Clinical trial NCT02497469
Conditions: Colitis, Ulcerative
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2015-06-29; Completion date: 2019-01-18
Enrollment: 771 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of vedolizumab intravenous (IV) treatment compared to adalimumab subcutaneous (SC) treatment over a 52-week treatment period.

Detailed description:
The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat people who have ulcerative colitis. This study will look at the stool frequency, rectal bleeding and findings on endoscopy of people who take vedolizumab compared to those who take adalimumab.

The study will enroll approximately 658 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Vedolizumab 300 mg IV
* Adalimumab 160 mg on Day 1 followed by 80 mg on Week 2 then 40 mg every 2 weeks SC

All participants will receive 1 intravenous infusion on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. All participants will also receive 4 SC injections on Day 1 or 2 SC injections each on Days 1 and 2, followed by 2 SC injections in 1 day on Week 2 and then 1 SC injection every 2 weeks for up to Week 50. All participants will be asked to record the symptoms of ulcerative colitis in a daily diary.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is 79 weeks. Participants will make approximately 11 visits to the clinic, and will be contacted by telephone 6 months after last dose of study drug for a follow-up assessment.

Arms: arm 1: Vedolizumab 300 milligram (mg), infusion, intravenously over 30 minutes on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. Adalimumab placebo-matching injection, subcutaneously on Day 1, Week 2, and every 2 weeks thereafter up to Week 50. arm 2: Adalimumab 160 mg, injection, subcutaneously on Day 1, adalimumab 80 mg, injection, subcutaneously at Week 2, then adalimumab 40 mg, injection, subcutaneously every 2 weeks thereafter up to Week 50. Vedolizumab placebo-matching infusion, intravenously on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46.
Interventions: intervention 1: Vedolizumab intervention 2: Adalimumab placebo intervention 3: Adalimumab intervention 4: Vedolizumab placebo
Intervention descriptions: intervention 1: Vedolizumab infusion intervention 2: Adalimumab placebo-matching injection intervention 3: Adalimumab injection intervention 4: Vedolizumab placebo-matching infusion

Protocol documents:
Prot_000.pdf: 


•
Title: A Randomized, Double-Blind, Double-Dummy, Multicenter, Active-Controlled Study to 
Evaluate the Efficacy and Safety of Vedolizumab IV Compared to Adalimumab SC in Subjects 
with Ulcerative Colitis
NCT Number: NCT02497469
Protocol Approve Date: 26 February 2014 
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.


PROTOCOL
A Randomized, Double-Blind, Double-Dummy, Multicenter, Active-Controlled Study to 
Evaluate the Efficacy and Safety of Vedolizumab IV Compared to Adalimumab SC in 
Subjects With Ulcerative Colitis 
Efficacy and Safety of Vedolizumab IV Compared to Adalimumab SC in Subjects With 
Ulcerative Colitis
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway, Deerfield, IL 60015, USA
Takeda Development Centre Europe, Ltd.
61 Aldwych, London, WC2B 4AE, United Kingdom
Takeda Development Center Asia, Pte. Ltd.2 
Shenton Way#15-02, SGX Centre 1. Singapore 068804
Study Number:
MLN0002-3026
IND Number:
009125
EudraCT Number:
2015-000939-33
Compound:
Vedolizumab IV
Date:
26 February 2014 
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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


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


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


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ....................................................................................................10
3.0
STUDY REFERENCE INFORMATION ......................................................................13
3.1
Study-Related Responsibilities.................................................................................13
3.2
Principal Investigator/Coordinating Investigator ......................................................13
3.3
List of Abbreviations ...............................................................................................14
3.4
Corporate Identification...........................................................................................15
4.0
INTRODUCTION.........................................................................................................16
4.1
Background .............................................................................................................16
4.1.1
Ulcerative Colitis and Current Treatments ...............................................................16
4.1.2
Vedolizumab IV.................................................................................................17
4.1.2.1 Nonclinical...................................................................................................18
4.1.2.2 Human Experience .......................................................................................18
4.1.3
Adalimumab ......................................................................................................19
4.2
Rationale for the Proposed Study.............................................................................20
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................22
5.1
Objectives................................................................................................................22
5.1.1
Primary Objective(s)..........................................................................................22
5.1.2
Secondary Objectives.........................................................................................22
5.1.3
Additional Objectives.........................................................................................22
5.2
Endpoints.................................................................................................................22
5.2.1
Primary Endpoints .............................................................................................22
5.2.2
Secondary Endpoints..........................................................................................22
5.2.3
Additional Endpoints .........................................................................................23
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................25
6.1
Study Design ...........................................................................................................25
6.2
Justification for Study Design, Dose, and Endpoints ................................................26
6.3
Premature Termination or Suspension of Study or Investigational Site.....................27
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................27
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........27
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................27


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............28
7.1
Inclusion Criteria .....................................................................................................28
7.2
Exclusion Criteria ....................................................................................................29
7.3
Excluded Medications..............................................................................................31
7.3.1
Permitted Medications .......................................................................................32
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................32
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................33
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................35
8.1
Study Medication and Materials...............................................................................35
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................35
8.1.1.1 Vedolizumab IV or Matching Placebo..........................................................35
8.1.1.2 Adalimumab SC or Matching Placebo..........................................................35
8.1.2
Storage...............................................................................................................35
8.1.3
Overdose............................................................................................................36
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................36
8.3
Investigational Drug Blind Maintenance ..................................................................37
8.4
Unblinding Procedure..............................................................................................37
8.5
Accountability and Destruction of Sponsor-Supplied Drugs.....................................37
9.0
STUDY PLAN ..............................................................................................................39
9.1
Study Procedures.....................................................................................................39
9.1.1
Informed Consent Procedure..............................................................................39
9.1.1.1 Pharmacogenomic Informed Consent Procedure...........................................39
9.1.2
Demographics, Medical History, and Medication History Procedure..................39
9.1.3
Physical Examination Procedure ........................................................................39
9.1.4
Weight, Height...................................................................................................40
9.1.5
Vital Sign Procedure..........................................................................................40
9.1.6
Primary Efficacy Measurement ..........................................................................40
9.1.6.1 Diary Completion and Review......................................................................40
9.1.6.2 Flexible Sigmoidoscopy and Biopsy.............................................................40
9.1.7
Documentation of Concomitant Medications......................................................40
9.1.8
Documentation of Concurrent Medical Conditions.............................................41
9.1.9
Procedures for Clinical Laboratory Samples.......................................................41
9.1.10 Fecal Calprotectin Sample Collection.................................................................42
9.1.11 Stool Sample......................................................................................................43
9.1.12 Contraception and Pregnancy Avoidance Procedure...........................................43


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9.1.13 Pregnancy ..........................................................................................................44
9.1.14 ECG Procedure..................................................................................................44
9.1.15 Pharmacogenomic Sample Collection ................................................................44
9.1.16 Immunogenicity Sample Collection ...................................................................46
9.1.17 Tuberculosis Screening ......................................................................................46
9.1.18 PML Checklist...................................................................................................46
9.1.19 Patient Reported Outcome Measures..................................................................46
9.1.19.1
Inflammatory Bowel Disease Questionnaire ...........................................46
9.1.20 Documentation of Screen Failure .......................................................................46
9.1.21 Documentation of Randomization......................................................................47
9.2
Monitoring Subject Treatment Compliance..............................................................47
9.2.1
Schedule of Observations and Procedures ..........................................................47
9.2.2
Screening...........................................................................................................47
9.2.3
Randomization...................................................................................................48
9.2.4
Final Visit or Early Termination.........................................................................48
9.2.5
Follow-up ..........................................................................................................48
9.2.6
Post Study Care..................................................................................................48
9.3
Biological Sample Retention and Destruction ..........................................................48
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................50
10.1
Definitions...............................................................................................................50
10.1.1 PTEs..................................................................................................................50
10.1.2 AEs....................................................................................................................50
10.1.3 Additional Points to Consider for PTEs and AEs................................................50
10.1.4 SAEs..................................................................................................................52
10.1.5 Special Interest AEs...........................................................................................53
10.1.6 Severity of PTEs and AEs..................................................................................53
10.1.7 Causality of AEs ................................................................................................54
10.1.8 Relationship to Study Procedures.......................................................................54
10.1.9 Start Date...........................................................................................................54
10.1.10
Stop Date .....................................................................................................54
10.1.11
Frequency ....................................................................................................54
10.1.12
Action Concerning Study Medication...........................................................54
10.1.13
Outcome.......................................................................................................55
10.2
Procedures...............................................................................................................55
10.2.1 Collection and Reporting of AEs........................................................................55


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10.2.1.1
PTE and AE Collection Period ...............................................................55
10.2.1.2
PTE and AE Reporting ...........................................................................55
10.2.1.3
Adverse Event Collection Involving Medically Anticipated Clinical 
Events ..........................................................................................................56
10.2.1.4
Special Interest AE Reporting.................................................................57
10.2.2 Collection and Reporting of SAEs......................................................................58
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................58
10.3
Follow-Up of SAEs .................................................................................................59
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....59
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................60
11.1
Adjudication Committee..........................................................................................60
11.1.1 Risk Minimization Action Plan for PML (RAMP Program) ...............................60
12.0
DATA HANDLING AND RECORDKEEPING............................................................61
12.1
CRFs (Electronic and Paper)....................................................................................61
12.2
Record Retention .....................................................................................................61
13.0
STATISTICAL METHODS..........................................................................................63
13.1
Statistical and Analytical Plans ................................................................................63
13.1.1 Analysis Sets......................................................................................................63
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................63
13.1.3 Efficacy Analysis...............................................................................................63
13.1.4 OtherAnalyses....................................................................................................64
13.1.5 Safety Analysis ..................................................................................................64
13.2
Interim Analysis and Criteria for Early Termination ................................................65
13.3
Determination of Sample Size..................................................................................65
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................66
14.1
Study-Site Monitoring Visits ...................................................................................66
14.2
Protocol Deviations..................................................................................................66
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................66
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................67
15.1
IRB and/or IEC Approval ........................................................................................67
15.2
Subject Information, Informed Consent, and Subject Authorization .........................68
15.3
Subject Confidentiality ............................................................................................69
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................69
15.4.1 Publication and Disclosure.................................................................................69
15.4.2 Clinical Trial Registration..................................................................................70


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15.4.3 Clinical Trial Results Disclosure ........................................................................70
15.5
Insurance and Compensation for Injury....................................................................70
16.0
REFERENCES..............................................................................................................71
LIST OF IN-TEXT TABLES
Table 8.a
Dose and Regimen .............................................................................................36
Table 9.a
Clinical Laboratory Tests...................................................................................42
Table 10.a
Takeda Medically Significant AE List................................................................53
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................26
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................74
Appendix B
Responsibilities of the Investigator.....................................................................76
Appendix C
Elements of the Subject Informed Consent.........................................................78
Appendix D
Investigator Consent to Use of Personal Information..........................................81
Appendix E
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity............82


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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.
Compound:
Vedolizumab IV
Title of Protocol: A Randomized, Double-Blind, 
Double-Dummy, Multicenter, Active-Controlled Study to 
Evaluate the Efficacy and Safety of Vedolizumab IV 
Compared to Adalimumab SC in Subjects With Ulcerative 
Colitis 
IND No.:
009125
EudraCT No.:
2015-000939-33
Study Number: MLN0002-3026
Phase: 3b
Study Design:
This is a phase 3b randomized, double-blind, double-dummy, multicenter, active-controlled study to evaluate the 
efficacy and safety of vedolizumab compared to adalimumab over a 52-week treatment period followed by 18-week 
follow-up period. The study will be conducted globally and will include 658 subjects with moderately to severely 
active ulcerative colitis (UC). 
On Day 1, subjects who meet the inclusion criteria and who meet none of the exclusion criteria will be randomly 
assigned in a 1:1 ratio to double-blind medication for 50 weeks. Subjects in the vedolizumab treatment group will 
receive a 300 mg intravenous (IV) infusion on Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46, as well as placebo 
subcutaneous (SC) injection on Day 1, Week 2, and once every 2 weeks (Q2W) thereafter until Week 50. 
Subjects in the adalimumab treatment group will receive a 160 mg SC injection on Day 1 (four 40 mg injections in one 
day or two 40 mg injections per day for two consecutive days), 80 mg at Week 2 (two 40 mg injections in one day), 
then 40 mg Q2W thereafter until Week 50, as well as a placebo IV infusion at Day 1 and Weeks 2, 6, 14, 22, 30, 38, 
and 46. Subjects who do not respond to treatment based on the investigator’s discretion should be withdrawn and 
treated according to standard of care. 
Primary Objectives:
To determine the effect of vedolizumab IV compared to adalimumab SC on clinical remission at Week 52.
Secondary Objectives:
To evaluate the effect of vedolizumab IV compared to adalimumab SC on mucosal healing at Week 52.
To evaluate the effect of vedolizumab IV compared to adalimumab SC on corticosteroid-free remission at Week 52.
Subject Population: Adult subjects 18-80 years inclusive with moderately to severely active UC
Number of Subjects:
Estimated total: 658 (329 per treatment group)
Number of Sites: 
Estimated total: 250 in all regions
Dose Level(s):
Vedolizumab IV 300 mg
Adalimumab SC 160 mg (four 40 mg injections), 80 mg 
(two 40 mg injections), 40 mg
Route of Administration:
Vedolizumab intravenous 
Adalimumab subcutanous


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Duration of Treatment:
52-week treatment period
Period of Evaluation:
The study includes a 3-week Screening Period, a 
52-week Treatment Period (with last dose at Week 50), 
and an 18-week Follow-up Period following last dose. 
The duration of the study will be approximately 
71 weeks. Additionally, subjects 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.
Main Criteria for Inclusion:
The subject has a diagnosis of UC established at least 6 months prior to enrollment, 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 14 days prior to randomization.
The subjects has evidence of UC extending proximal to the rectum (≥15 cm of involved colon).
The subject has had previous treatment with tumor necrosis factor–alpha (TNF-α) antagonists without documented 
clinical response to treatment or the subject is naïve to TNF-α antagonist therapy but is failing current conventional 
treatment.
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 before the 
administration of study drug. 
The subject has received any investigational or approved biologic or biosimilar agent within 60 days or 5 half lives 
prior to screening (whichever is longer).
The subject has had prior exposure to vedolizumab, natalizumab, efalizumab, adalimumab or rituximab.
Main Criteria for Evaluation and Analyses:
The primary endpoint for the study is proportion of subjects achieving clinical remission (defined as a complete Mayo 
score of ≤2 points and no individual subscore >1 point) at Week 52.
Secondary endpoints for this study are:

Proportion of subjects achieving mucosal healing (defined as Mayo endoscopic subscore ≤1 point) at Week 52.

Proportion of subjects using oral corticosteroids at Baseline who have discontinued corticosteroids and are in 
clinical remission at Week 52.
Statistical Considerations:
All efficacy analyses will be based on the full analysis set (FAS), with the exception of corticosteroid-free remission, 
which will be based on FAS subjects with baseline concomitant oral corticosteroid use. All statistical inference will be 
2-sided at a 0.05 level of significance.
All proportion-based efficacy endpoints will be analyzed using Cochran-Mantel-Haenszel (CMH) tests stratified by 
randomization stratification factors. The p-values and point estimates of risk difference along with 95% CIs will be 
provided. All subjects with missing data for determination of endpoint status will be considered as a non-responder in 
the analysis.
To control the overall Type I error rate of the primary and secondary endpoints, a hierarchical approach will be applied 
to the statistical testing of the secondary endpoints. The first secondary endpoint will only be tested if statistical 
significance is achieved with the primary endpoint, the second secondary endpoint will only be tested if statistical 
significance is achieved with the first secondary endpoint.


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Sample Size Justification: 
A sample size of 329 subjects per group will provide 86% power at 2-sided 0.05 level of significance for Week 52 
clinical remission, assuming a remission rate of 28% for vedolizumab and 18% for adalimumab; this sample size will 
also provide 80% power at 2-sided 0.05 level of significance for Week 52 mucosal healing, assuming a mucosal 
healing rate of 35% for vedolizumab and 25% for adalimumab.


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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 transaminase
ADA
anti-drug antibodies
CD
Crohn’s disease
CRP
C-reactive protein
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GALT
gut-associated lymphoid tissue
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
GI
gastrointestinal(ly)
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRQOL
health-related quality of life 
IAC
Independent Adjudication Committee
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBDQ
inflammatory bowel disease questionnaire
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
Ig
immunoglobin
INR
international normalized ratio
IRB
institutional review board
IV
intravenous(ly)
IVRS
interactive voice response system
IWRS
interactive web response system
LFT
liver function test
mAb
monoclonal antibody


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Term
Definition
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
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
TB
tuberculosis
TEAE
treatment-emergent adverse event
TNF-α
tumor necrosis factor- alpha
UC
ulcerative colitis
ULN
upper limit of normal
US
United States 
WBC
white blood cell
WHO
World Health Organization
3.4
Corporate Identification 
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Asia, TDC Europe and/or TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
4.1.1
Ulcerative Colitis 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 a chronic, relapsing, inflammatory disorder of the GI tract. 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]. 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 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 severe disease. Despite its use, the benefit is 
debatable in moderate to severely active UC [4,5]. 
Corticosteroids are often required for the 1/3 of patients who fail to respond to 5-ASAs [6,7]. 
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 [8]. 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 [9-11]. 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 [12,13]. Induction of remission with infliximab occurs in only 31% to 
39% of patients with UC [14] 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 [15]. 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 [9,10]. The TNF-α antagonists are also associated with a 
number of serious safety concerns based on their suppression of systemic immunity[9,10].
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 [16], female 
infertility [17], and a cumulative incidence of pouchitis of 50% at 10 years [18]. The limitations of 
current therapies for UC indicate that there is a significant need for safer and more effective 
therapies.
4.1.2
Vedolizumab IV
Vedolizumab (also called MLN0002) is a humanized immunoglobulin (Ig) G1 mAb directed 
against the human lymphocyte integrin α4β7. The α4β7integrin mediates lymphocyte trafficking to 
GI mucosa and gut-associated lymphoid tissue (GALT) through adhesive interaction with mucosal 
addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed on the endothelium of 
mesenteric lymph nodes and GI mucosa [19-22]. Vedolizumab binds the α4β7 integrin, 
antagonizing its adherence to MAdCAM-1 and as such, impairs the migration of gut homing 
leukocytes into GI mucosa. As a result, vedolizumab acts as a gut-selective immunomodulator 
[23]. Vedolizumab has been developed as a treatment for UC and CD, which are characterized by 
inflammation of the GI tract. 
Vedolizumab IV (also known as ENTYVIO; KYNTELES; Vedolizumab for Injection, for 
Intravenous Use; Vedolizumab Powder for Concentrate for Solution for Infusion; or MLN0002 
IV) has been granted marketing approval in several regions, including the US and European 
Union, for the treatment of adult patients with moderately to severely active UC or CD who have 
failed conventional treatment. The initial approved dosing and administration regimen consists of 


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300 mg vedolizumab IV infused intravenously, over approximately 30 minutes, at Weeks 0 and 2, 
then once every 8 weeks (Q8W) thereafter, beginning at Week 6
Previously conducted clinical studies have characterized the efficacy, safety, tolerability, 
pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of vedolizumab. 
4.1.2.1
Nonclinical
Nonclinical in vitro and in vivo studies have been conducted with vedolizumab and its murine 
homologue, Act-1. Act-1 has demonstrated clinical and histomorphologic evidence of efficacy in 
an animal model of IBD (cotton-top tamarins). Extensive nonclinical evaluations of the 
cardiovascular, acute, local, subchronic, chronic, immunologic, and reproductive toxicity of 
vedolizumab in pharmacologically responsive species (New Zealand white rabbits and 
cynomolgus monkeys) have been conducted and support its clinical development. Nonclinical 
studies also show that vedolizumab does not antagonize 4β1 integrin [23].
4.1.2.2
Human Experience
Single- and multiple-dose PK of vedolizumab IV have been studied in healthy subjects and in 
patients with moderately to severely active UC or CD and similar PK was observed. Vedolizumab 
exhibits target-mediated drug disposition; hence, its elimination is characterized by linear and 
nonlinear processes. Following IV infusion, vedolizumab serum concentrations generally fell in a 
biexponential fashion until approximately 1 to 10 µg/mL, with a linear total body clearance of 
approximately 0.157 L/day and a serum half-life of around 25 days. Thereafter, the serum 
concentrations fell in a nonlinear fashion. The volume of distribution for vedolizumab IV is 
approximately 5 L.
To date, more than 3400 subjects have received at least 1 dose of vedolizumab across all studies in 
the clinical development program (see current version of Investigator’s Brochure [IB]). Phase 3 
placebo-controlled studies enrolled 2427 subjects with UC or CD, of whom 1434 subjects were 
administered 300 mg of vedolizumab for induction followed by once every 4 weeks (Q4W) or 
Q8W for up to a total of 52 weeks and 488 subjects were administered 300 mg vedolizumab for 
induction only [24-26]. As of 20 July 2014, vedolizumab exposure has extended for ≥12 months in 
1667 subjects, ≥24 months in 1119 subjects, ≥36 months in 793 subjects, and ≥48 months in 374 
subjects.
In subjects with moderately to severely active UC (Study 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 
[24-26]. 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.


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Vedolizumab has shown an acceptable safety profile based on an analysis of safety data from both 
completed and ongoing studies (see current version of IB). In phase 1 and 2 clinical trials 
(7 completed phase 1 studies in healthy subjects and 8 completed phase 1b/2 studies in UC or CD 
patients), there was no consistent evidence of any dose-toxicity relationships, and vedolizumab 
was well-tolerated up to doses of 10 mg/kg. The majority of the safety data is from 3 
well-controlled, phase 3 clinical studies that evaluated the safety of vedolizumab for up to 12 
months in subjects with UC (Study C13006 [52 weeks]) or CD (Studies C13007 [52 weeks] and 
C13011 [10 weeks]). In addition, an interim assessment of safety was performed for the ongoing, 
uncontrolled extension study (Study C13008) for subjects who participated in Studies C13004, 
C13006, C13007, or C13011 as well as de novo subjects.
Vedolizumab has shown an acceptable and consistent safety profile in clinical trials. In the pivotal 
phase 3 studies (C13006 and C13007), the most common (≥5% and at a higher incidence than 
placebo) adverse reactions in subjects administered vedolizumab were nausea, nasopharyngitis, 
upper respiratory tract infection, arthralgia, pyrexia, fatigue, headache, and cough. Most serious 
adverse events 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 antivedolizumab antibodies 16 weeks following the last dose of 
vedolizumab. Results from the clinical program to date do not suggest an increased risk for 
malignancy with vedolizumab treatment. Overall, the safety profile following long-term treatment 
with vedolizumab in Study C13008 is consistent with safety in the completed studies. 
No cases of PML have been reported to date. 
Concomitant use of corticosteroids and/or conventional immunomodulators did not appear to be
associated with any increased rate of infections based on the comparative rates of infections in the 
phase 3 trials among subjects who had and had not received these medications. 
As of 20 July 2014, a total of 14 on-study deaths (including 1 in a placebo-treated subject) were 
reported in the vedolizumab clinical development program, including the ongoing open-label 
long-term extension study C13008. The causes of death varied and detailed information can be 
found in the current version of the IB. 
Overall, vedolizumab IV was well tolerated in clinical studies.
4.1.3
Adalimumab
Adalimumab (HUMIRA) is a recombinant human IgG1 monoclonal antibody specific for human 
tumor necrosis factor (TNF). Adalimumab was created using phage display technology resulting 
in an antibody with human derived heavy and light chain variable regions and human IgG1:k 
constant regions. Adalimumab binds specifically to TNF-alpha and blocks its interaction with the 


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p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in 
vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin 
(TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and 
immune responses. TNF plays an important role in both the pathologic inflammation and the joint 
destruction that are hallmarks of inflammatory diseases. Adalimumab also modulates biological 
responses that are induced or regulated by TNF, including changes in the levels of adhesion 
molecules responsible for leukocyte migration.
The Ulcerative colitis Long-Term Remission and maintenance with Adalimumab- (ULTRA-2) 
clinical trial was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of 
adalimumab SC in induction and maintenance of clinical remission in 494 subjects with moderate 
to-severe UC who received concurrent treatment with oral corticosteroids or immune-suppressants 
[27]. Subjects were randomly assigned to groups administered adalimumab 160 mg at Week 0, 
80 mg at Week 2, and then 40 mg or placebo once every 2 weeks (Q2W). The co-primary 
endpoints were remission at Weeks 8 and 52. Adalimumab induced statistically significant 
reponse in remission rates at both Week 8 and 52. This was observed in both group of patients 
naïve to treatment with tumor necrosis factor-alpha (TNF-α) antagonists, among subjects who had 
previously received TNF-α antagonists. Adalimumab was safe and more effective than placebo in 
inducing and maintaining clinical remission in subjects with moderate-to-severe UC who did not 
have an adequate response to conventional therapy with steroids or immunosuppressants [27-29]. 
Current treatments have been effective for many patients with UC but have numerous limitations 
indicating that there is still a need for safer and more effective therapies.
4.2
Rationale for the Proposed Study
The aim of the current study is to evaluate the efficacy and safety of vedolizumab IV compared 
with adalimumab SC in the treatment of subjects with moderately to severely active UC. UC is a 
progressive inflammatory disease that usually leads to irreversible damage to the GI tract. There is 
a growing consesus that the ultimate goal of treatment should be to achieve complete disease 
control and stop progression, thus altering the natural course of UC. The most recent therapeutic 
outcomes have expanded beyond clinical symptom control to include steroid-free remission and 
mucosal healing. Clinical remission is one of the most commonly used treatment goals for subjects 
with UC. There are different treatment agents and combinations used currently in clinical practice 
to achieve this goal. 
Mucosal healing is another important goal in UC therapy, it is associated with a potential 
improvement in quality of life, prevention of relapses, reduction in hospitalizations, reduction in 
disease complications and can potentially alter the natural course of the disease. Mucosal healing 
is assessed by colonoscopy. Mucosal inflammation manifests in its early stages with vascular 
congestion, erythema, edema and granularity. More advanced inflammation includes friability, 
spontaneous bleeding, macroscopic ulcerations, along with small or large ulcers. Many attempts 
have been made to define mucosal healing. The most commonly used endoscopic definition is the 
absence of ulcerations and inflammation. Another stricter definition of mucosal healing is the 
absence of friability, blood, erosions, and ulcers in all visualized segments of the gut. Additional 


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definitions suggest that an abnormal pattern of vascularity along with absence of the other features 
previosuly described would still be comparable with mucosal healing. There are additional 
challenges that need to be considered when looking at mucosal healing besides the definition, type 
of treatment, duration of treatment, timing of the endoscopy, and endoscopic index used. The 
Mayo score is the most commonly used index used to assess disease activity both in practice and 
clinical trials.
There are different treatment options for subjects with UC, including salicylates, steroids, 
immunomodulators, and biologics.These agents are used both alone and in combination. 
Endoscopy provides a useful way to evaluate and guide treatment response in subjects with UC. 
This study will evaluate mucosal healing, alongwith the effficacy and safety, of two current 
available treatments for subjects with moderately to severely active UC, namely,vedolizumab IV 
and adalimumab SC.
The proposed vedolizumab IV dose (300 mg at Weeks 0, 2, and 6 and Q8W, thereafter) is 
consistent with the approved label information [30].
The proposed adalimumab SC dose regimen (160 mg SC injection on Day 1, 80 mg SC injection at 
Week 2 and 40 mg Q2W thereafter) is consistent with the approved label information [10].
Pharmacogenomic analysis may be conducted to investigate the contribution of genetic variance 
on drug response, for example, its efficacy and safety. Participation of study subjects in 
pharmacogenomic sample collection is optional.
As pharmacogenomics is an evolving science, currently many genes and their function are not yet 
fully understood. Future data may suggest a role of some of these genes in drug response or 
diseases, which may lead to additional hypothesis-generating exploratory research on stored 
samples.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective(s) 

To determine the effect of vedolizumab IV compared to adalimumab SC on clinical remission 
at Week 52.
5.1.2
Secondary Objectives 

To evaluate the effect of vedolizumab IV compared to adalimumab SC on mucosal healing at 
Week 52.

To evaluate the effect of vedolizumab IV compared to adalimumab SC on corticosteroid-free 
remission at Week 52.
5.1.3
Additional Objectives 

To evaluate the safety of vedolizumab IV compared to adalimumab SC.

To evaluate the impact of vedolizumab IV on health-related quality-of-life (HRQOL) using 
inflammatory bowel disease questionnaire (IBDQ) at Weeks 30 and 52. 
In this study, samples for pharmacogenomics will be collected and stored for possible exploratory 
investigation of drug response or disease. In this study, using vedolizumab, or in a set of clinical 
trials, if variability is seen in responsiveness to study medication and it is suspected to be 
attributable to gene polymorphism, pharmacogenomics analyses may be conducted to explore 
gene polymorphism relationships, as indicated by the observations.
5.2
Endpoints
5.2.1
Primary Endpoints 

Proportion of subjects achieving 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 achieving mucosal healing (defined as Mayo endoscopic subscore 
≤1 point) at Week 52.

Proportion of subjects using oral corticosteroids at Baseline who have discontinued 
corticosteroids and are in clinical remission at Week 52.


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5.2.3
Additional Endpoints

Proportion of subjects achieving clinical response (defined as a reduction in complete Mayo 
score of ≥3 points and ≥30% from baseline [or a 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) at Week 52.

Proportion of subjects achieving clinical remission (defined as a complete Mayo score of 
≤2 points and no individual subscore >1 point) at Week 14.

Proportion of subjects with rectal bleeding subscore indicative of mild disease (≤1) at 
Week 52.

Proportion of subjects with a Physician’s Global Assessment (PGA) subscore indicative of 
mild disease (≤1) at Week 52.

Proportion of subjects with stool frequency subscore indicative of mild disease (≤1) at 
Week 52.

Proportion of subjects with complete Mayo score of ≤2 points and no individual subscore 
>1 point where rectal bleeding subscore of 0 and endoscopy subscore of 0 at Week 52.

Proportion of subjects with endoscopy subscore of 0, rectal bleeding subscore of 0, and stool 
frequency subscore decreases or no change from Baseline at Week 52.

Proportion of subjects with endoscopy subscore ≤1, rectal bleeding subscore of 0, and stool 
frequency subscore of 0 at Week 52.

Proportion of subjects with endoscopy subscore ≤1, rectal bleeding subscore of 0, and stool 
frequency subscore ≤1 at Week 52.

Proportion of subjects with endoscopy subscore ≤1, rectal bleeding subscore of 0, stool
frequency subscore decreases or no change from Baseline, and total score (sum of these 3) 
≤1 at Week 52.

Proportion of subjects with IBDQ score change of ≥16 points from Baseline to Week 52.

Proportion of subjects reaching clinical remission based on IBDQ score >170 at Week 52.

Change in oral corticosteroid use from Baseline to Week 52.

Proportion of subjects using oral corticosteroids at Baseline who have discontinued 
corticosteroids and are in clinical remission at Week 14.

Time to major UC-related events (eg, hospitalizations, colectomies, and procedures).

Change in fecal calprotectin concentrations from Baseline to Weeks 14, 30, and 52.

Proportion of subjects with a change in histology from baseline to Week 52. 


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
Safety for maintenance therapy as assessed by AEs, adverse events of special interest (AESIs, 
including serious infections including opportunistic infection such as PML, liver injury, 
malignancies, infusion-related or injection site reactions or systemic reactions and 
hypersensitivity), serious adverse events (SAEs), vital signs, results of standard laboratory 
tests (clinical chemistry, hematology, coagulation, urinalysis), and results of 12 lead 
electrocardiograms (ECGs).


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6.0
STUDY DESIGN AND DESCRIPTION.
6.1
Study Design
This is a phase 3b randomized, double-blind, double-dummy, multicenter, active-controlled study 
to evaluate the efficacy and safety of vedolizumab compared to adalimumab over a 52-week 
treatment period. The study will be conducted globally and will include 658 subjects (329 per 
treatment group) with moderately to severely active UC.
The study consists of a 3-week Screening Period, a 52-week Treatment Period (with last dose at 
Week 50), and an 18-week Follow-up Period following last dose. Additionally, subjects 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. The duration of the study will be approximately 71 weeks for all 
subjects.
Subjects who have moderately to severely active UC, defined as Mayo score 6-12 and endoscopic 
subscore ≥2 both anti-TNF-α naïve and failures, will be screened. Previous use of TNF-α therapy 
other than adalimumab will be permitted. Subjects who are naïve to TNF-α antagonist treatment 
and those who failed TNF-α therapy will be allowed to enroll; however, the proportion of TNF-α 
antagonist naïve subjects shall not exceed approximately 50% of the total number of subjects 
enrolled into the study. 
On Day 1, subjects who meet the inclusion criteria and who meet none of the exclusion criteria will 
undergo baseline evaluations and be randomly assigned in a 1:1 ratio to double-blind medication 
for 50 weeks. Randomization will be stratified by:

Concomitant use of oral corticosteroids.

Previous failure of TNF-α antagonist therapy or naïve to TNF-α antagonist therapy.
Subjects in the vedolizumab treatment group will receive a 300 mg IV infusion on Day 1 and 
Weeks 2, 6, 14, 22, 30, 38, and 46, as well as placebo SC injection on Day 1, Week 2, and Q2W 
thereafter until Week 50. 
Subjects in the adalimumab treatment group will receive a 160 mg SC injection on Day 1 (four 40 
mg injections in one day or two 40 mg injections per day for two consecutive days), 80 mg at Week 
2 (two 40 mg injections in one day), then 40 mg Q2W thereafter until Week 50, as well as a 
placebo IV infusion at Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. Subjects who do not respond 
to treatment based on the investigator’s discretion should be withdrawn and treated according to 
standard of care. After the Week 52 or End of Study Visit, all subjects will have a Follow-Up Visit, 
approximately 18 weeks (approximately 5 half-lives for vedolizumab) 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
18-week 
follow-up 
period
Follow-up 
safety survey
Treatment period
Active Vedolizumab IV and Placebo Adalimumab SC
300 
mg IV
300 
mg IV
300 mg 
IV
300 mg 
IV
300 mg 
IV
300 mg 
IV
300 mg 
IV
300 mg 
IV
300 mg 
IV
SC 
PBO
SC 
PBO
SC 
PBO 
(Q2W)
OR
Screening Period 
(Maximum 21 Days)
Active Adalimumab SC and Placebo Vedolizumab IV
160 
mg SC
80 mg 
SC
40 mg 
SC 
(Q2W)
IV 
PBO
IV 
PBO
IV 
PBO
IV 
PBO
IV 
PBO
IV 
PBO
IV 
PBO
IV 
PBO
IV 
PBO
Week
2
4
6
14
22
30
38
46
50
52/ ET
68 
Day 1
Follow-
up Visit
6 Months 
After last dose
6.2
Justification for Study Design, Dose, and Endpoints
The aim of the current study is to evaluate the efficacy and safety of vedolizumab IV compared 
with adalimumab SC in the treatment of subjects with moderately to severely active UC. Clinical 
remission is one of the treatment goals for subjects with UC. There are different treatment agents 
and combinations used currently in clinical practice to achieve this goal. 
Vedolizumab has a unique, highly gut-selective immunomodulatory mechanism of action that 
provides the basis for its development as a treatment for UC. In a pivotal phase 3 clinical trial, 
vedolizumab IV was effective for induction and maintenance therapy in subjects with UC [24].
The primary endpoint evaluated in this study will be clinical remission at Week 52. Because UC is 
a progressive disease with long-term structural and functional complications, the duration of the 
study is proposed as 52 weeks to provide a long-term comparison of the efficacy data. Other 
secondary endpoints, will include mucosal healing, corticosteroid-free remission, and additional 
endpoints will also be patient-reported outcomes (PROs) and AEs. Mucosal healing has been 
associated with better outcomes for UC patients, such as reduction in colectomies and less 
treatment failure [27]. Corticosteroid use is associated with inadequate disease control and can 
lead in some subjects to adverse reactions; therefore, minimizing corticosteroid use as a treatment 
goal will benefit subjects [28]. PROs provide a complement to the clinical data collected as they 
focus on the subject’s assessment of their disease.


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Subjects will receive vedolizumab IV 300 mg on Day 1, Weeks 2 and 6, and Q8W thereafter until 
Week 46 or adalimumab 160 mg SC on Day 1, 80 mg SC at Week 2 and 40 mg SC Q2W thereafter 
until Week 50, and subjects in each arm will receive matching placebo injections or infusions. The 
initial dosing recommendations in the dosing regiment for both vedolizumab IV and adalimumab 
SC follows the approved labels [30] [10].
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk
/benefit is no longer acceptable for subjects participating in the study. 

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study 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 institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization. 
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. The subject has moderately to severely active UC as determined by a Mayo score of 6 to 12 
with an endoscopic subscore ≥2 within 14 days prior to the randomization.
6. The subject has evidence of UC proximal to the rectum (≥15 cm of involved colon).
7. The subject with extensive colitis (up to the hepatic flexure) or pancolitis of >8 years duration 
or left-sided colitis of >12 years duration must have documented evidence that a surveillance 
colonoscopy was performed within 12 months of the initial screening visit (may be performed 
during the Screening Period).
8. The subject with a family history of colorectal cancer, personal history of increased colorectal 
cancer risk, age >50 years, or other known risk factor must be up-to-date on colorectal cancer 
surveillance (may be performed during screening).
9. The subject has had previous treatment with TNF-α antagonists without documented clinical 
response to treatment or the subject is naïve to TNF-α antagonist therapy but is failing current 
treatment.
10. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use adequate contraception* from signing of informed consent throughout 
the duration of the study and for 18 weeks after last dose. 
11. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 18 weeks after last dose. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.12 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.13 Pregnancy.


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7.2
Exclusion Criteria
The exclusion criteria are divided into 3 categories: gastrointestinal exclusion criteria, infectious 
disease exclusion criteria, and general exclusion criteria. Any subject who meets any of the 
following criteria will not qualify for entry into the study: 
Gastrointestinal Exclusion Criteria
1. The subject has clinical evidence of abdominal abscess or toxic megacolon at the Screening 
Visit.
2. The subject has had an 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 a diagnosis of Crohn’s colitis or indeterminate colitis, ischaemic colitis, 
radiation colitis, diverticular disease associated with colitis, or microscopic colitis.
5. The subject has received any of the following for the treatment of underlying disease within 30 
days of screening:
a) Non-biologic therapies (eg. cyclosporine, tacrolimus, thalidomide) other than those 
specifically listed in Section Permitted Medications For Treatment of UC.
b) An approved non-biologic therapy in an investigational protocol.
6. The subject has received any investigational or approved biologic or biosimilar agent within 60
days or 5 half lives prior to the screening (whichever is longer).
7. The subject has previously received natalizumab, efalizumab, adalimumab, or rituximab.
8. The subject has previously received vedolizumab.
9. The subject currently requires or is anticipated to require surgical intervention for UC during 
the study.
10. The subject has history or evidence of adenomatous colonic polyps that have not been 
removed, or colonic mucosal dysplasia.
Infectious Disease Exclusion Criteria 
1. The subject has evidence of an active infection during the Screening Period.
2. The subject has evidence of, or treatment for, C. difficile infection or other intestinal pathogen 
within 28 days prior to the first dose of study drug.
3. The subject has chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
4. The subject has active or latent tuberculosis (TB), regardless of treatment history, as evidenced 
by any of the following:
a) History of TB,


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b) A diagnostic TB test performed within 30 days of enrollment that is positive, defined as:
–
Positive QuantiFERON® test or 2 successive indeterminate QuantiFERON tests OR
–
A TB skin test reaction ≥10 mm (≥5 mm in subjects receiving the equivalent of 
>15 mg/day prednisone)
c) Chest X-ray within 3 months of enrollment in which active or latent pulmonary TB cannot 
be excluded.
5. The subject has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus (HIV) infection, organ transplantation).
6. The subject has any live vaccination within 30 days prior to screening or is planning to receive 
live vaccination during participation in the study.
7. The subject has a clinically significant infection (eg, pneumonia, pyelonephritis) within 30 
days prior to screening, or ongoing chronic infection.
8. The subject has used a topical (rectal) treatment with (5-ASA) or corticosteroid 
enemas/suppositories within 2 weeks of the administration of the first dose of study drug.
General Exclusion Criteria 
1. The subject has a history of hypersensitivity or allergies to vedolizumab or adalimumab.
2. 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.
3. The subject has history of lupus or lupus-related conditions.
4. The subject has had a surgical procedure requiring general anesthesia within 30 days prior to 
screening or is planning to undergo major surgery during the study period.
5. The subject has a history of malignancy, except for the following: adequately-treated 
nonmetastatic basal cell skin cancer; squamous cell skin cancer that has been adequately 
treated and that has not recurred for at least 1 year prior to screening; and history of cervical 
carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years 
prior to screening. Subject 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.
6. The subject has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, demyelinating, or neurodegenerative disease.
7. The subject has a positive PML subjective symptom checklist prior to the administration of the 
first dose of study drug.


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8. The subject has any of the following laboratory abnormalities during the Screening Period:

Hemoglobin <8 g/dL.

White blood cells (WBC) <3 × 109/L.

Lymphocyte <0.5 × 109/L.

Platelet count <100 × 109/ L or >1200 ×109/L.

ALT or AST >3 × upper limit of normal (ULN).

Alkaline phosphatase >3 × ULN.

Serum creatinine >2 × ULN.
9. 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 the Screening Visit. 
10. The subject has an active psychiatric problem that, in the investigator’s opinion, may interfere 
with compliance with study procedures.
11. The subject is unable to attend all the study visits or comply with study procedures.
12. The subject is required to take excluded medications listed in Section 7.3.
13. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 18 weeks after participating in this study; or intending to donate ova during such time 
period. 
14. If male, the subject intends to donate sperm during the course of this study or for 18 weeks 
thereafter. 
15. The subject is an immediate family member, study site employee, or is in a dependant 
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
The following medications are excluded from the study:

Any treatment for UC other than those listed in Section 7.3.1 (either approved or 
investigational).

All live vaccines, during study treatment and for at least 6 months after the last dose of study 
drug.

Either approved or investigational biological agents for the treatment of non-IBD conditions, 

Chronic nonsteroidal anti-inflammatory (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.) 


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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
The following medications are permitted during the study: 

Topical (rectal) corticosteroid enemas/suppositories.

The subject may be receiving a therapeutic dose of the following agents:
–
Oral 5-ASA compounds with a dose stable at least 2 weeks prior to screening.
–
Oral corticosteroid therapy (prednisone at a stable dose ≤30 mg/day, or equivalent steroid) 
provided that the dose has been stable for at least 4 weeks prior to screening, if 
corticosteroids have been just initiated, or 2 weeks prior to screening if corticosteroids are 
being tapered.
–
Probiotics, provided that the dose has been stable for at least 2 weeks prior to screening.
–
Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic 
diarrhea.
–
Azathioprine, 6-mercaptopurine, or methotrexate, provided that the dose has been stable 
for 8 weeks immediately prior to screening. 
Any new medication or any increase in dose of a baseline medication required to treat new or 
unresolved UC symptoms (other than anti-diarrheals for control of chronic diarrhea) is considered 
a rescue medication. Administration of a rescue medication constitutes treatment failure (ie, lack 
of efficacy) and the subject should be withdrawn from the study according to Section 7.4. 
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 case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.20.
1. Pretreatment event (PTE) or adverse event (AE). The subject has experienced a PTE or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE.

Liver Function Test (LFT) Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.9), if the following circumstances occur at any time 
during study medication treatment:
–
ALT or AST >8 × upper limit of normal (ULN), or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or


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–
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. Leukopenia or Lymphopenia. WBC and lymphocyte counts will be monitored for all subjects. 
Azathioprine, 6-mercaptopurine, or methotrexate, if applicable, should be discontinued and the 
dose of study drug held for an absolute lymphocyte count <0.5 × 109/L at any point in the 
study. The absolute lymphocyte count must be repeated at appropriate intervals as determined 
by the investigator. The next dose of study drug can be administered only if the absolute 
lymphocyte count is ≥0.5 × 109/L. If the absolute lymphocyte count remains <0.5 × 109/L, 
study drug should be discontinued and the subject withdrawn from the study
3. 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.
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
5. 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.
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
7. 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 9.1.13.
8. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
9. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.5
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.4. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 


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the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. Discontinued or withdrawn subjects will not be replaced.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to all or any of the drugs defined below.
8.1.1.1
Vedolizumab IV or Matching Placebo
The study sites will be supplied by the sponsor with the following medication in an open-label 
manner: vedolizumab IV 300 mg/vial, for single use, in 20 mL vials. The study medication will be 
provided in a glass vial as a lyophilized solid formulation for reconstitution using sterile water. 
Each vial will be packaged in an appropriately labeled single vial carton. 
The placebo infusion will be 250 mL of 0.9% sodium chloride. For both active vedolizumab and 
placebo infusions, the investigational pharmacist or designee will mask the IV bags after 
preparation in order to maintain the study blind.
All infusions will be administered IV over approximately 30 minutes. Longer infusion times of up 
to 60 minutes may be used based on study observations. Subjects should be observed for 2 hours 
following the first 2 infusions, at a minimum, and one hour after each subsequent infusion. in a 
room where appropriate treatment for infusion-related reactions is available. The subject should be 
considered clinically stable by the investigator or designee prior to discharge.
Additional reference information and administration instructions can be found in the pharmacy 
manual.
8.1.1.2
Adalimumab SC or Matching Placebo
The study sites will be supplied by the sponsor with the following medication in a blinded manner: 
adalimumab 40 mg/SC placebo in pre-filled syringes.
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.
Additional reference information and administration instructions can be found in the pharmacy 
manual. 
8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug must be transported and 


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stored under the conditions specified on the label, and remain in the original container until 
dispensed. A daily temperature log of the drug storage area must be maintained every working day.
Vedolizumab IV, adalimumab SC, and SC placebo must be stored at 2ºC to 8ºC (36ºF to 46ºF), 
protected from light. Do not freeze adalimumab SC and do not use adalimumab SC if frozen. 
The dose and regimen for the treatment groups is summarized in Table 8.a.
Table 8.a
Dose and Regimen
Treatment 
Group
Dose
Treatment Description
Active
Placebo
A
Vedolizumab IV 
300 mg/placebo
Vedolizumab IV 300 mg 
Day 1, Weeks 2, 6, 14, 22, 
30, 38, and 46 (Q8W)
Placebo for Adalimumab SC 160 mg Day 1, 
80 mg Week 2, 40 mg Weeks 4 to 50 (Q2W)
B
Adalimumab SC 
160 mg, 80 mg, 
40 mg/placebo
Adalimumab SC 160 mg 
Day 1, 80 mg Week 2, 
40 mg Weeks 4 to 50 
(Q2W)
Placebo for Vedolizumab IV 300 mg Day 1, 
Weeks 2, 6, 14, 22, 30, 38, and 46 (Q8W)
Dosing regimen follow approved vedolizumab IV and adalimumab SC labels [10,30].
8.1.3
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0, Pretreatment 
Events and Adverse Events.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Investigational Drug Assignment and Dispensing Procedures
Subjects will receive treatment according to study schedule.
The investigator or investigator’s designee will access the interactive voice response system 
(IVRS)/ interactive web response system (IWRS) at Screening to obtain the subject study number. 
The investigator or the investigator’s designee will utilize the IVRS/IWRS to randomize the 
subject into the study. During this contact, the investigator or designee will provide the necessary 
subject-identifying information, including the subject number assigned at screening. The 
medication identification (ID) number of the investigational drug to be dispensed will then be 


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provided by the IVRS/IWRS by email notification to the unblinded site pharmacist/nurse. To 
maintain the blind the IVRS/IWRS will ensure the investigator or designee is unaware of a 
medication ID assigned to the subject. If sponsor-supplied drug (vials or pre-filled syringes) is lost 
or damaged, the unblinded site staff can request a replacement from IVRS/IWRS. Refer to 
IVRS/IWRS manual provided separately.
At subsequent drug-dispensing visits, the investigator or designee will again contact the 
IVRS/IWRS to request additional investigational drug for a subject. The medication ID number of 
the investigational drug to be dispensed will be provided by the IVRS/IWRS to the unblinded site 
staff only. 
8.3
Investigational Drug Blind Maintenance 
The investigational drug blind will be maintained using the IVRS/IWRS. All subjects and study 
personnel except for those directly involved with study drug preparation will be blinded to study 
drug assignment for the entire study
8.4
Unblinding Procedure 
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding.
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the IVRS/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 the same 
information (except the time) must be recorded on the eCRF.
8.5
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee 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, the investigator or designee must maintain records of all 
sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each subject, and 
return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment by recording in IVRS/IWRS. If there are any 
discrepancies between the packing list versus the actual product received, Takeda must be 


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contacted to resolve the issue. The packing list should be filed in the investigator’s essential 
document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the Medication ID used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IVRS/IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
(vedolizumab IV 300 mg, adalimumab SC 40 mg) on a sponsor-approved drug accountability log. 
The following information will be recorded at a minimum: protocol number and title, name of 
investigator, site identifier and number, description of sponsor-supplied drugs, expiry date and 
amount dispensed including initials, seal, or signature of the person dispensing the drug, and the 
date and amount returned to the site by the subject, including the initials, seal, or signature of the 
person receiving the sponsor-supplied 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 on the drug accountability log.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
In the event of expiry date extension of sponsor-supplied drug already at the study site, 
sponsor-supplied drugs may be relabeled with the new expiry date at that site. In such cases, 
Takeda or its designee will prepare additional labels, certificates of analyses, and all necessary 
documentation for completion of the procedure at the sites.


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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.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.1.1
Pharmacogenomic Informed Consent Procedure
A separate informed consent form pertaining to storage of the sample must be obtained prior to 
collecting a blood sample for Pharmacogenomic Research for this study. The provision of consent 
to collect and analyze the pharmacogenomic sample is independent of consent to the other aspects 
of the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth or age, sex, Hispanic ethnicity 
(as applicable), race as described by the subject, and smoking status of the subject at Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.8).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped within 30 days prior to signing of informed consent.
In addition, all prior biologic medication history for the treatment of ulcerative colitis disease with 
the reason for discontinuation is to be collected for subjects where possible.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of investigational 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; 
(7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes;; and 
(11) other. All subsequent physical examinations should assess clinically significant changes from 
the assessment prior to first dose examination.


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9.1.4
Weight, Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters without decimal places and for 
weight it is kilograms (kg) with 1 decimal place. 
9.1.5
Vital Sign Procedure
Vital signs will include body temperature, respiratory rate, blood pressure, and pulse (bpm). On 
dosing days, vital signs are taken predose.
9.1.6
Primary Efficacy Measurement 
Primary and secondary efficacy assessments will be based on Mayo scores. A complete Mayo 
score will be obtained within 14 days prior to randomization to determine eligibility. Results 
obtained during Screening will be the Baseline complete Mayo score. Sigmoidoscopy will be done 
during screening, Weeks 14 and 52 (or ET visit), and complete Mayo score will be calculated for 
these visits. The baseline complete Mayo score will be used for the comparison with the Week 14 
and 52 complete Mayo score to determine response and remission at Weeks 14 and 52.
A partial Mayo score will be derived for the visits at which endoscopy will not performed. These 
scores will be used to determine clinical response or disease worsening during the study.
The Mayo endoscopic subscore determination will be based upon central readings to eliminate 
assessment bias. Refer to Appendix E for information on the Mayo Scoring System.
9.1.6.1
Diary Completion and Review
Diary entries will be made daily by subjects and will be used for Mayo score calculation. During 
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 system. Entries should be 
reviewed and monitored by the study staff. 
9.1.6.2
Flexible Sigmoidoscopy and Biopsy
Flexible sigmoidoscopy will be perfomed during screening, Week 14, and Week 52 (or ET vist). 
Results of sigmoidoscopy will be used for calculation of complete Mayo score at these visits. On 
the days sigmoidoscopy is done biopsy samples will be collected from all subjects to evaluate 
changes in histology.
Additional information regarding the sigmoidoscopy requirements and central reader assessments 
can be found in the 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 


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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.
9.1.8
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, electrocardiogram 
(ECG), or physical examination abnormalities noted at screening examination. The condition (ie, 
diagnosis) should be described.
9.1.9
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 25 mL, and the approximate total volume of 
blood for the study is 165 mL. Details of these procedures and required safety monitoring will be 
given in the laboratory manual. 
The clinical laboratory tests to be conducted during the study are summarized in Table 9.a. The 
central laboratory will perform laboratory tests for hematology, serum chemistries, and urinalysis. 
The results of laboratory tests will be returned to the investigator, who is responsible for reviewing 
and filing these results.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48-72 hours after the abnormality was noted.
(Please refer to Section 7.4 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in 
conjunction with total bilirubin >2 ×ULN.)
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements)


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry 
Urinalysis
Red blood cells
White blood cells
Hemoglobin
Hematocrit
Platelets
PT/INR
Alanine aminotransferase
Albumin
Alkaline phosphatase
Amylase
Aspartate aminotransferase 
Bicarbonate
Calcium
Chloride
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Glucose
Lipase
Magnesium
Phosphorus
Potassium
Sodium
Total and direct bilirubin
Total protein
Uric acid
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:
Serum
Urine
Stool
CRP
Hepatitis panel, including HBsAg 
and anti-HCV
ADA
Quantiferon
Pharmacogenomic sample
Follicle-stimulating hormone 
(FSH)
If menopause is suspected:
Beta hCG (female subjects of 
childbearing potential)
Urine pregnancy hCG
(female subjects of childbearing 
potential)
Fecal calprotectin
C. Difficile test
CRP=C-reactive protein, FSH=follicle-stimulating hormone, GGT= γ-Glutamyl transferase, HBsAg=hepatitis B 
surface antigen, hCG=human chorionic gonadotropin, PT=prothrombin time, RBC=red blood cells
9.1.10 Fecal Calprotectin Sample Collection
A stool sample will be collected on Day 1, Weeks 14, 30, and 52 (or ET Visit) for the analysis of 
fecal calprotectin, a biomarker of intestinal inflammatory activity.


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9.1.11 Stool Sample
A stool sample will be obtained to perform C. difficile assay. A sample will be collected and 
cultured during screening and at any point in the study when a patient becomes symptomatic, 
including worsening or return of disease activity.
9.1.12 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study medication, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with spermicidal 
cream or jelly). In addition, they must be advised not to donate sperm during this period.
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with an FSH >40 IU/L or at least 5 years since last 
regular menses, confirmed before any study medication is implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are included the only 
acceptable methods of contraception are:
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, regular urine hCG pregnancy tests will be performed only for 
women of childbearing potential and subjects will receive continued guidance with respect to the 
avoidance of pregnancy and sperm donation as part of the study procedures (Appendix A). In 
addition to a negative serum hCG pregnancy test at screening, subjects also must have a negative 
urine hCG pregnancy test prior to receiving any dose of study medication as close as possible and 
prior to first dose of study medication, preferably on the same day. 
In addition, male subjects must be advised not to donate sperm from signing of informed consent 
to 18 weeks after the last dose of study medication.
9.1.13 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 18 weeks after the last dose, should also be 
recorded following authorization from the subject’s partner. 
If the pregnancy occurs during administration of active study medication, eg, after Visit on Day 1 
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. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable).
All pregnancies in subjects on active study drug including comparator will be followed up to final 
outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted.
9.1.14 ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. 
9.1.15
Pharmacogenomic Sample Collection
When sampling of whole blood or tissue for pharmacogenomic analysis occurs, every subject must 
sign informed consent/be consented in order to participate in the study.


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Two whole blood samples (3 mL per sample) for DNA isolation will be collected into plastic K2 
ethylenediamine-tetraacetic acid (EDTA) spray coated tubes before dosing on Day 1 from each 
subject in the study, and stored under frozen conditions.
Two whole blood samples (2.5 mL per sample) for RNA isolation will be collected into 
PAXgeneTM tubes before dosing on Day 1 from each subject in the study. Samples should be 
collected on ice and stored in the 2-8°C refrigerator for a maximum of 3 days and samples will be 
frozen at -20°C or lower and shipped separately on dry ice prior to RNA extraction and storage at 
-20°C or lower.
Ileocolonoscopy tissue samples that are collected may also be used to look for changes in mRNA 
expression patterns associated with disease or response to therapy. The specimens should be 
placed into the formalin-fixed bottle prefilled with 10% neutral-buffered formalin and the second 
specimen should be placed into the RNA later bottle prefilled with RNA later solution.
DNA and RNA form the basis for the genes that make the body produce proteins such as enzymes, 
drug transporters or drug targets. DNA and RNA may be evaluated for the genetic 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 the study drug.

Finding out more information about how vedolizumab works.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to vedolizumab.

Identifying variations in genes related to the biological target of vedolizumab.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of vedolizumab and other study medications, and for improving the efficiency, design and 
study methods of future research studies.
If necessary and feasible, a second aliquot of blood may be taken if isolation of DNA from the first 
sample was not successful or possible. Please refer to the Study Manual for information on sample 
collection and preparation.
The samples will be stored for no longer than 15 years after completion of the study. No samples 
will be stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification from Takeda. “Stored samples” are defined as samples that are key-coded (the 
samples are stripped of all personal identifying information but a key links the samples to the 
clinical data collected from the sample donor) and are used in the analysis of investigational drug 
or related drugs.
Detailed instructions for the handling and shipping of samples are provided in the Study Manual.


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9.1.16 Immunogenicity Sample Collection
Blood specimens for the assessment of ADA will be collected as shown in the schedule of events, 
for both vedoluzimab and adalimumab. ADA and its impact may be assessed at a later time point if 
warranted by the data. Please refer to the Study Manual for information on sample collection and 
preparation.
9.1.17 Tuberculosis Screening 
All subjects will complete TB screening to determine eligibility. All subjects must complete a 
diagnostic test during screening either a QuantiFERON® test or a tuberculin skin test. Subjects will 
be excluded from the study if they have active or latent TB, regardless of treatment history, as 
defined in Section 7.2. 
9.1.18 PML Checklist 
Clinic staff will administer the subjective PML checklist during screening to exclude subjects with 
positive responses from enrolling into the study. The subjective PML checklist will be 
administered (prior to intravenous dosing, if applicable) at each visit, as shown in Appendix A, to 
evaluate symptoms suggestive of PML. Any subjects reporting signs or symptoms of PML will 
undergo objective testing and may be referred to a neurologist for a full evaluation, as described in 
the Risk Assessment and Minimization for PML (RAMP). The symptoms from a positive PML 
checklist will be recorded as an AE. Additional information and tools for the RAMP can be found 
in the Study Manual. 
9.1.19 Patient Reported Outcome Measures 
Subjects will complete the IBDQ questionnaire at the time points specified in the schedule of 
events. 
9.1.19.1 Inflammatory Bowel Disease Questionnaire
The IBDQ is a valid and reliable [31] instrument used to assess quality of life in adult patients with 
IBD. It includes 32 questions on 4 domains of health-related quality of life (HRQOL): Bowel 
Systems (10 items), Emotional Function (12 items), Social Function (5 items), and Systemic 
Function (5 items). Patients are asked to recall symptoms and quality of life from the last 2 weeks 
and rate each item on a 7-point Likert scale (higher scores equate to higher quality of life). A total 
IBDQ score is calculated by summing the scores from each domain; the total IBDQ score ranges 
from 32 to 224. An increase of ≥16 points in the IBDQ total score represents a clinically 
meaningful improvement in health-related quality of life of patients [32]. A total IBDQ score ≥170 
is associated with clinical remission [32,33].
9.1.20 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.


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If the subject is found to be not eligible at this visit, the investigator should complete the eCRF. 
The IVRS/IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal.

Study termination.

Other.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.21 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
Randomization will be stratified by:

Concomitant use of oral corticosteroids.

Previous failure of TNFα antagonist therapy or naïve to TNFα antagonist therapy.
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.
9.2.1
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).
9.2.2
Screening 
Subjects will be screened within 21 days prior to randomization. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.20 for procedures for documenting screening failures.


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Procedures to be completed at Screening can be found in the schedule of events. 
9.2.3
Randomization
Randomization will take place on Day 1. If the subject has satisfied all of the inclusion criteria and 
none of the exclusion criteria, the subject should be randomized using the IVRS/IWRS, as 
described in Section 8.2. Subjects will be instructed on when the first dose of investigational drug 
will be given as described in Section 6.1. The procedure for documenting screening failures is 
provided in Section 9.1.20.
9.2.4
Final Visit or Early Termination
The Final Visit will be performed on Week 52 or at the Early Termination Visit. 
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
9.2.5
Follow-up
Follow-up will begin after last dose of study drug and will continue for 18 weeks thereafter.
Additionally, upon completion of or early termination from the study, all subjects will participate 
in a LTFU safety questionnaire. The questionnaire will be administered by telephone at 6 months 
from the last dose of study drug. 
9.2.6
Post Study Care
The study medication will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies as required.
Subject to applicable laws and feasibility, access to the study medication may be available to 
individual subjects for whom no standard therapy exists, and the subject is at risk of significant 
morbidity or mortality. The investigator should contact the medical monitor to determine if access 
is possible.
9.3
Biological Sample Retention and Destruction
In this study, specimens for genome/gene analysis will be collected as described. After extraction 
and purification, the genetic material will be preserved and retained for up to but not longer than 
15 years or as required by applicable law. The sponsor has put into place a system to protect the 
subjects’ personal information to ensure optimal confidentiality and defined standard processes for 
sample and data collection, storage, analysis, and destruction.
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The sponsor and researchers working with the sponsor will have access to 
the samples collected and any test results. All samples collected during the study will be stored 
securely with limited access and the sponsor will require anyone who works with the samples to 
agree to hold the research information and any results in confidence.


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The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided pharmacogenomic samples can withdraw their consent and 
request disposal of a stored sample at any time. Notify sponsor of consent withdrawal.
In this study, ileocolonoscopy tissue samples will be preserved and retained for up to but not 
longer than 15 years or as required by applicable law. The sponsor has put into place a system to 
protect the subjects’ personal information to ensure optimal confidentiality and defined standard 
processes for sample and data collection, storage, analysis, and destruction.
The tissue samples will be sent to a central laboratory that serves as a secure storage facility. The 
sponsor and researchers working with the sponsor will have access to the samples collected. All 
samples collected during the study will be stored securely with limited access and the sponsor will 
require anyone who works with the samples to agree to hold the research information in 
confidence.
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided ileocolonoscopy tissue samples can withdraw their consent 
and request disposal of a stored sample at any time. Notify sponsor of consent withdrawal.


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


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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. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:


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
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 non-serious) is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by 
the investigator to Takeda may be appropriate. Such events may require further investigation in 
order to characterize and understand them and would be described in protocols and instructions 
provided for investigators as to how and when they should be reported to Takeda.
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.


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


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10.1.13
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death. 

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period

Start of AE collection: AEs must be collected from start of study medication administration. 

End of AE collection: AEs must be collected for 18 weeks following the last dose of study 
medication. 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication or until 
screen failure. For subjects who discontinue prior to study medication administration, PTEs are 
collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication. Routine collection of AEs will continue until 18 weeks after last dose.
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 


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laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date.
3. Severity.
4. Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related) (not completed for PTEs).
5. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
6. Action concerning study medication (not applicable for PTEs).
7. Outcome of event.
8. Seriousness.
IBDQ is patient reported instrument used to measure health related quality of life in this study. It
will not be used as a primary means to collect AEs. However, should the investigator become 
aware of a potential AE through the information collected with this instrument, proper follow-up 
with the patient for medical evaluation should be undertaken. Through this follow-up if it is 
determined that an AE not previously reported has been identified, normal reporting requirements 
should be applied.
10.2.1.3 Adverse Event Collection Involving Medically Anticipated Clinical Events 
Ulecrative colitis is associated with certain characteristic signs and symptoms including diarrhea, 
rectal bleeding, and abdominal pain that may be present at baseline and persist or fluctuate based 
on the individual subject’s disease history during the course of the study. These signs and 
symptoms will not be collected as AEs. 
Exacerbations of disease activity (eg, increase in the daily amount of rectal bleeding or abdominal 
pain beyond the subject’s normal fluctuation, new signs and symptoms of UC) will be collected as 
AEs and reported according to regulatory reporting requirements. 
Extra-intestinal manifestations of the subject’s disease (eg, arthalgia, arthritis, uveitis) that develop 
or worsen during the study are considered AEs. 


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10.2.1.4 Special Interest AE Reporting
If this special interest AE occurs during the Treatment Period or the Follow-up Period is 
considered to be clinically significant based on the criteria below, it should be recorded in the 
special interest AE eCRF or an SAE Form. The applicable form should be completed and reported 
to the SAE reporting contact in Section 1.1 within 24 hours.
Injection and/or Infusion Site Reactions and Hypersensitivity
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence such 
premedications are unlikely to be necessary or beneficial. At the discretion of the investigator, 
however, subjects may be administered premedication prior to any study drug administration. 
Corticosteroids, if given as a premedication, should be limited to the day of administration. 
Vedolizumab IV should be administered by a health care professional prepared to manage 
hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and 
medical support measure should be available for immediate use.
Subjects should be observed for 2 hours following the first 2 infusions, at a minimum, and one 
hour after each susequent infusion.
Subjects should be instructed to report the development of rash, hives, pruritus, flushing, urticaria, 
injection site pain, redness and/or swelling etc. that may represent an administration-related 
reaction (ie, injection-site reactions or infusion-related reactions) to study medication. If signs or 
symptoms of infusion-related reaction are observed during the administration of study, it should be 
immediately discontinued and the subject treated as medically appropriate. In the case of a mild 
reaction, study drug administration may be reinitiated (with appropriate premedication) at the 
discretion of the investigator. Subjects with severe or serious administration-related reactions (eg, 
stridor, angioedema, life-threatening change in vital signs) must be withdrawn from the study. 
In all cases of administration-related reaction, the medical monitor must be informed as soon as 
practical. The disposition of subjects with less severe 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.
Malignancies 
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 


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


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10.3
Follow-Up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first awareness 
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be 
submitted to the regulatory authorities as expedited report within 7 days for fatal and 
life-threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial. The investigational site also will forward a 
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11.0
STUDY-SPECIFIC COMMITTEES
No Data Monitoring Committee will be used in this study.
11.1
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. 
11.1.1 Risk Minimization Action Plan for PML (RAMP Program)
Natalizumab (TYSABRI), another integrin receptor antagonist, has been associated with 
progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection 
of the central nervous system. PML is caused by the John Cunningham virus (JCV) and typically 
only occurs in patients who are immunocompromised [34,35]. Natalizumab is a pan-α4 integrin 
antagonist that binds to both the α4β1 and α4β7 integrins and inhibits cellular adhesion to VCAM-1 
and MAdCAM-1 [36,37]. In contrast, vedolizumab binds to the α4β7 integrin only [23] and inhibits 
adhesion to MAdCAM-1, but not VCAM-1. Although no cases of PML have been reported in 
clinical trials with vedolizumab to date, a risk of PML cannot be ruled out.
To address the theoretical risk of the development of PML in subjects treated with vedolizumab, 
the sponsor, with input from renowned PML experts, has developed a Risk Minimization Action 
Plan for PML, the RAMP. The complete description of the RAMP program, including materials 
and instructions for its implementation and monitoring, is included in the Study Manual. 
The RAMP is focused on early clinical detection and management of that specific safety risk, 
including the discontinuation of study drug, if applicable. Subjects are assessed for signs and 
symptoms of PML prior to the administration of each dose of study drug using a PML subjective 
symptom checklist. Subjects with a positive PML subjective symptom checklist at any time after 
enrollment in a vedolizumab clinical study will be evaluated according to a prespecified algorithm 
(the PML Case Evaluation Algorithm). The next dose of study drug will be held until the 
evaluation is complete and results are available. Subsequent doses of study will be administered 
only if the possibility of PML is definitively excluded, as described in the RAMP algorithm. An 
IAC has been stabled as part of the RAMP program to review new neurological signs and 
symptoms potentially consistent with PML, and will provide input regarding subject evaluation 
and management as defined in the IAC charter. 
To ensure success of the RAMP program, site personnel will be trained to recognize the features of 
PML, and subjects will be trained to report specific neurological signs and symptoms without 
delay. Educational materials for teaching site personnel and subjects about PML and the RAMP 
procedures will be distributed to all sites and are included in the Study Manual. Formal teaching 
and training will be performed for site personnel prior to the start of the study. Subjects will 
receive training and educational materials prior to receiving treatment. The informed consent form 
will contain specific information on the hypothetical risk of PML. Any documented case of PML 
will be reported as an SAE, regardless of whether hospitalization occurs. Adjudication Committee 


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary.
12.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 


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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.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
A blinded data review meeting will be conducted prior to unblinding of subject’s treatment 
assignment. 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 PP Population dataset will be 
made prior to the unblinding of the study. Analyses using the per-protocol population may be 
provided as a sensitivity analysis.
The Safety Analysis Set will include all subjects who receive at least 1 dose of study drug. Subjects 
in this set will be analyzed according to the treatment they actually received.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment group and overall 
based on all randomized subjects. Additional summaries will be provided for the Full Analysis Set 
as appropriate. For continuous variables, summary statistics (non-missing values, mean, median, 
SD, minimum and maximum) will be generated. For categorical variables, the counts and 
percentages of each possible value will be generated.
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 efficacy analyses will be based on the FAS, with the exception of corticosteroid-free 
remission, which will be based on FAS subjects with baseline concomitant oral corticosteroid use. 
All statistical inference will be 2-sided at a 0.05 level of significance.
All proportion-based efficacy endpoints will be analyzed using Cochran-Mantel-Haenszel (CMH) 
tests stratified by randomization stratification factors. The p-values and point estimates of risk 


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difference along with 95% CIs will be provided. All subjects with missing data for determination 
of endpoint status will be considered as a non-responder in the analysis.
To control the overall Type I error rate of the primary and secondary endpoints, a hierarchical 
approach will be applied to the statistical testing of the secondary endpoints. The first secondary 
endpoint, proportion of subject achieving mucosal healing at Week 52, will only be tested if 
statistical significance is achieved with the primary endpoint. The second secondary endpoint, 
proportion of subjects using oral corticosteriods at Baseline who have discontinued corticosteriods 
and in clinical remission at Week 52, will only be tested if statistical significance is achieved with 
the first secondary endpoint.
Testing of the additional efficacy endpoints will not be multiplicity-controlled. The following 
analyses will be performed on endpoints that are not proportion-based:

Change from Baseline in oral corticosteroid use will be summarized for FAS subjects with 
baseline concomitant oral corticosteroids use, and tested using Wilcoxon rank-sum test.

Change from Baseline in fecal calprotectin will be analyzed with an analysis of covariance 
model with treatment and randomization stratification factors as factors and Baseline fecal 
calprotectin as a covariate.
13.1.4 OtherAnalyses
Time to UC-related hospitalizations, colectomies, and UC-related hospitalizations procedures will 
be analyzed using a Wei-Lin-Weissfeld (WLW) 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 Month 6 and Month 12 event rates presented.
13.1.5 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 treatment-emergent adverse events (TEAEs, defined 
as any AEs, regardless of relationship to study drug), AESIs (ie, serious infections, PML, 
malignancies, liver injury, infusion reactions, injection site reactions), and SAEs which occur on 
or after the first dose date and up to 18 weeks after the last dose date of the study drug will be 
summarized by 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. 
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.


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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
A sample size of 329 subjects per group will provide 86% power at 2-sided 0.05 level of 
significance for Week 52 clinical remission, assuming a remission rate of 28% for vedolizumab 
and 18% for adalimumab; this sample size will also provide 80% power at 2-sided 0.05 level of 
significance for Week 52 mucosal healing, assuming a mucosal healing rate of 35% for 
vedolizumab and 25% for adalimumab.


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


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


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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


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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. 
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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Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab 
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McIntyre PB, Pemberton JH, Wolff BG, Beart RW, Dozois RR. Comparing functional 
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sample. Gastroenterology 2002;122(1):15-9.
18.
Penna C, Dozois R, Tremaine W, Sandborn W, LaRusso N, Schleck C, et al. Pouchitis after 
ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in 
patients with associated primary sclerosing cholangitis. Gut 1996;38(2):234-9.
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Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking and 
regional immunity. Adv Immunol 1999;72:209-53.
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Salmi M, Jalkanen S. Lymphocyte homing to the gut: attraction, adhesion, and 
commitment. Immunol Rev 2005;206:100-13.
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Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, et al. Human 
mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract 
and associated lymphoid tissue. Am J Pathol 1997;151(1):97-110.
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Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. Expression 
and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. 
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Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and 
selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in 
development for inflammatory bowel diseases. J Pharmacol Exp Ther 
2009;330(3):864-75.
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Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. 
Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 
2013;369(8):699-710.
25.
Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. 
Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 
2013;369(8):711-21.
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Sands B, Feagan B, Rutgeerts P, Colombel J-F, Sandborn W, Sy R, et al. Vedolizumab 
induction therapy for patients with Crohn's disease and prior anti-tumour necrosis factor 
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Journal of Crohn's and Colitis 2013;7(Suppl. 1):Pages S5–S6. 8th Congress of the 
European Crohn's and Colitis Organisation.
27.
Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D'Haens G, Wolf DC, et al. 
Adalimumab induces and maintains clinical remission in patients with moderate-to-severe 
ulcerative colitis. Gastroenterology 2012;142(2):257-65 e1-3.
28.
Laharie D, Filippi J, Roblin X, Nancey S, Chevaux JB, Hebuterne X, et al. Impact of 
mucosal healing on long-term outcomes in ulcerative colitis treated with infliximab: a 
multicenter experience. Aliment Pharmacol Ther 2013;37(10):998-1004.
29.
Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S, Schreiber S, et al. 
Adalimumab for induction of clinical remission in moderately to severely active ulcerative 
colitis: results of a randomised controlled trial. Gut 2011;60(6):780-7.
30.
Entyvio (vedolizumab) for injection, for intravenous use. Full Prescribing Information. 
Deerfield, IL: Takeda Pharmaceuticals America, Inc., Issued May 2014.
31.
Irvine EJ. Development and subsequent refinement of the inflammatory bowel disease 
questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel 
disease. J Pediatr Gastroenterol Nutr 1999;28(4):S23-7.
32.
Gregor JC, McDonald JW, Klar N, Wall R, Atkinson K, Lamba B, et al. An evaluation of 
utility measurement in Crohn's disease. Inflamm Bowel Dis 1997;3(4):265-76.
33.
Irvine EJ, Feagan B, Rochon J, Archambault A, Fedorak RN, Groll A, et al. Quality of life: 
a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel 
disease. Canadian Crohn's Relapse Prevention Trial Study Group. Gastroenterology 
1994;106(2):287-96.
34.
Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory 
therapies. Annu Rev Med 2010;61:35-47.
35.
Steiner I, Berger JR. Update on progressive multifocal leukoencephalopathy. Curr Neurol 
Neurosci Rep 2012;12(6):680-6.
36.
Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. 
Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med 
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Idec Inc., Revised June 2013.


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Appendix A
Schedule of Study Procedures
Screen-
ing
Treatment week
Study Day/Week:
Days 21 
to -1
Day 
1
(a)
2
4
6
8,
10,
12
14
16,
18,
20
22
24,
26,
28
30
32,
34,
36
38
40,
42,
44
46
48,
50
Final Visit or 
Early 
Termination Visit
Week 52(b)
Follow-up 
visit week 
68
Visit Windows (Days):
± 2
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Informed consent
X
Inclusion/exclusion 
criteria
X
X (a)
Demographics and 
medical history
X
Concurrent medical 
conditions
X
Medication history
X
Physical examination
X
X (a)
X
X
X
X
X
X
X
X
X
X
Vital signs (b)
X
X (a)
X
X
X
X
X
X
X
X
X
X
Weight and height
X
Flexible sigmoidoscopy 
(c)
X
X
X
Mayo score
X
X
X
Partial mayo score
X
X
X
X
X
X
X
X
Patient diary
X
X (a)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory testing 
(d)
X
X (a)
X
X
X
X
X
X
ADA testing (e)
X (a)
X
X
X
X
X
X
X
HIV/Hepatitis panel
X
Tuberculosis screening (f)
X
Pharmacogenomic DNA 
and RNA sample 
collection
X (a)
Serum pregnancy test (g)
X
Urine pregnancy test (g)
X (a)
X
X
X
X (g)
X
X 
(g)
X
X (g) 
X
X (g)
X
X (g)
X
X (g)
X
X


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Screen-
ing
Treatment week
Study Day/Week:
Days 21 
to -1
Day 
1
(a)
2
4
6
8,
10,
12
14
16,
18,
20
22
24,
26,
28
30
32,
34,
36
38
40,
42,
44
46
48,
50
Final Visit or 
Early 
Termination Visit
Week 52(b)
Follow-up 
visit week 
68
Visit Windows (Days):
± 2
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
IBDQ
X (a)
X
X
ECG
X
X
Stool sample for C. 
difficile
X
Stool sample for 
calprotectin
X
X
X
X
PML checklist
X
X (a)
X
X
X
X
X
X
X
X
X
X
SC dosing (adalimumab or 
placebo)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IV dosing (vedolizumab or 
placebo)
X
X
X
X
X
X
X
X
PTE assessment (h)
X
X
Adverse Events (i)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
(j)
X (a)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(a) Assessments to be completed predose.
(b) Vital signs will include body temperature, respiratory rate, blood pressure, and pulse (bpm). On dosing days, vital signs are taken predose. 
(c) Biopsies to be collected at Screening and Week 14 and 52. For subjects without cancer surveillance endoscopy performed in last 12 months, the investigator can perform a
colonoscopy at screening. Evaluation of endoscopy results will be perfomed by the central reader.
(d) Blood sample obtained during screening should be in fasted state
(e) Blood samples for the ADA (anti-drug antibodies against vedoluzimab or adalimumab) assessment will be collected from all subjects at Day 1 and Weeks 6, 30, 38, 52, and 68. On 
dosing days, blood samples must be taken pre-dose.
(f) Assessed by QuantiFERON® test, A TB skin test reaction or chest X-ray within 3 months of enrollment 
(g) Women of childbearing potential only. Urine preganancy test should be done before every IV infustion and on Weeks 10, 18, 26, 34, 42, and 50.
(h) PTEs will be captured immediately following the signing of the informed consent at the Screening Visit, up until the first dose of study drug. Collection of AEs will begin 
following first dose of study drug and will continue through Week 68/Final Safety Visit. 
(i) Collection of all SAEs will begin once the informed consent is signed and will continue through Week 68/Final Safety Visit. 
(j) Monitoring of concomitant medications will begin at signing of the informed consent. 


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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 56, 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.


Vedolizumab IV
Study No. MLN0002-3026
Page 82 of 82
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CONFIDENTIAL
Appendix E
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity
Categorya
Stool frequencyb
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 bleedingc
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 assessmentd
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 


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Protected Personal Data

SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Double-Blind, Double-Dummy, Multicenter, Active-Controlled Study to 
Evaluate the Efficacy and Safety of Vedolizumab IV Compared to Adalimumab SC in Subjects 
with Ulcerative Colitis
NCT Number: NCT02497469
SAP Approve Date: 18 October 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
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: MLN0002-3026
A Randomized, Double-Blind, Double-Dummy, Multicenter, Active-Controlled Study to 
Evaluate the Efficacy and Safety of Vedolizumab IV Compared to Adalimumab SC in 
Subjects with Ulcerative Colitis
PHASE 3b
Version: Final 2.0
Date: 18 October 2018
Prepared by:
Based on:
Protocol Version: Amendment 7
Protocol Date: 08 March 2017
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda.
Protected Personal Data


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1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Approvers:
Protected Personal Data


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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objectives ....................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Additional Objectives ................................................................................................8
4.4
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoints ...................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Additional Endpoints ...............................................................................................10
5.3.1
Additional Efficacy Endpoints ...........................................................................10
5.3.2
PK Endpoint ......................................................................................................11
5.3.3
Immunogenicity Endpoints ................................................................................11
5.3.4
Safety Assessments............................................................................................11
5.3.5
Exploratory Efficacy Endpoint(s).......................................................................12
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................14
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................15
7.1
General Principles....................................................................................................15
7.1.1
Study Definitions ...............................................................................................15
7.1.2
Definition of Study Days....................................................................................16
7.1.3
Definition of Study Visit Windows ....................................................................16
7.1.4
Conventions for Missing Adverse Event Dates...................................................19
7.1.5
Conventions for Missing Concomitant Medication Dates...................................20
7.1.6
Convention for Calculation of Mayo Scores.......................................................20
7.1.7
Methods for Handling of Missing Efficacy Data ................................................21
7.1.8
Convention for Calculation of Inflammatory Bowel Disease Questionnaire 
(IBDQ) ..............................................................................................................22
7.2
Analysis Sets ...........................................................................................................22
7.2.1
Full Analysis Set (FAS) .....................................................................................22
7.2.2
Per-Protocol Set (PPS).......................................................................................23
7.2.3
Pharmacokinetic Set (PKS)................................................................................23


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7.2.4
Safety Analysis Set ............................................................................................23
7.2.5
Randomized Set.................................................................................................23
7.3
Disposition of Subjects ............................................................................................24
7.4
Demographic and Other Baseline Characteristics.....................................................25
7.5
Medical History and Concurrent Medical Conditions...............................................25
7.6
Medication History and Concomitant Medications...................................................26
7.7
Study Drug Exposure and Compliance.....................................................................26
7.8
Efficacy Analysis.....................................................................................................27
7.8.1
Primary Efficacy Endpoint(s).............................................................................27
7.8.2
Secondary Efficacy Endpoint(s).........................................................................29
7.8.3
Additional Efficacy Endpoint(s).........................................................................29
7.8.4
Exploratory Efficacy Endpoint(s).......................................................................30
7.8.5
Summary of Efficacy Analyses ..........................................................................31
7.8.6
Subgroup Analysis .............................................................................................33
7.8.7
Immunogenicity Analysis...................................................................................34
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................35
7.9.1
Pharmacokinetic Analysis ..................................................................................35
7.9.2
Pharmacodynamic Analysis ...............................................................................36
7.10
Other Outcomes.......................................................................................................36
7.11
Safety Analysis........................................................................................................36
7.11.1 Adverse Events ..................................................................................................36
7.11.2 Clinical Laboratory Evaluations .........................................................................38
7.11.3 Vital Signs .........................................................................................................39
7.11.4 12-Lead ECGs ...................................................................................................40
7.11.5 Other Observations Related to Safety.................................................................40
7.12
Interim Analysis ......................................................................................................40
7.12.1 Interim I.............................................................................................................40
7.12.2 Interim II............................................................................................................40
7.13
Changes in the Statistical Analysis Plan...................................................................41
7.13.1 Revision History ................................................................................................41
8.0
REFERENCES..............................................................................................................42
LIST OF IN-TEXT TABLES
Table 7.a
Visit windows for endoscopic measurement (eg, Mayo endoscopic subscore, 
mucosal healing)................................................................................................17


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Table 7.b
Visit windows for other efficacy endpoints (eg, partial Mayo score, IBDQ, 
FCP). .................................................................................................................17
Table 7.c
Visit windows for safety vital signs....................................................................18
Table 7.d
Visit windows for safety lab parameters – Hematology and Chemistry...............18
Table 7.e
Visit windows for safety lab parameters – Urinalysis. ........................................18
Table 7.f
List of subgroups of interest...............................................................................34
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic study design........................................................................................9
LIST OF APPENDICES
Appendix A
Mayo Score Calculation Worksheet ...................................................................43
Appendix B
Rescue Medication and Potentially Effective Medication Rules .........................45
Appendix C
AEs of Special Interest.......................................................................................47
Appendix D
Criteria for Identification of Markedly Abnormal Laboratory Values and Vital 
Sign Values........................................................................................................50
Appendix E
Criteria for Markedly Abnormal Values for Vital Signs......................................51
Appendix F
Geographic Regions...........................................................................................52


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3.0
LIST OF ABBREVIATIONS
ADA
Anti-Drug Antibody 
AVA
Anti-Vedolizumab Antibody
AE
adverse event
AESI
Adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AVA
anti-vedolizumab antibodies
BMI
body mass index
BUN
blood urea nitrogen
CMH
Cochran-Mantel-Haenszel
CPK
creatine phosphokinase
CRF
case report form
ECG
electrocardiogram
FAS
full analysis set
GGT
-glutamyl transferase
HLT
high level term
HRQOL
health-related quality-of-life 
IBDQ
inflammatory bowel disease questionnaire
IV
intravenous
IWRS
Interactive Web Response System
KM
Kaplan-Meier
LDH
lactate dehydrogenase
LOCF
last observation carried forward
LTFU
long-term follow-up 
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PK
pharmacokinetics
PKS
Pharmacokinetics Set
PML
progressive multifocal leukoencephalopathy
PPS
Per-Protocol Set
PRO
patient-reported outcome
PT
Preferred term
QOL
quality-of-life
RHI
Robarts Index
SAE
serious adverse event
SAP
statistical analysis plan
SC
Subcutaneous
SOC
system organ class


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TEAE
Treatment emergent adverse event
TNF-α
tumor necrosis factor- alpha
UC
Ulcerative colitis
WHODrug
World Health Organization Drug Dictionary
WLW
Wei-Lin-Weissfeld


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4.0
OBJECTIVES
4.1
Primary Objectives

To determine the effect of vedolizumab IV compared to adalimumab SC on clinical
remission at Week 52.
4.2
Secondary Objectives

To evaluate the effect of vedolizumab IV compared to adalimumab SC on mucosal healing at
Week 52.

To evaluate the effect of vedolizumab IV compared to adalimumab SC on corticosteroid-free 
remission at Week 52.
4.3
Additional Objectives

To evaluate the safety of vedolizumab IV compared to adalimumab SC.

To evaluate the impact of vedolizumab IV on health-related quality-of-life (HRQOL) using 
inflammatory bowel disease questionnaire (IBDQ) at Weeks 30 and 52.

To characterize the PK (serum concentration) of vedolizumab IV at Day 1, Weeks 6, 14, 22, 
30, 38, and 52.

To assess the immunogenicity of multiple doses of vedolizumab IV at Day 1, Weeks 6, 14, 
22, 30, 38, and 52.
4.4
Study Design
This is a phase 3b randomized, double-blind, double-dummy, multicenter, active-controlled 
study to evaluate the efficacy and safety of vedolizumab IV compared to adalimumab SC over a 
52-week treatment period. The study will be conducted globally and will include 658 to 758 
subjects (329 to 379 per treatment group) with moderately to severely active UC.
The study consists of a 4-week Screening Period, a 52-week Treatment Period (with last dose at 
Week 50), and an 18-week Follow-up Period following last dose. Additionally, subjects 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. The duration of the study will be approximately 72 weeks for all 
subjects.
Subjects who have moderately to severely active UC, defined as complete Mayo score 6-12 and 
endoscopic subscore ≥2, both anti-TNF-α naïve, exposed, and failures, will be screened. 
Previous use of TNF-α antagonist therapy other than adalimumab will be permitted. Subjects 
who are naïve to TNF- α antagonist treatment but with written documentation of current 
treatment failure (eg, corticosteroids, 5-ASA, or immunomodulators), those who have previously 
used a TNF-α antagonist (except adalimumab) and discontinued its use due to reasons other than 
safety, and those who have had previous TNF-α antagonist therapy without documented response 
to treatment (eg, due to lack of response, loss of response, or intolerance) will be allowed to 


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enroll; however, the proportion of TNF- α antagonist naïve subjects shall comprise 
approximately 75% of the total number of subjects enrolled into the study.
On Day 1, subjects who meet the inclusion criteria and who meet none of the exclusion criteria 
will undergo baseline evaluations and be randomly assigned in a 1:1 ratio to double-blind 
medication for 50 weeks. Randomization will be stratified by:

Concomitant use of oral corticosteroids.

Previous exposure/failure of TNF- α antagonist therapy or naïve to TNF- α antagonist 
therapy.
Subjects in the vedolizumab treatment group will receive a 300 mg IV infusion on Day 1 and 
Weeks 2, 6, 14, 22, 30, 38, and 46, as well as placebo SC injection on Day 1, Week 2, and Q2W 
thereafter until Week 50.
Subjects in the adalimumab treatment group will receive a 160 mg SC injection on Day 1 (four 
40 mg injections in one day or two 40 mg injections per day for two consecut ive days), 80 mg at 
Week 2 (two 40 mg injections in one day), then 40 mg Q2W thereafter until Week 50, as well as 
a placebo IV infusion at Day 1 and Weeks 2, 6, 14, 22, 30, 38, and 46. Subjects who do not 
respond to treatment based on the investigator’s discretion should be withdrawn and treated 
according to standard of care. After the Week 52 or End of Study Visit, all subjects will have a 
Follow-Up Visit, approximately 18 weeks (approximately 5 half-lives for vedolizumab) after the 
last dose of study drug.
Figure 4.a
Schematic study design


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints

Proportion of subjects achieving 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 achieving mucosal healing (defined as Mayo endoscopic subscore ≤1 
point) at Week 52.

Proportion of subjects using oral corticosteroids at Baseline who have discontinued 
corticosteroids and are in clinical remission at Week 52.
5.3
Additional Endpoints
5.3.1
Additional Efficacy Endpoints

Proportion of subjects achieving clinical response (defined as a reduction in complete Mayo 
score of ≥3 points and ≥30% from baseline [or a 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) at Week 52.

Proportion of subjects achieving clinical remission (defined as a complete Mayo score of ≤2 
points and no individual subscore >1 point) at Week 14.

Proportion of subjects with rectal bleeding subscore indicative of mild disease (≤1) at Week 
52.

Proportion of subjects with a Physician’s Global Assessment (PGA) subscore indicative of 
mild disease (≤1) at Week 52.

Proportion of subjects with stool frequency subscore indicative of mild disease (≤1) at Week 
52.

Proportion of subjects with clinical remission (complete Mayo score of ≤2 points and no 
individual subscore >1 point) where rectal bleeding subscore of 0 and endoscopy subscore of 
0 at Week 52.

Proportion of subjects with endoscopy subscore of 0, rectal bleeding subscore of 0, and stool 
frequency subscore decreases or no change from Baseline at Week 52.

Proportion of subjects with endoscopy subscore ≤1, rectal bleeding subscore of 0, and stool 
frequency subscore of 0 at Week 52.

Proportion of subjects with endoscopy subscore ≤1, rectal bleeding subscore of 0, and stool 
frequency subscore ≤1 at Week 52.


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
Proportion of subjects with endoscopy subscore ≤1, rectal bleeding subscore of 0, stool 
frequency subscore decreases or no change from Baseline, and total score (sum of these 3) ≤1 
at Week 52.

Proportion of subjects with IBDQ score change of ≥16 points from Baseline to Week 52.

Proportion of subjects reaching clinical remission based on IBDQ score >170 at Week 52.

Change in oral corticosteroid use from Baseline to Week 52. It will be evaluated in three 
manners: 
–
Cumulative exposure of corticosteroids, defined as the total amount of corticosteroids 
taken by a subject throughout the study (in mg of prednisone equivalent).
–
Duration of corticosteroid use, defined as the number of days from baseline to the date of 
discontinuation of corticosteroid in those subjects who were on corticosteroid at baseline.
–
Change in median oral corticosteroid dose (in mg of prednisone equivalent) from baseline 
up to Week 52.

Proportion of subjects using oral corticosteroids at Baseline who have discontinued 
corticosteroids and are in clinical remission at Week 14.

Time to major UC-related events (eg, hospitalizations, colectomies, and procedures). Due to 
data collection limitation, time to major UC-related events will be evaluated via UC-related 
hospitalization, bowel resection, and procedures in the data analysis. 

Change in fecal calprotectin concentrations from Baseline to Weeks 14, 30, and 52.

Proportion of subjects with a change in histology from Baseline to Week 52, per Geboes
only.

Proportion of subjects with histological remission at Week 14, per Geboes and per RHI 
separately.

Proportion of subjects with histological remission at Week 52, per Geboes and per RHI 
separately.
5.3.2
PK Endpoint

Observed serum concentration at the end of a dosing interval (Ctrough) of vedolizumab.
5.3.3
Immunogenicity Endpoints

Proportion of subjects with positive AVA during the study.

Proportion of subjects with positive neutralizing AVA.
5.3.4
Safety Assessments
Safety for maintenance therapy as assessed by AEs, adverse events of special interest (AESIs, 
including serious infections including opportunistic infection such as PML, liver injury, 


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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).
5.3.5
Exploratory Efficacy Endpoint(s)
The following exploratory endpoints were not defined in the protocol, but will be included in the 
final analysis. 

Clinical response at Week 14.

Proportion of subjects with complete Mayo ≤1 and rectal bleeding subscore = 0 at Week 52.

Proportion of subjects with durable clinical remission, defined as clinical remission at Week 
52 amongst those in clinical remission at Week 14. (Note the denominator will be the 
subjects in Full Analysis Set.)

Proportion of subjects in clinical remission at Week 52 and in clinical remission for ≥14 
weeks leading up to Week 52. Clinical remission is defined by complete Mayo score, or 
partial Mayo score if the complete Mayo score was not performed at the visit. (Note the 
denominator will be the subjects in Full Analysis Set.)

Proportion of subjects with disease control at Week 52, defined as complete Mayo ≤2 rectal 
bleeding subscore = 0, endoscopy subscore = 0, CRP <5 mg/L, FCP <100 ug/g and in 
histological remission (either by Geboes or by RHI).

Proportion of subjects with rectal bleeding subscore = 0 at Week 52.

Proportion of subjects with major UC-related events (eg, hospitalizations, bowel resection, 
and procedures) throughout the study up to Week 52.

Proportion of subjects with FCP ≤250 ug/g at Week 14, 30, 52 (among those with FCP >250 
ug/g at baseline). (Note the denominator will be a subset of subjects with FCP >250 ug/g at 
baseline in Full Analysis Set.)

Proportion of subjects still on adalimumab or vedolizumab at Week 68.

Change from baseline in IBDQ-specific domain at Week 30 and Week 52, including bowel 
symptoms, systemic symptoms, emotional function, and social function.

Time to first clinical remission. Clinical remission is defined by complete Mayo score, or 
partial Mayo score if the complete Mayo score was not performed at the visit. 

Time to first clinical response, Clinical response is defined by complete Mayo score, or 
partial Mayo score if the complete Mayo score was not performed at the visit.

Clinical remission by visit (eg, Week 2, Week 4, Week 6, Week 14, Week 22, Week 30, 
Week 38, Week 46, Week 52). Clinical remission is defined by complete Mayo score, or
partial Mayo score if the complete Mayo score was not performed at the visit.


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
Clinical response by visit (eg, Week 2, Week 4, Week 6, Week 14, Week 22, Week 30, Week 
38, Week 46, Week 52). Clinical response is defined by complete Mayo score, or partial 
Mayo score if the complete Mayo score was not performed at the visit.

Proportion of subjects with minimum histological disease activity per Geboes, defined as 
Geboes score <3.2, at Week 14 and Week52.

Proportion of subjects with minimum histological disease activity per Robarts index (RHI), 
defined as RHI <5, at Week 14 and Week 52.


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6.0
DETERMINATION OF SAMPLE SIZE
A sample size of 329 subjects per group will provide 86% power at 2-sided 0.05 level of 
significance for Week 52 clinical remission, assuming a remission rate of 28% for vedolizumab 
and 18% for adalimumab; this sample size will also provide 80% power at 2-sided 0.05 level of 
significance for Week 52 mucosal healing, assuming a mucosal healing rate of 35% for 
vedolizumab and 25% for adalimumab.
The study design employs promising zone design, an adaptive sample size re-assessment 
approach [1,2] that strongly controls the overall type I error rate. The first interim analysis will 
be conducted after approximately 100 subjects have been randomized into the study for 52 weeks 
and who have completed the Week 52 Final Visit or Early Termination Visit. The conditional 
power will be calculated based on clinical remission results at Week 52 and Week 30. If the 
conditional power falls in the promising zone, the sample size will be increased according to a 
pre-specified sample size adaptation rule; if the conditional power falls in the futility zone, the 
study may stop for futility; otherwise the study will continue with the sample size unadjusted.
The maximum sample size increase for the study is capped at 100 subjects (50 subjects per 
group). With this maximum increase, the power will be maintained at 80% with 2-sided test at 
α=0.05 level for Week 52 clinical remission, assuming a remission rate increase to 45% for 
vedolizumab and 35% for adalimumab. The sample size adaptation rule is a pre-specified 
stepwise function to avoid the back calculation problem because 1 sample size can correspond to 
either barely promising or highly promising interim results. The sample size rule will be
designed by the sponsor independent design statistician and approved by the sponsor head of 
biostatistics. Both the sponsor independent design statistician and sponsor head of biostatistics 
are not involved in the study conduct.
The adaptation rule will be described in a separate document and will not be accessible to the 
study team until completion of the study. During study conduct, it will only be available to the 
sponsor independent design statistician, the sponsor head of biostatistics, the DMC, and the 
statistics representative in the sponsor executive committee (if different from the sponsor head of 
biostatistics).


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All data will be provided in data listings sorted by treatment group and subject number. Tabular 
summaries will be presented by treatment group. 
All efficacy data will be analyzed using the analysis visits. The analysis visit windowing 
convention will be defined based on study days of post-baseline. The details of analysis visit 
windowing convention will be described in Section 7.1.3.
Unless otherwise stated, all efficacy analyses will be conducted with a two-sided test at a 
significance level of α = 0.05. Nominal p-values will be provided without multiplicity 
adjustment. 
In addition, the following conventions will be applied to all data presentations and analyses.

All statistical analyses will be conducted using SAS® version 9.2 (SAS Institute Inc., Cary, 
NC) or higher.

Nominal p-values will be rounded to four decimal places prior to assessment of statistical 
significance using the following algorithm. If the fifth digit of the p-value is less than or equal to 
4 the p-value will be rounded down. If the fifth digit of the p-value is greater than or equal to 5, 
the p-value will be rounded up. All p-values rounded to 0.0000 will be presented as “<0.0001” 
and p-values rounded to 1.0000 will be presented as “>0.9999”. 

Where appropriate, variables will be summarized descriptively by study visit and by 
treatment group. For the categorical variables, the count and proportions of each possible 
value will be tabulated by treatment group. The denominator for the proportion will be based 
on the number of subjects in each treatment group (column total) unless otherwise specified. 
For continuous variables, the number of subjects with non-missing values, arithmetic mean, 
median, SD, minimum, and maximum values will be tabulated. 

For continuous endpoints, arithmetic mean, and median will be formatted to one more decimal 
place than the measured value. The standard deviation (SD) will be formatted to two more 
decimal places than the measured value. Minimum and maximum values will be presented with
the same number of decimal places as the measured value. Confidence intervals about a 
parameter estimate will be presented to the same decimal places as the parameter estimate. 

Screen failure subjects will be grouped and listed at the end.
7.1.1
Study Definitions
For any variable, unless otherwise defined, the baseline value is the last non-missing assessment 
taken prior to the first investigation product administration. The change from baseline will be 
calculated by subtracting the baseline values from the individual post-baseline values. If either 
the baseline or post-baseline value is missing, the change from baseline is set to missing.


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Other study terms and definitions are provided below.
Term
Definition 
Clinical Remission by 
Complete Mayo score
Defined as a complete Mayo score of ≤2 points and no individual subscore >1 point.
Clinical Remission by 
Partial Mayo score
Defined as a partial Mayo score of ≤2 points and no individual subscore >1 point.
Corticosteroid-free 
Remission
Defined as Proportion of subjects using oral corticosteroids at baseline who have 
discontinued corticosteroids and are in clinical remission.
Mucosal Healing
Defined as Mayo endoscopic subscore ≤1 point.
Clinical Response
Defined as a reduction in complete Mayo score of ≥3 points and ≥30% from baseline 
(or a 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.
Disease Worsening
An increase in partial Mayo score of 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 
partial Mayo score 5 points. 
Durable Clinical 
Remission
Defined as clinical remission at Week 52 amongst those in clinical remission at Week 
14.
Histological Remission
Histological remission per Geboes is defined as Geboes score <2.
Histological remission per Robarts Index (RHI) is defined as RHI <3.
Minimal Histological 
Disease Activity
Minimal histological disease activity per Geboes is defined as Geboes score <3.2.
Minimal histological disease activity per RHI is defined as RHI <5.
Rescue Medication
Any new medication or any increase in dose of a baseline medication required to treat 
new or unresolved UC symptoms (other than anti-diarrheals for control of chronic 
diarrhea).
7.1.2
Definition of Study Days
Day 1 will be defined as the day of first investigational product administration. 
Study day will be calculated relative to the date of the first dose of study drug. Study days prior 
to the first dose of study drug will be calculated as:
Date of assessment/event – Date of first dose of study drug.
Study days 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.
7.1.3
Definition of Study Visit Windows
Subjects do not always adhere strictly to the visit timing stated in the protocol. Therefore the 
designation of visits will be based on the day of evaluation relative to the start of study drug 
rather than the nominal visit recorded in the data. Accordingly, the study is divided into 
continuous, mutually exclusive analysis windows.


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7.1.3.1
Visit Windows for Efficacy Data
The visit windows for efficacy data are defined in Table 7.a. If a subject has more than one visit 
with an efficacy measurement included within a window, the assessment closest to the target day 
will be used. In case of ties between observations located on different sides of the target day, the 
later assessment will be used. In case of ties located on the same side of the target day (ie, more 
than one value for the same day), the mean of the values will be used.
Table 7.a
Visit windows for endoscopic measurement (eg, Mayo endoscopic subscore, 
mucosal healing).
Visit
Target Day
Day Range
Baseline
1
≤1
Week 14
99
2 – 238
Week 52
365
≥239
Table 7.b
Visit windows for other efficacy endpoints (eg, partial Mayo score, IBDQ, 
FCP).
Visit
Target Day
Day Range
Screening
≤-1
Day 1
1
1
Week 2
15
2 – 21
Week 4
29
22 – 35
Week 6
43
36 – 70
Week 14
99
71 – 126
Week 22
155
127 – 182
Week 30
211
183 – 238
Week 38
267
239 – 294
Week 46
323
295 – 343
Week 52
365
≥344


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7.1.3.2
Visit Windows for Safety Data
Duplicate safety assessments: If the same parameter is reported more than once on the same date, 
the mean of that parameter will be used in the analyses.
Table 7.c
Visit windows for safety vital signs.
Visit
Target Day
Day Range
Screening
≤-1
Day 1
1
1
Week 2
15
2 – 21
Week 4
29
22 – 35
Week 6
43
36 – 70
Week 14
99
71 – 126
Week 22
155
127 – 182
Week 30
211
183 – 238
Week 38
267
239 – 294
Week 46
323
295 – 343
Week 52
365
344 – 420
Week 68 (FU)
477
≥421
Table 7.d
Visit windows for safety lab parameters – Hematology and Chemistry.
Visit
Target Day
Day Range
Screening
≤-1
Day 1
1
1
Week 6
43
2 – 70
Week 14
99
71 – 154
Week 30
211
155 – 266
Week 46
323
267– 343
Week 52
365
344 – 420
Week 68 (FU)
477
≥421
Table 7.e
Visit windows for safety lab parameters – Urinalysis.
Visit
Target Day
Day Range
Screening
≤-1
Week 52
365
≥1
ECG assessments are measured at screening and Week 52/Early Termination visit. Any ECG 
performed post-baseline will summarized as Week 52 assessment. 


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7.1.4
Conventions for Missing Adverse Event Dates
Every effort will be made to determine the actual onset date for the event or to obtain a reliable 
estimate for the onset date from the investigator.
For AEs or SAEs, a missing or incomplete onset date will be imputed according to the following 
conventions:
1. If an onset date is missing, the derived onset date will be calculated as the first non-missing 
valid date from the following list (in order of precedence):

First study medication date.

Consent date (for SAEs only).
2. If an onset date is incomplete, the derived onset date will be calculated following:

Missing day, but month and year present: the day will be imputed as the 15th of the 
month. If the month and year are equal to the month and year of the first study 
medication dose and the first study medication dose occurs after the imputed date, the 
derived onset date will be set equal to the first study medication date. If the AE end date 
occurs prior to the imputed date, the derived onset date will be set equal to the AE end 
date.

Missing day and month, but year present: the day and month will be imputed as the 30th
June of the year. If the year is equal to the year of the first study medication dose and the 
first study medication dose occurs after the imputed date, the derived onset date will be 
set equal to the first study medication date. If the AE end date occurs prior to the imputed 
date, the derived onset date will be set equal to the AE end date.

If the imputed AE onset date occurs after the database lock date, the imputed AE onset 
date will be imputed as the database lock date. 
For AEs or SAEs, a missing or incomplete end date will be imputed according to the following 
conventions:
1. If an end date is missing, the derived end date will be imputed as the last assessment date, 
assuming that the last assessment occurs after the AE start. If the last assessment occurs prior 
to the AE start date, the derived end date will be imputed as the AE start date.
2. If an end date is incomplete, the derived end date will be calculated following:

Missing day, but month and year present: the day will be imputed as the last date (for
example February 2009 will be imputed as 28 February 2009) of the month.

Missing day and month, but year present: the day and month will be imputed as the 31st 
December of the year. 

If the imputed AE end date occurs after the database lock date, the imputed AE end date 
will be imputed as the database lock date. 


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7.1.5
Conventions for Missing Concomitant Medication Dates
Start and stop dates for medication history and concomitant medications are collected on the 
eCRF. Definitions of medication history and concomitant medications are defined in Section 7.6. 
Missing or partial dates for medication history will not be imputed. However, in case of missing 
or partial dates for concomitant medications, the following rules will be used:
If the start date is partial or unknown:

If the day is missing, the start day will be the first day of the month.

If the month is missing, the start month will be the month corresponding to 90 days prior to 
the date of first dose of study drug.

If the year is missing, the start year will be the minimum of the year of the first clinic visit or 
the year of the informed consent date.

If the entire date is unknown, the start date will be the date of first dose of study drug.
If the stop date is partial, unknown or “ongoing”:

If the day is missing, the stop day will be the last day of the month reported.

If the month is missing, the stop month will be to the month during which the last assessment 
occurred.

If the year is missing or the entire date is unknown or if the medication is “ongoing”, the stop 
year will be the year in which the last assessment occurred.
No dates will be imputed for previous medications.
7.1.6
Convention for Calculation of Mayo Scores
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). 
The Mayo scoring system is a composite index of 4 disease activity variables (see Appendix A
for details):
–
Stool frequency,
–
Rectal bleeding,
–
Findings on sigmoidoscopy, and
–
Physician’s global assessment.
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. 


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Mayo scores will be derived from first principles. All subscores should be rounded to the nearest
integers; apply rounding as final subscores are created and prior to calculation of total score.
1. Use the date of the visit where PGA was performed to identify analysis visit using the 
analysis visit windowing rules defined in Section 7.1.3.
2. Identify PGA results (subscores).
3. Calculate the sigmoidoscopy subscore (based on adjudicated data) using the visit windows 
defined in Section 7.1.3.
4. Calculate rectal bleeding subscore and stool frequency subscore:
a) Select the diary data from 7 days prior to the visit date identified in (1).
b) Merge in sigmoidoscopy dates (including dates of attempted sigmoidoscopy) and set 
diary data one day prior, on the day and one day after the sigmoidoscopy to missing.
c) For Screening visit, if less than 3 days of data remain then a subscore cannot be 
calculated. Otherwise, sum the 3 most recent non-missing results and divide by 3. 
Patients who have less than 3 days of eDiary data during Screening are not eligible for 
enrollment.
d) For post-Screening visits, sum the 3 most recent consecutive non-missing results and 
divide 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 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. 
5. Calculate total score:
a) For complete Mayo, sum the PGA subscore, sigmoidoscopy subscore, rectal bleeding 
subscore and stool frequency subscore. All 4 subscores must be available.
b) For partial Mayo, sum the PGA subscore, rectal bleeding subscore and stool frequency 
subscore. All 3 subscores must be available.
c) For the Day 1 visit, sum the Screening endoscopy score and the Day 1 partial Mayo to 
create a Day 1 complete Mayo score.
7.1.7
Methods for Handling of Missing Efficacy Data
Through the end of the double-blind period, the missing efficacy data will be handled as follows:

Missing data for dichotomous (ie, proportion-based) endpoints will be handled using the non-
responder imputation method, ie, any subject with missing information for determination of 
endpoint status will be considered as a non-responder in the analysis. Sensitivity analysis 
may be conducted to assess the impact of dropouts for different missing mechanisms using a 
hybrid approach where discontinuation due to AE or lack of efficacy will be imputed as non-


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responder (under missing not at random mechanism) and other discontinuation/missing will
be imputed using multiple imputation (under missing at random).

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 (eg, multiple imputations or repeated 
measure mixed effects model) may be explored.
7.1.8
Convention for Calculation of Inflammatory Bowel Disease Questionnaire (IBDQ)
The IBDQ is a widely used, health-related quality of life questionnaire used for subjects with 
ulcerative colitis and Crohn’s disease. The questionnaire asks about the subject’s bowel 
problems and how they affect his or her life during the past 2 weeks. The IBDQ consists of 32 
questions, with each question response ranging from 1 to 7, in which 1 indicates worse IBD and 
7 indicates better IBD. 
IBDQ Sub-domain
Calculation
IBDQ Bowel symptoms score
Sum of (Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, Q29). Ranging from 10 to 
70. 10 questions.
IBDQ Emotional function score
Sum of (Q3, Q7, Q11, Q15, Q19, Q21, Q23, Q25, Q27, Q30, Q31 and Q32). 
Ranging from 12 to 84. 12 questions. 
IBDQ Social function score
Sum of (Q4, Q8, Q12, Q16 and Q28). Ranging from 5 to 35. 5 questions.
IBDQ systemic symptoms score
Sum of (Q2, Q6, Q10, Q14 and 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.
To calculate the IBDQ total score, the scores for Bowel symptom, Emotion function, Social 
function, and Systemic symptoms are summed. The IBDQ total score ranges from 32 to 224, 
with a higher score indicating better quality of life. If any of the component score is missing at a 
visit, the imputed value will be set to missing.
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 
in this set will be analyzed according to the treatment they were randomized to receive.
This population will be used for the efficacy analysis. 


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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 from the PPS will be made prior to the unblinding of the study. 
Patients will be included in the per protocol population if they meet the following criteria 
according to the specified hierarchy:

Confirmed diagnosis of UC of at least three months duration and an enrolling Mayo score 
between 6 and 12 (inclusive) with an endoscopic sub-score of ≥2.

Received the correct study medication as assigned.

Remained blinded through Week 52 (i.e., per Protocol Amendment 5) or unblinded prior to 
Week 52 per protocol (e.g., lack of efficacy, medical emergency).

Received at least 80% of doses of study drug, as assigned.

Had a valid Week 52/ET assessment for a non-missing complete Mayo score.

Did not receive any non-study drug due to lack of efficacy (eg, corticosteroid for rescue 
medication or any other rescue medications). And did not receive any concomitant use of 
corticosteroids or other potentially effective medications (except as permitted per protocol) 
for an unrelated comorbid condition (eg, prednisone for idiopathic thrombocytopenic 
purpura). See Appendix B for details. 
If any clinical site has detected or reported significant noncompliance with regulatory 
requirement, all subjects from that site will be excluded from the PPS. Additional exclusion from 
the PPS may be finalized as part of a final data review and documented prior to database lock.
7.2.3
Pharmacokinetic Set (PKS)
The PKS will include all subjects who receive at least 1 dose of study drug and have at least 1 
measurable concentration of vedolizumab. 
This population will be used for the PK analysis. 
7.2.4
Safety Analysis Set
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.
This population will be used for the safety analysis. 
7.2.5
Randomized Set
The Randomized set will include all subjects who are randomized into the study regardless 
whether they receive any dose of investigational product or not. Subjects will be analyzed 
according to their randomized treatment group. 


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7.3
Disposition of Subjects
The following summaries of subject disposition will be produced:

Study Information
This summary will include details of the date that the first subject signed the informed 
consent form, the date of the last subject’s last visit/contact, the date of the last subject’s last 
procedure for collection of data for the primary endpoint and the Medical Dictionary for 
Regulatory Activities (MedDRA), World Health Organization Drug Dictionary (WHODrug) 
and SAS® Versions used for reporting.

Summary of Screen Failures
This summary will include the total number of screen failures, descriptive statistics for age, 
counts and percentages for gender, ethnicity, race and the primary reason for screen failure. 

Number of Subjects Randomized by Site 
This summary will be performed by the randomization stratification factors: concomitant use 
of oral corticosteroids and previous exposure/failure of TNF-α antagonist therapy or naïve to 
TNF-α antagonist therapy; as well as by geographic region, country and site.

Disposition of Subjects
This summary will be performed on the Randomized Set and will summarize subjects 
randomized but not treated, subjects completing or prematurely discontinuing study drug 
along with the primary reason for study drug discontinuation, subjects completing or not 
completing all study visits along with the primary reason for discontinuation of study visits. 
In addition, discontinuation of study drug by visit window and discontinuation of study visit 
by visit window will be summarized and presented.

Significant Protocol Deviations
This summary will be performed on the Randomized Set and will summarize the significant 
protocol deviations captured on the electronic case report form.

Reasons for Exclusion From PPS
This summary will be performed on the Randomized Set and will summarize the reasons 
subjects are excluded from PP Set based on the evaluability determinations.

Analysis Sets
The analysis sets defined in Section 7.2 will be summarized, including randomized but not 
treated if necessary.
All subject disposition information will be listed.


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7.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics data will be summarized by treatment group and 
overall using the Randomized Set. If there is a large difference between the Randomized Set and 
FAS and/or Safety Analysis Set (ie, >5%) then additional summaries may be performed on the 
FAS and/or Safety Analysis Set.
The summary will include descriptive statistics for age, height, weight and body mass index 
(BMI). BMI will be calculated using the subject’s height at screening and baseline weight 
measurement. Counts and percentages will be displayed for age groups (adults [18-64 years], 
from 65 to 85 years), gender, ethnicity, race, smoking classification and female reproductive 
status. 
Other baseline characteristics will be summarized by treatment group and overall. The 
summaries will include descriptive statistics for the following baseline UC characteristics: 
Baseline Characteristics
Summarized as
Categories
Disease duration
Continuous
Disease duration category
Categorical
<1 years, ≥1 - <3 years, ≥3 - <7 years, ≥7 years
Baseline Mayo score
Continuous
Baseline disease activity based on 
complete Mayo
Categorical
Mild (<6), Moderate (6 to 8), Severe (9 to 12)
Baseline partial Mayo score
Continuous
Baseline disease activity based on 
partial Mayo
Categorical
Mild (2-4), Moderate (5-6), Severe (7-9)
Baseline fecal calprotectin
Continuous
Baseline fecal calprotectin category
Categorical
≤250, >250 to ≤500 ug/g, >500 ug/g
Concomitant use of oral 
corticosteroids
Categorical
Yes/No, based on iterative web response system 
(IWRS) data
Prior use of TNF-α antagonist
Categorical
Naïve, Exposure/Failure, based on IWRS data
Baseline endoscopic subscore 
Continuous and 
Categorical
0, 1, 2, 3, based on adjudicated data
Baseline concomitant use of 
immunomodulators
Categorical
Yes, No
Baseline CRP
Continuous
All demographic, baseline characteristics and baseline disease characteristics will be listed.
7.5
Medical History and Concurrent Medical Conditions
The Safety Analysis Set will be used for all summaries in this section.
Medical history is defined as any significant conditions or diseases relevant to the disease under 
study that stopped at or prior to signing of informed consent. Medical history will be coded using 


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MedDRA and will be summarized by system organ class and preferred term, by treatment group 
and overall.
Concurrent medical conditions are defined as any significant conditions or diseases relevant to 
the disease under study that were ongoing at signing of informed consent. Concurrent medical 
conditions will be coded using MedDRA and will be summarized by system organ class and 
preferred term, by treatment group and overall. 
Medical history and concurrent medical conditions will be presented in data listings.
7.6
Medication History and Concomitant Medications
The Safety Analysis Set will be used for all summaries in this section.
Medication history is defined as any medication relevant to eligibility criteria stopped at or 
within 30 days prior to signing off informed consent. Medication history will be coded using 
WHODrug and will be summarized by therapeutic classification, standardized medication name, 
treatment group and overall.
Prior biologic medication history for the treatment of UC is defined as prior biologic medications 
stopped at or prior to signing of informed consent. Prior biologic medication history will be 
coded using WHODrug and will be summarized by therapeutic classification, standardized 
medication name, treatment group and overall.
Concomitant medications are defined as any drugs used in addition to the study medication from 
signing of informed consent through the end of the study. Concomitant medications will be 
coded using WHODrug and categorized as follows:

Concomitant medications that started and stopped prior to baseline.

Concomitant medications that started prior to and were ongoing at baseline and those that 
started after baseline.
Each category of concomitant medications will be summarized by standardized medication 
name, treatment group and overall.
Medication history, prior biologic medication history and concomitant medications will be listed.
7.7
Study Drug Exposure and Compliance
The Safety Analysis Set will be used for all summaries in this section. Study drug exposure, 
completed injections/infusions, and compliance will be summarized by treatment group. Similar 
summary tables will be provided by treatment group and by prior TNF-α antagonist status as 
well. The exposure to IV and SC will be calculated separately.
Completed infusions are defined as IV dosing where the total amount of study drug is infused. 
Completed injections are defined as SC dosing where the total amount of study drug is injected. 
SC dosing is recorded in the eCRF for clinic visits and electronic diaries (e-diaries) for at-home 
dosing. Duplicate entries will be handled as follows prior to summarizing:


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
If a clinic visit SC dose is also recorded in the e-diary, data will be taken from the eCRF for 
analysis.

If an e-diary contains multiple dosing records on a single date, the record with the most drug 
injected (complete vs partial) will be used for analysis, regardless of time or location.
The extent of exposure will be calculated as the duration between the first and last dose of study 
drug plus approximately 5 times of half-life of the study drug. Given that the mean terminal half-
life of Adalimumab is approximately 2 weeks, the extent of exposure will be calculated as 
follows:

Vedolizumab: Date of last dose of Vedolizumab – Date of first dose of Vedolizumab + 1 + 
126 days (18 weeks).

Adalimumab: Date of last dose of Adalimumab – Date of first dose of Adalimumab + 1 + 70 
days (10 weeks).
The extent of exposure will be summarized using descriptive statistics by treatment group. 
Compliance for IV dosing will be calculated as the percentage of completed infusions out of the 
total number of infusions, and as the percentage of completed and partial infusions out of the 
total number of infusions, respectively. 
Compliance for SC dosing will be calculated as the percentage of completed injections out of the 
total number of injections and as the percentage of completed and partial injection out of the total 
number of injections, respectively. 
Study drug administration data will be presented in data listings.
7.8
Efficacy Analysis
All efficacy analysis will be based on the FAS, with exception of corticosteroid-free remission, 
which will be based on FAS subjects with baseline concomitant oral corticosteroid use. The 
sensitivity analysis will be based on the PPS. 
All statistical inference will be 2-sided at a 0.05 level of significance. The statistical testing of 
primary and secondary efficacy endpoints will be based on a hierarchical approach to control the 
overall Type I error rate. The testing of the additional efficacy endpoints will not be multiplicity-
adjusted. 
7.8.1
Primary Efficacy Endpoint(s)
The primary endpoint is the proportion of subjects achieving clinical remission, defined as a 
complete Mayo score of ≤2 points and no individual subscore >1 point, at Week 52. 
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. Bar chart 
for clinical remission at Week 52 with 95% CI by treatment group will be provided as well.


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The null and alternative hypotheses for the primary efficacy endpoint, clinical remission at 
Week 52, are: 
H0: Clinical Remission Vedolizumab at W52 = Clinical Remission Adalimumab at W52
versus
HA: Clinical Remission Vedolizumab at W52 ≠ Clinical Remission Adalimumab at W52
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 (Yes/No); 

Previous exposure/failure of TNFα antagonists or naïve to TNFα antagonists therapy 
(Yes/No).
The primary comparison of interest will be vedolizumab IV versus adalimumab SC at Week 52. 
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. In the event that the number of remissions is too small (ie, ≤5), 
the exact method (eg, 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.
The following sensitivity analyses will be performed for the primary efficacy endpoint:

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. 

Similar analysis will be repeated for clinical remission at Week 52 in the PPS as a sensitivity 
analysis for the primary efficacy endpoint. 

The impact of dropouts may be explored by using a hybrid approach for sensitivity analysis 
where discontinuation due to AE or lack of efficacy will be imputed as non-responder (under 
MNAR) and other discontinuation/missing will be imputed using multiple imputation (under 
MAR). For multiple imputation, each component of the complete Mayo score will be 
imputed by treatment group via a multivariate step-wise approach using fully conditional 
specification (FCS ordinal Logistic) methods (Ratitch, Lipkovich, and O’Kelly, 2013), 
respectively. Missing baseline Mayo score, if any, will be imputed using relevant 
demographic and baseline disease characteristic data (namely, age, duration of UC, baseline 
disease severity). And subsequent visits will be imputed using all the previous visits in a 
stepwise fashion. Fifty (50) imputation datasets will be computed for each component of 
complete Mayo score. The complete and/or partial Mayo score will be derived subsequently. 
Additional sensitivity analysis may be performed as appropriate.


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7.8.2
Secondary Efficacy Endpoint(s)
The secondary efficacy endpoints are mucosal healing at Week 52 and corticosteroid-free 
remission at Week 52. Similarly to the primary efficacy endpoint, mucosal healing at Week 52
will be analyzed for the FAS subjects and corticosteroid-free remission at Week 52 will be 
analyzed in a subset of the FAS subjects with baseline concomitant oral corticosteroid use, using 
the CMH test stratified by randomization stratification factors. In the event that the number of 
remissions is too small (ie, ≤5), the exact method will be performed instead. Bar charts for 
mucosal healing at Week 52 and corticosteroid-free remission at Week 52 with 95% CI by 
treatment group will be provided as well. All subjects with missing data for determination of the 
secondary efficacy endpoints will be considered as not in mucosal healing or non-remitters in the 
analysis. 
The null and alternative hypotheses for the first secondary efficacy endpoint, mucosal healing at 
Week 52, are: 
H0: Mucosal Healing Vedolizumab at W52 = Mucosal Healing Adalimumab at W52
versus
HA: Mucosal Healing Vedolizumab at W52 ≠ Mucosal Healing Adalimumab at W52
The null and alternative hypotheses for the second secondary efficacy endpoint, corticosteroid-
free remission at Week 52, are: 
H0: Corticosteroid-free Remission Vedolizumab at W52 = Corticosteroid-free Remission Adalimumab at W52
versus
HA: Corticosteroid-free Remission Vedolizumab at W52 ≠ Corticosteroid-free Remission Adalimumab at W52
To control the overall Type I error rate of the primary and secondary endpoints, a hierarchical 
approach will be applied to the statistical testing of the secondary endpoints. The first secondary 
endpoint will only be tested if statistical significance is achieved with the primary efficacy 
endpoint, clinical remission at Week 52 (p <0.05). The second secondary endpoint will only be 
tested if statistical significance is achieved with the first secondary endpoint, mucosal healing at 
Week 52 (p <0.05). 
In addition, the same CMH analysis will be repeated for the secondary efficacy endpoints in the 
PPS for mucosal healing at Week 52, and in a subset of PPS with baseline concomitant oral 
corticosteroid use for corticosteroid-free remission at Week 52 as sensitivity analysis. The 
impact of dropouts may be explored by using the hybrid approach.
Additional sensitivity analysis may be performed as appropriate.
7.8.3
Additional Efficacy Endpoint(s)
All other proportion-based efficacy endpoints except proportion of subjects with a change in 
histology from Baseline to Week 52 will be analyzed for the FAS subjects or a subset of FAS 
subjects with baseline concomitant oral corticosteroid use using the CMH test stratified by 


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randomization stratification factors, similarly as the primary efficacy endpoint. Missing data will 
be imputed using the non-responder imputation.
Proportion of subjects with a change in histology from baseline to Week 52 (per Geboes), will be 
summarized by shift table to describe the status shift of change in histology from baseline to 
Week 52, as observed. In particular, the baseline histology data will be categorized into two 
groups: <3 and ≥3. The change in histology data from baseline to Week 52 will be categorized 
into 3 groups: no change (-1< change <1), worsening (change ≥1), and improving (change ≤-1). 
Missing data in change in histology from baseline to Week 52 will not be imputed.
Change from baseline in oral corticosteroid use will be evaluated in terms of change in median 
corticosteroid dose, cumulative exposure of oral corticosteroid, and duration of oral 
corticosteroid. These endpoints will be summarized in a subset of the FAS subjects with baseline 
concomitant oral corticosteroid use, and tested using Wilcoxon rank-sum test. Corticosteroid use 
is defined as prednisone or equivalent.
Change from baseline in fecal calprotectin will be analyzed for the FAS subjects using an 
analysis of covariance model (ANCOVA) with treatment and randomization stratification factors 
as factors and baseline fecal calprotectin as a covariate. Missing data will be imputed using the 
LOCF method.
Time to UC-related hospitalizations, bowel resection, and UC-related procedures will be 
analyzed using a Wei-Lin-Weissfeld (WLW) 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 Month 6 and Month 12 event rates presented. Subjects without 
documented UC-related events before reaching the end of study will be censored at the date of 
last assessment/visit/contact, whichever occurs last. 
7.8.4
Exploratory Efficacy Endpoint(s)
The exploratory endpoints were not defined in the protocol, but will be included in the final 
analysis. 
Clinical remission by visit and clinical response by visit will be summarized descriptive by 
treatment group for the FAS subjects. Line chart with 95% CI over time will be provided. 
All other proportion-based exploratory efficacy endpoints will be summarized by treatment 
group descriptively, and analyzed for the FAS subjects using the CMH test stratified by 
randomization stratification factors, similarly as the primary efficacy endpoint. In the event of 
small number of responders (ie, ≤5), the exact method will be performed instead. In addition, the 
analysis for proportion of subjects with FCP ≤250 ug/g at Week 14, 30, 52 (among those with 
FCP >250 ug/g at baseline) will be based on a subset of FAS subjects with baseline FCP >250 
ug/g. Missing data will be imputed using the non-responder imputation.
For continuous exploratory efficacy endpoints (eg, IBDQ specific-domains), baseline, post 
baseline and change from baseline will be summarized by study visit and by treatment group 


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descriptively. Change from baseline at each post baseline study visit will be analyzed for the 
FAS subjects using ANCOVA with treatment and randomization stratification factors as factors 
and baseline value as a covariate. Missing data will be imputed using the LOCF method.
Time to event endpoints (eg, time to first clinical remission, time to first clinical response) will be 
analyzed by the stratified log-rank test to compare treatment groups during double-blind 
treatment period, stratifying by randomization stratification factors. Kaplan-Meier (KM) 
estimates and KM curves will be provided. Subjects without documented clinical remission or 
clinical response before reaching the end of study will be censored at the date of last 
assessment/visit/contact, whichever occurs last.
7.8.5
Summary of Efficacy Analyses
In summary, the primary, secondary and additional efficacy endpoints will be analyzed using the 
methods specified the table below.
Endpoints
Imputation
Analysis Type

Clinical remission at W52
Non-responder imputation
Hybrid approach for 
missing data imputation
Descriptive statistics, bar 
chart, CMH test in FAS 
and PPS, and FAS 
excluding the 
noncompliant site, CMH 
test in FAS using the 
hybrid approach for 
missing data imputation

Mucosal healing at W52
Non-responder imputation
Descriptive statistics, bar 
chart, CMH test in FAS 
and PPS

Corticosteroid-free remission at W52
Non-responder imputation
Descriptive statistics, bar 
chart, CMH test in a 
subset of FAS with 
baseline concomitant oral 
corticosteroid use and 
PPS

Clinical response at W52

Clinical remission at W14

Proportion of subjects with rectal bleeding subscore 
indicative of mild disease (≤1) at Week 52.

Proportion of subjects with a Physician’s Global 
Assessment (PGA) subscore indicative of mild disease 
(≤1) at Week 52.

Proportion of subjects with stool frequency subscore 
indicative of mild disease (≤1) at Week 52.

Proportion of subjects with complete Mayo score of 
≤2 points and no individual subscore >1 point where 
rectal bleeding subscore of 0 and endoscopy subscore 
of 0 at Week 52.
Non-responder imputation
Descriptive statistics, 
CMH test in FAS


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Endpoints
Imputation
Analysis Type

Proportion of subjects with endoscopy subscore of 0, 
rectal bleeding subscore of 0, and stool frequency 
subscore decreases or no change from Baseline at 
Week 52.

Proportion of subjects with endoscopy subscore ≤1, 
rectal bleeding subscore of 0, and stool frequency 
subscore of 0 at Week 52.

Proportion of subjects with endoscopy subscore ≤1, 
rectal bleeding subscore of 0, and stool frequency 
subscore ≤1 at Week 52.

Proportion of subjects with endoscopy subscore ≤1, 
rectal bleeding subscore of 0, stool frequency subscore 
decreases or no change from Baseline, and total score 
(sum of these 3) ≤1 at Week 52.

Proportion of subjects with IBDQ score change of ≥16 
points from Baseline to Week 52. 

Proportion of subjects reaching clinical remission 
based on IBDQ score >170 at Week 52.

Proportion of subjects using oral corticosteroids at 
Baseline who have discontinued corticosteroids and 
are in clinical remission at Week 14.

Proportion of subjects with histological remission at 
Week 14, per Geboes and per RHI separately.

Proportion of subjects with histological remission at 
Week 52, per Geboes and per RHI separately.

Proportion of subjects with a change in histology from 
Baseline to Week 52, per RHI only.
No imputation
Shift table in FAS

Change in oral corticosteroid use from baseline to 
W52 in terms of cumulative exposure of oral 
corticosteroid use, duration of oral corticosteroid use, 
change in median oral corticosteroid dose up to W52
No imputation
Descriptive statistics, 
Wilcoxon rank-sum test 
in a subset of FAS with 
baseline concomitant oral 
corticosteroid use 

Change in fecal calprotectin from baseline to W14, 
W30, and W52
LOCF
Descriptive statistics, 
ANCOVA in FAS

Time to major UC-related events (eg, hospitalizations, 
bowel resection, and procedures).
No imputation
Descriptive statistics, 
WLW Cox-regression 
model in FAS

Clinical response at Week 14.

Proportion of subjects with complete Mayo ≤1 and 
rectal bleeding subscore = 0 at Week 52.

Proportion of subjects with durable clinical remission, 
defined as clinical remission at Week 52 amongst 
those in clinical remission at Week 14.

Proportion of subjects in clinical remission at Week 
52 and in clinical remission for ≥14 weeks leading up 
Non-responder imputation 
Descriptive statistics, 
CMH test in FAS


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Endpoints
Imputation
Analysis Type
to Week 52.

Proportion of subjects with disease control at Week
52, defined as complete Mayo ≤2 and rectal bleeding 
subscore = 0 and endoscopy subscore = 0, CRP <5, 
FCP <100, histologic remission.

Proportion of subjects with rectal bleeding subscore = 
0 at Week 52.

Proportion of subjects with major UC-related events 
(eg, hospitalizations, bowel resection, and procedures) 
throughout the study up to Week 52.

Proportion of subjects with FCP ≤250 ug/g at Week 
14, 30, 52 (among those with FCP >250 ug/g at 
baseline).

Proportion of subjects still on adalimumab or 
vedolizumab at Week 68.

Proportion of subjects with minimal histological 
disease activity at Week 14, per Geboes and per RHI 
separately.

Proportion of subjects with minimal histological 
disease activity at Week 52, per Geboes and per RHI 
separately.

Clinical remission by visit.

Clinical response by visit.
Non-responder imputation
Descriptive statistics and 
line chart in FAS

Change from baseline in IBDQ-specific domain at 
Week 30 and Week 52.
LOCF
Descriptive statistics, 
ANCOVA in FAS

Time to first clinical remission.

Time to first clinical response.
No imputation
Stratified log-rank test 
and KM curve in FAS
7.8.6
Subgroup Analysis
This section applies to the following selected efficacy endpoints:

Clinical remission at Week 14 and Week 52,

Mucosal healing at Week 52, and

Corticosteroid-free remission at Week 52.
The subpopulations of interest are defined by the following baseline characteristics outlined in 
Table 7.f.


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Table 7.f
List of subgroups of interest.
Subgroup of Interest
Subgroup Categories
Age 
<35, ≥35 years
<65, ≥65 years
Gender 
Female, Male 
Race 
White, Non-White
Duration of UC
<1 years, ≥1 - <3 years, ≥3 - <7 years, ≥7 years
Baseline Disease Activity (based on 
baseline complete Mayo score)
Moderate (6-8), Severe (>8)
(excluding subjects with baseline complete Mayo score <6)
Baseline Fecal Calprotectin
≤250, >250 ug/g
≤500, >500 ug/g
Prior use of anti-TNFα antagonist
Naïve, Exposure/Failure
Concomitant use of oral corticosteroids 
Yes, No
Baseline use of immunomodulator
Yes, No
Descriptive analyses will be performed to summarize the treatment effects across 
subpopulations. The treatment effect in proportions in Vedolizumab and Adalimumab and 
associated 95% confidence interval using Clopper-Pearson method will be provided for each
subgroup. Point estimate of the absolute treatment difference between Vedolizumab and 
Adalimumab based on crude estimate and associated 95% confidence interval (using normal 
approximation method) will be presented. In the event that the number of remissions 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.
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. 
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), or 
Fisher’s exact test in the event of small number responders (ie, ≤5).
In addition, corticosteroid-free remission analysis will be based on a subset of subjects with 
baseline concomitant oral corticosteroid use in FAS. If the size of the subgroups of interest for 
corticosteroid-free remission is too small to perform meaningful subgroup analysis (eg, <10 
subjects), the subgroup analysis will not be presented for corticosteroid-free remission at Week 
52. Note that concomitant use of oral corticosteroids subgroup analysis is not applicable to 
corticosteroid-free remission, and thus it will not be presented for corticosteroid-free remission at 
Week 52.
7.8.7
Immunogenicity Analysis
The presence of anti-drug antibodies (ADA) to vedolizumab or adalimumab for subjects 
randomized will be assessed and reported. Immunogenicity results will be summarized by the 


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number and percentage of subjects who develop detectable ADAs (against vedolizumab or
adalimumab).
The protocol defines a positive ADA subject as a subject who has at least 1 positive ADA result 
in any postbaseline sample, and is further categorized as:

Transiently positive: defined as subjects with confirmed positive ADA in 1 sample at a 
postdose visit.

Persistently positive: defined as subjects with confirmed positive ADA in 2 or more 
consecutive positive ADA samples at postdose visits.
In addition, an alternative definition for positive ADA will be explored in the final analysis.

Negative ADA: defined as a sample that is evaluated as negative in the ADA screening 
assay. Samples that are determined to be positive in the ADA screening assay but the result is 
not confirmed in the ADA confirmatory assay are considered negative.

Positive ADA: defined as a sample that was evaluated as positive in both the ADA screening 
and confirmatory assays.
–
Transiently positive: defined as patients with confirmed positive ADA in 1 sample.
–
Persistently positive: defined as patients with confirmed positive ADA in 2 or more 
consecutive positive ADA samples. 
–
Positive neutralizing ADA: defined as a sample that was evaluated as positive in the 
neutralizing ADA assay. Note only confirmed positive anti-vedolizumab sample will be
tested for its neutralizing ability against vedolizumab in this study.
The proportion of subjects with positive ADA (transient and persistent) and the proportion of 
subjects with positive neutralizing ADA during the study will be summarized by treatment group 
using FAS, based on protocol defined ADA positive and the alternative definition of ADA 
positive, respectively. Missing ADA data will not be imputed. 
The ADA data will also be summarized descriptively by study visit and by titer separately. The 
impact of ADA on the PK (for vedolizumab only), efficacy, and safety will be examined if 
applicable. In particular, clinical remission at Week 52 and mucosal healing at Week 52 will be 
summarized descriptively by ADA status. The correlation between the ADA status and 
investigator defined infusion related AEs will be explored.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Samples from subjects randomized to vedolizumab will be analysed for PK. All PK analyses will 
be performed using the PK Set. Measured serum concentrations of vedolizumab and Ctrough of 
vedolizumab by time will be summarized overall and by prior TNF-α antagonist status using 
descriptive statistics (nonmissing values, mean, SD, median, minimum, and maximum). 
Individual serum concentration data versus time will be presented in a data listing.


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7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Not applicable. 
7.11
Safety Analysis
Safety analysis will be performed using the Safety Analysis Set with the actual treatment 
received. The analysis of safety endpoints will include AEs, clinical laboratory values, vital 
signs, and ECG. No statistical inference will be made for safety analyses.
7.11.1 Adverse Events
Adverse events (AE) will be coded by MedDRA (v20.0 or higher) and the type incidence, 
severity and relationship to study investigational product will be summarized. All AEs and SAEs 
collected in the database (including those starting prior to first dose of study drug) will be listed. 
Any other information collected (eg, relatedness to study drug, action taken etc.) will be listed as 
appropriate.
A Treatment Emergent AE (TEAE) is 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. The number of percentage of subjects with TEAEs will be summarized. Exposure-
adjusted AE rates will be summarized as well. AEs with missing or unknown severity will be 
considered as severe. AEs with missing or unknown relationship to study drug will be counted as 
related.
Specific adverse events will be counted once for each subject for calculating percentages. Key 
guidelines for determining the incidence of AEs are as follows:

Where a patient has the same AE, based on preferred terminology, reported multiple times in 
a single analysis period, the patient will only be counted once at the preferred terminology 
level in AE tables.

When a patient has the same AE, based on preferred terminology, reported multiple times in 
a single analysis phase, the following criteria, in order of precedence, will be used to select 
the event to be included in summary tables. 
–
Relationship to study medication.
–
Intensity of event.
–
Onset date and time (where applicable).

When reporting AEs by intensity, in addition to providing a summary table based on the 
event selection criteria detailed in Item 2 above, summary tables will also be provided based 
on the most intense event during the analysis phase – independent of relationship to study 
medication. For these tables, the following criteria, in order of precedence, will be used to 
select the event to be included in summary tables.


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–
Intensity of event.
–
Onset date and time (where applicable).
7.11.1.1 TEAEs
The number and percentage of subjects experiencing the TEAEs will be summarized by system 
organ class (SOC), high level term (HLT), and preferred term (PT) and by treatment groups.
Exposure-adjusted AE rates will be summarized as appropriate. 

TEAEs by SOC, HLT and PT.

TEAEs by severity and by SOC, HLT and PT.

TEAEs by relationship to relationship to the investigational product and by SOC, HLT, and 
PT.

Most frequent non-serious TEAEs (ie, AEs occurring in ≥5% of subjects in any treatment 
group) by PT in descending order of frequency.
7.11.1.2 Serious Adverse Events (SAE)
The number and percentage of subjects experiencing the SAEs will be summarized by SOC, 
HLT and PT and by treatment group. Exposure-adjusted SAE rates will be summarized as 
appropriate. All SAEs will be listed.

SAEs by SOC, HLT and PT.

SAEs by severity and by SOC, HLT and PT.

SAEs by relationship to the investigational product and by SOC, HLT, and PT.
In addition, a summary table will be provided for the number of SAEs and related SAEs by SOC 
and PT.
7.11.1.3 Deaths
All on-study deaths recorded on the AE page, or death page (with a death date, cause of death, 
and outcome) of the CRF will be considered a death in the analysis. All deaths will be listed, and 
summarized by PT.
7.11.1.4 TEAEs Resulting in Discontinuation of Study Drug
TEAEs resulting in permanent discontinuation of study drug will be listed and summarized by 
SOC, HLT and PT and by treatment group. 
7.11.1.5 TEAEs of Special Interest
Based on the mechanism of action of Vedolizumab, certain adverse events of special interest 
have been predefined. These AEs of special interest will be summarized by SOC, HLT and PT 
and by treatment group.


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The categories of AEs of special interest are as follows (see Appendix C for details):

Injection and/or Infusion Site Reactions and Hypersensitivity.

Serious Infections.

Malignancies.

PML.

Liver Injury.

Other.
7.11.2 Clinical Laboratory Evaluations
Hematology, serum chemistry, urinalysis, and stool testing parameters will be collected in this 
study, and analyzed by central laboratory. All laboratory results will be listed for each subject. 
Individual laboratory test values outside the standard reference range will be flagged. For 
continuous variables of laboratory tests, all data at baseline and at each scheduled visit will be 
summarized by treatment group using descriptive statistics. Changes from baseline by visit will 
also be summarized using descriptive statistics. For categorical variables of laboratory tests, the 
frequency and percentage in each category of the item at baseline and at each post-baseline visit 
will be presented for each treatment group. The analysis visit will be derived using the visit 
windowing convention defined in Section 7.1.3. Subjects with markedly abnormal values for 
laboratory tests will be tabulated (see Appendix D for details). 


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Hematology
Serum Chemistry
Urinalysis
RBC
WBC w/differential
Hemoglobin
Hematocrit
Platelets
PT/INR
Alanine aminotransferase
Albumin
Alkaline phosphatase Amylase
Aspartate aminotransferase
Bicarbonate
Calcium
Chloride
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Glucose
Lipase
Magnesium
Phosphorus
Potassium
Sodium
Total and direct bilirubin
Total protein
Uric acide
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 Serum 
Urine 
Stool 
CRP
Hepatitis panel
ADA
Serum concentration
QuantiFERON
Pharmacogenomic sample
FSH
Beta hCG
Urine pregnancy hCG (female subjects 
of childbearing potential)
Fecal calprotectin
C. Difficile test
7.11.3 Vital Signs
Vital signs parameters, including blood pressure, body temperature, pulse rate and respiration 
rate, will be obtained according to study schedule procedures. Change from baseline in all vital 
signs parameters will be summarized by visit and by treatment group. Subjects with markedly 
abnormal vital signs values will be tabulated (see Appendix E for details). 


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7.11.4 12-Lead ECGs
12-lead Electrocardiogram (ECG) measurements will be performed according to the study 
schedule. The overall interpretation of the ECG results (Normal; Abnormal, not Clinically 
Significant; and Abnormal, Clinically Significant) will be summarized using frequency count and 
percentages by visit and treatment groups. The shift in ECG interpretation from baseline will be 
summarized by treatment group. The ECG interpretation data will be listed.
7.11.5 Other Observations Related to Safety
Physical examination findings and PML checklist data will be presented in data listings.
7.12
Interim Analysis
Two interim analyses will be conducted.
7.12.1 Interim I
The first interim analysis will be conducted after approximately 100 subjects have been 
randomized into the study for 52 weeks and who have completed the Week 52 Final Visit or 
Early Termination Visit. This analysis will be used to determine the conditional power of the 
study and assess whether a sample size increase is required. The analysis will be carried out by 
an independent statistical team in a manner that maintains the blinding of the study to the team 
and subjects and presented for review to the DMC. The interim results will not be shared with 
the sponsor. During this interim analysis enrollment to the study will continue. Further details on 
the first interim analysis will be documented in the Interim Analysis Statistical Plan and DMC 
Charter.
7.12.2 Interim II
The second interim analysis will be conducted for the purpose of publication when all subjects 
have completed the Week 52 Final Visit or ET Visit. Following the Week 52 or ET Visit subjects 
continue onto the 18-week off-study-treatment Safety Follow-up Period. No changes to study 
conduct or final analysis will be made based on the second interim results and subjects will 
continue to the Follow-up Period. All available data will be included in the second interim 
analysis. The analysis will be performed on unblinded treatment groups by a firewalled
independent statistical team who are not involved in the conduct of the study. Note that all 
efficacy endpoints are measured at (or before) Week 52. The second interim analysis is intended to 
assist publication and does not allow for stopping the study early due to overwhelming efficacy or 
futility. There is no alpha adjustment required in the statistical analyses. The aggregate unblinded 
results (i.e., no individual data listings or datasets) may be released to the general public via 
press release and/or scientific presentations. 
Only a limited number of sponsor personnel will be unblinded to the treatment assignment for 
individual subjects to avoid introducing bias to the remaining study conduct and final analyses.
This group of unblinded sponsor personnel will not be involved in any day-to-day site or subject 


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level activities during this off-study-treatment safety follow-up period from the time they 
become unblinded.
Sponsor personnel directly associated with the ongoing daily conduct of this study including 
oversight and trial management will have the same access to the aggregate unblinded results from the 
second interim analysis as the general public and remain blinded with no access to the treatment 
assignment for individual subjects until the completion of study. The details of the strategy for 
maintaining confidentiality of the unblinded individual treatment assignment until final database 
lock of MLN0002-3026 will be described in a separate document (i.e., data access management 
plan).
The second interim analysis will follow all methodology outlined in this SAP. The deliverables 
will include all outputs for final analysis except PK and immunogenicity analyses.
7.13
Changes in the Statistical Analysis Plan 
The following changes from the protocol have been made in this SAP: 

Additional exploratory efficacy endpoints were defined and included in this SAP. Refer to 
Sections 5.3.5 and 7.8.4 for details. 

Due to data collection limitation, time to major UC-related events will be evaluated via UC-
related hospitalization, bowel resection, and UC-related procedures in the data analysis. 

Only a limited number of sponsor personnel will be unblinded to the treatment assignment 
for individual subjects and this group of unblinded sponsor personnel will not be involved in 
any day-to-day site or subject level activities during the 18-week off-study-treatment safety 
follow-up period from the time they become unblinded. The aggregate unblinded results may 
be released to the general public via press release and/or scientific presentations.
7.13.1 Revision History
Version 
Date
Description of Revision
1.0
07Feb2018
N/A
2.0
11Sept2018

Clarified the definition of disease control in Section 5.3.5. 

Added the conventions of calculation of Mayo Score per draft FDA UC 
guidance (August 2016) in Section 7.1.3.

Updated the definition of PPS in Section 7.2.2 and Appendix B.

Added sensitivity analysis to explore the impact of dropouts using a hybrid 
approach in Section 7.8.1.

Updated the definition for persistently positive AVA samples in Section 7.8.7.

Modified the definition of change in histology at Week 52 in Section 7.8.3.

Updated immunogenicity analysis by adding anti-adalimumab in Section 7.8.7.

Updated the deliverables of the second interim analysis and clarified the 
logistics of the second interim analysis in Section 7.12.2.


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8.0
REFERENCES
1.
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: 
a practical guide with examples. Stat Med 2011;30(28):3267-84.
2.
Liu Y, Hu M. Testing multiple primary endpoints in clinical trials with sample size 
adaptation. Pharm Stat 2016;15(1):37-45.
3.
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
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 B
Rescue Medication and Potentially Effective Medication Rules
The following rules have been established in order to determine the medication is rescue 
medication or potentially effective. This determination is necessary to include in the overall set 
of PPS rules. 
For rescue medications, the patient will be excluded from the PPS if they have received any of 
the following non-study drug due to lack of efficacy after the first dose of study drug and 
remained in the study:

Corticosteroids as rescue medication (eg, new corticosteroids given to the patient or 
cumulative corticosteroid dose greater than the baseline dose).

Immunomodulators.
–
Any exposure over a continuous 14-day period.

Anti-TNF (after the first dose date).
–
Any exposure.

Ciclosporin or Tacrolimus.
For potentially effective medications, the patient will be excluded from the PPS if they have 
received any of the following medications for an unrelated comorbid condition after the first 
dose of study drug (except as permitted per protocol, eg, stable corticosteroid dose used for UC 
or tapering per protocol):

Corticosteroids by the following routes: IV/IM/PO/PR.
–
Any cumulative exposure of >150 mg prednisone or equivalent IV/IM/PO/PR over a 
continuous 5-day period. If >30 days has passed between last day of cumulative exposure 
and Week 52 Mayo determination, then do not consider the steroid as potentially 
effective medication.
–
Any cumulative exposure of >300mg prednisone or equivalent IV/IM/PO/PR over a 
continuous 30-day period. If >30 days has passed between last day of cumulative 
exposure and Week 52 Mayo determination, then do not consider the steroid as 
potentially effective medication.
–
Any single day exposure of >10 mg/day prednisone or equivalent over the last 3 days 
prior to Mayo determination (Week 52).

Immunomodulators.
–
Any exposure over a continuous 14-day period.

Anti-TNF (after the first dose date).
–
Any exposure.

Ciclosporin or Tacrolimus.


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–
Any exposure.
The final rescue medication and potentially effective medication list may be finalized as part of a 
final data review and documented prior to database lock.


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Appendix C
AEs of Special Interest
Based on the mechanism of action of vedolizumab, certain adverse events of special interest 
(AESIs) have been predefined. The categories of adverse events of special interest, and other 
planned analyses, are described below. 
1. Injection and/or Infusion Site Reactions, including Hypersensitivity Reactions 
The clinical database will be searched for possible injection and/or infusion site reactions during 
the reporting period using the following MedDRA 20.0 search criteria:

Anaphylactic/anaphylactoid shock conditions Standard MedDRA Query (SMQ) (broad).

Angioedema SMQ (broad).

Hypersensitivity SMQ (broad).

Infusion related reaction HLT.

Injection site reactions HLT.
An AE that is indicated as an infusion site reaction or injection site reaction in the eCRF will also 
be considered an injection and/or infusion site reactions AESI.
2. Upper Respiratory Tract Infections
The infections retrieved from the clinical database will be evaluated for upper respiratory tract 
infections during the reporting period using the MedDRA 20.0 search criteria of: 

Upper respiratory tract infections HLT in the Infections and Infestations SOC.

Bronchitis PT.

Influenza PT.
3. Gastrointestinal (GI) Infections
The infection reports retrieved from the clinical database were evaluated for GI infections during 
the reporting period using the MedDRA 20.0 search criteria of: 

Abdominal and gastrointestinal infections HLT in the Infections and Infestations SOC.

Gastrointestinal infections HLT of the Gastrointestinal SOC.
4. Suspected Progressive Multifocal Leukoencephalopathy (PML)
The protocol incorporates an active screening program in order to identify and manage any case 
of PML. This program is known as the Risk Assessment and Minimization for PML (RAMP). 
The clinical database will be searched for suspected PML reports received within the Infection 
and Infestation SOC using the MedDRA 20.0 search criteria of: 

Human polyomavirus infection PT.


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
JC virus infection PT.

JC virus test positive PT.

Leukoencephalopathy PT.

Polyomavirus test positive PT.

Progressive multifocal leukoencephalopathy PT.
5. Other Infections, including Opportunistic Infections
The infection reports retrieved from the clinical database, not classified as upper respiratory tract 
infections (URTIs), GI infections, or suspected PML will be searched using the MedDRA 20.0 
search criteria of: 

Infections and Infestations SOC.
The following reports will then be excluded:

Abdominal and gastrointestinal infections HLT.

URTI HLT.

Bronchitis PT.

Influenza PT.

Human polyomavirus infection PT.

JC virus infection PT.

JC virus test positive PT.

Leukoencephalopathy PT.

Polyomavirus test positive PT.

Progressive multifocal leukoencephalopathy PT.
6. Liver Injury
The clinical database will be searched for reports of liver injury using the following MedDRA 
20.0 search criteria:

Cholestasis and jaundice of hepatic origin SMQ (broad).

Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions SMQ 
(broad).

Hepatitis, non-infectious SMQ (broad).

Liver related investigations, signs and symptoms SMQ (narrow).

Liver infections SMQ (broad).


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7. Malignancies
The clinical database will be searched for reports of malignancy using the MedDRA 20.0 search 
criteria of: 

Neoplasms benign, malignant and unspecified (incl cysts and polyps) SOC.


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Appendix D
Criteria for Identification of Markedly Abnormal Laboratory Values and 
Vital Sign 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 E
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85 
>180 
Diastolic blood pressure
mm Hg
<50 
>110
Body temperature
oC
<35.6
>37.7
oF
<96.1
>99.9


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