The subject has estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at 
Screening.
7.3
Excluded Medications and Treatments
The following medications are excluded from use during the study: 

Any treatment for CD other than those listed in Section 7.3.1 (either approved or 
investigational).

All live vaccines during the study treatment period and for 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). 
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 following medications are permitted during the study: 

Immunomodulators (methotrexate, azathioprine, 6-mercaptopurine), stable for at least 8 weeks 
prior to enrollment.

Oral 5-ASAs, probiotics, or antibiotics for CD, stable for at least 2 weeks prior to enrollment.

Anti-diarrheals for control of chronic diarrhea.
7.3.1.1
Oral Corticosteroid Dosing and Tapering 
The maximum dose of oral corticosteroids for the treatment of CD that may be co-administered 
with vedolizumab as a long-term regimen is 30 mg/day prednisone or 9 mg/day budesonide with 
6 mg/day for maintenance (or equivalent) as long as they have been stable for at least 4 weeks prior 
to enrollment or for 2 weeks prior to enrollment if being tapered. Short-term use of higher doses is 
acceptable; however, patients who require consistent higher doses should be withdrawn from the 
study. 


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It is strongly recommended that patients receiving oral corticosteroids should begin a tapering 
regimen once they either achieve clinical response or if, in the opinion of the Investigator, they 
have demonstrates sufficient improvement. The recommended 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. 

Budesonide should be reduced at a rate of 3 mg every 3 weeks.
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence, such premedication 
is unlikely to be necessary or beneficial. At the discretion of the investigator, however, subjects 
may be administered premedication prior to any study drug administration. Corticosteroids, if 
given as a premedication, should be limited to the day of administration. 
7.4
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the electronic case report form (eCRF) using the following 
categories. For screen failure subjects, refer to Section 9.1.20.
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.

Liver Function Test (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%).
2. Significant protocol deviation. The discovery after the first dose of study medication that the 
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health.


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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 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. 
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.11.
7. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
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 ET 
Visit. 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
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. 
Each vial will be packaged in an appropriately labeled single vial carton. 
Each carton will have a single-panel or multilingual booklet label that will contain, but will not be 
limited to the following: sponsor’s name and address, protocol number, packaging job/lot number, 
name and strength of the product, medication identification number, subject information, caution 
statement, directions for use, and storage conditions.
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 should be observed for 2 hours 
following the first 2 infusions, at a minimum, and one hour after each subsequent infusion in a 
room where appropriate treatment for infusion-related reactions is available. The subject should be 
considered clinically stable by the investigator or designee prior to discharge.
Additional reference information and administration instructions can be found in the pharmacy 
manual.
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). A daily temperature log of the drug 
storage area must be maintained every working day.
8.1.3
Dose and Regimen
The dose and dosing regimen for all subjects is provided in Table 8.a.


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Table 8.a
Dose and Regimen
Treatment Group
Dose
Treatment Description
All Subjects 
Vedolizumab IV 300 mg 
Open-label
Part A: Day 1, Weeks 2, 6, 14, 22
Part B: Weeks 30, 38, 46
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
Subjects will receive treatment according to the study schedule.
The investigator or investigator’s designee will access the interactive voice response system 
(IVRS)/interactive web response system (IWRS) at Screening to obtain the subject study number. 
The investigator or the investigator’s designee will utilize the IVRS/IWRS to enroll the subject 
into the study. The medication identification (ID) number of the investigational drug to be 
dispensed will then be provided by the IVRS/IWRS as well as at subsequent visits. If 
sponsor-supplied drug is lost or damaged, the site can request a replacement from IVRS/IWRS. 
Refer to the study manual provided separately for additional information. 
8.3
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee 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 investigator or designee must maintain 
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.


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Upon receipt of sponsor-supplied drug, the investigator or designee 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, investigator or designee 
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.
The investigator or designee 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:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed with the medication identification used to prepare each 
dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IVRS/IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs on a 
sponsor-approved drug accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, description 
of sponsor-supplied drugs, date and amount dispensed including initials, seal, or signature of the 
person dispensing the drug.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time of screening; this subject number will be used throughout the study.
9.1.1.1 Pharmacogenomic Informed Consent Procedure
A separate informed consent form pertaining to storage of any sample which may be used for 
pharmacogenomic analysis must be obtained prior to collecting for Pharmacogenomic Research 
for this study. The provision of consent to collect and analyze the pharmacogenomic sample is 
independent of consent to the other aspects of the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth or age, sex, Hispanic ethnicity 
(as applicable), 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.
In addition, all prior biologic medication history for the treatment of Crohn’s disease with the 
reason for discontinuation is to be collected for subjects where possible.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of investigational 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; 
(7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other. 
All subsequent physical examinations should assess clinically significant changes from the 
assessment prior to first dose examination.


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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. 
9.1.5
Vital Sign Procedure
Vital signs will include body temperature, respiratory rate, blood pressure, and pulse (bpm).
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, vitals are taken predose. 
9.1.6
Efficacy Measurements
Efficacy assessments will include ileocolonoscopy with biopsies (when applicable per the 
schedule of events) to evaluate endoscopic remission and histological response. MREn will be 
used to evaluate bowel wall activity for a subgroup of subjects. Only confirmed eligible subjects 
from the pre-selected sites will be included in the MREn substudy.
All efficacy assessments will be reviewed by independent central review. Additional information 
regarding the central reader assessments and collection and preparation of ileocolonoscopy tissue 
samples can be found in the Study Manual. 
Ileocolonoscopy tissue samples will be collected and stored for future analysis. 
9.1.6.1
Magnetic Resonance Enterography Substudy
The MREn will be conducted at selected sites qualified to perform MREn as assessed by the 
imaging core lab designated by the sponsor. A standardized MREn acquisition protocol will be 
implemented across sites and detailed in an Imaging Manual. eGFR to be assessed prior to MREn 
being performed. MREn will be performed prior to ileocolonoscopy. De-identified MREn images 
will be transmitted to the imaging core lab where they will be independently analyzed by expert 
reviewers. Variables evaluated may include, but are not limited to, wall thickness, enhancement of 
bowel wall after contrast, mural edema, ulcerations, and perienteric vascularity. Bowel 
assessments will be made in a segmental manner to allow for direct comparison with 
ileocolonoscopy assessments (terminal ileum plus ascending, transverse, descending and sigmoid 
colon, and rectum). More proximal small bowel may also be assessed for abnormalities on MREn 
only. Several MREn-based activity indices have been proposed and are undergoing validation 
[28,29]. One or more of these (including MaRIA) will be used to assess therapeutic response and 
will be compared to endoscopic response (SES-CD) and clinical response (CDAI) scores.


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9.1.7
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through to the 
final study visit), 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 screening or baseline examination. The 
condition (ie, diagnosis) should be described.
9.1.9
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures at the time 
points specified in the schedule of events. The maximum volume of blood at any single visit is 
approximately 35 mL, and the approximate total volume of blood for the study is 141 mL (94 mL 
for Part A and 47 mL for Part B). Details of these procedures and required safety monitoring will 
be given in the laboratory manual.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis (dipstick)
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 
eGFR (for MREn subjects only)
Bilirubin
Blood 
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein 
Specific Gravity 
Other:
HIV
Hepatitis panel, including HBsAg and anti-HCV
CRP
AVA
Pharmacogenomic sample 
Quantiferon for TB
Beta hCG and Urine Pregnancy hCG
(female subjects of childbearing potential)
FSH, if menopause is suspected
Stool:
Fecal calprotectin
FSH=follicle-stimulating hormone, GGT= γ-Glutamyl transferase, HBsAg=hepatitis B surface antigen, hCG=human 
chorionic gonadotropin, PT=prothrombin time, RBC=red blood cells.
A central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis as well as specialty testing outlined above. The results of safety laboratory tests will be 
returned to the investigator, who is responsible for reviewing and filing these results.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests should be performed by 
the central laboratory 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.)


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If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements).
9.1.10 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study medication, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period.
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with an FSH >40 IU/L or at least 5 years since last 
regular menses, confirmed before any study medication is implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
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:
Intrauterine devices (IUDs):
#Hormonal contraceptives:

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.
Barrier methods (eg, male condom PLUS spermicide, cap (plus spermicidal cream or jelly) PLUS 
male condom and spermicide, diaphragm (plus spermicidal cream or jelly) PLUS male condom 


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and spermicide) can be used each time the subject has intercourse in addition to methods listed in 
the table above to ensure acceptable protection level.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study.
During the course of the study, regular 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 donation as part of the study procedures (Appendix A). In addition to a 
negative hCG pregnancy test at Screening, subjects also must have a negative hCG pregnancy test 
prior to receiving any dose of study medication. 
9.1.11 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 18 weeks after the last dose (for subjects not 
transitioning into the XAP study), should also be recorded following authorization from the 
subject’s partner.
If the pregnancy occurs during administration of study medication or within 18 weeks of the last 
dose of study medication, the pregnancy should be reported immediately, using a pregnancy 
notification form, to the contact listed in Section 1.0.
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 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received.
All pregnancies in subjects on active study drug will be followed up to final outcome, using the 
pregnancy form. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted.
9.1.12 ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. 
9.1.13
Immunogenicity Sample Collection 
Blood specimens for the assessment of AVA will be collected as shown in the schedule of events. 
A sample will be assessed for neutralizing AVA if a positive AVA is detected. 
Serum titers of AVA will be determined using a validated assay. Neutralizing AVA will be 
determined using a validated assay. 


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Please refer to the Study Manual for information on sample collection and preparation.
9.1.14
Pharmacogenomic Sample Collection
When sampling of whole blood for pharmacogenomic analysis occurs, every subject must sign 
informed consent/be consented in order to participate in the study. 
Two whole blood samples (3 mL per sample) for deoxyribonucleic acid (DNA) isolation will be 
collected before dosing on Day 1 from each subject in the study, into plastic K2 
ethylenediamine-tetraacetic acid (EDTA) spray-coated tubes, and stored under frozen conditions. 
Two whole blood RNA samples (2.5 mL per sample) for RNA pharmacogenomic analysis will be 
collected on Day 1 from each subject in the study, into a PaxGeneTM tube. If DNA or RNA samples 
are not obtained on Day 1, they may be collected at any point in the study.
DNA forms the basis for the genes that make the body produce proteins such as enzymes, drug 
transporters or drug targets. RNA has multiple vital roles in the codes, decoding, regulation, 
expression of genes and sensing and communicating responses to cellular signals. Both DNA and 
RNA from tissues such as blood may be evaluated for the genetic contribution of how the drug is 
broken down, or how the drug affects the body. This is called a “Pharmacogenomics research 
study.” Specific purposes of this study include:

Identifying genetic reasons why certain people respond differently to vedolizumab.

Finding out more information about how vedolizumab works.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to vedolizumab.

Identifying variations in genes related to the biological target of vedolizumab.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of vedolizumab and other study medications, and for improving the efficiency, design and 
study methods of future research studies.
If necessary and feasible, a second aliquot of blood may be taken if isolation of DNA from the first 
sample was not successful or possible. Please refer to the Study Manual for information on sample 
collection and preparation.
The samples will be stored for no longer than 15 years after completion of the study. No samples 
will be stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification from Takeda. “Stored samples” are defined as samples that are key-coded (the 
samples are stripped of all personal identifying information but a key links the samples to the 
clinical data collected from the sample donor) and are used in the analysis of investigational drug 
or related drugs.
Detailed instructions for the handling and shipping of samples are provided in Appendix G.


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9.1.15 Tuberculosis Screening 
All subjects will complete TB screening to determine eligibility. All subjects must complete a 
diagnostic test during screening either a QuantiFERON® test or a tuberculin skin test. Subjects will 
be excluded from the study if they have active or latent TB, regardless of treatment history, as 
defined in Section 7.2. 
9.1.16 PML Checklist 
Clinic staff will administer the subjective PML checklist during screening to exclude subjects with 
positive responses from enrolling into the study. The subjective PML checklist will be 
administered (prior to dosing) at each visit, as shown in Appendix A, to evaluate symptoms 
suggestive of PML. Any subjects reporting signs or symptoms of PML will undergo 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 referenced in Section 11.1.1. 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. 
9.1.17 Crohn’s Disease Activity Index
A CDAI score will be evaluated during screening to determine eligibility, using subject diary 
entries within 14 days prior to enrollment, and hematocrit results collected during Screening. A 
CDAI score will also be derived at the time points specified in the Schedule of Events and at any 
unscheduled visit(s) due to disease exacerbation. See Appendix E.
9.1.18 Diary Completion and Review
Diary entries will be made daily by subjects and will be used for CDAI score calculation. During 
screening, subjects will be instructed on how to appropriately complete the daily diary. The 
symptoms of CD must be recorded throughout the study, including the screening period. Diary 
entries will be made daily by the subject through an electronic system. Entries should be reviewed 
and monitored by the study staff. 
9.1.19 Patient Reported Outcome Measures 
Subjects will complete the IBDQ and EQ-5D health related QOL questionnaires at the time points 
specified in the schedule of events. Subjects will also complete the WPAI:CD to assess the impact 
on loss of work productivity and activity impairment.
9.1.19.1 Inflammatory Bowel Disease Questionnaire
The IBDQ is a valid and reliable [30] instrument used to assess quality of life in adult patients with 
IBD. It includes 32 questions on 4 domains of health-related quality of life (HRQOL): Bowel 
Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic 
Function (5 items). Patients are asked to recall symptoms and quality of life from the last 2 weeks 
and rate each item on a 7-point Likert scale (higher scores equate to higher quality of life). A total 


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IBDQ score is calculated by summing the scores from each domain; the total IBDQ score ranges 
from 32 to 224.
9.1.19.2 EQ-5D Questionnaire
The EQ-5D questionnaire, developed by EuroQol, is a simple, valid, and reliable [31,32]
instrument used to measure general health-related quality of life in patients and includes five 
domain items - mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
Patients choose the level of health problems they currently have on each item as “None”, 
“Moderate”, or “Extreme” and are scored a 1, 2, or 3, respectively. A composite EQ-5D score can 
be calculated from the individual scores to assess overall HRQOL. The EQ-5D VAS score is a 
self-assigned rating of overall health using a 20 cm visual, vertical scale, with a score of 0 as the 
worst and 100 as best possible health. The EQ-5D total score and EQ-5D VAS score have been 
shown in many studies to be valid and reliable instruments for measuring HRQOL in patients with 
GI diseases.
9.1.19.3 Work Productivity and Activity Impairment-CD
The WPAI questionnaire is a valid and reliable [33,34] 6-item instrument that consists of four 
metrics: absenteeism (the percentage of work time missed because of one’s health in the past seven 
days), presenteeism (the percentage of impairment experienced while at work in the past seven 
days because of one’s health), overall work productivity loss (an overall impairment estimate that 
is a combination of absenteeism and presenteeism), and activity impairment (the percentage of 
impairment in daily activities because of one’s health in the past seven days). The sum of specific 
health problem impairment and impairment due to other health reasons is equal to impairment due 
to all health reasons. WPAI outcomes are expressed as impairment percentages, with higher 
numbers indicating greater impairment and less productivity, ie, worse outcomes. WPAI-CD is the 
specific disease version of the questionnaire.
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 IVRS/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 <specify reason>.

Study termination.


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
Other <specify reason>.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.21 Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the treatment phase.
If the subject is found to be not eligible for treatment phase, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
If a subject is persistently noncompliant with the study medication, it may be appropriate to 
withdraw the subject from the study. All subjects should be reinstructed about the dosing 
requirement during study contacts. The authorized study personnel conducting the re-education 
must document the process in the subject source records.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening 
Subjects will be screened within 28 days prior to enrollment. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.20 for procedures for documenting screening failures.
Procedures to be completed at Screening can be found in the schedule of events. 
9.3.2
Enrollment
Enrollment will take place on Day 1. If the subject has satisfied all of the inclusion criteria and 
none of the exclusion criteria, the subject should be enrolled using the IVRS/IWRS. Subjects will 
be instructed on when the first dose of investigational drug will be given as described in 
Section 6.1. The procedure for documenting screening failures is provided in Section 9.1.20.
9.3.3
Final Visit or Early Termination
The Final Visit will be performed on Week 52 or at ET. Subjects who are not participating in the 
26-week treatment extension (Part B) will have the Final Visit performed at Week 26.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.


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9.3.4
Postdose 18-Week Safety Follow-up
Upon receipt of the last dose of study drug (completers and ETs), all subjects not transitioning into 
the XAP study will complete a safety follow-up visit 18 weeks postdose.
Assessments will be completed per the schedule of events for the Postdose 18-week Safety 
Follow-up visit. 
Subjects who transition into the XAP study do not need to attend the Postdose 18-week Safety 
Follow-up Visit in MLN0002-3028. The safety of these subjects will be monitored as part of the 
XAP study.
9.3.5
Poststudy Long-term Follow-up 
Upon completion of or early termination from the study, all subjects not transitioning into the XAP 
study will participate in a 6-month follow-up safety questionnaire. The questionnaire will be 
administered at 6 months from the last dose of study drug. 
Subjects who transition into the XAP study do not need to take part in the Poststudy Long-term 
Follow-up survey in MLN0002-3028. The safety of these subjects will be monitored as part of the 
XAP study.
9.3.6
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.
Subjects will have the option to transition to the XAP study for continued access to vedolizumab
provided that:
1. Vedolizumab is not currently available to the subject through commercial channels, including 
reimbursement for the subject’s particular clinical scenario, and 
2. In the opinion of the investigator, the subject will continue to derive benefit from vedolizumab 
and continued treatment with vedolizumab is desired because there is no other comparable 
product available, or the subject may be expected to develop worsening of disease if they were 
to modify treatment.
9.3.7
Unscheduled Visits Due to Disease Exacerbation 
Subjects who are seen by the investigator or site staff at a time point not required by the protocol 
(ie, unscheduled visit) due to disease exacerbation will undergo the following: 

Physical examination. 

Vital Signs assessment. 

Diary review. 

Neurological examination. 


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
Collection of concomitant medications and procedures.

Collection of AEs and SAEs.

Clinical chemistry and hematology, as indicated.

CDAI. 

AVA sample collection. 
There is no minimum time for repeat evaluation by unscheduled visit in order to determine if a 
subject meets the criteria for disease worsening. In general, however, enough time should be 
provided for clinically meaningful change to occur (eg, 1 week). 
9.4
Biological Sample Retention and Destruction 
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.14. 
After extraction and purification, the genetic material will be preserved and retained for up to but 
not longer than 15 years or as required by applicable law. The sponsor has put into place a system 
to protect the subjects’ personal information to ensure optimal confidentiality and defined standard 
processes for sample and data collection, storage, analysis, and destruction.
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The sponsor and researchers working with the sponsor will have access to 
the samples collected and any test results. All samples collected during the study will be stored 
securely with limited access and the sponsor will require anyone who works with the samples to 
agree to hold the research information and any results in confidence.
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided pharmacogenomic samples can withdraw their consent and 
request disposal of a stored sample at any time. Notify sponsor of consent withdrawal.
In this study, ileocolonoscopy tissue samples will be preserved and retained for up to but not 
longer than 15 years or as required by applicable law. The sponsor has put into place a system to 
protect the subjects’ personal information to ensure optimal confidentiality and defined standard 
processes for sample and data collection, storage, analysis, and destruction.
The tissue samples will be sent to a central laboratory that serves as a secure storage facility. The 
sponsor and researchers working with the sponsor will have access to the samples collected. All 
samples collected during the study will be stored securely with limited access and the sponsor will 
require anyone who works with the samples to agree to hold the research information in 
confidence.


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The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided ileocolonoscopy tissue samples can withdraw their consent 
and request disposal of a stored sample at any time. Notify sponsor of consent withdrawal.


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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 vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
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. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.


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
Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute liver failure
Hepatic necrosis
Acute renal failure
Malignant hypertension
Acute respiratory failure/acute respiratory distress 
syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Agranulocytosis
Pulmonary fibrosis 
Anaphylactic shock
Pulmonary hypertension
Aplastic anemia
Spontaneous abortion / stillbirth and fetal death
Confirmed or suspected endotoxin shock
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Confirmed or suspected transmission of infectious 
agent by a medicinal product
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Convulsive seizure
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Special Interest AEs
A Special Interest Adverse Event (serious or 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.
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 – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE eg, 
the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE.

Dose Interrupted – the dose was interrupted due to the particular AE.


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10.1.13
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by one 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

Start of AE collection: AEs must be collected from start of study medication administration. 

End of AE collection: for subjects who do not transition into the XAP study AEs must be 
collected for 18 weeks following the last dose of study medication. If the subject is transitioned 
into the XAP study AEs must be collected until the Final Visit, Week 52. 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication or until 
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. Routine collection of AEs will continue until 18 weeks after last dose for subjects not
transitioning into the XAP study. For subjects who transition into the XAP study, routine 
collection of AEs will continue until the Final Visit, Week 52.


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10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date.
3. Severity.
4. Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related) (not completed for PTEs).
5. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
6. Action concerning study medication (not applicable for PTEs).
7. Outcome of event.
8. Seriousness.
Several QOL instruments will be used in this study (eg, IDBQ, EQ5D, WPAI:CD). They will not 
be used as a primary means to collect AEs. However, should the investigator become aware of a 
potential AE through the information collected with this instrument, proper follow-up with the 
patient for medical evaluation should be undertaken. Through this follow-up if it is determined that 
an AE not previously reported has been identified, normal reporting requirements should be 
applied.
10.2.1.3 Adverse Event Collection Involving Medically Anticipated Clinical Events 
Crohn’s Disease is associated with certain characteristic signs and symptoms including diarrhea, 
rectal bleeding, 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. 


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Exacerbations of disease activity (eg, increase in the daily amount of rectal bleeding or 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, arthalgia, arthritis, uveitis) that develop 
or worsen during the study are considered AEs. 
10.2.1.4 Special Interest AE Reporting
If this special interest AE, which occurs during the treatment period or the follow-up period, is 
considered to be clinically significant based on the criteria below, it should be recorded in the 
Special Interest AE eCRF or SAE Form. The applicable form should be completed and reported to 
the SAE reporting contact in Section 1.1 within 24 hours.
Hypersensitivity Reactions 
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence such 
premedications are unlikely to be necessary or beneficial. At the discretion of the investigator, 
however, subjects may be administered premedication prior to any study drug administration. 
Corticosteroids, if given as a premedication, should be limited to the day of administration. 
Vedolizumab should be administered by 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 one hour after each subsequent infusion.
Subjects should be instructed to report the development of rash, hives, pruritus, flushing, urticaria, 
etc. that may represent an infusion-related reaction to study medication. If signs or symptoms of 
infusion-related reaction are observed during the administration of study drug, 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) at the 
discretion of the Investigator. Subjects with severe or serious infusion-related reactions (eg, 
stridor, angioedema, life-threatening change in vital signs) must be withdrawn from the study. 
In all cases of administration-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. 
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 x 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 x 109/L. If the 
absolute lymphocyte count remains <0.5 x 109/L, study drug should be discontinued and the 
patient withdrawn from the study. 


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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 hepatoxicity and PML, which are discussed in Sections 10.2.3
and 11.1.1 respectively. 
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE eCRF or Form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE eCRF should be completed within 24 hours of first onset or notification of the event. 
However as a back-up, if required, the SAE Form should be completed and reported to Takeda 
Pharmacovigilance or designee within 24 hours to the attention of the contact listed in Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.


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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 (LFTI) 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 LFTI eCRF must be 
completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), 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
No data safety monitoring committee will be used in this study. 
11.1
Adjudication Committee 
A PML Independent Adjudication Committee (IAC) will be instituted for this study. The PML 
IAC will consist of a panel of leading PML experts, including a neurologist, neuroradiologist, and 
a virologist. 
11.1.1 Risk Minimization Action Plan for PML (RAMP Program)
Natalizumab (TYSABRI), another integrin receptor antagonist, has been associated with 
progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection 
of the central nervous system. PML is caused by the John Cunningham virus (JCV) and typically 
only occurs in patients who are immunocompromised [24,25]. Natalizumab is a pan-4 integrin 
antagonist that binds to both the α4β1 and α4β7 integrins and inhibits cellular adhesion to VCAM-1 
and MAdCAM-1 [26,27]. In contrast, vedolizumab binds to the α4β7 integrin only [20] 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 each dose of study drug using a PML subjective 
symptom checklist. Subjects with a positive PML subjective symptom checklist at any time after 
enrollment in a vedolizumab clinical study will be evaluated according to a prespecified algorithm 
(the PML Case Evaluation Algorithm). The 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 
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 RECORDKEEPING
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 
(WHO) 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 eCRFs. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
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), 
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 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 


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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. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
13.1.1 Analysis Sets
The Part A analyses will be performed on the following analysis sets:

The full analysis set (FAS) will include all enrolled subjects who receive at least 1 dose of 
study drug.

The FAS-MREn is the FAS within the MREn substudy. 

The modified full analysis set (mFAS) is a subset of the FAS and consists of all subjects who 
do not violate the terms of the protocol in a way that would impact the study outcome 
significantly.

The per protocol analysis set (PPS) is a subset of the FAS and consists of all subjects who do 
not deviate the terms of the protocol in a way that would impact the study outcome 
significantly.
The Part B analyses will performed on the following analysis sets:

The FAS-Extension is the subset of subjects in the FAS who continue into Part B.

The FAS-MREn-Extension is the subset of subjects in the FAS-MREn who continue into 
Part B.

The mFAS-Extension is the subset of subjects in the mFAS who continue into Part B.

The PPS-Extension is the subjects of subjects in the PPD who continue into Part B.
Significant protocol violations and significant protocol deviations will be identified prior to 
database lock.
The FAS and FAS-Extension will be used in both efficacy and safety analyses. The FAS-MREn 
and FAS-MREn-Extension will be used in the MREn analyses. Analyses using mFAS, 
mFAS-Extension, PPS, and PPS-Extension populations may be provided as sensitivity analyses.
Sensitivity analyses using PPS/PPS-Extension will be conducted only if more than 15% of the 
subjects in the FAS/FAS-Extension have at least 1 significant protocol deviation.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized. For continuous variables, summary 
statistics (non-missing values, mean, median, SD, minimum and maximum) will be generated. For 
categorical variables, the counts and percentages of each possible value will be generated. 


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Medical history and concurrent medical conditions will be summarized by system organ class and 
preferred term. Medication history and concomitant medications will be summarized by preferred 
term.
13.1.3 Efficacy Analysis
All proportion-based efficacy endpoints will be summarized by presenting the point estimate and 
95% confidence intervals for the proportion. All subjects with missing data for determination of 
endpoint status will be considered as a non-responder in the analysis.
All change from baseline efficacy endpoints will be summarized descriptively by time point. 
The correlation between change from Baseline in CDAI, change from Baseline in SES-CD, 
change from Baseline in MaRIA, and change from Baseline in histology score will be explored. 
The relationship between SES-CD and MREn-based indices will be assessed at both the subject 
and intestinal segment levels. The relationship between the various remission statuses as defined 
by CDAI, endoscopic, imaging, and histological assessments will also be explored. 
Change from baseline in QOL measures will be summarized descriptively overall and also by 
endoscopic remission status.
13.1.4 Pharmacogenomic Analysis
In the event that pharmacogenomic analysis is undertaken, the following will apply.

RNA / DNA-profiling and testing from tissues.
Further details will be outlined in the Pharmacogenomics Statistical Analysis Plan.
13.1.5 Other Analysis
The proportion of subjects with positive AVA and proportion of subjects with positive neutralizing 
AVA during the study will be summarized. The impact of AVA on efficacy and safety may be 
explored. 
13.1.6 Safety Analysis
Safety analysis will be performed using the FAS.
The number and percentage of subjects with treatment-emergent adverse events 
(treatment-emergent adverse events [TEAEs]; defined as any AEs, regardless of relationship to 
study drug), AEs of special interest (ie, PML, malignancies, infusion reactions, infection, 
hypersensitivity, leukopenia, lymphopenia, hepatotoxicity), AEs leading to discontinuation, and 
SAEs that occur on or after the first dose date and up to 18 weeks after the last dose date of the 
study drug, or until the Final Visit, Week 52 (if the subject is transitioned into the XAP study), will 
be summarized by MedDRA System Organ Class, High Level Term, and Preferred Term overall, 
by severity, and by relationship to study drug. Separate summaries will also be generated for 
treatment-related AEs overall and by severity. 


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Change from Baseline in clinical laboratory tests and vital signs will be summarized. Subjects with 
markedly abnormal values for laboratory tests and vital signs will be tabulated.
Physical examination findings and PML checklist data will be presented in data listings.
13.2
Interim Analysis and Criteria for Early Termination
Three interim analyses will be conducted for final efficacy at Weeks 14, 26 and 52, and for safety.
Further details about the endpoints to be analyzed at each interim analysis will be outlined in the 
SAP.
13.3
Determination of Sample Size
A sample size of 100 subjects will be sufficient to provide a 95% confidence interval based on 
normal approximation for the primary endpoint (endoscopic remission rate at Week 26) that 
extends no more than 10% in each direction from the estimated rate.


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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 Food and Drug Administration [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 once the sponsor has confirmed 
the adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the trial. Until the site receives notification no 
protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
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 American 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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Tysabri (natalizumab) injection. Full Prescribing Information. Cambridge, MA: Biogen 
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Stenson WF. Inflammatory Bowel Disease. In: Yamada T, Alpers DH, Laine L, Owyang 
C, Powell DW, editors. Textbook of Gastroenterology. 3rd ed. Philadelphia, PA: 
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Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, et al. Human 
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Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. Expression 
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Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and 
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2009;330(3):864-75.
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Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. 
Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 
2013;369(8):699-710.
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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 
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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. 
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Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory 
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Steiner I, Berger JR. Update on progressive multifocal leukoencephalopathy. Curr Neurol 
Neurosci Rep 2012;12(6):680-6.
26.
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 
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27.
TYSABRI (natalizumab) injection. Full Prescribing Information. Cambridge, MA: Biogen 
Idec Inc., Revised June 2013.
28.
Pola S, Santillan C, Levesque BG, Feagan BG, Sandborn WJ. An Overview of Magnetic 
Resonance Enterography for Crohn’s Disease. Dig Dis Sci 2014.
29.
Ordas I, Rimola J, Rodriguez S, Paredes JM, Martinez-Perez MJ, Blanc E, et al. Accuracy 
of magnetic resonance enterography in assessing response to therapy and mucosal healing 
in patients with Crohn’s disease. Gastroenterology 2014;146(2):374-82 e1.
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.
Stark RG, Reitmeir P, Leidl R, Konig HH. Validity, reliability, and responsiveness of the 
EQ-5D in inflammatory bowel disease in Germany. Inflamm Bowel Dis 2010;16(1):42-51.
32.
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.
33.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics 1993;4(5):353-65.
34.
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.
35.
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.
36.
Daperno M, D’Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. 
Development and validation of a new, simplified endoscopic activity score for Crohn’s 
disease: the SES-CD. Gastrointest Endosc 2004;60(4):505-12.


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Appendix A
Schedule of Events
Screening
Treatment
Final 
Visit or 
ET
Postdose 
Follow-up 
visit (p)
Part A
Part B
Study Day/Week:
Days -28 
to -1
Day 
1
Week 
2
Week 
6
Week 
10
Week 
14
Week 
22
Week
26 (a)
Week 
30
Week 
38
Week 
46
Week 
52
18-week 
Safety 
Follow-up
Visit Windows (Days):
±3
±3
±3
±7
±3
±7
±7
±7
±7
±7
±7
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
Informed consent
X
Inclusion/exclusion criteria
X
X (b)
Demographics /medical and 
medication history/ concurrent 
medical conditions
X
CD prior biologics history (c)
X
Physical examination
X
X (b)
X (b)
X
X (b)
X
X (b)
X(b)
X (b)
X
X
Vital Signs 
X
X (b)
X (g)
X (b)
X (b)
X (b)
X
X(b)
X(b)
X(b)
X
X
Height and weight (d)
X
X
X
X
X
X
X
X
X
X
CDAI 
X (e)
X (f)
X (f)
X
X (f)
X(f)
X(f)
X
X(f)
Patient diary
X
X
X
X
X
X
X
X
X
X
X
X
Ileocolonoscopy (g)
X
X
X
X
MREn (h)
X
X
X
Sample Collection:
Fecal calprotectin (i)
X
X
X
X
X
Tuberculosis screening (j)
X
Hematology
X (k)
X (b)
X (b)
X
X(b)
X
X(b)
X
X
Footnotes are on last table page.


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Appendix A
Schedule of Events (continued)
Screening
Treatment
Final 
Visit or 
ET
Postdose
Follow-up 
visit (p)
Part A
Part B
Study Day/Week:
Days -28 
to -1
Day 
1
Week 
2
Week 
6
Week 
10
Week 
14
Week 
22
Week 
26 (a)
Week 
30
Week 
38
Week 
46
Week 
52
18-week
Safety 
Follow-up
Visit Windows (Days):
±3
±3
±3
±7
±3
±7
±7
±7
±7
±7
±7
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
Clinical chemistry
X (k)
X (b)
X
X(b)
X
X
Serum creatinine (for MREn)
X (l)
X(l)
Urinalysis
X
X
X
AVA
X (b)
X
X
X
CRP
X
X (b)
X
X
X
X
Pharmacogenomic DNA and 
RNA samples (m)
X (b)
Pregnancy testing (n)
X
X (b)
X (b)
X (b)
X
X (b)
X (b)
X
X (b)
X (b)
X (b)
X
X
QOLs
X (b)
X (b)
X
X
X
WPAI:CD
X (b)
X (b)
X
X (b)
X
ECG
X
Dosing (IV)
X
X
X
X
X
X
X
X
PML Checklist (b)
X
X
X
X
X
X
X
X
X
X
X
X
PML Wallet Card
X
X (o)
X (o)
Concomitant medications / 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
PTE assessment
X
X(b)
AE/SAE assessment
X
X
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.


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(a) Week 26 is the final visit for subjects completing at Week 26 (Part A) and for subjects who continue to extension of treatment (Part B) this is a standard visit.
(b) Assessment completed or sample taken pre-dose.
(c) Collect prior biologic medications that stopped prior to screening.
(d) Height collected only at the Screening Visit.
(e) The components of the CDAI score to determine eligibility must be completed within 14 days prior to enrollment using hematocrit results collected during 
Screening.
(f) CDAI score components are to be performed prior to dosing; the total CDAI score will be calculated once results are available for all components.
(g) Biopsies to be collected at Screening, Week 26, and Week 52/ET for those completing the study.
(h) MREn conducted only at pre-identified sites. During the Screening period MREn should be performed prior to ileocolonoscopy. At Week 26 and Week 52 
MREn to be performed prior to ileocolonoscopy either on the same day or at least 7 days before the ileocolonoscopy within the permitted time window for Week 26 
or Week 52 procedures. Sites participating in MREn will need to check eGFR prior to procedure at Screening, Week 26, and Week 52 (using eGFR calculated from 
the Week 22 Visit for the Week 26 MREn and from the Week 46 Visit for the Week 52 MREn).
(i) Stool sample to be collected and sent to central laboratory for evaluation of fecal calprotectin. 
(j) QuantiFERON® test or tuberculin skin test only.
(k) Hepatitis and HIV testing only done at the Screening Visit.
(l) Only subjects participating in MREn to have a sample for serum creatinine collected at Week 22 and Week 46. Samples will be sent to central laboratory for 
evaluation of eGFR.
(m) DNA and RNA samples will be collected on Day 1 only for subjects that have consented to the Pharmacogenomic study.
(n) Serum pregnancy completed at Screening and at the Postdose 18-week Safety Follow-up Visit (where applicable); urine pregnancy to be completed at other 
visits. 
(o) Long-term Follow-up Wallet card will be given to subjects at the last clinical visit.
(p) Not required for subjects transitioning from MLN0002-3028 into the XAP study.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on Investigators from the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572) which must be completed and 
signed before the Investigator may participate in this study. 
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
6. 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.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. 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.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
(e)CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. 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.


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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) That personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) It is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) That personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) That subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and


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e) That the subject’s identity will remain confidential in the event that study results are 
published.
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening throughout the duration of the study. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study medication will be discontinued and the investigator 
will offer the subject the choice to receive unblinded treatment information.
26. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening throughout the duration of the study. If the partner or wife of the subject is found to 
be pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix E
Crohn’s Disease Activity Index (CDAI)
Category
Count
Initial 
Total
Multiplication 
Factor
Total
Number of liquid or very soft 
stools
7-day total number of liquid or very soft 
stools (reported on the 7 days immediately 
prior to the study visit)
2
Abdominal pain
7-day total of daily abdominal pain scores 
on a 3-point scale: 0 = none, 1 = mild, 
2 = moderate, 3 = severe (reported on the 7 
days immediately prior to the study visit)
5
General well being
7-day total of daily general well-being 
scores on a 4-point scale: 0 = generally 
well, 1 = slightly under par, 2 = poor, 
3 = very poor, 4 = terrible (reported on the 
7 days immediately prior to the study visit)
7
Extra-intestinal 
manifestations of Crohn’s 
Disease 
Total number of checked boxes (check all
that apply):
Arthritis/arthralgia
Iritis/uveitis
Erythema nodosum/pyoderma 
gangrenosum/aphthous stomatitis
Anal fissure, fistula, or abscess
Other fistula
Fever over 37.8°C during past week
20
Lomotil/Imodium/opiates for 
diarrhea
Yes = 1
No = 0
30
Abdominal mass
None = 0
Questionable = 2
Definite = 5
10
Hematocrit (%) (a)
Males: subtract value from 47
Females: subtract value from 42
6
Body Weight (b)
(1 – (Body weight/
Standard Weight)) 100 
1
Final Score
Add totals:
Source: Adapted from: Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s disease activity 
index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70 (3):439-44 [35].
(a) If hematocrit subtotal < 0, enter 0.
(b) If body weight subtotal < -10, enter -10.


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Appendix F
Simple Endoscopic Score for Crohn’s Disease (SES-CD)
Source: Adapted from Daperno M, D’Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development 
and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc 
2004;60(4):505-12 [36].


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Appendix G
Collection, Storage, and Shipment of Pharmacogenomic Samples 
Instructions for processing and shipping of plasma samples for DNA pharmacogenomics
1. Collect two tubes of venous blood (3 mL per tube) into a plastic tube containing K2EDTA.
2. Mix immediately by gently inverting the tube several times (at least 8-10 times) to mix the 
additive with the collected blood.
3. Freeze immediately at -70°C until shipment. If a -70°C freezer is not available, freeze 
immediately at -20°C. 
4. Ship samples frozen on dry ice with preprinted air-bill per the instructions in the laboratory 
manual.
Instructions for processing and shipping of whole blood samples for RNA 
pharmacogenomics 
1. Ensure that the PAXGeneTM Blood RNA Tube is at room temperature prior to collection.
2. Collect the venous blood into 2 plastic PAXGeneTM Blood RNA 2.5 mL tubes for each 
timepoint.
3. Mix immediately by gently inverting the tube several times (at least 8-10 times) to mix the 
additive with the collected blood.
4. Keep tubes on ice while collecting then store in refrigerator (2-8°C) for up to 3 days.
5. Then freeze at -70°C until shipment. If a -70°C freezer is not available, freeze at -20°C. 
6. Ship samples frozen on dry ice with preprinted air-bill per the instructions in the laboratory 
manual.
The storage provider has validated procedures in place for transport, delivery, retention, retrieval, 
and destruction of the specimens, and will appropriately retain the specimens for up to but not 
longer than 15 years as required by applicable law.


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Appendix H
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 05 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Allow all subjects (who complete Part B) in countries where vedolizumab is either not 
commercially available or is not reimbursed, continued access to vedolizumab by transition into an 
Extended Access Program (XAP), Vedolizumab-4013.
The primary change occurs in Section 6.1 Study Design
Added text:Subjects who consent to Part B will have the option to voluntarily enroll into an 
XAP study after the Final Visit or Week 52 of MLN0002-3028. Subjects who 
transition into the XAP study will not take part in the 18-week follow-up period 
or the 6-month safety follow-up telephone call following their last dose in 
MLN0002-3028. The end of trial will be the Week 52 visit for these subjects and 
the duration of the study will be approximately 56 weeks.
Rationale for Change:
Allow all subjects (who complete Part B) in countries where vedolizumab is either not 
commercially available or is not reimbursed, continued access to vedolizumab by transition into an 
XAP, Vedolizumab-4013.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Figure 6.b Schematic of Study Design: For Subjects on 52 Weeks of Treatment.

Section 9.1.11 Pregnancy.

Section 9.3.6 Poststudy Care.

Section 13.1.6 Safety Analysis.

Appendix A Schedule of Events.
Change 2: Remove the requirement for subjects who transition into the XAP study to attend the 
18-week Safety Follow-up Visit in the MLN0002-3028 study. The safety of these subjects will be 
monitored as part of the XAP study.
The primary change occurs in Section 6.1 Study Design


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Added text:Subjects who consent to Part B will have the option to voluntarily enroll into an 
XAP study after the Final Visit or Week 52 of MLN0002-3028. Subjects who 
transition into the XAP study will not take part in the 18-week follow-up period 
or the 6-month safety follow-up telephone call following their last dose in 
MLN0002-3028. The end of trial will be the Week 52 visit for these subjects and 
the duration of the study will be approximately 56 weeks.
Rationale for Change:
Remove the requirement for subjects who transition into the XAP study to attend the 18-week 
Safety Follow-up Visit in the MLN0002-3028 study. The safety of these subjects will be 
monitored as part of the XAP study.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 5.2.3 Additional Endpoints.

Figure 6.b Schematic of Study Design: For Subjects on 52 Weeks of Treatment.

Section 9.3.4 Postdose 18-Week Safety Follow-up.

Appendix A Schedule of Events.
Change 3: Remove the requirement for subjects who transition into the XAP study to participate 
in the 6-month long-term follow-up safety questionnaire in the MLN0002-3028 study. The safety 
of these subjects will be monitored as part of the XAP study.
The primary change occurs in Section 6.1 Study Design
Added text:Subjects who consent to Part B will have the option to voluntarily enroll into an 
XAP study after the Final Visit or Week 52 of MLN0002-3028. Subjects who 
transition into the XAP study will not take part in the 18-week follow-up period 
or the 6-month safety follow-up telephone call following their last dose in 
MLN0002-3028. The end of trial will be the Week 52 visit for these subjects and 
the duration of the study will be approximately 56 weeks.
Rationale for Change:
Remove the requirement for subjects who transition into the XAP study to participate in the 
6-month long-term follow-up safety questionnaire in the MLN0002-3028 study. The safety of 
these subjects will be monitored as part of the XAP study.


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The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Figure 6.b Schematic of Study Design: For Subjects on 52 Weeks of Treatment.

Section 9.3.5 Poststudy Long-term Follow-up.

Appendix A Schedule of Events.
Change 4: Amend the adverse event, serious adverse event, and concomitant medication reporting 
instructions for subjects who transition into the XAP study, such that the MLN0002-3028 
collection period ends at the time the subject is consented into the XAP.
The primary change occurs in Section 10.2.1.1 PTE and AE Collection Period
Formerly 
read:

Start of AE collection: AEs must be collected from start of study medication 
administration. 

End of AE collection: AEs must be collected for 18 weeks following the last dose 
of study medication. 
Collection of PTEs will commence from the time the subject signs the informed 
consent to participate in the study and continue until the subject is first administered 
study medication or until 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. Routine collection of AEs will continue until 18 weeks after last 
dose.


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Now reads: !
Start of AE collection: AEs must be collected from start of study medication 
administration. 
!
End of AE collection: for subjects who do not transition into the XAP study 
AEs must be collected for 18 weeks following the last dose of study medication. If 
the subject is transitioned into the XAP study AEs must be collected until the 
Final Visit, Week 52. 
Collection of PTEs will commence from the time the subject signs the informed 
consent to participate in the study and continue until the subject is first administered 
study medication or until 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. Routine collection of AEs will continue until 18 weeks after last 
dose for subjects not transitioning into the XAP study. For subjects who 
transition into the XAP study, routine collection of AEs will continue until the 
Final Visit, Week 52.
Rationale for Change:
Amend the adverse event, serious adverse event, and concomitant medication reporting 
instructions for subjects who transition into the XAP study, such that the MLN0002-3028 
collection period ends at the time the subject is consented into the XAP.
Change 5: Administrative change to the Responsible Medical Officer.
The primary change occurs in Section 1.1 Contacts
Formerly 
read:
Now reads: PPD
PPD


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Rationale for Change:
Administrative change to the Responsible Medical Officer.
Section 1.2 Administrative information also contains this change.


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SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: An Open-Label Phase 3b Study to Assess Mucosal Healing in Subjects with Moderately to
Severely Active Crohn’s Disease Treated With Vedolizumab IV
Effect of Vedolizumab IV on Mucosal Healing in Crohn’s Disease
NCT Number: NCT02425111
SAP Approve Date: 21 March 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


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Page 3 of 60 
 
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CONFIDENTIAL INFORMATION 
Do not distribute outside of Takeda without a confidentiality agreement. 
 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE 
1 
1.1 
APPROVAL SIGNATURES .......................................................................................... 2 
2.0 
TABLE OF CONTENTS .................................................................................................................. 3 
3.0 
LIST OF ABBREVIATIONS ............................................................................................................ 5 
4.0 
OBJECTIVES .................................................................................................................................. 7 
4.1 
PRIMARY OBJECTIVE ....................................................................................................... 7 
4.2 
SECONDARY OBJECTIVES ................................................................................................ 7 
4.3 
ADDITIONAL OBJECTIVES................................................................................................. 7 
4.4 
STUDY DESIGN ............................................................................................................... 8 
5.0 
ANALYSIS ENDPOINTS ............................................................................................................... 10 
5.1 
PRIMARY ENDPOINT ...................................................................................................... 10 
5.2 
SECONDARY ENDPOINTS ............................................................................................... 10 
5.3 
ADDITIONAL ENDPOINTS ............................................................................................... 10 
6.0 
DETERMINATION OF SAMPLE SIZE .......................................................................................... 13 
7.0 
METHODS OF ANALYSIS AND PRESENTATION ...................................................................... 14 
7.1 
GENERAL PRINCIPLES ................................................................................................... 14 
7.1.3 
Definition of Baseline Values ...................................................................................... 14 
7.1.4 
Definition of Screen Failure ........................................................................................ 15 
7.1.5 
Definitions of Study Visit Windows ............................................................................. 15 
7.1.6 
Convention for Calculation of SES-CD Scores .......................................................... 18 
7.1.7 
Convention for Calculation of CDAI Scores ............................................................... 18 
7.1.8 
Conventions for Missing Adverse Events Dates ........................................................ 20 
7.1.9 
Conventions for Missing Concomitant Medications Dates ......................................... 21 
7.1.10 
Conventions for Missing Previous Medications Dates ............................................... 21 
7.1.11 
Conventions for Calculation of Duration of CD........................................................... 22 
7.2 
ANALYSIS SETS ............................................................................................................ 22 
7.3 
DISPOSITION OF SUBJECTS ........................................................................................... 23 
7.4 
MAJOR PROTOCOL VIOLATIONS ..................................................................................... 24 
7.5 
SIGNIFICANT PROTOCOL DEVIATIONS ............................................................................. 25 
7.6 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .......................................................... 25 
7.7 
MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS ......................................... 26 
7.8 
MEDICATION HISTORY AND CONCOMITANT MEDICATIONS ............................................... 27 
7.9 
STUDY DRUG EXPOSURE AND COMPLIANCE ................................................................... 28 
7.10 
EFFICACY ANALYSIS...................................................................................................... 28 
7.10.1 
Primary Efficacy Endpoint .......................................................................................... 29 
7.10.2 
Secondary Efficacy Endpoints .................................................................................... 29 


 
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7.10.3 
Additional Efficacy Endpoints ..................................................................................... 31 
7.11 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS ........................................................ 36 
7.12 
OTHER OUTCOMES ....................................................................................................... 36 
7.12.1 
IBDQ ........................................................................................................................... 36 
7.12.2 
EQ-5D Questionnaire ................................................................................................. 37 
7.12.3 
WPAI-CD .................................................................................................................... 37 
7.13 
SAFETY ANALYSIS ......................................................................................................... 37 
7.13.1 
Adverse Events .......................................................................................................... 37 
7.13.2 
Clinical Laboratory Evaluations .................................................................................. 41 
7.13.3 
Vital Signs ................................................................................................................... 43 
7.13.4 
12-Lead ECGs ............................................................................................................ 44 
7.13.5 
Other Observations Related to Safety ........................................................................ 44 
7.14 
INTERIM ANALYSIS ........................................................................................................ 44 
7.15 
CHANGES IN THE STATISTICAL ANALYSIS PLAN ............................................................... 46 
8.0 
REFERENCES ............................................................................................................................... 47 
9.0 
APPENDICES ................................................................................................................................ 48 
 
 


 
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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
AVA 
anti-vedolizumab antibody; also called HAHA 
BMI 
body mass index 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
CI 
confidence interval 
CRP 
C-reactive protein 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EQ-5D 
Euro Quality of Life-5D 
ET 
early termination 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone 
GGT 
γ-glutamyl transferase 
GHAS 
Global Histological Disease Activity Score 
GI 
gastrointestinal 
HAHA 
human antihuman antibody 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLT 
high level term 
HRQOL 
health-related quality of life  
IBDQ 
inflammatory bowel disease questionnaire 
INR 
international normalized ratio 
IRR 
infusion-related reactions 
IV 
intravenous 
LOCF 
Last available post-baseline Observation Carried Forward 
MaRIA 
Magnetic Resonance Index of Activity 
MAV 
markedly abnormal value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
magnetic resonance  
MREn 
magnetic resonance enterography 
PML 
progressive multifocal leukoencephalopathy 
PPS 
per protocol set 
PRO 
patient reported outcome 
PT 
preferred term 
PT 
prothrombin time 
PTE 
pretreatment event 
QOL 
quality of life 
RAMP 
Risk Assessment and Minimization for PML 
RBC 
red blood cell 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SES-CD 
simple endoscopic score for Crohn’s Disease 
SI 
International System of Units 
SMQ 
standard MedDRA query 


 
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SOC 
system organ class 
TEAE 
treatment emergent adverse event 
TNF-α 
tumor necrosis factor-alpha 
URTI 
upper respiratory tract infection 
VAS 
visual analog scale 
WBC 
white blood cell 
WHODrug 
World Health Organization Drug Dictionary 
WPAI 
Work Productivity and Activity Impairment 
WPAI-CD 
Work Productivity and Activity Impairment for Crohn’s Disease 
 


 
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4.0 
OBJECTIVES 
4.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate endoscopic remission of Crohn's Disease (CD) 
at Week 26 as assessed by ileocolonoscopy. 
4.2 
SECONDARY OBJECTIVES 
The secondary objectives for Study Part A are: 
 To examine the relationship among endoscopic, imaging, histological, and clinical 
assessments of CD. 
 To evaluate endoscopic remission at Week 14. 
 To evaluate endoscopic response at Weeks 14 and 26. 
 To evaluate clinical response assessed by Crohn’s Disease Activity Index (CDAI) at 
Weeks 10 and 26. 
 To evaluate clinical remission assessed by CDAI at Weeks 10 and 26.  
The secondary objectives for Study Part B are: 
 To examine the relationship among endoscopic, imaging, histological, and clinical 
assessments of CD. 
 To evaluate endoscopic remission at Week 52. 
 To evaluate endoscopic response at Week 52. 
 To evaluate clinical response assessed by CDAI at Week 52. 
 To evaluate clinical remission assessed by CDAI at Week 52. 
 To evaluate durable endoscopic remission at Week 52 in patients with endoscopic 
remission at Week 26. 
4.3 
ADDITIONAL OBJECTIVES 
The additional objectives for Study Part A are: 
 To evaluate changes in transmural bowel wall activity and other measures of bowel wall 
inflammation using magnetic resonance enterography (MREn) at Week 26.  
 To assess histological response at Week 26. 
 To evaluate C-reactive protein (CRP) at Weeks 10 and 26. 
 To evaluate fecal calprotectin at Weeks 14 and 26. 
 To evaluate immunogenicity of vedolizumab. 
 To evaluate health-related quality of life (as assessed by inflammatory bowel disease 
questionnaire [IBDQ] and Euro Quality of Life-5D [EQ-5D]) at Weeks 14 and 26. 


 
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 To explore the relationship between endoscopic remission and health-related quality of 
life (QOL). 
 To evaluate impact on loss of work productivity and activity impairment assessed by 
Work Productivity and Activity Impairment (WPAI):CD at Weeks 14 and 26. 
The additional objectives for Study Part B are: 
 To evaluate changes in transmural bowel wall activity and other measures of bowel 
wall inflammation using MREn at Week 52. 
 To assess histological response at Week 52. 
 To evaluate CRP at Weeks 38 and 52. 
 To evaluate fecal calprotectin at Weeks 38 and 52. 
 To evaluate immunogenicity of vedolizumab. 
 To evaluate clinical response assessed by CDAI at Weeks 38 and 46. 
 To evaluate clinical remission assessed by CDAI at Weeks 38 and 46. 
 To evaluate health-related quality of life (IBDQ and EQ-5D) at Weeks 38 and 52. 
 To explore the relationship between endoscopic remission and health-related QOL. 
 To evaluate impact on loss of work productivity and activity impairment assessed by 
WPAI:CD at Week 52. 
4.4 
STUDY DESIGN 
This is a phase 3b single-arm, open-label multicenter study to evaluate the efficacy and safety of 
vedolizumab 300 mg intravenous (IV) infusion over a 26-week treatment period using 
ileocolonoscopy for the assessment in subjects with moderately to severely active CD (Study 
Part A) followed by a 26-week treatment extension period (Part B). Biopsies will be collected for 
histological assessments per the schedule of events for all subjects. The study will be conducted 
at sites in North America and Europe. The 26-week treatment extension (Study Part B) is 
included as part of Protocol Amendment No. 04 (dated 27 April 2016), ongoing subjects at the 
time of the amendment will have the option to either stop treatment at Week 26 (Study Part A) or 
continue treatment into Part B. Subjects who enroll into the study after Protocol Amendment No. 
04 will be treated directly for 52 weeks (Study Parts A and B). 
Approximately 100 subjects with moderately to severely active CD who have failed treatment 
with corticosteroids, immunosuppressants, and/or biologics will be enrolled. Subjects who are 
tumor necrosis factor-alpha (TNF-α) antagonist naïve as well as those who are TNF-α antagonist 
failures will be included, such that approximately 50% of enrolled subjects are TNF-α antagonist 
naïve.  
The study consists of a 4-week screening period, a 26-week treatment period (Study Part A), 
followed by a 26-week extension treatment period (Part B from 7 days after Week 26 to 52 with 
last dose at Week 46), and an 18-week follow-up period following the last dose. The duration of 
the study will be approximately 44 weeks for subjects completing Study Part A and 70 weeks for 
subjects completing Study Part B. All subjects included in the study will also have a 6 month 


 
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safety follow-up telephone call following last dose. End of trial will be the date of the last visit of 
the last subject at the Postdose 18 Week Safety Follow-up visit. 
Subjects that meet all the inclusion criteria and none of the exclusion criteria will be dosed on 
site with vedolizumab 300 mg IV. Subjects will visit the site for dosing at Day 1, Weeks 2, 6, 14, 
and 22 for Study Part A and at Weeks 30, 38, and 46 for Study Part B. Ileocolonoscopy will be 
performed at the Screening, Week 14, Week 26 (Study Part A), and Week 52 (Study Part B) or 
early termination (ET) visits. Biopsies will be taken during the Screening, Week 26 (Study Part 
A), and Week 52 (Study Part B) or ET visit. All ileocolonoscopies will be evaluated by a blinded 
central reader.  
An MREn substudy will be conducted at selected qualified centers using a standardized magnetic 
resonance (MR) acquisition and procedure to assess bowel wall activity. Only subjects from the 
pre-selected sites will be included in this study; these subjects will undergo an MREn assessment 
at the Screening, Week 26 (Study Part A), and Week 52 (Study Part B) or ET visit, unless they 
have contraindications to the procedure. All MREn results will be evaluated by a blinded 
independent central reader. 
Additional procedures will be performed according to the Schedule of Study Procedures 
(Appendix A). 
Figure 4.a 
Schematic of Study Design - For Subjects on 26 Weeks of Treatment 
 
Figure 4.b 
Schematic of Study Design - For Subjects on 52 Weeks of Treatment 
 


 
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5.0 
ANALYSIS ENDPOINTS 
5.1 
PRIMARY ENDPOINT 
The primary endpoint is the proportion of subjects achieving endoscopic remission at Week 26. 
Endoscopic Remission is assessed by ileocolonoscopy and defined as simple endoscopic score 
for Crohn’s Disease (SES-CD) score of ≤ 4. 
5.2 
SECONDARY ENDPOINTS 
The secondary endpoints for Study Part A are: 
 Proportion of subjects achieving complete mucosal healing at Week 26. Complete 
mucosal healing is defined as absence of ulceration. 
 Proportion of subjects achieving endoscopic remission at Week 14.  
 Proportion of subjects with endoscopic response at Week 14. Endoscopic response is 
defined as SES-CD reduction by ≥ 50%.  
 Proportion of subjects with endoscopic response at Week 26.  
 Proportion of subjects achieving clinical response at Week 10. Clinical response is 
defined as CDAI decrease from Baseline of ≥ 100 points.  
 Proportion of subjects achieving clinical response at Week 26. 
 Proportion of subjects achieving clinical remission at Week 10. Clinical remission is 
defined as CDAI ≤ 150.  
 Proportion of subjects achieving clinical remission at Week 26. 
The secondary endpoints for Study Part B are: 
 Proportion of subjects achieving complete mucosal healing at Week 52. Complete 
mucosal healing is defined as absence of ulceration. 
 Proportion of subjects achieving endoscopic remission at Week 52. 
 Proportion of subjects with endoscopic response at Week 52. Endoscopic response is 
defined as SES-CD reduction by ≥ 50%.  
 Proportion of subjects achieving clinical response at Week 52. Clinical response is 
defined as CDAI decrease from Baseline of ≥ 100 points.  
 Proportion of subjects achieving clinical remission at Week 52. Clinical remission is 
defined as CDAI ≤ 150.  
 Proportion of subjects with durable clinical remission.  Durable clinical remission is 
defined as clinical remission at Week 26 and Week 52. 
5.3 
ADDITIONAL ENDPOINTS 
The additional endpoints for Study Part A are: 


 
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 Change from Baseline to Week 26 in individual MREn parameters (including wall 
thickening, relative contrast enhancement, presence of ulcerations, presence of 
edema) for each ileocolonic segment and for more proximal bowel segments, if 
evaluable. 
 Proportion of subjects achieving Magnetic Resonance Index of Activity (MaRIA) 
score <7 at Week 26 globally and on a per segment basis.  
 Proportion of subjects with 25% and 75% reduction of SES-CD at Weeks 14 and 26.  
 Proportion of subjects with no granulocytes present in bowel biopsy at Week 26. 
 Proportion of subjects with a change in histology at Week 26.  
 Proportion of subjects with elevated CRP at Baseline who achieve normalization of 
CRP at Weeks 10 and 26.  
 Change from Baseline to Weeks 14 and 26 in fecal calprotectin. 
 Proportion of subjects positive for anti-vedolizumab antibody (AVA; also called 
human antihuman antibody [HAHA]) at Baseline, Week 26, and at the Postdose 18 
Week Safety Follow-up Visit.  
 Proportion of subjects with positive neutralizing AVA at Baseline, Week 26, and at 
the Postdose 18 Week Safety Follow-up Visit.  
 Change from Baseline to Weeks 14 and 26 in the IBDQ total and subscale scores.  
 Change from Baseline to Weeks 14 and 26 in the EQ-5D utility score and visual 
analog scale (VAS) score.  
 Change from Baseline to Weeks 14 and 26 in percent work time missed due to CD.  
 Change from Baseline to Weeks 14 and 26 in percent impairment while working due 
to CD.  
 Change from Baseline to Weeks 14 and 26 in percent overall work impairment due to 
CD.  
 Change from Baseline to Weeks 14 and 26 in percent activity impairment due to CD.  
 Adverse events (AEs), serious AEs (SAEs), vital signs, and laboratory tests. 
The additional endpoints for Study Part B are: 
 Change from Baseline to Week 52 in individual MREn parameters (including wall 
thickening, relative contrast enhancement, presence of ulcerations, presence of 
edema) for each ileocolonic segment and for more proximal bowel segments, if 
evaluable. 
 Proportion of subjects achieving MaRIA score < 7 at Week 52 globally and on a per 
segment basis.  
 Proportion of subjects with 25% and 75% reduction of SES-CD at Week 52. 
 Proportion of subjects with no granulocytes present in bowel biopsy at Week 52. 


 
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 Proportion of subjects with a change in histology at Week 52.  
 Proportion of subjects with elevated CRP at Baseline who achieve normalization of 
CRP at Weeks 38 and 52. 
 Change from Baseline to Weeks 38 and 52 in fecal calprotectin. 
 Proportion of subjects positive for AVA at Week 52 and at the Postdose 18 Week 
Safety Follow-up Visit.  
 Proportion of subjects with positive neutralizing AVA at Week 52 and at the Postdose 
18 Week Safety Follow-up Visit.  
 Proportion of subjects achieving clinical response at Weeks 38 and 46.  Clinical 
response is defined as CDAI decrease from Baseline of ≥ 100 points. 
 Proportion of subjects achieving clinical remission at Weeks 38 and 46. Clinical 
remission is defined as CDAI ≤ 150. 
 Change from Baseline to Weeks 38 and 52 in the IBDQ total and subscale scores.  
 Change from Baseline to Weeks 38 and 52 in the EQ-5D utility score and VAS score. 
 Change from Baseline to Week 52 in percent work time missed due to CD.  
 Change from Baseline to Week 52 in percent impairment while working due to CD.  
 Change from Baseline to Week 52 in percent overall work impairment due to CD.  
 Change from Baseline to Week 52 in percent activity impairment due to CD.  
 AEs, SAEs, vital signs, and laboratory tests. 


 
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6.0 
DETERMINATION OF SAMPLE SIZE 
A sample size of 100 subjects will be sufficient to provide a 95% confidence interval based on 
normal approximation for the primary endpoint (endoscopic remission rate at Week 26) that 
extends no more than 10% in each direction from the estimated rate. 


 
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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
GENERAL PRINCIPLES  
Where appropriate, variables will be summarized descriptively by study visit and subgroups. For 
categorical variables, counts and proportions will be tabulated. Percentages will be calculated out 
of the total number of patients in the analysis set and by subgroups, when applicable. 
Percentages will be presented to 1 decimal place. Every effort will be made to limit the amount 
of missing data; however, if any missing data is present in the clinical database, a Missing 
category will be added in the tabulation, unless otherwise stated. 
For continuous variables, the number of subjects with non-missing values, mean, median, 
standard deviation (SD), minimum, and maximum values will be tabulated. Means and medians 
will be presented to 1 more decimal place than the recorded data. The SDs will be presented to 2 
more decimal places than the recorded data. Confidence intervals about a parameter estimate will 
be presented using the same number of decimal places as the parameter estimate. 
All confidence intervals will be reported as 2-sided and will be assessed at the α=0.05 
significance level. No inferential statistics are planned for this study. 
The data summaries will be accompanied by individual subject data listings. 
A windowing convention will be used to determine the analysis value for a given study visit for 
observed data analyses. Details are provided in section 7.1.5. 
All statistical analyses will be conducted using SAS System® Version 9.2, or higher. 
7.1.1 Study Terms and Definitions 
Study terms and definitions are provided below. 
Term  
Definition 
Endoscopic Remission 
SES-CD score ≤ 4 
Complete Mucosal Healing  
Absence of ulcerations 
Endoscopic Response 
SES-CD reduction by ≥ 50% 
Clinical Response 
CDAI decrease from baseline of ≥ 100 points  
Clinical Remission 
CDAI ≤ 150 points 
7.1.2 Definition of Study Days 
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication, as recorded on the electronic case report form (eCRF) dosing page. Other study days 
are defined relative to the Study Day 1 with Day 1 being Study Day 1 and Day -1 being the day 
prior to Study Day 1. 
All protocol-specified study visit dates are defined relative to Study Day 1 (for example, the date 
for the scheduled Week 2 Visit should be Study Day 15). 
7.1.3 Definition of Baseline Values 
Unless otherwise specified, baseline values are defined as the last observed value before the first 
dose of study medication. Values measured on Day 1 must be prior to administration of study 
medication to be classified as Baseline. 


 
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7.1.4 Definition of Screen Failure 
Screen failure subjects are subjects who signed the informed consent and were not enrolled in the 
study. The primary reason for screen failure is collected in the eCRF using the following 
categories: 
 Pretreatment Event (PTE)/AE 
 Did Not Meet Entrance Criteria 
 Significant Protocol Deviation 
 Lost to Follow-Up 
 Voluntary Withdrawal 
 Study Termination 
 Other 
7.1.5 Definitions of Study Visit Windows 
Day 1 will be analyzed as Day 1, provided that the date of the assessment matches the date of the 
first dose of study drug. Assessments recorded as Day 1 on the eCRF but occurring prior to the 
date of first dose will be windowed to Baseline. 
Unless otherwise specified the rules provided below in Table 7.a, Table 7.b, Table 7.c, and Table 
7.d will be used for all variables. The lower and upper bounds of each window are the 
approximate midpoints between the scheduled days for the current visit and its adjacent 
scheduled visits. The value used in analysis for by-visit summaries is the value within the 
specified window. If a patient has more than one measurement within an analysis window, the 
assessment closest to the target day will be used. In case of ties between observations located on 
different sides of the target day, the later assessment will be used in analyses. In case of ties 
located on the same side of the target day (i.e., more than one value for the same day), the mean 
of the values will be used for continuous parameters and the worst result will be chosen over a 
more positive one for categorical parameters (i.e., an abnormal electrocardiogram [ECG] value 
will be chosen over a normal ECG value).  
For safety measurements (laboratory tests and vital signs), descriptive statistics are presented for 
each scheduled visit including the Final Visit. Final Visit during the Treatment Period will be 
defined as the last visit (inclusive of both scheduled and unscheduled) which falls between 
Baseline and Week 26 or date of early termination, whichever comes first, using the visit 
analysis windows defined above. Final Visit during the Treatment Extension Period will be 
defined as the last visit (inclusive of both scheduled and unscheduled) which falls just after 
Week 26 and up to Week 52 or date of early termination, whichever comes first, using the visit 
analysis windows defined above. 
Data identified on the eCRF as coming from an “unscheduled” visit will be eligible for 
windowing and Final Visit summaries. There will not be a separate “unscheduled” categorization 
for the reporting of these observations. 
The visit windows and applicable study day ranges are presented below for study.  


 
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Table 7.a 
Visit Analysis Windows for Efficacy Variables Evaluated by Visit (Subjects on 26 Weeks of Treatment) 
Visit  
Target Day 
CDAI Scheduled at 
Baseline and Weeks 6, 10, 
14,  and 26  
AVA, Biopsies, and MREn 
Scheduled at Baseline and 
Week 26  
C-reactive protein 
Scheduled at Baseline and 
Weeks 10 and 26 
Ileocolonoscopy Scheduled 
at Baseline and Weeks 14 
and 26 
Fecal calprotectin and 
PRO related QOLs 
Scheduled at Baseline and 
Weeks 14 and 26 
Baseline 
1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Week 2 
15 
 
 
 
 
 
Week 6 
43 
2 – 56 
 
 
 
 
Week 10 
71 
57 – 84 
 
2 ‒ 126 
 
 
Week 14 
99 
85 – 140 
 
 
2 – 140 
2 – 140 
Week 22 
155 
 
 
 
 
 
Final / Week 26 
183 
141 – 224 
2 – 232 
127 ‒ 224 
141 – 232 
141 – 224 
 
Table 7.b 
 Visit Analysis Windows for Safety Variables Evaluated by Visit (Subjects on 26 Weeks of Treatment) 
Visit  
Target Day 
Weight and 
Hematology 
laboratory tests 
Scheduled at Baseline 
and Weeks 6, 10, 14,  
and 26  
Chemistry laboratory 
tests and Urinalysis 
laboratory tests 
Scheduled at Baseline 
and Week 26  
Serum Creatinine 
and eGFR for MREn 
subjects Scheduled at 
Baseline and Weeks 
22 and 26 
Dosing and variables 
Scheduled at Baseline 
and Weeks 2, 6, 14, 
and 22 
Vital Signs Scheduled 
at Baseline and 
Weeks 2, 6, 14, 22, 
and 26 
Safety Variables by 
Visit 
Visit days are relative to the first dose of open-label medication. 
Baseline 
1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Week 2 
15 
 
 
 
2 – 28  
2 ‒ 28 
2 ‒ 28 
Week 6 
43 
2 – 56 
 
 
29 – 70 
29 ‒ 70 
29 ‒ 56 
Week 10 
71 
57 – 84 
 
 
 
 
57 ‒ 84 
Week 14 
99 
85 – 140 
 
 
71 – 126 
71 ‒ 126 
85 ‒ 126 
Week 22 
155 
 
 
2 ‒ 168 
127 – 196 
127 ‒ 168 
127 ‒ 168 
Final / Week 26 
183 
141 – 196 
2 – 196 
169 ‒ 196 
 
169 ‒ 196 
169 ‒ 196 
 
 


 
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Table 7.c 
Visit Analysis Windows for Efficacy Variables Evaluated by Visit (Subjects on 52 Weeks of Treatment) 
Visit  
Target Day 
CDAI Scheduled at 
Baseline and Weeks 6, 10, 
14,  26, 38, 46 and 52 
AVA, Biopsies, and MREn 
Scheduled at Baseline and 
Weeks 26, and 52 
C-reactive protein 
Scheduled at Baseline and 
Weeks 10, 26, 38, and 52 
Ileocolonoscopy Scheduled 
at Baseline and Weeks 14, 
26, and 52 
Fecal calprotectin and 
PRO related QOLs 
Scheduled at Baseline and 
Weeks 14, 26, 38, and 52 
Baseline 
1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Week 2 
15 
 
 
 
 
 
Week 6 
43 
2 – 56 
 
 
 
 
Week 10 
71 
57 – 84 
 
2 ‒ 126 
 
 
Week 14 
99 
85 – 140 
 
 
2 – 140 
2 – 140 
Week 22 
155 
 
 
 
 
 
Week 26 
183 
141 – 224 
2 – 232 
127 ‒ 224 
141 – 232 
141 – 224 
Week 30 
211 
 
 
 
 
 
Week 38 
267 
225 – 294 
 
225 ‒ 315 
 
225 ‒ 315 
Week 46 
323 
295 – 343 
 
 
 
 
Final / Week 52 
365 
344 – 406 
233 – 406 
316 ‒ 406 
233 – 406 
316 ‒ 406 
 
Table 7.d 
Visit Analysis Windows for Safety Variables Evaluated by Visit (Subjects on 52 Weeks of Treatment) 
Visit  
Target Day 
Weight 
Scheduled at 
Baseline and 
Weeks 6, 10, 
14, 26, 30, 38, 
46 and 52 
Urinalysis 
laboratory tests 
Scheduled at 
Baseline and 
Weeks 26, and 
52 
Hematology 
laboratory tests 
Scheduled at 
Baseline and 
Weeks 6, 10, 
14, 26, 38, and 
52 
Chemistry 
laboratory tests 
Scheduled at 
Baseline and 
Weeks 26, 38, 
and 52 
Serum 
Creatinine and 
eGFR for 
MREn subjects 
Scheduled at 
Baseline and 
Weeks 22, 26, 
38, 46, and 52 
Dosing 
Scheduled at 
Baseline and 
Weeks 2, 6, 14, 
22, 30, 38, and 
46 
Vital signs 
Scheduled at 
Baseline and 
Weeks 2, 6, 14, 
22, 26, 30, 38, 
46, and 52 
Safety 
Variables by 
Visit 
Visit days are relative to the first dose of open-label medication. 
Baseline 
1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Week 2 
15 
 
 
 
 
 
2 – 28  
2 – 28  
2 ‒ 28 
Week 6 
43 
2 – 56 
 
2 ‒ 56 
 
 
29 – 70 
29 – 70 
29 ‒ 56 
Week 10 
71 
57 – 84 
 
57 ‒ 84 
 
 
 
 
57 ‒ 84 
Week 14 
99 
85 – 140 
 
85 ‒ 140 
 
 
71 – 126 
71 – 126 
85 ‒ 126 
Week 22 
155 
 
 
 
 
2 ‒ 168 
127 – 196 
127 ‒ 168 
127 ‒ 168 
Week 26 
183 
141 – 196 
2 – 196  
141 ‒ 196 
2 ‒ 196 
169 ‒ 196 
 
169 – 196 
169 ‒ 196 
Week 30 
211 
197 ‒ 238 
 
 
 
 
197 – 238 
197 – 238 
197 ‒ 231 
Week 38 
267 
239 – 294 
 
197 ‒ 315 
197 ‒ 315 
197 ‒ 294 
239 – 294 
239 – 294 
239 – 294 
Week 46 
323 
295 ‒ 343 
 
 
 
295 ‒ 343 
295 – 392 
295 – 343 
295 – 343 
Final / Week 52 
365 
344 – 392 
197 – 392 
316 ‒ 392 
316 ‒ 392 
344 ‒ 392 
 
344 – 392 
344 – 392 
 


 
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Data identified on the eCRF as coming from the “follow-up” visit (i.e., Postdose 18 Week Safety 
Follow-up) will be summarized as collected and entered. These study visits will not be 
windowed. 
 
The study window convention will not be applied to data listings; the data listings will display 
the visits as collected and entered in the eCRF. 
7.1.6 Convention for Calculation of SES-CD Scores 
The SES-CD has been shown to be comparable to the Crohn’s Disease Endoscopic Index of 
Severity and a straightforward scoring system for Crohn’s disease [2]. The overall SES-CD score 
ranges from 0 to 56 and is the sum of 4 variables (i.e., size of ulcers [cm], ulcerated surface [%], 
affected surface [%], and presence of narrowing) across 5 bowel segments (i.e., rectum, 
descending and sigmoid colon, transverse colon, ascending colon, and ileum). Each variable is 
coded from 0 to 3 based on severity, where 0 is none or not severe and 3 is the most severe case, 
with the sum of the scores for each variable ranging from 0 to 15, except for presence of 
narrowing. Presence of narrowing ranges from 0 to 11 since a severity of 3 represents a 
narrowing which a colonscope cannot be passed and, thus, can only be observed once among the 
bowel segments. The segmental SES-CD score is the sum of the 4 variables for each bowel 
segment and can range from 0 to 12, where each individual variable score ranges from 0 to 3 (see 
Appendix B). 
7.1.7 Convention for Calculation of CDAI Scores 
The CDAI score is the summation of 8 components, including number of liquid or very soft 
stools, abdominal pain, general well-being, extra-intestinal manifestations of Crohn’s Disease, 
Lomotil/Imodium/opiates for diarrhea usage, abdominal mass, hematocrit level, and body weight 
(see Appendix C). 
Number of liquid or very soft stools, abdominal pain, and general well-being are self-reported 
via subject electronic diary entries. To calculate subscores at each visit, the diary data from the 
10 days prior to the date of CDAI calculation were used and the following rules were applied: 
1. Take the 7 most recent days of diary data prior to the date of CDAI calculation. If the 
CDAI analysis visit is Screening and less than 7 days of data are present, a subscore 
cannot be calculated. 
2. For number of liquid or very soft stools only, if any of the 7 most recent days of diary 
data have stool frequency values greater than 24, set the value for the stool record for that 
day to missing. 
3. If less than 4 non-missing results remain, the subscore cannot be calculated, and the 
subject will be categorized as a non-responder. Otherwise, calculate the subscore by 
summing the values, dividing by the number of non-missing records included in the 
summation, and multiplying by the factor appropriate for the given subscore. 
a. For stool, the factor is 2. 
b. For abdominal pain, the factor is 5. 


 
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c. For general well-being, the factor is 7. 
Table 7.e provides examples of calculated CDAI scores using various eDiary scenarios 
(excluding eligibility). Table 7.f provides examples of calculated CDAI scores using various 
eDiary scenarios for eligibility. Patient diaries can be completed 14 days prior to the eligibility 
visit. Any on-study colonoscopies and/or MREn are taken into account such that the diary data 
from the day prior, day of, and day after are excluded from the visit’s CDAI calculation. 
Table 7.e 
Examples of eDiary Subscore Entries and Corresponding Subscore 
Derivation (Excluding Eligibility) 
Day 
-14 
Day 
-13 
Day 
-12 
Day 
-11 
Day 
-10 
Day 
-9 
Day 
- 8 
Day 
-7 
Day 
-6 
Day 
-5 
Day 
-4 
Day 
-3 
Day 
-2 
Day 
-1 
Raw 
Sum 
Final 
Subtotal 
(factor = x 2) 
1 
2 
M 
2 
2 
2 
2 
1 
1 
1 
1 
1 
1 
1 
7 
14 
1 
X 
MRE 
X 
3 
X 
C 
X 
1 
1 
1 
1 
1 
1 
9 
18 
1 
2 
M 
2 
M 
3 
M 
3 
M 
3 
M 
3 
3 
3 
21 
42 
1 
2 
M 
2 
M 
2 
M 
M 
M 
1 
3 
2 
2 
M 
14 
28 
1 
M 
M 
2 
3 
X 
MRE 
X 
X 
C 
X 
3 
3 
3 
21 
42 
1 
M 
X 
MRE 
X 
C 
X 
M 
2 
M 
M 
M 
2 
0 
N/A 
N/A 
M = Missing data. 
C = Colonoscopy. 
N/A = Not Available. 
Used days are highlighted. 
Table 7.f 
Examples of eDiary Subscore Entries for Eligibility and Corresponding 
Subscore Derivation (for Eligibility, only rule #1 applies) 
Day 
-14 
Day 
-13 
Day 
-12 
Day 
-11 
Day 
-10 
Day 
-9 
Day 
- 8 
Day 
-7 
Day 
-6 
Day 
-5 
Day 
-4 
Day 
-3 
Day 
-2 
Day 
-1 
Raw 
Sum 
Final 
Subtotal 
(factor = x 2) 
1 
2 
M 
2 
2 
2 
2 
1 
1 
1 
1 
1 
1 
1 
7 
14 
X 
MRE 
X 
3 
3 
3 
X 
C 
X 
3 
3 
3 
3 
M 
21 
42 
1 
2 
M 
2 
3 
3 
3 
M 
1 
2 
2 
3 
R 
1 
17 
34 
1 
2 
M 
2 
3 
3 
3 
3 
2 
2 
2 
R 
2 
3 
18 
36 
1 
X 
MRE 
X 
3 
X 
C 
X 
2 
2 
3 
R 
3 
1 
N/A 
N/A 
2 
3 
2 
2 
3 
X 
C 
X 
3 
2 
2 
2 
3 
3 
18 
36 
1 
3 
M 
M 
2 
1 
2 
3 
X 
C 
X 
3 
R 
2 
N/A 
N/A 
M = Missing data. 
C = Colonoscopy. 
R = Subscore requested. 
N/A = Not Available. 
Used days are highlighted. 
In addition to the subscores originating from the subject electronic diary entries, subscores for 
extra-intestinal manifestations of Crohn’s Disease, usage of Lomotil/Imodium/opiates for 
diarrhea, abdominal mass, hematocrit level, and body weight are calculated. 
Extra-intestinal manifestations of Crohn’s Disease include arthritis/arthralgia, iritis/uveitis, 
erythema nodosum/pyoderma gangrenosum/aphthous stomatitis, anal fissure fistula, or abscess, 


 
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other fistula, and fever over 37.8°C during the past week. The total number of extra-intestinal 
manifestations is summed and multiplied by a factor of 20. 
If a subject used Lomotil/Imodium/opiates for diarrhea, they have a subscore of 30. Otherwise, 
their usage of Lomotil/Imodium/opiates for diarrhea subscore is 0. 
For a definite, questionable, or no abdominal mass, a subject receives a subscore of 50, 20, or 0, 
respectively. 
Hematocrit results are subtracted from 47 for males and from 42 for females to obtain the 
hematocrit subtotal. The hematocrit subtotal is then multiplied by a factor of 6 to determine the 
hematocrit subscore. If the hematocrit subtotal is 0, the hematocrit subscore is also 0. 
Lastly, the body weight subscore is obtained with the following formula: 
[1 −(
Body Weight
Standard Weight)] × 100 
where standard weight is calculated as (height in m)2 × 22.1 for males and (height in m)2 × 20.8 
for females. If the body weight subscore is < -10, the body weight subscore is set to -10. 
To calculate the total CDAI score for a study visit, sum all 8 component subscores at that 
particular study visit. If any of the 8 subscores are missing, the total CDAI score cannot be 
calculated for that study visit. 
7.1.8 Conventions for Missing Adverse Events Dates 
Every effort will be made to determine the actual onset date for the event or to obtain a reliable 
estimate for the onset date from the investigator. 
For AEs or SAEs, a missing or incomplete onset date will be imputed according to the following 
conventions: 
1. If an onset date is missing, the derived onset date will be calculated as the first non-
missing valid date from the following list (in order of precedence): 
 First study medication date 
 Informed consent date (for SAEs only) 
2. If an onset date is incomplete, the derived onset date will be calculated following: 
 Missing day, but month and year present: the day will be imputed as the 15th of the 
month. If the month and year are equal to the month and year of the first study 
medication dose and the first study medication dose occurs after the imputed date, the 
derived onset date will be set equal to the first study medication date. If the AE end 
date occurs prior to the imputed date, the derived onset date will be set equal to the 
AE end date. 
 Missing day and month, but year present: the day and month will be imputed as the 
30th June of the year. If the year is equal to the year of the first study medication dose 
and the first study medication dose occurs after the imputed date, the derived onset 


 
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date will be set equal to the first study medication date. If the AE end date occurs 
prior to the imputed date, the derived onset date will be set equal to the AE end date. 
 If the imputed AE onset date occurs after the database lock date, the imputed AE 
onset date will be imputed as the database lock date. 
For AEs or SAEs, a missing or incomplete end date will be imputed according to the following 
conventions: 
1. If an end date is missing, the derived end date will be imputed as the last assessment date, 
assuming that the last assessment occurs after the AE start. If the last assessment occurs 
prior to the AE start date, the derived end date will be imputed as the AE start date. 
2. If an end date is incomplete, the derived end date will be calculated following:  
 Missing day, but month and year present: the day will be imputed as the last date (for 
example February 2009 will be imputed as 28 February 2009) of the month. 
 Missing day and month, but year present: the day and month will be imputed as the 
31st December of the year. 
 If the imputed AE end date occurs after the database lock date, the imputed AE end 
date will be imputed as the database lock date. 
7.1.9 Conventions for Missing Concomitant Medications Dates 
Start and stop dates for all concomitant medications are collected on the eCRF. However, in case 
of missing or partial information in these dates, the following rules will be used: 
If the start date is missing or partial: 
 If the day is missing, the start day will be the first day of the month. 
 If the month is missing, the start month will be the month corresponding to 90 days prior 
to the first study medication date. 
 If the year is missing, the start year will be the minimum of the year of the first clinic 
visit or the year of the informed consent date. 
 If the entire date is missing, the start date will be the date of first study drug 
administration. 
If the stop date is missing, partial or “continuing”: 
 If the day is missing, the stop day will be the last day of the month reported. 
 If the month is missing, the stop month will be the month during which the last dose of 
treatment was administered. 
 If the year or the entire date is missing or if the medication is “continuing”, the stop year 
will be the year in which the last dose of treatment was administered. 
7.1.10 Conventions for Missing Previous Medications Dates 
No dates will be imputed for previous medications. 


 
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7.1.11 Conventions for Calculation of Duration of CD 
Duration of CD is calculated as the number of years from CD diagnosis date to first dose date: 
1 + datefirst dose −datediagnosis
365.25
 
The duration of CD will be included in the baseline CD characteristics listing. If the date CD was 
diagnosed is partially missing, the following rules will take effect: 
 Missing day, but month and year are present: the day will be imputed as the 15th day of 
the month. 
 Missing day and month, but year is present: the day and month will be imputed as 30th 
June of the year. 
7.1.12 Calculation of Body Mass Index 
BMI will be calculated as the ratio of patient’s weight (in kilograms) to the square of the 
patient’s height (in meters): 
BMI (kg
m2) = weight(kg)
[height(m)]2 
7.1.13 Methods for Handling of Missing Efficacy Data 
Through the end of the treatment period, the missing efficacy data will be handled as follows: 
 Missing data for dichotomous (i.e., proportion-based) endpoints will be handled using the 
non-responder imputation method, i.e. any subject with missing information for 
determination of endpoint status will be considered as a non-responder in the analysis.  
 Missing data for continuous endpoints will be imputed using last available post-baseline 
observation carried forward (LOCF) method. 
7.2 
ANALYSIS SETS 
 The Study Part A analyses will be performed on the following analysis sets: 
 The Full Analysis Set (FAS) will include all enrolled subjects who receive at least 1 dose 
of study drug. 
 The FAS-MREn is the FAS within the MREn substudy. 
 The Per Protocol Analysis Set (PPS) is a subset of the FAS and consists of all subjects 
who do not violate the terms of the protocol in a way that would impact the study 
outcome significantly. Major protocol violations that exclude a subject from the PPS are 
listed in Section 7.4. Efficacy analyses for the primary and secondary endpoints using the 
PPS population may be provided as part of a sensitivity analysis. 
 The PPS-MREn is a subset of the FAS-MREn and consists of all subjects who do not 
violate the terms of the protocol in a way that would impact the study outcome 
significantly. Major protocol violations that exclude a subject from the PPS-MREn are 


 
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listed in Section 7.4. Efficacy analyses for the MREn endpoints using the PPS-MREn 
population may be provided as part of a sensitivity analysis. 
The Study Part B analyses will performed on the following analysis sets: 
 The FAS-Extension is the subset of subjects in the FAS who consented to Part B. 
 The FAS-MREn-Extension is the subset of subjects in the FAS-MREn who consented to 
Part B. 
 The PPS-Extension is the subset of subjects in the FAS-Extension and consists of all 
subjects who do not violate the terms of the protocol in a way that would impact the 
study outcome significantly. Major protocol violations that exclude a subject from the 
PPS-Extension are listed in Section 7.4. Efficacy analysis for the primary and secondary 
endpoints using the PPS-Extension population may be provided as part of a sensitivity 
analysis. 
 The PPS-MREn-Extension is the subset of subjects in the FAS-MREn-Extension and 
consists of all subjects who do not violate the terms of the protocol in a way that would 
impact the study outcome significantly. Major protocol violations that exclude a subject 
from the PPS-MREn-Extension are listed in Section 7.4. Efficacy analysis for the MREn 
endpoints using the PPS-MREn-Extension population may be provided as part of a 
sensitivity analysis. 
The FAS and FAS-Extension will be used in both efficacy and safety analyses. The FAS-MREn 
and FAS-MREn-Extension will be used in the MREn analyses. Analyses using PPS, PPS-
Extension, PPS-MREn, and PPS-MREn-Extension populations may be provided as sensitivity 
analyses.  
Sensitivity analyses for the primary and secondary efficacy endpoints using PPS/PPS-Extension 
will be conducted only if more than 15% of the subjects in the FAS/FAS-Extension have at least 
1 significant protocol deviation. 
7.3 
DISPOSITION OF SUBJECTS 
Disposition will be evaluated for the following study periods: screening and treatment period.  
Disposition of all screened subjects (denominator) will be tabulated (count and percent).  
Disposition of screen failures (denominator) will be tabulated according to primary screen failure 
reason (e.g., pretreatment event, major protocol deviation, lost to follow-up, etc.) as entered on 
the eCRF. 
Disposition of all enrolled subjects will be tabulated as:  
 All enrolled subjects (denominator)  
 Subjects who were enrolled but not treated, if applicable  
 All subjects who completed the study drug/visits 
 All subjects who prematurely discontinued (permanently) study drug/visits 


 
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Primary reasons for discontinuation of study drug/visits, as entered on the eCRF, will be 
tabulated; the reasons include adverse event, significant protocol deviation, lost to follow-up, 
voluntary withdrawal, study termination, pregnancy, lack of efficacy and other.  
Disposition of enrolled subjects by analysis set will be also tabulated.  
The date of first dose, date of last dose, duration of treatment and the reason for premature 
discontinuation of study drug/study visit will be listed for each enrolled subject. A listing of 
inclusion/exclusion criteria responses by subject will also be provided. A separate listing of 
screen failures and criteria will be presented.  
Study information, including date first subject signed ICF, date of last subject’s last visit/contact, 
date of last subject’s last procedure for collection of data for primary endpoint, Medical 
Dictionary for Regulatory Activities (MedDRA) version, World Health Organization Drug 
Dictionary (WHODrug) version, and SAS Version will be presented. 
Summary of eligibility from entrance into the treatment phase will be tabulated and listed. 
The enrolled subjects who did not meet at least one inclusion criteria or who did meet at least 
one exclusion criteria will be listed. 
The number of subjects enrolled by site will be tabulated and listed. 
7.4 
MAJOR PROTOCOL VIOLATIONS 
Major protocol violations used to exclude subjects from the PPS population include: 
1. A missing Week 26 ileocolonoscopy. 
2. An Entry Criteria significant protocol deviation. 
Additional major protocol violations for exclusion from the PPS population may be finalized as 
part of a final data review and documented prior to database lock. 
Major protocol violations used to exclude subjects from the PPS-Extension population include: 
1. A missing Week 52 ileocolonoscopy. 
2. An Entry Criteria significant protocol deviation. 
Additional major protocol violations for exclusion from the PPS-Extension population may be 
finalized as part of a final data review and documented prior to database lock. 
Major protocol violations used to exclude subjects from the PPS-MREn population include: 
1. Missing numeric scores in more than 3 ileocolonic bowel segments at both Baseline and 
Week 26. 
Major protocol violations used to exclude subjects from the PPS-MREn-Extension population 
include: 
1. Missing numeric scores in more than 3 ileocolonic bowel segments at both Baseline and 
Week 52. 
All major protocol violations will be tabulated and listed. 


 
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7.5 
SIGNIFICANT PROTOCOL DEVIATIONS 
Significant protocol deviations will be collected onto the eCRF throughout the conduct of the 
study. Significant deviations will be tabulated using the following categories: 
 Entry Criteria 
 Concomitant Medication 
 Procedures Not Performed Per Protocol (Primary Endpoint or Safety Related) 
 Study Medication 
 Withdrawal Criteria 
Significant protocol deviations will be also listed by subject. 
7.6 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Table 7.g lists the variables which will be tabulated in the demographic and baseline 
characteristics table for enrolled subjects. 
Table 7.g 
Summaries of Demographic and Baseline Characteristics 
Demography (unit) 
Summarized as 
Categories 
Age (years) 
Continuous and 
Categorical 
<35, ≥ 35 
<65, ≥ 65 
<75, ≥ 75 
Gender 
Categorical 
Male 
Female 
Racea 
Categorical 
American Indian or Alaska Native 
Asian 
Black or African American 
Native Hawaiian or Other Pacific Islander 
White 
Ethnicity 
Categorical 
Hispanic or Latino 
Non-Hispanic and Latino 
Height (cm) 
Continuous 
 
Weight (kg) 
Continuous 
 
Body Mass Index (BMI) (kg/m2) 
Continuous 
 
Smoking Classification 
Categorical 
Subject has never smoked 
Subject is a current smoker 
Subject is an ex-smoker 
Female Reproductive Status 
Categorical 
Postmenopausal 
Surgically Sterile 
Female of Childbearing Potential 
N/A (Subject is a Male) 
a recorded on the eCRF. Subjects who identify themselves as more than one race on the eCRF will be classified as Multiracial 
for tabulation, and will be included only in the Multiracial category. 
Screen failures will be tabulated and listed for age, age group, gender, ethnicity and race. All 
other demographic and baseline characteristic summaries will be tabulated and listed using the 
FAS, the FAS-Extension, the FAS-MREn, and the FAS-MREn-Extension. In addition, original 
read MREn parameters (i.e., image adequacy, adequacy reason, relative contrast enhancement, 


 
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wall thickness, ulceration, edema, global MaRIA score, segmental MaRIA score, presence of 
fistulas, fistulas description, presence of obstructive lesions, fluid collections, fluid collection 
change, inflammatory mass, and inflammatory mass change) at the Screening visit for screen 
failures at the selected MREn substudy centers will be summarized for each ileocolonic segment 
and more proximal bowel segments, if evaluable, using the FAS-MREn and the FAS-MREn-
Extension. Ileocolonic bowel segments include the ascending colon, descending colon, 
transverse colon, sigmoid colon, rectum, and terminal ileum. Proximal bowel segments include 
the jejunum J-1, jejunum J-2, proximal ileum PI-1, and proximal ileum PI-2. 
Table 7.h lists the CD-related baseline characteristics which will be tabulated and listed. 
Table 7.h 
Summaries of CD-Related Baseline Characteristics 
Characteristics (unit) 
Summarized as 
Categories 
Duration of Crohn’s Disease (years) 
Continuous and 
Categorical 
< 1 year 
≥ 1 to < 3 years 
≥ 3 to < 7 years 
≥ 7 years 
Baseline CRP (mg/L) 
Continuous and 
Categorical 
≤ 2.87 mg/L 
> 2.87 mg/L ≤ 5 mg/L 
> 5 mg/L ≤ 10 mg/L 
> 10 mg/L 
Elevated baseline CRP (mg/L) 
Continuous and 
Categorical 
Yes (CRP > 2.87 mg/L) 
No  (CRP ≤ 2.87 mg/L) 
Concomitant use of oral corticosteroids 
Categorical 
Yes 
No 
Prior TNF-alpha status 
Categorical 
Naïve 
Failure 
Baseline Fecal Calprotectin (µg/g) 
Continuous and 
Categorical 
≤ 250 µg/g 
> 250 µg/g ≤ 500 µg/g 
> 500 µg/g 
Baseline CDAI Activity 
Continuous and 
Categorical 
≤ 330 
> 330 
Baseline SES-CD Score 
Continuous and 
Categorical 
<7 
7-15 (moderate) 
>15 (severe) 
In addition, Baseline MREn parameters for enrolled subjects at the selected MREn substudy 
centers will be summarized for each ileocolonic segment and more proximal bowel segments, if 
evaluable, using the FAS-MREn and the FAS-MREn-Extension. 
All individual demographic and baseline characteristics will be listed by region, site, and subject 
number. 
7.7 
MEDICAL HISTORY AND CONCURRENT MEDICAL CONDITIONS 
Summaries of medical history, defined as significant conditions or diseases that stopped at or 
prior to the time of informed consent, and concurrent medical conditions, defined as significant 
ongoing conditions or diseases present at signing of informed consent, will be summarized based 
on the FAS.  


 
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Medical history and concurrent medical conditions will be coded using the MedDRA (Version 
19 or higher) coding system. Medical history and concurrent medical conditions will be 
summarized by system organ class (SOC) and preferred term (PT). The tables will be sorted in 
alphabetic order by SOC and in decreasing frequency based on the total number of reports by 
preferred terms in each SOC. The number and percentage of subjects with any significant 
medical history and concurrent medical conditions will be summarized for each SOC and 
preferred term. The denominator used for calculating the percentages will be the total number of 
subjects. For the tables, if a subject reports the same preferred term multiple times, then that 
preferred term will be counted only once for that subject. Similarly, if a subject reports multiple 
conditions within the same SOC, then that SOC will be counted only once for that subject in the 
tables.  
All medical history and concurrent medical condition data will be listed by site and subject 
number. The listing will contain subject identifier, treatment, SOC, PT, whether there was any 
medical history or concurrent condition, and if yes, a detail of the medical history or concurrent 
condition. 
7.8 
MEDICATION HISTORY AND CONCOMITANT MEDICATIONS 
Summaries of medication history and concomitant medications will be tabulated based on the 
FAS.  
Medication history information to be obtained and recorded on the eCRF includes any 
medication relevant to eligibility criteria that stopped at or within 30 days prior to signing of 
informed consent. The CD prior biologic medication which have been stopped are recorded on 
the eCRF as well. 
Concomitant medications are recorded on the eCRF and include any medication other than study 
drug taken at any time between the times of informed consent through the end of the study. Any 
ongoing CD biologic medications are included with the Concomitant Medications.  
Medication history, CD prior biologic medications, and concomitant medications will be coded 
using the WHODrug dictionary (Version 01March 2015 or higher).  
Concomitant medications will be summarized by therapeutic classification and preferred 
medication name and will include only those medications taken at any time between the times of 
informed consent and on or prior to the last dose date of study drug. Concomitant medications 
will be classified and summarized separately as follows:  
 Concomitant medications that started and stopped prior to baseline: any medication 
stopped after time of informed consent and prior to the first dose of the study medication.  
 Concomitant medications that started prior to and were ongoing at baseline: any 
medication that started before and was not stopped prior to the first dose of the study 
medication.  
 Concomitant medications that started after baseline: any medication that started at or after 
the first dose of the study medication.  


 
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 Concomitant medications that were ongoing and started after baseline: any medication 
that started before and was not stopped prior to the first dose of the study medication or 
any medication that started at or after the first dose of the study medication. 
The tables for medication history and CD prior biologic medications will present the number and 
percentage of subjects by preferred medication name using the total number of subjects in the 
treatment arm as the denominator. Preferred medication names are sorted by decreasing 
frequency based on the total number of subjects. 
Separate listings for medication history, CD prior biologic medications, and concomitant 
medications will be produced by site and subject number. The listing for medication history will 
contain site number, subject number, treatment, WHODrug preferred medication name, dose, 
frequency, unit, route, end date, and whether the medication was ongoing. The listing for CD 
prior biologics medications which have been stopped will contain site number, subject number, 
treatment, WHODrug preferred medication name, dose, unit, frequency, route, start date, end 
date, reason for discontinuation, and primary reason for intolerance. The listing for concomitant 
medication will contain site number, subject number, treatment, WHODrug preferred medication 
name, dose, unit, frequency, route, start date, end date, study day, and whether the medication 
was given to treat PTE/AE. 
7.9 
STUDY DRUG EXPOSURE AND COMPLIANCE 
Study drug exposure will be summarized based on the FAS and the FAS-Extension.  
Exposure will be presented as the frequency and percentage of subjects who received complete 
infusions. A subject has received complete infusion if the total amount was infused as per data 
collected in eCRF.  
Duration of exposure will be calculated as (date of last dose – date of first dose) + 127. Duration 
of exposure will be summarized continuously and categorically. For Study Part A, duration of 
exposure will be summarized in the following categories: <20 Weeks, 20 – <24 Weeks, 24 - <32 
Weeks, 32 – <40 Weeks, and ≥ 40 Weeks. For Study Part B, duration of exposure will be 
summarized in the following categories: <56 Weeks, 56 - <64 Weeks, and ≥ 64 Weeks. 
Since all doses will be administered at in-clinic visits compliance will not be presented.  
All study drug administration and accountability data will be listed by site and subject number. 
The following variables will be listed: subject number, treatment, dose dates and times, dose 
interruption dates and times (if applicable), and completion status of infusion and reason for 
incomplete infusion. 
7.10 EFFICACY ANALYSIS 
This section describes the analyses to be conducted on the primary, secondary, and additional 
efficacy endpoints. 
All proportion-based efficacy endpoints will be summarized by presenting the point estimate and 
2-sided 95% confidence intervals (CIs) for the proportion. All subjects with missing data for 
determination of endpoint status will be considered as a non-responder in the analysis.  


 
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All change from Baseline-based efficacy endpoints will be summarized descriptively by time 
point for observed and change from Baseline values. Missing data will be imputed using the 
LOCF method. 
7.10.1 Primary Efficacy Endpoint 
Primary efficacy analysis will be summarized based on the FAS.  
The primary endpoint is the proportion of subjects achieving endoscopic remission, defined as a 
total SES-CD score of ≤ 4 at Week 26. The proportion of subjects with endoscopic remission and 
its 2-sided 95% CI will be calculated using the Clopper-Pearson method.  
Subjects with a missing SES-CD score at Week 26 will be considered as non-responders.   
All SES-CD score components will be listed by site and subject number for each bowel segment. 
7.10.1.1 
Sensitivity Analyses for Primary Efficacy Endpoint 
To assess the robustness of the primary efficacy analysis, the following additional analyses will 
be performed for the primary endpoint. 
 The proportion of subjects with endoscopic remission and its 2-sided 95% CI will be 
calculated excluding subjects with a Screening SES-CD score <7.  
 The proportion of subjects with endoscopic remission and its 2-sided 95% CI will be 
calculated using the PPS (if applicable). 
 The proportion of subjects with endoscopic remission and its 2-sided 95% CI will be 
calculated using the LOCF method. 
7.10.1.2 
Summaries of Primary Efficacy Endpoint within Subgroups 
The primary efficacy endpoint of endoscopic remission will be summarized for the following 
subgroups using the FAS, and the PPS (if applicable): 
 Baseline Disease Activity (CDAI) (≤330, > 330) 
 Duration of CD (<1 year, 1 – <3 years, 3 – <7 years, ≥7 years) 
 Geographic Region (North America, Western / Northern Europe, Central Europe, Eastern 
Europe, Africa / Asia / Australia) 
 Baseline CRP (≤5 mg/L, >5 mg/L; ≤10 mg/L, >10 mg/L) 
 Baseline Fecal Calprotectin (≤250 μg/g, >250 μg/g; ≤500 μg/g, >500 μg/g) 
 Prior TNF-alpha Status (Naïve, Failure) 
 Baseline SES-CD (<7, 7 to 15 (Moderate), >15 (Severe)) 
7.10.2 Secondary Efficacy Endpoints 


 
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Secondary efficacy analyses will be summarized based on the FAS and FAS-Extension. 
Subgroup analyses will be performed using prior TNF-alpha status (naïve, failure). 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for the observed and 
change from baseline values for the segmental SES-CD scores, the overall SES-CD score, and 
the CDAI score will be presented. 
The details collected on each of the below endpoints will be listed. 
7.10.2.1 
Complete Mucosal Healing 
The proportions of subjects with ulcerations at Baseline who achieve complete mucosal healing 
at Week 26 and Week 52 and their 2-sided 95% CI will be calculated. Complete mucosal healing 
is defined as the absence of ulceration, which is demarcated as an SES-CD variable ‘Size of 
Ulcers’ score of 0 (Appendix B), from the presence of ulceration at Baseline. Subjects with any 
missing ’Size of Ulcers’ score at Week 26 or Week 52 will be considered as non-responders. 
Complete mucosal healing will also be summarized for the subgroups listed in section 7.10.1.2 
based on the FAS, FAS-Extension, PPS, and PPS-Extension. 
7.10.2.2 
Endoscopic Remission  
Endoscopic remission at Week 14 and Week 52 will be analyzed following a similar approach 
outlined in section 7.10.1. 
7.10.2.3 
Endoscopic Response 
The proportions of subjects with endoscopic response (defined as SES-CD reduction by at least 
50% from baseline) at Week 14, Week 26, and Week 52 and their CIs will be calculated by 
bowel segment and overall. Subjects with a missing SES-CD at Week 14, Week 26, and/or Week 
52 will be considered as non-responders.  A sensitivity analysis will be performed for the 
proportion of subjects with endoscopic response and its 2-sided 95% CI using the LOCF method. 
Analyses for endoscopic response will also be performed overall and by prior TNF-alpha status 
(naïve, failure) based on the PPS and PPS-Extension. 
7.10.2.4 
Clinical Response 
The proportions of subjects achieving clinical response (CDAI score decrease from baseline of at 
least 100 points) at Week 10, Week 26, and Week 52 and their CIs will be calculated. Subjects 
with a missing CDAI score at Week 10, Week 26, and/or Week 52 will be considered as non-
responders. 
Analyses for clinical response will also be performed overall and by prior TNF-alpha status 
(naïve, failure) based on the PPS and PPS-Extension. 
 
 


 
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7.10.2.5 
Clinical Remission 
The proportions of subjects achieving clinical remission (CDAI score of at most 150) at Week 
10, Week 26, and Week 52 and their CIs will be calculated. Subjects with a missing CDAI score 
at Week 10, Week 26, and/or Week 52 will be considered as non-responders. 
Analyses for clinical remission will also be performed overall and by prior TNF-alpha status 
(naïve, failure) based on the PPS-Extension. 
7.10.2.6 
Durable Clinical Remission 
The proportion of subjects in Study Part B with durable clinical remission (defined as clinical 
remission at Week 26 and Week 52) at Week 52 and its CI will be calculated. Subjects with a 
missing CDAI score at Week 52 will be considered as non-responders. 
Analyses for durable clinical remission will also be performed overall and by prior TNF-alpha 
status (naïve, failure) based on the PPS-Extension. 
7.10.3 Additional Efficacy Endpoints 
Additional efficacy analyses will be summarized based on the FAS, FAS-Extension, FAS-
MREn, and FAS-MREn-Extension, as applicable. Subgroup analyses will be performed using 
prior TNF-alpha status (naïve, failure). 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) for the observed and 
change from baseline values for the ileal, colonic, and total Global Histological Disease Activity 
Scores (GHAS) will be presented. 
The correlation between subjects’ SES-CD scores and MaRIA scores by study visit will be 
explored by bowel segment and overall using scatter plots. The correlation between subjects’ 
CDAI score and global MaRIA score by study visit will be explored using scatter plots. 
The relationship between the various remission statuses, as defined by CDAI (i.e., clinical 
response and clinical remission), endoscopic (i.e., endoscopic response, endoscopic remission, 
and complete mucosal healing), imaging (i.e., ileocolonic remission by MREn, overall remission 
by MREn, ileocolonic response by MREn, and overall response by MREn), and histological (i.e., 
total GHAS ≤ 4) assessments, will also be explored using Pearson’s correlation coefficient in the 
following combinations:  
 Clinical Response and Endoscopic Response 
 Clinical Response and Endoscopic Remission 
 Clinical Response and Ileocolonic Remission by MREn 
 Clinical Response and Overall Remission by MREn 
 Clinical Response and Total GHAS ≤ 4 
 Clinical Remission and Endoscopic Response 
 Clinical Remission and Endoscopic Remission 


 
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 Clinical Remission and Ileocolonic Remission by MREn 
 Clinical Remission and Overall Remission by MREn 
 Clinical Remission and Total GHAS ≤ 4 
 Endoscopic Response and Ileocolonic Remission by MREn 
 Endoscopic Response and Overall Remission by MREn 
 Endoscopic Response and Total GHAS ≤ 4 
 Endoscopic Remission and Ileocolonic Remission by MREn 
 Endoscopic Remission and Overall Remission by MREn 
 Endoscopic Remission and Total GHAS ≤ 4 
 Complete Mucosal Healing and Ileocolonic Remission by MREn 
 Complete Musocal Healing and Ileocolonic Response by MREn 
 Ileocolonic Remission by MREn and Total GHAS ≤ 4 
 Overall Remission by MREn and Total GHAS ≤ 4 
The correlation between subjects’ change from Baseline in CDAI, change from Baseline in SES-
CD, change from Baseline in MaRIA, and change from Baseline in GHAS by study visit will be 
explored using scatter plots. 
The details collected on each of the below endpoints will be listed. 
7.10.3.1 
 
MREn Parameters 
Only original read MREn parameters will be utilized for analyses. 
Continuous individual MREn parameters (i.e., relative contrast enhancement, wall thickness, 
global MaRIA score, and segmental MaRIA score) for each ileocolonic segment (i.e., ascending 
colon, transverse colon, descending colon, sigmoid colon, rectum, and terminal ileum) and more 
proximal bowel segments (i.e., jejunum J-1, jejunum J-2, proximal ileum PI-1, and proximal 
ileum PI-2), if evaluable, will be summarized descriptively at Baseline, each post-Baseline visit, 
and change from Baseline to each post-Baseline visit. 
Shifts in categorical individual MREn parameters (i.e., ulceration, edema, presence of fistulas, 
fistulas description, presence of obstructive lesions, fluid collections, fluid collection change, 
inflammatory mass, and inflammatory mass change) between baseline and each post-baseline 
visit for each ileocolonic segment and more proximal bowel segments, if evaluable, will be 
presented as cross-tabulations of responses with missing, if applicable, and total categories. 
Scheduled visits for MREn are at Baseline, Week 26, and Week 52. 
Missing data will not be imputed. Original read and re-read MREn parameters will be listed. 
 
 


 
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7.10.3.2 
MaRIA Scores 
The proportions of subjects achieving segmental MaRIA score <7 at Baseline, Week 26, and 
Week 52 and their CIs will be calculated. The proportions of subjects achieving segmental 
MaRIA score <11 will be calculated similarly. In addition, the proportion of subjects achieving 
ileocolonic remission and response by MREn and overall remission and response by MREn at 
Baseline, Week 26, and Week 52 and their CIs will be calculated. The MREn-based measures of 
interest are defined as follows: 
 Ileocolonic remission is defined as a post-Baseline segmental MaRIA score <7 in every 
ileocolonic segment from a Baseline segmental MaRIA score ≥7 in any ileocolonic 
segment. 
 Overall remission is defined as a post-Baseline segmental MaRIA score <7 in every 
segment, whether ileocolonic or proximal, from a Baseline segmental MaRIA score ≥7 in 
any segment.  
 Ileocolonic response is defined as a post-Baseline segmental MaRIA score <11 in every 
ileocolonic segment from a Baseline segmental MaRIA score ≥11 in any ileocolonic 
segment. 
 Overall response is defined as a post-Baseline segmental MaRIA score <11 in every 
segment, whether ileocolonic or proximal, from a Baseline segmental MaRIA score ≥11 
in any segment. 
The proportion of subjects with 25%, 50%, and 75% reduction in ileocolonic MaRIA score at 
Week 26 and Week 52 and their CIs will be calculated by ileocolonic bowel segment. 
In addition, the correlation between the SES-CD size of ulcers parameter and the MaRIA 
ulceration parameter (Yes/No) at Baseline, Week 26, and Week 52 will be explored by bowel 
segment using the chi-squared test. For comparison purposes between SES-CD, GHAS, and 
MaRIA, the following assumptions will be taken: 
 The SES-CD size of ulcers parameter will be dichotomized with ‘None’ and ‘Aphthous 
ulcers’ as ‘Aphthous or None’ and ‘Large ulcers’ and ‘Very large ulcers’ as ‘Ulcers > 0.5 
cm’. 
 The MaRIA ulceration parameter for the descending colon and sigmoid colon will be 
combined into ‘descending and sigmoid colon’, where a ‘No’ response requires a lack of 
ulceration in both the descending colon and the sigmoid colon. 
 The MaRIA scores for the descending colon and sigmoid colon will be added together to 
create ‘descending and sigmoid colon’ for continuous comparisons. 
7.10.3.3 
SES-CD Score Reduction 
The proportions of subjects with 25% and 75% reduction of SES-CD at Week 14, Week 26, and 
Week 52 and their CIs will be calculated by bowel segment and overall. 
 
 


 
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7.10.3.4 
Granulocyte Presence 
The proportion of subjects with no granulocytes present in the bowel biopsy at Baseline, Week 
26, and Week 52 and their CIs will be calculated. The presence of granulocytes is defined by the 
presence of lamina propria neutrophils and/or neutrophils in the epithelium, which are described 
in Section 7.10.3.5. In addition, the proportion of subjects with no granulocytes present in the 
bowel biopsy at Week 26 and Week 52 will be presented for subjects with granulocytes present 
at Baseline. 
7.10.3.5 
Histology Change 
Histology parameters, classified as features of chronicity or features of activity, are given a score 
by a pathologist as follows: 
Classification 
Parameter 
Score 
 
Features of Chronicity 
 
Structural (Architectural) Change 
0 
None 
 
1 
Not severe 
 
2 
Severe 
Chronic Inflammatory Infiltrate 
0 
None 
 
1 
Increased but not very dense infiltrate 
 
2 
Very dense infiltrate 
Features of Activity 
Lamina Propria Neutrophils 
0 
None 
 
1 
Some but not readily detectable 
 
2 
Easily detectable at low magnification 
Neutrophils in Epithelium 
0 
None 
 
1 
In surface epithelium 
 
2 
In crypt epithelium, with or without 
abscesses 
Epithelial Damage 
0 
None 
 
1 
Some degenerative or regenerative 
changes, less than half of epithelium, 
irrespective of surface or crypts 
 
2 
Some degenerative or regenerative 
changes, more than half of epithelium, 
irrespective of surface or crypts 
Erosion or Ulceration 
0 
None 
 
1 
Strictly defined by the presence of 
granulation tissue 
Epithelioid Granuloma 
0 
None 
 
1 
Present 
The modified GHAS is calculated as the sum of all individual scores for each parameter listed 
above, for each individual biopsy [4]. The features of chronicity GHAS, features of activity 
GHAS, and total segmental GHAS will be calculated for each bowel segment using the highest 
total score in that segment. The ileal GHAS (IGHAS) is defined as the segmental GHAS for the 
ileum. The colonic GHAS (CGHAS) is defined as the highest segmental GHAS amongst the 
rectum, descending/sigmoid colon, transverse colon, and ascending colon. The features of 
chronicity score ranges between 0 and 4, and the features of activity score ranges between 0 and 
8. The IGHAS, CGHAS, and segmental GHAS range between 0 and 12. 


 
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The proportions of subjects meeting the following criteria will be presented: 
 IGHAS ≤ 4 at Baseline, Week 26, and Week 52 and their CIs 
 CGHAS ≤ 4 at Baseline, Week 26, and Week 52 and their CIs 
 Both IGHAS and CGHAS ≤ 4 at Baseline, Week 26, and Week 52 and their CIs 
The proportions listed above will also be presented for subjects who had a modified GHAS score 
> 4 at Baseline. 
The proportions of subjects with an IGHAS or CGHAS ≤ 4 and no neutrophils, defined as no 
lamina propria neutrophils and no neutrophils in the epithelium, at Baseline, Week 26, and Week 
52 and their CIs will be calculated. Also, the proportions of subjects with an IGHAS or CGHAS 
≤ 4 and no neutrophils at Week 26 and Week 52 will be presented for subjects with a modified 
GHAS score > 4 or neutrophils at Baseline. 
Change from baseline in features of chronicity GHAS, features of activity GHAS, total 
segmental GHAS, and CGHAS will be presented using descriptive statistics. 
7.10.3.6 
Normalization of CRP 
The proportions of subjects with elevated CRP at Baseline (CRP > 2.87 mg/L) who achieve 
normalization of CRP (CRP ≤ 2.87 mg/L) at Week 10, Week 26, Week 38, and Week 52 and 
their CIs will be calculated. 
CRP results will be summarized at Baseline, each post-Baseline visit, and change from Baseline 
to each post-Baseline visit. Scheduled visits collection for CRP are at Baseline, Week 10, Week 
26, Week 38, and Week 52. 
7.10.3.7 
Fecal Calprotectin 
Fecal calprotectin results from stool samples will be summarized at Baseline, each post-Baseline 
visit, and change from Baseline to each post-Baseline visit. Scheduled visits for stool sample 
collection for fecal calprotectin evaluation are at Baseline, Week 14, Week 26, Week 38, and 
Week 52. 
7.10.3.8 
Positive for AVA 
A positive AVA subject is defined as a subject who has at least 1 positive AVA result in any 
postbaseline sample. The proportions of subjects positive for AVA at Baseline, Week 26, Week 
52, and the Postdose 18 Week Safety Follow-up Visit and their CIs will be calculated. 
7.10.3.9 
Positive Neutralizing AVA 
A positive neutralizing AVA is defined as a sample that was evaluated as positive in the 
neutralizing AVA assay. The proportions of subjects with positive neutralizing AVA at Baseline, 
Week 26, Week 52, and the Postdose 18 Week Safety Follow-up Visit and their CIs will be 
calculated. 


 
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7.10.3.10 Clinical Response 
Clinical response at Week 38 and Week 46 will be analyzed following a similar approach 
outlined in section 7.10.2.4. 
7.10.3.11 Clinical Remission 
Clinical remission at Week 38 and Week 46 will be analyzed following a similar approach 
outlined in section 7.10.2.5. 
7.10.3.12 Corticosteroid-Free Remission 
The proportions of subjects with any corticosteroid use at Baseline who discontinue all 
corticosteroids by Week 10, Week 14, Week 26, and Week 52 and their CIs will be calculated. 
The proportions of subjects with corticosteroid-free remission at Week 10, Week 14, Week 26, 
and Week 52 and their CIs will be calculated. Corticosteroid-free remission is defined as the 
achievement of clinical remission with the discontinuation of corticosteroid use post-Baseline 
from the use of corticosteroids at Baseline. 
7.11 PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS 
There is no pharmacokinetic or pharmacodynamic analysis planned for this study. 
7.12 OTHER OUTCOMES 
The patient reported outcomes (PRO) analysis includes the change from baseline in QOL 
measures that will be summarized descriptively overall and by endoscopic remission status. 
Subjects will complete the IBDQ, EQ-5D, and WPAI-CD health related QOL questionnaires at 
Baseline, Week 14, Week 26, Week 38, and Week 52. The QOL questionnaires will be 
summarized at Baseline, each post-Baseline visit, and change from Baseline to each post-
Baseline visit. Missing data will be imputed using the LOCF method. 
Derivation guidelines for IBDQ, EQ-5D, and WPAI-CD are documented in Appendix G of the 
SAP. 
The responses collected on each of the QOL questionnaires will be listed. 
7.12.1 IBDQ 
The IBDQ is a valid and reliable instrument used to assess quality of life in adult patients with 
IBD. It includes 32 questions on 4 domains of health-related quality of life (HRQOL): Bowel 
Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic 
Function (5 items). Patients are asked to recall symptoms and quality of life from the last 2 
weeks and rate each item on a 7-point Likert scale (higher scores equate to higher quality of life). 
A total IBDQ score is calculated by summing the scores from each domain; the total IBDQ score 
ranges from 32 to 224. 
 
 


 
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7.12.2 EQ-5D Questionnaire 
The EQ-5D questionnaire, developed by EuroQol, is a simple, valid, and reliable instrument used 
to measure general health-related quality of life in patients and includes five domain items - 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Patients choose the 
level of health problems they currently have on each item as “None”, “Moderate”, or “Extreme” 
and are scored a 1, 2, or 3, respectively. A composite EQ-5D score can be calculated from the 
individual scores to assess overall HRQOL. The EQ-5D VAS score is a self-assigned rating of 
overall health using a 20 cm visual, vertical scale, with a score of 0 as the worst and 100 as best 
possible health. The EQ-5D total score and EQ-5D VAS score have been shown in many studies 
to be valid and reliable instruments for measuring HRQOL in patients with GI diseases. 
7.12.3 WPAI-CD 
The WPAI questionnaire is a valid and reliable 6-item instrument that consists of four metrics: 
absenteeism (the percentage of work time missed because of one’s health in the past seven days), 
presenteeism (the percentage of impairment experienced while at work in the past seven days 
because of one’s health), overall work productivity loss (an overall impairment estimate that is a 
combination of absenteeism and presenteeism), and activity impairment (the percentage of 
impairment in daily activities because of one’s health in the past seven days). WPAI outcomes 
are expressed as impairment percentages, with higher numbers indicating greater impairment and 
less productivity, i.e., worse outcomes. WPAI-CD is the specific disease version of the 
questionnaire for Crohn’s Disease. 
7.13 SAFETY ANALYSIS 
Safety analyses include AEs, clinical laboratory values, vital signs, and ECGs. All safety 
summaries will be based on the FAS and FAS-Extension. The analysis of safety data will be 
restricted to descriptive statistics only, unless otherwise specified.  
7.13.1 Adverse Events 
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.  
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. Pretreatment events and AEs will be coded using MedDRA Version 19 or higher. AEs 
will be summarized using the MedDRA SOC, high level term (HLT), and PT. 
Treatment-emergent adverse events (TEAEs) will be defined as any AE that occurs after the first 
dose of study drug and up to the last dose or early termination plus applicable follow up (i.e., 18 
weeks). 
If the onset date of an AE is equal to the date of first dose of study medication and the AE was 
documented as a PTE on the eCRF, the AE will be classified as a PTE. Otherwise, the AE will 
be flagged as a TEAE. 


 
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When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or HLT or PT when multiple TEAEs are coded to the same 
SOC or HLT or PT. Thus, if a subject has two distinct AEs, each of which corresponds to a 
distinct PT but both of which correspond to the same HLT, then that subject will be counted once 
at that HLT subject-count summary level and once at each of the two preferred-term subject-
count summary levels within an HLT. This same logic is extended to all PT nested within HLT 
that is in-turn nested within an SOC. For the intensity summaries, if a subject reports multiple 
treatment-emergent AEs coded to the same SOC or HLT or PT then the TEAE with maximum 
intensity will be included in the summary.  
TEAEs with missing intensity will be listed as such in the TEAE listings, however, will be 
summarized as severe in summary tables. If the relationship of a TEAE is missing, the 
relationship for the TEAE will be considered to have been related. In the cases where a subject 
has multiple TEAEs with the same SOC or HLT or PT, the TEAE with the maximum intensity or 
strongest relationship will be summarized.  
Most frequent TEAEs are defined as events that occur in at least 3% of subjects within the 
treatment group.  
TEAEs will include the number and percentage of subjects as follows:  
 Overview of Treatment-Emergent Adverse Events  
 Treatment-Emergent Adverse Events by System Organ Class, High Level Term, and 
Preferred Term 
 Subject Mappings of Treatment-Emergent Adverse Events 
 Treatment-Emergent Adverse Events by System Organ Class  
 Treatment-Emergent Adverse Events by High Level Term  
 Treatment-Emergent Adverse Events by Preferred Term  
 Treatment-Emergent Adverse Events by Baseline AVA Status, System Organ Class, 
High Level Term, and Preferred Term 
 Most Frequent Treatment Emergent Adverse Events by Preferred Term  
 Most Frequent Non-Serious Treatment Emergent Adverse Events by Preferred Term  
 Relationship of Treatment-Emergent Adverse Events to Study Drug by System Organ 
Class, High Level Term, and Preferred Term  
 Intensity of Treatment-Emergent Adverse Events by System Organ Class, High Level 
Term, and Preferred Term  
 Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ Class, 
High Level Term, and Preferred Term  
 Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System 
Organ Class, High Level Term, and Preferred Term 


 
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 Subject Mappings for Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation 
 Serious Treatment-Emergent Adverse Events by System Organ Class, High Level Term, 
and Preferred Term 
 Subject Mappings for Serious Treatment-Emergent Adverse Events 
 Serious Treatment-Emergent Adverse Events by Baseline AVA Status, System Organ 
Class, High Level Term, and Preferred Term 
 Adverse Events Related to Study Procedures by System Organ Class, High Level Term, 
and Preferred Term 
 Treatment-Emergent Infections by System Organ Class, High Level Term, and Preferred 
Term 
 Pretreatment Events by System Organ Class, High Level Term, and Preferred Term 
 Pretreatment Serious Events by System Organ Class, High Level Term, and Preferred 
Term 
Data listings will be provided for PTEs, TEAEs, TEAEs leading to study drug discontinuation, 
SAEs, AEs that resulted in death, and AEs occurring more than 30 days post treatment. 
7.13.1.1 
Adverse Events of Special Interest 
Based on the mechanism of action of vedolizumab, certain adverse events of special interest 
(AESIs) have been predefined. The categories of adverse events of special interest, and other 
planned analyses, are described below.  
Infusion-Related Reactions (IRRs), including Hypersensitivity Reactions  
The clinical database will be searched for possible IRRs during the reporting period using the 
following MedDRA 19.0 search criteria: 
 Anaphylactic/anaphylactoid shock conditions Standard MedDRA Query (SMQ) (broad) 
 Angioedema SMQ (broad)  
 Hypersensitivity SMQ (broad) 
 Infusion related reaction HLT 
An AE that is indicated as an infusion site reaction in the eCRF will also be considered an IRR 
AESI. 
Infusion-related AEs will be summarized by SOC, HLT, and PT. In addition, all AEs beginning 
on, or one calendar day after, the dates of study drug infusions will be similarly analyzed.  
Upper Respiratory Tract Infections 
The infections retrieved from the clinical database will be evaluated for upper respiratory tract 
infections during the reporting period using the MedDRA 19.0 search criteria of:  


 
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 Upper respiratory tract infections HLT in the Infections and Infestations SOC 
 Bronchitis PT 
 Influenza PT 
Upper respiratory tract infections will be summarized by SOC, HLT, and PT. 
Gastrointestinal (GI) Infections 
The infection reports retrieved from the clinical database were evaluated for GI infections during 
the reporting period using the MedDRA 19.0 search criteria of:  
 Abdominal and gastrointestinal infections HLT in the Infections and infestations SOC 
 Gastrointestinal infections HLT of the Gastrointestinal disorders SOC 
GI infections will be summarized by SOC, HLT, and PT. 
Suspected Progressive Multifocal Leukoencephalopathy (PML) 
The protocol incorporates an active screening program in order to identify and manage any case 
of PML (Protocol Section 11.1.1). This program is known as the Risk Assessment and 
Minimization for PML (RAMP). The clinical database will be searched for suspected PML 
reports received within the Infection and Infestation SOC using the MedDRA 19.0 search criteria 
of:  
 Human polyomavirus infection PT 
 JC virus infection PT 
 JC virus test positive PT 
 Leukoencephalopathy PT 
 Polyomavirus test positive PT 
 Progressive multifocal leukoencephalopathy PT 
Suspected PML will be summarized by SOC, HLT and PT along with the results of the RAMP 
screening program. 
Other Infections, including Opportunistic Infections 
The infection reports retrieved from the clinical database, not classified as upper respiratory tract 
infections (URTIs), GI infections, or suspected PML will be searched using the MedDRA 19.0 
search criteria of:  
 Infections and Infestations SOC  
The following reports will then be excluded: 
 Abdominal and gastrointestinal infections HLT  
 URTI HLT 
 Bronchitis PT 


 
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 Influenza PT 
 Human polyomavirus infection PT 
 JC virus infection PT 
 JC virus test positive PT 
 Leukoencephalopathy PT 
 Polyomavirus test positive PT 
 Progressive multifocal leukoencephalopathy PT 
Other infections will be summarized by SOC, HLT and PT. 
Liver Injury 
The clinical database will be searched for reports of liver injury using the following MedDRA 
19.0 search criteria: 
 Cholestasis and jaundice of hepatic origin SMQ (broad)  
 Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions SMQ 
(broad) 
 Hepatitis, non-infectious SMQ (broad)  
 Liver related investigations, signs and symptoms SMQ (narrow)  
 Liver infections SMQ (broad) 
Liver Injuries will be summarized by SOC, HLT and PT. 
Malignancies 
The clinical database will be searched for reports of malignancy using the MedDRA 19.0 search 
criteria of:  
 Neoplasms benign, malignant and unspecified (incl cysts and polyps) SOC. 
Malignancies will be summarized by SOC, HLT, and PT. 
7.13.2 Clinical Laboratory Evaluations 
Clinical laboratory tests will be evaluated and presented using the International System of Units 
(SI) unless otherwise stated. Refer to Appendix A for scheduled measurements for clinical 
laboratory tests and to Table 7.i for a list of all Protocol-specified clinical laboratory tests. The 
central laboratory will perform laboratory tests for serum chemistries, hematology, and 
urinalysis. All laboratory test parameters will be displayed in individual subject data listings in 
SI units. For test results not in SI units, the conversion to SI units will be done in the derived 
analysis data sets using the known conversion factors. If necessary, SI units from the central 
laboratory may be converted to Takeda’s preferred SI units in the derived dataset. All summaries 
and analyses will be based on the values using these preferred SI units. If a lab test with 
quantitative results has a value that is reported using a non-numeric qualifier (e.g., less than (<) a 


 
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certain value, or greater than (>) a certain value), the given numeric value will be used in the 
summary statistics, ignoring the non-numeric qualifier. 
The following summaries of hematology, serum chemistry and urinalysis lab tests will be 
presented for each scheduled time point (Baseline, each post-Baseline visit, and Final Visit). 
The observed and change from Baseline values will be based on a single data value selected 
according to the window conventions described in Table 7.a, Table 7.b, Table 7.c, and Table 7.d. 
Note that “character” urinalysis parameters will only be listed. 
Shifts in laboratory test values will be presented as cross-tabulations (Baseline versus each post-
Baseline visit and Final Visit) of numbers of subjects with low, normal, and high values relative 
to the normal range used at the central laboratory. This classification will be based on the low, 
normal, and high alert flags reported by the central laboratory. If a subject has multiple values 
within a particular visit window, the most extreme result will be used for summary. Shift tables 
will be produced for all clinical laboratory tests with reference ranges.  
Listings of all clinical safety laboratory data will be provided, including hematology, serum 
chemistry, and urinalysis. Laboratory data outside of the normal reference range will be 
indicated in the listings. In addition, markedly abnormal values (MAVs) will be flagged. The 
listing will also include the site, subject number, age (at informed consent), gender, treatment 
group, study visit, and sample collection date. 


 
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Table 7.i 
Protocol-Specified Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis (dipstick) 
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  
eGFR (for MREn subjects only) 
Bilirubin 
Blood  
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein  
Specific Gravity  
Other: 
HIV 
Hepatitis panel, including HBsAg and anti-HCV 
CRP 
AVA 
Quantiferon for TB 
Beta hCG and Urine Pregnancy hCG 
(female subjects of childbearing potential) 
FSH, if menopause is suspected 
Stool: 
Fecal calprotectin 
 
FSH=follicle-stimulating hormone, GGT= γ-Glutamyl transferase, HBsAg=hepatitis B surface antigen, hCG=human chorionic 
gonadotropin, PT=prothrombin time, RBC=red blood cells. 
MAV laboratory results, identified as defined by the criteria in Appendix E, will be tabulated. 
MAV tables will include all laboratory parameters with available MAV criteria. 
Additionally, for each subject with a MAV for a parameter, all the subject’s values of that 
parameter will be listed.  
Subject mappings for the MAV summary table will be provided. 
7.13.3 Vital Signs 
Vital signs, including pulse, systolic blood pressure (SBP), diastolic blood pressure (DBP), 
temperature, respiration rate, and weight, will be summarized. Vital sign values will be tabulated 
at Baseline and at each post-Baseline visit, and change from Baseline will be calculated for each 
post-Baseline visit and Final Visit. Refer to Appendix A for scheduled measurements for vital 
signs. 
Criteria for MAV vital signs are listed in Appendix F. The number and percentage of subjects 
who meet MAV vital signs criteria will be summarized.  


 
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Vital signs data will be listed by site number and subject number. In addition, markedly 
abnormal values (MAVs) will be flagged. The listing will include site number, subject number, 
treatment group, age, gender, study visit, and assessment date. 
7.13.4 12-Lead ECGs 
Overall ECG interpretation category (normal, not clinically significant abnormal, clinically 
significant abnormal) is collected by eCRF at Screening.  
ECG data will be listed by site number and subject number. The listing will include site number, 
subject number, treatment group, age, gender, study visit, and assessment date. 
7.13.5 Other Observations Related to Safety 
The other safety endpoints to be included in the listings are the liver function tests for increase, 
sign and symptoms, event history, and test results. Also included are the details of infection, their 
diagnostic tests, cause/origin, history preceding events, and associated symptoms. The 
malignancy status based on diagnostic tests, stage, the risk factors, and details will also be listed. 
The PML checklist that includes the PML criteria, their response, symptoms, result, and 
abnormality will be listed by visit. The listings will also include the PML algorithm and the 
responses by visit. 
7.14 INTERIM ANALYSIS 
Formal interim analyses will be conducted for final efficacy at Weeks 14, 26, and 52, and for 
safety using the FAS and FAS-Extension, unless otherwise noted. 
The Week 14 interim analysis will include the secondary and additional endpoints along with all 
safety endpoints, including: 
 Disposition of Subjects 
 Demographic and Baseline Characteristics 
 Medication History and Concomitant Medications 
 Study Drug Exposure and Compliance 
 Secondary Efficacy Endpoints: endoscopic remission at Week 14, endoscopic response at 
Week 14, clinical response at Week 10, clinical remission at Week 10 
 Additional Efficacy Endpoints: 25% and 75% reduction of SES-CD at Week 14, 
normalization of CRP at Week 10, change from Baseline to Week 14 in fecal 
calprotectin, change from Baseline to Week 14 in IBDQ total and subscale scores, change 
from Baseline to Week 14 in EQ-5D utility score and VAS score, change from Baseline 
to Week 14 in percent work time missed due to CD, change from Baseline to Week 14 in 
percent impairment while working due to CD, change from Baseline to Week 14 in 
percent overall work impairment due to CD, change from Baseline to Week 14 in percent 
activity impairment due to CD 
 Safety Endpoints: AEs, AESIs, laboratory results, vital signs, ECGs 


 
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For subjects who have completed the Week 26 visit by the Week 14 interim lock date, the 
endpoints listed below for Week 26 will be included in the Week 14 interim analysis for 
publication purposes. 
The Week 26 interim analysis will include the endpoints listed above for Week 14 as well as 
added primary, secondary, and additional endpoints, including: 
 Primary Efficacy Endpoint: endoscopic remission at Week 26 
 Secondary Efficacy Endpoints: complete mucosal healing at Week 26, endoscopic 
response at Week 26, clinical response at Week 26, clinical remission at Week 26 
 Additional Efficacy Endpoints: 25% and 75% reduction of SES-CD at Week 26, no 
granulocytes present in bowel biopsy at Week 26, change in histology at Week 26, 
normalization of CRP at Week 26, change from Baseline to Week 26 in fecal 
calprotectin, change from Baseline to Week 26 in IBDQ total and subscale scores, change 
from Baseline to Week 26 in EQ-5D utility score and VAS score, change from Baseline 
to Week 26 in percent work time missed due to CD, change from Baseline to Week 26 in 
percent impairment while working due to CD, change from Baseline to Week 26 in 
percent overall work impairment due to CD, change from Baseline to Week 26 in percent 
activity impairment due to CD 
The Week 52 interim analysis will include the endpoints listed above for Weeks 14 and 26 as 
well as added secondary and additional endpoints, including: 
 Secondary Efficacy Endpoints: complete mucosal healing at Week 52, endoscopic 
response at Week 52, clinical response at Week 52, clinical remission at Week 52, 
durable clinical remission 
 Additional Efficacy Endpoints: change from Baseline to Week 26 in individual MREn 
parameters for each ileocolonic segment and for more proximal bowel segments (using 
the FAS-MREn), change from Baseline to Week 52 in individual MREn parameters for 
each ileocolonic segment and for more proximal bowel segments (using the FAS-MREn), 
MaRIA score < 7 at Week 26 and Week 52 globally and on a per segment basis, 25% and 
75% reduction of SES-CD at Week 52, no neutrophils present in bowel biopsy at Week 
52, change in histology at Week 52, normalization of CRP at Weeks 38 and 52, change 
from Baseline to Weeks 38 and 52 in fecal calprotectin, AVA positive at Week 52, 
positive neutralizing AVA at Week 52, clinical response at Weeks 38 and 46, clinical 
remission at Week 38 and 46, change from Baseline to Weeks 38 and 52 in IBDQ total 
and subscale scores, change from Baseline to Weeks 38 and 52 in EQ-5D utility score 
and VAS score, change from Baseline to Week 52 in percent work time missed due to 
CD, change from Baseline to Week 52 in percent impairment while working due to CD, 
change from Baseline to Week 52 in percent overall work impairment due to CD, change 
from Baseline to Week 52 in percent activity impairment due to CD 
For the interim analyses outlined above, subgroup analysis of the primary, secondary, and 
additional efficacy endpoints will be conducted on prior TNF-alpha status (naïve, failure). 


 
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7.15 CHANGES IN THE STATISTICAL ANALYSIS PLAN  
Not applicable. 


 
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8.0 
REFERENCES 
1. An Open-Label Phase 3b Study to Assess Mucosal Healing in Subjects With Moderately to 
Severely Active Crohn’s Disease Treated With Vedolizumab IV, Takeda Development 
Center Americas, Inc., Protocol No. MLN0002-3028, Amendment 04, dated 28 April, 2016. 
2. Daperno M, D’Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development 
and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-
CD. Gastrointest Endosc 2004; 60(4):505-12. 
3. 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. 
4. Geboes K and Dalle I. Influence of treatment on morphological features of mucosal 
inflammation. Gut 2002; 50 Suppl 3:iii37-iii42. 
 
 


 
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9.0 
APPENDICES 
Appendix A Schedule of Study Procedures 
 
 
 


 
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(a) Week 26 is the final visit for subjects completing at Week 26 (Study Part A) and for subjects who continue to extension of treatment (Study Part B) this is a standard visit. 
(b) Assessment completed or sample taken pre-dose. 
(c) Collect prior biologic medications that stopped prior to screening. 
(d) Height collected only at the Screening Visit. 
(e) The components of the CDAI score to determine eligibility must be completed within 14 days prior to enrollment using hematocrit results collected during Screening. 
(f) CDAI score components are to be performed prior to dosing; the total CDAI score will be calculated once results are available for all components. 
(g) Biopsies to be collected at Screening, Week 26, and Week 52 for those completing the study. 
(h) MREn conducted only at pre-identified sites. During the Screening period MREn should be performed prior to ileocolonoscopy. At Week 26 and Week 52 MREn to be performed prior 
to ileocolonoscopy either on the same day or at least 7 days before the ileocolonoscopy within the permitted time window for Week 26 or Week 52 procedures. Sites participating in 
MREn will need to check eGFR prior to procedure at Screening, Week 26, and Week 52 (using eGFR calculated from the Week 22 Visit for the Week 26 MREn and from the Week 46 
Visit for the Week 52 MREn). 
(i) Stool sample to be collected and sent to central laboratory for evaluation of fecal calprotectin. 
(j) QuantiFERON® test or tuberculin skin test only. 
(k) Hepatitis and HIV testing only done at the Screening Visit. 
(l) Only subjects participating in MREn to have a sample for serum creatinine collected at Week 22 and Week 46. Samples will be sent to central laboratory for evaluation of eGFR. 
(m) DNA and RNA samples will be collected on Day 1 only for subjects that have consented to the Pharmacogenomic study. 
(n) Serum pregnancy completed at Screening and at the Postdose 18 Week Safety Follow-up Visit; urine pregnancy to be completed at other visits. 
(o) Long Term Follow-up Wallet card will be given to subjects at the last clinical visit.


 
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Appendix B Simple Endoscopic Score for Crohn's Disease (SES-CD) 
 
Simple Endoscopic Score for Crohn’s Disease values 
Variable 
0 
1 
2 
3 
Size of ulcers 
None 
Aphthous ulcers 
 (Ø 0.1 to 0.5 cm) 
Large ulcers 
 (Ø 0.5 to 2 cm) 
Very large ulcers 
 (Ø >2 cm) 
Ulcerated surface 
None 
<10% 
10-30% 
>30% 
Affected surface 
Unaffected segment 
<50% 
50-75% 
>75% 
Presence of narrowings 
None 
Single, can be passed 
Multiple, can be passed 
Cannot be passed 
Ø, Diameter. 
Source: 
Adapted from Daperno M, D’Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development and validation of a new, 
simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc 2004; 60(4):505-12 [2]. 
 
 


 
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Appendix C Crohn's Disease Activity Index (CDAI) 
 
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 [3]. 
(a) If hematocrit subtotal < 0, enter 0. 
(b) If body weight subtotal < -10, enter -10. 
 


 
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Appendix D Geographic Regions 
Region 
Countries 
North America 
Canada 
Puerto Rico 
United States 
Western / Northern 
Europe 
Austria 
France 
Ireland 
Norway 
Sweden 
Belgium 
Germany 
Italy 
Portugal 
Switzerland 
Denmark 
Iceland 
Netherlands 
Spain 
United Kingdom 
Central Europe 
Czech Republic 
Poland 
Slovak Republic 
Greece 
Romania 
Hungary 
Serbia 
Eastern Europe 
Bulgaria 
Latvia 
Turkey 
Estonia 
Malta 
Ukraine 
Israel 
Russia 
Africa / Asia / Australia 
Australia 
New Zealand 
Taiwan 
South Africa 
Hong Kong 
South Korea 
China 
India 
Malaysia 
Singapore 
 
 


 
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Appendix E Criteria for Identification of Markedly Abnormal Laboratory Values  
Hematology—Criteria for Markedly Abnormal Values 
 
 
 
 
 
 
 
 
 
Conventional Units 
 
Takeda Preferred SI Units 
 
 
 
 
Markedly 
 
 
 Markedly 
 
 
 
 
Abnormal 
 
 
Abnormal 
Parameter 
Gender 
Age 
Units 
Value 
 
Units 
Value 
Red Blood 
Cells 
Both 
Adult 
×106 
cells/µL 
< 0.8 × LLN, > 1.2 × 
ULN 
 
×1012 
cells/L 
< 0.8 × LLN, > 1.2 × 
ULN 
White Blood 
Cells 
Both  
Adult 
×103 
cells/µL 
<0.5 × LLN, > 1.5 × 
ULN 
 
×109 cells/L 
< 0.5 × LLN, > 1.5 × 
ULN 
Hemoglobin 
Both 
Adult 
g/dL 
< 0.8 × LLN, > 1.2 
× ULN 
 
g/L 
< 0.8 × LLN, > 1.2 × 
ULN 
Hematocrit 
Both 
Adult 
% 
< 0.8 × LLN, > 1.2 
× ULN 
 
Fraction of 
1 
< 0.8 × LLN, > 1.2 × 
ULN 
Platelets 
Both 
Adult 
×103/µL 
< 75, > 600 
 
×109 /L 
< 75, > 600 
MCV 
Both 
Adult 
fL 
< 70, > 110 
 
fL 
< 70, > 110 
Segmented 
Neutrophils 
(Absolute) 
Both 
Adult 
×103 
cells/µL 
< 0.5 × LLN, > 1.5 
× ULN 
 
× 109 
cells/L 
< 0.5 × LLN, > 1.5 × 
ULN 
Segmented 
Neutrophils 
(Relative) 
Both 
Adult 
% 
< 0.5 × LLN, > 1.5 
× ULN 
 
Fraction of 
1 
< 0.5 × LLN, > 1.5 × 
ULN 
Lymphocytes 
(Absolute) 
Both 
Adult 
×103 
cells/µL 
< 0.5 × LLN, > 1.5 
× ULN 
 
× 109 
cells/L 
< 0.5× LLN, > 1.5 × 
ULN 
Lymphocytes 
(Relative) 
Both 
Adult 
% 
< 0.5 × LLN, > 1.5 
× ULN 
 
Fraction of 
1 
< 0.5 × LLN, > 1.5 × 
ULN 
Monocytes 
(Absolute) 
Both 
Adult 
×103 
cells/µL 
> 2 × ULN 
 
× 109 
cells/L 
> 2 × ULN 
Monocytes 
(Relative) 
Both 
Adult 
% 
> 2 × ULN 
 
Fraction of 
1 
> 2 × ULN 
Eosinophils 
(Absolute) 
Both 
Adult 
×103 
cells/µL 
> 2 × ULN 
 
× 109 
cells/L 
> 2 × ULN 
Eosinophils 
(Relative) 
Both 
Adult 
% 
> 2 × ULN 
 
Fraction of 
1 
> 2 × ULN 
Basophils 
(Absolute) 
Both 
Adult 
×103 
cells/µL 
> 3 × ULN 
 
× 109 
cells/L 
> 3 × ULN 
Basophils 
(Relative) 
Both 
Adult 
% 
> 3 × ULN 
 
Fraction of 
1 
> 3 × ULN 
Reticulocytes 
(Relative) 
Both 
Adult 
% of 
erythrocyte
s 
> 3.0 
 
Fraction of 
1 
> 0.030 
PT 
Both 
Adult 
Sec 
> 1.5 × ULN 
 
Sec 
> 1.5 × ULN 
APTT 
Both 
Adult 
Sec 
> 1.5 × ULN 
 
Sec 
> 1.5 × ULN 
INR† 
Both 
Adult 
NA 
> 1.5 
 
NA 
> 1.5 
LLN = lower limit of normal or lower reference limit; ULN = upper limit of normal or upper reference limit 
† Values are for subjects without anticoagulation, based on the normal range provided above for PT. 
 
 


 
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Chemistry—Criteria for Markedly Abnormal Values 
 
 
 
 
 
 
 
 
 
Conventional Units 
 
Takeda Preferred SI Units 
 
 
 
 
Markedly  
 
 
Markedly 
 
 
 
 
Abnormal 
 
 
Abnormal 
Parameter 
Gender 
Age 
(years) 
Units 
Values 
 
Units 
Value 
Alanine 
Aminotransferase 
Both 
Adult 
U/L 
>3 × ULN 
 
U/L 
>3 × ULN 
Albumin 
Both 
Adult 
g/dL 
< 2.5 
 
g/L  
< 25 
Alkaline 
Phosphatase 
Both 
>20 
U/L 
>3 × ULN 
 
U/L 
>3 × ULN 
Aspartate 
Aminotransferase 
Both 
Adult 
U/L 
>3 × ULN 
 
U/L 
> 3 × ULN 
Total Bilirubin 
Both 
Adult 
mg/dL 
> 2.0 
 
µmol/L 
> 34.2 
Total Protein 
Both 
Adult 
g/dL 
< 0.8 × LLN, > 1.2 
× ULN 
 
g/L 
< 0.8 × LLN, > 
1.2 × ULN 
Creatinine 
Both 
Adult 
mg/dL 
> 2 
 
µmol/L 
> 177  
Blood Urea 
Nitrogen 
Both 
Adult 
mg/dL 
> 30 
 
mmol/L 
> 10.7    
Creatine Kinase 
Both 
Adult 
U/L 
>5 × ULN 
 
U/L 
>5 × ULN 
-Glutamyl 
Transferase 
Both 
Adult 
U/L 
>3 × ULN 
 
U/L 
>3 × ULN 
Potassium (serum) 
Both 
Adult 
mEq/L 
< 3.0, > 6.0 
 
mmol/L 
< 3.0, > 6.0 
Sodium 
Both 
Adult 
mEq/L 
< 130, > 150 
 
mmol/L 
< 130, > 150 
Direct Bilirubin  
Both 
Adult 
mg/dL 
>2 × ULN 
 
µmol/L 
>2 × ULN 
Calcium 
Both 
Adult 
mg/dL 
< 7.0, > 11.5 
 
mmol/L 
< 1.75, > 2.88 
Uric Acid 
Both 
Adult 
mg/dL 
> 13.0 
 
µmol/L 
> 773 
Glucose 
Both 
Adult  
mg/dL 
 
< 50, > 350 
 
mmol/L 
< 2.8, > 19.4 
Magnesium 
Both 
Adult 
mg/dL 
< 1.2, > 3.0 
 
mmol/L 
< 0.5, > 1.2 
Phosphorus 
Both 
Adult 
mg/dL 
< 1.6, > 6.2 
 
mmol/L 
< 0.52, > 2.000 
Total Cholesterol 
Both 
Adult 
mg/dL 
> 300 
 
mmol/L 
> 7.72 
Triglycerides 
Both 
Adult 
mg/dL 
> 2.5 × ULN 
 
mmol/L 
> 2.5 × ULN 
Chloride 
Both 
Adult 
mEq/L 
< 75, > 126 
 
mmol/L 
< 75, > 126 
HbA1c 
Both 
Adult 
% 
> 7 
 
Fraction 
of 1 
> 0.07 
Bicarbonate 
Both 
Adult 
mEq/L 
< 8.0 
 
mmol/L 
< 8.0 
Prolactin 
Both 
Adult 
µg/L 
>10 × ULN 
 
pmol/L 
>10 × ULN 
Progesterone 
Female 
Adult 
ng/mL 
Progesterone/  
Estrogen - 26:1† 
 
nmol/L 
Progesterone/  
Estrogen - 26:1† 
LLN = lower limit of normal or lower reference limit; ULN = upper limit of normal or upper reference limit  
†Any abnormal values should be interpreted with the ratio progesterone/estrogen and SHBP values: Higher levels of SHBP lower 
levels of free progesterone. 
 
 


 
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Serum Chemistry—Criteria for Markedly Abnormal Values (Continued) 
 
 
 
 
 
 
 
 
 
Conventional Units 
 
Takeda Preferred SI Units 
 
 
 
 
Markedly  
 
 
Markedly 
 
 
 
 
Abnormal 
 
 
Abnormal 
Parameter 
Gender 
Age 
(years) 
Units 
Values 
 
Units 
Value 
Thyroid 
Stimulating 
Hormone 
Both 
Adult 
mU/L 
< 0.8 × LLN,  
> 2.0 × ULN 
 
mU/L 
< 0.8 × LLN, 
> 2.0 × ULN 
Vitamin B12 
Both 
Adult 
pg/mL 
< 125 
 
pmol/L 
< 92 
Folate 
Both 
Adult 
ng/mL 
< 2.2, > 17.5 
 
nmol/L 
< 5.0, > 39.7 
Amylase 
Both 
Adult 
U/L 
>2 × ULN 
 
U/L 
>2 × ULN 
Lipase 
Both 
Adult 
U/L 
>3 × ULN 
 
U/L 
>3 × ULN 
LLN = lower limit of normal or lower reference limit; ULN = upper limit of normal or upper reference limit  
†Any abnormal values should be interpreted with the ratio progesterone/estrogen and SHBP values: Higher levels of SHBP lower 
levels of free progesterone. 
 


 
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Appendix F Criteria for Abnormal Changes from Baseline of Vital Signs  
Parameter 
Unit 
Lower Criteria 
Upper Criteria 
Systolic Arterial Pressure 
(mmHg) 
< 85 
> 180 
Diastolic Arterial Pressure 
(mmHg) 
< 50 
> 110 
Pulse 
(bpm) 
< 50 
> 120 
Body Temperature 
oC 
< 35.6 
> 37.7 
 
oF 
< 96.1 
> 99.9  
 
Both the criterion value and the change from Baseline must be met. 
 


 
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Appendix G: Patient Related Outcomes 
 
 
Quality of Life questionnaire: IBDQ 
 
Sub-score 
Calculation 
 
IBDQ Bowel symptoms score 
Sum of (Q1, Q5, Q9, Q13, Q17, Q20, Q22, 
Q24, Q26, Q29), Ranging from 10 to 70, 10 
questions 
 
IBDQ Emotional function score 
Sum of (Q3, Q7, Q11, Q15, Q19, Q21, Q23, 
Q25, Q27, Q30, Q31, Q32), Ranging from 12 
to 84, 12 questions 
 
IBDQ Social function score 
Sum of (Q4, Q8, Q12, Q16,Q28), Ranging 
from 5 to 35, 5 questions 
 
IBDQ Systemic symptoms score 
Sum of (Q2, Q6, Q10, Q14,Q18), Ranging 
from 5 to 35, 5 questions 
Note 
For each component score above, if 50% or less of the component score is missing at a visit, the 
MEAN of the remaining component score will be imputed as the value for the missing 
component score. If more than 50% of the component score is missing for the item, the imputed 
value will be set to missing. 
 
IBDQ score 
Sum of (bowel, emotion, social, system) 
Note 
If any of the component score is missing at a visit, the imputed value will be set to missing. 
 
 
 


 
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Quality of Life questionnaire: EQ-5D 
 
Sub-score 
Calculation 
 
EQ-5D mobility component score 
Ranging from 1 to 3 
 
EQ-5D self-care component score 
Ranging from 1 to 3 
 
EQ-5D usual activities component 
score 
Ranging from 1 to 3 
 
EQ-5D pain/discomfort component 
score 
Ranging from 1 to 3 
 
EQ-5D anxiety/depression 
component score 
Ranging from 1 to 3 
EQ-5D Index Score 
1. If any of the 5 components above are missing, the index score is 
missing. Skip the remaining steps below. 
2. Count the number of component scores with a response > 1. If the count 
is non-zero, subtract 1. If the count is zero, leave it as 0. 
3. Count the number of component scores with a response equal to 2. If the 
count is non-zero, subtract 1. If the count is zero, leave it as 0. 
4. Count the number of component scores with a response equal to 3. If the 
count is non-zero, subtract 1. If the count is zero, leave it as 0. 
5. Calculate the index score using the following formula: 
EQ −5D index score = 1 − 0.146016 × (1, if mobility =
2; 0, if mobility ≠2) −0.557685 × (1, if mobility =
3; 0, if mobility ≠3) −0.1753425 × (1, if self −care = 2; 0, if self −
care ≠2) − 0.4711896 × (1, if self −care = 3; 0, if self −care ≠
3) −0.1397295 × (1, if usual activities = 2; 0, if usual activities ≠
2) −0.3742594 × (1, if usual activities = 3; 0, if usual activities ≠
3) −0.1728907 × (1, if pain/discomfort = 2; 0, if pain/
discomfort ≠2) − 0.5371011 × (1, if pain/discomfort =
3; 0, if pain/discomfort ≠3) −0.156223 × (1, if anxiety/
depression = 2; 0, if anxiety/depression ≠2) −0.4501876 ×
(1, if anxiety/depression = 3; 0, if anxiety/depression ≠3) +
0.1395949 × (result from Step #2) −0.0106868 ×
(result from Step #3)2 + 0.1215579 × (result from Step #4) +
0.0147963 × (result from Step #4)2  
EQ5D VAS 
On a scale of 0 to 100, where 0 is the worst imaginable health state and 
100 is the best imaginable health state. 
 
 
 


 
Page 60 of 60 
 
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Quality of Life questionnaire: WPAI-CD 
 
Dimension 
Calculation 
 
Absenteeism 
Percent work time missed due to health 
Q2
Q2+Q4  
 
Presenteeism 
Percent impairment while working due to health 
Q5
10  
 
Overall Work Impairment 
Percent overall work impairment due to health 
Q2
Q2+Q4 + [(1 −
Q2
Q2+Q4) ×
Q5
10]  
 
Daily Activities Impairment 
Percent activity impairment due to health 
Q6
10  
Note 
WPAI-CD dimension scores are multiplied by 100 to be expressed in percentages.