Clinical trial NCT02611830
Conditions: Colitis, Ulcerative
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2015-12-18; Completion date: 2018-08-21
Enrollment: 383 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effect of vedolizumab subcutaneous (vedolizumab SC) maintenance treatment on clinical remission at Week 52 in participants with moderately to severely active ulcerative colitis (UC) who achieved clinical response following administration of vedolizumab intravenous (vedolizumab IV) induction therapy.

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

The study enrolled 383 patients. All participants will enter into a 6-week Induction Phase where they will be administered open-label vedolizumab IV 300 mg via intravenous infusion (IV) at Week 0 (Day 1) and Week 2 (Day 15), and will then be assessed for a clinical response at Week 6. Participants who achieve a clinical response at Week 6 will be randomly assigned to one of the three treatment groups:

Vedolizumab SC 108 mg Q2W and Placebo IV Q8W Vedolizumab IV 300 mg Q8W and Placebo SC Q2W Placebo SC Q2W and Placebo IV Q8W

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

This multi-center trial will be conducted worldwide. The overall time to participate in this study is up to 71 weeks (up to 4 weeks of screening, 52 weeks of treatment and 18 weeks of safety follow-up). Participants will make multiple visits to the clinic, plus a final visit 18 weeks after last dose of study drug for a follow-up assessment. Participants will also participate in a long-term safety follow-up, by phone, at 6 months after the last dose of study drug.

After the Week 52 assessments, participants meeting protocol-defined criteria were eligible to enroll in Study MLN0002SC-3030 (NCT02620046; Long-term Safety) to receive open-label vedolizumab treatment. Participants who withdrew early (prior to Week 52) due to sustained nonresponse, disease worsening, or the need for rescue medications may also have been eligible for Study MLN0002SC-3030. Participants who did not enroll into Study MLN0002SC-3030 were to complete a final on-study safety assessment at Week 68 (or final safety visit 18 weeks after the last dose) in the Maintenance Phase of Study MLN0002SC-3027.

Arms: arm 1: Participants received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab SC in maintenance phase. Vedolizumab SC, 108 mg, injection, Q2W and placebo-matching IV infusions, Q8W, starting at Week 6 up to approximately Week 50. arm 2: Participants received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab IV in maintenance phase. Vedolizumab 300 mg, IV infusion, Q8W and placebo-matching SC injection, Q2W starting at Week 6 up to approximately Week 50. arm 3: Participants received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive placebo in maintenance phase. Placebo-matching subcutaneous (SC) injections, once every 2 weeks (Q2W) and placebo-matching IV infusions, once every 8 weeks (Q8W) starting at Week 6 up to approximately Week 50.
Interventions: intervention 1: Vedolizumab 300 mg IV intervention 2: Placebo IV intervention 3: Vedolizumab 108 mg SC intervention 4: Placebo SC
Intervention descriptions: intervention 1: Vedolizumab intravenous infusion intervention 2: Vedolizumab intravenous infusion placebo intervention 3: Vedolizumab subcutaneous injection intervention 4: Vedolizumab subcutaneous injection placebo

Protocol documents:
Prot_001.pdf: 


•
Title: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study, with a Vedolizumab IV 
Reference Arm, to Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as 
Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis Who 
Achieved Clinical Response Following Open-Label Vedolizumab Intravenous Therapy
NCT Number: NCT02611830
Protocol Approve Date: 28 September 2016
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.


[TYPE TEXT]
PROTOCOL
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study, with a Vedolizumab IV 
Reference Arm, to Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as 
Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis Who 
Achieved Clinical Response Following Open-Label Vedolizumab Intravenous Therapy
Efficacy and Safety of Vedolizumab SC as Maintenance Therapy in Ulcerative Colitis 
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway, Deerfield, IL 60015
Takeda Development Centre Europe, Ltd.
61 Aldwych, London, WC2B 4AE
United Kingdom
Takeda Development Center Asia, Pte. Ltd.
Biopolis Road, Nucleos North Tower Level 4
Singapore, 138567
Takeda Pharmaceutical Company Limited, 
1-1, Doshomachi 4-Chome, Chuo-ku Osaka 540-8645, Japan
Study Number:
MLN0002SC-3027 
IND Number:
118980
EudraCT Number:
2015-000480-14
Compound:
Vedolizumab SC
Date:
28 September 2016
Amendment Number:
05
Amendment History: 
Date
Amendment Number
Amendment Type
Region
26 February 2015
Initial Protocol
Not applicable
Global
10 November 2015
01
Substantial
Global
10 February 2016
02
Substantial
Global
12 May 2016
03
Substantial
Global
26 July 2016
04
Substantial
Global
28 September 2016
05
Substantial
Japan
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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


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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
PPD


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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure or 
package insert, as applicable, and any other product information provided by the sponsor. I agree 
to conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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1.3
Protocol Amendment 05 Summary of Changes 
This document describes the changes in reference to the Protocol Incorporating Amendment No. 
05.
The primary purpose of this amendment is to amend the visit window for Week 6a. Full details on 
changes of text are given in Appendix G. The following is a summary of the changes made in the 
amendment:
1. Amendment of visit window for Week 6a.
2. Administrative change to the sponsor address in Japan.
3. Corrected typographical errors, punctuation, grammar, and formatting.


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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 ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Principal Investigator/Coordinating Investigator ......................................................15
3.3
List of Abbreviations ...............................................................................................16
3.4
Corporate Identification...........................................................................................18
3.5
Study Definitions.....................................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.1.1
Diseases and Current Treatments .......................................................................19
4.1.2
Vedolizumab......................................................................................................20
4.1.2.1 Nonclinical...................................................................................................21
4.1.2.2 Clinical Experience With Vedolizumab IV...................................................21
4.1.2.3 Clinical Experience With Vedolizumab SC ..................................................24
4.2
Rationale for the Proposed Study.............................................................................26
4.3
Benefit-Risk Assessment .........................................................................................26
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................28
5.1
Objectives................................................................................................................28
5.1.1
Primary Objective(s)..........................................................................................28
5.1.2
Secondary Objectives.........................................................................................28
5.1.3
Exploratory Objectives.......................................................................................28
5.2
Endpoints.................................................................................................................29
5.2.1
Primary Endpoints .............................................................................................29
5.2.2
Secondary Endpoints..........................................................................................29
5.2.3
Patient Reported Outcome (PRO) Endpoints......................................................30
5.2.4
Exploratory Endpoints .......................................................................................30
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................32
6.1
Study Design ...........................................................................................................32
6.2
Justification for Study Design, Dose, and Endpoints ................................................36


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6.3
Premature Termination or Suspension of Study or Investigational Site.....................38
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................38
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........38
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................38
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............39
7.1
Inclusion Criteria .....................................................................................................39
7.2
Exclusion Criteria ....................................................................................................41
7.2.1
Gastrointestinal Exclusion Criteria.....................................................................41
7.2.2
Infectious Disease Exclusion Criteria .................................................................41
7.2.3
General Exclusion Criteria .................................................................................42
7.3
Excluded Medications and Treatments.....................................................................44
7.3.1
Permitted Medications and Treatments...............................................................44
7.3.1.1 Oral Corticosteroid Dosing and Tapering .....................................................45
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................46
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................47
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................48
8.1
Study Medication and Materials...............................................................................48
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................48
8.1.1.1 Vedolizumab for Injection, for Intravenous Use (Vedolizumab 
IV) ...............................................................................................................48
8.1.1.2 Vedolizumab Injection, for Subcutaneous Use (Vedolizumab 
SC)...............................................................................................................48
8.1.1.3 Sponsor-Supplied Drug ................................................................................49
8.1.1.4 Other Protocol-Specified Materials...............................................................49
8.1.2
Storage...............................................................................................................49
8.1.3
Dose and Regimen .............................................................................................49
8.1.4
Overdose............................................................................................................50
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................50
8.3
Randomization Code Creation and Storage..............................................................51
8.4
Investigational Drug Blind Maintenance and Unblinding .........................................52
8.5
Accountability and Destruction of Sponsor-Supplied Drugs.....................................52
9.0
STUDY PLAN ..............................................................................................................54
9.1
Study Procedures.....................................................................................................54
9.1.1
Informed Consent Procedure..............................................................................54


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9.1.1.1 Pharmacogenomic Informed Consent Procedure...........................................54
9.1.2
Demographics, Medical History, and Medication History Procedure..................54
9.1.3
Physical Examination Procedure ........................................................................54
9.1.4
Weight and Height .............................................................................................55
9.1.5
Vital Sign Procedure..........................................................................................55
9.1.6
Primary Efficacy Measurement ..........................................................................55
9.1.6.1 Diary Completion and Review......................................................................55
9.1.7
Documentation of Concomitant Medications......................................................56
9.1.8
Documentation of Concurrent Medical Conditions.............................................56
9.1.9
Procedures for Clinical Laboratory Samples.......................................................56
9.1.10 Contraception and Pregnancy Avoidance Procedure...........................................58
9.1.11 Pregnancy ..........................................................................................................59
9.1.12 ECG Procedure..................................................................................................59
9.1.13 Histological Sample Collection..........................................................................60
9.1.14 Immunogenicity Sample Collection ...................................................................60
9.1.15 Pharmacokinetic Sample Collection...................................................................60
9.1.16 Pharmacogenomic Sample Collection ................................................................60
9.1.17 Tuberculosis Screening ......................................................................................61
9.1.18 Fecal Calprotectin Sample Collection.................................................................61
9.1.19 Stool Sample......................................................................................................62
9.1.20 PML Checklist...................................................................................................62
9.1.21 Patient-Reported Outcomes Instruments.............................................................62
9.1.21.1 Inflammatory Bowel Disease Questionnaire..............................................62
9.1.21.2 EQ-5D Questionnaire................................................................................62
9.1.21.3 Work Productivity and Activity Impairment-UC.......................................63
9.1.22 Documentation of Screen Failure .......................................................................63
9.1.23 Documentation of Study Entrance......................................................................63
9.2
Monitoring Subject Treatment Compliance..............................................................64
9.3
Schedule of Observations and Procedures................................................................64
9.3.1
Screening...........................................................................................................64
9.3.2
Enrollment/Randomization.................................................................................64
9.3.2.1 Non-responders............................................................................................65
9.3.3
Final Visit or Early Termination.........................................................................65
9.3.4
Final Safety Follow-up Visit ..............................................................................65
9.3.5
Post Study 6-Month Long-Term Follow-Up Survey...........................................65


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9.3.6
Unscheduled Visits Due to Disease Exacerbation...............................................65
9.4
Biological Sample Retention and Destruction ..........................................................66
10.0
PRETREATMENT EVENTS (PTE), ADVERSE EVENTS (AE) AND PRODUCT 
COMPLAINTS (PC).....................................................................................................67
10.1
Definitions...............................................................................................................67
10.1.1 PTEs..................................................................................................................67
10.1.2 AEs....................................................................................................................67
10.1.3 Additional Points to Consider for PTEs and AEs................................................67
10.1.4 SAEs..................................................................................................................69
10.1.5 Special Interest AEs...........................................................................................70
10.1.6 Severity of PTEs and AEs..................................................................................70
10.1.7 Causality of AEs ................................................................................................71
10.1.8 Relationship to Study Procedures.......................................................................71
10.1.9 Start Date...........................................................................................................71
10.1.10
Stop Date .....................................................................................................71
10.1.11
Frequency ....................................................................................................71
10.1.12
Action Concerning Study Medication...........................................................71
10.1.13
Outcome.......................................................................................................72
10.1.14
Product Complaints......................................................................................72
10.2
Procedures...............................................................................................................72
10.2.1 Collection and Reporting of AEs........................................................................72
10.2.1.1 PTE and AE Collection Period..................................................................72
10.2.1.2 PTE and AE Reporting .............................................................................73
10.2.1.3 Adverse Event Collection Involving Medically Anticipated 
Clinical Events.............................................................................................74
10.2.1.4 Special Interest AE Reporting...................................................................74
10.2.2 Collection and Reporting of SAEs......................................................................75
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................76
10.3
Follow-up of SAEs ..................................................................................................76
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....76
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................78
11.1
Data Safety Monitoring Board .................................................................................78
11.2
Adjudication Committee..........................................................................................78
11.2.1
...............................78
12.0
DATA HANDLING AND RECORD KEEPING...........................................................80
CCI


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12.1
Electronic CRFs.......................................................................................................80
12.2
Record Retention .....................................................................................................80
13.0
STATISTICAL METHODS..........................................................................................82
13.1
Statistical and Analytical Plans ................................................................................82
13.1.1 Analysis Sets......................................................................................................82
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................82
13.1.3 Efficacy Analysis...............................................................................................82
13.1.4 Resource Utilization and Patient Reported Outcomes (PRO)..............................83
13.1.5 Pharmacokinetic Analysis ..................................................................................83
13.1.6 Other Analysis ...................................................................................................83
13.1.7 Safety Analysis ..................................................................................................84
13.2
Interim Analysis and Criteria for Early Termination ................................................85
13.3
Determination of Sample Size..................................................................................85
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................86
14.1
Study-Site Monitoring Visits ...................................................................................86
14.2
Protocol Deviations..................................................................................................86
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................87
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................88
15.1
IRB and/or IEC Approval ........................................................................................88
15.2
Subject Information, Informed Consent, and Subject Authorization .........................89
15.3
Subject Confidentiality ............................................................................................90
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................90
15.4.1 Publication and Disclosure.................................................................................90
15.4.2 Clinical Trial Registration..................................................................................91
15.4.3 Clinical Trial Results Disclosure ........................................................................91
15.5
Insurance and Compensation for Injury....................................................................91
16.0
REFERENCES..............................................................................................................92
LIST OF IN-TEXT TABLES
Table 4.a
Efficacy of Vedolizumab IV in Subjects With UC During the Induction Phase 
(Week 6, C13006)..............................................................................................22
Table 4.b
Efficacy of Vedolizumab IV in Subjects With UC During the Maintenance 
Phase (Week 52, C13006)..................................................................................23
Table 7.a
Eligibility for Study MLN0002SC-3030 Based on Reason for Withdrawal.........47
Table 8.a
Dose and Dosing Regimen.................................................................................50


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Table 9.a
Clinical Laboratory Tests...................................................................................57
Table 10.a
Takeda Medically Significant AE List................................................................70
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................35
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures: Screening, Induction and Non-Responders.........95
Appendix B
Responsibilities of the Investigator...................................................................101
Appendix C
Elements of the Subject Informed Consent.......................................................103
Appendix D
Investigator Consent to Use of Personal Information........................................106
Appendix E
Collection, Shipment, and Storage of Pharmacogenomic Samples....................107
Appendix F
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity..........108
Appendix G
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. 
Takeda Development Center Asia, Pte. Ltd.
Takeda Pharmaceutical Company, Ltd.
Compound:
Vedolizumab SC
Title of Protocol: A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Study, With a Vedolizumab IV Reference Arm, to 
Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as 
Maintenance Therapy in Subjects With Moderately to Severely Active 
Ulcerative Colitis Who Achieved Clinical Response Following Open-Label 
Vedolizumab Intravenous Therapy
IND No.:
118980
EudraCT No.:
2015-000480-14
Study Number: MLN0002SC-3027
Phase: 3
Study Design:
This is a pivotal, phase 3, multicenter, multinational, randomized, double-blind, double-dummy, placebo-controlled 
trial, including a vedolizumab intravenous (vedolizumab IV) reference arm, designed to evaluate the efficacy and 
safety of maintenance treatment with vedolizumab subcutaneous (vedolizumab SC) in adult subjects with moderately 
to severely active ulcerative colitis (UC) who achieved a clinical response at Week 6 following open-label therapy 
with 300 mg vedolizumab IV administered at Weeks 0 and 2. The study includes a vedolizumab IV reference arm to 
allow for within study descriptive comparisons on efficacy, safety, and immunogenicity between the two vedolizumab 
presentations.
Moderately to severely active UC is defined as a complete Mayo score of 6 to 12 points with endoscopic subscore of 
≥2. Subjects that are tumor necrosis factor-alpha (TNF-α) antagonist naïve or with TNF-α antagonist failure will be 
included, ensuring that approximately 50% of subjects with TNF-α antagonist failure are enrolled. Subjects with 
previous use of TNF-α antagonist but not failed will NOT be enrolled.
Primary Objectives:

To assess the effect of vedolizumab SC maintenance treatment on clinical remission at Week 52 in subjects with 
moderately to severely active UC who achieved clinical response at Week 6 following administration of 
vedolizumab IV at Weeks 0 and 2.
Secondary Objectives:

To determine the effect of vedolizumab SC maintenance treatment on mucosal healing at Week 52 in subjects 
who achieved clinical response at Week 6 following administration of vedolizumab IV at Weeks 0 and 2.

To determine the effect of vedolizumab SC maintenance treatment on durable clinical response at Week 52 in 
subjects who achieved clinical response at Week 6 following administration of vedolizumab IV at Weeks 0 and 2.

To determine the effect of vedolizumab SC maintenance treatment on durable clinical remission at Week 52 in 
subjects who achieved clinical response at Week 6 following administration of vedolizumab IV at Weeks 0 and 2.

To determine the effect of vedolizumab SC maintenance treatment on corticosteroid free remission at Week 52 in 
subjects who achieved clinical response at Week 6 following administration of vedolizumab IV at Weeks 0 and 2.
Subject Population: Adult subjects with UC, aged 18-80 years inclusive.
Number of Subjects: 
Approximately 400 subjects enrolled to enable approximately 188 subjects 
to be randomized for maintenance treatment.
Number of Sites: 
Approximately 250 sites globally.


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Dose Level(s):
Vedolizumab SC, 108 mg
Vedolizumab IV, 300 mg
Route of Administration:
Subcutaneous
Intravenous
Duration of Treatment:
52-week treatment period
Period of Evaluation:
The study includes a 4-week (28-day) 
Screening Period, a 6-week open-label 
vedolizumab IV Induction Phase, a 
46-week randomized, double-blind, 
double-dummy, placebo-controlled 
Maintenance Phase with vedolizumab 
SC or vedolizumab IV with a final visit 
at Week 52.
Subjects who do not participate in the 
open-label extension (OLE) study will 
be required to participate in a Final 
Safety Visit 18-weeks after the last 
study drug dose (Week 50 or early 
termination [ET]) and a long-term 
follow-up (LTFU) safety survey by 
telephone, 6 months after the last dose 
of study drug.
Main Criteria for Inclusion:
The subject has a diagnosis of UC established at least 6 months prior to screening, by clinical and endoscopic evidence 
and corroborated by a histopathology report.
The subject has moderately to severely active UC as determined by a complete Mayo score of 6-12 with an endoscopic 
subscore ≥2 within 10 days prior to the first dose of study drug.
The subject has evidence of UC extending proximal to the rectum (≥15 cm of involved colon).
The subject has demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the 
following agents: immunomodulators, corticosteroids, or TNF-α antagonists.
Main Criteria for Exclusion:
The subject has had extensive colonic resection, subtotal or total colectomy.
The subject has any evidence of an active infection during screening. 
The subject has a positive progressive multifocal leukoencephalopathy (PML) subjective checklist at Screening (or at 
Week 0 before the administration of study drug). 
The subject has received any investigational or approved biologic or biosimilar within 60 days or 5 half-lives of 
screening, whichever is longer.
The subject has had prior exposure to vedolizumab.
The subject has had prior exposure to natalizumab, efalizumab, or rituximab.
Main Criteria for Evaluation and Analyses: 
The primary endpoint for this study is the proportion of subjects with clinical remission, defined as a complete Mayo 
score of ≤2 points and no individual subcore >1 point, at Week 52.
Secondary endpoints for this study are:

Proportion of subjects with mucosal healing (defined as Mayo endoscopic subscore of ≤1 point) at Week 52.

Proportion of subjects with durable clinical response (defined as clinical response at Weeks 6 and 52, where 


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clinical response is defined as a reduction in complete Mayo score of ≥3 points and ≥30% from Baseline (Week 0) 
with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 
point).

Proportion of subjects with durable clinical remission (defined as clinical remission at Weeks 6 and 52).

Proportion of subjects with corticosteroid-free remission (defined as subjects using oral corticosteroids at 
Baseline (Week 0) who have discontinued oral corticosteroids and are in clinical remission at Week 52). 
Statistical Considerations:
All statistical testing will be performed at 2-sided 0.05 level of significance. To control the overall Type I error rate for 
the comparison between vedolizumab SC and placebo groups for the primary and secondary endpoints, the statistical 
inference for the first secondary endpoint will only be performed if the primary endpoint is statistically significant and 
so on for each subsequent secondary endpoint. 
All dichotomous efficacy endpoints will be analyzed using Cochran-Mantel-Haenszel tests for risk differences, 
stratified by randomization stratum. All subjects with missing data for determination of endpoint status will be 
considered as a nonresponder in the analysis.
Sample Size Justification: 
Assuming a clinical remission rate of 42% for vedolizumab and 16% for placebo at Week 52, a sample size of 
94 subjects in the vedolizumab SC group, 47 subjects in the placebo group will provide 90% power at 2-sided 0.05 
level of significance. To ensure a randomized sample size of 188 subjects, assuming 47% of the subjects entering 
induction will achieve clinical response at Week 6, approximately 400 subjects will need to be enrolled into the study.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.


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3.3
List of Abbreviations
Term
Definition
5-ASA
5-aminosalicylate
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AVA
anti-vedolizumab antibody; also called HAHA
Cav,ss
average serum concentration over the dosing interval at steady state 
CD
Crohn’s disease
Cmax
maximum observed serum concentration
Cmax,ss
maximum observed serum concentration at steady-state
CRO
contract research organization
Ctrough
trough serum concentration levels 
DNA
deoxyribonucleic acid
DSMB
data safety monitoring board
ECG
electrocardiogram
ECL
electrochemiluminescence
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EQ-5D
Euro Quality of Life-5D
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GALT
gut-associated lymphoid tissue
GCAP
granulocytapheresis
GCP
Good Clinical Practice
GI
gastrointestinal(ly)
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCP
healthcare provider
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRQOL
health-related quality of life 
IAC
Independent Adjudication Committee
IB
Investigator’s Brochure


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Term
Definition
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
Ig
immunoglobin
IM
intramuscular(ly)
INR
international normalized ratio
IRB
institutional review board
IV
intravenous(ly)
IWRS
interactive web response system
JCV
John Cunningham virus
LCAP
leukocytapheresis
LFT
liver function test
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
NSAID
nonsteroidal anti-inflammatory drug
OLE
open-label extension
PVC
polyvinyl chloride
PD
pharmacodynamic(s)
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PRO
patient-reported outcome
PTE
pretreatment event
Q2W
once every 2 weeks
Q4W
once every 4 weeks
Q8W
once every 8 weeks
QOL
quality of life
RAMP
Risk Assessment and Management Program for PML
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous(ly)
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TEAE
treatment-emergent adverse event


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Term
Definition
tmax
time to reach Cmax
TPMT
thiopurine S-methyltransferase 
TNF-α
tumor necrosis factor- alpha
UC
ulcerative colitis
ULN
upper limit of normal
US
United States 
USPI
United States Package Insert
VAS
visual analog scale
WBC
white blood cell
WHODRUG
World Health Organization Drug Dictionary
WPAI
Work Productivity and Activity Impairment
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
3.5
Study Definitions
Term
Definition
Clinical remission by 
complete Mayo score
A complete Mayo score of ≤2 points and no individual subscore >1 point.
Clinical response
A reduction in complete Mayo score of ≥3 points and ≥30% from Baseline (Week 0) (or 
partial Mayo score of ≥2 points and ≥25% from Baseline, if the complete Mayo score was 
not performed at the visit) with an accompanying decrease in rectal bleeding subscore of 
≥1 point or absolute rectal bleeding subscore of ≤1 point.
Corticosteroid-free 
remission
Defined as subjects using oral corticosteroids at Baseline (Week 0) who have discontinued 
oral corticosteroids and are in clinical remission at Week 52.
Disease worsening
An increase in partial Mayo score ≥3 points from the Week 6 value on 2 consecutive visits 
(or an increase to 9 points on 2 consecutive visits if the Week 6 value >6) and a minimum 
partial Mayo score of ≥5 points.
Durable clinical remission Clinical remission at Weeks 6 and 52.
Durable clinical response Clinical response at Weeks 6 and 52.
Mucosal healing
A Mayo endoscopic subscore of ≤1 point.
Treatment failure
Defined as disease worsening, need for rescue medications (as defined in Section 7.3.1), or 
need for surgical intervention for treatment of ulcerative colitis.


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4.0
INTRODUCTION
4.1
Background
4.1.1
Diseases and Current Treatments 
Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder of the 
gastrointestinal (GI) tract that includes 2 entities, namely ulcerative colitis (UC) and Crohn’s 
disease (CD). 
UC is characterized by diffuse, superficial inflammation of the colonic mucosa that begins in the 
rectum and extends proximally to involve any contiguous length of colon. The prevalence of UC is 
approximately 200/100,000 of the United States population and approximately 150/100,000 of the 
population in Western Europe [1-3] and 63.6/100,000 of the population in Japan [4]. A genetic 
contribution to the disease is indicated by the increased incidence of UC (of 30 to 100 times that of 
the general population) among first-degree relatives of patients with UC. The characteristic 
pathology is one of chronic inflammation characterized by large numbers of lymphocytes and 
histiocytes in the diseased mucosa and submucosa with an acute inflammatory infiltrate composed 
of neutrophils variably present.
Clinical manifestations of UC include diarrhea, typically bloody, as well as abdominal pain, fecal 
urgency, and incontinence. Systemic features such as fever, weight loss, malaise, and fatigue are 
indicators of more extensive disease. Extra-intestinal manifestations such as uveitis, arthritis, 
ankylosis spondylitis, or primary sclerosing cholangitis may also be seen in conjunction with IBD. 
The diagnosis of UC is usually made by the clinical presentation and key features of the history, 
physical examination, in combination with laboratory and imaging studies.
Current treatments have been effective for many patients with UC but have numerous limitations 
for patients with moderately to severely active disease. 5-aminosalicylates (5-ASAs) are the 
mainstay of UC pharmacotherapy for induction and maintenance of remission for patients with 
mild to moderate disease, but are less effective in moderate to severe disease. [5,6]. 
Corticosteroids are often required for the 1/3 of patients who fail to respond to 5-ASAs [7,8]. 
While highly effective for induction of remission, corticosteroids are not recommended for 
maintenance of remission and carry significant undesirable side effects, including osteoporosis, 
glucose intolerance, and increased risk of infection. 
Immunomodulatory agents, including 6-mercaptopurine and azathioprine, have a role in 
maintenance of remission in moderately to severely active UC. Their relatively slow onset of 
action precludes their use during flares of disease, and the use of these agents has been reported to 
potentially increase the risk of lymphoma in patients with IBD [9]. Other severe adverse events 
(AEs) associated with use of immunomodulators include cytopenias, hepatitis, and infection.
Intravenous (IV) cyclosporine has a role in the management of severely active UC; however, it is 
impractical in non-hospitalized patients, requires intense monitoring, and may cause irreversible 
nephrotoxicity, all of which limit its use. 


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Monoclonal antibodies (mAbs) directed against tumor necrosis factor-alpha (TNF-α) have been 
approved for the treatment of UC in many countries world-wide, including infliximab (Remicade), 
which is administered by IV infusion, and adalimumab (Humira) and golimumab (Simponi), 
which are administered by subcutaneous (SC) injection [10-12]. These agents have substantially 
improved the care of patients with UC by inducing and maintaining remission and decreasing the 
need for hospitalizations and surgeries, and other complications. Although TNF-α antagonists 
represent an important addition to the UC pharmacologic armamentarium, they are effective in 
only a subset of patients, with roughly 2/3 of patients in controlled trials not in remission at the end 
of the first year of therapy [13,14]. Induction of remission with infliximab occurs in only 31% to 
39% of patients with UC [15] and durable clinical remission (ie, defined as clinical remission at 
Weeks 8, 30, and 54) occurs in only 26% of patients with UC. In addition, controlled studies have 
demonstrated that, after failure of 1 TNF-α antagonist, a patient’s response to a second TNF-α 
antagonist is substantially lower [16]. The TNF-α antagonists are also associated with a number of 
serious safety concerns based on their suppression of systemic immunity, including reactivation of 
tuberculosis (TB); various bacterial, viral, fungal, and opportunistic infections; and malignancies, 
such as hepatosplenic T cell lymphoma [10,11].
Failure of pharmacological therapy leads to colectomy in 9% to 35% of patients with UC within 
5 years. Colectomy is considered to be an important adjunct treatment for refractory UC; however, 
colectomy with ileal pouch anal anastomosis (the standard surgical therapy) has many limitations 
and is associated with its own set of complications, including high stool frequency [17], female 
infertility [18], and a cumulative incidence of pouchitis of 50% at 10 years [19]. The limitations of 
current therapies for UC indicate that there is a significant need for safer and more effective 
therapies.
4.1.2
Vedolizumab
Vedolizumab (also known as MLN0002) is a novel recombinant humanized mAb composed of 
2 light chains of the subclass and 2 immunoglobulin (Ig) G1 heavy chains. Vedolizumab binds 
specifically to the human lymphocyte integrin 47. The α4β7integrin mediates lymphocyte 
trafficking to GI mucosa and gut-associated lymphoid tissue (GALT) through adhesive interaction 
with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed on the 
endothelium of mesenteric lymph nodes and GI mucosa [20-23]. As a result, vedolizumab impairs 
the migration of gut-homing leukocytes into GI mucosa [24] and acts as a gut-selective 
immunomodulator.
Vedolizumab IV (also known as ENTYVIO; KYNTELES; Vedolizumab for Injection, for 
Intravenous Use; Vedolizumab Powder for Concentrate for Solution for Infusion; or MLN0002 
IV) has been granted marketing approval in several regions, including the United States (US) and 
European Union (EU). Vedolizumab IV is approved for the treatment of adult patients with 
moderately to severely active UC and CD, who have failed conventional treatment, such as 
immunomodulators, corticosteroids, or TNF-α antagonists. The approved dosing and 
administration regimen is 300 mg vedolizumab IV infused intravenously at Weeks 0 and 2, then 
once every 8 weeks (Q8W) thereafter, beginning at Week 6.


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Vedolizumab SC (also known as Vedolizumab Injection, for Subcutaneous Use; Vedolizumab 
Solution for Injection in Pre-filled Syringe; or MLN0002 SC) is a new liquid presentation that has 
been developed for SC administration. 
 
 
 
 
 
Therefore, the nonclinical and clinical information from studies with vedolizumab 
IV are considered relevant.
As of 19 May 2015 (data lock point), more than 3600 subjects have received at least 1 dose of 
vedolizumab across all studies in the clinical development program. Phase 3 placebo-controlled 
studies enrolled 2427 subjects with UC or CD, of whom 1434 subjects were administered 300 mg 
of vedolizumab IV for induction followed by once every 4 weeks (Q4W) or Q8W for up to a total 
of 52 weeks and 488 subjects were administered 300 mg vedolizumab for induction only [25-27]. 
As of 19 May 2015, vedolizumab exposure has extended for ≥12 months in 1667 subjects, 
≥24 months in 1306 subjects, ≥36 months in 935 subjects, ≥48 months in 676 subjects, 
≥60 months in 267 subjects, and ≥72 months in 26 subjects. Based on the most recent drug 
shipment data (19 November 2015), the cumulative patient exposure to vedolizumab since its 
marketing approval in May 2014 is estimated to be approximately 25,831 patient-years.
Previously conducted clinical studies have characterized the efficacy, safety, tolerability, 
pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of vedolizumab in healthy 
subjects and subjects with UC or CD. Please refer to the current edition of the Investigator’s 
Brochure (IB) for the most recent data for vedolizumab.
4.1.2.1
Nonclinical
Nonclinical in vitro and in vivo studies have been conducted with vedolizumab and its murine 
homologue, Act-1. Act-1 has demonstrated clinical and histomorphologic evidence of efficacy in 
an animal model of IBD (cotton-top tamarins). Extensive nonclinical evaluations of the 
cardiovascular, acute, local, subchronic, chronic, immunologic, and reproductive toxicity of 
vedolizumab in pharmacologically responsive species (New Zealand white rabbits and 
cynomolgus monkeys) have been conducted and support its clinical development. Nonclinical 
studies also show that vedolizumab does not antagonize #4∃1 integrin [24].
A single-dose local tolerance study was conducted to determine the local irritancy potential of 
vedolizumab SC when administered by SC injection to rabbits. Macroscopic and histological 
examinations of the injection sites indicated no findings of concern with the vehicle or formulated 
vedolizumab SC. 
4.1.2.2
Clinical Experience With Vedolizumab IV
Single- and multiple-dose PK of vedolizumab have been studied in healthy subjects and in subjects 
with moderately to severely active UC or CD and similar PK was observed. Vedolizumab exhibits 
CCI


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target-mediated drug disposition; hence, its elimination is characterized by linear and nonlinear 
processes. Following IV infusion, vedolizumab serum concentrations generally fell in a 
biexponential fashion until approximately 1 to 10 µg/mL, with a linear total body clearance of 
approximately 0.157 L/day and a serum half-life of around 25 days. Thereafter, the serum 
concentrations fell in a nonlinear fashion. The volume of distribution for vedolizumab is 
approximately 5 L.
In subjects with moderately to severely active UC (C13006), vedolizumab IV 300 mg 
administered as an IV infusion at Weeks 0 and 2 (induction) followed by either Q4W or Q8W 
administration from Week 6 through Week 52 (maintenance) induced a statistically-significant 
increase in rates of clinical response at Week 6 and clinical remission at Week 52 (primary 
endpoint for the Induction Phase and Maintenance Phase, respectively) compared with placebo. 
The study also met important secondary endpoints, including durable clinical response, durable 
clinical remission, and mucosal healing at Weeks 6 and 52, and corticosteroid-free clinical 
remission at Week 52 (Table 4.a and Table 4.b). Given the significant morbidity associated with 
chronic corticosteroid treatment, the corticosteroid-sparing effects of vedolizumab provide an 
important benefit to patients with UC.
Table 4.a
Efficacy of Vedolizumab IV in Subjects With UC During the Induction Phase 
(Week 6, C13006)
Endpoint
PBO
N=149
VDZ
N=225
Difference
p-value
Primary endpoint
Clinical response (%)
25.5
47.1
21.7
<0.0001
Secondary endpoints
Clinical remissions (%)
5.4
16.9
11.5
0.0009
Mucosal healing (%)
24.8
40.9
16.1
0.0012
Source: C13006 Clinical Study Report.
PBO=placebo, VDZ=vedolizumab.


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Table 4.b
Efficacy of Vedolizumab IV in Subjects With UC During the Maintenance 
Phase (Week 52, C13006)
Endpoint
PBO/VDZ 
(a)
N=126
VDZ/VDZ
Q8W
N=122
VDZ/VDZ
Q4W
N= 25
Difference
Q8W vs PBO/VDZ
Q4W vs PBO/VDZ
p-value
Primary endpoint
Clinical remission at 52 wks (%)
15.9
41.8
44.8
26.1
29.1
<0.0001
<0.0001
Secondary endpoints
Durable clinical response 
(6 wks and 52 wks) (%)
23.8
56.6
52.0
32.8
28.5
<0.0001
<0.0001
Mucosal healing at 52 wks (%)
19.8
51.6
56.0
32.0
36.3
<0.0001
<0.0001
Durable clinical remission (6 
wks and 52 wks) (%)
8.7
20.5
24.0
11.8
15.3
0.0079
0.0009
Corticosteroid-free remission 
(b) at 52 wks (%)
N=72
13.9
N=70
31.4
N=73
45.2
17.6
31.4
0.0120
<0.0001
Source: C13006 Clinical Study Report
PBO=placebo, VDZ=vedolizumab.
(a) This group includes those subjects who received vedolizumab at Weeks 0 and 2, and were randomized to receive 
placebo from Week 6 through Week 52.
(b) Corticosteroid-free remission was analyzed in subjects on oral corticosteroids at Baseline.
Vedolizumab has shown an acceptable safety profile based on an analysis of safety data from both 
completed and ongoing studies (see current edition of IB). In phase 1 and 2 clinical trials 
(7 completed phase 1 studies in healthy subjects and 8 completed phase 1b/2 studies in UC or CD 
subjects), there was no consistent evidence of any dose-toxicity relationships, and vedolizumab 
was well-tolerated. The majority of the safety data is from 3 well-controlled, phase 3 clinical 
studies that evaluated the safety of vedolizumab IV for up to 12 months in subjects with UC 
(Study C13006 [52 weeks]) or CD (Studies C13007 [52 weeks] and C13011 [10 weeks]). In 
addition, an interim safety assessment is available for an ongoing long-term open-label extension 
(OLE) study (C13008), in which subjects are administered vedolizumab IV Q4W.
In the pivotal phase 3 studies (C13006 and C13007), the most common (≥5% and at a higher 
incidence than placebo) adverse reactions in subjects administered vedolizumab IV were nausea, 
nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, fatigue, headache, and 
cough. Most serious adverse events (SAEs) have been related to exacerbations or complications of 
the underlying UC or CD. For those infections that were reported more frequently in 
vedolizumab-treated subjects, the sites of these infections correlated with the known tissue 
distribution of MAdCAM-1 binding sites. Anal abscess, abdominal abscess, and gastroenteritis 
were the most frequently reported serious infections. Extraintestinal infections (bronchitis, 
pneumonia, urinary tract infection, sepsis) occurred at low frequency (<1%). A total of 4% of 
vedolizumab-treated subjects and 3% of placebo-treated subjects experienced an infusion-related 
reaction. In Studies C13006 and C13007, 10% of subjects were positive for anti-vedolizumab 


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antibodies (AVA) 16 weeks following the last dose of vedolizumab. Results from the clinical 
program to date do not suggest an increased risk for malignancy with vedolizumab treatment. 
Overall, the safety profile following long-term treatment with vedolizumab IV in Study C13008 is 
consistent with safety in the completed studies.
Concomitant use of corticosteroids and/or conventional immunomodulators did not appear to be 
associated with any increased rate of infections based on the comparative rates of infections in the 
phase 3 trials among subjects who had and had not received these medications. 
One death occurred in a vedolizumab-treated subject during Study C13006 and 5 deaths occurred 
during Study C13007, including 1 death in a placebo-treated subject. As of 19 May 2015, a total of 
26 deaths from multiple causes were reported in the vedolizumab clinical development program, 
including the ongoing long-term Study C13008. Twenty-five of the 26 subjects were randomized 
to the vedolizumab treatment group. Of these deaths, 14 occurred within 18 weeks of the last dose 
of study drug in phase 3 clinical studies and 11 occurred more than 18 weeks after the last dose of 
vedolizumab was administered. The causes of death varied and detailed information can be found 
in the current edition of the IB. 
Overall, vedolizumab was well tolerated in clinical studies.
4.1.2.3
Clinical Experience With Vedolizumab SC
The feasibility of administering the vedolizumab IV formulation by alternative dosing routes SC 
or intramuscular (IM) injection was explored in an open-label, single dose, parallel-group 
bioavailability study (C13010) in healthy male subjects. In this study, 42 subjects were enrolled 
and 14 subjects each received a single dose of 180 mg vedolizumab IV as IV infusion (over 
30 minutes), SC injections (2 × 1.5 mL × 60 mg/mL), or IM injections (2 × 1.5 mL × 60 mg/mL). 
Following SC administration, absorption of vedolizumab was gradual, achieving maximum 
concentration at 7 days post-injection (time to reach maximum serum concentration [tmax]). The 
maximum observed serum concentration (Cmax) following SC injection was approximately 1/3 of 
the Cmax following 30 minute IV infusion. There was no difference in the terminal elimination 
profile of the SC cohort compared to the IV cohort, indicating that the elimination of vedolizumab 
is not absorption rate-limited. The absolute bioavailability of vedolizumab was approximately 
75% for SC administration. Vedolizumab was well tolerated when administered at a dose of 
180 mg by SC injection. Five of the 14 subjects (36%) in the IV infusion cohort and 3 of the 
14 subjects (21%) in the SC cohort experienced a drug-related AE (assessed by the investigator). 
Most AEs were mild or moderate in severity. Three of the 14 subjects (21%) in the IV infusion 
cohort and 2 of the 14 subjects (14%) in the SC cohort in this study were AVA positive using the 
originally developed AVA assay that was used in the phase 3 studies with vedolizumab IV. While 
all 3 AVA positive subjects in the IV infusion cohort had neutralizing AVA, no neutralizing AVA 
was observed in the SC cohort.
The bioavailability and PK of vedolizumab following a single SC injection of vedolizumab SC at 
3 dose levels (54, 108, and 160 mg) relative to a single IV infusion of vedolizumab IV 300 mg was 
examined in a phase 1, open-label study (MLN0002SC-101). Forty-eight (24 Japanese and 


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24 non-Japanese) healthy, adult male and female subjects were randomized, A total of 12 subjects 
received a single dose of vedolizumab IV 300 mg and 36 subjects received a single dose of 
vedolizumab SC at 54, 108, or 160 mg (12 subjects per dose group).
The bioavailability following a single SC injection of vedolizumab SC was 75.1%, independent of 
the vedolizumab SC dose evaluated (54, 108, or 160 mg). Vedolizumab reached maximum serum 
concentrations around 1 week after a single SC injection. Vedolizumab was eliminated by both 
linear and nonlinear pathways following SC injection, with more rapid elimination with 
decreasing dose/concentration. Compared with non-Japanese subjects, Japanese subjects generally 
showed similar or slightly higher exposure; however, ethnicity did not have an impact on clearance 
or central volume of distribution based on the population PK analysis, likely due to the fact that 
weight was included as a covariate for various population PK parameters. Simulations further 
confirmed that vedolizumab SC at 108 mg every 2 weeks (Q2W) is expected to provide lower 
trough concentrations at steady state than vedolizumab IV 300 mg Q4W and similar steady-state 
exposures (average serum concentration at steady state [Cav,ss]) to that from the approved 
vedolizumab IV 300 mg Q8W maintenance regimen.
An electrochemiluminescence (ECL) assay has been developed to determine serum titers of AVA. 
This assay has improved drug tolerance as compared to the prior enzyme-linked immunosorbent 
assay (ELISA) method used in the vedolizumab clinical development program and, as a result, is 
more sensitive. Both assays were used in Study MLN0002SC-101; the ECL assay data were used 
in the analysis of PK and safety.
Overall, 75.0% (36/48) of subjects had treatment-emergent adverse events (TEAEs), and the 
percentage of subjects with a TEAE was identical in subjects who received vedolizumab SC 
compared with subjects who received vedolizumab IV. All TEAEs were considered by the 
investigator to be mild or moderate in intensity; no TEAEs of severe intensity were reported. The 
percentage of subjects with mild or moderate TEAEs was similar between subjects who received 
vedolizumab SC and vedolizumab IV; the percentages were also similar across the dose groups. 
No subjects had clinical laboratory test results, vital signs, or electrocardiogram (ECG) results that 
were reported as AEs. Two subjects had elevated bilirubin levels that met the predefined markedly 
abnormal value criteria; however, no subject had abnormal liver function test (LFT) results 
involving aspartate aminotransferase (AST) or alaninine aminotransferase (ALT).
Two AEs of special interest were reported: 1 subject in the vedolizumab SC 108 mg group 
experienced erythema at the injection site on the left thigh, and 1 subject in the vedolizumab SC 
CCI


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160 mg group experienced an injection site reaction. Both events occurred on Day 1, and were 
observed at the 30 minute postdose observation time point (a protocol-defined time point). In each 
case, the event resolved at the 1.5 hour postdose observation time point and was considered by the 
investigator to be mild in intensity and related to study drug. Both subjects recovered without any 
sequelae.
No SAEs, severe AEs, or deaths were reported in Study MLN00002SC-101. The observed AEs are 
consistent with the overall safety profile of vedolizumab.
4.2
Rationale for the Proposed Study
As IV infusion may not be convenient as long-term therapy for some patients, vedolizumab SC has 
been developed to enable injection by patients or their caregivers. 
This phase 3 study is designed to evaluate the efficacy, safety, PK, and immunogenicity of 
multiple injections of the new presentation, vedolizumab SC, as maintenance therapy in subjects 
with UC.
 
 
 Therefore, all nonclinical and 
clinical information from studies with vedolizumab IV is considered relevant. 
The vedolizumab exposure-efficacy relationship has been demonstrated in UC subjects in the 
phase 3 vedolizumab IV study (C13006), where higher serum vedolizumab concentrations were 
associated with higher efficacy (Source: Population PK Efficacy Report 2013). The proposed 
vedolizumab SC maintenance dosing regimen (108 mg Q2W) was selected to provide lower 
steady-state trough concentrations than the vedolizumab IV Q4W dosing regimen and similar 
Cavg steady-state exposures to that from the approved vedolizumab IV Q8W dosing regimen, and 
the safety and efficacy of the vedolizumab SC presentation are expected to be similar to those of 
vedolizumab IV, outside of expected local administration site events, such as injection-site 
reactions.
4.3
Benefit-Risk Assessment
The proposed study (MLN0002SC-3027) is designed to evaluate the efficacy and safety of 
vedolizumab SC as maintenance therapy in subjects with moderately to severely active UC who 
achieved clinical response following open-label vedolizumab IV therapy. Because IV infusion 
may not be convenient as long-term therapy, vedolizumab SC has been developed to ultimately 
enable injection by patients or their caregivers. 
 
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Therefore, the 
nonclinical and clinical information from studies with vedolizumab IV are considered relevant.
The study population in Study MLN0002SC-3027 is consistent with the approved vedolizumab IV 
label. The proposed vedolizumab SC maintenance dosing regimen (108 mg Q2W) was selected to 
provide similar steady-state exposure to that from the approved vedolizumab IV dosing regimen 
(300 mg Q8W). It is expected that similar steady-state exposure to vedolizumab will result in 
similar maintenance efficacy, independent of the dosing route or presentation. In addition, safety 
of the vedolizumab SC presentation is expected to be similar to that of vedolizumab IV due to 
similar exposure, outside of expected local administration site events, such as injection-site 
reactions. Results from a phase 1 study suggest that administration of vedolizumab SC (rather than 
IV) may result in higher immunogenicity; however, the clinical significance of these results is 
unclear, since this was a single-dose study in healthy subjects. The observed AEs with 
vedolizumab SC are consistent with the vedolizumab IV safety profile. 
Overall, vedolizumab has been well tolerated in clinical studies, including a phase 1 study of 
vedolizumab SC, and has a positive benefit-risk profile in the treatment of UC.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective(s)
!
To assess the effect of vedolizumab SC maintenance treatment on clinical remission at 
Week 52 in subjects with moderately to severely active UC who achieved clinical response at 
Week 6 following administration of vedolizumab IV at Weeks 0 and 2.
5.1.2
Secondary Objectives
!
To determine the effect of vedolizumab SC maintenance treatment on mucosal healing at 
Week 52 in subjects who achieved clinical response at Week 6 following administration of 
vedolizumab IV at Weeks 0 and 2.
!
To determine the effect of vedolizumab SC maintenance treatment on durable clinical 
response at Week 52 in subjects who achieved clinical response at Week 6 following 
administration of vedolizumab IV at Weeks 0 and 2.
!
To determine the effect of vedolizumab SC maintenance treatment on durable clinical 
remission at Week 52 in subjects who achieved clinical response at Week 6 following 
administration of vedolizumab IV at Weeks 0 and 2.
!
To determine the effect of vedolizumab SC maintenance treatment on corticosteroid free 
remission at Week 52 in subjects who achieved clinical response at Week 6 following 
administration of vedolizumab IV at Weeks 0 and 2.
5.1.3
Exploratory Objectives 
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5.2
Endpoints
The endpoints pertain to the vedolizumab SC and placebo arms only.
5.2.1
Primary Endpoints
!
Proportion of subjects with clinical remission, defined as a complete Mayo score of ≤2 points 
and no individual subscore >1 point, at Week 52.
5.2.2
Secondary Endpoints
!
Proportion of subjects with mucosal healing, defined as Mayo endoscopic subscore of 
≤1 point, at Week 52.
!
Proportion of subjects with durable clinical response, defined as clinical response at Weeks 6 
and 52, where clinical response is defined as a reduction in complete Mayo score of ≥3 points 
and ≥30% from Baseline (Week 0) with an accompanying decrease in rectal bleeding subscore 
of ≥1 point or absolute rectal bleeding subscore of ≤1 point.
!
Proportion of subjects with durable clinical remission, defined as clinical remission at Weeks 6 
and 52.
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!
Proportion of subjects with corticosteroid-free remission, defined as subjects using oral 
corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in 
clinical remission at Week 52.
5.2.3
Patient Reported Outcome (PRO) Endpoints
!
Changes in IBDQ total score and subscores, from Baseline (Week 0) to Week 52 and from 
Week 6 to Week 52.
!
Changes in EQ-5D utility scores and EQ-5D VAS score from Baseline (Week 0) to Week 52 
and Week 6 to Week 52.
!
Changes in WPAI-UC instrument endpoints (% work time missed, % impairment while 
working, % overall work impairment, % activity impairment) from baseline (week 0) to 
Week 52 and Week 6 to Week 52.
5.2.4
Exploratory Endpoints
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a pivotal, phase 3, multicenter, multinational, randomized, double-blind, double-dummy, 
placebo-controlled trial, including a vedolizumab IV reference arm, designed to evaluate the 
efficacy and safety of maintenance treatment with vedolizumab SC in adult subjects with 
moderately to severely active UC who achieved a clinical response at Week 6 with open-label 
therapy with 300 mg vedolizumab IV at Weeks 0 and 2. The study includes a vedolizumab IV 
reference arm to allow for within study descriptive comparisons on efficacy, safety, and 
immunogenicity between the two vedolizumab presentations.
Moderately to severely active UC is defined as a complete Mayo score of 6 to 12 points with 
endoscopic subscore of ≥2. Subjects that are either TNF-α antagonist naïve or with TNF-α 
antagonist failure will be included, ensuring that approximately 50% of subjects with TNF-α 
antagonist failure are enrolled. Subjects with previous use of TNF-α antagonist but not failed will 
NOT be enrolled.
The study includes a 4-week (28-day) Screening Period, a 6-week open-label vedolizumab IV 
Induction Phase, and a 46-week randomized, double-blind, double-dummy, placebo-controlled 
Maintenance Phase with vedolizumab SC or vedolizumab IV with a final visit at Week 52. All 
endoscopic assessments (ie, for disease severity at baseline and for clinical endpoints at the end of 
the Induction and Maintenance Phases) will be performed via central reading.
Eligible subjects, will be enrolled into the Induction Phase at Week 0, will receive open-label 
infusions of vedolizumab IV 300 mg at Weeks 0 and 2, and will be assessed for clinical response 
by full Mayo score (endoscopy score determined by central reading) at Week 6, as follows:

Subjects who achieve a clinical response at Week 6 will be randomized into the Maintenance 
Phase. Upon completion of the Week 52 assessment or upon early discontinuation due to 
treatment failure (ie, disease worsening or need for rescue medications) these subjects will be 
eligible to enter the OLE study. 

Subjects who do not achieve a clinical response at Week 6 will not be randomized in to the 
Maintenance Phase, and instead will receive a third infusion of vedolizumab IV 300 mg at 
Week 6. Subjects who achieve a clinical response at Week 14 (by partial Mayo score) will be 
eligible to enroll in the OLE study, while subjects who do not achieve clinical response will be 
discontinued. 
Subjects with clinical response at Week 6 will be randomized at a 2:1:1 ratio in the double-blind, 
double-dummy Maintenance Phase, where each treatment arm will receive both SC injections 
Q2W and IV infusions Q8W, beginning at Week 6 through Week 50, as follows:

Injections of vedolizumab SC 108 mg Q2W and placebo IV infusions every 8 weeks (Q8W) 
(N=94).

Infusions of vedolizumab IV 300 mg Q8W and placebo SC injections Q2W (N=47).


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
Placebo SC injections Q2W and placebo IV infusions Q8W (N=47).
Randomization will be stratified by:

Concomitant use of oral corticosteroids.

Clinical remission status at Week 6.

Previous TNF-α antagonists failure or concomitant immunomodulator (azathioprine or 
6-mercaptopurine) use.
At Week 6, subjects receiving oral corticosteroids who achieved a clinical response and are 
randomized into the Maintenance Phase will begin a corticosteroid tapering regimen.
After receiving training from the health care provider (HCP; investigator or designee) on the 
proper SC injection technique and how to manage hypersensitivity reactions potentially associated 
with the injection, subjects or their caregivers will inject vedolizumab SC/placebo SC under the 
supervision of the HCP during at least the Week 6 and 8 clinic visits, to ensure proper injection 
technique prior to home dosing and to allow for direct observation by the HCP of any potential 
hypersensitivity or injection-site reactions associated with SC injection. Subjects and caregivers 
may attend the clinic at Weeks 10 and 12 if further training is required. Subjects or their caregivers 
will also administer SC injections during the scheduled clinic visits at Weeks 14, 22, 30, 38, 46, 
and 50 under the supervision of the HCP to allow continued observation of injection technique and 
AEs; while all other scheduled SC injections should occur outside of the clinic. All IV infusions 
will be administered by a HCP during clinic visits at Weeks 6, 14, 22, 30, 38, and 46. HCPs will 
have appropriate monitoring and treatment for hypersensitivity reactions available for use 
following administration of study drug. Subjects who experience a severe hypersensitivity 
reaction associated with study drug administration will be discontinued from the study (see 
Section 7.4). 
Subjects and their caregivers will be instructed to inject SC doses into the thigh, abdomen, or upper 
arm, and to rotate the injection sites. Subjects and their caregivers will be instructed that the upper 
arm is to be used only when the caregiver administers the SC injection. Details on the training 
protocol and injection technique will be included in the appropriate Study Manual. For all SC 
dosing occurring outside of the clinic, subjects will receive a phone call from their HCP within 
24 hours prior to every injection to administer the PML subjective checklist and enquire about 
general health status and experience with prior injections. In accordance with the Risk Assessment 
and Management Plan for PML (RAMP), any positive PML subjective finding must be evaluated 
via the physician administered PML objective checklist prior to the subject receiving the 
respective dose (refer to RAMP Site Staff Brochure). Subjects will also receive a phone call from 
their HCP within 12 hours after the home injection at Weeks 10 and 12 to enquire about health
status and experience with injection unless they attended the clinic on these days. AEs reported by 
the subject will be handled in accordance with Section 10.0 of the protocol.
Subjects who do not participate in the OLE trial or are discontinued, will complete the 
End-of-Study Visits or Early Termination visit and then complete the Final Safety Visit 18 weeks 


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(ie, 5 vedolizumab half-lives) after the last dose of study drug. For subjects that are not in response 
at Week 14, early termination procedures will be performed at the Week 14 visit.
Additionally, subjects who do not participate in the OLE trial will be required to participate in a 
long-term follow-up (LTFU) safety-survey by telephone, 6 months after the last dose of study 
drug.
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 
WEEK 6 RESPONDERS
Screening
Period
Induction 
Phase
Maintenance 
Phase
Follow-up 
Period
Additional
Follow-up
LTFU Safety 
Survey by 
Telephone (b)
(6 months 
after the last dose 
of study drug)
Responder at Wk 6:
Vedolizumab SC 
108 mg Q2W and 
placebo IV Q8W
or
Vedolizumab IV 
300 mg Q8W and 
placebo SC Q2W
or
Placebo SC Q2W 
and placebo IV Q8W
Final Safety 
Visit (b) 
(18 weeks after 
the last dose of 
study drug)
OL 
Vedolizumab IV 
300 mg
End-of-Study 
(a)/
Early 
Termination 
procedures
R
Extension Study 
MLN0002SC-
3030 (c)
Days
Wk
Wk Wk
Wk
Wk
Wk
-28 to -1
0
6
7
51
52
68
Visit: 1
2
5
6
14
15
16
WEEK 6 NONRESPONDERS
Follow-up 
Period
Additional
Follow-up
Responder at 
Wk 14
Extension Study 
MLN0002SC-
3030 (c)
Nonresponder at Wk 6:
Vedolizumab IV 300 mg
Discontinued
Final Safety Visit 
(b) 
(18 weeks after the 
last dose of study 
drug)
LTFU Safety 
Survey by 
Telephone (b)
(6 months 
after the last dose 
of study drug)
Nonresponder at 
Wk 14:
Early Termination 
procedures
Days
Wk
Wk
Wk
-28 to -1
0
6
14
Visit: 1
2
5
OL=open-label, R=randomization.
(a) Subjects who consent to participate in the extension study (MLN0002-3030) may begin extension study dosing after 
End-of-Study Visit procedures have been completed at the Week 52 Visit.
(b) Subjects who do not enter the extension study (MLN0002SC-3030) (including early terminators and Week 14 nonresponders) 
will complete the Final Safety Visit 18 weeks after their last dose of study drug and participate in a Follow-up Safety Survey by 
Telephone 6 months after the last dose of study drug. 
(c) Visit 1 of Extension Study MLN0002SC-3030 is within 1 week of completing Week 52 (Visit 15) procedures. Subjects not
randomized into the Maintenance Phase (Week 6 Nonresponders) and respond at Week 14 on vedolizumab IV 300 mg are also 
eligible for entry into the Extension Study.


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6.2
Justification for Study Design, Dose, and Endpoints
This phase 3 study is designed to evaluate the efficacy, safety, PK, and immunogenicity of 
multiple injections of the new presentation, vedolizumab SC, as maintenance therapy in subjects 
with UC. The proposed vedolizumab SC maintenance dosing regimen (108 mg Q2W) was 
selected to provide similar steady-state exposures to that from the approved vedolizumab IV 
dosing regimen (300 mg Q8W), and the safety and efficacy of the vedolizumab SC presentation is 
expected to be similar to that of vedolizumab IV, outside of expected local administration site 
events, such as injection-site reactions. 
The study design allows for independent assessments of vedolizumab SC efficacy as maintenance 
therapy in subjects who responded to vedolizumab IV by comparing the active vedolizumab SC 
therapy group to the placebo group during the Maintenance Phase. It also permits double-blind, 
placebo-controlled comparisons of safety parameters during the Maintenance Phase. Additional 
measures will be taken to collect safety parameters beyond the 52-week duration of the trial, where 
subjects who do not enroll in OLE will have a Final Safety Visit conducted 18 weeks after the 
subject’s last dose of study drug, and additional safety information will be collected by telephone 
using a LTFU survey at 6 months after the last study dose (for both SC and IV dosing).
Consistent with the currently approved vedolizumab IV label, subjects who do not achieve a 
clinical response at Week 6 and are not randomized into the Maintenance Phase will receive an 
additional vedolizumab IV infusion at Week 6 and will be eligible to participate in the OLE study 
if clinical response is achieved at Week 14.
The entry criteria ensure that subjects who are appropriate for treatment with biologic agents, as 
assessed by severity of disease and failure of one or more standard therapies (ie, corticosteroids, 
immunomodulators, or TNF-α antagonists), will be enrolled into the study. Entry criteria will also 
exclude subjects who might not benefit from drug or who might be at risk for treatment toxicities. 
Additional measures to ensure the safety of enrolled subjects include protocol-mandated criteria 
for withdrawal from the study of subjects who experience worsening of disease or require rescue 
medication (ie, any new medication or any increase in dose of a baseline medication required to 
treat new or unresolved UC symptoms, other than antidiarrheals for control of chronic diarrhea). 
Thus, subjects who may be treated with placebo (inactive treatment) between Weeks 6 and 52 will 
be withdrawn from the study if they experience treatment failure (ie, disease worsening, need for 
rescue medications), but may be eligible to enroll in the OLE study.
At Week 6, subjects receiving oral corticosteroids who achieve clinical response must begin a 
corticosteroid tapering regimen as described in Section 7.3.1.1. Subjects are allowed to continue 
background therapy such as 5-ASAs or immunomodulators, as indicated in the Permitted 
Medications and Treatments in Section 7.3.1.
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The primary efficacy endpoint of this study is clinical remission at Week 52 in subjects who 
receive vedolizumab SC maintenance therapy compared to placebo SC therapy. This primary 
efficacy endpoint is generally accepted as the standard indicator of disease activity in UC subjects. 
Exposure-efficacy analyses were conducted using either observed or population model predicted 
vedolizumab concentrations from the phase 3 vedolizumab IV studies. There was an apparent 
exposure-efficacy relationship in subjects with UC for both the Induction and Maintenance 
Phases, where higher vedolizumab concentrations were associated with higher efficacy. Based on 
the exposure-efficacy relationship for vedolizumab IV, the vedolizumab SC dosing regimen was 
selected to provide lower trough concentrations than vedolizumab IV Q4W and similar exposure 
to that from the approved vedolizumab IV Q8W regimen during the Maintenance Phase. It is 
expected that similar exposure to vedolizumab will result in similar efficacy and safety during 
maintenance, independent of the dosing route or formulation.
In addition to efficacy and safety evaluations, the multiple dose PK and immunogenicity of 
vedolizumab SC in subjects during the Maintenance Phase will be evaluated in this study. Given 
the long half-life of vedolizumab (approximately 25 days), blood samples will be collected up to 
18 weeks (>5 half-lives) after the last dose of study drug to assess the PK of vedolizumab.
During the Maintenance Phase of this study, vedolizumab SC or placebo SC injections will be 
administered by the subjects or their caregivers both at clinic visits (Weeks 6, 8, 14, 22, 30, 38, 46 
and 50 under HCP supervision) and outside of the clinic, while vedolizumab IV and placebo IV 
infusions will be administered by HCP only during clinic visits (Weeks 6, 14, 22, 30, 38, and 46). 
HCPs will train the subjects (and their caregivers) on the adequate technique to prepare and inject 
study drug during at least at the Week 6 and 8 office visits, and will also provide instructions on 
adequate storage of vedolizumab SC, disposal of used prefilled syringe, hypersensitivity reaction 
management, and contact information for any questions on vedolizumab SC use. Details on the 
training protocol and injection technique will be included in the appropriate Study Manual. 
Pharmacogenomic analysis may be conducted to evaluate the contribution of genetic variance on 
drug response, eg, its efficacy and safety. Participation of study subjects in pharmacogenomic 
sample collection is optional (Section 9.1.16). As pharmacogenomics is an evolving science, 
currently many genes and their function are not yet fully understood. Future data may suggest a 
role of some of these genes in drug response and disease, which may lead to additional 
hypothesis-generating exploratory research on stored samples.
If future analysis is required, the sponsor will create a research protocol for pharmacogenomics 
investigations and the research protocol will require prior approval by an institutional review 
board (IRB) prior to implementation (Japan only).
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6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

The Data Monitoring Committee recommends the study should be suspended or terminated. 

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an IRB/independent ethics committee (IEC) or regulatory authority 
elects to terminate or suspend the study or the participation of an investigational site, a 
study-specific procedure for early termination or suspension will be provided by the sponsor; the 
procedure will be followed by applicable investigational sites during the course of termination or 
study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to first dose. 
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures.
3. The subject has a diagnosis of UC established at least 6 months prior to screening, by clinical 
and endoscopic evidence and corroborated by a histopathology report.
4. The subject is male or female and aged 18 to 80 years, inclusive.
5. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use adequate contraception* from signing of informed consent throughout 
the duration of the study and for 18 weeks after last dose. 
6. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 18 weeks after last dose. 
*Definitions and acceptable methods of contraception are defined in Section 9.1.10
Contraception and Pregnancy Avoidance Procedure and reporting responsibilities are 
defined in Section 9.1.12 Pregnancy.
7. The subject has moderately to severely active UC as determined by a complete Mayo score of 
6-12 (with an endoscopic subscore ≥2) within 10 days prior to the first dose of study drug. The 
endoscopy can be performed during the Screening Period (Day -10 to Day -5 to allow for 
central reading prior to first dose at Week 0).
8. The subject has evidence of UC extending proximal to the rectum (≥15 cm of involved colon).
9. Subjects with extensive colitis or pancolitis of >8 years duration or left-sided colitis >12 years 
duration must have documented evidence that a surveillance colonoscopy was performed 
within 12 months of the initial Screening Visit (if not performed in previous 12 months, must 
be performed during Screening).
10. Subjects with a family history of colorectal cancer, personal history of increased colorectal 
cancer risk, age >50 years, or other known risk factors must be up-to-date on colorectal cancer 
surveillance (may be performed during screening).


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11. The subject has demonstrated an inadequate response to, loss of response to, or intolerance of 
at least 1 of the following agents as defined below:

Immunomodulators:
i.
The subject has signs and symptoms of persistently active disease despite a history of at 
least one 12-week regimen of oral azathioprine (≥1.5 mg/kg) or 6-mercaptopurine 
(≥0.75 mg/kg) (US, EU), or, at least one 8-week regimen of oral azathioprine (≥50 mg) 
or 6-mercaptopurine (≥30 mg) (Japan only), OR
ii. The subject has a history of intolerance of at least one immunomodulator (including but 
not limited to nausea/vomiting, abdominal pain, pancreatitis, liver function test 
abnormalities, lymphopenia, thiopurine S-methyltransferase [TPMT] genetic mutation, 
infection).

TNF-α antagonists: 
i.
The subject has signs and symptoms of persistently active disease despite a history of at 
least one induction with:

Infliximab: At least 4-week regimen of 5 mg/kg, 2 doses at 2 weeks apart, OR

Adalimumab: At least 160 mg on Day 1 and 80 mg on Day 15, OR

Golimumab: At least 200 mg at Week 0, and 100 mg at Week 2, OR
ii. The subject has recurrence of symptoms during scheduled maintenance dosing 
following prior clinical benefit (discontinuation despite clinical benefit does not 
qualify) OR
iii. The subject has a history of intolerance of at least 1 TNF-α antagonist (including, but 
not limited to infusion-related reaction, demyelination, congestive heart failure, 
infection).

Corticosteroids:
i.
The subject has signs and symptoms of persistently active disease despite a history of at 
least one 4-week induction regimen that included a dose equivalent to prednisone 
≥30 mg daily orally for 2 weeks or intravenously for 1 week, OR
ii. The subject has had 2 failed attempts to taper corticosteroids to below a dose equivalent 
to prednisone 10 mg daily orally on 2 separate occasions. In Japan, at least one failed 
attempt to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily 
orally or intravenously, OR
iii. The subject has a history of intolerance to corticosteroids (including, but not limited to, 
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and 
infection), OR
iv. The subject had a relapse within 3 months of stopping steroids.


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7.2
Exclusion Criteria
The exclusion criteria are divided into 3 categories: gastrointestinal, infectious disease, and 
general. Any subject who meets any of the following criteria will not qualify for entry into the 
study: 
7.2.1
Gastrointestinal Exclusion Criteria
1. The subject has evidence of abdominal abscess or toxic megacolon at the initial Screening 
Visit.
2. The subject has had extensive colonic resection, subtotal or total colectomy.
3. The subject has had ileostomy, colostomy, or known fixed symptomatic stenosis of the 
intestine.
4. The subject has received any of the investigational or approved non-biologic therapies 
(eg, cyclosporine, tacrolimus, thalidomide, methotrexate or tofacitinib except for those 
specifically listed in the protocol Section 7.3.1 Permitted Medications for the Treatment of 
UC) for the treatment of underlying disease within 30 days or 5 half-lives of screening 
(whichever is longer).
5. The subject has received any investigational or approved biologic or biosimilar agent within 
60 days or 5 half-lives of screening (whichever is longer). 
6. The subject currently requires or is anticipated to require surgical intervention for UC during 
the study.
7. The subject has a history or evidence of adenomatous colonic polyps that have not been 
removed, or has a history or evidence of colonic mucosal dysplasia.
8. The subject has a suspected or confirmed diagnosis of Crohn’s enterocolitis, indeterminate 
colitis, ischaemic colitis, radiation colitis, diverticular disease associated with colitis, or 
microscopic colitis.
7.2.2
Infectious Disease Exclusion Criteria
9. The subject has evidence of an active infection during the Screening Period.
10. The subject has evidence of, or treatment for, C. difficile infection or other intestinal pathogen 
with 28 days prior to first dose of study drug. 
11. The subject has chronic hepatitis B virus (HBV) infection* or chronic hepatitis C virus (HCV) 
infection.
* HBV immune subjects (ie, being hepatitis B surface antigen [HBsAg] negative and hepatitis 
B antibody positive) may, however, be included.
12. The subject has active or latent TB as evidenced by the following:


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i.
A positive diagnostic TB test within 30 days prior to screening or during the Screening 
Period, defined as:
1. A positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests, 
(or, A positive T-SPOT TB test [Japan only]), OR,
2. A tuberculin skin test reaction ≥5 mm.
Note: if subjects have received BCG vaccine then a QuantiFERON TB Gold test 
should be performed instead of the tuberculin skin test.
OR
ii.
Chest X-ray within 3 months prior to Week 0 which is suspicious for pulmonary TB, 
and a positive or 2 successive indeterminate QuantiFERON tests (or, A positive 
T-SPOT TB test [Japan only]) within 30 days prior to Screening or during the 
Screening Period.
Note: subjects with documented previously treated TB with a negative QuantiFERON 
test can be included in the study.
13. The subject has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
14. The subject has received any live vaccinations within 30 days prior to screening.
15. The subject has a clinically significant infection (eg, pneumonia, pyelonephritis) within 30 
days prior to screening, or ongoing chronic infection.
16. The subject has used a topical (rectal) treatment with 5-aminosalicylic acid (5-ASA) or 
corticosteroid enemas/suppositories within 2 weeks of the administration of the first dose of 
study drug.
7.2.3
General Exclusion Criteria
17. The subject has had previous exposure to approved or investigational anti-integrins 
(eg, natalizumab, efalizumab, etrolizumab, AMG 181), anti-MAdCAM-1 antibodies, or 
rituximab.
18. The subject has had prior exposure to vedolizumab.
19. The subject has had hypersensitivity or allergies to any of the vedolizumab excipients.
20. The subject has any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, 
genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other 
medical disorder that, in the opinion of the investigator, would confound the study results or 
compromise subject safety.
21. The subject has had any surgical procedure requiring general anesthesia within 30 days prior to 
screening or is planning to undergo major surgery during the study period.
22. The subject has any history of malignancy, except for the following: (a) adequately treated 
nonmetastatic basal cell skin cancer; (b) squamous cell skin cancer that has been adequately 


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treated and that has not recurred for at least 1 year prior to screening; and (c) history of cervical 
carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years 
prior to screening. Subjects with remote history of malignancy (eg, >10 years since completion 
of curative therapy without recurrence) will be considered based on the nature of the 
malignancy and the therapy received and must be discussed with the sponsor on a case-by-case 
basis prior to screening.
23. The subject has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, demyelinating or neurodegenerative disease.
24. The subject has a positive PML subjective symptom checklist at Screening (or prior to the 
administration of study drug at Week 0).
25. The subject has any of the following laboratory abnormalities during the Screening Period:
i.
Hemoglobin level <8 g/dL.
ii. White blood cell (WBC) count <3 × 109/L.
iii. Lymphocyte count <0.5 × 109/L.
iv. Platelet count <100 × 109/L or >1200 × 109/L.
v. ALT or AST >3 × the upper limit of normal (ULN).
vi. Alkaline phosphatase >3 × ULN.
vii. Serum creatinine >2 × ULN.
26. Removed in Amendment 03. 
27. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 1 year prior to screening. 
28. The subject has an active psychiatric problem that, in the investigator’s opinion, may interfere 
with compliance with study procedures.
29. The subject or caregiver is unable to attend all the study visits or comply with study 
procedures.
30. The subject is required to take excluded medications listed in Section 7.3.
31. The subject is unwilling or unable to self inject, or does not have a caregiver (defined as a legal 
adult) to inject the study medication.
32. Female subjects who are lactating or have a positive serum pregnancy test during the 
Screening Period or a positive urine pregnancy test at Week 0, prior to study drug 
administration.
33. If female, the subject is intending to become pregnant before, during, or within 18 weeks after 
participating in this study; or intending to donate ova during such time period. 


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34. If male, the subject intends to donate sperm during the course of this study or for 18 weeks 
thereafter. 
35. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress. 
7.3
Excluded Medications and Treatments
The following medications are excluded from use during the study: 

Any treatment for UC other than those listed in Section 7.3.1 (either approved or 
investigational).

All live vaccines from 30 days prior to screening to at least 6 months after the last dose of study 
drug. 

Either approved or investigational biological agents for the treatment of non-IBD conditions, 
other than localized injections (eg, intraocular injections for wet macular degeneration). 

Chronic nonsteroidal anti-inflammatory drug (NSAID) use. (Note: occasional use of NSAIDs 
and acetaminophen for headache, arthritis, myalgias, menstrual cramps, etc. and daily use of 
baby or low-dose [81-162.5 mg] aspirin for cardiovascular prophylaxis are permitted.) 

Leukocytapheresis (LCAP; white blood apheresis) or granulocytapheresis (GCAP) (Japan 
only).

Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
7.3.1
Permitted Medications and Treatments 

The subject may be receiving a therapeutic dose of the following drugs: 
–
Oral 5-ASAs compounds provided that the dose has been stable for the 2 weeks 
immediately prior to first dose of study drug. The dose for these medications should remain 
stable throughout the study.
–
Oral corticosteroid therapy (prednisone at a stable dose ≤30 mg/day, budesonide at a stable 
dose ≤9 mg/day, or equivalent steroid) provided that the dose has been stable for the 
4 weeks immediately prior to first dose of study drug if corticosteroids have just been 
initiated, or for the 2 weeks immediately prior to first dose of study drug if corticosteroids 
are being tapered. Corticosteroid doses should remain stable until the subject meets the 
criteria for initiating a corticosteroid tapering regimen (see Section 7.3.1.1).
–
Probiotics (eg, Culturelle, Saccharomyces boulardii) provided that the dose has been stable 
for the 2 weeks immediately prior to first dose of study drug. The dose for these 
medications should remain stable throughout the study.


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–
Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic 
diarrhea; stable doses are encouraged.
–
Azathioprine or 6-mercaptopurine, provided that the dose has been stable for the 8 weeks 
immediately prior to first dose of study drug. Dose(s) should remain stable, unless the 
medication is discontinued due to a toxicity related to the medication. Even if the toxicity 
resolves, azathioprine or 6-mercaptopurine will not be re-started.

For immunosuppressives, oral 5-ASAs, probiotics and antibiotics for UC, dose reduction or 
discontinuation per label will be allowed only due to adverse reactions. For oral corticosteroid, 
as per the tapering schedule (see Section 7.3.1.1).

Need for Rescue Medications: In this study, any new medication or any increase in dose of a 
baseline medication required to treat new or unresolved UC symptoms (other than 
antidiarrheals for control of chronic diarrhea) is considered a rescue medication. An increase in 
corticosteroid dose back to baseline for subjects undergoing corticosteroid tapering within the 
guidelines presented in Section 7.3.1.1 is not considered rescue medication. Administration of 
rescue medications, approved or investigational, constitutes treatment failure. Rescue 
medications should not be withheld if, in the opinion of the investigator, failure to prescribe 
them would compromise subject safety.
7.3.1.1
Oral Corticosteroid Dosing and Tapering 

At Week 6, subjects receiving oral corticosteroids who achieved clinical response will begin a
corticosteroid tapering regimen. The tapering schedule is as follows: 
–
For prednisone at doses >10 mg/day (or equivalent), the dose should be reduced at a rate of 
5 mg/week until a 10 mg/day dose is reached. 
–
For prednisone at doses ≤10 mg/day (or equivalent) or once a 10 mg/day dose (or 
equivalent) is achieved by tapering, the dose should be reduced at a rate of 2.5 mg/week 
until discontinuation.
For subjects who cannot tolerate the corticosteroid taper without recurrence of clinical symptoms, 
corticosteroids may be increased up to the original dose at the start of induction therapy (should 
not exceed baseline dose). In such cases, the tapering regimen above must be reinitiated within 
2 weeks. Subjects who consistently cannot be tapered should be withdrawn from the study 
according to Section 7.4.
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence, such premedication 
is unlikely to be necessary or beneficial. At the discretion of the investigator, however, subjects 
may be administered premedication prior to any study drug administration. Corticosteroids, if 
given as a premedication, should be limited to the day of administration. 


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7.4
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the electronic case report form (eCRF) using the following 
categories. For screen failure subjects, refer to Section 9.1.22.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.

LFT Abnormalities.
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.9), if the following circumstances occur at any time 
during study medication treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
2. Significant protocol deviation. The discovery after the first dose of study medication that the 
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Three attempts to contact the subject must be documented (ie, 2 attempts 
by phone and 1 attempt by registered letter).
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE or lack of efficacy should not be recorded in the “voluntary withdrawal” category). 
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.11.


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7. Lack of efficacy. The subject should be discontinued from the study if the following criteria 
apply:

Week 14 discontinuation in subjects not randomized to the Maintenance Phase, due to not 
achieving a clinical response at Week 6 who also did not achieve a clinical response at 
Week 14 after having received a third vedolizumab IV infusions at Week 6.

Treatment failure during the Maintenance Phase, defined as disease worsening (as defined 
in Section 3.5), need for rescue medications (as defined in Section 7.3.1), or need for 
surgical intervention for treatment of UC.

Leukopenia or Lymphopenia: WBC and lymphocyte counts will be monitored for all subjects. 
Azathioprine, or 6-mercaptopurine, if applicable, should be discontinued and the dose of study 
drug held for an absolute lymphocyte count <0.5 × 109/L at any point in the study. The absolute 
lymphocyte count must be repeated at appropriate intervals as determined by the investigator. 
The next dose of study drug can be administered only if the absolute lymphocyte count is ≥0.5 
× 109/L. If the absolute lymphocyte count remains <0.5 × 109/L, study drug should be 
discontinued and the subject withdrawn from the study.
8. Other: 
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
Subjects who discontinue due to lack of efficacy are permitted to enroll in the OLE study 
(MLN0002SC-3030) according to the criteria in Table 7.a.
Table 7.a
Eligibility for Study MLN0002SC-3030 Based on Reason for Withdrawal 
Reason for Withdrawal
Time Point
Prior to Week 6
Weeks 6-14
Beyond Week 14
Disease worsening (a)
Not applicable
Eligible
Eligible
Requires rescue medication, but does not meet 
criteria for disease worsening
Not applicable
Not Eligible
Eligible
AE related to study drug leading to discontinuation 
of study drug
Not eligible
Not eligible
Not eligible
Requires surgical intervention for UC
Not eligible
Not eligible
Not eligible
(a) See Section 3.5 for study definitions.
7.5
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.4. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the ET 
Visit, Final Safety Visit, and the LTFU survey. Discontinued or withdrawn subjects will not be 
replaced.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to all or any of the drugs defined below. 
8.1.1.1
Vedolizumab for Injection, for Intravenous Use (Vedolizumab IV)
The study sites will be supplied by the sponsor with the following medication in an open-label 
manner: vedolizumab IV 300 mg/vial, for single use, in 20 mL vials. The study medication will be 
provided in a glass vial as a lyophilized solid formulation for reconstitution using sterile water for 
injection. Each vial will be packaged in an appropriately labeled single vial carton. 
Each carton will have a single-panel or multilingual booklet label that will contain, but will not be 
limited to the following: sponsor’s name and address, protocol number, packaging job/lot number, 
name and strength of the product, medication identification number, subject information, caution 
statement, directions for use, and storage conditions.
The intravenous placebo will be 250 mL (100 mL in Japan) of 0.9% sodium chloride IV (for use 
only during double-blind, double-dummy, Maintenance Phase).
Additional reference information and administration instructions can be found in the Pharmacy 
Manual. 
8.1.1.2
Vedolizumab Injection, for Subcutaneous Use (Vedolizumab SC)
The study sites will be supplied with the following medication in a blinded manner: vedolizumab 
SC 
 or placebo in a pre-filled syringe. The study medication is a liquid 
presentation provided in pre-filled syringe with backstop and plunger rod assembled together. 
Each syringe will be packaged in folding box or carton.
The subcutaneous placebo is a liquid solution supplied at 
 in pre-filled syringes for SC 
injection with similar formulation composition as the vedolizumab SC solution, and administered 
via SC injection.
Each carton will have a single-panel or multilingual booklet label that will contain, but will not be 
limited to the following: sponsor’s name and address, protocol number, packaging job/lot number, 
name and strength of the product, medication identification number, subject information, caution 
statement, directions for use, and storage conditions.
CCI
CCI


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8.1.1.3
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following:

Vedolizumab for Injection, for Intravenous Use (vedolizumab IV).

Vedolizumab Injection, for Subcutaneous Use (vedolizumab SC)/vedolizumab SC placebo.
8.1.1.4
Other Protocol-Specified Materials
The following supplies will also be required for study drug administration and are to be provided 
by the clinical study center unless otherwise indicated:

Bottled sterile water for injection (for study drug reconstitution).

250 mL 0.9% sodium chloride for injection in polyvinyl chloride (PVC) IV bag(s) or 250 mL 
0.9% sodium chloride in alternative IV bags or bottles listed in the Pharmacy Manual. (100 mL 
in Japan).

PVC infusion line or alternative infusion line listed in the Pharmacy Manual.

Alcohol swabs.

Needle sharps container (provided by sponsor).
8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug must be stored under the 
conditions specified on the label, and remain in the original container until dispensed.
Vedolizumab IV and vedolizumab SC must be stored at 2ºC to 8ºC (36ºF to 46ºF). A daily 
temperature log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
The dose and dosing regimen for all subjects is provided in Table 8.a.


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Table 8.a
Dose and Dosing Regimen
Treatment Group
Dose
Treatment Description
All Subjects 
Vedolizumab IV 300 mg 
Open-label
Weeks 0 and 2
A (Week 6 Non-Responders)
Vedolizumab IV 300 mg 
Open-label
Week 6
B
Vedolizumab SC 108 mg
Blinded
Weeks 6-50 (Q2W)
Vedolizumab IV Placebo
Blinded
Weeks 6-46 (Q8W)
C
Vedolizumab IV 300 mg
Blinded
Weeks 6-46 (Q8W)
Vedolizumab SC Placebo
Blinded
Weeks 6-50 (Q2W)
D
Vedolizumab IV Placebo
Blinded
Weeks 6-46 (Q8W)
Vedolizumab SC Placebo
Blinded
Weeks 6-50 (Q2W)
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to the 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, Adverse Events, and Product Complaints.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically. 
8.2
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned to receive treatment according to the schedule allocated to each study 
site.
The investigator or investigator’s designee will access the interactive web response system 
(IWRS) at Screening to register a subject and obtain a subject identification number to identify the 
subject throughout the study. The investigator or the investigator’s designee will utilize the IWRS 
to enroll the subject into the study. The medication identification (ID) number of the 
investigational drug to be dispensed will then be provided by the IWRS as well as at subsequent 
visits. If sponsor-supplied drug is lost or damaged, the site can request a replacement from IWRS. 
Refer to the appropriate study manual provided separately for additional information. 
For IV infusion, subjects will receive a 300 mg dose of vedolizumab IV infusion over 
approximately 30 minutes. Longer infusion times of up to 60 minutes may be used based on study 
observations. Vedolizumab IV should be administered by a HCP prepared to manage 


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hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and 
medical support measures should be available for immediate use. Subjects should be observed for 
2 hours following the first 2 infusions, at a minimum, and one hour after each subsequent infusion
in a room where appropriate treatment for infusion-related reactions is available. The subject 
should be considered clinically stable by the investigator or designee prior to discharge.
For SC injection, the recommended sites are the abdomen (except for the 2-inch area around the 
navel), the outer area of the upper arms, or the front of the thighs. The upper arm injection site 
should be used only by caregivers administering the injection. The injection site should be changed 
for consecutive injections. Each new injection should be given at least 1 inch from a site used 
before.
During clinic visits, SC injections should be administered by the subject (or caregiver) under the 
supervision of a HCP prepared to manage hypersensitivity reactions including anaphylaxis, if they 
occur. Appropriate monitoring and medical support measures should be available for immediate 
use. Subjects should be observed during the SC administration and for one hour following 
completion of the administration.
Study medication storage, disposal and directions for use for the subject self-injections will be 
described in information provided to the subject.
For further investigational drug and dispensing information, please refer to the pharmacy and/or 
the appropriate study manual.
8.3
Randomization Code Creation and Storage
After receiving open-label infusions of vedolizumab IV 300 mg at Weeks 0 and 2, subjects will be 
assessed for clinical response (as determined by a central reader) at Week 6. 
Subjects with clinical response at Week 6 will be randomized at a 2:1:1 ratio to receive the 
following, beginning at Week 6 through Week 50:

Injections of active vedolizumab SC 108 mg Q2W and placebo IV infusions Q8W (N=94).

Infusions of active vedolizumab IV 300 mg Q8W and placebo SC injections Q2W (N=47).

Placebo SC injections Q2W and placebo IV infusions Q8W (N=47).
Randomization will be stratified by:

Concomitant use of oral corticosteroids.

Clinical remission status at Week 6.

Previous TNF-α antagonists failure or concomitant immunomodulator (azathioprine, 
6-mercaptopurine) use.
Randomization personnel of the sponsor or designee will generate the randomization schedule 
prior to the start of the study. An IWRS system will be used for subject randomization. All 


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randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.4
Investigational Drug Blind Maintenance and Unblinding
The investigational drug blind will be maintained using the IWRS. In addition, in order to maintain 
the blind, all study site personnel except the investigational pharmacist or pharmacy designee will 
be blinded to the treatment assignments for the duration of the study.
The investigational drug blind may be broken by the investigator if information concerning the 
investigational drug is essential for the medical treatment of the subject. The medical monitor must 
be informed of the unblinding at the earliest possible opportunity. In nonurgent cases, the medical 
monitor must be contacted before the subject is unblinded.
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the IWRS. The sponsor must be notified as soon as possible if the investigational drug 
blind is broken. The date, time, and reason the blind is broken must be recorded in the source 
documents and eCRF as appropriate.
8.5
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The blinded investigator or blinded designee and delegated unblinded pharmacy staff, must ensure 
that the sponsor-supplied drug is used in accordance with the protocol and is dispensed only to 
subjects enrolled in the study. To document appropriate use of sponsor-supplied drug, 
[vedolizumab IV vials and vedolizumab SC/placebo SC pre-filled syringes], the appropriate 
blinded or unblinded person must maintain respective records of all sponsor-supplied drug 
delivery to the site, site inventory, dispensation, and use, by each subject, and return to the sponsor 
or designee.
Records of the subject number, the date study drug was dispensed, and the study drug/cohort 
assignment will be maintained by the unblinded pharmacist.
Upon receipt of sponsor-supplied drug, the appropriate unblinded pharmacist must verify the 
contents of the shipments against the packing list. The verifier should ensure that the quantity is 
correct, and the medication is in good condition. If quantity and conditions are acceptable, they 
should acknowledge the receipt of the shipment (by signing the bottom half of the packing list and 
faxing per instructions provided on the form/ or by recording in IWRS). If there are any 
discrepancies between the packing list and the actual product received, Takeda must be contacted 
to resolve the issue. The packing list should be filed in the investigator’s essential document file 
(unblinded pharmacy file).


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The unblinded pharmacist must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed. Proper drug accountability includes, but is not limited to:

Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the (drug lot/medication ID/job number) used to prepare 
each dose.

Verifying that all containers used/assigned are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The unblinded pharmacist must record the current inventory of all sponsor-supplied drugs on a 
sponsor-approved drug accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, description 
of sponsor-supplied drugs, date and amount dispensed including initials, date and amount returned 
to the site by the subject, and the initials, seal, or signature of the person dispensing the drug. The 
log should include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
All study drug that was not returned to the site by a subject must be investigated by the site and 
appropriately documented in the subject’s medical records and on the drug accountability log.
Prior to site closure or at appropriate intervals, an unblinded representative from the sponsor or its 
designee will perform sponsor-supplied drug accountability and reconciliation before 
sponsor-supplied drugs are returned to the sponsor or its designee for destruction. The designated 
unblinded pharmacist will retain a copy of the documentation regarding sponsor-supplied drug 
accountability, return, and/or destruction, and originals will be sent to the sponsor or designee.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned by IWRS to each subject 
at the time of screening; this subject number will be used throughout the study.
9.1.1.1
Pharmacogenomic Informed Consent Procedure
A separate informed consent form pertaining to the storage of samples must be obtained prior to 
collecting blood samples and tissue samples for pharmacogenomic research for this study. The 
provision of consent to collect and analyze the pharmacogenomic samples is optional and 
independent of consent to the other aspects of the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include age or date of birth (depending on local 
regulations), sex, Hispanic ethnicity (as applicable, US only), race as described by the subject and 
smoking status of the subject at screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.8).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 30 days prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of investigational 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; 
(7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; (11) other. All 
subsequent physical examinations should assess clinically significant changes from the assessment 
prior to first dose examination.


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9.1.4
Weight and Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters without decimal places and for 
weight it is kilograms (kg) with 1 decimal place. 
9.1.5
Vital Sign Procedure
Vital signs will include body temperature, respiratory rate, blood pressure (sitting), and pulse 
(bpm).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before the scheduled blood draw. 
On dosing days, vital signs are taken predose. 
9.1.6
Primary Efficacy Measurement 
Primary and secondary efficacy assessments during the Maintenance Phase will be based on Mayo 
scores. A complete Mayo score will be obtained within 10 days prior to enrollment, using subject 
diary entries within the 10 days prior to enrollment and flexible sigmoidoscopy results obtained 
during the Screening Period; this assessment will be the baseline complete Mayo score for disease 
activity assessment. Sigmoidoscopy will be done at Week 6 and Week 52 (or ET Visit), and a 
complete Mayo score will be calculated for these visits for endpoints assessment. All endoscopies 
(Week 0, 6, and 52) will be centrally read. Additional information regarding the sigmoidoscopy 
requirements and central reader assessments can be found in the appropriate Study Manual.
The baseline complete Mayo score will be used for the comparison with the Week 6 complete 
Mayo score to determine response and remission at Week 6 and with the Week 52 complete Mayo 
score to determine response and remission at Week 52.
The Week 0, 6, and 52 complete Mayo score will be calculated by the investigator or designee and 
recorded in the subject’s source documents, with the endoscopic component subscore being 
provided by the central reader. The Week 6 assessment will determine whether the subject 
achieved clinical response at Week 6, and therefore, determine eligibility for randomization in to 
the Maintenance Phase. 
A partial Mayo score will be derived at the visits at which endoscopy will not performed. 
Refer to Appendix F for information on the Mayo scoring system.
9.1.6.1
Diary Completion and Review
Diary entries will be made daily by subjects from screening to end of study, and will be used for 
Mayo score calculation. At screening, subjects will be instructed on how to appropriately complete 
the daily diary. The symptoms of UC must be recorded throughout the study, including the 
Screening Period. Diary entries will be made daily by the subject through a validated electronic 


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system. In addition to the subject reported Mayo subscore components, subjects will use the 
validated electronic system to enter daily absolute stool frequency.
Because the flexible sigmoidoscopy preparation can interfere with the assessment of other clinical
parameters, diary entries used to calculate the complete Mayo score should not be taken from the 
day before (the preparation day), the day of, and the day after the flexible sigmoidoscopy is 
performed.
Entries should be reviewed and monitored by the study staff (see the appropriate Study Manual). 
9.1.7
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. Medications used 
specifically for premedication purposes will be collected separately in the eCRF.
9.1.8
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at screening or baseline examination. The condition (ie, 
diagnosis) should be described.
9.1.9
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures at the time 
points specified in the schedule of events. The maximum volume of blood at any single visit is 
approximately 22 mL, and the approximate total volume of blood for the study is 230 mL. Details 
of these procedures and required safety monitoring will be given in the laboratory manual.
Clinical laboratory tests to be performed in this study are summarized in Table 9.a. Refer to the 
Schedule of Events in Appendix A for timing of all assessments. See Laboratory Manual for 
testing regimen.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis 
RBC
WBC w/differential 
Hemoglobin
Hematocrit
Platelets
PT/INR
ALT
Albumin
Alkaline phosphatase
Amylase
Lipase
AST
Total and direct bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Calcium
Chloride
Bicarbonate
Magnesium
Phosphorus 
Uric Acid 
Glucose 
Bilirubin
Blood 
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein 
Specific Gravity 
Microscopic (to be 
obtained in the event of 
positive leukocyte esterase 
or blood, will include 
WBCs, RBCs, and cast[s])
Other:
HIV
Hepatitis panel, including HBsAg, HBsAb, and 
anti-HCV
Fecal Calprotectin
AVA
Pharmacogenomic sample 
Quantiferon for TB
PK
Beta hCG and Urine Pregnancy hCG
(female subjects of childbearing potential)
FSH (a)
C. difficile
FSH=follicle-stimulating hormone, GGT=γ-Glutamyl transferase, hCG=human chorionic gonadotropin, 
PT=prothrombin time, RBC=red blood cells.
(a) FSH level will be obtained for female subjects at Screening if they are postmenopausal by history (ie, last regular 
menstrual cycle >1 years) and not surgically sterile. The FSH result must be >40 IU/L for the subject to be permitted 
not to use adequate contraception.
Central laboratories will perform laboratory tests for hematology, serum chemistries, and 
urinalysis as well as specialty testing outlined above. The results of safety laboratory tests will be 
returned to the investigator, who is responsible for reviewing and filing these results. Refer to the 
schedule of events for timing of all assessments.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests should be performed 
within a maximum of 7 days and preferably within 48-72 hours after the abnormality was noted.
(Please refer to Section 7.4 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in 
conjunction with total bilirubin >2 ×ULN.)


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If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements).
9.1.10 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study medication, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period.
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with an FSH >40 IU/L or at least 5 years since last 
regular menses, confirmed before any study medication is implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are included, the only 
acceptable methods of contraception will be:
Barrier methods (each time the 
subject has intercourse):
Intrauterine devices 
(IUDs):
Hormonal contraceptives:

Male condom PLUS spermicide.

Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide.

Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide.

Copper T PLUS condom 
or spermicide.

Progesterone T PLUS 
condom or spermicide.

Implants.

Hormone shot/injection.

Combined pill.

Minipill.

Patch.

Vaginal ring PLUS male 
condom and spermicide.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 


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understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study.
During the course of the study, subjects will receive continued guidance with respect to the 
avoidance of pregnancy as part of the study procedures (Appendix A). 
All female subjects of child bearing potential will have a serum pregnancy test during screening 
and at Week 52 (or ET Visit) and Week 68 (or Final Safety Visit). A urine pregnancy test will be 
completed for all females of child bearing potential on a monthly basis prior to administration of 
study drug.
9.1.11 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued and returned to the study site. In 
addition, any pregnancies in the partner of a male subject during the study or for 18 weeks after the 
last dose, should also be recorded following authorization from the subject’s partner.
If the pregnancy occurs during administration of active study medication or within 18 weeks of the 
last dose of active study medication, the pregnancy should be reported immediately, using a 
pregnancy notification form, to the contact listed in Section 1.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator.
Subjects randomized to placebo need not be followed.
If the female subject, or female partner of a male subject, agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject was 
participating in a clinical study at the time the subject/female partner of the subject became 
pregnant and provide details of treatment the subject received.
All pregnancies from subjects on active study drug will be followed up to final outcome, using the 
pregnancy form. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted.
9.1.12 ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant.
Any findings from ECGs collected after study drug administration at Week 0 will be captured as 
AEs if, in the opinion of the investigator, there has been a clinically significant change from 
baseline.


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Subjects will be supine and will have rested for 5 or more minutes before any ECG is recorded. 
Tracings will include subject number and initials and the date and time of recording and all other 
subject identifiers will be removed or obscured.
9.1.13
Histological Sample Collection
At each endoscopy (Week 0, 6, and 52/ET) tissue biopsies will be performed and tissue specimens 
be harvested and stored for future histological analyses.
All tissue specimens will be reviewed by independent central review. Additional information 
regarding the central reader assessments and collection and preparation of tissue samples can be 
found in the appropriate Study Manual.
9.1.14
Immunogenicity Sample Collection 
Blood specimens for the assessment of AVA will be collected as shown in the schedule of events 
(Appendix A). A sample will be assessed for neutralizing AVA if AVA is detected. 
Serum titers of AVA will be determined using a validated assay. Neutralizing AVA will be 
determined using a validated assay. 
Please refer to the appropriate Study Manual for information on sample collection and preparation.
9.1.15
Pharmacokinetic Sample Collection
Blood specimens for the determination of the serum concentration of vedolizumab will be 
collected predose (within 30 minutes of dosing) and/or as shown in the schedule of events. Serum 
concentrations of vedolizumab will be determined using a validated sandwich ELISA. All samples 
will be analyzed regardless of the treatment groups.
9.1.16
Pharmacogenomic Sample Collection
When sampling of whole blood or mucosal tissue for pharmacogenomic analysis occurs, every 
subject must sign an additional informed consent/be consented in order to participate in the study.
Two whole blood samples (3 mL per sample) for deoxyribonucleic acid (DNA) isolation will be 
collected before dosing on Day 1 from each subject in the study. If DNA samples are not obtained 
on Day 1, they may be collected at any point in the study.
Two whole blood ribonucleic acid (RNA) samples (2.5 mL per sample) will be collected into 
PAXgeneTM tubes before dosing on Day 1.
If separately consented to by the subject, a small piece of tissue from the colonic tissue sample 
harvested for histological analysis (during the Screening, and Week 6, and 52 endoscopy) will be 
saved and stored for possible exploratory investigation to look for changes in mRNA expression 
patterns associated with disease or response to therapy.

Information regarding the collection and preparation of tissue samples for pharmacogenomic 
analysis can be found in the appropriate Study Manual. DNA forms the basis for the genes that 


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make the body produce proteins such as enzymes, drug transporters or drug targets. RNA has 
multiple vital roles in the coding, decoding, regulation, expression of genes, and sensing and
communicating responses to cellular signals. Both DNA and RNA samples may be evaluated 
for the genetic and expressional contribution how the drug is broken down, or how the drug 
affects the body. This is called a “Pharmacogenomics research study.” 
Specific purposes of this study include:

Identifying genetic reasons why certain people respond differently to vedolizumab.

Finding out more information about how vedolizumab works.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to vedolizumab.

Identifying variations in genes related to the biological target of vedolizumab.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of vedolizumab and other study medications, and for improving the efficiency, design and 
study methods of future research studies.
If necessary and feasible, a second aliquot of blood may be taken if isolation of DNA from the first 
sample was not successful or possible. Please refer to the appropriate Study Manual for 
information on sample collection and preparation.
The samples will be stored for no longer than 15 years after completion of the study. No samples 
will be stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification from Takeda. “Stored samples” are defined as samples that are key-coded (the 
samples are stripped of all personal identifying information but a key links the samples to the 
clinical data collected from the sample donor) and are used in the analysis of investigational drug 
or related drugs.
Future analysis of the stored pharmacogenomics (PGx) samples may be conducted as appropriate. 
Detailed instructions for the handling and shipping of samples are provided in the appropriate
Study Manual.
9.1.17 Tuberculosis Screening 
All subjects will complete TB screening to determine eligibility. Subjects will be excluded from 
the study if they have active or latent TB, regardless of treatment history, as defined in 
Section 7.2.2. 
9.1.18 Fecal Calprotectin Sample Collection
A stool sample will be collected for the analysis of fecal calprotectin, a biomarker of intestinal 
inflammatory activity, as shown in the Schedule of Events (Appendix A).


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9.1.19 Stool Sample
A stool sample will be obtained for culture, ova and parasite evaluation, and C. difficile assay. A 
sample will be collected and cultured during screening and at any point in the study when a subject 
becomes symptomatic, including worsening or return of disease activity.
9.1.20 PML Checklist 
9.1.21 Patient-Reported Outcomes Instruments 
Subjects will complete the IBDQ and EQ-5D health related quality of life (HRQOL) 
questionnaires at the time points specified in the schedule of events. Subjects will also complete 
the WPAI-UC to assess the impact on loss of work productivity and activity impairment.
9.1.21.1 Inflammatory Bowel Disease Questionnaire
The IBDQ is a valid and reliable [30] instrument used to assess health-related quality of life 
(HRQOL) 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.
9.1.21.2 EQ-5D Questionnaire
The EQ-5D questionnaire, developed by the ‘EuroQol Research Foundation’ is a simple, valid, 
and reliable [31] instrument used to measure general HRQOL in subjects and includes five domain 
items - mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Subjects 
choose the level of health problems they currently have on each item as “None”, “Moderate”, or 
“Extreme” and are scored a 1, 2, or 3, respectively. A composite EQ-5D score can be calculated 
from the individual scores to assess overall HRQOL. The EQ-5D visual analog score (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 
CCI


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shown in many studies to be valid and reliable instruments for measuring HRQOL in patients with 
GI diseases.
9.1.21.3 Work Productivity and Activity Impairment-UC
The WPAI questionnaire is a valid and reliable [32] 6-item instrument that consists of four metrics: 
absenteeism (the percentage of work time missed because of one’s health in the past seven days), 
presenteeism (the percentage of impairment experienced while at work in the past seven days 
because of one’s health), overall work productivity loss (an overall impairment estimate that is a 
combination of absenteeism and presenteeism), and activity impairment (the percentage of 
impairment in daily activities because of one’s health in the past seven days). The sum of specific 
health problem impairment and impairment due to other health reasons is equal to impairment due 
to all health reasons. WPAI outcomes are expressed as impairment percentages, with higher 
numbers indicating greater impairment and less productivity, ie, worse outcomes. WPAI-UC is the 
specific disease version of the questionnaire.
9.1.22 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible during screening, the investigator should contact the IWRS 
as a notification of screen failure and complete the Screen Failure eCRF. 
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria. 

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal <specify reason>.

Study termination.

Other <specify reason>.
Subject numbers assigned to subjects who fail screening should not be reused. Re-screening of 
subjects will be assessed by the Medical Monitor on a case by case basis.
9.1.23 Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria at Week 0 are 
eligible for enrolment into the Induction Phase.
At Week 6 subjects will be assessed for eligibility for randomization into the Maintenance Phase. 
If the subject is found to be not eligible for the study, the Investigator should record the primary 
reason for failure on the applicable eCRF.


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9.2
Monitoring Subject Treatment Compliance
If a subject is persistently noncompliant with the study medication, it may be appropriate to 
withdraw the subject from the study. All subjects should be reinstructed about the dosing 
requirement during study contacts. The authorized study personnel conducting the re-education 
must document the process in the subject source records.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening 
Subjects will be screened within 28 days prior to enrollment. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.22 for procedures for documenting screening failures.
Procedures to be completed at screening can be found in the schedule of events (Appendix A). 
9.3.2
Enrollment/Randomization 
Enrollment will take place at Week 0. If the subject has satisfied all of the inclusion criteria and 
none of the exclusion criteria, the subject should be enrolled using the IWRS. Subjects will be 
instructed on when the first dose of investigational drug will be given as described in Section 6.1. 
The procedure for documenting screening failures is provided in Section 9.1.22.
Eligible subjects will receive open-label infusions of vedolizumab IV 300 mg at Weeks 0 and 2, 
and will be assessed for clinical response (endoscopy score determined by a central reader) at 
Week 6. Subjects with clinical response at Week 6 will be randomized at a 2:1:1 ratio to receive 
beginning at Week 6 through Week 50:

Injections of active vedolizumab SC 108 mg Q2W and placebo IV infusions Q8W (N=94).

Infusions of active vedolizumab IV 300 mg Q8W and placebo SC injections Q2W (N=47).

Placebo SC injections Q2W and placebo IV infusions Q8W (N=47).
Randomization will be stratified by:

Concomitant use of oral corticosteroids.

Remission status at Week 6.

Previous TNF-α antagonists failure or concomitant immunomodulator (azathioprine, 
6-mercaptopurine) use.


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9.3.2.1
Non-responders
Subjects who are non-responders at Week 6 and hence are not randomized into the Maintenance 
Phase of the study will receive a third vedolizumab IV infusion at Week 6. Subjects who achieve a 
clinical response (by partial Mayo score) at Week 14 are eligible to enroll in the OLE study, while 
subjects who do not respond at Week 14 will be discontinued.
9.3.3
Final Visit or Early Termination
The Final Visit will be performed on Week 52 or at ET for all subjects.
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
Subjects who complete the study will be offered entry into the OLE study after completion of the 
Week 52 assessment.
Subjects who are withdrawn from the study due to disease worsening (Section 3.5) will be offered 
entry into the OLE study. 
From Week 14 onwards, subjects who are withdrawn from the study due to need for rescue 
medications, despite not meeting the criteria for disease worsening, will be offered entry into the 
OLE study. Need for rescue medications are defined in Section 7.3.1.
Subjects who are discontinued from the study due to study drug related AEs or to requiring 
surgical intervention for their UC will not be eligible to enroll into the OLE study. 
9.3.4
Final Safety Follow-up Visit
For those subjects not entering the OLE study or are discontinued, a Final Safety Follow-up Visit 
will be performed 18 weeks after the last dose of study drug. Assessments will be completed per 
the schedule of events Week 68 Visit. For subjects that are not in response at Week 14, ET 
procedures will be performed at the Week 14 visit.
9.3.5
Post Study 6-Month Long-Term Follow-Up Survey
Upon completion of or early termination from the study, all subjects not entering the OLE study 
will be required to participate by telephone in a 6 month LTFU safety questionnaire (from the last 
dose received).
9.3.6
Unscheduled Visits Due to Disease Exacerbation 
Subjects who are seen by the investigator or site staff at a time point not required by the protocol 
(ie, unscheduled visit) due to disease exacerbation will undergo the following: 

Physical examination. 

Vital signs assessment. 

Diary review. 


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
Collection of concomitant medications and procedures.

Collection of AEs and SAEs.

Clinical chemistry and hematology, as indicated.

Partial or complete Mayo score.

Flexible sigmoidoscopy, if indicated.

PK sample collection.

AVA sample collection.

C. difficile, if indicated.
There is no minimum time for repeat evaluation by unscheduled visit in order to determine if a 
subject meets the criteria for disease worsening. In general, however, enough time should be 
provided for clinically meaningful change to occur. 
9.4
Biological Sample Retention and Destruction
In this study, whole blood and mucosal tissue specimens for pharmacology and histology analysis 
will be collected as described. The samples will be sent to a central laboratory that processes the 
samples and serves as a secure storage facility. The sponsor and researchers working with the 
sponsor will have access to the samples collected and any test results. All samples collected during 
the study will be stored securely with limited access and the sponsor will require anyone who 
works with the samples to agree to hold the research information and any results in confidence.
Samples will be stored for no longer than 15 years after completion of the study. No samples will 
be stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification from Takeda. 
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided pharmacogenomic samples can withdraw their consent and 
request disposal of a stored sample (blood and/or tissue) at any time. The sponsor will be notified 
of consent withdrawal.


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10.0
PRETREATMENT EVENTS (PTE), ADVERSE EVENTS (AE) AND PRODUCT 
COMPLAINTS (PC)
10.1
Definitions
10.1.1 PTEs
A Pre-Treatment Event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
In addition, drug-device AEs related to quality or malfunction will be collected.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).


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Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).


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Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.


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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).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Special Interest AEs
A Special Interest Adverse Event (serious or nonserious) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by 
the investigator to Takeda may be appropriate. Such events may require further investigation in 
order to characterize and understand them and would be described in protocols and instructions 
provided for investigators as to how and when they should be reported to Takeda. Refer to 
Section 10.2.1.4 for information for special interest AE reporting. 
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.


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10.1.7 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related. 
10.1.9 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.10
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.11
Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.12
Action Concerning Study Medication 

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE eg, 
the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE.

Dose Interrupted – the dose was interrupted due to the particular AE.


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10.1.13
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death. 

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.1.14
Product Complaints
A product complaint (PC) is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product and/or device 
(eg, prefilled syringe).
An investigator who is made aware of or identifies a potential PC should immediately report the 
event to Takeda in accordance with the contact list provided to the site. Whenever possible, the 
associated product should be maintained in accordance with the instructions pending further 
guidance from a Takeda representative. Refer to the appropriate study manual provided separately 
for additional information (depending on local regulations).
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period

Start of AE collection: AEs must be collected from start of study medication administration. 

End of AE collection: AEs must be collected for 18 weeks following the last dose of study 
medication. 

Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication or 


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until screen failure. For subjects who discontinue prior to study medication administration, 
PTEs are collected until the subject discontinues study participation.

Collection of AEs will commence from the time that the subject is first administered study 
medication (enrollment). Routine collection of AEs will continue until 18 weeks after last 
dose.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date (and time, if deemed directly related to the study drug administration).
3. Severity.
4. Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related) (not completed for PTEs).
5. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
6. Action concerning study medication (not applicable for PTEs).
7. Outcome of event.
8. Seriousness.
Several patient-reported outcomes measures will be used in this study (eg, IBDQ, EQ5D, 
WPAI-UC). They will not be used as a primary means to collect AEs. However, should the 
investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up, if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied.


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10.2.1.3 Adverse Event Collection Involving Medically Anticipated Clinical Events 
UC is associated with certain characteristic signs and symptoms, including diarrhea and rectal 
bleeding, that may be present at baseline and persist or fluctuate based on the individual subject’s 
disease history during the course of the study. These signs and symptoms will not be collected as 
AEs. These characteristics of disease activity will be regularly captured in the Mayo score. 
Exacerbations of disease activity (eg, increase in the daily amount of rectal bleeding beyond the 
subject’s normal fluctuation, new signs and symptoms of UC) will be collected as AEs and 
reported according to regulatory reporting requirements. 
Extra-intestinal manifestations of the subject’s disease (eg, arthralgia, arthritis, uveitis) that 
develop or worsen during the study are considered AEs. 
10.2.1.4 Special Interest AE Reporting
If this special interest AE, which occurs during the treatment period or the follow-up period, is 
considered to be clinically significant based on the criteria below, it should be recorded in a special 
interest AE eCRF or SAE Form. The applicable form should be completed and reported to the 
SAE reporting contact in Section 1.1 within 24 hours.
Hypersensitivity Reactions (Including Injection Site Reactions)
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence such 
premedications are unlikely to be necessary or beneficial. At the discretion of the investigator, 
however, subjects may be administered premedication prior to any study drug administration. 
Corticosteroids, if given as a premedication, should be limited to the day of administration. 
Vedolizumab IV should be administered by a HCP prepared to manage hypersensitivity reactions 
including anaphylaxis, if they occur. Appropriate monitoring and medical support measure should 
be available for immediate use. Subjects should be observed for 2 hours following the first 
2 infusions, at a minimum, and one hour after each subsequent infusion.
During clinic visits, subjects should be observed during the SC administration and for one hour 
following completion of the administration. Vedolizumab SC should be administered by the 
subject or caregiver in the presence of a HCP prepared to manage hypersensitivity reactions 
including anaphylaxis, if they occur. Appropriate monitoring and medical support measures 
should be available for immediate use. 
Subjects and caregivers will be instructed to report the development of rash, hives, pruritus, 
flushing, urticaria, injections site pain, redness and/or swelling, etc. that may represent an 
administration-related reaction (ie, injection-site reaction or infusion-related reaction) to study 
medication. Subjects will be asked to report administration-related AEs to the sites immediately as 
they are experienced or after having received appropriate medical care. Appropriate treatment and 
follow-up will be determined by the investigator. If signs or symptoms of an 
administration-related reaction are observed during the administration of study medication, it 
should be immediately discontinued and the subject treated as medically appropriate. In the case of 


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a mild reaction, study drug administration may be reinitiated (with appropriate premedication and 
investigator supervision) at the discretion of the investigator. Subjects with a severe or serious 
administration-related reaction (eg, shortness of breath, wheezing, stridor, angioedema, 
life-threatening change in vital signs, severe injection site reactions) must be withdrawn from the 
study (see appropriate Study Manual). 
In all cases of administration-related reaction, the medical monitor must be informed as soon as 
practical. The disposition of subjects with less severe administration-related reactions should be 
discussed with the medical monitor. 
Serious Infections 
Subjects will be monitored for signs and symptoms of infection and for lymphopenia during the 
study. Subjects with signs and symptoms suggestive of infections, including GI infections, will be 
treated as clinically indicated. Interventions may include antibiotic treatment, if appropriate and/or 
discontinuation of concomitant immunomodulators. Blood, sputum, urine, and/or stool cultures 
should be obtained as appropriate for the detection and diagnosis of infection. Withholding or 
terminating study drug administration may be considered as described in Section 7.4.
Malignancy 
All cases of malignancies that are detected during the study will be reported as AEs. Local medical 
practices for the management of malignances will apply. Subjects with history of malignancy 
(except for specific cancers) or at high risk for malignancy will be excluded from the study per the 
exclusion criteria. 
Other 
Other special interest AEs include liver injury and PML, which are discussed in Sections 10.2.3
and 11.2.1 respectively.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE eCRF or Form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.


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The SAE eCRF should be completed within 24 hours of first onset or notification of the event. 
However, as a back-up, if required, the SAE Form should be completed and reported to Takeda 
Pharmacovigilance or designee within 24 hours to the attention of the contact listed in Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
*Note: For Japanese sites, the investigator should report the detailed paper SAE report provided by 
sponsor or by the institution without delay after notification of initial information. Additional 
detailed follow-up data surrounding the serious adverse event that becomes available following 
the initial report should be communicated through the same channels as outlined above.
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.9 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE Form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (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 


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submitted to the regulatory authorities as expedited report within 7 days for fatal and 
life-threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial. The investigational site also will forward a 
copy of all expedited reports to his or her IRB or IEC in accordance with national regulations.


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11.0
STUDY-SPECIFIC COMMITTEES
11.1
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) independent from the sponsor will be established to 
review unblinded safety data from this study on a regular basis and to make appropriate 
recommendations regarding the safe conduct of the study. 
A detailed charter will outline the activities and scope of the DSMB (eg, type of data reviewed, 
frequency of meetings and location of meetings). 
11.2
Adjudication Committee 
A PML Independent Adjudication Committee (IAC) will be implemented for this study. The PML 
IAC will consist of a panel of leading PML experts, including a neurologist, neuroradiologist, and 
a virologist. 
11.2.1 CCI
CCI


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CCI


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12.0
DATA HANDLING AND RECORD KEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary.
12.1
Electronic CRFs
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRFs. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
1. The following procedure is applied for the countries except for Japan.
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 


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International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
2. The following procedure is applied for Japanese site only.
The investigator and the head of the institution agree to keep the records stipulated in Section 12.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as thermal 
sensitive paper, source worksheets, all original signed and dated informed consent forms, subject 
authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Any source documentation printed on degradable thermal sensitive paper should be 
photocopied by the site and filed with the original in the subject’s chart to ensure long term 
legibility. Furthermore, International Conference on Harmonisation (ICH) E6 Section 4.9.5 
requires the investigator and the head of the institution to retain essential documents specified in 
ICH E6 (Section 8) until at least 2 years after the last approval of a marketing application for a 
specified drug indication being investigated or, if an application is not approved, until at least 
2 years after the investigation is discontinued and regulatory authorities are notified. In addition, 
ICH E6 Section 4.9.5 states that the study records should be retained until an amount of time 
specified by applicable regulatory requirements or for a time specified in the Clinical Study Site 
Agreement between the investigator and/or the head of the institution and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock and 
unblinding of subjects’ treatment assignments. This document will provide further details 
regarding the definition of analysis variables and analysis methodology to address all study 
objectives.
A blinded data review meeting will be conducted prior to unblinding of subjects’ treatment 
assignment and database lock. This review will assess the accuracy and completeness of the study 
database, subject evaluability, and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
The Full Analysis Set (FAS) will include all randomized subjects who receive at least 1 dose of 
study drug. Subjects in this set will be analyzed according to the treatment they were randomized 
to receive.
The per-protocol (PP) population is a subset of the intent-to-treat population. The PP population 
consists of all subjects who do not violate the terms of the protocol in a way that would impact the 
study output significantly. All decisions to exclude subjects for the per-protocol population dataset 
will be made prior to the unblinding of the study. Analyses using the per-protocol population may 
be provided as a sensitivity analysis.
The Safety Analysis Set will include all subjects who receive at least 1 dose of study drug. Subjects 
in this set will be analyzed according to the treatment they actually received.
The PK evaluable population is defined as all subjects who receive at least 1 dose of study drug 
and have sufficient blood sampling to allow for PK evaluation.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Baseline and demographic information will be listed and summarized by treatment group and 
overall. For continuous variables, the summary will consist of descriptive statistics (number of 
subjects, mean, standard deviation, minimum, median, and maximum). For categorical variables, 
the summary will consist of number and percentage of subjects in each category.
Medical history and concurrent medical conditions will be summarized by system organ class and 
preferred term. Medication history and concomitant medications will be summarized by preferred 
term.
13.1.3 Efficacy Analysis
All statistical testing will be performed at 2-sided 0.05 level of significance. To control the overall 
Type I error rate for the comparison between vedolizumab SC and placebo groups for the primary 
and secondary endpoints, a hierarchical approach will be applied to the statistical testing of the 
secondary endpoints. The statistical inference for the first secondary endpoint of mucosal healing 


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will only be performed if the primary endpoint, proportion of subjects with clinical remission at 
Week 52, is statistically significant. The second secondary endpoint of durable clinical response 
will only be tested if the first secondary endpoint is statistically significant. Similarly, the third 
secondary endpoint of durable clinical remission will only be tested if the second secondary 
endpoint is statistically significant, and the fourth secondary endpoint of corticosteroids-free 
clinical remission will only be tested if the third secondary endpoint is statistically significant. 
Multiplicity will not be adjusted across additional endpoints.
The descriptive statistics of treatment effects and corresponding 95% CIs for the IV arm versus 
placebo for the primary and secondary efficacy endpoints will be presented.
The comparison between vedolizumab IV and placebo groups will be considered exploratory and 
hence will not be included in the multiplicity control procedure described above. All dichotomous 
efficacy endpoints will be analyzed using Cochran-Mantel-Haenszel tests for risk differences, 
stratified by randomization stratum. The descriptive statistics of treatment effects and 
corresponding 95% CIs for the IV arm versus placebo for the primary and secondary efficacy 
endpoints will be presented. All subjects with missing data for determination of endpoint status 
will be considered as a non-responder in the analysis. 
13.1.4 Resource Utilization and Patient Reported Outcomes (PRO)
All statistical testing will be performed at 2-sided 0.05 level of significance. To control the overall 
Type I error rate for the comparison between vedolizumab SC and placebo groups, a hierarchy 
approach will be applied to the PRO endpoints if the primary endpoint is significant. 
The order of testing of PRO endpoints in Section 5.2.3 will be finalized in SAP before database 
lock. 
Changes from Baseline to Week 52 in IBDQ, EQ-5D scores and WPAI-UC components will be 
analyzed in an Analysis of Covariance model with treatment as a factor and baseline score as a 
covariate. Changes from Week 6 to Week 52 will be analyzed in a similar fashion.
13.1.5 Pharmacokinetic Analysis
Concentrations of vedolizumab in serum will be summarized by scheduled time points using 
descriptive statistics. Individual serum concentration data versus time will be presented in a data 
listing.
A separate Data Analysis Plan will be created to describe the population PK analysis approach for 
this study. The results of all PK parameters derived from population PK analysis will be described 
in more detail in a separate Population Pharmacokinetic Analysis Report. Other analyses or 
methods may be used, if appropriate.
13.1.6 Other Analysis
The proportion of subjects with positive AVA (transient and persistent) and proportion of subjects 
with positive neutralizing AVA during the study will be summarized at each visit. 


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A positive AVA subject is defined as a subject who has at least 1 positive AVA result in any 
post-baseline sample, and is further categorized as:

Transiently positive: defined as subjects with confirmed positive AVA in 1 sample at a 
post-dose visit.

Persistently positive: defined as subjects with confirmed positive AVA in 2 or more 
consecutive positive AVA samples at post-dose visits.
The serum titers of AVA are defined as low (<250), moderate (250-2500) and high (>6250). 
Note: these are subject to change depending on the dilution factor that is used at the time of testing.
The ECL assay has better drug tolerance than the ELISA assay used in previous clinical trials 
(including the phase 3 registration studies with vedolizumab IV), therefore allowing more samples 
that have higher drug levels or samples that have lower AVA titers to be detected. 
The impact of immunogenicity on PK, efficacy and safety (including injection site reactions and 
infusion related reactions) will be explored.
Time to UC-related hospitalizations, colectomies, and UC-related hospitalizations procedures will 
be analyzed using a Wei-Lin-Weissfeld Cox-regression model with treatment group, baseline 
complete Mayo score, randomization stratum, and geographic region as independent variables. For 
each of the components, the treatment groups will be compared by log-rank tests, with 
Kaplan-Meier estimates of Week 24 and Week 48 event rates presented.
13.1.7 Safety Analysis
Safety analysis will be performed using the Safety Analysis Set. No statistical inference will be 
made for safety analyses.
The number and percentage of subjects with TEAEs (defined as any AEs, regardless of 
relationship to study drug), AESIs (ie, serious infections including opportunistic infection such as 
PML, malignancies, liver injury, infusion reactions, injection site reactions), and SAEs which 
occur on or after the first dose date and up to 18 weeks after the last dose date of the study drug in 
subjects who do not enroll in open-label extension study or up to the first dose of the open-label 
extension study in those who do, will be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA) System Organ Class, High Level Term, and Preferred Term overall, by 
severity, and by relationship to study drug for each treatment group. Separate summaries will also 
be generated for treatment-related adverse events overall and by severity. In addition to incident 
rates, exposure adjusted AE rates will be summarized as well.
Change from baseline in clinical laboratory tests and vital signs will be summarized by treatment 
group. Subjects with markedly abnormal values for laboratory tests and vital signs will be 
tabulated.
Additional summaries of TEAEs will be provided that only include TEAEs that occur in the 
Maintenance Phase between the Week 6 dose and 18 weeks after the last dose date of the study 
drug, or up to the first dose of the open-label extension study, whichever comes first.


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Data from the LTFU survey will be summarized descriptively.
The shift in ECG interpretation from Baseline will be summarized by treatment group. Physical 
examination findings and PML checklist data will be presented in data listings.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
Assuming a clinical remission rate of 42% for vedolizumab and 16% for placebo at Week 52, a 
sample size of 94 subjects in the vedolizumab SC group and 47 subjects in the placebo group will 
provide 90% power at a 2-sided 0.05 level of significance. To ensure a randomized sample size of 
188 subjects, assuming 47% of the subjects entering induction will achieve clinical response at 
Week 6, approximately 400 subjects will need to be enrolled into the study.
Assuming a mucosal healing rate of 52% for vedolizumab and 20% for placebo at Week 52, with a 
sample size of 94 subjects in the vedolizumab group and 47 subjects in the placebo group the first 
secondary endpoint of mucosal healing at Week 52 will be powered to at least 97% at a 2-sided 
0.05 level of significance.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. 
Significant protocol deviations will be entered into the eCRF, which is reviewed by the study 
sponsor or designee.
The procedure below applies to Japanese sites only.
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the 
investigator should notify the sponsor and the head of the study site of the deviation or change as 
well as its reason in a written form, and then retain a copy of the written form. When necessary, the 
investigator may consult and agree with the sponsor on a protocol amendment. If the protocol 
amendment is appropriate, the amendment proposal should be submitted to the head of the study 
site as soon as possible and an approval from IRB should be obtained. The investigator should 
document all protocol deviations.


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14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration (FDA), the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator and institution guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug and notify site once the sponsor 
has confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor 
has received permission from competent authority to begin the trial. Until the site receives 
notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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Regarding any future pharmacogenomic investigation using collected and stored specimens for 
Japan; the sponsor will create a research protocol for pharmacogenomics investigations and the 
research protocol will require prior approval of the respective IRB in Japan prior to use.
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 


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investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 


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review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.


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16.0
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Appendix A
Schedule of Study Procedures: Screening, Induction and Non-Responders
Study Procedures
Screening
Induction
Open Label Treatment Period
Induction
Observation
Week 6 Non-Responders
Open Label Treatment Period
Days -28 to -1
Must occur 
Days -10 to -5
Week 0 (a)
Day 1
Week 2
Day 15
(±2 days)
Week 6a(b)
Day 43
(-5 days)
Week 6b(b)
Day 43
(+3 days)
Week 6b
Day 43
(+3 days)
Week 14
Day 99
(±3 days)
Clinic Visit Number
1
2
3
4
5
NR5
NR6
Informed consent 
X
PGx consent (optional)
X
Register Subject in IWRS
X
Demographics 
X
Tobacco use
X
Medical and UC history 
X
Prior therapies for UC
X
Physical examination (c)
X
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
Diary instruction
X
Diary review (f)
X
X
X
X
X
Concomitant medications and 
procedures
X (g)
X
X
X
X
X
12-lead ECG
X
TB screening
X
Mayo score (h)
X(i)
X
X(i)
X(i)
X
Flexi-Sigmoidoscopy (j)
X
X
Colonic tissue samples (k)
Including PGx mucosal tissue (tissue 
RNA) if consented to
X
X
PGx blood (Genomic DNA + RNA)
X
Footnotes are on last table page.
CCI
CCI


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Appendix A
Schedule of Study Procedures: Screening, Induction and Non-Responders (continued)
Study Procedures
Screening
Induction
Open Label Treatment Period
Induction 
Observation
Week 6 Non-Responders 
Open Label Treatment Period
Days -28 to -1
Must occur 
Days -10 to -5
Week 0 (a)
Day 1
Week 2
Day 15
(±2 days)
Week 6a (b)
Day 43
(-5 days)
Week 6b (b)
Day 43
(+3 days)
Week 6b
Day 43
(+3 days)
Week 14
Day 99
(±3 days)
Clinic Visit Number
1
2
3
4
5
NR5
NR6
Dosing IV Open Label (l)
X
X
X
Enrollment IWRS
X
Randomization IWRS
X
Dosing Blinded IV/SC
X
Assess eligibility for OLE
X (l)
PRO (IBDQ; EQ-5D)
X
X
X
WPAI-UC
X
X
X
UC-related events
X
X
X
PTE/AE assessment (m)
X
X
X
X
X
X
X
SAE assessment (n)
X
X
X
X
X
X
X
Sample collection for:
Serum pregnancy test (o)
X
Urine pregnancy test (o)
X
X
X
X
X
HBV, HCV, HIV Screening
X
FSH (p)
X
Clinical chemistry
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Coagulation
X
Urinalysis
X
X
X
X
PK assessment (q)
X
X
X
X
AVA assessment (q)
X
X
X
X
Fecal calprotectin (r)
X
X
X
C. difficile stool sample (s)
X
Footnotes are on the last table page.


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Footnotes:
Day=day after the first dose. AVA=anti-vedolizumab antibodies, HBV=hepatitis B virus, HCV=hepatitis C virus, PK=pharmacokinetics, PML=progressive multifocal 
leukoencephalopathy. 
Week 6A: Subjects will receive the clinical and endoscopical evaluation for Complete Mayo score determination at Week 6 (-5 days), as close as possible to the beginning of this 
evaluation period. Endoscopy subscore will be determined by central reading prior to Visit Week 6 (+3days).
Week 6B: Subjects who achieved clinical response (by Complete Mayo Score) will be randomized to receive vedolizumab blinded SC/IV/Placebo. Except for Non-Responders (NR 
by Complete Mayo Score) at Week 6 who will received a 3rd dose of open-label vedolizumab IV and be assessed at Week 14 for response (by partial Mayo Score).
(a) All Baseline (Week 0) assessments will be done pre-vedolizumab IV.
(b) Week 6a visit should be performed between Day 38 and 43 (inclusive) and Week 6b visit should be performed between Day 43 and 46 (inclusive). The Week 6a and 6b visits 
should not be performed on the same day.
(c) Physical examination: Clinically significant findings will be recorded as concurrent conditions if start prior to signing the informed consent, or as PTEs if start after signing of the 
informed consent and as AEs if starts after the first dose of study drug.
(d) Vital signs: Height (cm) and weight (kg; without shoes) will be measured during Screening. Weight and vital signs will also be measured on clinic dosing days prior to dosing.
(e) 
 
(f) Diary review: will be administered prior to each dosing event either in person at dosing occurring in the clinic during scheduled visits or over the phone when the subject is 
injecting outside of the clinic.
(g) Concomitant medications and procedures: Monitoring will begin at signing of the informed consent.
(h) The components of the Complete Mayo score to determine eligibility at Week 0 must be completed within 10 days prior to receiving the first dose of study drug. The components 
of the partial Mayo score are stool frequency, rectal bleeding, and physician rating of disease activity.
(i) Indicates Complete Mayo score calculation.
(j) Flexi-sigmoidoscopy: The endoscopy will be performed prior to Week 0 to assess eligibility for Enrollment and at Week 6a to assess eligibility for Randomization at Week 6b. 
Then at Wk52 or ET.
(k) Colonic tissue samples will be collected during each colonoscopy for histological analysis. The tissue samples taken for each collection timepoint for histology will be sub-divided 
prior to fixing for PGx tissue analysis if consented to by the subject.
(l) Week 0 and 2 dosing will be done with vedolizumab IV; from Week 6 randomization, dosing will be done with vedolizumab blinded SC/IV/Placebo. Non-Responders (NR by 
Complete Mayo Score) at Week 6 will received a 3rd dose of open-label vedolizumab IV and be assessed at Week 14 for response (by partial Mayo Score). Responders at Week 14 
will be assessed for eligible for the Open-Label Extension (OLE) study. Non-Responders at Week 14 will be discontinued and returned to routine medical care.
(m) PTEs will be captured immediately following the signing of the informed consent at Screening, up until the first dose of study drug. Collection of AEs, to include concomitant 
medications, will begin following first dose of study drug and will continue through Week 68/Final Safety Visit. To be performed in person at dosing occurring in the clinic during 
scheduled visits. 
(n) Collection of all SAEs will begin once the informed consent is signed and will continue through Week 68/ Final Safety Visit. To be performed in person at dosing occurring in the 
clinic during scheduled visits. 
(o) All females of child bearing potential must have a serum pregnancy test at Screening and WK52/ET and Final Safety Visit. A urine pregnancy test will be completed for all 
females of child bearing potential prior to each dose of study drug injected during clinic visits. 
(p) Follicle-stimulating hormone (FSH) level will be obtained for female subjects at Screening if they are postmenopausal by history (ie, last regular menstrual cycle >1 years) and not 
surgically sterile. The FSH result must be >40 IU/L for the subject to be permitted not to use adequate contraception.
(q) All PK and AVA samples will be obtained at predose (within 30 minutes prior to dosing). 
(r) Fecal calprotectin stool sample should be the first bowel movement on the day of collection.
(s) A stool sample for culture, ova and parasite evaluation, and C. difficile assay will be obtained (if indicated) at Screening and at any time point during the study when a subject 
becomes symptomatic, including worsening or return of disease activity.
CCI


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Appendix A
Schedule of Study Procedures (Maintenance Phase)
Study Procedures
Maintenance Period (a)
Final 
Safety 
Follow-
up Visit 
(b)
Un-
scheduled 
Visit (c)
46-Week Randomised, Double Blind, Double-Dummy, Maintenance Phase. 
(Week 7 must occur +7 days after Randomization)
Wk 7
Wk 8
Wk 
10, 12 
(d)
Wk 
14
Wk 
16, 
18, 20 
(d)
Wk 22
Wk 
24, 26, 
28 (d) Wk 30
Wk 
32, 34, 
36 (d) Wk 38
Wk 
40, 42, 
44 (d) Wk 46
Wk 48 
(d)
Wk 50 Wk 51
Wk 
52/ET
Wk 68
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 7 
days
±1 week
Clinic Visit Number
6
7
8
9
10
11
12
13
14
15
16
Physical examination (e)
X
X
X
X
X
X
X
X
X
Vital signs (f)
X
X
X
X
X
X
X
X
X
X
PML checklist (g)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PML wallet card
X
Diary review
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing - Blinded IV
X
X
X
X
X
Dosing - Blinded SC
X
X
X
X
X
X
X
X
X
X
X
X
X
Mayo score (h)
X
X
X
X
X
X
X(i)
X
Flexi-Sigmoidoscopy
X
Colonic tissue samples (j)
Including PGx mucosal 
tissue (tissue RNA) if 
consented to
X
PRO (IBDQ; EQ-5D)
X
X
WPAI-UC
X
X
UC-related events
X
Footnotes are on last table page.


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Appendix A
Schedule of Study Procedures (Maintenance Phase) (continued)
Study Procedures
Maintenance Phase (a)
Final 
Safety 
Follow-
up Visit 
(b)
Un-
scheduled 
Visit (c)
46-Week Randomised, Double Blind, Double-Dummy, Maintenance Phase. 
(Week 7 must occur +7 days after Randomisation)
Wk 7 Wk 8
Wks 
10, 12 
(d)
Wk 
14
Wks 
16, 
18, 20 
(d)
Wk 22
Wks 
24, 26, 
28 (d) Wk 30
Wks 
32, 34, 
36 (d) Wk 38
Wks 
40, 42, 
44 (d) Wk 46
Wk 48
(d)
Wk 50 Wk 51
Wk 
52/ET
Wk 68
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 3 
days
± 7 
days
± 1 week
Clinic Visit Number
6
7
8
9
10
11
12
13
14
15
16
12-lead ECG
X
PTE/AE assessment (k)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE assessment (l)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sample collection for:
Serum pregnancy test (m)
X
X
Urine pregnancy test (m)
wk 10
X
wk 18
X
wk 26
X
wk 34
X
wk 42
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Coagulation
X
X
Urinalysis
X
PK assessment (n)
X
X
X
X
X
X
X
X
X
X
X
X
AVA assessment (o)
X
X
X
X
X
X
X
X
X
Fecal calprotectin (p)
X
X
C. difficile stool sample 
(q)
X (q)
Footnotes are on the following page.


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Footnotes:
Day=day after the first dose. AVA=anti-vedolizumab antibodies, HBV=hepatitis B virus, HCV=hepatitis C virus, PK=pharmacokinetics, PML=progressive multifocal 
leukoencephalopathy. 
(a) Maintenance Phase: There should be a minimum of 7 days between 2 consecutive doses.
(b) Final Safety Follow-up visit: For subjects not enrolling in the OLE study. Subjects discontinued from the study for any reason will complete the Early Termination (ET) Visit and 
the Final Safety Visit (18-weeks post last dose) and LTFU survey (6-months post last dose).
(c) Subjects seen at an unscheduled visit for disease exacerbation or SAE will complete the Unscheduled Visit assessments.
(d) Non clinic visits. Subject will inject once the site has confirmed they can via the pre-dose phone call.
(e) Physical examination: Clinically significant findings will be recorded as AEs if they start after the first dose of study drug.
(f) Vital signs: Weight and vital signs will also be measured on clinic dosing days prior to dosing.
(g) PML checklist: will be administered prior to each dosing event. The PML subjective checklist will be administered in person at dosing occurring in the clinic during scheduled 
visits. The PML subjective checklist will be administered over the phone when the subject is injecting outside of the clinic.
(h) The components of the partial Mayo score are stool frequency, rectal bleeding, and physician rating of disease activity. 
(i) Indicates Complete Mayo score calculation.
(j) Colonic tissue samples will be collected during each colonoscopy for histological analysis. The tissue samples taken for each collection timepoint for histology will be sub-divided 
prior to fixing for PGx tissue analysis if consented to by the subject.
(k) Collection of AEs, to include concomitant medications, will begin following first dose of study drug and will continue through Week 68/Final Safety Visit. To be performed in 
person at dosing occurring in the clinic during scheduled visits. To be performed over the phone at dosing occurring outside of the clinic. 
(l) Collection of all SAEs will continue through Week 68/ Final Safety Visit. To be performed in person at dosing occurring in the clinic during scheduled visits. To be performed over 
the phone at dosing occurring outside of the clinic.
(m) All females of child bearing potential must have a serum pregnancy test at WK52/ET and Final Safety Visit. A urine pregnancy test will be completed for all females of child 
bearing potential prior to each dose of study drug injected during clinic visits, as well as at Weeks 10, 18, 26, 34, and 42 prior to injecting study drug outside of the clinic. 
(n) PK samples at Weeks 7, 51 and 52 can be collected at anytime during the visit. All other PK samples will be obtained at predose (within 30 minutes prior to dosing). The Week 68 
PK sample collection will only occur in subjects who will not enroll in the open label extension study.
(o) All AVA samples will be obtained at predose (within 30 minutes prior to dosing). The Week 68 AVA sample collection will only occur in subjects who will not enroll in the open 
label extension study.
(p) Fecal calprotectin stool sample should be the first bowel movement on the day of collection.
(q) A stool sample for culture, ova and parasite evaluation, and C. difficile assay will be obtained (if indicated) at any time point during the study when a subject becomes 
symptomatic, including worsening or return of disease activity.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on Investigators from the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572) which must be completed and 
signed before the Investigator may participate in this study. 
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
Screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
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.


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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.


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


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


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


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Appendix E
Collection, Shipment, and Storage of Pharmacogenomic Samples 
Sample Collection
Collect two whole blood samples (3 mL per sample) for deoxyribonucleic acid (DNA) isolation 
will be collected before dosing on Day 1 from each subject in the study, into plastic K2 
ethylenediamine-tetraacetic acid (EDTA) spray-coated tubes.
If necessary and feasible, a second aliquot of blood may be taken if isolation of DNA from the first 
sample was not successful or possible. Collect two whole blood samples (2.5 mL per sample) will 
be collected at each time point at predose on Day 1 for RNA pharmacogenomic analysis from each 
subject in the study, into a PaxGeneTM tube.
For detailed instructions on sample collection and storage follow the laboratory manual provided 
by the central laboratory.
Sample Shipment
Ship samples only on Monday, Tuesday, or Wednesday, and at least 2 days prior to a national 
holiday, to minimize the possibility of samples in transit over a weekend or holiday. The 
laboratory must confirm arrival of the shipped samples.
For instructions on shipping and packing follow the laboratory manual and shipping instructions 
provided by the central laboratory.
Before shipping, ensure the sample tubes are tightly sealed.
Sample Storage
The DNA and RNA samples will be stored in a secure storage space with adequate measures to 
protect confidentiality. The samples will be retained while research on vedolizumab continues for 
up to but not longer than 15 years or as required by applicable law.
For Japan, please refer to the appropriate study manual provided separately for additional 
information. 


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Appendix F
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity
Category (a)
Stool frequency (b)
0 = Normal no. of stools for this patient
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
Sub score, 0 to 3
Rectal bleeding (c)
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
Sub score, 0 to 3
Findings on endoscopy 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Sub score, 0 to 3; 0 = Normal or inactive disease
Physician’s global assessment (d)
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Sub score, 0 to 3
(a) The Mayo score ranges from 012, with higher scores indicating more severe disease. Partial Mayo score excludes 
endoscopy and ranges from 09.
(b) Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency.
(c) The daily bleeding score represents the most severe bleeding of the day.
(d) The physician’s global assessment acknowledges the 3 other criteria, the patient’s daily recollection of abdominal 
discomfort and general sense of well-being, and other observations, such as physical findings and the patient’s 
performance status.
Adapted from: Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 
1987; 317 (26):1625-9.


Vedolizumab SC
Study No. MLN0002SC-3027
Page 109 of 109
Protocol Incorporating Amendment No. 05
28 September 2016
CONFIDENTIAL
Appendix G
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 05 is indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Amendment of visit window for Week 6a.
The primary change occurs in Appendix A Schedule of Study Procedures: Screening, Induction 
and Non-Responders:
Formerly read:
Week 6a(b)
Day 43
(-3 days)
Now reads:
Week 6a(b)
Day 43
(-5 days)
Rationale for Amendment:
Visit window extended to adjust for clinical practice in Japan.
Sections that also contain this change are:

Footnotes in Appendix A Schedule of Study Procedures: Screening, Induction and 
Non-Responders.
Change 2: Clarification to sponsor address in Japan.
The primary change occurs on page 1.
Formerly read:
Takeda Development Center Japan, 
Takeda Pharmaceutical Company Limited, 
1-1, Doshomachi 4-Chome, Chuo-ku Osaka 540-8645, Japan
Now reads:
Takeda Pharmaceutical Company Limited, 
1-1, Doshomachi 4-Chome, Chuo-ku Osaka 540-8645, Japan
Rationale for Amendment:
Administrative change to the sponsor address in Japan. 
Change 3:Corrected typographical errors, punctuation, grammar, and formatting.


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PPD

SAP_000.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 Phase 3 Randomized, Double-Blind, Placebo-Controlled Study, with a vedolizumab IV
Reference Arm, to Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as
Maintenance Therapy in Subjects with Moderately to Severely Active Ulcerative Colitis
Who Achieved Clinical Response Following Open-Label Vedolizumab Intravenous
Therapy
NCT Number: NCT02611830
SAP Approve Date: 2 June 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
TAKEDA DEVELOPMENT CENTER
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: MLN0002SC-3027
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study, with a vedolizumab IV
Reference Arm, to Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as
Maintenance Therapy in Subjects with Moderately to Severely Active Ulcerative Colitis
Who Achieved Clinical Response Following Open-Label Vedolizumab Intravenous
Therapy
PHASE 3
Version: 1.0
Date: 12 June 2018
Prepared by:
Based on:
Protocol Version: <Amendment 4>
Protocol Date: <26 July 2016>
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


MLN0002SC-3027
Page 2 of 41
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CONFIDENTIAL
1.1
APPROVAL SIGNATURES
Electronic signatures can be found on the last page of this document.


MLN0002SC-3027
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CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
APPROVAL SIGNATURES.....................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objectives ....................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Exploratory Objectives ..............................................................................................8
4.4
Study Design .............................................................................................................9
5.0
ANALYSIS ENDPOINTS.............................................................................................12
5.1
Primary Endpoint.....................................................................................................12
5.2
Secondary Endpoints ...............................................................................................12
5.3
Patient Reported Outcome (PRO) Endpoints............................................................12
5.4
Exploratory Endpoints .............................................................................................12
5.4.1
Additional Exploratory Endpoints......................................................................14
5.5
Safety Assessments..................................................................................................14
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................15
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................16
7.1
General Considerations............................................................................................16
7.1.1
Study Terms and Definitions..............................................................................16
7.1.2
Convention for Calculations of Mayo Scores .....................................................17
7.1.3
Duplicate Records due to Patient Self-Entered Data ...........................................19
7.1.4
Convention for missing data...............................................................................19
7.1.5
Definition of Study Days and Visit Window ......................................................19
7.2
Analysis Sets ...........................................................................................................21
7.2.1
Full Analysis Set (FAS) .....................................................................................21
7.2.2
Per-Protocol Set (PPS).......................................................................................21
7.2.3
Safety Analysis Set ............................................................................................21
7.2.4
Pharmacokinetic Set...........................................................................................21
7.3
Disposition of Subjects ............................................................................................21
7.4
Demographic and Baseline Characteristics...............................................................22
7.5
Medical History and Concurrent Medical Conditions...............................................22
7.6
Medication History and Concomitant Medications and Procedures ..........................22
7.7
Study Drug Exposure and Compliance.....................................................................23
7.8
Efficacy Analysis.....................................................................................................23


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CONFIDENTIAL
7.8.1
Primary Efficacy Endpoint.................................................................................24
7.8.2
Secondary Efficacy Endpoints............................................................................24
7.8.3
Patient Reported Outcomes (PROs) Endpoints...................................................26
7.8.4
Exploratory and additional Efficacy Endpoints...................................................26
7.8.5
Subgroup Analysis .............................................................................................26
7.8.6
Sensitivity Analysis............................................................................................28
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................28
7.10
Other Outcomes.......................................................................................................28
7.10.1 Immunogenicity Endpoints ................................................................................28
7.10.2 Histological Endpoints.......................................................................................29
7.10.3 Resource Utilization and Patient-Reported Outcome Endpoints..........................29
7.11
Safety Analysis........................................................................................................30
7.11.1 Adverse Events ..................................................................................................30
7.11.2 Clinical Laboratory Evaluations .........................................................................31
7.11.3 Vital Signs .........................................................................................................31
7.11.4 12-Lead ECGs ...................................................................................................31
7.11.5 Other Observations Related to Safety.................................................................31
7.12
Interim Analysis ......................................................................................................32
7.13
Changes in the Statistical Analysis Plan...................................................................32
8.0
REFERENCES..............................................................................................................33
LIST OF IN-TEXT TABLES
Table 7.a
Example of eDiary Subscore Calculations for Eligibility Visit ...........................18
Table 7.b
Example of eDiary Subscore Calculations for Non-eligibility Visits...................18
Table 7.c
Visit Windows (Induction Period for Non-responders at Week 6) ......................20
Table 7.d
Visit Windows (Randomized Subjects) ..............................................................20
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ................................................................................11
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................34
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs......................................35
Appendix C
Mayo Score Calculation Worksheet ...................................................................36


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CONFIDENTIAL
Appendix D
Geographic Regions...........................................................................................38
Appendix E
AEs of Special Interest.......................................................................................39
Appendix F
Prior Therapies...................................................................................................40
Appendix G
Patient Reported Outcomes ................................................................................41


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CONFIDENTIAL
3.0
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
AESI
adverse event of special interest
AVA
anti-vedolizumab antibody; also called HAHA
CMH
Cochran-Mantel-Haenszel
Ctrough
trough serum concentration 
ECG
electrocardiogram
ECL
Electrochemiluminescence
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
EQ-5D
Euro Quality of Life-5D
FAS
full analysis set
HLT
high level term
IBDQ
Inflammatory Bowel Disease Questionnaire
IV
intravenous(ly)
KM
Kaplan-Meier
LTFU
long-term follow-up
MAR
Missing at random
MAV
markedly abnormal laboratory value
MedDRA
Medical Dictionary for Regulatory Activities
MNAR
Missing not at random
OLE
open-label extension
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PPS
per-protocol set
PRO
patient-reported outcome
PT
preferred term
Q2W
once every 2 weeks
Q8W
once every 8 weeks
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous(ly)
SI
Systeme International
TB
tuberculosis
TEAE
treatment-emergent adverse event
TRAE
treatment related AE
TNF-α
tumor necrosis factor- alpha
UC
ulcerative colitis
ULN
upper limit of normal
VAS
visual analog scale


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CONFIDENTIAL
Term
Definition
WHODRUG
World Health Organization Drug Dictionary
WPAI
Work Productivity and Activity Impairment


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4.0
OBJECTIVES
4.1
Primary Objectives
To assess the effect of vedolizumab subcutaneous (SC) maintenance treatment on clinical 
remission at Week 52 in subjects with moderately to severely active ulcerative colitis (UC) who 
achieved clinical response at Week 6 following administration of vedolizumab intravenous (IV) 
at Weeks 0 and 2.
4.2
Secondary Objectives
!
To determine the effect of vedolizumab SC maintenance treatment on mucosal healing at 
Week 52 in subjects who achieved clinical response at Week 6 following administration of 
vedolizumab IV at Weeks 0 and 2.
!
To determine the effect of vedolizumab SC maintenance treatment on durable clinical 
response at Week 52 in subjects who achieved clinical response at Week 6 following 
administration of vedolizumab IV at Weeks 0 and 2.
!
To determine the effect of vedolizumab SC maintenance treatment on durable clinical 
remission at Week 52 in subjects who achieved clinical response at Week 6 following 
administration of vedolizumab IV at Weeks 0 and 2.
!
To determine the effect of vedolizumab SC maintenance treatment on corticosteroid-free 
remission at Week 52 in subjects who achieved clinical response at Week 6 following 
administration of vedolizumab IV at Weeks 0 and 2.
4.3
Exploratory Objectives
CCI


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4.4
Study Design
This is a pivotal, phase 3, multicenter, multinational, randomized, double-blind, double-dummy, 
placebo-controlled trial, including a vedolizumab IV reference arm, designed to evaluate the 
efficacy and safety of maintenance treatment with vedolizumab SC in adult subjects with 
moderately to severely active UC who achieved a clinical response at Week 6 with open-label 
therapy with 300 mg vedolizumab IV at Weeks 0 and 2. The study includes a vedolizumab IV 
reference arm to allow for within-study descriptive comparisons on efficacy, safety, and 
immunogenicity between the two vedolizumab presentations.
The study includes a 4-week (28-day) Screening Period, a 6-week open-label vedolizumab IV 
Induction Phase, and a 46-week randomized, double-blind, double-dummy, placebo-controlled 
Maintenance Phase with vedolizumab SC or vedolizumab IV with a final visit at Week 52. All 
endoscopic assessments (ie, for disease severity at baseline and for clinical endpoints at the end 
of the Induction and Maintenance Phases) will be performed via central reading.
Eligible subjects, will be enrolled into the Induction Phase at Week 0, will receive open-label 
infusions of vedolizumab IV 300 mg at Weeks 0 and 2, and will be assessed for clinical response 
by full Mayo score (endoscopy score determined by central reading) at Week 6, as follows: 
CCI


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
Subjects who achieve a clinical response at Week 6 will be randomized into the Maintenance 
Phase. Upon completion of the Week 52 assessment or upon early discontinuation due to 
treatment failure (ie, disease worsening or need for rescue medications) these subjects will be 
eligible to enter the MLN0002SC-3030 open-label extension (OLE) study.

Subjects who do not achieve a clinical response at Week 6 will not be randomized in to the 
Maintenance Phase, and instead will receive a third infusion of vedolizumab IV 300 mg at 
Week 6. Subjects who achieve a clinical response at Week 14 (by partial Mayo score) will be 
eligible to enroll in the OLE study, while subjects who do not achieve clinical response will 
be discontinued.
Subjects with clinical response at Week 6 will be randomized at a 2:1:1 ratio in the double-blind, 
double-dummy Maintenance Phase, where each treatment arm will receive both SC injections 
Q2W and IV infusions Q8W, beginning at Week 6 through Week 50, as follows:

Injections of vedolizumab SC 108 mg Q2W and placebo IV infusions every 8 weeks (Q8W) 
(N=94).

Infusions of vedolizumab IV 300 mg Q8W and placebo SC injections Q2W (N=47).

Placebo SC injections Q2W and placebo IV infusions Q8W (N=47).
Randomization will be stratified by:

Concomitant use of oral corticosteroids.

Clinical remission status at Week 6.

Previous TNF-α antagonists failure or concomitant immunomodulator (azathioprine or 6-
mercaptopurine) use.
At Week 6, subjects receiving oral corticosteroids who achieved a clinical response and are 
randomized into the Maintenance Phase will begin a corticosteroid tapering regimen.
Subjects who do not participate in the OLE trial or are discontinued, will complete the End-of-
Study Visits or Early Termination visit and then complete the Final Safety Visit 18 weeks (ie, 5 
vedolizumab half-lives) after the last dose of study drug. For subjects that are not in response at 
Week 14, early termination procedures will be performed at the Week 14 visit.
Additionally, subjects who do not participate in the OLE trial will be required to participate in a 
long-term follow-up (LTFU) safety-survey by telephone, 6 months after the last dose of study 
drug.
A schematic of the study design is included as Figure 4.a. A schedule of assessments is listed in 
Appendix A of protocol.


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Figure 4.a
Schematic of Study Design
WEEK 6 RESPONDERS
Screening
Period
Induction 
Phase
Maintenance 
Phase
Follow-up 
Period
Additional
Follow-up
LTFU Safety 
Survey by 
Telephone (b)
(6 months 
after the last dose 
of study drug)
Responder at Wk 6:
Vedolizumab SC 
108 mg Q2W and 
placebo IV Q8W
or
Vedolizumab IV 
300 mg Q8W and 
placebo SC Q2W
or
Placebo SC Q2W 
and placebo IV 
Q8W
Final Safety 
Visit (b) 
(18 weeks after 
the last dose of 
study drug)
OL 
Vedolizumab 
IV 300 mg
End-of-Study 
(a)/
Early 
Termination 
procedures
R
Extension Study 
MLN0002SC-
3030 (c)
Days
Wk
Wk Wk
Wk
Wk
Wk
-28 to -1
0
6
7
51
52
68
Visit: 1
2
5
6
14
15
16
WEEK 6 NONRESPONDERS
Follow-up 
Period
Additional
Follow-up
Responder at 
Wk 14
Extension Study 
MLN0002SC-
3030 (c)
Nonresponder at Wk 6:
Vedolizumab IV 300 mg
Discontinued
Final Safety Visit 
(b) 
(18 weeks after the 
last dose of study 
drug)
LTFU Safety 
Survey by 
Telephone (b)
(6 months 
after the last dose 
of study drug)
Nonresponder at 
Wk 14:
Early 
Termination 
procedures
Days
Wk
Wk
Wk
-28 to -1
0
6
14
Visit: 1
2
5
OL=open-label, R=randomization.
(a) Subjects who consent to participate in the extension study (MLN0002-3030) may begin extension study dosing after End-of-
Study Visit procedures have been completed at the Week 52 Visit.
(b) Subjects who do not enter the extension study (MLN0002SC-3030) (including early terminators and Week 14 nonresponders) 
will complete the Final Safety Visit 18 weeks after their last dose of study drug and participate in a Follow-up Safety Survey by 
Telephone 6 months after the last dose of study drug. 
(c) Visit 1 of Extension Study MLN0002SC-3030 is within 1 week of completing Week 52 (Visit 15) procedures. Subjects not 
randomized into the Maintenance Phase (Week 6 Nonresponders) and respond at Week 14 on vedolizumab IV 300 mg are also 
eligible for entry into the Extension Study.


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5.0
ANALYSIS ENDPOINTS
The endpoints pertain to the vedolizumab SC and placebo arms only.
5.1
Primary Endpoint
!
Proportion of subjects with clinical remission, defined as a complete Mayo score of ≤2 points 
and no individual subscore >1 point, at Week 52.
5.2
Secondary Endpoints
!
Proportion of subjects with mucosal healing, defined as Mayo endoscopic subscore of 
≤1 point, at Week 52.
!
Proportion of subjects with durable clinical response, defined as clinical response at Weeks 6 
and 52, where clinical response is defined as a reduction in complete Mayo score of ≥3 
points and ≥30% from Baseline (Week 0) with an accompanying decrease in rectal bleeding 
subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point.
!
Proportion of subjects with durable clinical remission, defined as clinical remission at 
Weeks 6 and 52.
!
Proportion of subjects with corticosteroid-free remission, defined as subjects using oral 
corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in 
clinical remission at Week 52.
5.3
Patient Reported Outcome (PRO) Endpoints
!
Changes in Inflammatory Bowel Disease Questionnaire (IBDQ) total score and subscores, 
from Baseline (Week 0) to Week 52 and from Week 6 to Week 52.
!
Changes in Euro Quality of Life-5D (EQ-5D) utility scores and EQ-5D VAS score from 
Baseline (Week 0) to Week 52 and Week 6 to Week 52.
!
Changes in WPAI-UC instrument endpoints (% work time missed, % impairment while 
working, % overall work impairment, % activity impairment) from Baseline (Week 0) to 
Week 52 and Week 6 to Week 52.
5.4
Exploratory Endpoints
CCI


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CCI


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5.4.1
Additional Exploratory Endpoints
Following endpoints are not specified in the protocol but will be added to the final analysis.
5.5
Safety Assessments
Safety will be assessed by adverse events (AEs), adverse events of special interest (AESIs) 
(including serious infections including opportunistic infection such as progressive multifocal 
leukoencephalopathy (PML), liver injury, malignancies, infusion-related or injection site 
reactions or systemic reactions and hypersensitivity), serious adverse events (SAEs), vital signs, 
results of standard laboratory tests (clinical chemistry, hematology, coagulation, urinalysis), and 
results of 12-lead electrocardiograms (ECGs).
CCI
CCI


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6.0
DETERMINATION OF SAMPLE SIZE
Assuming a clinical remission rate of 42% for vedolizumab and 16% for placebo at Week 52, a 
sample size of 94 subjects in the vedolizumab SC group and 47 subjects in the placebo group 
will provide 90% power at a 2-sided 0.05 level of significance. To ensure a randomized sample 
size of 188 subjects, assuming 47% of the subjects entering induction will achieve clinical 
response at Week 6, approximately 400 subjects will need to be enrolled into the study.
Assuming a mucosal healing rate of 52% for vedolizumab and 20% for placebo at Week 52, with 
a sample size of 94 subjects in the vedolizumab group and 47 subjects in the placebo group the 
first secondary endpoint of mucosal healing at Week 52 will be powered to at least 97% at a 2-
sided 0.05 level of significance.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Considerations
Statistical analysis will be performed using the SAS System, Version 9.2 or higher.
All study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings. Continuous data will be summarized using number of subjects, mean, standard 
deviation, median, minimum, and maximum. Categorical data will be summarized using the 
number and percentage of subjects for each category where appropriate.
7.1.1
Study Terms and Definitions 
Term
Definition
Clinical remission by 
complete Mayo score
A complete Mayo score of ≤2 points and no individual subscore >1 point.
Clinical remission by 
partial Mayo score
A partial Mayo Score ≤2 and no individual subscore >1.
) 
 
 
 
Clinical response
A reduction in complete Mayo score of ≥3 points and ≥30% from Baseline (Week 0) 
(or partial Mayo score of ≥2 points and ≥25% from Baseline, if the complete Mayo 
score was not performed at the visit) with an accompanying decrease in rectal bleeding 
subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point.
Corticosteroid-free 
remission
Defined as proportion of subjects using oral corticosteroids at Baseline (Week 0) who 
have discontinued oral corticosteroids and are in clinical remission at Week 52.
Disease worsening
An increase in partial Mayo score ≥3 points from the Week 6 value on 2 consecutive 
visits (or an increase to 9 points on 2 consecutive visits if the Week 6 value >6) and a 
minimum partial Mayo score of ≥5 points.
Durable clinical remission
Clinical remission at Weeks 6 and 52.
Durable clinical response
Clinical response at Weeks 6 and 52.
Mucosal healing
A Mayo endoscopic subscore of ≤1 point.
CCI
CCI


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7.1.2
Convention for Calculations of Mayo Scores 
7.1.2.1
Gemini Approach
Primary method for calculation of Mayo Scores will be followed by the same approach used in 
Gemini study (MLN0002 C13006). Statistical programming will calculate the Mayo score and 
Partial Mayo score for each subject. The Mayo scoring system is a composite index of 4 disease 
activity variables. Each variable is scored individually on an integer scale of 0 to 3, with higher 
scores indicating greater disease activity. The individual components of the Mayo score are stool 
frequency, rectal bleeding, findings on sigmoidoscopy, and the physician’s global assessment. 
The Partial Mayo score is calculated analogously but excludes the sigmoidoscopy subscore. 
Mayo score calculation “points to remember” are in Appendix C.
Stool frequency and rectal bleeding subscores are derived from eDiaries completed by the 
subject seven days prior to a study visit. These subscores are calculated using the eDiary in the 
following order: 

The score from the 3 most recent days prior to the actual day of the study visit will be 
averaged and rounded to the nearest integer.

If diary entries from 3 days are not available, the scores from the 2 most recent entries will be 
averaged and rounded to the nearest integer.

If less than 2 days of diary data are available, the patient will be categorized as a non-
responder and the subscore will be considered missing.
The day of sigmoidoscopy must be entered into eDiary (not applicable at all study visits), and 
day of visit must be confirmed in eDiary. Table 7.a provides examples of Mayo subscore 
calculation using various eDiary scenarios (eligibility only); Table 7.b provides examples of 
Mayo subscore calculation using various eDiary scenarios (excluding eligibility).
Subjects who have less than 3 days of diary data during screening are not eligible for enrollment 
(ie, for eligibility, only Rule #1 will be applied). During screening, subjects should have 3 non-
missing diary out of 7 days immediately prior to eligibility visit so that they are eligible for score 
calculation (see example Diary# 5 and 6 in Table 7.a).
The day prior, day of, and day after sigmoidoscopy cannot be used for subject diary entry 
because of the bowel prep for the procedure could interfere with the assessment of these clinical 
parameters entered into eDiary.


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Table 7.a
Example of eDiary Subscore Calculations for Eligibility Visit
Example
Day(a)
-10
Day
-9
Day
-8
Day
-7
Day
-6
Day
-5
Day
-4
Day
-3
Day
-2
Day
-1
Day
1
Valid Days 
for
Calculation of 
Subscore
Average 
Subscore
Final 
Subscore
Diary #1
1
3
2
X
S
X
2
3
0
1
E
-1, -2, -3
1.33
1
Diary #2
2
3
2
3
X
S
X
1
M
2
E
-1. -3, -7
2
2
Diary #3
1
2
3
2
3
4
4
3
4
X
S & E
-2, -3, -4
3.67
4
Diary #4
4
3
4
4
4
X
S&E
X
-6, -7, -8
4
4
Diary #5
2
2
X
S & E
X
Not eligible
NA
M
Diary #6
2
4
2
3
3
X
S
X
M
M
E
Not eligible
NA
M
NA=not applicable.
(a) Days are named relative to Day 1, which is the first dose date. Subject diaries can be completed 10 days prior to 
eligibility visit.
S=sigmoidoscopy.
X=the score can’t be counted to prior or after sigmoidoscopy.
E=eligibility visit.
M=missing.
Table 7.b
Example of eDiary Subscore Calculations for Non-eligibility Visits
Example
Day(a)
-7
Day
-6
Day 
-5
Day
-4
Day
-3
Day
-2
Day
-1
Valid Days for 
Calculation of 
Subscore
Average 
Subscore
Final 
Subscore
Diary #1
X
S
X
2
3
0
1
-1, -2, -3
1.33
1
Diary #2
3
X
S
X
1
M
2
-1. -3, -7
2
2
Diary #3
S
X
3
M
M
M
0
-1, -5
1.5
2
Diary #4
4
4
X
S
X
3
3
-1, -2, -6
3.33
3
Diary #5
2
3
4
4
X
S
X
-4, -5, -6
3.67
4
Diary #6
2
M
M
X
S
X
2
-1, -7
2
2
Diary #7
M
3
X
S
X
M
M
M
NA
M
NA=not applicable.
(a) Days are named relative to Day 1, which is the study visit.
S=sigmoidoscopy.
X=the score can’t be counted to prior or after sigmoidoscopy.
M=missing.
7.1.2.2
FDA Guided Approach
As a sensitivity analysis, the complete Mayo score and partial Mayo score for each patient will 
be calculated for post-screening visit per FDA Draft Ulcerative Colitis guidance (August 2016). 
For post-screening visits, the stool frequency and rectal bleeding subscores will be calculated as 
the sum of the 3 most recent consecutive non-missing results divided by 3. For patients who do 
not have 3 consecutive days of non-missing eDiary data but have at least 4 days of data available 
in the last 7-day period prior to the visit, the non-missing scores from the total number of 
available days in the last 7-day period will be averaged. If less than 3 consecutive days or 4 days 


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of eDiary data in the last 7-day period are available, the patient will be categorized as a non-
responder and the subscore will be considered missing. 
7.1.3
Duplicate Records due to Patient Self-Entered Data
SC dosing done during mandatory site visits will be recorded into the eCRF. If patients 
accidentally recorded SC dosing done during site visits on the same day of clinic visit, data 
recorded on eCRF will be used;
If patients have multiple entries on the same day for either stool frequency or rectal bleeding, the 
worst results will be used for Mayo score calculation. If patients entered for “previous day” but 
have already entered the record one day before, the one entered for “previous day” will be 
ignored. 
7.1.4
Convention for missing data
!
Missing data for dichotomous (i.e., proportion-based) endpoints will be handled using the 
non-responder imputation method, i.e. any subject with missing information for 
determination of endpoint status will be considered as a non-responder in the analysis. 
!
Missing data for continuous endpoints will be imputed using last available post-baseline 
observation carried forward (LOCF) method. For subjects without any non-missing post-
baseline measurement, the missing data will be imputed using baseline observation carried 
forward method. Other missing data imputation method may be explored.
7.1.5
Definition of Study Days and Visit Window
Study day will be calculated relative to the date of the first dose of study drug (first dose of IV 
infusion) in the study. The study day prior to the first dose of study drug will be calculated as: 
Date of assessment/event – date of first dose of study drug.
The study day on or after the first dose of study drug will be calculated as: 
Date of assessment/event – date of first dose of study drug + 1.
Baseline is defined as the last non-missing measurement prior to or on the date of the first dose 
of study drug (Study Day 1). The visit windows for the postbaseline visits are defined in 
Table 7.c and Table 7.d. If a subject has more than 1 measurement in the same visit window, the 
measurement closest to the scheduled visit will be used. If 2 measurements in the same window 
are of equal distance to the scheduled visit, the measurement that occurs after the scheduled visit 
will be used. If 2 or more measurements occur on the same day, the last value obtained will be 
used.
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AEs that start more than 127 days after the last dose of study drug will be listed, but excluded 
from the summaries and analyses. 
If Endoscopy is taken other than protocol defined visits (baseline, week 6, or week 52), i.e. at 
early termination (ET), then the visit window for endoscopy will follow the one of partial Mayo 
Score, and the subject’s complete Mayo score at the corresponding protocol defined visits (i.e. 
week 6 or week 52) will be set to missing with one exception. If week 52 complete MAYO is 
missing, week 50 complete MAYO, if available, will be carried over.
Table 7.c
Visit Windows (Induction Period for Non-responders at Week 6)
Visit
Scheduled 
Day
Safety Labs Vital Signs Urinalysis
Partial 
Mayo Score, 
Corticosteroide Endoscopy
IBDQ, EQ-
5D, WPAI-
UC
Baseline
Day 1
1
1
1
1
1
1
Week 2
Day 14
2-28
2-28
2-28
NA
NA
NA
Week 6
Day 42
29-70
29-70
≥29
2-70
2-70
2-70
Week 14*a *b
Day 98
71-133
71-133
NA
71-133
NA
NA
Week 24*c
Day 168
≥134
≥134
NA
NA
NA
NA
*a Week 14 will end on Day 133 or the day prior to the first dosing of the extension study (for patients entering the 
extension study), whichever comes first.
*b For the purpose of diary compliance calculation and derivation of diary-based endpoints, the last visit day of 
study will not be included since the subject is not expected to have completed the diary entries for that day by the 
Final Visit. 
*c Safety follow up visit. Only for subjects who do not enter the Extension Study MLN002SC-3030 (including early 
terminators and Week 14 non-responders). 
Table 7.d
Visit Windows (Randomized Subjects)
Visit
Scheduled 
Day
Safety Labs Vital Signs ECG
Urinalysis
Partial 
Mayo Score, 
Corticosteroide
Endoscopy
IBDQ, 
EQ-5D, 
WPAI-
UC
Baseline 
Day 1
1
1
1
1
1
1
1
Week 2
Day 14
2-28
2-28
NA
2-28
NA
NA
NA
Week 6
Day 42
29-70
29-70
NA
29-70
2-70
2-70
2-70
Week 14
Day 98
71-126
71-126
NA
NA
71-126
NA
NA
Week 22
Day 154
127-182
127-182
NA
NA
127-182
NA
NA
Week 30
Day 210
183-238
183-238
NA
NA
183-238
NA
71-238
Week 38
Day 266
239-294
239-294
NA
NA
239-294
NA
NA
Week 46
Day 322
295-336
295-336
NA
NA
295-336
NA
NA
Week 50
Day 350
337-357
337-357
NA
NA
337-357
NA
NA
Week 52
Day 364
358-420
358-420
≥2
≥71
≥358
≥71
≥239
Week 68*
Day 476
≥ 421
≥ 421
NA
NA
NA
NA
NA
* Safety follow up visit. Only for subjects who do not enter the Extension Study MLN002SC-3030.


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7.2
Analysis Sets
7.2.1
Full Analysis Set (FAS)
The FAS will include all randomized subjects who receive at least 1 dose of study drug. Subjects 
who only receive induction IV therapy and not randomized into the maintenance phase will not 
be included in the FAS. Subjects in this set will be analyzed according to the treatment they were 
randomized to receive.
The FAS will be used for the efficacy analysis with exception of corticosteroid-free remission, 
which will be based on a subset of the FAS subjects with baseline concomitant oral 
corticosteroid use.
7.2.2
Per-Protocol Set (PPS)
The PPS is a subset of the FAS. The PPS consists of all subjects who do not violate the terms of 
the protocol in a way that would impact the study output significantly. All decisions to exclude 
subjects for the PPS dataset will be made prior to the unblinding of the study. Additional 
exclusion from the PPS may be finalized as part of a final data review and documented prior to 
database lock.
Analyses using the PPS may be provided as a sensitivity analysis.
7.2.3
Safety Analysis Set
The Safety Analysis Set (SAF) will include all subjects who receive at least 1 dose of study SC 
(placebo or vedolizumab) drug. Subjects in this set will be analyzed according to the treatment 
that was actually received. SAF-I will include all subjects who receive at least 1 induction dose, 
but were not randomized to maintenance phase. SAF-C will include all subjects who receive at 
least 1 dose of vedolizumab IV.
7.2.4
Pharmacokinetic Set
The PK evaluable population is defined as all subjects who receive at least 1 dose of study SC 
(placebo or vedolizumab) drug and have sufficient blood sampling to allow for PK evaluation.
PK-C will include all subjects who receive at least 1 dose of vedolizumab IV and have sufficient 
blood sampling to allow for PK evaluation. PK-I is all subjects who receive at least 1 induction 
dose but were not randomized into maintenance phase, with sufficient blood sampling to allow 
for PK evaluation.
7.3
Disposition of Subjects
A subject disposition summary will be provided. Subjects’ study completion data, including 
reasons for premature termination, will be provided in listings and be summarized. Significant 
protocol deviations captured on the electronic case report form (eCRF) will be summarized. A 
summary of screening failures will also be provided.


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7.4
Demographic and Baseline Characteristics
Demographic variables will be summarized for the SAF-C. If the actual treatment of any patient 
is different from the randomized treatment, the demographic variables will also be summarized 
for the FAS.
For continuous variables (age, weight, height, and body mass index [BMI]), summary statistics 
will be generated. BMI (in kg/m2) will be calculated using the subject’s baseline height and 
weight measurements and summarized. For categorical variables, the number and percentage of 
subjects in each category will be presented.
The following UC-related baseline characteristics will be summarized for subjects in the FAS: 

Duration of UC (<1 year, ≥1 to <3 years, ≥3 to <7 years, ≥7 years).

Subjects without concomitant corticosteroids or immunomodulators.

Subjects with only concomitant corticosteroids.

Subjects with only concomitant immunomodulators.

Subjects with concomitant corticosteroids and immunomodulators.

Subjects with prior tumor necrosis factor-alpha (TNF-α) antagonist use.

Subjects with prior immunomodulator and prior TNF-α antagonist failure.

Worst prior treatment failure (subjects with prior TNF-α anatomist failure, subjects with prior 
immunomodulator failure, subjects with prior corticosteroid failure). 

Baseline disease activity (baseline Mayo score: Mild <6, moderate=6 to 8, severe=9 to 12).

Baseline fecal calprotectin (≤250 µg/g, >250 to ≤500 µg/g, >500 µg/g).

Disease localization (proctosigmoiditis, left-sided colitis, extensive colitis, or pancolitis).

Smoking status.

Extraintestinal manifestations.
7.5
Medical History and Concurrent Medical Conditions
Medical history and concurrent medical conditions will be presented in a data listing and will be 
summarized for the SAF.
7.6
Medication History and Concomitant Medications and Procedures
All medication history and concomitant medications will be coded by therapeutic classification, 
subclassification, and medication using the World Health Organization Drug Dictionary 
(WHODrug). A concomitant medication is defined as a medication that is ongoing as of Study 
Day 1, ends on or after Study Day 1, or starts on or after Study Day 1 and no more than 127 days 
after the last dose of study drug.


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The number and percentage of subjects taking each concomitant medication during the induction 
phase and 46-week maintenance phase will be summarized for the SAF. Additional summary 
will be for SAF-I during the induction phase. A subject with 1 or more concomitant medications 
within the same level of the WHODrug classification will be counted only once in that level.
WHODrug preferred term and therapeutic classification will be used for summary:

Medication history that the study subjects stopped taking within 30 days prior to the 
Screening Visit.

Concomitant medications that started and stopped prior to Baseline.

Concomitant medications that started prior to and were ongoing at Baseline.

Concomitant medications that started after Baseline.

Concomitant medications that were ongoing at Baseline and those that started after Baseline.
Concomitant procedures will not be coded, but will be presented in listings for each subject.
7.7
Study Drug Exposure and Compliance
Overall study drug compliance (%) will be determined as (total count of complete injections or 
infusions taken / total number of injections or infusions expected during study treatment) 
100%. A subject must receive at least 75% of the infusion in order for it to be considered 
complete for each dose.
The total number of days on study drug (exposure) will be calculated as (date of last dose of 
study drug - date of first dose of study drug) + 127 days. Any gaps in dosing will be ignored 
when calculating the total. If last dose date is missing, then 127 days will be imputed as 
treatment period. Summary statistics for the total number of days on study drug and overall 
compliance will be generated for the SAF. 
The number and percentage of subjects with overall study drug compliance of <80%, 80 to 
<90%, and 90% will also be summarized for the SAF. Subjects with unreturned study drug will 
be assumed to have injected study drug Q2W for each 2 weeks of exposure for the calculation of 
overall compliance. Subjects with overall compliance 100% will be set to 100% in the analysis.
In addition, diary compliance will be determined as the percentage of days during treatment with 
a diary entry:
Diary Compliance = 
(Number of days with diary entries collected during treatment period)/(Number of days
with diary entries expected during treatment period) × 100%
7.8
Efficacy Analysis
The FAS will be used for the summary of the efficacy endpoints with exception of 
corticosteroid-free remission, which will be based on a subset of FAS subjects with baseline 
concomitant oral corticosteroid use.


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7.8.1
Primary Efficacy Endpoint
The primary endpoint is proportion of subjects with clinical remission, defined as a complete 
Mayo score of ≤2 points and no individual subscore >1 point, at Week 52.
The null and alternative hypotheses for the primary efficacy endpoint, clinical remission at 
Week 52, are: 
H0: Clinical Remission Vedolizumab SC at Week 52 = Clinical Remission Placebo at Week 52
versus
HA: Clinical Remission Vedolizumab SC at Week 52 ≠Clinical Remission Placebo at Week 52
Clinical remission at Week 52 will be analyzed in the FAS using Cochran-Mantel-Haenszel 
(CMH) tests stratified by randomization stratification factors according to: 
!
Concomitant use of oral corticosteroids.
!
Clinical remission status at Week 6.
!
Previous TNF-α antagonists failure or concomitant immunomodulator (azathioprine or
6-mercaptopurine) use.
Descriptive statistics will be presented by treatment group. Count, percentage and associated 
95% CI using the Clopper-Pearson method will be provided for each treatment group. The 
statistical significant treatment effect will be tested against 2-sided alpha level of 0.05. The 
p-value and point estimate of treatment difference based on the CMH method adjusted for 
stratification factors along with 95% confidence interval will be presented. The absolute 
treatment difference based on crude estimates with 95% CI using the normal approximation 
method will be displayed as well. If the number of remissions is too small (e.g., ≤ 5), the exact 
method (e.g., Fisher’s Exact test and exact unconditional confidence limits) will be performed 
instead. All subjects with missing data for determination of clinical remission at Week 52 will be 
considered as non-remitters in the analysis.
7.8.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
!
Proportion of subjects with mucosal healing, defined as Mayo endoscopic subscore of 
≤1 point, at Week 52.
!
Proportion of subjects with durable clinical response, defined as clinical response at Weeks 6 
and 52, where clinical response is defined as a reduction in complete Mayo score of ≥3 
points and ≥30% from Baseline (Week 0) with an accompanying decrease in rectal bleeding 
subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point.
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
Proportion of subjects with durable clinical remission, defined as clinical remission based on 
complete Mayo score at Weeks 6 and 52.

Proportion of subjects with corticosteroid-free remission, defined as subjects using oral 
corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in 
clinical remission based on complete Mayo score at Week 52.
Mucosal healing at Week 52, durable clinical response and durable clinical remission will be 
analyzed for the FAS subjects. Corticosteroid-free remission at Week 52 will be analyzed in a 
subset of the FAS subjects with baseline concomitant oral corticosteroid use. All secondary 
endpoints will be analyzed using CMH tests for risk differences, stratified by randomization 
stratification factors. The descriptive statistics will be presented for each of the secondary 
endpoints in a similar way to the primary endpoint.
The null and alternative hypotheses for the first secondary efficacy endpoint, mucosal healing at 
Week 52, are: 
H0: Mucosal Healing Vedolizumab SC at Week 52 = Mucosal Healing Placebo at Week 52
versus
HA: Mucosal Healing Vedolizumab SC at Week 52 ≠Mucosal Healing Placebo at Week 52
The null and alternative hypotheses for the second secondary efficacy endpoint, durable clinical 
response at Week 6 and 52, are: 
H0: Durable Clinical Response Vedolizumab SC at Week 52 = Durable Clinical Response Placebo at 
Week 52
versus
HA: Durable Clinical Response Vedolizumab SC at Week 52 ≠Durable Clinical Response Placebo at 
Week 52
The null and alternative hypotheses for the third secondary efficacy endpoint, durable clinical 
remission at Week 6 and 52, are: 
H0: Durable Clinical Remission Vedolizumab SC at Week 52 = Durable Clinical Remission Placebo at 
Week 52
versus
HA: Durable Clinical Remission Vedolizumab SC at Week 52 ≠Durable Clinical Remission Placebo at 
Week 52
The null and alternative hypotheses for the fourth secondary efficacy endpoint, corticosteroid-
free remission at Week 52, are: 
H0: Corticosteroid-free Remission Vedolizumab SC at Week 52 = Corticosteroid-free Remission Placebo at 
Week 52
versus


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HA: Corticosteroid-free Remission Vedolizumab SC at Week 52 ≠Corticosteroid-free Remission Placebo at 
Week 52
To control the overall Type I error rate for the comparison between vedolizumab SC and placebo 
groups for the primary and secondary endpoints, a hierarchical approach will be applied to the 
statistical testing of the secondary endpoints. The statistical inference for the first secondary 
endpoint of mucosal healing will only be performed if the primary endpoint, proportion of 
subjects with clinical remission at Week 52, is statistically significant (p < 0.05). The second 
secondary endpoint of durable clinical response will only be tested if the first secondary endpoint 
is statistically significant (p < 0.05). Similarly, the third secondary endpoint of durable clinical 
remission will only be tested if the second secondary endpoint is statistically significant (p < 
0.05), and the fourth secondary endpoint of corticosteroids-free clinical remission will only be 
tested if the third secondary endpoint is statistically significant (p < 0.05). 
Secondary efficacy endpoints will be analyzed in a similar way to the primary efficacy endpoint. 
The descriptive statistics of treatment effects and corresponding 95% CIs for the vedolizumab IV 
arm versus placebo for each of the secondary endpoints will be presented. The exact method will 
be performed if the number of observations is too small (e.g., ≤ 5). 
7.8.3
Patient Reported Outcomes (PROs) Endpoints
7.8.4
Exploratory and additional Efficacy Endpoints
7.8.5
Subgroup Analysis
Descriptive analyses will be performed on the primary and all secondary endpoints to summarize 
the treatment effects across subpopulations. The treatment effect in proportions in Vedolizumab 
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SC and placebo and associated 95% confidence interval using Clopper-Pearson method will be 
provided for each subgroup. Point estimate of the absolute treatment difference between 
Vedolizumab SC and placebo based on crude estimate and associated 95% confidence interval 
(using normal approximation method) will be presented. If the number of events is too small (ie, ≤ 
5), the exact method will be performed instead. The results will be tabulated and the corresponding 
forest plots for the subgroup analyses will be presented as well.
For subgroup analysis by prior use of anti-TNFα antagonist only, nominal p-value will be obtained 
by the CMH test stratifying by baseline concomitant use of oral corticosteroids (Yes/No) and 
remission status at week 6 (Yes/No), or Fisher’s exact test in the event of small number 
responders (ie, ≤ 5).
If the value of the baseline grouping variable cannot be determined, the subject will be excluded 
from the corresponding subgroup analysis. If the number of subjects in any subgroup is less than 
10, that subgroup will not be presented. 
Subpopulations will be defined by the following baseline characteristics. 

Age (<35, ≥35 to <65, ≥65 years).

Gender.

Race (Asian, Black or African American, White, Other).

Duration of UC (<1 year, ≥1 to <3 years, ≥3 to <7 years, ≥7 years).

Geographic region (Appendix C).

Baseline disease activity (baseline complete Mayo score: Mild <6, Moderate=6 to8, 
Severe=9 to 12).

Baseline fecal calprotectin (≤250 µg/g, >250 to ≤500 µg/g, >500 µg/g).

Disease localization (proctosigmoiditis, left-sided colitis, extensive colitis, or pancolitis).

Clinical remission status at Week 6.

Prior TNF-α antagonist therapy (naïve, failure. Failure will be further categorized by type of 
failure – Inadequate response, Loss of response, Intolerance). 

Prior immunomodulator and TNF-α antagonist failure (Y/N)

Prior corticosteroids failure (Y/N) 

Prior immunomodulator failure (Y/N) 

Concomitant therapies: corticosteroids and immunomodulators (Concomitant corticosteroids 
only, concomitant immunomodulators only, concomitant corticosteroids and 
immunomodulators, no concomitant corticosteroids or immunomodulators).

Worst prior treatment failure (subjects with prior TNF-α antagonist failure, subjects with 
prior immunomodulator failure but not TNF-α antagonist failure, subjects with prior 
corticosteroid failure). 


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7.8.6
Sensitivity Analysis
Analyses using the PPS population may be provided as a sensitivity analysis for primary 
endpoint and all secondary endpoints.
The Complete Mayo score and Partial Mayo score for each patient will be calculated for post-
Screening visit per FDA Draft Ulcerative Colitis guidance (August 2016). Refer to Section 
7.1.2.2 for details. Primary efficacy endpoint and all secondary endpoints will be derived using 
this FDA-guided Mayo score calculation convention. Sensitivity analysis will be performed for 
primary efficacy endpoint, all secondary endpoints, and subgroup analysis by prior use of anti-
TNFα antagonist.
In addition, if any clinical site has detected or reported significant noncompliance with 
regulatory requirements during the course of study, additional sensitivity analysis will be 
conducted for the primary efficacy endpoint in the FAS excluding all subjects from that 
particular site. 
7.9
Pharmacokinetic/Pharmacodynamic Analysis
Vedolizumab serum concentrations will be summarized by scheduled time points using 
descriptive statistics. Individual serum concentration data versus time will be presented in a data 
listing.
7.10
Other Outcomes
7.10.1 Immunogenicity Endpoints
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7.10.2 Histological Endpoints
7.10.3 Resource Utilization and Patient-Reported Outcome Endpoints
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7.11
Safety Analysis
All safety analyses will be performed using the SAF unless otherwise specified. Data will be 
summarized by treatment groups. No statistical inference will be made for safety analyses.
7.11.1 Adverse Events
All AEs will be coded using the Medical Dictionary for Regulatory Agencies (MedDRA). 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts or worsens on 
or after Study Day 1 (defined as day first dosed), and no more than 18 weeks/126 days after the 
last dose of study drug. All TEAEs will be listed by subject number and MedDRA coding. A 
listing of all unique coded terms will also be provided.
The number and percentage of subjects with TEAEs will be summarized in several different 
tables, in addition, exposure adjusted AE rates will be summarized as well:

An overview TEAE table in SAF-C.

All TEAEs by system organ class (SOC), high level term (HLT), and preferred term (PT).

Treatment-emergent adverse events of special interested (AESIs) (ie, serious infections 
including opportunistic infection such as PML, malignancies, liver injury, infusion reactions, 
injection site reactions and hypersensitivity).

Treatment-related TEAEs by SOC, HLT, and PT.

Serious TEAEs which occur on or after the first dose date and up to 18 weeks/126 days after 
the last dose date of the study drug in subjects who do not enroll in open-label extension 
study or up to the first dose of the open-label extension study in those who do.

Most frequent TEAEs by HLT and PT (sorted by frequency of HLT occurring in 5% of 
subjects). 

Most frequent treatment-related TEAEs by HLT and PT (sorted by frequency of HLT 
occurring in 2% of subjects). 

Severity of all TEAEs by SOC and PT (mild, moderate, or severe).

Severity of treatment-related TEAEs by SOC and PT (mild, moderate, or severe).

Relationship to study drug for all TEAEs by SOC and PT (not related, related).

Exposure-adjusted TEAEs and serious TEAEs by SOC, HLT, and PT

Exposure-adjusted treatment-emergent infections and serious treatment-emergent infections 
by SOC, HLT, and PT

Subject mapping of TEAEs by SOC, HLT, and PT
A subject with 2 or more TEAEs within the same level of the MedDRA term will be counted 
only once in that level using the most extreme incident (most severe for the severity tables and 
related for the relationship to study drug tables). 


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Additional summaries of TEAEs will be provided that only include TEAEs that occur in the 
Maintenance Phase between the Week 6 dose and 18 weeks/126 days after the last dose date of 
the study drug, or up to the first dose of the OLE study, whichever comes first.
Additionally, treatment-emergent SAEs, deaths, and TEAEs resulting in premature 
discontinuation from study drug will be listed and summarized by SOC, HLT, and PT. The most 
frequent treatment-emergent non-serious AEs will also be summarized by SOC, HLT, and PT.
A pretreatment event (PTE) will be defined as an AE that starts before Study Day 1. A list of 
pretreatment AEs by subject number and MedDRA coding will be presented separately. 
Pretreatment AEs will be summarized by SOC and PT using SAF.
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory variables will be summarized by treatment groups using descriptive statistics 
for baseline, postbaseline, and change from baseline to postbaseline values in SAF. Additional 
summary tables may be provided in SAF-I.
Individual results for clinical hematology and chemistry laboratory tests that are within the 
predefined “markedly abnormal laboratory value (MAV) criteria” (Appendix A) will be 
summarized in tables. All clinical laboratory data will be presented in data listings.
Elevated hepatic parameters will be summarized.
Summaries and listings of laboratory data will be presented in Système International (SI) and 
conventional units. MAV tables and listings will be presented in the unit specified in the MAV 
criteria in Appendix A.
7.11.3 Vital Signs
Vital signs will be summarized by treatment using descriptive statistics for Baseline, 
postbaseline, and change from Baseline to postbaseline values. 
Individual vital signs which meet predefined criteria for abnormal changes from Baseline of vital 
signs (Appendix B) will be summarized in tables. All vital sign data will be presented in data 
listings.
7.11.4 12-Lead ECGs
ECG results will be interpreted using 1 of the following categories: within normal limits, 
abnormal but not clinically significant, or abnormal and clinically significant. The shift in ECG 
interpretation from Baseline will be summarized by treatment group. 
All ECG data will be presented in a data listing.
7.11.5 Other Observations Related to Safety
Physical examination results will be presented in a data listing and will not be summarized. PML 
checklist data will be presented in data listings.
Data from the LTFU survey will be summarized descriptively.


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7.12
Interim Analysis
No interim analysis is planned. 
7.13
Changes in the Statistical Analysis Plan 
CCI


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8.0
REFERENCES
Ratitch, B.R., Lipkovich, I. and O’Kelly, M. (2013). Combining Analysis Results from Multiply 
Imputed Categorical Data. PharmaSUG Proceedings 2013 - Paper SP03.
https://www.pharmasug.org/proceedings/2013/SP/PharmaSUG-2013-SP03.pdf.


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Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
Hemoglobin
<0.8 × LLN,
>1.2 × ULN
Hematocrit
<0.8 × LLN,
>1.2 × ULN
RBC count 
<0.8 × LLN, 
>1.2 × ULN
WBC count 
<2.0 ×103/L
>1.5 × ULN
Platelet count
<70 ×103/L
>600 × 103/L
RBC=red blood cell, WBC=white blood cell. LLN=lower limit of normal, ULN=upper limit of normal.
Chemistry—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
ALT
--
>3x ULN
AST
--
>3x ULN
GGT
--
>3x ULN
Alkaline phosphatase
--
>3x ULN
Total bilirubin
--
>2.0 mg/dL
Albumin
<2.5 g/dL
--
Total protein
<0.8x LLN
>1.2x ULN
Creatinine
--
>2.0 mg/dL
Sodium
<130 mEq/L
>150 mEq/L
Potassium
<3.0 mEq/L
>6.0 mEq/L
Bicarbonate
<8.0 mmol/L
--
Chloride
<75 mmol/L
>126 mmol/L
Calcium
<1.50 mmol/L
>3.25 mmol/L
Glucose
≤2.8 mmol/L
≥20 mmol/L
Phosphorous
<0.52 mmol/L
>2.10 mmol/L
CPK
--
>5x ULN
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, CPK=creatine 
phosphokinase, LLN=lower limit of normal, ULN=upper limit of normal.


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Appendix B
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Criterion Value
Change Relative to Baseline
Pulse
120 beats/min
50 beats/min
Systolic blood pressure
180 mm Hg
85 mm Hg
Diastolic blood pressure
110 mm Hg
50 mm Hg
Body temperature
<35.6 °C
>37.7 °C


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Appendix C
Mayo Score Calculation Worksheet
Complete and Partial Mayo Scoring “Points to Remember”
The Mayo Score is widely used in clinical trials to assess Ulcerative Colitis disease activity. It is a combination of
two patient-reported and two physician-determined components. The Partial Mayo Score includes only the Stool 
Frequency, Rectal Bleeding, and PGA subscores. (Does not include endoscopy) 
Sub Scores
Stool Frequency
(Patient)
0 = Normal number of stools for this 
patient
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than 
normal
Stool frequency WILL:
Be derived from patient reported diary data in IVRS and 
will be the average of 3 days prior to visit

Be variable from patient to patient. Instruct patients to set the 
baseline of “normal” to whatever is “normal” for them. (eg, A 
patient normally has 1 stool per day and today has had 4 
stools. Therefore the patient has had 3 more than “normal”, 
which yields a value of 2 for that day)

Be defined as the passage of solid or liquid fecal material. 
Episodes of incontinence count. A non-productive trip to the 
bathroom or the simple passage of gas DO NOT COUNT as a 
stool.
Rectal Bleeding
(Patient)
0 = No blood seen 
1 = Streaks of blood with stool less 
than half the time 
2 = Obvious blood with stool most of 
the time 
3 = Blood alone passes
Rectal bleeding WILL:

Be derived from patient reported diary data in IVRS and will 
be the average of 3 days prior to visit

Represent the most severe bleeding of the day. Hemorrhoidal 
bleeding DOES NOT COUNT.
Findings on Endoscopy
(Physician)
0 = Normal or inactive disease 
1 = Mild disease (erythema, 
decreased vascular pattern, 
mild friability)
2 = Moderate disease (marked 
erythema, lack of vascular 
pattern, friability, erosions)
3 = Severe disease (spontaneous 
bleeding, ulceration)
Findings on Endoscopy WILL:

Be documented by photographic evidence

Be classified by the worst affected segment if mucosal 
appearance varies

Be characterized as follows
Moderate: Bleeds to touch (forceps applied to colonic 
mucosa for 1 second)
Severe: Bleeds spontaneously 

Endoscopy should be performed by the same endoscopist for 
any given patient


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Physician’s Global Assessment
(Physician)
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Physician’s Global Assessment WILL:

Be based on the patient’s overall status on the day of visit

Reflect how the patient is doing at present. Assessment 
SHOULD NOT reflect past disease severity or complexity or 
the number/kinds of medications the patient is receiving.

Be based on the
Other 3 components of the Mayo score
Patient’s recollection of abdominal discomfort and general 
sense of well-being
Patient’s performance status, fecal incontinence, and mood
Physician's observations and physical exam findings

Reflect disease activity, NOT disease severity (eg. Do not 
automatically give a high PGA to patients with pancolitis or 
severe/complicated disease, or patients requiring multiple 
medications.)

Subscores representing the average of 3 days of patient diary data can be obtained from the IVRS subscore 
report. If calculated manually, subscores should be rounded to the nearest integer.

The Mayo score is equal to the sum of the subscores.


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Appendix D
Geographic Regions
Region
Countries
North America
Canada
United States
South America
Argentina
Mexico
Brazil
Columbia
Western/ Northern Europe
Belgium
Italy
Spain
Denmark
Lithuania
Sweden
Germany
Netherlands
United Kingdom
Central Europe
Czech Republic
Hungary
Serbia
Poland
Slovak Republic
Eastern Europe
Bosnia and Herzegovina
Estonia
Turkey
Bulgaria
Israel
Ukraine
Croatia
Russia
Asia / Africa / Australia
Australia
South Africa
Japan
Republic of Korea


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Appendix E
AEs of Special Interest
Events
MedDRA Terms or definitions
Malignancies
SOC: NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS)
Infections
SOC: INFECTIONS AND INFESTATIONS
Infusion Related Reactions
Analysis for these AEs will occur on two levels:

Investigator defined Infusion Related Reactions (as indicated on the AE CRF).

All AEs that occur on or one calendar day after the infusion date.
Injection site reaction
Injection Site Reaction (HLT)
Hypersensitivity Reactions
Anaphylactic/anaphylactoid shock conditions SMQ (broad).
Angioedema SMQ (broad).
Hypersensitivity SMQ (broad).
PML
Human polyomavirus infection PT
JC virus infection PT
Leukoencephalopathy PT
Progressive multifocal leukoencephalopathy PT
JC virus CSF test positive PT
Polyomavirus test positive PT
JC polyomavirus test positive PT
Liver injury
Cholestasis and jaundice of hepatic origin SMQ (Broad) 
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions SMQ 
(Broad)
Hepatitis, non-infectious SMQ (Broad) 
Liver related investigations, signs and symptoms SMQ (Narrow) 
Liver infections SMQ (Broad)


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Appendix F
Prior Therapies
Systemic Corticosteroids
Immunomodulators
TNFα Antagonists
CRF label
Systemic Corticosteroids
Azathioprine
Infliximab
Budesonide
6-Merrcaptopurine
Adalimumab
Methotrexate
Golimumab


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Appendix G
Patient Reported Outcomes
Table G1: Patient Reported outcomes – IBDQ, EQ-5D and WPAI-UC
Variable
Subscore
Calculation
IBDQ
IBDQ bowel symptoms score
Sum of (Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, Q29), 
Ranging from 10 to 70, 10 questions
IBDQ emotional function score
Sum of (Q3, Q7, Q11, Q15, Q19, Q21, Q23, Q25, Q27, Q30, Q31, 
Q32), Ranging from 12 to 84, 12 questions
IBDQ social function score
Sum of (Q4, Q8, Q12, Q16,Q28), Ranging from 5 to 35, 5 
questions
IBDQ systemic symptoms score
Sum of (Q2, Q6, Q10, Q14,Q18), Ranging from 5 to 35, 5 
questions
Note
For each component score above, if 50% or less of the component score is missing at a visit, the MEAN 
of the remaining component score will be imputed as the value for the missing component score. If more 
than 50% of the component score is missing for the item, the imputed value will be set to missing.
IBDQ score
Sum of (bowel, emotion, social, system)
Note
If any of the component score is missing at a visit, the imputed value will be set to missing.
EQ-5D
EQ5D mobility component score
Ranging from 1 to 3
EQ5D self-care component score
Ranging from 1 to 3
EQ5D usual activities component
score
Ranging from 1 to 3
EQ5D pain/discomfort component 
score
Ranging from 1 to 3
EQ5D anxiety/depression component 
score
Ranging from 1 to 3
Note
If 2 or less out of 5 of the components are missing at a visit, the MEAN of the remaining component 
score will be imputed as the value for the missing component score. If 3 or more components are missing, 
the imputed value will be set to missing.
WPAI-
UC
Percentage of work time missed 
because of UC in the past seven days
Q2/(Q2+Q4)
Percentage of impairment 
experienced while at work in the past 
seven days because of UC
Q5/10
Overall work productivity loss
Q2/(Q2+Q4)+ [(1- Q2/(Q2+Q4))×Q5/10]
Percentage of impairment in daily 
activities due to UC in the past 7 days
Q6/10


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