Conditions: Crohn's Disease
Keywords: Drug therapy Fistulizing Crohn´s disease Perianal Fistula
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the percentage of participants with perianal fistula healing at Week 30 in 2 different dose regimens of vedolizumab intravenous (IV) 300 milligram (mg) in participants with fistulizing Crohn's disease (CD).

Detailed description:
The drug being tested in this study is called vedolizumab IV. Vedolizumab IV is being tested to treat people who have fistulizing CD. This study will look at fistula healing in people who take vedolizumab IV.

The study is planned to enroll approximately 100 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Group 1: Vedolizumab IV 300 mg dose at Weeks 0, 2, 6, 14 and 22, and a placebo infusion at Week 10 (dummy inactive infusion - this is a solution that looks like the study drug but has no active ingredient).
* Group 2: Vedolizumab IV 300 mg dose at Weeks 0, 2, 6, 10, 14 and 22.

This multi-center trial will be conducted worldwide. The overall time to participate in this study from screening to 18 weeks after the last dose is 44 weeks. Participants will make multiple visits to the clinic, and will be contacted by telephone 6 months after last dose of study drug for a follow-up assessment.

Arms:
arm 1: Vedolizumab 300 mg, IV infusion, once, at Weeks 0, 2, 6, 14, and 22, and vedolizumab placebo-matching, IV infusion once, at Week 10 to maintain the blind. arm 2: Vedolizumab 300 mg, IV infusion, once, at Weeks 0, 2, 6, 10, 14, and 22.

Interventions: intervention 1: Vedolizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Vedolizumab 300 mg IV infusion intervention 2: 0.9% sodium chloride IV infusion

Protocol document:
Prot_000.pdf: 


•
Title: A Randomized Double-Blind Phase 4 Study to Evaluate the Safety and Proportion of 
Subjects With Fistula Healing in 2 Dose Regimens of Entyvio (Vedolizumab IV) in the Treatment 
of Fistulizing Crohn’s Disease (ENTERPRISE)
NCT Number: NCT02630966
Protocol Approve Date: 20 April 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL AMENDMENT 
A Randomized Double-Blind Phase 4 Study to Evaluate the Safety and Proportion of 
Subjects With Fistula Healing in 2 Dose Regimens of Entyvio (Vedolizumab IV) in the
Treatment of Fistulizing Crohn’s Disease (ENTERPRISE)
Vedolizumab IV 300 mg in the Treatment of Fistulizing 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:
Vedolizumab-4003
IND Number:
009125
EudraCT Number:
2015-000852-12
Compound:
Vedolizumab IV
Date:
20 April 2017
Amendment Number: 
05
Amendment History: 
Date
Amendment Number
Amendment Type
Region
02 September 2015
Initial Protocol, Version 1
Not applicable
Global
29 February 2016
Amendment 01, Version 1
Substantial
Global
06 May 2016
Amendment 02, Version 1
Non-substantial
Global
11 May 2016
Amendment 03, Version 1
Non-substantial
France
08 July 2016
Amendment 04, Version 1
Non-substantial
France
20 April 2017
Amendment 05, Version 1
Substantial
Global
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.
Takeda Development Center Americas, Inc. (TDC Americas) 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
United States/Canada 
Contact
Europe
Contact
Serious adverse event and 
pregnancy reporting
Medical Monitor
(medical advice on protoco
and compound)
Responsible Medical 
Officer 
(carries overall 
responsibility for the 
conduct of the study)
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 study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer can be found on the signature page.
Electronic Signatures may be found on the last page of this document.
PPD


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1.3
Protocol Amendment 05 Summary of Changes
Rationale for Amendment 05
This document describes the changes in reference to the Protocol Incorporating Amendment 5.
The primary reasons for this amendment are to update the protocol to remove the eligibility 
requirement for a seton to be placed before randomization, to clarify inclusion and exclusion 
criteria, to revise the sample size calculation, to add a futility analysis, and to consolidate local 
country (France) modifications into a single global amendment. Other minor clarifications for 
procedures are included. Minor grammatical, editorial, and formatting changes, for clarification 
purposes only, are not listed below nor in Appendix K. For specific descriptions of text changes 
and where the changes are located, see Appendix K.
Changes in Amendment 05
1. Removed the requirement for perianal seton placement as part of standard of care before 
randomization.
2. Changed the requirements for seton removal, if applicable, from 10 to 22 weeks after 
randomization to 6 to 14 weeks after randomization.
3. Added a secondary endpoint to evaluate fistulas healed at both Week 22 and Week 30.
4. Modified inclusion criterion 6 such that both France-specific and global language is presented.
5. Modified inclusion and exclusion criteria to allow additional types of antibiotic to reduce the 
incidence of abscess.
6. Modified inclusion criteria 10 and 11 per updated safety language.
7. Modified exclusion criteria 6 and 7 per updated safety language.
8. Modified exclusion criterion 17 to remove the option of 5 half lives as washout window.
9. Modified exclusion criterion 19 to also exclude subjects with prior exposure to etrolizumab or 
anti-mucosal addressin cell adhesion molecule-1 therapy therapy.
10. Reduced the study sample size from 126 (63 per group) to 100 (50 per group).
11. Increased the number of study sites from 30 to 40.
12. Added a stratification factor for seton or no seton at randomization.
13. Added a futility analysis after 25 subjects complete the primary endpoint assessment 
(Week 30).
14. Updated background information per the current Investigator’s Brochure.
15. Revised the rationale for the proposed study given that perianal seton replacement no longer 
required.
16. Revised the benefit-risk assessment given that perianal seton replacement no longer required.


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17. Modified the Schematic of Study Design given the changes in this amendment.
18. Changed the maximum dose of oral corticosteroids from 30 to 20 mg/day and clarified that
tapering schedule provided is an example of one schedule; allowed for return to baseline 
corticosteroid dose.
19. Modified the criteria for discontinuation or withdrawal to add monitoring for leukopenia and 
lymphopenia and to clarify other criteria.
20. Clarified the medical history collection of smoking/nicotine usage status and collection of all 
medications for Crohn’s disease.
21. Clarified vital signs collection.
22. Clarified that all fistula draining assessments are preferably be done by the same qualified 
designee.
23. Clarified that confirmation from a central reader is required for magnetic resonance imaging 
eligibility.
24. Added the superficial category for the Parks classification.
25. Clarified the neutralizing anti-vedolizumab antibodies (AVA) analysis.
26. Replaced the existing Contraception and Pregnancy Avoidance language with 4 new 
subsections containing updated language for contraception and pregnancy avoidance, and 
clarified in Appendix C that highly effective contraception must be used.
27. Clarified the pregnancy form requirement for female partners of male subjects.
28. Added a requirement to document missed doses of antibiotic companion medication.
29. Changed wording in the safety section from severity to intensity.
30. Added frequency to list of pretreatment event and adverse event reporting.
31. Clarified that AVA titers are analyzed. 
32. Clarified that the subject diary for Crohn’s Disease Activity Index is electronic.
33. Clarified when serum versus urine pregnancy testing done.
34. Clarified that pregnancy testing is performed before study drug dosing at dosing visits.
35. Added an investigator responsibility per updated International Conference on Harmonisation
guideline.


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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, the 
vedolizumab IV (Entyvio) 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 study site agreement.

Responsibilities of the investigator (Appendix B).
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/Province)
Location of Facility (Country)


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 05 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Principal Investigator/Coordinating Investigator ......................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.1.1
Disease and Current Treatments.........................................................................20
4.1.2
Vedolizumab......................................................................................................20
4.1.2.1 Nonclinical...................................................................................................21
4.1.2.2 Human Experience .......................................................................................21
4.2
Rationale for the Proposed Study.............................................................................23
4.3
Benefit:Risk Assessment..........................................................................................23
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................25
5.1
Objectives................................................................................................................25
5.1.1
Primary Objective ..............................................................................................25
5.1.2
Secondary Objective ..........................................................................................25
5.1.3
Additional Objectives.........................................................................................25
5.1.4
Safety Objective.................................................................................................25
5.2
Endpoints.................................................................................................................25
5.2.1
Primary Endpoints .............................................................................................25
5.2.2
Secondary Endpoints..........................................................................................26
5.2.3
Additional Endpoints .........................................................................................26
5.2.4
Safety Endpoints................................................................................................27
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 Study Site...................................29


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6.3.1
Criteria for Premature Termination or Suspension of the Study..........................29
6.3.2
Criteria for Premature Termination or Suspension of Study Sites .......................30
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)..............................................................................30
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............31
7.1
Inclusion Criteria .....................................................................................................31
7.2
Exclusion Criteria ....................................................................................................32
7.3
Excluded Medications..............................................................................................35
7.3.1
Permitted Medications and Treatments...............................................................35
7.3.1.1 Oral Corticosteroid Dosing and Tapering .....................................................36
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................37
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................38
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................39
8.1
Study Drug and Materials ........................................................................................39
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................39
8.1.1.1 Vedolizumab IV and Placebo .......................................................................39
8.1.1.2 Companion Medication ................................................................................39
8.1.2
Storage...............................................................................................................39
8.1.3
Dose and Regimen .............................................................................................39
8.1.4
Overdose............................................................................................................40
8.2
Study Drug Assignment and Dispensing Procedures ................................................40
8.3
Randomization Code Creation and Storage..............................................................41
8.4
Study Drug Blind Maintenance................................................................................41
8.5
Unblinding Procedure..............................................................................................41
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................41
9.0
STUDY PLAN ..............................................................................................................43
9.1
Study Procedures.....................................................................................................43
9.1.1
Informed Consent Procedure..............................................................................43
9.1.2
Demographics, Medical History, and Medication History Procedure..................43
9.1.3
Crohn’s Disease History.....................................................................................43
9.1.4
Physical Examination Procedure ........................................................................43
9.1.5
Weight, Height...................................................................................................44
9.1.6
Vital Sign Procedure..........................................................................................44
9.1.7
PML Checklist...................................................................................................44
9.1.8
Documentation of Concurrent Medical Conditions.............................................44


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9.1.9
ECG Procedure..................................................................................................44
9.1.10 MRI Procedure...................................................................................................44
9.1.10.1
Parks Classification ................................................................................45
9.1.10.2
Van Assche MRI-Based Score................................................................46
9.1.11 Fistula Draining Assessment ..............................................................................46
9.1.12 Primary Endpoint Measurement.........................................................................46
9.1.13 PDAI .................................................................................................................46
9.1.14 CDAI.................................................................................................................46
9.1.15 CDAI Diary Completion ....................................................................................47
9.1.16 Patient Reported Outcome Measures..................................................................47
9.1.16.1
IBDQ .....................................................................................................47
9.1.16.2
EQ-5D Questionnaire .............................................................................47
9.1.16.3
Likert Perianal Pain Scale.......................................................................47
9.1.17 Pad Collection....................................................................................................48
9.1.18 Documentation of Concomitant Medications......................................................48
9.1.19 Documentation of Concurrent Medical Conditions.............................................48
9.1.20 Procedures for Clinical Laboratory Samples.......................................................48
9.1.21 Fecal Calprotectin Sample Collection.................................................................50
9.1.22 Pharmacokinetic Sample Collection...................................................................50
9.1.23 Anti-Vedolizumab Antibodies Sampling............................................................50
9.1.24 Tuberculosis Screening ......................................................................................50
9.1.25 Contraception and Pregnancy Avoidance Procedure...........................................51
9.1.25.1
Male Subjects and Their Female Partners ...............................................51
9.1.25.2
Female Subjects and Their Male Partners ...............................................51
9.1.25.3
Definitions and Procedures for Contraception and Pregnancy 
Avoidance....................................................................................................51
9.1.25.4
General Guidance With Respect to the Avoidance of Pregnancy.............53
9.1.26 Pregnancy ..........................................................................................................53
9.1.27 Documentation of Screen Failure .......................................................................54
9.1.28 Documentation of Randomization......................................................................54
9.2
Monitoring Subject Treatment Compliance..............................................................55
9.3
Schedule of Observations and Procedures................................................................55
9.3.1
Screening Visit 1................................................................................................55
9.3.2
Randomization (Day 1) (Visit 2) ........................................................................55
9.3.3
Week 30 or Early Termination (Visit 8) .............................................................55


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9.3.4
Week 40 Follow-up (or 18 Weeks Post-Treatment)............................................55
9.3.5
Post Study Long-Term Follow-Up (or 26 Weeks Post-Treatment)......................56
9.3.6
Unscheduled Visits Due to Exacerbation of CD .................................................56
9.3.7
Post Study Care..................................................................................................56
9.4
Biological Sample Retention and Destruction ..........................................................56
10.0
PRETREATMENT EVENTS (PTE) AND ADVERSE EVENTS (AE) .........................57
10.1
Definitions...............................................................................................................57
10.1.1 PTEs..................................................................................................................57
10.1.2 AEs....................................................................................................................57
10.1.3 Additional Points to Consider for PTEs and AEs................................................57
10.1.4 SAEs..................................................................................................................59
10.1.5 AEs of Special Interest.......................................................................................60
10.1.6 Intensity of PTEs and AEs .................................................................................61
10.1.7 Causality of AEs ................................................................................................62
10.1.8 Relationship to Study Procedures.......................................................................62
10.1.9 Start Date...........................................................................................................62
10.1.10
Stop Date .....................................................................................................62
10.1.11
Frequency ....................................................................................................62
10.1.12
Action Concerning Study Drug ....................................................................62
10.1.13
Outcome.......................................................................................................63
10.2
Procedures...............................................................................................................63
10.2.1 Collection and Reporting of AEs........................................................................63
10.2.1.1
PTE and AE Collection Period ...............................................................63
10.2.1.2
PTE and AE Reporting ...........................................................................64
10.2.1.3
Special Interest AE Reporting.................................................................64
10.2.2 Collection and Reporting of SAEs......................................................................65
10.2.3 Reporting of Abnormal LFTs.............................................................................65
10.3
Follow-up of SAEs ..................................................................................................65
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....66
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................67
11.1
Adjudication Committee..........................................................................................67
11.1.1 Risk Assessment and Minimization for PML (RAMP) Program.........................67
12.0
DATA HANDLING AND RECORDKEEPING............................................................68
12.1
Electronic CRFs.......................................................................................................68
12.2
Record Retention .....................................................................................................68


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13.0
STATISTICAL METHODS..........................................................................................70
13.1
Statistical and Analytical Plans ................................................................................70
13.1.1 Analysis Sets......................................................................................................70
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................70
13.1.3 Analysis of Fistula Healing ................................................................................70
13.1.4 PK Analysis .......................................................................................................71
13.1.5 Anti-vedolizumab Antibodies Analysis ..............................................................71
13.1.6 Safety Analysis ..................................................................................................71
13.1.7 Other Analyses...................................................................................................72
13.2
Futility Analysis and Criteria for Early Termination ................................................72
13.3
Determination of Sample Size..................................................................................72
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................73
14.1
Study Site Monitoring Visits....................................................................................73
14.2
Protocol Deviations..................................................................................................73
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................73
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................74
15.1
IRB and/or IEC Approval ........................................................................................74
15.2
Subject Information, Informed Consent, and Subject Authorization .........................75
15.3
Subject Confidentiality ............................................................................................76
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................76
15.4.1 Publication and Disclosure.................................................................................76
15.4.2 Clinical Trial Registration..................................................................................77
15.4.3 Clinical Trial Results Disclosure ........................................................................77
15.5
Insurance and Compensation for Injury....................................................................77
16.0
REFERENCES..............................................................................................................78
LIST OF IN-TEXT TABLES
Table 8.a
Dose and Regimen .............................................................................................40
Table 9.a
Clinical Laboratory Tests...................................................................................49
Table 10.a
Takeda Medically Significant AE List................................................................60
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................29


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LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................82
Appendix B
Responsibilities of the Investigator.....................................................................86
Appendix C
Elements of the Subject Informed Consent.........................................................88
Appendix D
Investigator Consent to Use of Personal Information..........................................91
Appendix E
PDAI .................................................................................................................92
Appendix F
CDAI.................................................................................................................94
Appendix G
Table for Determining Standard Body Weight (CDAI Variable) ........................95
Appendix H
IBDQ.................................................................................................................96
Appendix I
EQ-5D .............................................................................................................106
Appendix J
Likert Scale for Perianal Pain...........................................................................108
Appendix K
Detailed Description of Amendments to Text...................................................109


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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: A Randomized Double-Blind Phase 4 
Study to Evaluate the Safety and Proportion of Subjects 
With Fistula Healing in 2 Dose Regimens of Entyvio 
(Vedolizumab IV) in the Treatment of Fistulizing Crohn’s 
Disease (ENTERPRISE)
IND No.: 
009125
EudraCT No.:
2015-000852-12
Study Number: Vedolizumab-4003
Phase: 4
Study Design:
This is a phase 4, randomized, double-blind, multicenter study to evaluate the safety and the proportion of subjects 
with fistula healing in 2 dose regimens of Entyvio (vedolizumab IV) over a 30-week treatment period (with the last 
dose at Week 22). Approximately 100 subjects with moderately to severely active Crohn’s disease (CD) with 1 to 3 
draining perianal fistula(e) will be enrolled. Subjects must have historically had an inadequate response with, lost 
response to, or been intolerant to either conventional therapy or a tumor necrosis factor-alpha (TNF-α) antagonist for 
their underlying CD to be eligible. Subjects will be followed for approximately 52 weeks, including screening and 
post-study telephone follow-up.
Primary Objectives:
To evaluate the proportion of subjects with perianal fistula healing at Week 30 with 2 different dose regimens of 
vedolizumab IV 300 mg in subjects with fistulizing CD.
Secondary Objective:
To evaluate fistula healing over a 30-week evaluation period.
Additional Objectives:

To evaluate magnetic resonance imaging (MRI) assessment of fistula healing at Week 30 compared to Screening.

To evaluate clinical disease activity assessed by Perianal Disease Activity Index (PDAI) and Crohn’s Disease 
Activity Index (CDAI) from Day 1 to Weeks 2, 6, 10, 14, 22, and 30.

To evaluate perianal pain at Week 30 compared to Day 1.

To explore biomarkers (fecal calprotectin and C-reactive protein [CRP]) at Week 30 compared to Day 1.

To evaluate quality of life measures (Inflammatory Bowl Disease Questionnaire [IBDQ] and EuroQol-5 
dimensions [EQ-5D]) at Weeks 14 and 30 compared to Day 1.

To assess perianal fistula draining by number of pads used at Week 30 compared to Baseline (at selected study 
sites).

To evaluate pharmacokinetics of vedolizumab in CD subjects with fistula(e) over 30-week treatment period.

To assess immunogenicity of vedolizumab over 40 weeks of follow-up.
Safety Objective:
The safety objective is to assess safety of vedolizumab IV in CD subjects with fistula(e) over 40 weeks of follow-up.
Subject Population: Adult subjects, aged 18 to 80 years, inclusive, with moderately to severely active CD and 1 to 3 
draining perianal fistula(e) of at least 2 weeks duration.
Number of Subjects:
Approximately 100 Subjects
Number of Sites: 
Approximately 40 sites in North America and Europe 


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Dose Level(s):
Group 1: Vedolizumab IV 300 mg dose at Weeks 0, 2, 6, 
14 and 22, and a placebo infusion at Week 10.
Group 2: Vedolizumab IV 300 mg dose at Weeks 0, 2, 6, 
10, 14 and 22.
Route of Administration:
Intravenous (IV)
Duration of Treatment:
30-week Treatment Period (with last dose at Week 22) 
Period of Evaluation:
The study includes a 4-week Screening Period, a 
30-week Treatment Period (with last dose at Week 22), 
and an 18-week Follow-up Period following last dose. 
The duration of the study from Screening to 18 weeks 
post last dose at Week 22 will be approximately 44 
weeks. All subjects will participate in a long-term, 
follow-up (LTFU) safety survey by telephone 6 
months after their last dose.
Main Criteria for Inclusion:
Adult subjects, aged 18 to 80 years, inclusive, with moderately to severely active CD and 1 to 3 draining perianal 
fistula(e) of at least 2 weeks duration. 
Subjects who have historically had an inadequate response with, lost response to, or were intolerant to either 
conventional therapy or a TNF-α antagonist for their underlying CD (does not require treatment failure for currently 
active draining fistula); for subjects from France only: subjects who have historically failed (ie, had an inadequate 
response with, lost response to, or was intolerant to) infliximab for treatment of their underlying CD or fistulizing CD.
Main Criteria for Exclusion:
Subjects who have perianal abscesses greater than 2 cm or an abscess that the investigator feels requires drainage 
based on either clinical assessment or MRI.
Subjects who have a CDAI score greater than 400.
Subjects who have ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
Subjects who have significant anal or rectal stenosis.
Subjects who have any evidence of an active infection (eg, sepsis, cytomegalovirus, or listeriosis) during Screening
other than related to the fistula(e).
Subjects who have a positive progressive multifocal leukoencephalopathy (PML) subjective checklist.
Subjects who have received any investigational or approved biologic or biosimilar agent within 60 days of 
randomization.
Subjects who have had prior exposure to vedolizumab, natalizumab, efalizumab, rituximab, etrolizumab, or anti-
mucosal addressin cell adhesion molecule-1 (MAdCAM-1) therapy.
Subjects who have active or latent tuberculosis.
Subjects who have a known history of hepatitis B virus (HBV), hepatitis C virus (HCV), acquired human 
immunodeficiency virus (HIV), or are found to be seropositive at Screening.
Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is the proportion of subjects with a reduction of at least 50% from Day 1 in number 
of draining perianal fistulae at Week 30 (where closed fistulae are no longer draining despite gentle finger 
compression).
Secondary endpoints for this study are:

The proportion of subjects with a reduction of at least 50% from Day 1 in the number of draining perianal fistulae 
at both Week 22 and Week 30 (where closed fistulae are no longer draining despite gentle finger compression).


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
The proportion of subjects with 100% perianal fistulae closure at Week 30 (where all fistulae are no longer 
draining despite gentle finger compression).

Time to first perianal fistula closure.

Time to last (100%) perianal fistulae closure.

Duration of perianal fistula response (eg, number of days with drainage).
Additional endpoints for this study are:

Proportion of subjects with reduction of fluid collections/abscess (reduction in relative mean T2 intensity on 
MRI) at Week 30 compared to Screening.

Percentage reduction in relative mean T2 intensity on MRI at Week 30 compared to Screening.

Change in Van Assche total MRI score at Week 30 compared to Screening.

Change in individual MRI descriptors from post-contrast enhanced T1-weighted images at Week 30 compared to 
Screening.

Changes in PDAI scores from Day 1 to Weeks 2, 6, 10, 14, 22 and 30.

Changes in CDAI scores from Day 1 to Weeks 2, 6, 10, 14, 22 and 30, for subset with CDAI >220 at Day 1. 

Proportion of subjects with ≥30% decrease in mean perianal pain as assessed by Likert scale for the 7 days prior to 
Week 30 compared to the 7 days prior to Day 1.

Change in biomarkers (fecal calprotectin and CRP) at Week 30 compared to Day 1.

Change in IBDQ total and subscale scores from Day 1 to Weeks 14 and 30.

Change in the EQ-5D utility score and visual analog scale from Day 1 to Weeks 14 and 30.

Change in number of pads used for perianal fistula drainage from Baseline to Week 30 (selected study sites only).

Trough concentrations of vedolizumab.

Proportion of subjects with positive anti-vedolizumab antibodies (AVAs) and neutralizing AVAs.
Safety will be assessed by adverse events (AEs), adverse events of special interest (AESIs), serious adverse events 
(SAEs), vital signs, and results of standard laboratory tests (clinical chemistry, hematology, coagulation, and 
urinalysis).
Statistical Considerations: For all dichotomous endpoints, corresponding rates and a 95% confidence intervals (CIs) 
will be reported by treatment group. The rate differences between treatment groups and their 95% CIs will also be 
reported.
Time to first fistula closure and time to last fistula closure will be analyzed by survival analysis procedures. Fistula 
closure rates from the time of randomization to the end of the study period will be estimated by Kaplan-Meier product 
limit methods and presented with appropriate 95% CIs.
Other endpoints will be summarized descriptively by treatment group.
Sample Size Justification: 
A sample size of 100 subjects (50 per group) will generate 95% CIs for fistulae closure rates for each treatment group 
with half widths no wider than 13.9%; in addition, the 95% CIs for the difference in fistulae closure rates between the 
2 groups will be no wider than 19.6%. The sample size calculation was not based on statistical power considerations 
but on estimates of precision.


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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 document. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
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 drug, 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
6-MP
6-mercaptopurine
ACCENT II 
A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment 
Regimen in Patients With Fistulizing Crohn’s Disease
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AVA
anti-vedolizumab antibody
BID
twice daily
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CI
confidence interval
CRA
clinical research assistant 
CRO
contract research organization
CRP
C-reactive protein
CSR
clinical study report
Ctrough
trough serum concentration
ECG
electrocardiogram
eCRF
electronic case report form 
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
ENTYVIO
vedolizumab IV
EQ-5D
Euro Quality of Life-5D
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
GI
gastrointestinal
HBsAg
hepatitis B virus surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
hCG
human chorionic gonadotropin
HRQOL
health-related quality of life
IAC
Independent Adjudication Committee
IAG
Image Acquisition Guidelines
IB
Investigator’s Brochure


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IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonisation
IEC
independent ethics committee
Ig
immunoglobulin
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
IV
intravenous(ly)
JCV
John Cunningham virus
LFT
liver function tests
LTFU
long-term follow-up
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
Med ID
medication identification number
MRI
magnetic resonance image
nAVA
neutralizing anti-vedolizumab antibodies
NSAID
nonsteroidal anti-inflammatory drug
PDAI
Perianal Disease Activity Index
PD
pharmacodynamics
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PO
orally
PP
per protocol
PTE
pretreatment event
Q4W
once every 4 weeks
Q8W
once every 8 weeks
QD
once daily
QuantiFERON
test for mycobacterium tuberculosis
RAMP
Risk Assessment and Minimization for PML
RF
radiofrequency
SAE
serious adverse event
SAP
statistical analysis plan
SmPC
Summary of Product Information 
SUSAR
suspected unexpected serious adverse reaction
T1
T1 weighted MRI image
T2
T2 weighted MRI image
TB
tuberculosis


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TID
3 times daily
TNF-α
tumor necrosis factor-alpha
TYSABRI
natalizumab
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
VAS
visual analog scale
VCAM-1
vascular cell adhesion molecule-1
WBC
white blood cell
WHODRUG
World Health Organization Drug Dictionary
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
Disease 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). 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 United States 
(US) population and approximately 125/100,000 of population in Western Europe [1-3]. The
characteristic pathology involves a chronic inflammatory infiltrate consisting of neutrophils and 
macrophages. Hallmarks of CD include granulomatous inflammation and aphthous ulceration.
CD is neither medically or surgically curable at the current time. Fistulizing disease complicates 
CD in up to 40% of patients [4,5]. Patients with fistulizing CD experience symptoms of anal pain, 
purulent discharge, and incontinence, which result in high morbidity and impaired quality of life 
[6,7].
Fistulae rarely heal spontaneously and usually require medical therapy or surgery. Although a 
range of medical and surgical options is available for CD, effective treatment options for 
fistulizing disease are limited. There is no demonstrated role for aminosalicylates or 
corticosteroids in perianal CD [8]. While antibiotics may contribute to healing, they are 
recommended as adjunctive therapy for fistulae [8]. Thiopurines may have a moderate effect in 
treating fistulizing CD, however the data are limited or mixed [8-10]. Infliximab, a tumor necrosis 
factor-alpha (TNF-a) antagonist monoclonal antibody, has been shown to be effective in fistula 
healing in 2 prospective randomized controlled trials [11,12]. A Crohn’s Disease Clinical Trial 
Evaluating Infliximab in a New Long-term Treatment Regimen in Patients with Fistulizing 
Crohn’s Disease (Accent II) study reported that 36% of patients who responded to induction 
therapy and received maintenance infliximab therapy maintained complete fistula closure 
compared with 19% receiving placebo (p=0.009) [13]. Infliximab has approved indications in 
fistulizing CD by both the US and European regulatory agencies. Other TNF-a antagonist 
therapies (eg adalimumab, certolizumab) have post hoc subgroup analyses and limited prospective 
data dedicated to fistulizing CD [14-16].
The management of perianal CD is challenging and often requires a comprehensive approach 
including medical and surgical interventions. The recent global consensus guidelines on fistulizing 
CD contain algorithms including medical therapy +/- surgical seton [8,17], and a recent 
meta-analysis suggests an advantage of combination of medical and surgical therapy compared to 
either therapy alone [18]. 
4.1.2
Vedolizumab
Vedolizumab (also called MLN0002) is a humanized immunoglobulin (Ig) G1 monoclonal 
antibody (mAb) directed against the human lymphocyte integrin α4β7. The α4β7integrin mediates 


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lymphocyte trafficking to the GI mucosa and gut-associated lymphoid tissue 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 [19-22]. Vedolizumab binds the 
α4β7 integrin, antagonizing its adherence to MAdCAM-1 and as such, impairs the migration of gut 
homing lymphocytes into gastrointestinal mucosa. As a result, vedolizumab acts as a gut-selective 
immunomodulator [23].
Vedolizumab IV (also known as ENTYVIO; KYNTELES; or MLN0002 IV) has been granted 
marketing approval in several regions, including the United States and European Union. 
Vedolizumab IV is approved for the treatment of adult patients with moderately to severely active 
UC and CD, who have failed conventional treatment, such as immunomodulators, corticosteroids, 
or TNF-α antagonists. The approved dosing and administration regimen is 300 mg vedolizumab 
IV infused intravenously at Weeks 0, 2 and 6, then once every 8 weeks (Q8W) thereafter.
Previously conducted clinical studies have characterized the efficacy, safety, tolerability, 
pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of vedolizumab in healthy 
subjects and subjects with UC or CD.
4.1.2.1
Nonclinical
No nonclinical studies have been conducted to evaluate vedolizumab specifically for fistulizing 
CD.
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 α4β1 integrin [23].
4.1.2.2
Human Experience
In the clinical development program, more than 4200 subjects have received at least 1 dose of 
vedolizumab (see Investigator’s Brochure [IB], Edition 19). 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 [24,25] [26]. 
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 Weeks 0 and 2 (induction) followed by administration Q4W or Q8W from Weeks 6 
through 52 (maintenance) demonstrated statistically significant differences in efficacy compared 
to placebo for both the induction and maintenance phases. 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 (Crohn’s Disease Activity Index [CDAI]-100) at Week 6 in the overall 


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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 [25].
In Study C13007, 37% of subjects had a history of fistulizing disease and 15% had active draining 
fistulae at Baseline (Week 0) [25]. The majority of fistulae were located perianally (72% placebo; 
82% vedolizumab group). At Week 52, 41.2% of subjects administered vedolizumab Q8W and 
22.7% of subjects administered vedolizumab Q4W compared to 11.1% of placebo subjects 
achieved complete closure of baseline draining fistulae [27]. In a post hoc, exploratory analysis of 
the subpopulation with baseline draining fistula, 28% of subjects who received vedolizumab 
(combined Q4W and Q8W) had closure at Week 14 compared with 11% of subjects who received 
placebo. Kaplan-Meier probability estimates of fistula closure with vedolizumab were 29% and 
33% at 6 and 12 months, respectively; notably, the number of subjects at risk was small. The 
hazard ratio for fistula closure for the vedolizumab treatment group was 2.54 (95% confidence 
interval [CI], 0.54-11.96) [28].
Vedolizumab has shown an acceptable and consistent safety profile in clinical trials (see current 
version of IB). In the pivotal phase 3 studies (C13006 in UC and C13007 in CD), the most 
common (≥5% and at a higher incidence than placebo) adverse reactions in subjects administered 
vedolizumab were nausea, nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, 
fatigue, headache, and cough. Most serious adverse events (SAEs) have been related to 
exacerbations or complications of the underlying UC or CD. For those infections that were 
reported more frequently in vedolizumab-treated subjects, the sites of these infections correlated 
with the known tissue distribution of MAdCAM-1 binding sites. Anal abscess, abdominal abscess, 
and gastroenteritis were the most frequently reported serious infections. Extraintestinal infections 
(bronchitis, pneumonia, urinary tract infection, sepsis) occurred at low frequency (<1%). 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 
anti-vedolizumab antibodies (AVAs) 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, a long-term safety study, 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.
Overall, vedolizumab was well tolerated in clinical studies. For additional safety related 
information from the clinical trial experience, see the current edition of the IB. 


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4.2
Rationale for the Proposed Study
The treatment of fistulizing CD is challenging and there are limitations in the available CD 
literature, which further complicates an evidence-based approach to treatment. Well-designed 
prospective clinical trials specific to the fistulizing CD patient population are needed. 
The current study will generate meaningful data with vedolizumab IV in the treatment of perianal 
fistula(e) and is expected to provide guidance on an optimal dose regimen for this complex patient 
population.
The study will evaluate perianal fistula(e) healing rates in 2 vedolizumab treatment arms: the 
standard dosage regimen and the standard dosage regimen plus an additional Week 10 dose. It is 
postulated that addition of a Week 10 dose may be beneficial based on data from nonresponders at 
Week 6 that continued Q4W dosing in the C13007 study, where it was suggested that subjects who 
do not respond by Week 6 should be given an additional dose at Week 10. Week 10 dosing is an 
approved dose regimen for the treatment of CD in the European Union. The study hypothesis is 
that both treatment arms will be efficacious and safe for the treatment of perianal fistula(e) in 
subjects with CD with or without setons, and the intention is to estimate perianal fistula healing 
rates at Week 30 in both treatment arms, although no formal comparison between the groups will 
be performed.
4.3
Benefit:Risk Assessment
Perianal fistulae are a debilitating complication of CD. The treatment approach is challenging and 
therapeutic outcome is often insufficient or has limitations. Results from Study C13007 showed 
that treatment with vedolizumab IV 300 mg Q8W or Q4W maintained remission in the broad CD 
population and achieved fistula closure in a subpopulation of subjects who had draining fistulae at 
Baseline. 
Study Vedolizumab-4003 is designed to investigate vedolizumab IV in the treatment of perianal 
fistulae and is expected to provide guidance on an optimal dosing regimen for this complex patient 
population. The study will evaluate perianal fistula healing rates in 2 vedolizumab treatment arms: 
the standard dosage regimen and the standard dosage regimen plus an additional Week 10 dose. 
Week 10 dosing is an approved dose regimen for the treatment of CD in the European Union (EU). 
The study hypothesis is that both treatment arms will be efficacious and safe for the treatment of 
perianal fistula in subjects with CD, and the intention is to estimate perianal fistula healing rates at 
Week 30 in both treatment arms, although no formal comparison between the groups will be 
performed. Diagnostic procedures to be used in this study (eg, MRI) are commonly used in 
medical practice and in this patient population. 
The dosing and administration regimen are consistent with the approved vedolizumab IV label in 
the EU [29]. The proposed protocol will include safety measures similar to those conducted in the 
vedolizumab IV UC and CD clinical programs, including sufficient safety measures, evaluations, 
and discontinuation criteria to assure safety in the individual subjects in the planned study.


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Overall, vedolizumab IV has been well tolerated in clinical studies and the benefit-risk profile is 
positive.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to evaluate the proportion of subjects with perianal fistula healing at 
Week 30 in 2 different dose regimens of vedolizumab IV 300 mg in subjects with fistulizing CD.
5.1.2
Secondary Objective
The secondary objective is to evaluate fistula healing over a 30-week evaluation period.
5.1.3
Additional Objectives 
Additional objectives include:

To evaluate magnetic resonance imaging (MRI) assessment of fistula healing at Week 30 
compared to Screening.

To evaluate clinical disease activity assessed by Perianal Disease Activity Index (PDAI) and 
CDAI from Day 1 to Weeks 2, 6, 10, 14, 22 and 30.

To evaluate perianal pain using a Likert scale at Week 30 compared to Day 1.

To explore biomarkers of disease activity (fecal calprotectin and C-reactive protein [CRP]) at 
Week 30 compared to Day 1.

To evaluate quality of life measures (inflammatory bowel disease questionnaire [IBDQ] and 
Euro Quality of Life-5D [EQ-5D]) at Week 14 and Week 30 compared to Day 1.

To assess perianal fistula draining by number of pads used at Week 30 compared to Baseline 
(selected study sites only).

To evaluate the PK of vedolizumab in CD subjects with fistula(e) over the treatment period.

To assess immunogenicity of vedolizumab over 40 weeks of follow-up.
5.1.4
Safety Objective

To assess safety of vedolizumab IV in CD subjects with fistula(e) over 40 weeks of follow-up.
5.2
Endpoints
5.2.1
Primary Endpoints 
The primary endpoint for this study is the proportion of subjects with a reduction of at least 50% 
from Day 1 in the number of draining perianal fistulae at Week 30 (where closed fistulae are no 
longer draining despite gentle finger compression).


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5.2.2
Secondary Endpoints 
Secondary endpoints are as follows:

The proportion of subjects with a reduction of at least 50% from Day 1 in the number of 
draining perianal fistulae at both Week 22 and Week 30 (where closed fistulae are no longer 
draining despite gentle finger compression).

The proportion of subjects with 100% perianal fistulae closure at Week 30 (where all fistulae 
are no longer draining despite gentle finger compression).

Time to first perianal fistula closure.

Time to last (100%) perianal fistulae closure.

Duration of perianal fistula response (number of days with drainage).
5.2.3
Additional Endpoints 
Additional endpoints include the following:

Proportion of subjects with reduction of fluid collections/abscess (reduction in relative mean 
T2 intensity on MRI) at Week 30 compared to Screening.

Percentage reduction in relative mean T2 intensity on MRI at Week 30 compared to Screening.

Change in Van Assche total MRI score at Week 30 compared to Screening.

Change in individual MRI descriptors from post-contrast enhanced T1-weighted images at 
Week 30 compared to Screening.

Changes in PDAI scores from Day 1 to Weeks 2, 6, 10, 14, 22 and 30.

Changes in CDAI scores from Day 1 to Weeks 2, 6, 10, 14, 22 and 30, for subset with CDAI 
>220 at Day 1. 

Proportion of subjects with ≥30% decrease in mean perianal pain as assessed by Likert scale 
for the 7 days prior to Week 30 compared to the 7 days prior to Day 1.

Change in biomarkers (fecal calprotectin and CRP) at Week 30 compared to Day 1.

Change in IBDQ total and subscale scores from Day 1 to Weeks 14 and 30.

Change in the EQ-5D utility score and visual analog scale from Day 1 to Weeks 14 and 30.

Change in number of pads used for perianal fistula drainage from Baseline to Week 30 
(selected study sites only).

Trough serum concentrations (Ctrough) of vedolizumab.

Proportion of subjects with positive (AVAs), and neutralizing anti-vedolizumab antibodies 
(nAVAs).


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5.2.4
Safety Endpoints
Safety will be assessed by adverse events (AEs), adverse events of special interest (AESIs), SAEs, 
vital signs, and results of standard laboratory tests (clinical chemistry, hematology, coagulation, 
and urinalysis).


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 4, randomized, double-blind, multicenter study to evaluate the safety and the 
proportion of subjects with fistula healing in 2 dose regimens of vedolizumab IV 300 mg, 
administered as a 30-minute infusion, over a 30-week treatment period (with the last dose at 
Week 22) in the healing of draining perianal fistulae in subjects with active CD. Subjects in both 
treatment groups entering the study may have had surgical seton placement as standard of care 
prior to enrollment in the study.
Approximately 100 CD subjects with moderately to severely active CD and 1 to 3 draining
perianal fistula(e) of at least 2 weeks duration will be included. To be eligible, subjects must have 
historically had an inadequate response with, lost response to, or been intolerant to either 
conventional therapy or a TNF-α antagonist for their underlying CD; for subjects from France 
only: subjects must have historically failed (ie, had an inadequate response with, lost response to, 
or was intolerant to) infliximab for treatment of their underlying CD or fistulizing CD. Subjects 
will be randomized in a 1:1 ratio into 1 of 2 treatment groups:

Group 1: vedolizumab IV 300 mg dose at Week 0, 2, 6, 14, 22 and a placebo IV dose at 
Week 10. 

Group 2: vedolizumab IV 300 mg dose at Week 0, 2, 6, 10, 14, and 22.
The study consists of a 4-week Screening Period, a 30-week Treatment Period (with last dose at 
Week 22), and an 18-week Follow-up Period following the last dose. The duration of the study 
from Screening to 18 weeks post last dose at Week 22 will be approximately 44 weeks for all 
subjects. All subjects in the study will also be required to complete a long-term follow-up (LTFU) 
safety survey by telephone 6 months following the last dose. The end of trial will be the date of the 
last visit of the last subject at the Week 40 Follow-up Visit.
In both groups, for subjects with a seton at study entry, setons may be removed at or after Week 6 
at the discretion of the investigator, provided that significant reduction in fistula drainage has 
occurred. All setons must be removed by Week 14.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.


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Figure 6.a
Schematic of Study Design
6.2
Justification for Study Design, Dose, and Endpoints
Perianal fistulae are a debilitating complication of CD. The treatment approach is challenging and 
therapeutic outcome is often insufficient or has limitations [30]. Results from the maintenance 
study C13007 showed that treatment with vedolizumab IV 300 mg Q8W or Q4W maintained 
remission in the broad CD population and achieved fistula(e) closure in a subpopulation of 
subjects who had draining fistula(e) at Baseline.
The objective of this study is to prospectively evaluate vedolizumab IV in the treatment of 
fistulizing CD using 2 dose regimens. All subjects who meet the eligibility criteria will randomly 
be assigned to 1 of the 2 treatment groups. The choice of different active treatment groups, rather 
than a placebo comparator group was made due to ethical considerations. MRI, read by a central 
reader, will be used to ensure consistent classification of perianal fistulae as per Parks’ criteria for 
classification as simple or complex fistulae [31], for scoring using the Van Assche MRI score [32], 
and to objectively measure perianal fistulae healing by reduction in T2 hyperintensity from 
Baseline and assess change in inflammatory process from Baseline on post-contrast enhanced 
T1-weighted images.
6.3
Premature Termination or Suspension of Study or Study 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:


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
New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for vedolizumab, such that the risk/benefit 
is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.

At the futility analysis, if the probability of success does not meet the predetermined futility 
threshold and the study is stopped for futility at this point.
6.3.2
Criteria for Premature Termination or Suspension of Study 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 Study 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 
study site, a study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable study sites during the course of termination 
or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization. In the case of 
subject screen failure, the subject may be considered for rescreening on a case-by-case basis but 
only with the consultation of the medical monitor.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative has signed and 
dated a written, informed consent form and any required privacy authorization prior to the 
initiation of any study procedures. 
3. The subject is male or female and aged 18 to 80 years, inclusive.
4. The subject has a diagnosis of CD established at least 3 months prior to randomization by 
clinical and endoscopic evidence and corroborated by a histopathology report. 
5. The subject has a diagnosis of a minimum of 1 perianal draining fistula of at least 2 weeks 
duration as a complication of moderately to severely active CD, as identified on MRI at 
Screening. Other types of fistulae (enterocutaneous, abdominal) except rectovaginal fistulae 
are permitted, but the number of draining perianal fistulae is limited to 3.
6. All countries except France: The subject, historically, had an inadequate response with, lost 
response to, or was intolerant to either conventional therapy or a TNF-α antagonist for their 
underlying CD (does not require treatment failure for currently active draining fistula). 
France only: The subject, historically, failed (ie, had an inadequate response with, lost 
response to, or was intolerant to) infliximab for treatment of their underlying CD or fistulizing 
CD.
7. If the subject had noncutting perianal seton placement as part of standard care, seton must be 
removed by Week 14 of the study.
8. The subject is willing and able to undergo MRI per protocol requirements.
9. The subject is willing and able to take antibiotic treatment (metronidazole, ciprofloxacin, 
amoxicillin clavulanate, or tinidazole, as per local label) from Day 1 through study Week 6.
10. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use a barrier method of contraception (eg, condom with spermicide)* from 
signing of informed consent throughout the duration of the study and for 18 weeks after last 
dose. The female partner of a male subject should also be advised to use a highly effective 
method of contraception*.


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11. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use a highly effective method of contraception* from signing of informed 
consent throughout the duration of the study and for 18 weeks after last dose. 
*Definitions and highly effective methods of contraception are defined in 
Section 9.1.25 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.26 Pregnancy.
12. 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 as standard of care).
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 a diagnosis of ulcerative colitis or indeterminate colitis.
2. The subject has a perianal abscess greater than 2 cm or an abscess that the investigator feels 
requires drainage based on either clinical assessment or MRI. (Note: if subject has an abscess 
larger than 2 cm, and abscess is drained and seton placed, then subject may be rescreened with 
consultation from the medical monitor).
3. The subject has a CDAI score >400.
4. The subject has an ileostomy, colostomy, or known fixed symptomatic stenosis of the 
intestine.
5. The subject has significant anal or rectal stenosis.
6. The subject has active or latent tuberculosis (TB), regardless of treatment history, as 
evidenced by any of the following:
a.
A diagnostic TB test performed during Screening that is positive, as defined by:
i. A positive test for tuberculosis (QuantiFERON) or 2 successive 
indeterminate QuantiFERON tests OR
ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in subjects receiving the 
equivalent of >15 mg/day prednisone)
b. Chest X-ray within 3 months prior to Day 1, that is suspicious for pulmonary TB, 
and a positive or 2 successive indeterminate QuantiFERON tests within 30 days 
prior to Screening or during the Screening Period.
Note: if the subject has a documented negative diagnostic TB test in the previous 3 
months, screening testing does not need to be repeated provided subject has no risk 
factors for exposure.
7. The subject has chronic hepatitis B virus (HBV) infection* or chronic hepatitis C virus 
(HCV) infection** or a known history of human immunodeficiency virus (HIV) infection 


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(or is found to be seropositive at Screening) or subject is immunodeficient (eg, due to organ 
transplantation, history of common variable immunodeficiency). 
* Subjects who are positive for hepatitis B virus surface antigen (HBsAg) will be excluded. 
For subjects who are negative for HBsAg but are positive for either surface antibodies 
and/or core antibodies, HBV DNA polymerase chain reaction will be performed and if any 
test result meets or exceeds detection sensitivity, the subject will be excluded.
** If the subject is HCV antibody positive, then a viral load test will be performed. If the 
viral load test is positive, then the subject will be excluded.
8. The subject has evidence of active C. difficile infection or is having treatment for C. difficile
infection or other intestinal pathogens during Screening.
9. The subject has evidence of an active infection (eg, sepsis, cytomegalovirus, or listeriosis) 
during Screening, other than related to the fistula(e).
10. The subject currently requires or has a planned surgical intervention for CD during the study.
11. The subject has a contraindication for MRI. See MRI Image Acquisition Guidelines (IAG) for 
additional information.
12. The subject has allergies to and/or contraindications for metronidazole and ciprofloxacin and 
amoxicillin clavulanate and tinidazole (including interacting drugs such as tizanidine).
13. In the opinion of the investigator, the subject is likely to require greater than 6 weeks of 
treatment after Day 1 with metronidazole, ciprofloxacin, amoxicillin clavulanate, or tinidazole 
for the treatment of abscess.
14. The subject is taking, has taken, or is required to take any excluded medications (as listed in 
Section 7.3).
15. The subject has received non-biologic investigational therapy within 30 days prior to 
randomization.
16. The subject has received an approved non-biologic therapy (including 5-aminosalicylate
[5-ASA], corticosteroid, azathioprine, 6-mercaptopurine [6-MP], etc.) in an investigational 
protocol within 30 days prior to randomization.
17. The subject has received any investigational or approved biologic or biosimilar agent within 60 
days of randomization.
18. The subject has a history of hypersensitivity or allergies to vedolizumab or its components.
19. The subject has any prior exposure to vedolizumab, natalizumab, efalizumab, rituximab,
etrolizumab, or anti-MAdCAM-1 therapy.
20. The subject has received any live vaccinations within 30 days prior to randomization.
21. The subject has current rectovaginal fistula.
22. The subject currently has more than 3 draining perianal fistulae.


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23. The subject has a positive progressive multifocal leukoencephalopathy (PML) subjective 
symptom checklist at Screening or Day 1 visit.
24. 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; or 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 randomization.
25. The subject has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, demyelinating or neurodegenerative disease.
26. The subject has conditions which, in the opinion of the investigator, may interfere with the
subject’s ability to comply with the study procedures.
27. The subject has any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI,
genitourinary, hematological, coagulation, immunological, endocrine/metabolic, neurologic 
or other medical disorder that, in the opinion of the investigator, would confound the study 
results or compromise subject safety.
28. The subject has any of the following laboratory abnormalities during the Screening Period:
i.
Hemoglobin level <8 g/dL.
ii.
White blood cell (WBC) count <3 × 109/L.
iii.
Lymphocyte count <0.5 × 109/L.
iv.
Platelet count <100 × 109/L or >1200 × 109/L.
v.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>3 × the upper limit of normal (ULN).
vi.
Alkaline phosphatase >3 × ULN.
vii.
Serum creatinine >1.5 × ULN.
Note: Retesting laboratory values during the screening interval may be considered with 
consultation from the medical monitor.
29. 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.
30. If male, the subject intends to donate sperm during the course of this study or for 18 weeks
thereafter.


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31. 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. 
32. 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 Visit 1.
7.3
Excluded Medications 
The following medications are excluded from use during the study from the time of screening 
unless specified otherwise:

Any treatment for CD other than those listed below in Section 7.3.1 (either approved or
investigational).

Within 30 days prior to randomization and throughout the study, any of the following for the 
treatment of CD:
–
Nonbiologic therapies (eg, cyclosporine, thalidomide) other than those specifically listed 
in Section 7.3.1.
–
A nonbiologic investigational therapy.
–
An approved nonbiologic therapy in an investigational protocol.

Any investigational or approved biologic or biosimilar agent within 60 days or of 
randomization and throughout the study. 

All live vaccines within 30 days prior to randomization, throughout the study treatment period 
and for at least 6 months after the last dose of study drug.

Either approved or investigational biologic agents for the treatment of non-IBD conditions,
other than localized injections (eg, intraocular injections for wet macular degeneration).

Metronidazole, ciprofloxacin, amoxicillin clavulanate, or tinidazole after Week 6. Additional 
courses of antibiotics may be allowed, as needed, and in consultation with the medical monitor.

Oral corticosteroids for CD, except as described in Section 7.3.1.1.

Chronic nonsteroidal anti-inflammatory drug (NSAID) use. (Note: occasional use of NSAIDs 
for headache, arthritis, myalgias, menstrual cramps, etc, and daily use of baby or low-dose 
[81162.5 mg] aspirin for cardiovascular prophylaxis are permitted.)
Subjects must be instructed not to take any medications, including over-the-counter products,
without first consulting with the investigator.
7.3.1
Permitted Medications and Treatments
The following medications for CD are permitted during the study:


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
Oral 5-ASA compounds, probiotics (eg, Culturelle, Saccharomyces boulardii), with a stable 
dose for at least 2 weeks prior to randomization.

5-ASA or corticosteroid enemas/suppositories, with a stable dose for at least 2 weeks prior to 
randomization.

Oral corticosteroid therapy for CD, with mandatory tapering started by Week 4 as described in 
Section 7.3.1.1.

Antidiarrheals for control of chronic diarrhea.

Immunomodulators (methotrexate, azathioprine, 6-mercaptopurine), stable for at least 8 weeks
prior to randomization.

Antibiotics to be provided to all subjects from Day 1 through Week 6 (ciprofloxacin, 
metronidazole, amoxicillin clavulanate, or tinidazole, as per local label) to decrease incidence 
of abscess. Subjects may have been on antibiotics prior to randomization. Additional 
courses of antibiotics may be allowed, as needed, and in consultation with the medical 
monitor. 
7.3.1.1
Oral Corticosteroid Dosing and Tapering
The maximum dose of oral corticosteroids for the treatment of CD that may be coadministered
with vedolizumab IV is 20 mg/day prednisone or 9 mg/day budesonide (or equivalent) as long 
as the corticosteroid dose has been stable for at least 4 weeks prior to randomization.
It is required that subjects receiving oral corticosteroids begin a tapering regimen by Week 4. 
An example 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 until discontinuation.
For patients who could not tolerate the corticosteroid taper without recurrence of clinical 
symptoms, corticosteroids may have been increased up to the original dose at the start of the study 
(should not exceed baseline dose). In such cases, the tapering regimen must be reinitiated within 
2 weeks.


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7.4
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.27.
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 drug 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 9.1.20), if the following circumstances occur at any 
time during study drug treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).

Leukopenia or lymphopenia: WBC and lymphocyte counts will be monitored for all 
subjects. Azathioprine, 6-MP, or methotrexate, if applicable, should be discontinued and 
the dose of vedolizumab held for an absolute lymphocyte count <0.5×109/L at any point in 
the study. The absolute lymphocyte count must be repeated at appropriate intervals as 
determined by the investigator. The next dose of vedolizumab can be administered only if 
the absolute lymphocyte count is ≥0.5×109/L. If the absolute lymphocyte count remains 
<0.5×109/L, study drug should be discontinued and the subject withdrawn from the study.
2. Significant protocol deviation. The discovery post-randomization that the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 


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AE should not be recorded in the voluntary withdrawal category. Similarly, lack of efficacy 
should not be recorded in the voluntary withdrawal category).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.26.
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 
Early Termination Visit as well as safety follow-up visits 18 and 26 weeks post-treatment. 
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 Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Vedolizumab IV and Placebo
The study sites will be supplied by the sponsor with the following medication for infusion in an 
open-label manner: vedolizumab IV 300 mg/vial, for single use, in 20 mL vials. The study drug 
will be provided in a glass vial as a lyophilized solid for reconstitution using 4.8 ml of sterile water 
for injection and dilution in 250 mL of sterile 0.9% sodium chloride. Each vial will be packaged in 
an appropriately labeled single vial carton. 
The placebo infusion will be 250 mL of commercially available 0.9% sodium chloride. For both 
active vedolizumab and placebo infusions, the unblinded investigational pharmacist or designee 
will mask the IV bags after preparation in order to maintain the study blind.
Additional reference information and administration instructions can be found in the pharmacy 
manual.
8.1.1.2
Companion Medication 
Treatment with antibiotics is required per protocol from Day 1 until Week 6 in order to ensure 
adequate care of subjects with perianal abscesses/fistulae. Antibiotics (metronidazole 250 mg 
orally [PO] 3 times daily [TID], or ciprofloxacin 500 mg twice daily [BID], or amoxicillin 
clavulanate 875 mg BID, or tinidazole 500 mg once daily [QD]) must be prescribed by the 
investigator as per the local label to decrease incidence of abscess. 
8.1.2
Storage
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study 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.
8.1.3
Dose and Regimen
The vedolizumab IV dose and regimen for both randomized groups is provided in Table 8.a. The 
infusion will be administered intravenously over 30 minutes. Instructions for reconstitution and 
blinded administration will be provided in the pharmacy manual. Subjects should be observed for 
2 hours following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion.


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All subjects must also be prescribed companion antibiotic medication (metronidazole 250 mg PO 
TID, ciprofloxacin 500 mg PO BID, amoxicillin clavulanate 875 mg BID, or tinidazole 500 mg 
QD) from Day 1 until Week 6.
Table 8.a
Dose and Regimen
Treatment Group Dose
Treatment Description
1
300 mg IV
IV infusion with vedolizumab at Weeks 0, 2, 6, 14, 22
IV infusion with placebo at Week 10
2
300 mg IV
IV infusion with vedolizumab at Weeks 0, 2, 6, 10, 14, 22
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study 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 eCRF(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
Study Drug Assignment and Dispensing Procedures
The investigator or the investigator’s designee will access the interactive web response system 
(IWRS) at Screening to obtain the study-specific subject identification number (subject number). 
The investigator or the investigator’s designee will utilize the IWRS to randomize the subject into 
the study. During this contact, the investigator or designee will provide the necessary 
subject-identifying information, including the subject number assigned at Screening. At 
drug-dispensing visits, the investigator or designee will again contact the IWRS to register the 
visits.
At Weeks 0, 2, 6, 14, and 22, for all subjects in both treatment groups, a medication identification 
number (Med ID) will be assigned by IWRS and provided to the site by email notification. At 
Week 10, if the subject was randomized to the active treatment arm the Med ID number of the 
study drug to be dispensed will then be provided by the IWRS by email notification to the 
unblinded site pharmacist/nurse. At Week 10, if the subject was randomized to receive placebo at 
Week 10, the IWRS will provide email notification to the unblinded site/pharmacist/nurse, but no 
Med ID will be assigned. 


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To maintain the blind the IWRS will ensure the investigator or designee is unaware if a Med ID has 
been assigned. If sponsor-supplied drug (active vials) is lost or damaged, the site can request a 
replacement from IWRS by the unblinded site pharmacist/nurse. Refer to IWRS manual provided 
separately.
8.3
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. Subjects will be randomized to the 2 dose regimens of vedolizumab in a 1:1 ratio using 
an IWRS. Randomization will be stratified by TNF naïve versus TNF non-naïve (TNF failed) and 
by seton or no seton at Baseline.
8.4
Study Drug Blind Maintenance 
The investigational drug blind will be maintained using the IWRS. All subjects and study 
personnel except for those directly involved with study drug preparation will be blinded to study 
drug assignment for the entire study. In order to maintain the blind, unblinded individuals 
preparing study drug will cover the product in a blinding bag prior to dispensing. All unblinded 
dosing information must be maintained in a secured area, accessible only by unblinded personnel, 
and separate from blinded information.
8.5
Unblinding Procedure 
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. In the event of a medical 
emergency, if possible, the medical monitor should be contacted before the study drug blind is 
broken to discuss the need for unblinding.
The investigator can perform emergency unblindings using the IWRS, if medically necessary. In 
all scenarios, the sponsor must be notified as soon as possible if the study drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF.
If any site personnel (with the exception of the dispensing pharmacist or pharmacy personnel) are 
unblinded, study drug must be stopped immediately and the subject must be withdrawn from the 
study. 
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator and investigator’s designated site pharmacy 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),
the investigator pharmacy 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 designated site pharmacy 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, designated site 
pharmacy should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and by recording in IWRS. 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’s designated site pharmacy 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:

Monitoring expiration dates (monitored via IWRS).

Frequently verifying that actual inventory matches documented inventory.

Verifying that the drug accountability log is completed for the Med ID 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 IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator’s designated site pharmacy must record the current inventory of all 
sponsor-supplied drugs (vedolizumab IV) 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, expiry date and 
amount dispensed, and amount returned to the pharmacy (if applicable) including initials, seal, or 
signature of the person dispensing the drug. The log should include all required information as a 
separate entry for each subject (by subject identifier) to whom sponsor-supplied drug is dispensed. 
The investigator’s designated site staff administering the study drug infusion must complete an 
individual subject accountability log to document if infusion was complete or if incomplete and 
study drug was returned to the pharmacy, including the date and amount returned to the pharmacy, 
including the initials, seal, or signature of the person administering the infusion. Only unblinded 
site personnel and unblinded clinical research assistants (CRAs) can perform drug accountability 
and drug returns in order to preserve blinding.
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 process are described in Section 15.2 and Appendix C.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained through the IWRS system; this subject number will be used 
throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth or age, sex, Hispanic 
ethnicity (as applicable), race as described by the subject, and smoking/nicotine usage 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 resolved 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 and/or any medication history for the treatment of CD, including 
date of diagnosis, with the reason for discontinuation is to be collected for subjects where 
possible.
9.1.3
Crohn’s Disease History
CD history will include details of CD diagnosis, disease severity, surgery, hospitalizations, and 
extraintestinal manifestations.
9.1.4
Physical Examination Procedure
A Visit 1 (Screening) physical examination 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 


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significant changes from the assessment prior to first dose examination. Additionally, abdominal 
mass assessment will be performed at all visits where CDAI is calculated.
9.1.5
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.
9.1.6
Vital Sign Procedure
Vital signs will include body temperature, respiratory rate, supine blood pressure (systolic and 
diastolic, resting more than 5 minutes), and pulse (resting more than 5 minutes).
When vital signs are scheduled at the same time as blood draws, vital signs take priority and vital 
signs will be taken within 5 minutes before the scheduled blood draw.
9.1.7
PML Checklist
Site 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. The symptoms from a positive 
PML checklist obtained after randomization will be recorded as an AE. Additional information 
and tools will be found in the Investigator Site File.
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 the screening or baseline examination. The 
condition (ie, diagnosis) should be described.
9.1.9
ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the study 
site) will interpret the ECG using 1 of the following categories: within normal limits, abnormal but 
not clinically significant, or abnormal and clinically significant. A copy of the ECG trace should be 
kept with the subject’s notes.
9.1.10 MRI Procedure
Subjects must have safety laboratory results reviewed prior to MRI scan being performed. If a 
subject’s serum creatinine is > 1.5 times the ULN (>1.5x ULN), the subject should not undergo the 
MRI procedure (see Exclusion Criteria 28).


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A comprehensive description of MRI procedures is provided in the IAG and the Site Operations 
Manual.
MRI is the imaging modality of choice for evaluation of perianal fistulizing CD as it allows 
accurate localization and assessment of disease. In addition, MRI has been found to be sensitive to 
the degree of perianal disease activity and thereby offers an assessment of response to therapy in 
clinical trials.
A pelvic MRI will be performed at Screening (Visit 1) and Week 30 (Visit 8). Sites will use a 
1.5T/3T Whole Body MRI scanner retrofitted with body radiofrequency (RF) coil for pelvic MRI. 
MRIs will be assessed by central radiologists for eligibility and scoring.
At Screening (Visit 1), the site radiologist will measure any perianal abscess for assessment of 
eligibility criteria (an abscess greater than 2 cm on MRI is exclusionary). Confirmation must be 
obtained from the central reader to confirm MRI eligibility.
An assigned central radiologist will classify fistulae using the simple and complex schema, the 
Parks’ classification, and Van Assche score components.
Van Assche et al have developed an MRI-based scoring method for assessment of disease severity 
in patients with perianal fistulizing CD [32]. This objective scoring method will be used in this 
study for assessing response to therapy. Briefly, central radiologist will classify fistula(e) after 
reviewing T1- and T2-weighted images of the perianal region (pelvic MRI) which demonstrate the 
full extent of the perianal disease. Local inflammatory activity, an important parameter, will be 
assessed on T2-weighted images. Active fistulae and abscesses with active inflammatory process 
are visible on T2 images as hyperintense lesions due to their fluid contents, while scar tissue 
appears hypointense. 
Relative mean T2 signal intensity changes will be assessed by comparing normalized T2 signal 
intensity values of inflamed perianal regions including fistula tracts to T2 signal intensity of 
healthy tissue (eg, muscle or fat) at follow-up time point with baseline values. In addition, post 
Gadolinium contrast enhanced T1-weighted imaging will be performed as part of the study MRI 
protocol in all subjects. Follow-up contrast-enhanced T1-weighted images will be compared to 
baseline images by the central reader in order to assess response to therapy. 
9.1.10.1 Parks Classification
Parks described a classification system for perianal fistula [31], that will be used at Screening for 
classification of active fistula(e) as superficial, intersphincteric, transsphincteric, suprasphincteric, 
or extrasphincteric. 


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9.1.10.2 Van Assche MRI-Based Score
The Van Assche MRI-based score for severity of perianal CD [32] will be calculated at Screening 
(Visit 1) and Week 30 (Visit 8). The 6 components of the score, summarized below are summed to 
a total score of 0 to 24.
Number of fistula tracks
None = 0
Single, unbranched = 1
Single, branched = 2
Multiple = 3
Location
None/Not applicable = 0
Extra- or intersphincteric = 1
Transsphincteric = 2
Suprasphincteric = 3
Extension
None/Not applicable = 0
Infralevatoric = 1
Supralevatoric = 2
Hyperintensity on T2-weighted images
Absent = 0
Mild = 4
Pronounced = 8
Collections (cavities 3 mm diameter)
Absent = 0
Present = 4
Rectal wall involvement
Normal = 0
Thickened = 2
9.1.11 Fistula Draining Assessment 
Fistula(e) (perianal, enterocutaneous) will be assessed for draining or closed status at each visit, as 
shown in Appendix A. Fistula draining assessment will preferably be performed by the same 
qualified designee for all assessments.
9.1.12 Primary Endpoint Measurement
The primary endpoint measure is ≥50% reduction from Day 1 in number of draining perianal 
fistulae at Week 30 (where closed fistulae are assessed by the investigator to be no longer draining 
despite gentle finger compression).
9.1.13 PDAI
The PDAI [33] includes 5 elements: the presence or absence of discharge, pain or restriction of 
activities of daily living, restriction of sexual activity, the type of perianal disease, and the degree 
of induration. Scores range from 0 to 20, with higher scores indicating more severe disease. See 
Appendix E.
9.1.14 CDAI
A CDAI [34] score will be evaluated during Screening, using subject diary entries within 14 days 
prior to enrollment, and hematocrit results collected during Screening. A CDAI score will also be 


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derived at the time points specified in the Schedule of Events and at any unscheduled visit(s) due 
to disease exacerbation. See Appendix F. A Standard Weight Table is provided in Appendix G.
9.1.15 CDAI Diary Completion
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.
9.1.16 Patient Reported Outcome Measures
Subjects will complete the IBDQ and EQ-5D health-related quality of life (HRQOL) 
questionnaires at the time points specified in the schedule of events (Appendix A). Subjects will 
also complete a Likert scale daily to assess perianal pain.
9.1.16.1 IBDQ
The IBDQ is a valid and reliable [35-37] instrument used to assess quality of life in adult subjects 
with IBD. It includes 32 questions on 4 domains of HRQOL: Bowel Systems (10 items), 
Emotional Function (12 items), Social Function (5 items), and Systemic Function (5 items). 
Subjects are asked to recall symptoms and 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. 
See Appendix H.
9.1.16.2 EQ-5D Questionnaire
The EQ-5D questionnaire, developed by EuroQol, is a simple, valid and reliable [38] instrument 
used to measure general HRQOL in patients and includes 5 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 visual analog scale (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 [39,40]. See 
Appendix I.
9.1.16.3 Likert Perianal Pain Scale
Subjects will complete an 11-point Likert scale as part of the subject diary to assess perianal pain, 
where 0 represents no perianal pain and 10 represents the worst possible perianal pain. Subjects 
will complete this scale every day. A mean score will be calculated for the 7 days prior to every 
visit. See Appendix J.


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9.1.17 Pad Collection
The number of pads used daily will be collected to measure fistula drainage at selected study sites 
only.
9.1.18 Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the sponsor. At each study visit, subjects will be asked whether they have taken any medication 
other than the study drug (used from signing of informed consent through the end of the study), 
and all medication including vitamin supplements, over-the-counter medications, and oral herbal 
preparations, must be recorded in the eCRF.
9.1.19 Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at screening/baseline examination. The condition (ie, diagnosis) 
should be described as current on the Medical History eCRF.
9.1.20 Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 30 mL, and the approximate total volume of 
blood for the study is 166 mL. Details of these procedures, specimen handling and required safety 
monitoring will be given in the laboratory manual.
The clinical laboratory tests to be conducted during the study are summarized in Table 9.a. 


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBC
WBC with differential (a)
Hemoglobin
Hematocrit (b)
Platelets
PT/INR
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Calcium
Chloride
Magnesium
Phosphorus
Uric Acid
Glucose
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Specific Gravity
Other: 
HIV
Hepatitis panel, including HBsAg and anti-HCV
Serum
Urine
Stool
CRP
Pharmacokinetic samples
AVA/nAVA
QuantiFERON for TB
hCG (for pregnancy in female 
subjects of childbearing potential only) 
Fecal calprotectin
beta hCG (for pregnancy in female subjects of 
childbearing potential only)
FSH, if menopause is suspected (Screening Visit only)
(a) WBC differential to include lymphocytes, monocytes, basophils, eosinophils, and neutrophils.
(b) Hematocrit only collected at Visits 3, 4, and 6
AVA=Anti-vedolizumab antibodies, nAVA=neutralizing anti-vedolizumab antibodies, FSH=follicle-stimulating 
hormone, GGT=γ-glutamyl transferase, HBsAg = hepatitis B surface antigen, hCG=human chorionic gonadotropin, 
PT=prothrombin time, RBC=red blood cells.
The central laboratory will perform laboratory tests for hematology, serum chemistries, stool, and 
urinalysis. 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 (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted.


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(Please refer to Section 7.4 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal LFTs in relation to ALT or AST >3 ×ULN in conjunction 
with total bilirubin >2 ×ULN.)
If the ALT or AST remains elevated >3 ×ULN on 2 consecutive occasions the investigator must 
contact the medical monitor for consideration of additional testing, close monitoring, possible 
discontinuation of study drug, 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 LFTs for reporting requirements).
9.1.21 Fecal Calprotectin Sample Collection
A stool sample will be collected at Day1 and at Weeks 14 and 30 for the analysis of fecal 
calprotectin, a biomarker of intestinal inflammatory activity.
9.1.22 Pharmacokinetic Sample Collection 
Blood samples will be drawn for serum PK analysis in all subjects within 30 minutes prior to the 
start of infusion on Day 1, Weeks 6, 10, 14, 22, and at Week 30. One additional PK sample will be 
collected at Week 10 post end of infusion (as close to the end of the infusion as feasible and within 
30 minutes of the end of the infusion). Serum concentrations of vedolizumab will be measured by 
a sandwich enzyme-linked immunosorbent assay (ELISA) assay with a validated range of 0.20 to 
8.0 µg/mL.
9.1.23 Anti-Vedolizumab Antibodies Sampling
Blood samples for AVA assessment will be obtained within 30 minutes prior to dosing on Day 1, 
Weeks 6, 10, 14, 22, 30, and 40. All subjects will have a sample for AVA collected at Week 10 
regardless of treatment group. A Week 40 follow-up AVA sample will be collected 18 weeks after 
the last dose of vedolizumab for subjects who do not continue on to commercial supply 
vedolizumab post-study (eg, last dose of vedolizumab at Week 22). 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 (nAVA) will 
be determined on AVA positive samples using a validated assay.
Please refer to the laboratory manual for information on sample collection and preparation.
9.1.24 Tuberculosis Screening
All subjects will complete TB screening to determine eligibility, unless a negative test result is 
available from within 3 months prior to Screening and the subject has no risk factors for 
exposure. If required during screening, either a QuantiFERON test or a tuberculin skin test will 
be performed. Subjects will be excluded from the study if they have active or latent TB, 
regardless of treatment history.


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9.1.25 Contraception and Pregnancy Avoidance Procedure
9.1.25.1 Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study drug, 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. Women of 
childbearing potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list of highly effective contraception below.
9.1.25.2 Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use a highly effective method of contraception (from the list 
below). 
In addition, they must be advised not to donate ova during this period.
9.1.25.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential (ie, fertile) following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral oophorectomy. A post-menopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone 
(FSH) level in the post-menopausal range (FSH >40 IU/L) may be used to confirm a 
post-menopausal state in younger women (ie, younger than age 45) or women who are not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those that, alone or in combination, 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, the 
only acceptable methods of contraception are: 

Non-hormonal methods: 

Intrauterine device (IUD). 

Bilateral tubal occlusion. 


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
Vasectomised partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomised partner has received medical assessment of 
the surgical success. 

Hormonal methods: 

Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study 
drug OR combined with a barrier method (male condom, female condom or 
diaphragm) if for shorter duration until she has been on contraceptive for 3 months;

Oral. 

Intravaginal (eg, ring).

Transdermal. 

Progestogen-only hormonal contraception associated with inhibition of ovulation1 
initiated at least 3 months prior to the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has 
been on contraceptive for 3 months;

Oral. 

Injectable.

Implantable.
2. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
3. Subjects will be provided with information on highly effective 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.
4. During the course of the study, regular urine human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women of childbearing potential and all subjects (male and 
female) will receive continued guidance with respect to the avoidance of pregnancy and sperm 


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donation as part of the study procedures. Such guidance should include a reminder of the 
following:
a.
Contraceptive requirements of the study
b. Reasons for use of barrier methods (ie, condom) in males with pregnant partners
c.
Assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last 
visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual 
cycles a pregnancy test must be performed if the answer is “yes”)?
iv. Is there a chance you could be pregnant?
5. In addition to a negative serum hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative urine hCG pregnancy test prior to receiving each IV dosing.
9.1.25.4 General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

Contraceptive requirements of the study.

Reasons for use of barrier methods (ie, condom) in males with pregnant partners.

Assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)?
–
Is there a chance you could be pregnant?
9.1.26 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and vedolizumab 
should be immediately discontinued. In addition, any pregnancies in the partner of a male subject 
during the study or for 18 weeks after the last dose, should also be recorded following 
authorization from the subject’s partner.
If the pregnancy occurs during administration of active study drug, eg, after Visit 1 or within 18 
weeks of the last dose of active study drug, the pregnancy should be reported immediately, using a 
pregnancy notification form, to the contact listed in Section 1.0.


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Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
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 (blinded or unblinded, as applicable).
All pregnancies in subjects, including female partners of male subjects, on active study drug 
including comparator will be followed up to final outcome, using the pregnancy form. Pregnancies 
will remain blinded to the study team. The outcome, including any premature termination, must be 
reported to the sponsor. An evaluation after the birth of the child will also be conducted.
9.1.27 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible at the Screening visit, the investigator should complete the 
eCRF. The IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria (specify reason).

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other, specify.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.28 Documentation of Randomization
Randomization will be performed through the IWRS system. Only subjects who meet all of the 
inclusion criteria and none of the exclusion criteria are eligible for randomization into the 
treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.


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9.2
Monitoring Subject Treatment Compliance
A vedolizumab dispensing log, including records of drug received from the sponsor and volume of 
vedolizumab dispensed to each subject intravenously, will be maintained by the site. 
The site will also document missed doses of antibiotic companion medication.
If a subject is persistently noncompliant with the study drug, it may be appropriate to withdraw the 
subject from the study. 
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 Visit 1
Subjects will be screened within 28 days prior to randomization. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.27 for procedures for documenting screening failures.
Procedures to be completed at Screening Visit 1 can be found in the Schedule of Study Procedures 
(Appendix A). 
9.3.2
Randomization (Day 1) (Visit 2)
Randomization will take place on Day 1. The Day 1 procedures are documented in Appendix A.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IWRS as described in Section 8.2. 
Subjects will be given infusion instructions for the first dose of study drug as described in Section 
8.1.3. The procedure for documenting screening failures is provided in Section 9.1.27.
9.3.3
Week 30 or Early Termination (Visit 8)
The final treatment period visit will be performed at Week 30 (Visit 8) or at the Early Termination 
Visit, if applicable (see Appendix A).
For all subjects randomized, the investigator must complete the End of Study Drug and End of 
Study Visits eCRF pages.
9.3.4
Week 40 Follow-up (or 18 Weeks Post-Treatment)
Follow-up will begin the first day after the last dose of vedolizumab and will continue for 
18 weeks. This follow-up visit will be scheduled for safety for all subjects and for AVA 
assessments for all subjects who stopped vedolizumab during study (ie, not for those who continue 
on commercial supply vedolizumab therapy post-study) as per Appendix A.


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9.3.5
Post Study Long-Term Follow-Up (or 26 Weeks Post-Treatment)
Upon completion of or early termination from the study, all subjects will complete a LTFU safety 
survey by telephone. This questionnaire will be administered at 6 months from the last dose of 
study drug.
9.3.6
Unscheduled Visits Due to Exacerbation of CD
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.

Urine pregnancy test (for females of childbearing potential).

Clinical chemistry and hematology, if indicated.

AVA sample.

Concomitant mediations.

AE/SAE assessment.
9.3.7
Post Study Care
Vedolizumab IV treatment will not be supplied 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. The subject may be continued on commercial supply of vedolizumab, at the discretion of 
their physician.
9.4
Biological Sample Retention and Destruction
In this study, samples for AVA analysis will be collected as described in Section 9.1.23.
The AVA samples will be stored for up to but not longer than 15 years from when the study results 
are reported or as required under applicable law or until consent is withdrawn. After that time, the 
samples will be destroyed. 
The samples will be sent to a sponsor identified laboratory that will serve as a secure storage 
facility. The sponsor, its agents and affiliated companies will have access to the samples. 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 
individual results in confidence.
The samples will be labeled with a unique sample identifier. The samples 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.


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10.0
PRETREATMENT EVENTS (PTE) AND ADVERSE EVENTS (AE)
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 drug; 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 value), 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 or 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 drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings 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 


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laboratory or ECG re-test and/or continued monitoring of an abnormal finding are not 
considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent medical condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study drug) or an AE 
(worsening or complication occurs after start of study drug). 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 concurrent medical condition (eg, asthma, epilepsy) any 
occurrence of an episode should only be captured as a PTE/AE if the condition becomes more 
frequent, serious or severe in nature. 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 medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if occurring to a 
greater extent to that which would be expected. 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 drug, 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 
drug, 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 intensity of AEs /Serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity is recorded.
Preplanned procedures (surgeries or interventions):

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 


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performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be recorded 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.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 AEs of Special Interest
An AESI (serious or non-serious) is an AE 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.
AESIs for this compound are serious infections including opportunistic infection such as PML, 
liver injury, malignancies, infusion-related or systemic reactions and hypersensitivity, as 
described in further detail below.
Hypersensitivity Reactions (Including Infusion-Related Reactions)
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence such 
premedications are unlikely to be necessary or beneficial. At the discretion of the investigator, 
however, subjects may be administered premedication prior to any study drug administration. 
Corticosteroids, if given as a premedication, should be limited to the day of administration. 
Vedolizumab IV should be administered by a health care practitioner prepared to manage 
hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and medical 
support measure should be available for immediate use. Subjects should be observed for 2 hours 
following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion.
Subjects and caregivers will be instructed to report the development of rash, hives, pruritus, flushing, 
urticaria, injection site pain, redness and/or swelling, etc. that may represent an 


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administration-related reaction (ie, infusion-related reaction) to study drug. Subjects will be asked to 
report administration-related AEs to the sites immediately as they are experienced. Appropriate 
treatment and follow-up will be determined by the investigator. If signs or symptoms of an 
administration-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 and 
investigator supervision) at the discretion of the investigator. Subjects with a severe or serious 
administration-related reaction (eg, shortness of breath, wheezing, stridor, angioedema, 
life-threatening change in vital signs, severe injection site reactions) must be withdrawn from the 
study. 
In all cases of administration-related reaction, the medical monitor must be informed as soon as 
practical. The disposition of subjects with less severe administration-related reactions should be 
discussed with the medical monitor.
Serious Infections 
Subjects will be monitored for signs and symptoms of infection and for lymphopenia during the 
study. Subjects with signs and symptoms suggestive of infections, including GI infections, will be 
treated as clinically indicated. Interventions may include antibiotic treatment, if appropriate and/or 
discontinuation of concomitant immunomodulators. Blood, sputum, urine, and/or stool cultures 
should be obtained as appropriate for the detection and diagnosis of infection. Withholding or 
terminating study drug administration may be considered as described in Section 7.4.
Malignancy 
All cases of malignancies that are detected during the study will be reported as AEs. Local medical 
practices for the management of malignances will apply. Subjects with history of malignancy 
(except for specific cancers) or at high risk for malignancy will be excluded from the study per the 
exclusion criteria. 
Other 
Other special interest AEs include liver injury and PML, which are discussed in Sections 10.2.3
and 11.1.1, respectively.
10.1.6 Intensity 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 drug(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, and the time, if available.
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, and the time, if available.
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 Drug 

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study drug was stopped for a reason other than the particular AE (eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE).

Dose Interrupted – the dose was interrupted due to the particular AE.


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10.1.13
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – the AEs/PTEs which are considered as the cause of death. 

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Start of PTE collection:
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 drug (Day 1; Visit 
2) or until screen failure. For subjects who discontinue prior to study drug administration, PTEs are 
collected until the subject discontinues study participation.
Start of AE collection: 
AEs must be collected from the time that the subject is first administered study drug (Day 1; Visit 
2). Any drugs provided by the sponsor are considered study drugs, including placebo.
End of AE collection: 
Routine collection of AEs will continue until the end of study follow-up (Week 40; Visit 9).


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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 drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date, and time (if available).
3. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug (s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
CDAI, PDAI and quality of life instruments 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 Special Interest AE Reporting
If an AESI, which occurs during the treatment period or the follow-up period, is considered to be 
clinically significant based on the criteria in Section 10.1.5, it should be recorded in a 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.


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The special interest AEs have to be recorded as AEs in the eCRF. An evaluation form along with 
all other required documentation must be submitted to the sponsor.
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 drug(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.
10.2.3 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.20 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 


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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 study 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 Assessment and Minimization for PML (RAMP) Program
Natalizumab (TYSABRI), another integrin receptor antagonist, has been associated with 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 
[41,42]. Natalizumab is a pan-α4 integrin antagonist that binds to both the α4β1 and α4β7 integrins 
and inhibits cellular adhesion to vascular cell adhesion molecule-1 (VCAM-1) and MAdCAM-1 
[43,44]. In contrast, vedolizumab binds to the α4β7 integrin only [23] 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 RAMP program. The
complete description of the RAMP program, including materials and instructions for its 
implementation and monitoring, is included in the Investigator Site File.
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 drug will be 
administered only if the possibility of PML is definitively excluded, as described in the RAMP 
algorithm. An IAC has been established 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 Investigator Site File. 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 
Drug Dictionary (WHODRUG).
12.1
Electronic CRFs 
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor or 
delegated contract research organization (CRO) will make arrangements to train appropriate site 
staff in the use of the eCRF. These forms are used to transmit the information collected in the 
performance of this study to the sponsor and regulatory authorities. eCRFs must be completed in 
English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
The principal investigator must review the data change for completeness and accuracy, and must 
sign, or sign and seal, and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 


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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 applicable regulatory requirements or for a 
time specified in the study site agreement between the investigator and sponsor.
Refer to the 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 unblinding of any subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
A blinded data review will be conducted prior to unblinding of subjects’ treatment assignments. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
All subjects who received at least 1 dose of study drug and have a post-randomization assessment 
of fistula healing will be included in the full analysis set (FAS). The FAS population will be used 
for the analysis of the proportion of subjects with fistula healing and constitutes the primary 
analysis population for the endpoints associated with fistula healing. 
All FAS subjects who do not have any major protocol violations will be included in the per 
protocol (PP) population. Major protocol violations will be specified in the SAP. All decisions to 
exclude subjects from the PP population dataset will be made prior to the unblinding of the study. 
Analyses using the PP population may be provided as a sensitivity analysis.
Safety analyses will be based on the safety analysis set. All subjects who received at least 1 dose of 
study drug will be included in the safety analysis set.
The PK evaluable population is defined as all subjects who receive at least 1 dose of study drug 
and have sufficient blood sampling to allow for PK evaluation.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Baseline and demographic information will be listed and summarized. For continuous variables, 
the summary will consist of descriptive statistics (number of subjects, mean, SD, minimum, 
median, and maximum). For categorical variables, the summary will consist of number and 
percentage of subjects in each category.
Medical history and concurrent medical conditions will be summarized by system organ class and 
preferred term. Medication history and concomitant medications will be summarized by preferred 
term.
13.1.3 Analysis of Fistula Healing
No inferential statistical testing will be performed in this study. Instead, an estimation approach 
will be taken.
The primary endpoint for this study is the proportion of subjects with a reduction of at least 50% 
from Day 1 in the number of draining fistulae at Week 30 (where closed fistulae are no longer 
draining despite gentle finger compression). 


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The first secondary endpoint is the proportion of subjects with a reduction of at least 50% from 
Day 1 in the number of draining perianal fistulae at both Week 22 and Week 30 (where closed 
fistulae are no longer draining despite gentle finger compression).
Other secondary endpoints include the proportion of subjects with 100% fistulae closure at Week 
30 (where all fistulae are no longer draining despite gentle finger compression), time to first fistula 
closure, time to last (100%) fistula closure, and duration of fistula response (eg, number of days 
with drainage). 
For all dichotomous endpoints (proportion of subjects a reduction of at least 50% from Screening 
in the number of draining fistulae at Week 30 and proportion of subjects with 100% fistulae 
closure at Week 30), corresponding rates and 95% CIs will be reported by treatment group. The 
rate differences between treatment groups and their 95% CIs will also be reported.
Time to first fistula closure and time to last fistula closure will be analyzed by survival analysis 
procedures. Fistula closure rates from the time of randomization to the end of the study period will 
be estimated by Kaplan-Meier product limit methods and presented with appropriate 95% CIs.
Other endpoints will be summarized descriptively by treatment group.
13.1.4 PK Analysis 
Serum concentrations of vedolizumab will be summarized by collection time points, and by 
treatment group using descriptive statistics. Individual serum concentration data versus time will 
be presented in a data listing.
Data might be pooled with data from other studies. The results from these analyses will not be 
reported in the clinical study report (CSR) and will be part of a stand-alone report.
13.1.5 Anti-vedolizumab Antibodies Analysis
The proportion of subjects with positive and titers of AVA (transient and persistent), and 
proportion of subjects with positive neutralizing AVA during the study will be summarized. The 
impact of AVA on serum concentration, safety, and efficacy will be explored.
13.1.6 Safety Analysis
Safety analyses will be based on the safety analysis set.
No formal statistical tests or inference will be performed for safety analyses. Safety data will be 
presented by treatment group.
The number and percentage of subjects with AEs (regardless of relationship to study drug), AEs of 
special interest (ie, serious infections including opportunistic infection such as PML, liver injury, 
malignancies, infusion-related or systemic reactions, and hypersensitivity), 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 will be summarized by MedDRA System Organ Class, High Level 
Term, and Preferred Term overall, by intensity, and by relationship to study drug. If a subject 


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experienced more than 1 AE for a given PT, intensity is defined as the intensity of the most severe 
event and relationship to study drug is the relationship of the most related event. 
Change from Baseline in clinical laboratory tests, vital signs and weight will be summarized by 
treatment group. 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.
Data from the LTFU survey will be summarized descriptively.
13.1.7 Other Analyses
Changes from Baseline to Weeks 14 and 30 in EQ-5D and IBDQ will be summarized.
13.2
Futility Analysis and Criteria for Early Termination
A futility analysis will be performed after 25 patients per treatment arm complete to Week 30. 
There is no intention to stop for efficacy at this point. 
13.3
Determination of Sample Size
A sample size of 100 subjects (50 per group) will generate 95% CIs for fistula closure rate with a 
half width no wider than 13.9%; in addition, the 95% CIs for the difference in fistula closure rates 
between the 2 groups will be no wider than 19.6%. The sample size was not based on statistical 
power considerations but on an estimate of precision.


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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 (CRO) 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 drug, 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. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
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 IB, the vedolizumab IV (Entyvio) 
package insert, 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/notify site once} the sponsor has confirmed the adequacy of site regulatory documentation 
and, when applicable, the sponsor has received permission from competent authority to begin the 
trial. Until the site receives [drug/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.


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Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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 


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medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject 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 the monitor or the sponsor’s designee, 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 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 


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this section and the study site agreement. In the event of any discrepancy between the protocol and 
the study site agreement, the study site agreement will prevail.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/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 study 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 the sponsor providing this information to callers must provide the 
sponsor 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 and/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 study subjects. Refer to 
the 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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Appendix A
Schedule of Study Procedures
Screen
Treatment
Final 
Visit 
or ET
Follow-up
Post Study
Study Day/Week:
Days
-28 to -1
Wk0
/ Day 
1
Wk 
2
Wk 
6
Wk 
10
Wk 
14
Wk 
22
Wk 
30
Wk 40
(or 18 wks 
post-tx if 
ET)
LTFU by 
Telephone
Wk 48 
(or 26 wks 
post-tx if 
ET)
Visit Windows (Days):
±2
±2
±3
±7
±7
±7
±7
±7
Visit Number:
1
2
3
4
5
6
7
8
9
10
Informed consent
X
Assess 
inclusion/exclusion 
criteria
X
X
Demographics /medical 
and medication history/ 
concurrent medical 
conditions 
X
Crohn’s disease history
X
Tuberculosis 
QuantiFERON or skin 
test
X
Physical examination (a)
X
X 
X
X
X
X
X
X
Fistula draining 
assessment (b)
X
X
X
X
X
X
X
X
Vital signs 
X
X 
X 
X 
X
X 
X 
X
Height and weight (c)
X
X
X
X
X
CDAI 
X (d)
X (e)
X (e)
X (e)
X (e)
X (e)
X (e)
X (e)
PDAI
X
X
X
X
X
X
X
ECG
X
MRI 
X (f)
X (f)
Hematology, serum 
chemistry 
X 
X 
X 
X
X
Hematocrit (for CDAI 
scoring)
X
X
X
HIV/Hepatitis Panel
X
Urinalysis
X
X
X
X
AVA (g)
X 
X
X 
X
X
X
X (h)
PK (i)
X
X
X
X
X
X
CRP (j)
X 
X 
X
X
Fecal calprotectin (k) 
X
X
X
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures (continued)
Screen
Treatment
Final 
Visit 
or ET
Follow-up
Post Study
Study Day/Week:
Days
-28 to -1
Wk0
/ Day 
1
Wk 
2
Wk 
6
Wk 
10
Wk 
14
Wk 
22
Wk 
30
Wk 40
(or 18 wks 
post-tx if 
ET)
Phone
Wk 48 
(or 26 wks 
post-tx if 
ET)
Visit Windows (Days):
±2
±2
±3
±7
±7
±7
±7
±7
Visit Number:
1
2
3
4
5
6
7
8
9
10
PML checklist
X
X (l) 
X (l)
X (l)
X (l)
X (l)
X (l) 
X
X
Provide PML wallet card
X
X
Serum Pregnancy test (m)
X
X
Urine Pregnancy test (m)
X 
X 
X 
X
X 
X 
X
IBDQ 
X
X
X
EQ-5D
X
X
X
Mean Likert perianal pain 
score (n)
X
X
X
X
X
X
X
X
Subject diary (n)
X
X
X
X
X
X
X
X
Review subject diary
X
X
X
X
X
X
X
Daily # of pads used 
(selected sites only)
X
X
X
X
X
X
X
X
Dosing (IV) (o)
X
X
X
X
X
X
Antibiotic dosing 
X
X
X (p)
Seton removal (q)
[X (q)] [X (q)]
X (q)
Concomitant medications
X
X
X
X
X
X
X
X
PTE assessment
X
X 
AE/SAE assessment
X
X
X
X
X
X
X
X
Long-term follow-up 
safety questionnaire
X
Access IWRS to obtain 
subject ID
X
Access IWRS for 
randomization
X
Access IWRS to register 
visit
X
X
X
X
X
X
X
X
Footnotes are on the following page.


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ET=early termination, tx=treatment, wk=week.
(a) Including abdominal mass assessment for CDAI calculation.
(b) Fistula(e) (perianal, enterocutaneous) will be assessed for draining or closed status at each visit. Fistula draining assessment will 
preferably be performed by the same qualified designee for all assessments. At Screening and Week 30, the assessment of perianal 
fistula draining is for eligibility or primary endpoint assessment, respectively.
(c) Height collected only at the Screening Visit.
(d) Hematocrit results collected during Screening will be used to calculate the CDAI score to determine eligibility.
(e) CDAI score components are to be performed prior to dosing; the total CDAI score will be calculated once results are available 
for all components.
(f) Subjects must have safety laboratory results reviewed prior to MRI scan being performed. If a subject’s serum creatinine is >1.5 
times the ULN (>1.5x ULN), the subject should not undergo the MRI procedure. MRI will be performed at Screening and Week 30; 
MRIs will be centrally read.
(g) AVA to be collected prior to dosing. If positive AVA is detected, a sample will be assessed for neutralizing AVA.
(h) The 18-week postdose AVA sample should be collected for all subjects who stopped vedolizumab during study (ie, not for those 
who continue on commercial supply vedolizumab therapy post-study).
(i) PK samples to be collected at predose on Day 1, Weeks 6, 10, 14 and 22 and at Week 30. One additional PK sample will be 
collected at Week 10 postdose (as close to the end of the infusion as feasible, and must be obtained within 30 minutes after the end 
of the infusion).
(j) CRP will be measured from the hematology/serum chemistry blood draw at all weeks except Week 14. Week 14 will require a 
separate blood draw as hematology and serum chemistry are not taken at this time.
(k) Stool sample to be collected and sent to central laboratory for evaluation of fecal calprotectin.
(l) PML checklist must be administered prior to dosing at every dosing visit.
(m) Women of childbearing potential only. Urine pregnancy testing will be conducted at the site and serum pregnancy testing will 
be conducted by the central laboratory. At visits with study drug dosing, testing to be performed before any study drug dosing.
(n) Subject electronic diary to be completed as per training instruction during screening interval. Subject electronic diary (CDAI 
and perianal pain) to be completed daily from Screening to Week 30.
(o) Subjects should be observed for 2 hours following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion 
for monitoring for potential hypersensitivity reactions.
(p) Antibiotic companion medication that was started (or continued if subject already taking antibiotics) from Day 1, must be 
stopped at Week 6. Additional courses of antibiotics may be allowed, as needed, and in consultation with the medical monitor.
(q) Applicable for subjects who had a seton at study enrollment. Setons may be removed at or after Week 6 at the discretion of the 
investigator, provided that significant reduction in fistula drainage has occurred. All setons must be removed by Week 14.


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Schedule of Samples With Dosing Sequence Requirements 
Visit 1, 
Screening
Visit 2, 
Day 1
Visit 3, 
Wk 2
Visit 4, 
Wk 6
Visit 5, 
Wk10
Visit 6, 
Wk 14
Visit 7, 
Wk 22
Visit 8
Wk 30
Visit 9 
Wk 40
PK sample 
Within 30 
min before 
dose
Within 30 
min before 
dose
Within 30 
min before 
dose AND 
Immedi-
ately after 
infusion 
(within 30 
minutes of 
end of 
infusion)
Within 30 
min before 
dose
Within 30 
min 
before 
dose
Anytime during 
visit (before any 
commercial 
supply 
vedolizumab 
dose, if 
applicable)
AVA testing
Within 30 
min before 
dose
Within 30 
min before 
dose
Within 30 
min before 
dose
Within 30 
min before 
dose
Within 30 
min 
before 
dose
Anytime during 
visit (before any 
commercial 
supply 
vedolizumab 
dose, if 
applicable)
(Anytime 
during visit 
[only for 
subjects who 
stopped 
vedolizumab 
during study])
Pregnancy 
test
Anytime 
during visit
Before 
dose
Before 
dose
Before 
dose
Before dose Before 
dose
Before 
dose
Anytime during 
visit
Anytime during 
visit


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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 
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 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 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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.
13. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.


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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 drug(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 highly effective 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 drug will be discontinued and the investigator will 
offer the subject the choice to receive unblinded treatment information.
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent 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 drug.

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
PDAI


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Appendix F
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)
x 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)
x 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)
x 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
x 20
Lomotil/Imodium/opiates 
for diarrhea
Yes = 1
No = 0
x 30
Abdominal mass
None = 0
Questionable = 2
Definite = 5
x 10
Hematocrit (%) (a)
Males: subtract value from 47
Females: subtract value from 42
x 6
Body Weight (b)
(1 – (Body weight/
Standard Weight)) × 100
x 1
Final Score
Add totals:
Source: Adapted from: Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s disease activity 
index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70 (3):439-44. 
(a) If hematocrit subtotal <0, enter 0. (b) If body weight subtotal <-10, enter -10.


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Appendix G
Table for Determining Standard Body Weight (CDAI Variable)


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Appendix H
IBDQ


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Appendix I
EQ-5D
EQ-5D-3L PDA version
English (USA)
Health Questionnaire
English version for the USA
On the following screens please tap the statement that best describes your health 
TODAY.
Your mobility TODAY
I have no problems in walking about
I have some problems in walking about
I am confined to bed
Your self-care TODAY
I have no problems with self-care
I have some problems washing or dressing myself
I am unable to wash or dress myself
Your usual activities TODAY (e.g. work, study, housework, family or leisure activities)
I have no problems with performing my usual activities
I have some problems with performing my usual activities
I am unable to perform my usual activities
Your pain / discomfort TODAY
I have no pain or discomfort
I have moderate pain or discomfort
I have extreme pain or discomfort
Your anxiety / depression TODAY
I am not anxious or depressed
I am moderately anxious or depressed


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I am extremely anxious or depressed
We would like to know how good or bad your health is TODAY.
On the next screen you will see a scale numbered 0 to 100.
100 means the best health you can imagine.
0 means the worst health you can imagine.
Please tap on the scale to indicate how your health is TODAY.
The best health you can imagine
The worst health you can imagine
YOUR HEALTH TODAY
© EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation
Disclaimer: This is a preview of the EQ-5D instrument. It demonstrates the text, questions and response 
options included in this version. This preview does not represent the final product and should not be used 
as an official EQ-5D instrument.


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Appendix J
Likert Scale for Perianal Pain
This 11-point Likert rating scale will be used by subjects to assess their perianal pain each day, as 
below. Likert scale for perianal pain will be completed as part of the subject diary.
“How would you rate your perianal pain in the last 24 hours?”
0
1
2
3
4
5
6
7
8
9
10
No 
pain
Worst 
possible 
pain
Source: Adapted from: Likert, R. A technique for the measurement of attitudes. Archives of Psychology 
1932;140:1–55.


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Appendix K
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: Removed the requirement for perianal seton placement as part of standard of care 
before randomization.
The primary change occurs in Section 7.1 Inclusion Criteria: 
Initial 
wording:
The subject had noncutting perianal seton placement as part of standard care within 1 
to 4 weeks prior to randomization.
Amended 
or new 
wording:
If Tthe subject had noncutting perianal seton placement as part of standard care within 
1 to 4 weeks prior to randomization, seton must be removed by Week 14 of the 
study.
Rationale for Change:
Study population modified to allow subjects with or without seton.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 4.2 Rationale for the Proposed Study.

Section 6.1 Study Design. 

Appendix A Schedule of Study Procedures, footnote q.
Change 2: Changed the requirements for seton removal, if applicable, from 10 to 22 weeks after 
randomization to 6 to 14 weeks after randomization.
The primary change occurs in Section 6.1 Study Design:
Initial 
wording:
In both groups, setons may be removed at or after Week 10 at the discretion of the 
investigator, provided that significant reduction in fistula drainage has occurred. All 
setons are recommended to be removed by Week 14 and must be removed by Week 
22.
Amended 
or new 
wording:
In both groups, for subjects with a seton at study entry, setons may be removed at or 
after Week 106 at the discretion of the investigator, provided that significant reduction 
in fistula drainage has occurred. All setons are recommended to be removed by Week 
14 and must be removed by Week 2214.


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Rationale for Change:
Updated the text to apply only to subjects who have a seton at study entry, as setons are no longer 
required in this amendment; updated the window for seton removal so they are removed earlier in 
the study and do not confound endpoint assessment.
Appendix A Schedule of Study Procedures also contains this change.
Change 3: Added a secondary endpoint to evaluate fistulas healed at both Week 22 and Week 30.
The primary change occurs in Section 5.2.2 Secondary Endpoints:
Added text:
The proportion of subjects with a reduction of at least 50% from Day 1 in the 
number of draining perianal fistulae at both Week 22 and Week 30 (where 
closed fistulae are no longer draining despite gentle finger compression).
Rationale for Change:
New endpoint added that is considered clinically relevant
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 13.1.3 Analysis of Fistula Healing.
Change 4: Modified inclusion criterion 6 such that both France-specific and global language is 
presented.
The primary change occurs in Section 7.1 Inclusion Criteria:
Added text:6. All countries except France: The subject, historically, had an inadequate response 
with, lost response to, or was intolerant to either conventional therapy or a TNF-α 
antagonist for their underlying CD (does not require treatment failure for currently 
active draining fistula). 
France only: The subject, historically, failed (ie, had an inadequate response 
with, lost response to, or was intolerant to) infliximab for treatment of their 
underlying CD or fistulizing CD.
Rationale for Change:
To consolidate prior region-specific protocols into a single global protocol amendment.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 6.1 Study Design.


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Change 5: Modified inclusion and exclusion criteria to allow additional types of antibiotic to 
reduce the incidence of abscess.
The primary changes occur in Section 7.1 Inclusion Criteria and Section 7.2 Exclusion Criteria:
Initial 
wording:
7.1 Inclusion Criteria
…
9. The subject is willing and able to take antibiotic treatment (metronidazole or 
ciprofloxacin, as per local label) from Day 1 through study Week 6.
…
7.2 Exclusion Criteria
…
12. The subject has allergies to and/or contraindications for metronidazole and 
ciprofloxacin (including interacting drugs such as tizanidine).
13. In the opinion of the investigator, the subject is likely to require greater than 6 
weeks of treatment after Day 1 with metronidazole or ciprofloxacin for the 
treatment of abscess.
Amended 
or new 
wording:
7.1 Inclusion Criteria
…
9. The subject is willing and able to take antibiotic treatment (metronidazole, or
ciprofloxacin, amoxicillin clavulanate, or tinidazole, as per local label) from 
Day 1 through study Week 6.
…
7.2 Exclusion Criteria
…
12. The subject has allergies to and/or contraindications for metronidazole and 
ciprofloxacin and amoxicillin clavulanate and tinidazole (including interacting 
drugs such as tizanidine).
13. In the opinion of the investigator, the subject is likely to require greater than 6 
weeks of treatment after Day 1 with metronidazole, or ciprofloxacin, amoxicillin 
clavulanate, or tinidazole for the treatment of abscess.
Rationale for Change:
To allow additional options for antibiotics (amoxicillin clavulanate 875 mg BID, or tinidazole 500 
mg QD)


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The following sections also contain this change:

Section 7.3 Excluded Medications.

Section 7.3.1 Permitted Medications and Treatments.

Section 8.1.1.2 Companion Medication.

Section 8.1.3 Dose and Regimen.

Appendix A Schedule of Study Procedures.
Change 6: Modified inclusion criteria 10 and 11 per updated safety language.
The primary change occurs in Section 7.1 Inclusion Criteria:
Initial 
wording:
10. 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.
11. 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 9.1.25 Contraception and Pregnancy Avoidance Procedure 
and reporting responsibilities are defined in Section 9.1.26
Pregnancy.
Amended 
or new 
wording:
10. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential* agrees to use adequatea barrier method of contraception
(eg, condom with spermicide)* from signing of informed consent throughout the 
duration of the study and for 18 weeks after last dose. The female partner of a 
male subject should also be advised to use a highly effective method of 
contraception*.
11. A female subject of childbearing potential* who is sexually active with a 
nonsterilized* male partner agrees to use routinely adequate a highly effective 
method of contraception* from signing of informed consent throughout the 
duration of the study and for 18 weeks after last dose. 
*Definitions and acceptable highly effective methods of 
contraception are defined in Section 9.1.25 Contraception and 
Pregnancy Avoidance Procedure and reporting responsibilities are 
defined in Section 9.1.26 Pregnancy.


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Rationale for Change:
To clarify study inclusion criteria per current safety requirements.
Change 7: Modified exclusion criteria 6 and 7 per updated safety language.
The primary change occurs in Section 7.2 Exclusion Criteria:
Initial 
wording:
6. The subject has active or latent tuberculosis (TB), 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 test for tuberculosis (QuantiFERON) or 2 successive 
indeterminate QuantiFERON tests OR
ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in subjects 
receiving the equivalent of >15 mg/day prednisone)
Note: if the subject has a documented negative diagnostic TB test in the 
previous 3 months, screening testing does not need to be repeated provided 
subject has no risk factors for exposure.
7. The subject has a known history of infection with human immunodeficiency 
virus (HIV), hepatitis B (HBV) or hepatitis C (HCV) or is found to be 
seropositive at Screening.
Amended 
or new 
wording:
6. The subject has active or latent tuberculosis (TB), regardless of treatment 
history, as evidenced by any of the following:
a.
History of TB.
a.
A diagnostic TB test performed during Screening that is positive, as 
defined by:
iii. A positive test for tuberculosis (QuantiFERON) or 2 successive 
indeterminate QuantiFERON tests OR
iv. A tuberculin skin test reaction ≥10 mm (≥5 mm in subjects 
receiving the equivalent of >15 mg/day prednisone)
b. Chest X-ray within 3 months prior to Day 1 that is suspicious for 
pulmonary TB, and a positive or 2 successive indeterminate 
QuantiFERON test within 30 days prior to Screening or during 
the Screening Period.
Note: if the subject has a documented negative diagnostic TB test in the 
previous 3 months, screening testing does not need to be repeated provided 


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subject has no risk factors for exposure.
7.  The subject has chronic hepatitis B virus (HBV) infection* or chronic 
hepatitis C virus (HCV) infection** or a known history of infection 
withhuman immunodeficiency virus (HIV), hepatitis B (HBV) or hepatitis C 
(HCV) infection (or is found to be seropositive at Screening) or subject is 
immunodeficient (eg, due to organ transplantation, history of common 
variable immunodeficiency). 
*Subjects who are positive for hepatitis B virus surface antigen (HBsAg) will 
be excluded. For subjects who are negative for HBsAg but are positive for 
either surface antibodies and/or core antibodies, HBV DNA polymerase 
chain reaction will be performed, and if any test result meets or exceeds 
detection sensitivity, the subject will be excluded.
** If the subject is HCV antibody positive, then a viral load test will be 
performed. If the viral load test is positive, then the subject will be excluded.
Rationale for Change:
To clarify exclusion criteria per preferred safety wording.
Change 8: Modified exclusion criterion 17 to remove the option of 5 half lives as washout 
window.
The primary change occurs in Section 7.2 Exclusion Criteria:
Deleted 
text:
17. The subject has received any investigational or approved biologic or biosimilar 
agent within 60 days or 5 half lives (whichever is longer) of randomization.
Rationale for Change:
To clarify that 60 days is considered a sufficient washout period.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 7.3 Excluded Medications.
Change 9: Modified exclusion criterion 19 to also exclude subjects with prior exposure to 
etrolizumab or anti-mucosal addressin cell adhesion molecule-1 therapy therapy.
The primary change occurs in Section 7.2 Exclusion Criteria:
Initial 
wording:
19. The subject has any prior exposure to vedolizumab, natalizumab, efalizumab, or 
rituximab.
Amended 
or new 
wording:
19. The subject has any prior exposure to vedolizumab, natalizumab, efalizumab, or
rituximab, etrolizumab, or anti-MAdCAM-1 therapy.


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Rationale for Change:
To exclude subjects with exposures to etrolizumab or anti-MAdCAM-1 therapy
Section 2.0 STUDY SUMMARY also contain this change.
Change 10: Reduced the study sample size from 126 (63 per group) to 100 (50 per group).
The primary change occurs in Section 13.3 Determination of Sample Size:
Initial 
wording:
A sample size of 126 subjects (63 per group) will generate 95% CIs for fistula closure 
rate with a half width no wider than 12.4%; in addition, the 95% CIs for the difference 
in fistula closure rates between the 2 groups will be no wider than 17.6%. The sample 
size was not based on statistical power considerations but on an estimate of precision.
Amended 
or new 
wording:
A sample size of 126100 subjects (6350 per group) will generate 95% CIs for fistula 
closure rate with a half width no wider than 12.413.9 %; in addition, the 95% CIs for 
the difference in fistula closure rates between the 2 groups will be no wider than 
17.619.6%. The sample size was not based on statistical power considerations but on 
an estimate of precision.
Rationale for Change:
To modify the study sample size.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 6.1 Study Design.
Change 11: Increased the number of study sites from 30 to 40.
The primary change occurs in Section 2.0 STUDY SUMMARY:
Initial 
wording:
Approximately 30 sites in North America and Europe
Amended 
or new 
wording:
Approximately 3040 sites in North America and Europe
Rationale for Change:
To increase study recruitment


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Change 12: Added a stratification factor for seton or no seton at randomization.
The primary change occurs in Section 8.3 Randomization Code Creation and Storage:
Added text:Randomization will be stratified by TNF naïve versus TNF non-naïve (TNF failed) 
and by seton or no seton at Baseline.
Rationale for Change:
To balance groups by seton use, given that setons are no longer required as of this amendment.
Change 13: Added a futility analysis after 25 subjects complete the primary endpoint assessment 
(Week 30).
The primary change occurs in Section 13.2 Futility Analysis and Criteria for Early Termination:
Initial 
wording:
13.2 Interim Analysis and Criteria for Early Termination
No interim analysis, nor criteria for early termination of the study are planned.
Amended 
or new 
wording:
13.2 InterimFutility Analysis and Criteria for Early Termination
No interim analysis, nor criteria for early termination of the study are planned.A 
futility analysis will be performed after 25 patients per treatment arm complete 
to Week 30. There is no intention to stop for efficacy at this point.
Rationale for Change:
To add a futility analysis 
The following sections also contain this change:

Section 6.3.1 Criteria for Premature Termination or Suspension of Study Sites.

Section 13.2 Futility Analysis and Criteria for Early Termination.
Change 14: Updated background information per the current Investigator’s Brochure.
The primary change occurs in Section 4.1.2.2 Human Experience:
Initial 
wording:
In the clinical development program more than 3400 subjects have received at least 1 
dose of vedolizumab (see Investigator’s Brochure [IB], Edition 17). 
Amended 
or new 
wording:
In the clinical development program more than 3400 4200 subjects have received at 
least 1 dose of vedolizumab (see Investigator’s Brochure [IB], Edition 1719).
Rationale for Change:
Updated per Investigator’s Brochure Edition 19.


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Change 15: Revised the rationale for the proposed study given that perianal seton replacement no 
longer required.
The primary change occurs in Section 4.2 Rationale for the Proposed Study:
Deleted 
text:
Treatment in both arms will be combined with standard of care surgical intervention 
(seton) based on recent literature, which suggests benefit of a combined surgical and 
medical approach for patients with CD perianal fistulae [8,17,45].
Rationale for Change:
Updated on the basis of changes to the study population as of this amendment.
Change 16: Revised the benefit-risk assessment given that perianal seton replacement no longer 
required.
The primary change occurs in Section 4.3 Benefit:Risk Assessment:
Deleted 
text:
Treatment in both arms will be combined with standard of care surgical intervention 
(seton) based on recent literature, which suggests benefit of a combined surgical and 
medical approach for patients with CD perianal fistulae [8,17,45]. The combination of 
vedolizumab therapy with surgical standard of care is intended to minimize the risk of 
treatment failure.
Rationale for Change:
Updated on the basis of changes to the study population as of this amendment.
Change 17: Modified the Schematic of Study Design given the changes in this amendment.
The primary change occurs in Figure 6.a
Schematic of Study Design:
Description 
of Change:

Removed standard care seton before randomization.

Modified sample size to 100 subjects randomized.

Clarified that “If baseline seton” then removal beween Weeks 6 and 14.

Added endpoint assessment at Week 22.
Rationale for Change:
Updated the figure on the basis of changes to the study design as of this amendment
Change 18: Changed the maximum dose of oral corticosteroids from 30 to 20 mg/day and 
clarified that tapering schedule provided is an example of one schedule; allowed for return to 
baseline corticosteroid dose.
The primary change occurs in Section 7.3.1.1 Oral Corticosteroid Dosing and Tapering:
Initial 
wording:
The maximum dose of oral corticosteroids for the treatment of CD that may be
coadministered with vedolizumab IV is 30 mg/day prednisone or 9 mg/day 
budesonide (or equivalent) as long as the corticosteroid dose has been stable for at 


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least 4 weeks prior to randomization.
It is required that subjects receiving oral corticosteroids begin a tapering regimen 
by Week 4. The tapering schedule is as follows:

For prednisone at doses >10 mg/day (or equivalent), the dose should be reduced at 
a rate of 5 mg/week until a 10 mg/day is reached.

For prednisone at doses ≤10 mg/day (or equivalent) or once a 10 mg/day dose (or 
equivalent) is achieved by tapering, the dose should be reduced at a rate of 2.5 
mg/week until discontinuation.

Budesonide should be reduced at a rate of 3 mg every 3 weeks until 
discontinuation.
Amended 
or new 
wording:
The maximum dose of oral corticosteroids for the treatment of CD that may be
coadministered with vedolizumab IV is 3020 mg/day prednisone or 9 mg/day 
budesonide (or equivalent) as long as the corticosteroid dose has been stable for at 
least 4 weeks prior to randomization.
It is required that subjects receiving oral corticosteroids begin a tapering regimen 
by Week 4. TheAn example 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 until 
discontinuation.
For patients who could not tolerate the corticosteroid taper without recurrence 
of clinical symptoms, corticosteroids may have been increased up to the original 
dose at the start of study (should not exceed baseline dose). In such cases, the 
tapering regimen must be reinitiated within 2 weeks.
Rationale for Change:
To reduce maximum dose of concomitant corticosteroid, to allow sites to follow their standard 
tapering schedule, and to clarify that that steroids can be increased back to the baseline dose if 
needed.


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Change 19: Modified the criteria for discontinuation or withdrawal to add monitoring for 
leukopenia and lymphopenia and to clarify other criteria.
The primary change occurs in Section 7.4 Criteria for Discontinuation or Withdrawal of a Subject: 
Initial 
wording:
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 9.1.20), 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%).
…
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should 
be recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded 
(eg, withdrawal due to an AE or lack of efficacy).
Amended 
or new 
wording:
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 medicationdrug should be discontinued immediately with appropriate 
clinical follow-up (including repeat laboratory tests, until a subject’s 


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laboratory profile has returned to normal/baseline status, see Section 9.1.20), if 
the following circumstances occur at any time during study medicationdrug
treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × 
ULN or international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).

Leukopenia or lymphopenia: WBC and lymphocyte counts will be 
monitored for all subjects. Azathioprine, 6-MP, or methotrexate, if 
applicable, should be discontinued and the dose of vedolizumab held for 
an absolute lymphocyte count <0.5×109/L at any point in the study. The 
absolute lymphocyte count must be repeated at appropriate intervals as 
determined by the investigator. The next dose of vedolizumab can be
administered only if the absolute lymphocyte count is ≥0.5×109/L. If the 
absolute lymphocyte count remains <0.5×109/L, study drug should be 
discontinued and the subject withdrawn from the study.
…
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 in 
the subject’s source documents.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should 
be recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded 
(ieeg, withdrawal due to an AE should not be recorded in the voluntary 
withdrawal category. Similarly, or lack of efficacy should not be recorded in 
the voluntary withdrawal category).
Rationale for Change:
To add monitoring for leukopenia and lymphopenia and to add clarifications to criteria 3 and 4.


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Change 20: Clarified the medical history collection of smoking/nicotine usage status and 
collection of all medications for Crohn’s disease.
The primary change occurs in Section 9.1.2 Demographics, Medical History, and Medication 
History Procedure:
Initial 
wording:
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.)
…
In addition, all prior biologic medication history for the treatment of CD, including 
date of diagnosis, with the reason for discontinuation is to be collected for subjects 
where possible.
Amended 
or new 
wording:
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/nicotine usage 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 
stoppedresolved at or prior to signing of informed consent. Ongoing conditions 
are considered concurrent medical conditions (see Section 9.1.8.)
…
In addition, all prior biologic and/or any medication history for the treatment of 
CD, including date of diagnosis, with the reason for discontinuation is to be 
collected for subjects where possible.
Rationale for Change:
To capture relevant medical history information


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Change 21: Clarified vital signs collection.
The primary change occurs in Section 9.1.6 Vital Sign Procedure:
Initial 
wording:
Vital signs will include body temperature (oral measurement), respiratory rate, supine 
blood pressure (resting more than 5 minutes), and pulse (resting more than 5 minutes).
Amended 
or new 
wording:
Vital signs will include body temperature (oral measurement), respiratory rate, supine 
blood pressure (systolic and diastolic, resting more than 5 minutes), and pulse 
(resting more than 5 minutes).
Rationale for Change:
To allow for sites that use tympanic body temperature and to clarify that blood pressure collection 
includes both systolic and diastolic.
Change 22: Clarified that all fistula draining assessments are preferably be done by the same 
qualified designee.
The primary change occurs in Section 9.1.11 Fistula Draining Assessment:
Added text:Fistula draining assessment will preferably be performed by the same qualified 
designee for all assessments.
Rationale for Change:
For consistency in endpoint measurement.
Appendix A Schedule of Study Procedures, footnote b, also contains this change.
Change 23: Clarified that confirmation from a central reader is required for magnetic resonance 
imaging eligibility.
The primary change occurs in Section 9.1.10 MRI Procedure:
Added text:Confirmation must be obtained from a central reader to confirm MRI eligibility.
Rationale for Change:
To clarify MRI eligibility requirements.


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Change 24: Added the superficial category for the Parks classification.
The primary change occurs in Section 9.1.10.1 Parks Classification:
Added text:Parks described a classification system for perianal fistula [31], that will be used at 
Screening for classification of active fistula(e) as superficial, intersphincteric, 
transsphincteric, suprasphincteric, or extrasphincteric. 
Rationale for Change:
To provide all categories for Parks classification.
Change 25: Clarified the neutralizing anti-vedolizumab antibodies (AVA) analysis.
The primary change occurs in Section 9.1.23 Anti-Vedolizumab Antibodies Sampling:
Added text:A sample will be assessed for neutralizing AVA if a positive AVA is detected.
Rationale for Change:
To clarify when neutralizing AVA will be analyzed.
Change 26: Replaced the existing Contraception and Pregnancy Avoidance language with 4 new 
subsections containing updated language for contraception and pregnancy avoidance, and clarified 
in Appendix C that highly effective contraception must be used.
The primary change occurs in Section 9.1.25 Contraception and Pregnancy Avoidance Procedure:
Deleted 
text:
For male subjects:
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.
For female subjects of childbearing potential:
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 post-vasectomy and have confirmed that 


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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:
Barrier methods (each time 
the subject has intercourse):
Intrauterine devices 
(IUDs):
Hormonal 
contraceptives:

Male condom PLUS 
spermicide.

Cap (plus spermicidal cream 
or jelly) PLUS male 
condom and spermicide.

Diaphragm (plus 
spermicidal cream or jelly) 
PLUS male condom and 
spermicide.

Copper T PLUS 
condom or 
spermicide.

#Progesterone T 
PLUS condom or 
spermicide.

Implants.

Hormone 
shot/injection.

Combined pill.

Minipill.

Patch.

Vaginal ring PLUS 
male condom and 
spermicide.
Subjects will be provided with information on acceptable methods of contraception as 
part of the subject informed consent process and will be asked to sign a consent form 
stating that they understand the requirements for avoidance of pregnancy, donation of 
ova, and sperm donation during the course of the study.
During the course of the study, regular urine hCG pregnancy tests will be performed 
only for women of childbearing potential and subjects will receive continued guidance 
with respect to the avoidance of pregnancy and sperm donation as part of the study 
procedures (Appendix A). In addition to a negative serum hCG pregnancy test at 
Screening, subjects also must have a negative urine hCG pregnancy test prior to 
receiving each IV dosing. At final study visit or early termination, subjects will have 
an additional serum pregnancy test.
Added text:9.1.25.1 Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 
18 weeks after last dose of study drug, 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. Women of childbearing 
potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list of highly effective contraception below.
9.1.25.2 Female Subjects and Their Male Partners


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From signing of informed consent, throughout the duration of the study, and for 
18 weeks after last dose of study drug, female subjects of childbearing potential* 
who are sexually active with a nonsterilized male partner** must use a highly 
effective method of contraception (from the list below). 
In addition, they must be advised not to donate ova during this period.
9.1.25.3 Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance 
procedures.
* A woman is considered a woman of childbearing potential (ie, fertile) following 
menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, and bilateral 
oophorectomy. A post-menopausal state is defined as no menses for 12 months 
without an alternative medical cause. A high follicle-stimulating hormone (FSH) 
level in the post-menopausal range (FSH >40 IU/L) may be used to confirm a 
post-menopausal state in younger women (ie, younger than age 45) or women 
who are not using hormonal contraception or hormonal replacement therapy. 
However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have 
confirmed that they have obtained documentation of the absence of sperm in the 
ejaculate or have had bilateral orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
6. Highly effective methods of contraception are defined as “those that, alone or 
in combination, result in a low failure rate (ie, less than 1% failure rate per 
year when used consistently and correctly). In this study, where medications 
and devices containing hormones are included, the only acceptable methods 
of contraception are: 

Non-hormonal methods: 

Intrauterine device (IUD). 

Bilateral tubal occlusion. 

Vasectomised partner (provided that partner is the sole sexual 
partner of the trial participant and that the vasectomised partner 
has received medical assessment of the surgical success. 

Hormonal methods: 

Combined (estrogen and progestogen) hormonal contraception 
associated with inhibition of ovulation initiated at least 3 months 
prior to the first dose of study drug OR combined with a barrier 
method (male condom, female condom or diaphragm) if for 
shorter duration until she has been on contraceptive for 3 months;


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
Oral. 

Intravaginal (eg, ring).

Transdermal. 

Progestogen-only hormonal contraception associated with 
inhibition of ovulation1 initiated at least 3 months prior to the first 
dose of study drug OR combined with a barrier method (male 
condom, female condom or diaphragm) if shorter till she has been 
on contraceptive for 3 months;

Oral. 

Injectable.

Implantable.
7. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
8. Subjects will be provided with information on highly effective 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.
9. During the course of the study, regular urine human chorionic gonadotropin 
(hCG) pregnancy tests will be performed only for women of childbearing 
potential and all subjects (male and female) will receive continued guidance 
with respect to the avoidance of pregnancy and sperm donation as part of the 
study procedures. Such guidance should include a reminder of the following:
a. Contraceptive requirements of the study
b. Reasons for use of barrier methods (ie, condom) in males with 
pregnant partners
c.
Assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly 
since the last visit?
ii. Have you forgotten to use contraception since the last 
visit?
iii. Are your menses late (even in women with irregular or 
infrequent menstrual cycles a pregnancy test must be 
performed if the answer is “yes”)?


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iv. Is there a chance you could be pregnant?
10. In addition to a negative serum hCG pregnancy test at Screening, female 
subjects of childbearing potential must also have confirmed menses in the 
month before first dosing (no delayed menses) and a negative urine hCG 
pregnancy test prior to receiving each IV dosing.
9.1.25.4 General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

Contraceptive requirements of the study.

Reasons for use of barrier methods (ie, condom) in males with pregnant 
partners.

Assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last 
visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in women with irregular or infrequent 
menstrual cycles a pregnancy test must be performed if the answer is 
“yes”)?
–
Is there a chance you could be pregnant?
Rationale for Change: 
To add updated language for contraception and pregnancy avoidance to clarify 
acceptable/unacceptable forms of contraception and appropriate guidance for patients with regard 
to pregnancy avoidance during course of study and to clarify that highly effective contraception 
must be used in Appendix C.
Appendix C Elements of the Subject Informed Consent also contains this change.
Change 27: Clarified the pregnancy form requirement for female partners of male subjects.
The primary change occurs in Section 9.1.26 Pregnancy:
Added text:All pregnancies in subjects, including female partners of male subjects, on active 
study drug including comparator will be followed up to final outcome, using the 
pregnancy form.
Rationale for Change:
To clarify that pregnancy is followed for female partners of male subjects
Change 28: Added a requirement to document missed doses of antibiotic companion medication.
The primary change occurs in Section 9.2 Monitoring Subject Treatment Compliance:
Added text:The site will also document missed doses of antibiotic companion medication.


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Rationale for Change:
To clarify that missed doses of companion medication should be documented.
Change 29: Changed wording in the safety section from severity to intensity.
The primary change occurs in Section 10.1.3 Additional Points to Consider for PTEs and AEs:
Initial 
wording:
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 is recorded.
Amended 
or new 
wording:
Changes in severityintensity of AEs/Serious PTEs:

If the subject experiences changes in severityintensity of an AE/serious PTE, the 
event should be captured once with the maximum severityintensity is recorded.
Rationale for Change:
Update to preferred safety language
The following sections also contain this change:

Section 10.1.6 Intensity of PTEs and AEs.

Section 10.2.1.2 PTE and AE Reporting.

Section 13.1.6 Safety Analysis.
Change 30: Added frequency to list of pretreatment event and adverse event reporting.
The primary change occurs in Section 10.2.1.2 PTE and AE Reporting:
Added text:3. Frequency
Rationale for Change:
Added per preferred safety language.
Change 31: Clarified that AVA titers are analyzed.
The primary change occurs in Section 13.1.5 Anti-vedolizumab Antibodies Analysis:
Added text:The proportion of subjects with positive and titers of AVA (transient and persistent), 
and proportion of subjects with positive neutralizing AVA during the study will be 
summarized.
Rationale for Change:
To clarify that titers of AVA are included in analysis.
Change 32: Clarified that the subject diary for Crohn’s Disease Activity Index is electronic.


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The primary change occurs in Appendix A Schedule of Study Procedures, footnote n:
Added text: (n) Subject electronic diary to be completed as per training instruction during screening 
interval. Subject electronic diary (CDAI and perianal pain) to be completed daily from 
Screening to Week 30.
Rationale for Change:
To clarify that footnote (n) in Appendix A refers to electronic diary.
Section 9.1.15 CDAI Diary Completion also contains this change.
Change 33: Clarified when serum versus urine pregnancy testing done.
The primary change occurs in Appendix A Schedule of Study Procedures:
Description
of change:

Row for “Pregnancy Testing” split into two rows to depict serum versus urine 
pregnancy testing. 

Serum pregnancy testing note at Screening and Final Visit/Early Termination.

Urine pregnancy testing noted at Day 1, Weeks 2, 6, 10, 14, 22 and 40.
Rationale for Change:
To clarify when serum or urine testing is required in the table instead of in the footnotes.
Change 34: Clarified that pregnancy testing is performed before study drug dosing at dosing 
visits.
The primary change occurs in Appendix A Schedule of Study Procedures, footnote m:
Initial 
wording:
(m) Women of childbearing potential only. Urine pregnancy testing will be conducted 
at the site and serum pregnancy testing will be conducted by the central laboratory. 
Serum pregnancy completed at Screening and Week 30/Early Termination; urine 
pregnancy to be completed at other visits.
Amended 
or new 
wording:
(m) Women of childbearing potential only. Urine pregnancy testing will be conducted 
at the site and serum pregnancy testing will be conducted by the central laboratory.
Serum pregnancy completed at Screening and Week 30/Early Termination; urine 
pregnancy to be completed at other visits.At visits with study drug dosing, to be 
performed before any study drug dosing.
Rationale for Change:
To clarify in footnote (m) that pregnancy testing must be performed before study drug dosing.
Change 35: Added an investigator responsibility per updated International Conference on 
Harmonisation guideline.
The primary change occurs in Appendix B Responsibilities of the Investigator:


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CONFIDENTIAL
Added text:13.  If the investigator/institution retains the services of any individual or party 
to perform trial-related duties and functions, the investigator/institution should 
ensure that this individual or party is qualified to perform those trial-related 
duties and functions and should implement procedures to ensure the integrity of 
the trial-related duties and functions performed and any data generated.
Rationale for Change:
Added anew investigator responsibility per update in ICH guideline


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PPD

SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized Double-Blind Phase 4 Study to Evaluate the Safety and Proportion of 
Subjects With Fistula Healing in 2 Dose Regimens of Entyvio (Vedolizumab IV) in the 
Treatment of Fistulizing Crohn’s Disease (ENTERPRISE)
NCT Number: NCT02630966
SAP Approve Date: May 29, 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
NOTE: In the final SAP, dated May 29, 2019, in Appendix E Criteria for Identification of Markedly 
Abnormal Laboratory Values (p. 51) the MAV criteria for Calcium in conventional units (mg/dL) are 
not accurate.  The MAV criteria for Calcium in the conventional units are <6.9 mg/dL and >13.0 mg/dL. 
Since the MAV criteria for Calcium in the Takeda Preferred SI unit mmol/L were correctly specified, 
the SAP was not amended.  


STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Vedolizumab-4003
A Randomized Double-Blind Phase 4 Study to Evaluate the Safety and Proportion of 
Subjects With Fistula Healing in 2 Dose Regimens of Entyvio (Vedolizumab IV) in the 
Treatment of Fistulizing Crohn’s Disease (ENTERPRISE)
Vedolizumab IV 300 mg in the Treatment of Fistulizing Crohn’s Disease
PHASE 4
Version: Final
Date: May 29, 2019
Prepared by:
Based on:
Protocol Version: Amendment 5
Protocol Date: 20 April 2017
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.
PPD


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CONFIDENTIAL
1.1
Approval Signatures
Study Title:
A Randomized Double-Blind Phase 4 Study to Evaluate the Safety and 
Proportion of Subjects With Fistula Healing in 2 Dose Regimens of 
Entyvio (Vedolizumab IV) in the Treatment of Fistulizing Crohn’s 
Disease (ENTERPRISE)
Approvals:
PPD


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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
2.1
List of In-Text Tables ................................................................................................5
2.2
List of In-Text Figures...............................................................................................5
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objective......................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Additional Objectives ................................................................................................8
4.4
Safety Objective ........................................................................................................8
4.5
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Additional Endpoints ...............................................................................................10
5.4
Safety Endpoints......................................................................................................11
5.5
Other Data and Variables Collected .........................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................13
7.1.3
Definition of Baseline Values.............................................................................13
7.1.4
Definition of Last Visit ......................................................................................13
7.1.5
Definition of Screen Failure ...............................................................................13
7.1.6
Covariates and Subgroups..................................................................................14
7.1.7
Definition of Study Visit Windows ....................................................................14
7.1.8
Convention for Calculation of CDAI Scores.......................................................15
7.1.9
Conventions for Missing Adverse Event Dates...................................................17
7.1.10 Conventions for Missing Concomitant Medication Dates...................................18
7.1.11 Conventions for Calculation of Duration of CD..................................................19
7.1.12 Conventions for Calculation of Duration of Fistulizing Disease..........................19
7.1.13 Other Missing Data Handling Conventions ........................................................19


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7.2
Analysis Sets ...........................................................................................................20
7.3
General Study Information and Disposition of Subjects ...........................................20
7.4
Significant Protocol Deviations................................................................................21
7.5
Demographic and Other Baseline Characteristics.....................................................21
7.6
Medical History and Concurrent Medical Conditions...............................................23
7.7
Medication History and Concomitant Medications...................................................24
7.8
Study Drug Exposure...............................................................................................25
7.9
Efficacy Analysis.....................................................................................................25
7.9.1
General Considerations for the Efficacy Data Analysis ......................................25
7.9.2
Overall Fistulae Status Summaries.....................................................................26
7.9.3
Primary Efficacy Endpoint.................................................................................27
7.9.4
Secondary Efficacy Endpoints............................................................................27
7.9.5
Additional Efficacy Endpoints ...........................................................................29
7.10
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................32
7.10.1 Pharmacokinetic Analysis ..................................................................................32
7.10.2 Immunogenicity Analysis...................................................................................33
7.10.3 Pharmacodynamic Analysis ...............................................................................33
7.11
Other Outcomes.......................................................................................................33
7.12
Safety Analysis........................................................................................................34
7.12.1 Adverse Events ..................................................................................................34
7.12.2 Clinical Laboratory Evaluations .........................................................................36
7.12.3 Vital Signs .........................................................................................................38
7.12.4 12-Lead ECGs ...................................................................................................38
7.12.5 Other Observations Related to Safety.................................................................38
7.13
Interim Analysis ......................................................................................................39
7.14
Changes in the Statistical Analysis Plan...................................................................39
8.0
REFERENCES..............................................................................................................41
9.0
APPENDICES...............................................................................................................42


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2.1
List of In-Text Tables
Table 7.a
Visit Windows for Efficacy and Safety Variables
Table 7.b
Demographic and Baseline Characteristics
Table 7.c
CD-Related Baseline Characteristics
Table 7.d
Fistula Related Baseline Characteristics 
Table 7.e
Components of the Van Assche MRI-Based Score 
Table 7.f
Clinical Laboratory Parameters
2.2
List of In-Text Figures
Figure 4.a
Schematic of Study Design


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
anti-TNF
tumor necrosis factor-alpha antagonist
AVA
anti-vedolizumab antibody
BMI
body mass index
CD
Crohn’s Disease
CDAI
Crohn’s Disease Activity Index
CI
confidence interval
eCRF
electronic case report form
CRP
C-reactive protein
Ctrough
trough serum concentrations
%CV
coefficient of variation
CV
conventional units
ECG
electrocardiogram
EQ-5D(-3L)
Euro Quality of Life-5D questionnaire (3 level version)
FAS
full analysis set
FC
fecal calprotectin
HLT
high level term
IBDQ
inflammatory bowel disease questionnaire
ICF
informed consent form
IV
intravenous
IRR
Infusion-Related Reactions
LTFU
long-term follow-up
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
nAVA
neutralizing anti-vedolizumab antibody
PK
pharmacokinetics
PML
Progressive Multifocal Leukoencephalopathy
PTE
pretreatment event
PDAI
Perianal Disease Activity Index
PPS
per protocol set
RAMP
Risk Assessment and Minimization for PML
SAE
serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SD
standard deviation


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SI
International System of Units
SMQ
Standard MedDRA Query
TNF-α
tumor necrosis factor-alpha
VAS
Visual analog scale
WHODrug
World Health Organization Drug Dictionary


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4.0
OBJECTIVES
4.1
Primary Objective
The primary objective is to evaluate the proportion of subjects with perianal fistula healing at 
Week 30 in 2 different dose regimens of vedolizumab IV 300 mg in subjects with fistulizing 
Crohn’s Disease (CD).
4.2
Secondary Objectives
The secondary objective is to evaluate fistula healing over a 30-week evaluation period.
4.3
Additional Objectives
Additional objectives include:

To evaluate magnetic resonance imaging (MRI) assessment of fistula healing at Week 30
compared to Screening.

To evaluate clinical disease activity assessed by Perianal Disease Activity Index (PDAI) and 
Crohn’s Disease Activity Index (CDAI) from Day 1 to Weeks 2, 6, 10, 14, 22 and 30.

To evaluate perianal pain using a Likert scale at Week 30 compared to Day 1.

To evaluate biomarkers of disease activity (fecal calprotectin [FC] and C-reactive protein 
[CRP]) at Week 30 compared to Day 1.

To evaluate quality of life measures (inflammatory bowel disease questionnaire [IBDQ] and 
Euro Quality of Life-5D [EQ-5D]) at Week 14 and Week 30 compared to Day 1.

To evaluate the pharmacokinetics (PK) of vedolizumab in CD subjects with fistula(e) over 
the treatment period.

To assess immunogenicity of vedolizumab over 40 weeks of follow-up.
4.4
Safety Objective
The safety objective is to assess the safety of vedolizumab IV in CD subjects with fistula(e) over 
40 weeks of follow-up.
4.5
Study Design
This is a phase 4, randomized, double-blind, multicenter study to evaluate the safety and the 
proportion of subjects with fistula healing in 2 dose regimens of vedolizumab IV 300 mg over a 
30-week treatment period (with the last dose at Week 22) in the healing of draining perianal 
fistulae in subjects with active CD. 
Approximately 100 CD subjects with moderately to severely active CD and 1 to 3 draining 
perianal fistula(e) of at least 2 weeks duration (with or without seton) were planned to be 
included. To be eligible, subjects must have historically had an inadequate response with, lost 
response to, or been intolerant to either conventional therapy or a tumor necrosis factor-alpha 


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CONFIDENTIAL
(TNF-α) antagonist (anti-TNF) for their underlying CD; for subjects recruited in France only: 
subjects must have historically failed (i.e., had an inadequate response with, lost to, or was 
intolerant to) infliximab for treatment of their underlying CD or fistulizing CD. 
Subjects entering the study may have had surgical seton placement as standard of care prior to 
enrollment in the study. For subjects enrolled before implementation of protocol amendment 5, 
seton placement was mandatory as part of the inclusion criteria and the seton was required to be 
removed between Week 10 and Week 22. For subjects enrolled after protocol amendment 5 
seton placement was optional. For subjects with a seton placement as part of the standard care at 
study entry, setons had to be removed at or after Week 6 at the discretion of the investigator, 
provided that significant reduction in fistula drainage has occurred; all setons had to be removed 
by Week 14. Only for subjects enrolled after implementation of protocol amendment 5, seton 
placement was added as randomization stratification factor.
Subjects were randomized in a 1:1 ratio, stratified by prior anti-TNF use (naïve or failure) and 
seton placement at baseline (no or yes; only implementation of protocol amendment 5), to the 
following 2 treatment arms:

Arm 1: vedolizumab IV 300 mg dose at Week 0, 2, 6, 14, 22 and a placebo IV dose at 
Week 10, administered as a 30-minute infusion;

Arm 2: vedolizumab IV 300 mg dose at Week 0, 2, 6, 10, 14 and 22, administered as a 
30-minute infusion.
The study consists of a 4-week Screening Period, a 30-week Treatment Period (with last dose at 
Week 22) and an 18-week Follow-up Period following the last dose. The duration of the study 
from Screening to 18 weeks post last dose at Week 22 was approximately 44 weeks for all 
subjects. All subjects in the study were required to complete a long-term follow-up (LTFU) 
safety survey by telephone 6 months following the last dose. 
A schematic of the study design is shown in Figure 4.a. A schedule of study procedures is 
provided in Appendix A.
Figure 4.a
Schematic of Study Design


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5.0
ANALYSIS ENDPOINTS
Perianal fistulae were to be assessed for draining or closed status at Screening and during each 
visit as scheduled in Appendix A. From those assessments, the fistulae-related efficacy endpoints 
listed below will be derived.
5.1
Primary Endpoint
The primary endpoint for this study is the reduction in the number of draining perianal fistulae 
draining at Baseline of at least 50% at Week 30 (where closed fistulae are no longer draining 
despite gentle finger compression).
5.2
Secondary Endpoints
Secondary endpoints are:

Reduction in the number of perianal fistulae draining at Baseline of at least 50% at both 
Week 22 and Week 30 (where closed fistulae are no longer draining despite gentle finger 
compression).

100% perianal fistulae closure of the fistulae draining at Baseline at Week 30 (i.e., all fistulae 
draining at Baseline are no longer draining despite gentle finger compression).

Time to first perianal fistula closure among the fistulae draining at Baseline.

Time to 100% perianal fistulae closure of the fistulae draining at Baseline.

Duration of perianal fistula response, where perianal fistula response is defined as reduction 
in the number of draining perianal fistulae draining at Baseline of at least 50%.
5.3
Additional Endpoints
Additional endpoints are:

Reduction of fluid collections/abscess (reduction in relative mean T2 intensity on MRI) at 
Week 30 compared to Screening.

Percent reduction in relative mean T2 intensity on MRI at Week 30 compared to Screening.

Change in Van Assche total score at Week 30 compared to Screening.

Change in individual MRI descriptors from post-contrast enhanced T1-weighted images at 
Week 30 compared to Screening.

Changes in PDAI total score from Day 1 to Weeks 2, 6, 10, 14, 22 and 30.

Changes in CDAI total score from Day 1 to Weeks 2, 6, 10, 14, 22 and.

Decrease ≥30% in mean perianal pain for the 7 days prior to Week 30 compared to the 7 days 
prior to Day 1.

Change in biomarkers (FC and CRP) at Week 30 compared to Day 1.


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
Change in IBDQ total and subscale scores from Day 1 to Weeks 14 and 30.

Change in the EQ-5D utility score and visual analog scale (VAS) from Day 1 to Weeks 14 
and 30.

Trough serum concentrations (Ctrough) of vedolizumab for Day 1, Weeks 6, 10, 14, 22 and 
30.

Presence of positive anti-vedolizumab antibodies (AVAs) and neutralizing anti-vedolizumab 
antibodies (nAVAs) for Day 1, Weeks 6, 10, 14, 22, 30 and 40.
5.4
Safety Endpoints
Safety will be assessed by adverse events (AEs), adverse events of special interest (AESIs), 
serious adverse events (SAEs), vital signs and results of standard laboratory tests (clinical 
chemistry, hematology, coagulation and urinalysis).
5.5
Other Data and Variables Collected
Other data and variables collected and mapped to the study database include:

Demographic data (see section 7.5)

Baseline disease characteristics (see details in section 7.5)

Medical history (see details in section 7.6)

Prior and concomitant medications (see details in section 7.7)

Study drug exposure (see details in section 7.8)

Significant protocol deviations (see details in section 7.4)
6.0
DETERMINATION OF SAMPLE SIZE
The sample size was not based on statistical power considerations but on the estimates of 
precision. A sample size of 100 subjects (50 per dosing regimen/treatment arm) would generate 
95% confidence interval (CIs) using Wald asymptotic approximation for fistula closure rates 
within each treatment arm with half widths no wider than 13.9%; in addition, the 95% CIs for the 
difference in fistula closure rates between the 2 groups would be no wider than 19.6%. 
Based on the final sample size of 34 subjects overall (assuming 17 subjects per treatment arm), 
the 95% CI for fistula closure rates within each treatment arm will have half widths no wider 
than 23.8%.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
This statistical analysis plan (SAP) is written based on the study protocol (Amendment 05 
version 01, dated 20 Apr 2017).
Due to significant and increasing difficulties in enrollment into this study the enrolment was 
closed early before the planned sample size was reached. This decision was made in February 
2018 [4]. Where deemed reasonable, statistical methods have been adapted to the lower sample 
size (see also details in section 7.14).
7.1
General Principles 
In general, unless stated otherwise below, all data summaries will be provided by treatment arm 
and overall for the applicable analysis set. Where appropriate, variables will be further 
summarized by study visit and/or subgroups defined in section 7.1.6.
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. CIs for a parameter estimate will be presented using 
the same number of decimal places as the parameter estimate.
For categorical variables, the number (and %) of subjects falling into each category will be 
presented. Percentages will be calculated based only on non-missing observations in the 
respective analysis set and will, in general, be displayed with 1 decimal place. The number of 
missing observations will be reported in category “Missing” (no percentage shown for this 
category). The same handling applies to similar categories like “not collected”, “not applicable”.
All study-related raw data and relevant derived data will be presented in data listings. The 
listings will be sorted by treatment arm and by subject. In general, listings will be done for all 
subjects randomized; listings showing data that was collected also for screen failures will be 
produced for all screened subjects with the data from screen failures being grouped and 
presented at the end of  listing.
When no data are available for a table or listing, an empty page with the title will be produced 
with suitable text (e.g., “There were no subjects with markedly abnormal values of laboratory 
parameters.”).
All statistical analyses will be conducted using SAS System® Version 9.4.
7.1.1
Study Definitions
The following treatment arm labels will be used in the outputs:

Vedolizumab IV 300 mg

Vedolizumab IV 300 mg + Placebo
A perianal fistula is considered closed when it is no longer draining despite gentle finger 
compression.


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Perianal fistula response is defined as reduction in the number of draining perianal fistulae (of 
those draining at Baseline) of at least 50%, where a fistula is considered closed if it is no longer 
draining despite gentle finger compression.
7.1.2
Definition of Study Days
Study Day 1 (Day 1) is defined as the day on which a subject is administered their first dose of 
study medication, as recorded on the electronic case report form (eCRF) dosing page. Other 
study days are defined relative to the Day 1.
7.1.3
Definition of Baseline Values
Unless otherwise specified, baseline values are defined as the last observed value before the first 
dose/administration of study medication.
For procedures performed on the same day as the first dose of study medication (Day 1), it is 
generally assumed that the procedures are performed prior to the administration of the study 
medication (and data is considered pre-treatment, baseline). For Day 1 procedures, for which the 
assessment time is collected (e.g., questionnaire data), then the values collected prior to the time 
of the administration of the study medication will be considered as baseline values.
For questionnaire data, if no pre-treatment data is reported at Day 1 or in the baseline window
defined in section 7.1.7 and if fistula assessment was done on Day 1, data reported at Day 2 will 
be considered as baseline data.
7.1.4
Definition of Last Visit
In general, “last visit” is defined as the last available observation of a subject after the first dose 
of study medication until either Week 30 or the date of early discontinuation, whichever comes 
first. 
7.1.5
Definition of Screen Failure
Screen failure subjects are subjects who signed the informed consent form (ICF) and were not 
enrolled in the study. The primary reason for screen failure was 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


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7.1.6
Covariates and Subgroups
The following subgroups may be used in the data summaries:

Previous anti-TNF treatment: anti-TNF naive, anti-TNF experienced;
in the protocol referred to as TNF naïve and TNF non-naive (failed).

Seton placement at baseline: yes, no;
subjects with multiple fistulae will be counted under “yes” if a seton is placed at baseline 
for at least one fistula; see section 7.1.13 for handling of missing data.

CDAI total score at baseline: ≤ 330, >330.
7.1.7
Definition of Study Visit Windows
The visit windows to be used in the data analysis are shown in Table 7.a. Unless otherwise 
specified, data will be allocated to and summarized for the respective study visits according to 
the actual assessment date and the analysis visit windows below. Furthermore, the following 
additional ordered rules will be applied to identify an analysis record/value to be used in the 
analysis and summaries:

Only data falling within one of the analysis visit windows below will be used in the 
analysis for the schedule visits; data recorded at days outside the define visit windows 
will not be included in the by-visit summaries. However, data recorded at days outside 
the define visit windows will be considered for the derivation and analysis for the “last 
visit”.

A value falling within the specified visit window will be used in the analysis for that 
respective visit. Data identified on the eCRF as coming from an “unscheduled” visit will 
be eligible for windowing.

If a subject has multiple measurements 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 (e.g., an 
abnormal vital sign value will be chosen over a normal vital sign value).
Table 7.a
Visit Windows for Efficacy and Safety Variables
Visit
Target Day
Visit Window
Analysis Visit Window
Baseline
1
--
-28d – 1d
Week 2
14
±2
±4d (10 – 18)
Week 6
42
±2
±7d (35 – 49)
Week 10
70
±3
±7d (63 – 77)
Week 14
98
±7
±14d (84 – 112)


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Visit
Target Day
Visit Window
Analysis Visit Window
Week 22
154
±7
±14d (140 – 168)
Week 30
210
±7
±21d (189 – 231)
Follow-up
280
±7
±21d (259 – 301)
The following additional rules do apply:

If for a parameter an assessment was done at Screening and after Screening up to Day 1, 
i.e., the Screening value is not considered the baseline value, in the data listings those 
records will be labelled accordingly as Screening and Baseline, respectively (even if both 
assessments fall into the defined baseline window).

For questionnaire data, if no pre-treatment data is reported at Day 1 or in the baseline 
window defined below and if fistula assessment was done on Day 1, data reported at Day 
2 will be considered as baseline data.

All assessments, including the assessments that do not fit within any defined analysis 
visit window, will be listed. Data recorded at days outside the above visit windows will 
be shown in the data listings as “unscheduled” visit.
7.1.8
Convention for Calculation of CDAI Scores
The CDAI consists of 8 components: number of liquid or very soft stools, abdominal pain, 
general well-being, extra-intestinal manifestations of CD, use of Lomotil/Imodium/opiates for 
diarrhea, abdominal mass, hematocrit level and body weight. The CDAI total score is derived 
from the 8 components as described below (see also Appendix C).
CDAI scores will be derived at each scheduled visit utilizing the most recent available patient 
reported components (number of liquid or very soft stools, abdominal pain, general well-being 
and use of Lomotil/Imodium/opiates for diarrhea are self-reported by subjects via eDiary on a 
daily basis), physician reported outcomes components (extra-intestinal manifestations of CD, 
abdominal mass) and body weight, and hematocrit values as described below:
1. Identify the completion date of the physician reported CDAI components, and set it as the 
CDAI calculation/assessment date.
2. Calculate the 3 eDiary subscores (liquid/soft stool frequency, abdominal pain and general 
well-being) as follows:
a.
Select the diary data from 10 days prior to the CDAI calculation date identified in (1).
b. Take 7 most recent days of diary data.
c.
If less than 4 days of diary are non-missing for a component, then the respective 
component subscore cannot be calculated and is set to missing. 
Otherwise:
i.
If 4 to 6 days of diary are non-missing, calculate the average of non-missing diary
days (sum over non-missing entries/number of non-missing entries), multiply by 


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7, then multiplying by the factor appropriate for the respective component
subscore (x2 for liquid/soft stools, x5 for abdominal pain, x7 for general well-
being) and round to the nearest integer.
ii.
If 7 or more days of diary are non-missing, calculate the sum of the most recent 7 
days of non-missing diary and multiply the sum by the appropriate for the 
respective component subscore (see above).
3. Extra-intestinal manifestations of CD subscore: 
Count the number of check boxes ticked for extra-intestinal manifestations of CD and 
multiply that count by a factor of 20.
4. Lomotil/Imodium/opiates for diarrhea subscore: 
If use of Lomotil/Imodium/opiates for diarrhea is reported (“Yes”), then the subscore is 30;
otherwise (“No”), the subscore is 0. Information on Lomotil/Imodium/opiates use was 
recorded by the subject on a daily basis e Diary. Therefore the following rule will be applied:
a.
Select the diary data from 10 days prior to the CDAI calculation date identified in (1).
b. Take 7 most recent days of diary data.
c.
If any use of Lomotil/Imodium/opiates for diarrhea is reported on those days, then the 
subscore is 30; if no use is reported on those days, the subscore is 0.
If no information on use of Lomotil/Imodium/opiates is available for the last 10 days, 
then the subscore is set to missing.
5. Abdominal Mass subscore: 
Responses “Definite”, “Questionable” and “None” will be assigned subscores of 50, 20, and
0, respectively.
6. Hematocrit subscore: 
a.
Identify the corresponding hematocrit result using the visit windows and rules defined 
in section 7.1.7. 
b. Subtract hematocrit value (in %) from 47 for males and from 42 for females, multiply 
result by a factor of 6 and round to the nearest integer. 
If the hematocrit subscore is <0, set it to 0.
7. Body Weight subscore: 
a.
Identify the corresponding body weight result using the visit windows and rules 
defined in section 7.1.7.
b. Identify the standard weight based on subject’s gender and baseline height (cm) as 
follows:
i. Standard weight for men in kilogram = (height in cm/100)2×22.1
ii. Standard weight for women in kilogram = (height in cm/100)2×20.8


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c.
Calculate the maximum of {(1 – (Body weight/Standard Weight)) ×100, -10}; the 
value rounded to the nearest integer is the body weight subscore.
8. The total CDAI score is the sum of the 8 subscores above. If any of the subscores are 
missing, the total CDAI score is set to be missing.
7.1.9
Conventions for Missing Adverse Event Dates
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)
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 
30 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 
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 of 
the month.

Missing day and month, but year present: the day and month will be imputed as the 
31 December of that year.


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
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.
7.1.10 Conventions for Missing Concomitant Medication Dates
In case of missing or partial concomitant medication start and stop dates, the following rules will 
be used.
If the medication start date is (partially) missing:

If the day is missing, the start day will be the first day of the month.

If the day and month are missing, and year is the same as in the date of first dose of study 
medication, the start day will be the first day of the month corresponding to 90 days prior 
to the date of first dose of study medication (if the month of first dose is Jan, Feb, or Mar, 
the start day will be 1 Jan of that year instead). 

If the day and month are missing, and the year is not the same as the year of first dose of 
study medication, the start day will be 1 Jan of that year.

If the year is missing, the start year will be the minimum of the year of the first site visit 
or the year of the ICF date.

If the entire date is unknown:
-
If the eCRF indicates that the medication ended prior to the ICF date, then the 
medication start date will be imputed as ICF date - 1.
-
Otherwise the start date will be imputed as minimum of the date of first dose of study 
medication and the medication end date.
If the medication stop date is (partially) missing and medication is not flagged as "ongoing":

If the day is missing, the stop day will be the last day of the month reported. If the CRF 
indicates the medication ended prior to ICF date, and month is the month of ICF, the end 
date will be imputed as ICF date - 1. 

If the day and month are missing:
-
If the year is the same as the date of last assessment, then the stop day will be 
imputed by the last day of the month during which the last assessment occurred.
-
If the year is not the same as the year of the last assessment, then the stop day will be 
imputed as 31 December of that year.

If the year is missing or the entire date is unknown, the stop year will be the year in 
which the last assessment occurred. If information collected on the CRF indicate that the 
medication ended prior to the ICF date, the medication end date will be imputed as ICF 
date - 1.


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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
(Day 1):
date	
  −date		 + 1
365.25
If the CD diagnosis date 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 
30 June of the year.
7.1.12 Conventions for Calculation of Duration of Fistulizing Disease
Duration of fistulizing disease is calculated as the number of years from the onset date of the first 
fistulizing episode to first dose date (Day 1):
datefirst dose −dateonset of first fistulizing episode + 1
365.25
If the onset date of the first fistulizing episode 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 
30 June of the year.
If a subject does not have a history of fistulizing disease prior to the current fistulizing episode
(present at baseline), the date of onset of the current fistulizing episode will be used for the 
calculation.
7.1.13 Other Missing Data Handling Conventions
In general, missing data will not be imputed. Exceptions and rules for these exceptions are 
summarized hereafter:

Missing data for AE onset and end dates will be imputed as described in section 7.1.9.

Missing data for concomitant medication start and stops dates will be imputed as 
described in section 7.1.10.

A (partially) missing CD diagnosis date will be imputed as described in section 7.1.11.

A (partially) missing fistulae episode onset date will be imputed as described in section
7.1.12.


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
Missing seton placement information at baseline:
For subjects who were enrolled prior to implementation of protocol amendment 5 and for 
whom the seton placement status at baseline is not collected, the baseline status is 
imputed as ‘Yes’ (seton placed for all draining fistulae), since seton placement was 
mandatory as prior to implementation of protocol amendment 5.
For subjects who were enrolled after implementation of protocol amendment 5 with 
missing seton placement status at baseline, no imputation will be done (unless later data 
informs about seton removal without record of seton placement after Day 1, then seton 
placement baseline status will be imputed as ‘Yes’).
Further missing data handling rules are described in the respective sections as applicable.
7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data:

The safety population (SAF) consists of all randomized subjects, who received at least 1 
dose of study medication.

The full analysis set (FAS) consists of all randomized subjects who received at least 1 
dose of study medication and have a post baseline assessment of fistula healing.  

The modified full analysis set (mFAS) consists of all subjects in the FAS who had at least 
one draining fistula at baseline (Day 1).

The PK analysis set consists of all randomized subjects who received at least 1 dose of 
study drug and have sufficient blood sampling to allow for PK evaluation.
In addition, the populations “all screened subjects”, “screening failures” and “all randomized 
subjects” may be used for particular data summaries.
7.3
General Study Information and Disposition of Subjects
General study information and subject eligibility will be summarized as follows:

Study information, 
including date first subject signed ICF, date of first/last study drug dose, date of last 
subject’s last visit/contact, and date of last subject’s last procedure for collection of data 
for primary endpoint.

Demographic data for screen failures, 
showing age, gender, race, ethnicity. 

Eligibility for randomization, 
including number of subjects screened, number of subjects eligible/not eligible for 
randomization, and primary reason for subjects not eligible for randomization.
Subject disposition will be summarized for all randomized subjects as follows:

Number subjects randomized by country and site.


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
Number (and %) of subjects who completed study drug.

Number (and %) of subjects who prematurely discontinued study drug and the reason for 
discontinuation.

Number (and %) of subjects who complete all planned study visits.

Number (and %) of subjects who did not complete all planned study visits and the reason 
for discontinuation.

Incidence of significant protocol deviations by category (see also section 7.4).

Eligibility of subjects for each of the defined analysis sets:
number of subjects eligible for each analysis set.

Reasons for exclusion from analysis sets will be listed.
7.4
Significant Protocol Deviations
Significant protocol deviations were to be collected on the eCRF throughout the study conduct. 
Significant protocol deviations will be summarized for all randomized subjects using the 
following categories:

Entry Criteria

Concomitant Medication

Procedures Not Performed Per Protocol (Primary Endpoint or Safety Related)

Study Medication

Withdrawal Criteria
7.5
Demographic and Other Baseline Characteristics
Generally, demographic and baseline characteristics, CD-related baseline characteristics and 
fistula related baseline characteristics will be summarized for all subjects randomized, the SAF, 
the FAS and the mFAS. If all subjects randomized and the SAF are identical, only one 
(combined) summary will be provided (with population title All randomized subjects / Safety 
Analysis Set). If SAF, FAS or mFAS are identical, still separate summaries for each population 
will be presented. All summaries will be done by treatment arm and overall (in the respective 
analysis population).
Table 7.b lists the demographic and baseline characteristics that will be tabulated. 
Table 7.b
Demographic and Baseline Characteristics
Demography (unit)
Summarized as
Categories
Age (years)
Continuous
Gender
Categorical
Male
Female


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Demography (unit)
Summarized as
Categories
Ethnicity
Categorical
Hispanic or Latino
Non-Hispanic and Latino
Not Collected
Racea
Categorical
American Indian or Alaska Native
Asian
Black or African American
Native Hawaiian or Other Pacific Islander
White
Multiraciala
Height (cm)
Continuous
Weight (kg)
Continuous
Body Mass Index (BMI) (kg/m2)
Continuous
Smoking Classification
Categorical
Never-smoker
Current smoker
Ex-smoker
Female Reproductive Status
Categorical
Postmenopausal
Surgically Sterile
Female of Childbearing Potential
N/A (Subject is a Male)b
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.
b Category “N/A” will be excluded from calculations of percentages for the other categories.
The BMI will be derived as body weight (kg) / height (m)2 using the last body weight 
measurement prior to first dose of study medication (usually at Day 1) and the height measured 
at Screening.
Information on a subject’s smoking status might have been collected on two eCRF forms 
(‘Social History’ page and/or ‘Substance Use’). The following rules will be applied for 
determination of the smoking classification:

If smoking classification has been recorded the ‘Social History’ page, this information 
will be used (regardless of the information collected on ‘Substance Use’ page).

If the ‘Social History’ page is missing/not completed, the information collected on the 
‘Substance Use’ page is used.
Table 7.c lists the CD-related baseline characteristics that will be tabulated.
Table 7.c
CD-Related Baseline Characteristics
Characteristics (unit)
Summarized as
Categories
Duration of Crohn’s Disease (years)a
Continuous and 
Categorical
< 1 year
≥ 1 to < 3 years
≥ 3 to < 7 years
≥ 7 years


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Characteristics (unit)
Summarized as
Categories
Baseline CRP (mg/L)
Continuous and 
Categorical
≤ 2.87 mg/L
> 2.87 mg/L to ≤ 5 mg/L
> 5 mg/L to ≤ 10 mg/L
> 10 mg/L
Baseline FC (µg/g)
Continuous and 
Categorical
≤ 250 µg/g
> 250 µg/g to ≤ 500 µg/g
> 500 µg/g
Baseline CDAI (total score)b
Continuous and 
Categorical
≤ 220
> 220 – 330
> 330
Previous anti-TNF treatment
Categorical
anti-TNF naïve
anti-TNF experienced
a See section 7.1.11 for calculation rule for CD disease duration.
b See section 7.1.8 for CDAI total score calculation rules.
Table 7.d lists the fistula related baseline characteristics that will be tabulated. 
Table 7.d
Fistula Related Baseline Characteristics
Characteristics (unit)
Summarized as
Categories
Number of Draining Fistula at Baseline
Categorical
0
1
2
3
Duration of fistulizing disease (years) a
Continuous 
Baseline PDAI b
Continuous 
Location of Previous Fistulae
(multiple locations possible)
Categorical
Perianal
Enterocutaneous
Rectovaginal 
Rectovesicular
Other
Baseline Van Assche Score c
Continuous 
Baseline Mean Perianal Pain Score d
Continuous
Seton placement at Baseline e
Categorical
Yes
No
a See section 7.1.12 for calculation rule for duration of fistula.
b See section 7.9.5.2 for calculation rule for PDAI score.
c See section 7.9.5.1 for calculation rule for van Assche score.
d See section 7.9.5.2 for calculation rule for mean perianal pain score.
d See sections 7.1.6 and 7.1.13 for determination of seton placement status at baseline and handling of missing data.
7.6
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 ICF and concurrent medical conditions, defined as significant ongoing 


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conditions or diseases present at signing of ICF, will be provided based on the SAF, by treatment 
arm and overall.  
Medical history and concurrent medical conditions will be coded using the MedDRA dictionary, 
Version 21.0 Mixed. Medical history and concurrent medical conditions will be summarized by 
system organ class (SOC) and preferred term (PT), showing the number (and %) of subjects with 
medical history or condition (by SOC and PT); the tables will be sorted in alphabetic order by 
SOC and in decreasing frequency based on the total number of reports by PTs within each SOC. 
The denominator used for calculating the percentages will be the total number of subjects in the 
SAF (within treatment arm and overall, respectively). A subject having multiple reports the same 
PT will be counted only once for that PT. Similarly, a subject with multiple reports within the 
same SOC (even with different PTs) will be counted only once for that SOC.
The listings for medical history and concurrent medical condition data will contain at least one 
record per subject indicating if there was any medical history or concurrent condition reported, 
and, where applicable, showing the details of the medical history or concurrent medical 
condition (e.g., SOC, PT, start and end dates).
7.7
Medication History and Concomitant Medications
Summaries of medication history and concomitant medications will be tabulated based on the 
SAF.
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 the 
ICF.  Any CD prior biologic medications which have been stopped were to be recorded on the 
eCRF as well.  Medication history and CD prior biologic medications will be summarized and 
listed separately.
Concomitant medications were to be recorded on the eCRF and include any medication other 
than study drug taken at any time from signing the ICF to 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 2016 Expanded). 
Medication history and CD prior biologic medications will be summarized by therapeutic 
classification, subclassification, and preferred medication name.
Concomitant medications will be summarized by therapeutic classification, subclassification, and 
preferred medication name and will include only those medications taken at any time between 
the times of ICF and on or prior to the last dose date of study drug. Concomitant medications 
will be classified and summarized separately as follows: 

Prior medications, i.e., medications recorded on the concomitant medications eCRF page 
that started and stopped prior to Day 1. 

Concomitant medications, i.e., medications that were ongoing at Day 1 or started on or 
after Day 1 and before the Week 30 visit (or early discontinuation).


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The tables for medication history, CD prior biologic medications and concomitant medications 
will present the number and percentage of subjects by therapeutic classification, 
subclassification, and preferred medication name using the total number of subjects in the 
treatment arm as the denominator.  
Separate listings for medication history, CD prior biologic medications and concomitant 
medications will be produced by site and subject number. 
7.8
Study Drug Exposure
Study drug exposure will be summarized based on SAF, FAS and mFAS.
The following exposure data summaries will be provided (by treatment arm and overall):

Number (and %) of subjects by total number of intravenous infusions received, split by 
active (vedolizumab) and placebo infusions.

Number (and %) of subjects who received any incomplete infusion
(a subject has received complete infusion if the total amount was infused as per data 
collected in eCRF)

Descriptive statistics for the total vedolizumab dose (mg) received in the study

Descriptive statistics for duration of exposure (days)

Frequency table for duration of exposure, showing the number (and %) of subjects
according to the following categories: <20 weeks, 20 – <24 weeks, 24 - <32 weeks, 32 -
<40 weeks and ≥40 weeks.
Duration of exposure will be calculated as
duration of exposure (days) = date of last vedolizumab dose – date of first dose + 1 +126 
while adding 126 days accounts for 5 times the half live of vedolizumab. Only the last 
vedolizumab dose will be considered for the calculation, i.e., for subjects in the vedolizumab + 
placebo arm (treatment arm 1) who discontinued prematurely after having received the week 10 
dose (placebo), the duration will be calculated based on the previous vedolizumab dose 
administered (usually week 6).
7.9
Efficacy Analysis
This section describes the summaries to be provided for the primary, secondary and additional 
efficacy endpoints. Efficacy data will be summarized by treatment arm and overall analysis 
population. 
7.9.1
General Considerations for the Efficacy Data Analysis
Summaries for the primary and secondary efficacy endpoints (and related data used to derive 
those endpoints) will be provided based on the FAS and the mFAS. If not otherwise mentioned 
below, additional efficacy endpoints will be summarized for the FAS only.


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For response-type endpoints (such as the primary endpoint), frequency tables will be provided, 
showing 

the number and proportion (%) of subjects achieving and not achieving the response (for 
each treatment arm and overall)

corresponding 2-sided 95% CIs for the response rate (for each treatment arm and overall)

difference in response rates between treatment arms and corresponding 95% CI
The 95% CIs will be calculated using the Wald asymptotic method. If the number of responders 
within a treatment arm is too small (i.e., ≤ 5), the exact method will be used instead for the CI for 
the proportion in that treatment arm and for the CI for the response rate difference.
If not otherwise mentioned below, data summaries will be done on observed case basis (i.e., no 
imputation of missing data applied).
7.9.2
Overall Fistulae Status Summaries
Beside the specific tables requested by the primary and secondary endpoints below, fistulae data 
will be summarized based on observed cases as follows for the FAS and mFAS (as specified 
below), by treatment arm and overall (in the respective analysis population) and by visit 
(baseline to week 30 and last visit):

Frequency table showing the number (and %) of subjects by total number of draining 
fistulae (0, 1, 2, 3 (, >3 if applicable)); for FAS and mFAS.

Frequency table showing the number (and %) of subjects by number of draining fistulae 
of those draining at baseline (0, 1, 2, 3 (, >3 if applicable)); for mFAS.

Frequency table showing the number (and %) of subjects by number of newly draining 
fistulae (i.e., newly draining fistulae that were not draining at baseline); for FAS and 
mFAS.

Shift tables for total number of all draining fistulae, categorized as 0, 1, 2, 3 (, >3 if 
applicable); for FAS and mFAS.

Shift table for total number of draining fistulae of those draining at Baseline, categorized 
as 0, 1, 2, 3 (, >3 if applicable); for mFAS.

Frequency table showing the number (and %) of subjects with perianal fistula response 
(responders, defined as a reduction of at least 50% in the number of perianal fistulae 
draining at baseline) and non-responders, the 95% CI for the response rate and the 
difference in the response rate between treatment arms with corresponding 95% CI (for 
CI calculation methods see section 7.9.1 above) ; for mFAS.

Frequency table showing the number (and %) of subjects achieving/not achieving 100% 
closure of the perianal fistulae draining at baseline, the 95% CI for the 100%-closure rate 
and the difference in that rate between treatment arms with corresponding 95% CI (for CI 
calculation methods see section 7.9.1 above); for mFAS.


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The number of total draining perianal fistulae, change from baseline and percent change from 
baseline will be listed for each subject by study visit.
7.9.3
Primary Efficacy Endpoint
The primary efficacy endpoint is the perianal fistula response at Week 30, defined as reduction in 
the number of draining perianal fistulae (of those draining at Baseline) of at least 50% at Week 
30 (where closed fistulae are no longer draining despite gentle finger compression).
This endpoint will be summarized for the mFAS, by treatment and overall (in the respective 
analysis population), by a frequency table showing:

the number (and %) of responders (subjects with perianal fistula response) and non-
responders, the 95% CI for the response rate and the difference in the response rate 
between treatment arms with corresponding 95% CI for the difference (for CI calculation 
methods see section 7.9.1) based on observed cases (i.e., subjects who completed Week 
30 and fistulae assessment done at Week 30).

the number (and %) of responders (subjects with perianal fistula response) and non-
responders, the 95% CI for the response rate and the difference in the response rate 
between treatment arms with corresponding 95% CI for the difference (for CI calculation 
methods see section 7.9.1) based on observed cases (i.e., subjects who completed Week 
30 and fistulae assessment done at Week 30) with imputation of missing data/cases (e.g., 
early discontinuation before Week 30 or missing fistulae assessment at Week 30) as non-
response.
Additionally, similar summaries for the primary endpoint will be provided by previous anti-TNF 
treatment, by seton placement at baseline and by baseline CD disease activity (CDAI total score)
according to the categories defined in section 7.1.6.
7.9.4
Secondary Efficacy Endpoints
Secondary efficacy endpoints will be summarized for the mFAS, by treatment arm and for the 
overall analysis population. No summaries by subgroups will be done for secondary efficacy 
endpoints.
Perianal fistula response at both Week 22 and Week 30 (for fistulae draining at Baseline)
For the secondary endpoint, perianal fistulae response at both Week 22 and Week 30, similar 
summaries as for the primary endpoint will be provided, i.e., a frequency table showing the 
number (and %) of responders (with corresponding 95% CIs, see section 7.9.1) and non-
responders by treatment/overall, and treatment difference (and corresponding 95% CI, see 
section 7.9.1), calculated once on observed cases and once on observed cases with missing 
data/cases (at either Week 22 or Week 30) imputed as non-response. 
100% perianal fistulae closure of the fistulae draining at Baseline at Week 30
The secondary endpoint 100% closure of the perianal fistulae draining at Baseline at Week 30
will be summarized by reporting the number (and %) of subjects achieving/not achieving 100% 


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closure (with corresponding 95% CIs for responders, see section 7.9.1) by treatment/overall, and 
treatment difference (and corresponding 95% CI, see section 7.9.1), calculated once on observed 
cases and once on observed cases with missing data/cases (at Week 30) imputed as non-
response.
Time to first perianal fistula closure
The time point of first perianal fistula closure (of the fistulae draining at Baseline) is defined as 
the visit on which the first time at least one fistula that was draining at Baseline is classified as 
closed, regardless if they may drain again at following visits (Visit1stclosure). 
The time (days) to first perianal fistula closure will be derived as
time (days) = date of Visit1stclosure – date of Day 1 + 1
The time to first fistula closure will be analyzed descriptively using Kaplan-Meier product limit 
methods, with subjects for which no fistula closure is reported being censored at the time of their 
last fistulae assessment or date of last record (Week 30 or early discontinuation). Summaries will 
present the total number (and %) of subjects with event, total number of cases censored and 
number of subjects with event by visit (considering the analysis windows defined in section 
7.1.7); the time to event (first fistula closure) will be summarized by estimates of 25th, 50th
(median), and 75th percentiles with 95% CIs, and the range (Min, Max).
Furthermore, Kaplan-Meier plots (by treatment arm and overall) will be presented (time scale 
from Day 1 to Day 240), showing also the number of subjects at risk at the following time 
points: Week 2 (Day 14), Week 6 (Day 42), Week 10 (Day 70), Week 14 (Day 98), Week 22
(Day 154), Week 30 (Day 210). Corresponding Kaplan-Meier estimates (with 95% CI) and 
number of subjects at risk by time point will also be summarized.
Time to 100% perianal fistulae closure
The time point of 100% perianal fistula closure (of the fistulae draining at Baseline) is defined as 
the visit on which the first time all fistulae that were draining at Baseline are classified as closed, 
regardless if they may drain again at following visits (Visit100%closure). 
The time (days) to 100% perianal fistula closure will be derived as
time (days) = date of Visit100%closure – date of Day 1 + 1
The time to 100% perianal fistula closure will be analyzed in a similar manner as described 
above for time to first perianal fistula closure, with the same censoring rules applied.
Duration of perianal fistula response
Duration of perianal fistula response (days) will be derived as the sum of days with perianal 
fistula response between Day 1 and the end of the study (Week 30 or early discontinuation). 
For this, 

the day of the first visit on which perianal fistula response was reported will be 
considered the start date of perianal fistula response


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
if perianal fistula response was reported on two consecutive visit, it will be assumed that 
perianal fistula response was maintained throughout the whole interval between the two 
visits

if perianal fistula response was reported on visiti and but not on the following visit 
visiti+1, it will be assumed that perianal fistula response was maintained until the day 
before visiti+1 ( = date of visiti+1 - 1)

if perianal fistula response was achieved and lost multiple times, the duration of all 
intervals with response will be summed up.
The duration of perianal fistula response (days) will be presented using the following summaries:

descriptive statistics

frequency table using the following categories: 
0 days, 1 to ≤ 42 days, 43 to ≤ 84 days, 85 to ≤ 126 days, 127 to ≤168 days,
169 to ≤ 210 days, ≥ 211 days.
7.9.5
Additional Efficacy Endpoints
Additional efficacy endpoints will be summarized for the FAS, by treatment arm and for the 
overall analysis population.
7.9.5.1
MRI-Related Endpoints
A pelvic MRI was to be performed at Screening (Visit 1) and Week 30 (Visit 8) for evaluation of 
perianal fistulizing CD. 
A central radiologist (reader) classified fistula(e) after reviewing T1- and T2-weighted images of 
the perianal region (pelvic MRI). Local inflammatory activity was assessed on T2-weighted 
images. Active fistulae and abscesses with active inflammatory process are visible on T2 images 
as hyperintense lesions due to their fluid contents, while scar tissue appears hypointense.
MRI-related endpoints include:

Presence/absence of fluid collections with cavity diameter > 3mm

Mean relative T2 signal intensity of fistula tracks and associated fluid collections 
(relative to healthy tissue on the same image; on T2-weighted images)

Van Assche Score

Mean relative gadolinium contrast enhancement of fistula tracts (measured as MRI signal 
on the post-contrast image relative to the pre-contrast image of the same location) on T1-
weighted images.
Van Assche Score
The Van Assche MRI-based score for severity of perianal CD will be calculated at Screening and 
Week 30 (calculated by the central reader). The 6 components of the score, listed in Table 7.e, 


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are summed up to a total score (range 0 and 22). The Van Assche score and its change from 
Screening to Week 30 will be presented using summary statistics.
Table 7.e
Components of the Van Assche MRI-Based Score 
Component
Scoring
Number of fistula tracks
None=0
Single, unbranched = 1
Single, branched = 2
Multiple = 3
Location
None = 0 
Extra or intersphincteric = 1
Transsphincteric = 2
Suprasphincteric = 3
Extension
None = 0 
Infralevatoric = 1
Supralevatoric = 2
Hyperintensity on T2-weighted images
Absent = 0
Mild = 4
Pronounced = 8
Collections (cavities 3 mm diameter)
Absent = 0
Present = 4
Rectal wall involvement
Normal = 0
Thickened = 2
Other MRI-related endpoints
Number (and %) of subjects with presence/absence of fluid collections with cavity diameter > 
3mm will be summarized by visit (Screening, Week 30).
Mean relative T2 signal intensity of fistula tracks and associated fluid collections will be 
presented using summary statistics for reported values at Screening and Week 30, and for the 
change and percent change from Screening to Week 30 .
Mean relative gadolinium contrast enhancement of fistula tracts presented using summary 
statistics for reported values at Screening and Week 30, and for the change and percent change 
from Screening to Week 30.
7.9.5.2
Disease Activity Endpoints
PDAI
The PDAI includes 5 components: 1) presence or absence of discharge, 2) pain or restriction of
activities of daily living, 3) restriction of sexual activity, 4) type of perianal disease and 5) degree
of induration. Items 1 to 3 are answered directly by the subject, items 4 and 5 are completed by 
the physician. Each item is scored from 0 (absence) to 4 (worst case), see Appendix B. The total 
PDAI score is the sum of the 5 PDAI component scores and has a range from 0 to 20, with


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higher scores indicating more severe disease. If any component score is missing, the total PDAI 
score cannot derive and is set to missing.
The PDAI is assessed at Day 1 and weeks 2, 6, 10, 14, 22 and 30.
The total PDAI score and its change from baseline will be summarized by visit (including last 
visit) using descriptive statistics. Individual total PDAI scores at all visits and change from Day 1 
will be listed.
CDAI
For detailed description of the CDAI and calculation of the CDAI scores refer to section 7.1.8
and Appendix C.
The CDAI is assessed at Screening, Day 1 and weeks 2, 6, 10, 14, 22 and 30.
The total CDAI score and its change from baseline will be summarized by visit (including last 
visit) using descriptive statistics. Individual total CDAI scores at all visits (including Screening) 
and change from Day 1 will be listed.
Perianal pain
Perianal pain was to be assessed daily by the subject via the eDiary by answering the question
“How would you rate your perianal pain in the last 24 hours?”
on an 11-point Likert rating scale (0= no pain, 10=worst possible pain).
For each scheduled visit, the mean perianal pain score over last 7 days prior to the visit will be 
derived (rounded to integer). To calculate the mean perianal pain score, at least 3 days of diary 
entries for perianal pain out of the 7 days prior to the visit must be available; otherwise, the mean 
perianal pain score is considered as missing.
The mean perianal pain score and its change from Day 1 will be summarized by visit (including 
last visit) using descriptive statistics. In addition, the number (and %) of subjects with a decrease 
≥ 30% in mean perianal pain score from Day 1 will be summarized by visit (including last visit).
Individual mean perianal pain score, its change from Day 1 and percent change from Day 1 will 
be listed.
7.9.5.3
Quality of Life Questionnaires
IBDQ
The IBDQ is an instrument used to assess quality of life in adult subjects with IBD. It includes 
32 questions on 4 domains: bowel systems (10 items), emotional function (12 items), social 
function (5 items) and systemic function (5 items). Subjects 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 (see calculation rules in Appendix D).
The IBDQ was to be assessed at Day 1, Week 14 and Week 30. 


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IBDQ total score, the 4 subdomain scores and their changes from Day 1 will be presented by 
visit (Day 1, Week 14, Week 30 and last visit) using summary statistics. Individual IBDQ total
scores and its change from Day 1 will be listed.
EQ-5D
The EQ-5D questionnaire is an instrument used to measure general health-related quality of life 
and includes 5 domain items: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. This study used the EQ-5D 3 level (EQ-5D-3L) version and subjects had to 
assess their health state on each item as “None”, “Moderate” or “Extreme” with corresponding 
scores 1, 2 or 3, respectively. From the 5 items scores, the EQ-5D utility score is calculated (see 
calculation rules in Appendix D). In addition, subjects had to rate their overall health using the 
EQ-5D visual analogue scale (VAS), a 20 cm visual, vertical scale, with a score of 0 as the worst
and 100 as best possible health.
The EQ-5D was to be assessed at Day 1, Week 14 and Week 30.
The EQ-5D utility score and the EQ-5D VAS an their changes from Day 1 will be presented by 
visit (Day 1, Week 14, Week 30 and last visit) using summary statistics. Individual domain items 
will not be summarized. Individual EQ-5D data (domain items, utility score and VAS and their 
change from baseline) will be listed.
7.9.5.4
Biomarkers
FC was assessed at Day 1 (baseline), Week 14 and Week 30. CRP was assessed at Day 1 
(baseline), Week 10, Week 14 and Week 30.
FC (in μg/g) and CRP (in mg/L) and their change from baseline will be presented by visit 
(including last visit) using summary statistics. CRP and FC data will be listed along with other
laboratory parameters (see section 7.12.2).
7.10
Pharmacokinetic/Pharmacodynamic Analysis
Pharmacokinetic analysis will be done using the PK analysis set.
7.10.1 Pharmacokinetic Analysis
Blood samples were to be drawn for determination of serum vedolizumab trough concentrations
(Ctrough) in all subjects within 30 minutes prior to the start of infusion on Day 1, Weeks 6, 10, 
14, 22 and 30.  Another additional PK sample was to be collected at Week 10 within 30 minutes 
after the completion of infusion.  
Vedolizumab Ctrough values at each visit will be presented using summary statistics by 
treatment arm and overall.


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7.10.2 Immunogenicity Analysis
Blood samples for AVA and nAVA assessments were to be obtained within 30 minutes prior to 
the start of infusion on Day 1, Weeks 6, 10, 14, 22, 30 and 40.  For subjects who did not switch
to commercial supply vedolizumab post-study (e.g., last dose of vedolizumab at Week 22), a
Week 40 follow-up AVA sample was to be collected 18 weeks after the last dose of 
vedolizumab.
The number (and %) of subjects with positive (transient and persistent) AVA status, with
positive nAVA status, and with negative AVA status at each visit will be presented by treatment 
arm and overall. In addition, the number (and %) of AVA positive cases at each visit by titer will 
be summarized (by treatment arm and overall).
Definition of positive, negative and positive neutralizing AVA samples:

Negative AVA sample: defined as a sample that was evaluated as negative in the AVA 
screening assay. Samples that were determined to be positive in the AVA screening assay 
but the result was not confirmed in the AVA confirmatory assay were considered 
negative.

Positive AVA sample: defined as a sample that was evaluated as positive in both the 
AVA screening and confirmatory assays.

Positive neutralizing AVA sample: defined as a sample that was evaluated as positive in 
the neutralizing AVA assay.
AVA subject status will be grouped into 3 categories as follows:

Negative AVA subject status: subjects who did not have confirmed positive AVA results

Positive AVA subject status: subjects who had at least 1 positive AVA result

Transiently positive AVA subject status: subjects with confirmed positive AVA in 
at least 1 sample and no consecutive samples.

Persistently positive AVA subject status: subjects with confirmed positive AVA 
in 2 or more consecutive positive AVA samples.
AVA positive at baseline is defined as a positive AVA sample at Week 0/Day 1 (pre-dose).
7.10.3 Pharmacodynamic Analysis
Not applicable.
7.11
Other Outcomes
Not applicable.


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7.12
Safety Analysis
Safety analyses include AEs, clinical laboratory values, vital signs and electrocardiograms 
(ECGs). All safety summaries will be based on the SAF, and if not mentioned otherwise will 
show results by treatment arm and for the overall analysis population. 
7.12.1 Adverse Events
A pretreatment event is defined as any untoward medical occurrence in a clinical investigation 
subject who has signed ICF to participate in a study, but prior to administration of any study 
medication.  An adverse event (AE) is defined as any untoward medical occurrence in a clinical 
investigation subject who is administered a study medication.  Treatment-emergent adverse 
events (TEAEs) are defined as any AE that occurs on or after the first dose of study medication
and up to the last dose or early termination plus applicable follow up (i.e., 18 weeks). 
Adverse events were to be recorded throughout the study with assessment of intensity (mild, 
moderate, severe), relationship to study medication (related, not related) and seriousness (SAE or 
not). Further AE information collected include onset and end of AE, type (pretreatment or AE), 
relationship to study procedure, actions taken concerning study medication, and outcome.
Pretreatment events and AEs will be coded using MedDRA, Version 21.0 Mixed.
The following TEAE summaries will be provided using MedDRA SOC, high level term (HLT) 
and preferred term (PT):

Overview of Treatment-Emergent Adverse Events (TEAEs), 
showing the number (and %) of subjects with and number of TEAEs overall, TEAEs 
overall by intensity, TEAEs overall by drug relationship, TEAEs leading to study drug 
discontinuation, serious TEAEs overall, serious TEAEs by drug relationship, serious 
TEAEs, leading to study drug discontinuation, and the number of deaths.

Number (and %) of subjects with and number of TEAEs by SOC, HLT and PT

Number (and %) of subjects with and number of most frequent TEAEs by SOC, HLT and 
PT; most frequent TEAEs are events that occur in at least 5% of subjects within either 
treatment arm.

Number (and %) of subjects with and number of drug-related TEAEs by SOC, HLT and 
PT

Intensity of TEAEs by SOC, HLT and PT

Intensity of drug-related TEAEs by SOC, HLT and PT

Number (and %) of subjects with and number of TEAEs leading to study drug 
discontinuation by SOC, HLT and PT

Number (and %) of subjects with and number of serious TEAEs by SOC, HLT and PT


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The following pretreatment event summaries will be provided using MedDRA SOC, high level 
term (HLT) and PT:

Number (and %) of subjects with and number of pretreatment events by SOC, HLT and 
PT

Number (and %) of subjects with and number of serious pretreatment events by SOC, 
HLT and PT
For the number (and %) of subjects with TEAEs in above summaries, subjects who reported the 
same TEAE multiple times will be counted only once per PT; similarly, subjects who reported 
multiple TEAEs falling in the same HLT or SOC will be counted only once per HLT or SOC, 
respectively. For the intensity summaries, if a subject reported multiple TEAEs coded to the 
same SOC or HLT or PT then the maximum intensity reported will be considered. Similarly, for 
the summary of drug-related TEAEs, for subjects with multiple reports of the same PT (or within 
HLT or SOC), the worst case reported for the PT (within HLT or SOC) will be considered.
If the intensity for a TEAE is missing, it will be counted as “severe”. If the drug-relationship for 
a TEAE is missing, it will be counted as “related”.
Data listings will be provided for pretreatment events, TEAEs, TEAEs leading to study drug 
discontinuation, serious TEAEs, and AEs resulting in death.
7.12.1.1 Adverse Events of Special Interest
Based on the mechanism of action of vedolizumab, the following 5 AEs of special interest 
(AESIs) have been predefined with corresponding MedDRA search criteria.
Hypersensitivity Reactions including Infusion-Related Reactions (IRRs) 
Possible IRRs will be identified using the following MedDRA 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.
Suspected Progressive Multifocal Leukoencephalopathy (PML)
Suspected PMLs will be identified within the Infection and Infestation SOC using the 
following MedDRA search criteria: 

Human polyomavirus infection PT

JC virus infection PT

JC virus test positive PT


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
Leukoencephalopathy PT

Polyomavirus test positive PT

Progressive multifocal leukoencephalopathy PT
Liver Injury
Reports of liver injury will be identified using the following MedDRA 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)
Malignancies
Reports of malignancy will be identified using the following MedDRA criterion: 

Neoplasms benign, malignant and unspecified (incl. cysts and polyps) SOC.
An AE that is indicated as malignancy in the eCRF will also be considered an AESI.
Infections
Reports of infection will be identified using the following MedDRA criterion: 

Infections and infestations SOC.
Incidence of the 5 AESIs will be summarized showing the number (and %) of subjects with and 
the number of events by SOC, HLT and PT.
7.12.2 Clinical Laboratory Evaluations
The laboratory parameters for serum chemistries, hematology, stool and urinalysis shown in 
Table 7.f were recorded in this study. Refer to Appendix A for scheduled measurements for 
clinical laboratory tests.
In general, clinical laboratory parameters will be presented using the International System of 
Units (SI) unless otherwise stated. For test results not reported 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 data summaries 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 certain value, or greater than (>) a certain value), the given numeric 
value will be used in the summary statistics, ignoring the non-numeric qualifier.


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Table 7.f
Clinical Laboratory Parameters
Hematology
Serum Chemistry
Urinalysis
RBC
WBC with differential (a)
Hemoglobin
Hematocrit (b)
Platelets
PT/INR
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Calcium
Chloride
Magnesium
Phosphorus
Uric Acid
Glucose
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Specific Gravity
Other: 
HIV
Hepatitis panel, including HBsAg and anti-HCV
Serum
Urine
Stool
CRP
Pharmacokinetic samples
AVA/nAVA
QuantiFERON for TB
hCG (for pregnancy in female 
subjects of childbearing potential only) 
Fecal calprotectin
beta hCG (for pregnancy in female subjects of 
childbearing potential only)
FSH, if menopause is suspected (Screening Visit only)
(a) WBC differential to include lymphocytes, monocytes, basophils, eosinophils, and neutrophils.
(b) Hematocrit only collected at Visits 3, 4, and 6
AVA=Anti-vedolizumab antibodies, nAVA=neutralizing anti-vedolizumab antibodies, FSH=follicle-stimulating 
hormone, GGT=γ-glutamyl transferase, HBsAg = hepatitis B surface antigen, hCG=human chorionic gonadotropin, 
PT=prothrombin time, RBC=red blood cells.
Continuous laboratory parameters tabulated using summary statistics for observed values and 
change from baseline by visit (baseline, each post baseline visit and last visit). Categorical 
laboratory parameters (e.g. urinalysis) will only be listed.
Criteria for markedly abnormal values (MAV) of laboratory parameters are listed in Appendix E.
For laboratory parameters with available criteria, incidence of MAVs will be summarized as 
follows:

Overview table with number (and %) of subjects with any MAV reported overall and 
by visit


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
For each laboratory parameter for which at least one MAV was reported:
a summary table for number (and %) of subjects with MAV by visit.
If both the baseline and on-treatment values of a parameter are beyond the MAV limit for that 
parameter, then the on-treatment value will be considered a MAV only if it is more extreme than 
was the baseline value.
All laboratory parameters will be listed, with values outside the normal ranges flagged as above 
“(H)” or below “(L)”; additionally, MAV values will be flagged (either as “(H#)” or “(L#)”).
7.12.3 Vital Signs
Systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse, body temperature (in °C), 
weight (in kg), and respiration rate were measured at the time points indicated in the schedule of 
study procedures (refer to Appendix A).
For each vital sign parameter the observed values and change from baseline will be summarized 
by visit (including last visit) using descriptive statistics.
Criteria for MAV of vital signs (SBP, DBP, pulse and body temperature) are listed in Appendix 
F. For these vital signs parameters, incidence of MAV the number (and %) of subjects with
MAV will be summarized by visit.
Vital signs data will be listed with markedly abnormal values (MAVs) flagged, either as “(H#)” 
for values exceeding the upper criterion or as “(L#)” for values exceeding the lower criterion.
7.12.4 12-Lead ECGs
Overall ECG interpretation category (normal, not clinically significant abnormal, clinically 
significant abnormal) was collected at Screening.  ECG data will be listed only.
7.12.5 Other Observations Related to Safety
Other safety related data recorded include the following data. For those data only appropriate 
data listings will be provided:

Physical examination

Liver Function Test results (increase, sign and symptoms, event history and test results)

Infections (details of infection, their diagnostic tests, cause/origin, history preceding 
events and associated symptoms)

Malignancy (status based on diagnostic tests, stage, the risk factors and details) will also 
be listed.

Results from the PML checklist that includes the PML criteria, their response, symptoms, 
result and abnormality; data will be listed (by visit) only for subjects with any 
abnormality reported. 


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
Results from the PML algorithm; data will be listed (by visit) only for subjects with any 
abnormality reported
7.13
Interim Analysis
The futility analysis planned according to the study protocol, section 13.2, was not performed 
because the number of subjects planned for the futility analysis was never reached before the 
study enrolment was stopped.
7.14
Changes in the Statistical Analysis Plan
The following changes from protocol concerning the statistical analysis were applied:

Due to significant and increasing difficulties in enrollment into this study the enrollment was 
closed early before the planned sample size was reached. This decision was made in 
February 2018 [4]. The planned sample size was 100 subjects in total (50 per dosing 
regimen/treatment arm), due to the early termination of the enrollment, the resulting total 
number of subjects enrolled is 34.

The futility analysis planned as per the study protocol, section 13.2, was not performed 
because the number of subjects planned for the futility analysis was not reached prior to 
premature termination of the study.

During blinded data review it was noted that subjects without draining fistulae at baseline 
were included. Therefore, an additional analysis set was introduced: the modified full 
analysis set (mFAS), consisting of all subjects in the FAS who had at least one draining 
fistula at baseline (Day 1). Summaries of the primary and secondary endpoints (and related 
data used to derive those endpoints) will be provided for the mFAS.

Due to the early termination of the study and the resulting low total number of subjects 
enrolled, no Per-Protocol analysis set is defined in the SAP and no sensitivity analyses are 
foreseen.

The wording of several study endpoints was slightly altered for purpose of clarification; these 
alterations do not have an impact on the analysis of the endpoints.

In general, the wording “proportion of subjects with …” an event in the definition of 
response-type primary, secondary and additional efficacy endpoints was removed to clarify 
that the respective event itself is considered the endpoint.

The wording of the primary and secondary efficacy endpoints was clarified. Originally, those 
endpoints referred to draining or closure of “perianal fistula(e)” in general. Since subjects 
without draining fistulae at baseline were included, the wording of those endpoints was 
corrected and now refers to draining or closure of “perianal fistula(e) draining at Baseline”
(see revised wording in sections 5.1and 5.2).

The wording of the secondary endpoint “Duration of perianal fistula response (number of 
days with drainage)” was corrected to “Duration of perianal fistula response”. This change is 


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applied since perianal fistula response is defined as reduction in the number of draining 
perianal fistulae (of those draining at Baseline) of at least 50%.

Per the protocol, the secondary efficacy endpoints “Time to first perianal fistula closure” and 
“Time to 100% perianal fistula closure” were to be derived relative to time of randomization. 
This has been changed and both times will be derived from time of first administration of 
study medication (Day 1), see details in section 7.9.4.

Originally, it was planned to evaluate the additional endpoint “Change in total CDAI score 
from Day 1 to Weeks 2, 6, 10, 14, 22 and 30” only in the subset of subjects with CDAI total 
score >220 at Day 1. Due to the actual total number of subjects enrolled, the changes in total 
CDAI score will be evaluated for all subjects in the FAS. 

The initially planned additional endpoint “Change in number of pads used for perianal fistula 
drainage from Baseline to Week 30 (for selected study sites only)” was removed from the 
originally planned endpoint list, as the definition of this endpoint is very vague and no proper 
data collection was performed.

The medication history, CD prior biologic medications and concomitant medications will be 
summarized by therapeutic classification, subclassification, and preferred term rather than 
only by preferred term as specified in the protocol.


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8.0
REFERENCES
3. A Randomized Double-Blind Phase 4 Study to Evaluate the Safety and Proportion of 
Subjects With Fistula Healing in 2 Dose Regimens of Entyvio (Vedolizumab IV) in the
Treatment of Fistulizing Crohn’s Disease (ENTERPRISE), Takeda Development Center
Americas, Inc., Protocol Vedolizumab-4003, Amendment 05 Version 1, 20 April 2017.
4. Justification for Closure of Enrolment into Vedolizumab 4003 study, January 2018


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9.0
APPENDICES
Appendix A Schedule of Study Procedures
Screen
Treatment
Final 
Visit 
or ET
Follow-up
Post Study
Study Day/Week:
Days
-28 to -1
Wk0
/ Day 
1
Wk 
2
Wk 
6
Wk 
10
Wk 
14
Wk 
22
Wk 
30
Wk 40
(or 18 wks 
post-tx if 
ET)
LTFU by 
Telephone
Wk 48 
(or 26 wks 
post-tx if 
ET)
Visit Windows (Days):
±2
±2
±3
±7
±7
±7
±7
±7
Visit Number:
1
2
3
4
5
6
7
8
9
10
Informed consent
X
Assess 
inclusion/exclusion 
criteria
X
X
Demographics /medical 
and medication history/ 
concurrent medical 
conditions 
X
Crohn’s disease history
X
Tuberculosis 
QuantiFERON or skin 
test
X
Physical examination (a)
X
X 
X
X
X
X
X
X
Fistula draining 
assessment (b)
X
X
X
X
X
X
X
X
Vital signs 
X
X 
X 
X 
X
X 
X 
X
Height and weight (c)
X
X
X
X
X
CDAI 
X (d)
X (e)
X (e)
X (e)
X (e)
X (e)
X (e)
X (e)
PDAI
X
X
X
X
X
X
X
ECG
X
MRI 
X(f)
X(f)
Hematology, serum 
chemistry 
X 
X 
X 
X
X
Hematocrit (for CDAI 
scoring)
X
X
X
HIV/Hepatitis Panel
X
Urinalysis
X
X
X
X
AVA(g)
X 
X
X 
X
X
X
X(h)
PK (i)
X
X
X
X
X
X
CRP (j)
X 
X 
X
X
Fecal calprotectin (k) 
X
X
X
Footnotes are on last table page.


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Screen
Treatment
Final 
Visit 
or ET
Follow-up
Post Study
Study Day/Week:
Days
-28 to -1
Wk0
/ Day 
1
Wk 
2
Wk 
6
Wk 
10
Wk 
14
Wk 
22
Wk 
30
Wk 40
(or 18 wks 
post-tx if 
ET)
Phone
Wk 48 
(or 26 wks 
post-tx if 
ET)
Visit Windows (Days):
±2
±2
±3
±7
±7
±7
±7
±7
Visit Number:
1
2
3
4
5
6
7
8
9
10
PML checklist
X
X(l) 
X(l)
X(l)
X(l)
X(l)
X(l) 
X
X
Provide PML wallet card
X
X
Serum Pregnancy test 
(m)
X
X
Urine Pregnancy test (m)
X 
X 
X 
X
X 
X 
X
IBDQ 
X
X
X
EQ-5D
X
X
X
Mean Likert perianal 
pain score (n)
X
X
X
X
X
X
X
X
Subject diary (n)
X
X
X
X
X
X
X
X
Review subject diary
X
X
X
X
X
X
X
Daily # of pads used 
(selected sites only)
X
X
X
X
X
X
X
X
Dosing (IV)(o)
X
X
X
X
X
X
Antibiotic dosing 
X
X
X(p)
Seton removal(q)
[X(q)]
[X(q)]
X(q)
Concomitant medications
X
X
X
X
X
X
X
X
PTE assessment
X
X 
AE/SAE assessment
X
X
X
X
X
X
X
X
Long-term follow-up 
safety questionnaire
X
Access IWRS to obtain 
subject ID
X
Access IWRS for 
randomization
X
Access IWRS to register 
visit
X
X
X
X
X
X
X
X
Footnotes are on last table page.


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ET=early termination, tx=treatment, wk=week.
(a) Including abdominal mass assessment for CDAI calculation.
(b) Fistula(e) (perianal, enterocutaneous) will be assessed for draining or closed status at each visit. Fistula draining assessment 
will preferably be performed by the same qualified designee for all assessments. At Screening and Week 30, the assessment of 
perianal fistula draining is for eligibility or primary endpoint assessment, respectively.
(c) Height collected only at the Screening Visit.
(d) Hematocrit results collected during Screening will be used to calculate the CDAI score to determine eligibility.
(e) CDAI score components are to be performed prior to dosing; the total CDAI score will be calculated once results are available 
for all components.
(f) Subjects must have safety laboratory results reviewed prior to MRI scan being performed. If a subject’s serum creatinine is 
>1.5 times the ULN (>1.5x ULN), the subject should not undergo the MRI procedure. MRI will be performed at Screening and 
Week 30; MRIs will be centrally read.
(g) AVA to be collected prior to dosing. If positive AVA is detected, a sample will be assessed for neutralizing AVA.
(h) The 18-week postdose AVA sample should be collected for all subjects who stopped vedolizumab during study (ie, not for 
those who continue on commercial supply vedolizumab therapy post-study).
(i) PK samples to be collected at predose on Day 1, Weeks 6, 10, 14 and 22 and at Week 30. One additional PK sample will be 
collected at Week 10 postdose (as close to the end of the infusion as feasible, and must be obtained within 30 minutes after the 
end of the infusion).
(j) CRP will be measured from the hematology/serum chemistry blood draw at all weeks except Week 14. Week 14 will require a 
separate blood draw as hematology and serum chemistry are not taken at this time.
(k) Stool sample to be collected and sent to central laboratory for evaluation of fecal calprotectin.
(l) PML checklist must be administered prior to dosing at every dosing visit.
(m) Women of childbearing potential only. Urine pregnancy testing will be conducted at the site and serum pregnancy testing 
will be conducted by the central laboratory. At visits with study drug dosing, to be performed before any study drug dosing.
(n) Subject electronic diary to be completed as per training instruction during screening interval. Subject electronic diary (CDAI 
and perianal pain) to be completed daily from Screening to Week 30.
(o) Subjects should be observed for 2 hours following the first 2 infusions, at a minimum, and 1 hour after each subsequent 
infusion for monitoring for potential hypersensitivity reactions.
(p) Antibiotic companion medication that was started (or continued if subject already taking antibiotics) from Day 1, must be
stopped at Week 6. Additional courses of antibiotics may be allowed, as needed, and in consultation with the medical monitor.
(q) Applicable for subjects who had a seton at study enrollment. Setons may be removed at or after Week 6 at the discretion of 
the investigator, provided that significant reduction in fistula drainage has occurred. All setons must be removed by Week 14.


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Appendix B Perianal Crohn’s Disease Activity Index


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Appendix C 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)
x 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)
x 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)
x 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
x 20
Lomotil/Imodium/opiates 
for diarrhea
Yes = 1
No = 0
x 30
Abdominal mass
None = 0
Questionable = 2
Definite = 5
x 10
Hematocrit (%) (a)
Males: subtract value from 47
Females: subtract value from 42
x 6
Body Weight (b)
(1 – (Body weight/
Standard Weight)) × 100
x 1
Final Score
Add totals:
Source: Adapted from: Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s disease activity 
index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70 (3):439-44. 
(a) If hematocrit subtotal <0, enter 0. 
(b) If body weight subtotal <-10, enter -10.


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Appendix D: Quality of Life Questionnaires
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)> + 0.1215579 ×
(result from Step #4) + 0.0147963 × (result from Step #4)>
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.


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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
<2.0,
> 1.5 × ULN
×109 cells/L
< 2.0, 
> 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
< 70, > 600
×109 /L
< 70, > 600
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
PT
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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Serum Chemistry – Criteria for Markedly Abnormal Values
Conventional Units
Takeda Preferred SI Units
Markedly 
Markedly
Age
Abnormal
Abnormal
Parameter
Gender
(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
< 27, > 58.6
mmol/L
< 1.50, > 3.25
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
Chloride
Both
Adult
mEq/L
< 75, > 126
mmol/L
< 75, > 126
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.


Vedolizumab-4003
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Statistical Analysis Plan Final Draft
April 08, 2019
CONFIDENTIAL
Appendix F Criteria for Identification of Markedly Abnormal Values for 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