Conditions: Colitis, Ulcerative
Keywords: Drug Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 278
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate the efficacy and safety of vedolizumab intravenous (IV) dose optimization on mucosal healing compared with the standard vedolizumab IV dosing regimen over a 30 week treatment period in participants with moderately to severely active ulcerative colitis (UC) and high vedolizumab clearance, based on a Week 5 predefined serum vedolizumab concentration threshold less than (\<) 50 microgram per milliliter (microg/mL) and who are Week 6 non-responders based on partial Mayo score.

Detailed description:
The drug being tested in this study is called Vedolizumab. Vedolizumab will be administered as an IV infusion. It is being tested in this study with new doses. This study will investigate the efficacy and safety of dose optimization of vedolizumab IV, compared with standard dosing of vedolizumab IV, over a 30-week treatment period.

The study will enroll approximately 250 moderately to severely active subjects with UC in order to randomize approximately 100 non-responder subjects with high vedolizumab drug clearance. Subjects will receive induction therapy of vedolizumab IV 300 mg on Day 1 and Week 2 (Lead-in Period). At Week 5, serum vedolizumab concentration will be measured. At Week 6, subjects will be assessed for clinical response based on partial Mayo score.

Results of both Week 5 vedolizumab concentration and Week 6 clinical response will determine the treatment pathway. Those who are non-responders based on partial Mayo score at Week 6 and who are assessed as having high vedolizumab clearance, based on a predefined Week 5 serum vedolizumab concentration threshold (\<50 microg/mL) will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

* Vedolizumab IV Standard Treatment
* Vedolizumab IV Dose Optimized

All randomized subjects will receive vedolizumab IV either 300 mg or 600 mg every 4 or 8 weeks.

This multi-center trial will be conducted in United States of America and Canada. The overall time to participate in this study is 56 weeks. Subjects will make multiple visits to the clinic, and will be contacted by telephone, 6 months after last dose of study drug for a long term follow-up safety survey.

Arms:
arm 1: Vedolizumab 300 mg intravenous (IV) infusion once at Day 1 and at Week 2. Participants who were non-responders based on partial Mayo score at Week 6 and who had high vedolizumab clearance (\>0.14 L/day) at Week 5 were eligible for Randomized Treatment Period (RTP). Participants who were responders (Lead-In Failures) entered the 18-week follow-up period and discontinued the study. arm 2: Following Lead-in Period, participants received vedolizumab 300 mg, IV infusion, once every 8 weeks (Q8W) at Weeks 6, 14 and 22 as standard treatment plus 18 weeks follow-up. arm 3: Following Lead-in Period, participants received vedolizumab 600 mg, IV infusion at Week 6, followed by Regimen A: vedolizumab 300 mg once in every 4 weeks (Q4W) thereafter (Weeks 10, 14, 18, 22 and 26) plus 18 weeks follow-up, or Regimen B: vedolizumab 600 mg, IV infusion Q4W (Weeks 10, 14, 18, 22 and 26) plus 18 weeks follow-up based on drug clearance.

Interventions: intervention 1: Vedolizumab IV
Intervention descriptions: intervention 1: Vedolizumab intravenous infusion.

Protocol document:
Prot_000.pdf: 



Title: A Phase 4 Open-Label Study to Evaluate Vedolizumab IV Dose Optimization on Treatment 
Outcomes In Nonresponders With Moderately to Severely Active Ulcerative Colitis
NCT Number: NCT03029143
Protocol Approve Date: 19 April 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL AMENDMENT
A Phase 4 Open-Label Study to Evaluate Vedolizumab IV Dose Optimization on Treatment 
Outcomes In Nonresponders With Moderately to Severely Active Ulcerative Colitis
(ENTERPRET)
Vedolizumab IV Dose Optimization in Ulcerative Colitis
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
Study Number:
Vedolizumab-4014
IND Number:
009125
EudraCT Number:
Not Applicable
Compound:
Vedolizumab IV
Date:
19 April 2018
Amendment Number:
03
Amendment History
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
02 June 2016
Initial
Not applicable
Global
19 August 2016
01
Substantial
Global
16 December 2016
02
Substantial
Global
19 April 2018
03
Substantial
Global
Prope
Non-Commercial Use Only and Subject to the Applicable Terms of Use


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1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts 
A separate contact information list will be provided to each site.
Takeda Development Center Americas Inc., sponsored investigators per individual country 
requirements will be provided with emergency medical contact information cards to be carried by 
each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
United States/Canada Contact
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)
Property of Takeda: For Non-Commercial 
cia
 the Applicable Terms of Use
ntry 
ntry 
be carrie
be carr
r assign
assig
vant gu
vant g
s/Cana
Ca
the
PPD


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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
Prop
nly and Subject to the Applicable Terms of Use
dance
ance
wing:
wing:
olidated
lidate
a privac
priva
other sig
ther si
thihis doc
s do
PPD


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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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1.3
Protocol Amendment 03 Summary of Changes
This document describes the changes in reference to the protocol incorporating Amendment 
No. 03. The primary reason for this amendment is to increase the number of sites, increase the 
number of subjects, revise prohibited medications, clarify inclusion exclusion criteria, and 
document changes in study team members. Other minor changes in procedures are proposed. 
Minor grammatical and editorial changes are included for clarification purposes only. For specific 
descriptions of text changes and where the changes are located, see Appendix F. 
The following is a summary of the changes made in Amendment No. 03: 
1. Investigator agreement revised to remove provision of package insert. 
2. Subject number to enroll was increased from 200 to 250, to randomize approximately 100 
subjects.
3. Site number was increased from 70 to 80.
4. Section 5.2.2 Secondary Endpoints, Day 1 was removed from the complete Mayo score 
definition of Baseline.
5. Exclusion Criteria #7, clarified subjects with prior exposure to approved or investigational 
anti-integrin antibodies are excluded.
6. Exclusion Criteria #8, clarified subjects that previously received approved or investigational 
Vedolizumab (not just Vedolizumab IV) are excluded.
7. Exclusion Criteria #11, clarified timing of exclusion is during Screening. 
8. Exclusion Criteria #18, clarified timing of exclusion is 2 weeks prior to Screening. 
9. Exclusion Criteria #25, clarified timing of PML checklist administration. 
10. Section 7.4.1 Excluded Medications was updated.
11. Section 7.4.2 Permitted Medications was updated.
12. Section 7.4.2.1 Corticosteroid Taper, co-administration maximum dose and budesonide taper 
were added.
13. Section 7.6 Procedures for Discontinuation or Withdrawal of a Subject, replacement language 
was removed. 
14. Section 8.1.2 Storage, clarified storage requirements for Vedolizumab IV.
15. Section 8.2 Investigational Drug Assignment and Dispensing Procedures, clarified lower dose 
will resume once serum Vedolizumab is ≤90 µg/mL.
16. Section 9.1.2 Medication History and Prior UC Disease Treatment eCRF data entry was 
clarified.
17. Section 9.1.3 UC Disease History, clarified eCRF data entry for UC disease as concurrent 
condition. 
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18. Section 9.1.6 Vital Sign Procedure, 5 minute period for vital sign collection and order of 
procedure language were removed.
19. Section 9.1.9 Documentation of Concomitant Procedures, clarified last clinic visit.
20. Section 9.1.10 Documentation of Concurrent Medical Conditions, clarified this includes lab, 
ECG, or physical exam abnormalities found at Screening. 
21. Section 9.1.11 Procedures for Clinical Laboratory Samples, added that Screening labs may be 
repeated once at investigator discretion. 
22. Section 9.1.19 PK Sample Collection, clarified PK samples collection timing.
23. Section 9.1.21 Tuberculosis Screening was updated to clarify Chest X-Ray should only be 
performed if skin or QuantiFERON tests are indeterminate.
24. Section 9.1.24 Documentation of Screen Failure, added rescreening criteria.
25. Section 9.3.1 Screening Period, period for enrollment was clarified.
26. Section 13.1.3 Efficacy Analysis, primary efficacy analysis was updated.
27. Section 13.3 Determination of Sample Size was updated to note that additional subjects may be 
added to account for high drop-out rates.
28. Appendix A, Prior UC disease treatment was added to the schedule of procedures. 
29. Appendix A, concomitant medications was checked at Screening.
30. Appendix A, footnote (j), PK collection was clarified.
31. Appendix A, footnote (s), PML checklist administration was clarified.
32. Appendix B Responsibilities of the Investigator, added responsibility if investigator/institution 
retains the services of any individual or party to perform trial-related duties and functions, the 
investigator/institution should ensure that this individual or party is qualified to perform those 
trial-related duties and functions and should implement procedures to ensure the integrity of 
the trial-related duties and functions performed and any data generated.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Principal Investigator/Coordinating Investigator ......................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................19
3.5
Study Definitions.....................................................................................................20
4.0
INTRODUCTION.........................................................................................................21
4.1
Background .............................................................................................................21
4.1.1
Diseases and Current Treatments .......................................................................21
4.1.2
Vedolizumab IV.................................................................................................22
4.2
Rationale for the Proposed Study.............................................................................24
4.3
Benefit-Risk Assessment .........................................................................................25
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................27
5.1
Objectives................................................................................................................27
5.1.1
Primary Objective(s)..........................................................................................27
5.1.2
Secondary Objectives.........................................................................................27
5.1.3
Additional Objectives.........................................................................................27
5.2
Endpoints.................................................................................................................27
5.2.1
Primary Endpoint...............................................................................................27
5.2.2
Secondary Endpoints..........................................................................................27
5.2.3
Additional Endpoints .........................................................................................28
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................29
6.1
Study Design ...........................................................................................................29
6.2
Justification for Study Design, Dose, and Endpoints ................................................31
6.3
Premature Termination or Suspension of Study or Investigational Site.....................33
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................33
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........33
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................34
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............35
7.1
Inclusion Criteria .....................................................................................................35
7.2
Exclusion Criteria ....................................................................................................36
7.3
Week 6 Randomized Treatment Period Inclusion Criteria ........................................38
7.4
Excluded Medications, Procedures, and Treatments.................................................39
7.4.1
Excluded Medications........................................................................................39
7.4.2
Permitted Medications .......................................................................................39
7.4.2.1 Corticosteroid Taper.....................................................................................40
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................40
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................41
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................42
8.1
Study Medication and Materials...............................................................................42
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................42
8.1.1.1 Vedolizumab IV 300 mg ..............................................................................42
8.1.1.2 Vedolizumab IV 600 mg ..............................................................................42
8.1.2
Storage...............................................................................................................42
8.1.3
Dose and Regimen .............................................................................................42
8.1.4
Overdose............................................................................................................43
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................44
8.3
Randomization Code Creation and Storage..............................................................45
8.4
Accountability and Destruction of Sponsor-Supplied Drugs.....................................45
9.0
STUDY PLAN ..............................................................................................................47
9.1
Study Procedures.....................................................................................................47
9.1.1
Informed Consent Procedure..............................................................................47
9.1.1.1 Pharmacogenomic Informed Consent Procedure...........................................47
9.1.2
Demographics, Medical History, and Medication History Procedure..................47
9.1.3
UC Disease History............................................................................................47
9.1.4
Physical Examination Procedure ........................................................................48
9.1.5
Weight, Height...................................................................................................48
9.1.6
Vital Sign Procedure..........................................................................................48
9.1.7
Primary Efficacy Measurement ..........................................................................48
9.1.7.1 Diary Completion and Review......................................................................49
9.1.7.2 Flexible Sigmoidoscopy and Biopsy.............................................................49
9.1.8
Documentation of Concomitant Medications......................................................49
9.1.9
Documentation of Concomitant Procedures........................................................50
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9.1.10 Documentation of Concurrent Medical Conditions.............................................50
9.1.11 Procedures for Clinical Laboratory Samples.......................................................50
9.1.12 Fecal Calprotectin Sample Collection.................................................................52
9.1.13 Stool Sample for C. difficile...............................................................................52
9.1.14 Contraception and Pregnancy Avoidance Procedure...........................................52
9.1.14.1
Male Subjects and Their Female Partners ...............................................52
9.1.14.2
Female Subjects and Their Male Partners ...............................................52
9.1.14.3
Definitions and Procedures for Contraception and Pregnancy 
Avoidance....................................................................................................53
9.1.15 Pregnancy ..........................................................................................................55
9.1.16 ECG Procedure..................................................................................................55
9.1.17 PGx Sample Collection......................................................................................55
9.1.18 Immunogenicity Sample Collection ...................................................................57
9.1.19 PK Sample Collection........................................................................................57
9.1.20 Pharmacodynamic and Exploratory Biomarker Assessments..............................57
9.1.21 Tuberculosis Screening ......................................................................................57
9.1.22 PML Checklist...................................................................................................57
9.1.23 Patient Reported Outcome Measures..................................................................57
9.1.24 Documentation of Screen Failure .......................................................................58
9.1.25 Documentation of Study Entrance......................................................................58
9.1.26 Documentation of Lead-in Failure......................................................................58
9.2
Monitoring Subject Treatment Compliance..............................................................59
9.3
Schedule of Observations and Procedures................................................................59
9.3.1
Screening Period................................................................................................59
9.3.2
Enrollment and Lead-in Period...........................................................................60
9.3.3
Randomization (Week 6) and Randomized Treatment Period.............................60
9.3.3.1 Lead-in Failures ...........................................................................................60
9.3.4
Randomized Treatment Period and Dose Regimen Selection..............................60
9.3.5
Final Visit or Early Termination.........................................................................61
9.3.6
Week 40 (Q8W)/Week 44 (Q4W) Follow-up (18 Weeks Post-Treatment)..........61
9.3.7
Long-Term Follow-Up Safety Survey (6-Months Post-Treatment).....................61
9.3.8
Unscheduled Visits (if applicable)......................................................................61
9.3.9
Unscheduled Visits Due to Disease Exacerbation...............................................61
9.4
Biological Sample Retention and Destruction ..........................................................62
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................63
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10.1
Definitions...............................................................................................................63
10.1.1 PTEs..................................................................................................................63
10.1.2 AEs....................................................................................................................63
10.1.3 Additional Points to Consider for PTEs and AEs................................................63
10.1.4 SAEs..................................................................................................................65
10.1.5 Special Interest AEs...........................................................................................66
10.1.5.1
Hypersensitivity Reactions (Including Infusion-Related Reactions) ........66
10.1.5.2
Serious Infections...................................................................................67
10.1.5.3
Malignancy ............................................................................................67
10.1.5.4
Other......................................................................................................67
10.1.6 Severity of PTEs and AEs..................................................................................68
10.1.7 Causality of AEs ................................................................................................68
10.1.8 Relationship to Study Procedures.......................................................................68
10.1.9 Start Date...........................................................................................................68
10.1.10
Stop Date .....................................................................................................68
10.1.11
Frequency ....................................................................................................68
10.1.12
Action Concerning Study Medication...........................................................68
10.1.13
Outcome.......................................................................................................69
10.2
Procedures...............................................................................................................69
10.2.1 Collection and Reporting of AEs........................................................................69
10.2.1.1
PTE and AE Collection Period ...............................................................69
10.2.1.2
PTE and AE Reporting ...........................................................................70
10.2.1.3
Special Interest AE Reporting.................................................................70
10.2.2 Collection and Reporting of SAEs......................................................................71
10.2.3 Reporting of Abnormal LFTs.............................................................................71
10.3
Follow-up of SAEs ..................................................................................................72
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....72
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................73
11.1
PML Independent Adjudication Committee .............................................................73
11.1.1 Risk Assessment and Management Program (RAMP) for PML..........................73
12.0
DATA HANDLING AND RECORDKEEPING............................................................74
12.1
Electronic CRFs.......................................................................................................74
12.2
Record Retention .....................................................................................................74
13.0
STATISTICAL METHODS..........................................................................................76
13.1
Statistical and Analytical Plans ................................................................................76
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13.1.1 Analysis Sets......................................................................................................76
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................76
13.1.3 Efficacy Analysis...............................................................................................76
13.1.4 PK Analysis .......................................................................................................77
13.1.5 Other Analyses...................................................................................................77
13.1.6 Safety Analysis ..................................................................................................78
13.2
Interim Analysis and Criteria for Early Termination ................................................78
13.3
Determination of Sample Size..................................................................................78
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................79
14.1
Study-Site Monitoring Visits ...................................................................................79
14.2
Protocol Deviations..................................................................................................79
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................79
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................80
15.1
IRB and/or IEC Approval ........................................................................................80
15.2
Subject Information, Informed Consent, and Subject Authorization .........................81
15.3
Subject Confidentiality ............................................................................................82
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................82
15.4.1 Publication and Disclosure.................................................................................82
15.4.2 Clinical Trial Registration..................................................................................83
15.4.3 Clinical Trial Results Disclosure ........................................................................83
15.5
Insurance and Compensation for Injury....................................................................83
16.0
REFERENCES..............................................................................................................84
LIST OF IN-TEXT TABLES
Table 8.a
Vedolizumab IV Dose and Regimens.................................................................43
Table 9.a
Clinical Laboratory Tests...................................................................................51
Table 10.a
Takeda Medically Significant AE List................................................................66
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................31
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LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................88
Appendix B
Responsibilities of the Investigator.....................................................................93
Appendix C
Elements of the Subject Informed Consent.........................................................95
Appendix D
Investigator Consent to Use of Personal Information..........................................98
Appendix E
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity............99
Appendix F
Detailed Description of Amendments to Text...................................................100
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
Vedolizumab IV
Title of Protocol: A Phase 4, Open-Label Study to 
Evaluate Vedolizumab IV Dose Optimization on 
Treatment Outcomes In Nonresponders With Moderately 
to Severely Active Ulcerative Colitis (ENTERPRET)
IND No.: 009125
EudraCT No.:
Not applicable
Study Number: Vedolizumab-4014
Phase: 4
Study Design:
This is a phase 4, open-label, multicenter study to investigate the efficacy and safety of dose optimization of 
vedolizumab IV, compared with standard dosing of vedolizumab IV, over a 30-week treatment period. This study will 
enroll adult subjects with moderately to severely active ulcerative colitis (UC) who are eligible for treatment with 
vedolizumab IV. Approximately 250 subjects will be enrolled in order to randomize approximately 100 nonresponder 
subjects with high vedolizumab drug clearance.
All eligible subjects will receive induction therapy with vedolizumab IV 300 mg on Day 1 and Week 2 (Lead-in 
Period). Subjects who are assessed as having high vedolizumab clearance, based on a predefined Week 5 serum 
vedolizumab concentration threshold (<50 µg/mL) and who are nonresponders (based on partial Mayo score) at Week 
6 will be randomized into the Randomized Treatment Period to receive either standard or optimized doses of 
vedolizumab IV. Subjects who are determined to be responders or are nonresponders at Week 6 with a Week 5 level 
above the predefined vedolizumab concentration threshold (≥50 µg/mL) (ie, Lead-in Failures) will not be randomized 
and will receive the Week 6 study drug dose and thereafter appropriate treatment per physician discretion. The study is 
comprised of a 28-day Screening Period, a 6-week Lead-in Period, and a 24-week Randomized Treatment Period, 
followed by an 18-week Follow-Up Safety Visit and a long-term follow-up (LTFU) safety survey by telephone 6 
months after the last dose of study drug. 
Primary Objectives:
To determine the effect of vedolizumab IV dose optimization on mucosal healing compared with the standard 
vedolizumab IV dosing regimen at Week 30 in subjects with UC and high vedolizumab clearance based on a 
predefined week 5 serum vedolizumab concentration threshold (<50 µg/mL) and who are Week 6 nonresponders.
Secondary Objectives:
To determine the effect of vedolizumab IV dose optimization on clinical response and remission compared with the 
standard vedolizumab IV dosing regimen at Week 30 in subjects with UC and high vedolizumab clearance based on a 
Week 5 predefined serum vedolizumab concentration threshold (<50 µg/mL) and who are Week 6 nonresponders.
Subject Population: Adult subjects aged of 18 to 85 years, inclusive, with moderately to severely active UC 
established at least 1 month prior to Screening and who have high vedolizumab clearance based on a predefined 
Week 5 serum vedolizumab concentration threshold (<50 µg/mL) and who are nonresponders at Week 6.
Number of Subjects:
Estimated total: 250 enrolled/100 randomized (50 per 
treatment group)
Number of Sites: 
Estimated total: Approximately 80 in the United States 
and Canada
Dose Level(s):
Day 1 and Week 2:
Vedolizumab IV 300 mg (all subjects)
Week 6 and beyond:
Vedolizumab IV 300 mg every 8 weeks (Q8W), standard
Vedolizumab IV 300 mg every 4 weeks (Q4W) or 600 mg 
Q4W (optimized)
Route of Administration:
Intravenous
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Vedolizumab IV 300 mg Q8W (optimized arm lowest 
dose available following return to normalization from 
Ctrough >90 µg/mL) 
Duration of Treatment:
30-week treatment period
Period of Evaluation:
The study includes a 28-day Screening Period and a 
6-week Lead-in Period. For subjects randomized to 
study drug, it includes a 24-week Randomized 
Treatment Period. All subjects are required to participate 
in an 18-week Follow-up Period following last dose and 
a LTFU safety survey by telephone, 6 months after the 
last dose of study drug. The duration of the study will be 
approximately 56 weeks. 
Main Criteria for Inclusion:

The subject has been determined to be suitable for vedolizumab IV by their physician.

Age at Screening between 18 to 85 years of age, inclusive.

Diagnosis of UC established at least 1 month prior to Screening. 

Active moderate to severe UC as determined by a complete Mayo score of 6 to 12 with an endoscopic subscore of 
≥2 within 28 days prior to enrollment.

Subject has had an inadequate response with, lost response to, or intolerance of at least 1 of the following agents: 
immunomodulator, corticosteroids, or tumor necrosis factor-alpha (TNF-α) antagonist. Subjects who are TNF-α 
antagonist naïve or who have failed prior TNF-α antagonist treatment (primary and secondary nonresponders or 
intolerant) may be included. 
At Week 6, subjects must meet both of the following inclusion criteria to be eligible for randomization into the 
Randomized Treatment Period of the study:

The subject is assessed as having a high vedolizumab clearance, based on a predefined Week 5 serum 
vedolizumab concentration threshold (<50 µg/mL).

The subject is a nonresponder based on partial Mayo score at Week 6.
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 symptom checklist 
during Screening or prior to the administration of the first dose of study drug on Day 1.

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 approved or investigational anti-integrin antibodies (eg, vedolizumab, 
natalizumab, efalizumab, etrolizumab, AMG-181, mucosal addressin cell adhesion molecule [anti-MAdCAM-1] 
antibodies, or rituximab).
Main Criteria for Evaluation and Analyses:
Primary endpoint:

The proportion of subjects achieving mucosal healing, defined as Mayo endoscopic subscore ≤1 point, at 
Week 30.
Secondary endpoints:

Proportion of subjects achieving clinical remission, where clinical remission is defined as a complete Mayo score 
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of ≤2 points and no individual subscore >1 point at Week 30.

Proportion of subjects achieving clinical response, where clinical response is defined as a reduction in complete 
Mayo score of ≥3 points and ≥30% from Baseline with an accompanying decrease in rectal bleeding subscore of 
≥1 point or absolute rectal bleeding subscore of ≤1 point, at Week 30.

Proportion of subjects achieving clinical response (based on partial Mayo score), which is defined as a reduction 
in partial Mayo score of ≥2 points and ≥25% from Baseline with an accompanying decrease in rectal bleeding 
subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point at, Week 14. 

Proportion of subjects using oral corticosteroids at Baseline who have discontinued corticosteroids and are in 
clinical remission, at Week 30.

Proportion of subjects achieving durable clinical response, which is defined as clinical response based on partial 
Mayo score at Weeks 14 and 30.
Safety Endpoints:

Safety as assessed by adverse events (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, and results of 
standard laboratory tests (clinical chemistry, hematology, coagulation, urinalysis).
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 the subset of the FAS who are taking concomitant oral corticosteroids at Baseline. 
All proportion-based primary and secondary efficacy endpoints will be summarized by presenting the point estimate 
and 95% confidence intervals for the proportion by treatment group. The difference in proportions between treatment 
groups along with the 95% confidence interval will be presented. The primary efficacy analyses will be based on 
logistic model with treatment as a factor, natural logarithm of trough concentration at Week 6 and other important 
covariates as explanatory variables. Odds ratio and its 95% confidence interval for treatment effect will be provided
All subjects with missing data for determination of endpoint status will be considered as a nonresponder in the 
analysis.
Sample Size Justification: The sample size was based on an estimate of precision and not on statistical power 
considerations. A total sample size of approximately 250 subjects enrolled to achieve approximately 100 subjects 
randomized at Week 6, including 50 subjects per treatment group, will be sufficient to provide 95% confidence 
intervals for mucosal healing rates with a half width no wider than +/-13.9%. In addition, the maximum width of the 
95% confidence intervals (2-sided) for the difference in mucosal healing rates between the 2 groups will be no wider 
than +/-19.6%. If there is a high rate of patient drop out from the study, additional patients may be added.
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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 
Clinical Study Supplier document. The identified vendors in the template for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
5-ASAs
5-aminosalicylates
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AVA
antivedolizumab antibody
CD
Crohn’s disease
CLL
linear clearance
CRO
contract research organization
CRP
C-reactive protein
CSR
clinical study report
Ctrough
observed concentration at the end of a dosing interval
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form 
EMA
European Medicines Agency
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GALT
gut-associated lymphoid tissue
GCP
Good Clinical Practice
GGT
-glutamyl transferase
GI
gastrointestinal
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRQOL
health-related quality of life
IAC
Independent Adjudication Committee
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire 
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFX
infliximab
Ig
immunoglobulin
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INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
ITT
intent-to-treat
IUD
intrauterine device
IV
intravenous
JCV
John Cunningham virus
K2EDTA
potassium ethylenediamine-tetraacetic acid
LFT
liver function tests
LTFU
long-term follow-up
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
MED ID
medication identification number
PD
pharmacodynamics
PGx
pharmacogenomics
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PTE
pretreatment event
Q4W
every 4 weeks
Q8W
every 8 weeks
RAMP
Risk Assessment and Management Program for PML
RBC
red blood cell
RNA
ribonucleic acid
ROC
receiver operating characteristic 
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reactions
SVR
sustained virological response
TAXIT
Trough Level Adapted Infliximab Treatment
TB
tuberculosis
TDM
therapeutic drug monitoring
TEAE
treatment-emergent adverse events
TNF-α
tumor necrosis factor-alpha
TPN
total parenteral nutrition
TYSABRI
natalizumab
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
Vc
central compartment volume of distribution
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VCAM-1
vascular cell adhesion molecule-1
WBC
white blood cell
WOCBP
woman of child bearing potential 
WHODRUG
World Health Organization Drug Dictionary
3.4
Corporate Identification 
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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3.5
Study Definitions
Term
Definition
High clearance
Week 5 serum vedolizumab concentration <50 µg/mL
Very high clearance
Week 5 serum vedolizumab concentration <30 µg/mL
Complete Mayo score
A composite index of 4 disease activity variables (stool frequency, rectal bleeding, 
findings on sigmoidoscopy, and physician’s global assessment), each scored on a scale 
from 0 to 3 (higher scores indicate greater disease activity).
Partial Mayo score
A composite index of 3 disease activity variables (stool frequency, rectal bleeding, and 
physician’s global assessment), each scored on a scale from 0 to 3 (higher scores indicate 
greater disease activity). Partial Mayo score is calculated analogously to the complete 
Mayo score but excludes the sigmoidoscopy subscore.
Clinical remission by 
complete Mayo score
A complete Mayo score of ≤2 points and no individual subscore >1 point.
Clinical response by 
complete Mayo score
A reduction in complete Mayo score of ≥3 points and ≥30% from Baseline with an 
accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding 
subscore of ≤1 point.
Clinical response by 
partial Mayo score
A reduction in partial Mayo score of ≥2 points and ≥25% from Baseline (Day 1) with an 
accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding 
subscore of ≤1 point
Corticosteroid-free 
remission
Subjects using oral corticosteroids at Baseline (Day 1) who have discontinued oral 
corticosteroids and are in clinical remission at Week 30.
Durable clinical response A clinical response (based on partial Mayo score), which is defined as a reduction in partial 
Mayo score of ≥2 points and ≥25% from Baseline with an accompanying decrease in rectal 
bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point at Weeks 14 
and 30.
Mucosal healing
A Mayo endoscopic subscore of ≤1 point.
Vedolizumab IV standard 
dosing
Vedolizumab IV 300 mg infused intravenously at Weeks 0, 2, and 6 and then once every 
8 weeks (Q8W) thereafter.
Tumor necrosis factor-alpha (TNF-α) antagonist failure categories
Primary nonresponse
Persistently active disease despite induction treatment.
Secondary nonresponse
Recurrence of symptoms during maintenance dosing following prior clinical benefit.
Intolerance
Occurrence of treatment-related toxicities.
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4.0
INTRODUCTION
4.1
Background
4.1.1
Diseases and Current Treatments 
Ulcerative colitis (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 the colon. 
The prevalence of UC is approximately 200/100,000 of the United States population and 
approximately 150/100,000 of the population in Western Europe [1-3] and 63.6/100,000 of the 
population in Japan [4]. A genetic contribution to the disease is indicated by the increased 
incidence of UC (of 30 to 100 times that of the general population) among first-degree relatives of 
patients with UC. The characteristic pathology is one of chronic inflammation characterized by 
large numbers of lymphocytes and histiocytes in the diseased mucosa and submucosa with an 
acute inflammatory infiltrate composed of neutrophils variably present.
Clinical manifestations of UC include diarrhea, typically bloody, as well as abdominal pain, fecal 
urgency, and incontinence. Systemic features such as fever, weight loss, malaise, and fatigue are 
indicators of more extensive disease. Extra-intestinal manifestations which track intestinal activity 
such as peripheral arthritis (type1), episcleritis, and erythema nodosum are commonly associated 
with inflammatory bowel disease (IBD), whereas those that manifest independent of disease 
activity such as ankylosing spondylitis, pyoderma gangrenosum, primary sclerosing cholangitis, 
and uveitis may be seen as well. The diagnosis of UC is usually made by the clinical presentation 
and key features of the history, physical examination, in combination with laboratory and imaging 
studies.
Current treatments have been effective for many patients with UC but have numerous limitations 
for patients with moderately to severely active disease. 5-aminosalicylates (5-ASAs) are the 
mainstay of UC pharmacotherapy for induction and maintenance of remission for patients with 
mild to moderate disease, but are less effective in moderate to severe disease [5,6]. 
Corticosteroids are often required for the 1/3 of patients who fail to respond to 5-ASAs [7,8]. 
While highly effective for induction of remission, corticosteroids are not recommended for 
maintenance of remission and carry significant undesirable side effects, including osteoporosis, 
glucose intolerance, and increased risk of infection. 
Immunomodulatory agents, including 6-mercaptopurine and azathioprine, have a role in 
maintenance of remission in moderately to severely active UC. Their relatively slow onset of 
action precludes their use during flares of disease, and the use of these agents has been reported to 
potentially increase the risk of lymphoma in patients with IBD [9]. Other severe adverse events 
(AEs) associated with use of immunomodulators include cytopenias, hepatitis, and infection.
Intravenous (IV) cyclosporine has a role in the management of severely active UC; however, it is 
impractical in non-hospitalized patients, requires intense monitoring, and may cause irreversible 
nephrotoxicity, all of which limit its use. 
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Monoclonal antibodies (mAbs) directed against tumor necrosis factor-alpha (TNF-α) have been 
approved for the treatment of UC in many countries world-wide, including infliximab (Remicade), 
adalimumab (Humira) and golimumab (Simponi) [10-12]. These agents have substantially 
improved the care of patients with UC by inducing and maintaining remission and decreasing the 
need for hospitalizations and surgeries, and other complications. Although TNF-α antagonists 
represent an important addition to the UC pharmacologic armamentarium, they are effective in 
only a subset of patients, with roughly 2/3 of patients in controlled trials not in remission at the end 
of the first year of therapy [13,14]. Induction of remission with infliximab occurs in only 31% to 
39% of patients with UC [15] and durable clinical remission (ie, defined as clinical remission at 
Weeks 8, 30, and 54) occurs in only 26% of patients with UC. In addition, controlled studies have 
demonstrated that, after failure of 1 TNF-α antagonist, a patient’s response to a second TNF-α 
antagonist is substantially lower [16]. The TNF-α antagonists are also associated with a number of 
serious safety concerns based on their suppression of systemic immunity, including reactivation of 
tuberculosis (TB); various bacterial, viral, fungal, and opportunistic infections; and malignancies, 
such as hepatosplenic T cell lymphoma [10,11].
Failure of pharmacological therapy leads to colectomy in 9% to 35% of patients with UC within 
5 years. Colectomy is considered to be an important adjunct treatment for refractory UC; however, 
colectomy with ileal pouch anal anastomosis (the standard surgical therapy) has many limitations 
and is associated with its own set of complications, including high stool frequency [17], female 
infertility [18], and a cumulative incidence of pouchitis of 50% at 10 years [19]. The limitations of 
current therapies for UC indicate that there is a significant need for safer and more effective 
therapies.
4.1.2
Vedolizumab IV
Vedolizumab (also known as MLN0002) is a novel recombinant humanized mAb composed of 
2 light chains of the subclass and 2 immunoglobulin (Ig) G1 heavy chains. Vedolizumab binds 
specifically to the human lymphocyte integrin 47. The α4β7integrin mediates lymphocyte 
trafficking to gastrointestinal (GI) mucosa and gut-associated lymphoid tissue (GALT) through 
adhesive interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is 
expressed on the endothelium of mesenteric lymph nodes and GI mucosa [20-23]. As a result, 
vedolizumab impairs the migration of gut-homing leukocytes into GI mucosa [24] and acts as a 
gut-selective immunomodulator.
Vedolizumab IV (also known as ENTYVIO; KYNTELES; Vedolizumab for Injection, for 
Intravenous Use; Vedolizumab Powder for Concentrate for Solution for Infusion; or MLN0002 
IV) has been granted marketing approval in numerous regions, including the United States (US), 
Canada, and European Union (EU). Vedolizumab IV is approved for the treatment of adult 
patients with moderately to severely active UC and CD, who have failed conventional treatment, 
such as immunomodulators, corticosteroids, or TNF-α antagonists. The approved dosing and 
administration regimen is 300 mg vedolizumab IV infused intravenously at Weeks 0, 2, and 6 and 
then every 8 weeks (Q8W) thereafter and is the standard vedolizumab dosing regimen referred to 
in this protocol.
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Previously conducted clinical studies have characterized the efficacy, safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of vedolizumab IV, a 
lyophilized formulation. As of 19 May 2015, approximately 3600 subjects (309 healthy subjects, 
1393 subjects with UC, and 1896 subjects with Crohn’s disease [CD]) have received at least 1 dose 
of vedolizumab across completed and ongoing studies (Edition 18 of Investigator’s Brochure). 
Vedolizumab exposure has extended for ≥12 months in 1667 subjects, ≥24 months in 1306 
subjects, ≥36 months in 935 subjects, ≥48 months in 676 subjects, ≥60 months in 267 subjects, and 
≥72 months in 26 subjects. Based on drug shipment data (19 November 2015), the cumulative 
patient exposure to vedolizumab IV since its marketing approval in May 2014 is estimated to be 
approximately 25,831 patient-years. 
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 once every 4 weeks 
(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 Period and Maintenance Period, respectively) 
compared with placebo [25]. The study also met important secondary endpoints, including durable 
clinical response, durable clinical remission, mucosal healing at Weeks 6 and 52, and 
corticosteroid-free clinical remission at Week 52. Given the significant morbidity associated with 
chronic corticosteroid treatment, the corticosteroid-sparing effects of vedolizumab provide an 
important benefit to patients with UC.
Vedolizumab IV has shown an acceptable and consistent safety profile in clinical studies and 
postmarketing. In the pivotal phase 3 studies (C13006 in UC and C13007 in CD), the most 
common (≥5% and at a higher incidence than placebo) adverse reactions in subjects administered 
vedolizumab IV were nausea, nasopharyngitis, upper respiratory tract infection, arthralgia, 
pyrexia, fatigue, headache, and cough. Most serious adverse events (SAEs) have been related to 
exacerbations or complications of the underlying UC or CD. For those infections that were 
reported more frequently in vedolizumab-treated subjects, the sites of these infections correlated 
with the known tissue distribution of MAdCAM-1 binding sites. Anal abscess, abdominal abscess,
and gastroenteritis were the most frequently reported serious infections. Extraintestinal infections 
(bronchitis, pneumonia, urinary tract infection, sepsis) occurred at low frequency (<1%). A total of 
4% of vedolizumab-treated subjects and 3% of placebo-treated subjects experienced an 
infusion-related reaction. In C13006 and C13007, 10% of subjects were positive for 
antivedolizumab antibodies (AVA) 16 weeks following the last dose of vedolizumab IV. Results 
from the clinical program to date do not suggest an increased risk for malignancy with 
vedolizumab treatment. 
A similar safety profile was observed in subjects who received vedolizumab IV Q4W or Q8W. 
Overall, the safety profile following long-term treatment with vedolizumab in C13008, a 
long-term safety study, is consistent with safety in the completed studies. No cases of progressive 
multifocal leukoencephalopathy (PML) have been identified to date in the clinical or 
postmarketing setting. 
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Vedolizumab PK is described by a 2-compartment model with parallel linear and nonlinear 
elimination. Using reference covariate values, the linear elimination half-life of vedolizumab is 
25.5 days; linear clearance (CLL) is 0.159 L/day for UC and 0.155 L/day for CD; central 
compartment volume of distribution (Vc) is 3.19 L; and peripheral compartment volume of 
distribution is 1.66 L. Only extreme albumin and body weight values have been identified as 
potential clinically important predictors of vedolizumab CLL [26]. 
As higher therapeutic mAb concentrations have been associated with greater efficacy in patients 
with UC or CD, a better understanding of the determinants of vedolizumab clearance may help to 
optimize dosing [27].
4.2
Rationale for the Proposed Study
Medical management of UC, along with that of other chronic diseases, is evolving toward a 
personalized treatment approach. Therapeutic drug monitoring (TDM), the observed concentration 
at the end of a dosing interval (Ctrough) with dosing titration to achieve a prespecified therapeutic 
range, is one modality that is increasingly employed to enhance UC patient care [28]. 
Approximately 1/3 of patients fail to respond to induction therapy of TNF-α antagonists and up to 
60% experience secondary loss of response. Differences in drug clearance may be an important 
explanation for this observation. Patients who lose response are typically managed empirically by 
dose intensification, switching to another agent with the same mechanism of action, or moving to 
an agent with a different mechanism of action. With a limited number of therapeutic options 
available, health care providers are optimizing the use of TNF-α antagonists by taking advantage 
of TDM [27,29]. 
Several factors are associated with accelerated clearance of monoclonal antibodies, including the 
presence of anti-drug antibodies, sex, body size, concomitant immunosuppressant use, IBD type, 
albumin concentration, and degree of systemic inflammation [26]. Furthermore, a consistent 
relationship between efficacy and exposure, in distinction to drug dose, has been observed for 
many of these agents; that is, higher Ctrough values are associated with greater efficacy [30]. 
Recent studies suggest a correlation between serum drug concentrations and clinical outcomes 
such as clinical and endoscopic remission [27]. Very few prospective clinical studies that compare 
the optimal therapeutic ranges and clinical outcomes for biologic therapies for UC and CD 
(ie, TNF-α antagonists) have been conducted to date. The Trough Level Adapted Infliximab 
Treatment trial (TAXIT) was a randomized controlled trial of 251 UC and CD patients that dose 
optimized all patients into a therapeutic window and then compared patients dosed by drug 
concentration dosing versus clinically based dosing for infliximab (IFX) maintenance therapy.
After dose optimization, continued concentration-based dosing was not superior to clinically based 
dosing for achieving remission after 1 year, but was associated with fewer flares during the course 
of treatment [29]. 
A similar understanding of the optimal therapeutic target range for vedolizumab IV is particularly 
important given its mechanism of action. Data for multiple endpoints from the vedolizumab IV UC 
clinical studies [25,31] were analyzed to gain insight into the exposure-response relationships for 
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vedolizumab IV. During UC induction therapy at Week 6 in Study C13006, there was a strong 
relationship between vedolizumab Ctrough levels and clinical remission. In addition, endoscopic 
subscores were improved and mucosal healing was more common among subjects who had higher 
vedolizumab Ctrough levels at Weeks 6 and 46. Week 6 vedolizumab Ctrough levels for subjects with 
the highest endoscopic subscores were below the overall Week 6 median Ctrough levels in C13006
[26,32]. From this analysis at Week 6 (end of induction), patients with an endoscopic subscore of 
3 had on average 25% higher CLL, than patients with an endoscopic subscore of 0 [26]. 
In the C13006 UC study, 47% of subjects achieved clinical response at Week 6 [25]. Of those 
subjects who failed to respond, 89% had vedolizumab Ctrough levels <40 µg/mL, which may partly 
be attributed to high drug clearance. Clearance is the most important PK parameter for 
determination of dose. Individuals with vedolizumab clearance >0.14 L/day were associated with 
diminished efficacy outcomes. Improved outcomes may be seen by the administration of higher 
induction doses resulting in greater serum concentrations. Given the clearance cut-point of 
0.14 L/day and the approved vedolizumab IV dosing regimen, a target steady state vedolizumab 
trough concentration >12.7 µg/mL was calculated. Simulations with the published population PK 
model were conducted to evaluate strategies to (1) identify high clearance individuals, and 
(2) recommend dose adjustments necessary to achieve the steady-state target, both based on Week 
5 plasma vedolizumab concentrations in this study.
Additional support for this hypothesis is provided by the results from a small, prospective study 
with vedolizumab IV conducted in IBD patients (N=34) who failed 2 lines of TNF-α antagonist 
therapy [33]. Results from this study support the value of an early assessment of vedolizumab 
concentrations to predict whether dose-optimization is needed following administration of 
vedolizumab IV 300 mg on Day 1 and Weeks 2 and 6. A predictive threshold for sustained 
remission at Week 6 was analyzed using a receiver operating characteristic (ROC) curve (area 
under the curve: 0.84). A cut-off for vedolizumab (37 µg/mL) at Week 6 was predictive of 
sustained remission with a sensitivity of 100% and a specificity of 70%. Moreover, a cut-off for 
vedolizumab (41 µg/mL) at Week 6 was predictive of nonoptimization at Week 10, with a 
sensitivity of 75% and a specificity of 100%. 
This phase 4, prospective, open label, multi-center clinical study in adult subjects with moderately 
to severely active UC is being performed to evaluate the efficacy and safety of vedolizumab IV 
dose optimization, compared with standard dosing, in Week 6 nonresponders identified as having 
high vedolizumab clearance, based on a predefined Week 5 serum vedolizumab concentration 
threshold (<50 µg/mL). This study will evaluate the potential benefit of vedolizumab IV dose 
optimization on patient outcomes based on the derived target Ctrough levels. 
4.3
Benefit-Risk Assessment
The proposed Vedolizumab–4014 study is designed to evaluate the effect of vedolizumab IV dose 
optimization on mucosal healing compared with the standard vedolizumab IV dosing at Week 30. 
The target population consists of patients who have moderately to severely active UC who have 
had an inadequate response to prior therapy (consistent with the approved vedolizumab IV label) 
and who have not responded to standard vedolizumab induction therapy at Week 6 and have high 
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vedolizumab clearance, based on a predefined Week 5 serum vedolizumab concentration threshold 
(<50 µg/mL). Clinical outcomes for the standard vedolizumab dosing regimen will be compared 
with the dose-optimized regimens.
An unmet need exists for patients who do not respond to UC therapy. Fifty-three percent of 
subjects did not achieve clinical response at Week 6 in the C13006 study with vedolizumab IV. 
Higher doses are projected to produce exposure levels that have been safely studied in previous 
clinical studies and may result in efficacy in subjects who have high vedolizumab clearance, based 
on a predefined Week 5 serum vedolizumab concentration threshold (<50 µg/mL). In addition, if 
Ctrough levels exceed the exposure limit of 90 µg/mL, protocol instructions are designed to decrease 
subsequent doses and decrease exposure.
Overall, vedolizumab IV has been well tolerated in clinical studies and the benefit-risk profile is 
positive for the defined study population.
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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 dose optimization on mucosal healing compared with 
the standard vedolizumab IV dosing regimen at Week 30 in subjects with UC and high 
vedolizumab clearance, based on a predefined Week 5 serum vedolizumab concentration threshold 
(<50 µg/mL) and who are Week 6 nonresponders. 
5.1.2
Secondary Objectives
To determine the effect of vedolizumab IV dose optimization on clinical response and remission 
compared with the standard vedolizumab IV dosing regimen at Week 30 in subjects with UC and 
high vedolizumab clearance, based on a predefined Week 5 serum vedolizumab concentration 
threshold (<50 µg/mL) and who are Week 6 nonresponders.
5.1.3
Additional Objectives
Safety Objective:

To evaluate the safety of administering higher induction doses of vedolizumab IV compared 
with the standard dosing regimen over the 30-week treatment period in subjects with UC and 
high vedolizumab clearance, based on a predefined Week 5 serum vedolizumab concentration 
threshold (<50 µg/mL) and who are Week 6 nonresponders. 
Additional Objectives:

Additional proteomic or cellular biomarker analyses that correlate with response may be 
performed in the future and reported separately. 
5.2
Endpoints
5.2.1
Primary Endpoint
Proportion of subjects achieving mucosal healing (defined as Mayo endoscopic subscore ≤1 point) 
at Week 30.
5.2.2
Secondary Endpoints

Proportion of subjects achieving clinical remission, where clinical remission is defined as a 
complete Mayo score of ≤2 points and no individual subscore >1 point at Week 30.

Proportion of subjects achieving clinical response, where clinical response is defined as a 
reduction in complete Mayo score of ≥3 points and ≥30% from Baseline with an 
accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding 
subscore of ≤1 point, at Week 30.
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
Proportion of subjects achieving clinical response (based on partial Mayo score), which is 
defined as a reduction in partial Mayo score of ≥2 points and ≥25% from Baseline with an 
accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding 
subscore of ≤1 point, at Week 14. 

Proportion of subjects using oral corticosteroids at Baseline who have discontinued 
corticosteroids and are in clinical remission, at Week 30.

Proportion of subjects achieving durable clinical response, which is defined as clinical 
response based on partial Mayo score at Weeks 14 and 30.
5.2.3
Additional Endpoints

Change in C-reactive protein (CRP) levels from Baseline to Week 6, 14, and 30.

Change in fecal calprotectin concentrations from Baseline to Weeks 6, 14, and 30.

Proportion of subjects with positive AVAs and positive neutralizing AVAs.

Proportion of subjects with Ctrough values that fall below the threshold targets of 18.4 µg/mL at 
Week 14 and 12.7 µg/mL at Week 30.

Change from Baseline to Week 30 in health-related quality of life (HRQOL) based on 
inflammatory bowel disease questionnaire (IBDQ) scores.

Proportion of subjects achieving a stool frequency subscore = 0; rectal bleeding subscore = 0 
and endoscopy subscore = 0 or 1 (modified so that a score of 1 does not include friability).

Proportion of subjects achieving a stool frequency subscore = 0 or 1 and a prespecified specific 
change of 1 or more from Baseline and rectal bleeding subscore = 0; and endoscopy subscore = 
0 or 1 (modified so that a score of 1 does not include friability). 
Safety Endpoint

Safety 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), SAEs, 
vital signs, and results of standard laboratory tests (clinical chemistry, hematology, 
coagulation, urinalysis).
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 4, open-label, multicenter study to investigate the efficacy and safety of dose 
optimization of vedolizumab IV, compared with standard dosing of vedolizumab IV, over a 
30-week treatment period (ie, a 6-week Lead in Period followed by 24-week Randomized 
Treatment Period). This study will enroll adult subjects with moderately to severely active UC 
who are eligible for treatment with vedolizumab IV. Approximately 250 subjects will be enrolled 
in order to randomize approximately 100 nonresponder subjects with high vedolizumab drug 
clearance.
The study is comprised of a 28-day Screening Period, a 6-week Lead-in Period, and a 24-week 
Randomized Treatment Period, followed by an 18-week Follow-up visit and a long-term 
follow-up (LTFU) safety survey by telephone at 6 months after the last dose of study medication. 
The study visits schedule and assessments will be completed per the schedule of study procedures 
in Appendix A. A schematic of the study design is included in Figure 6.a. 
On Day 1 and Week 2 (Lead-in Period), all eligible subjects will receive vedolizumab IV 300 mg. 
At Week 5, serum vedolizumab concentration will be measured. At Week 6, subjects will be 
assessed for clinical response based on partial Mayo score (see definition of complete response by 
partial Mayo score in Section 3.5 Study Definitions).
Results of both Week 5 vedolizumab concentration and Week 6 clinical response will establish 
which of the following 2 treatment pathways a subject will follow at Week 6:

Pathway 1: Subjects who are nonresponders based on partial Mayo score at Week 6 and who 
are assessed as having high vedolizumab clearance, based on a predefined Week 5 serum 
vedolizumab concentration threshold (<50 µg/mL) will proceed with randomization at Week 6 
in a 1:1 ratio to receive either dose-optimized or standard vedolizumab IV therapy as described 
below.

Pathway 2: Subjects who respond at Week 6 or have levels above a predefined Week 5 serum 
vedolizumab concentration threshold (≥50 µg/mL) (Lead-in Failure) will not be randomized 
and will receive the Week 6 study dose (300 mg) and thereafter appropriate treatment per 
physician discretion. Following the last dose of study drug (Week 6), subjects will have the 
18-week Follow-Up Safety Visit and 6 month LTFU phone call. 
At Week 6, eligible subjects will be randomized 1:1 into the Standard Treatment arm or the Dose 
Optimized arm (ie, Pathway 1), stratified by TNF-antagonist naïve or failure status and receive the 
following treatments: 

Vedolizumab IV Standard Treatment Arm: 
Vedolizumab IV 300 mg Q8W (Weeks 6, 14, and 22).
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
Vedolizumab IV Dose Optimized Arm:
Week 6: Dose Assignments for Dose Optimization Arm
At Week 6, all subjects randomized to the Dose Optimization Arm will be assigned to either 
Regimen A or Regimen B (below) based on the subject’s Week 5 serum vedolizumab 
concentration. Subjects with serum vedolizumab concentration <50 µg/mL and ≥30 µg/mL 
will be assigned to Regimen A, and subjects with serum vedolizumab concentration 
<30 µg/mL will be assigned to Regimen B:
Regimen A: Vedolizumab IV 600 mg (Week 6) and 300 mg Q4W (Weeks 10, 14, 18, 22, 
and 26), OR
Regimen B: Vedolizumab IV 600 mg (Week 6) and 600 mg Q4W (Weeks 10, 14, 18, 22, 
and 26)
Week 14: Dose Optimization Arm 
At Week 14 and beyond, dosing will continue as previously scheduled unless the subject’s 
most recent preceding serum vedolizumab concentration is >90 µg/mL (eg, Week 13 PK 
sampling prior to Week 14 dosing). In the event that steady-state Ctrough levels exceed safety 
exposure limits of 90 µg/mL, the next dose will be withheld and another PK sample will be 
taken 1 week prior to the next scheduled dose. If at the next scheduled dose the Ctrough is still 
>90 µg/mL, the next dose will be similarly held and the PK repeated 1 week prior to the next 
scheduled dose. Once Ctrough is ≤90 µg/mL, the subject will move to the next lowest dose. For 
example
If subject was on 300 mg Q4W, then subject goes to next lower dose or 300 mg Q8W dose.
If subject was on 600 mg Q4W, then subject goes to next lower dose or 300 mg Q4W dose.
If subject was moved from 600 mg Q4W to 300 mg Q4W and subsequent Ctrough 
>90 µg/mL, then subject goes to next lowest dose (ie, 300 mg Q8W).
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Figure 6.a
Schematic of Study Design
Conc=concentration, EOT=end of treatment, VDZ=vedolizumab. 
(a) On Day 1 and Week 2 (Lead-in Period), all eligible subjects will receive vedolizumab IV 300 mg.
(b) Subjects who respond at Week 6 (by partial Mayo score) will not be randomized and will receive the Week 6 study 
drug dose and thereafter receive appropriate treatment per physician discretion. Following the last dose of study drug 
(Week 6), subjects will have the 18-week Follow-Up Safety Visit and 6 month LTFU telephone call.
(c) Subjects who are nonresponders at Week 6 and have levels above a predefined serum vedolizumab concentration 
threshold (≥50 µg/mL) at Week 5 (Lead-in Failures), will not be randomized and will receive the Week 6 study drug 
dose and thereafter receive appropriate treatment per physician discretion. Following the last dose of study drug 
(Week 6), subjects will have the 18-week Follow-Up Safety Visit and 6 month LTFU telephone call.
(d) At Week 14 and beyond, dosing will continue as previously scheduled unless the subject’s most recent preceding 
serum vedolizumab concentration is >90 µg/mL. The dose will be withheld and PK will be repeated 1 week prior to 
the next scheduled dose until Ctrough is ≤90 µg/mL. Once ≤90 µg/mL, the subject will move to the next lower dose. 
6.2
Justification for Study Design, Dose, and Endpoints
This phase 4, prospective, open label, multicenter trial in adult patients with moderately to 
severely active UC is designed to evaluate the efficacy and safety of vedolizumab IV dose 
optimization, compared with the standard vedolizumab dosing regimen, in Week 6 nonresponders 
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identified as having high vedolizumab clearance, based on a predefined Week 5 serum 
vedolizumab concentration threshold (<50 µg/mL). This study will evaluate the potential benefit 
of vedolizumab IV dose optimization on clinical outcomes based on derived target Ctrough levels. 
Vedolizumab doses ranging from 0.2 to 10 mg/kg and 180 to 750 mg in healthy subjects and in 
subjects with UC or CD have been tested in clinical studies. The highest exposures following 
multiple dose administration of vedolizumab IV were observed in the phase 2 study C13002 in 
subjects with UC [31]. In C13002, individual Ctrough levels ranged from 13.4 to 155 µg/mL at 
Day 85 following administration of 10 mg/kg vedolizumab IV at Weeks 0, 2, 4, and 12; the highest 
exposure was observed in a 95 kg subject weighing who received 900 mg of vedolizumab IV for 
each infusion. Safety in this study was consistent with the overall safety profile observed with 
vedolizumab IV. The median Ctrough concentration in this phase 2 study was 90 μg/mL, which was 
selected as the safe exposure limit for the current study. 
Phase 2 and 3 data from the vedolizumab clinical studies contributed to the population PK model 
that was used to simulate the estimated Ctrough following administration of vedolizumab IV 600 mg 
Q4W (the maximum dose to be administered in this study) in subjects with high clearance [26]. 
Based on simulations of Week 5 plasma vedolizumab concentrations, strategies to 1) identify high 
clearance subjects (eg, clearance >0.14 L/day), and 2) recommend dose adjustments were 
explored. Results revealed that a Week 5 plasma vedolizumab concentration <50 µg/mL cut point 
would capture most of the high-clearance subjects while minimizing the fraction of 
lower-clearance subjects who might be misclassified. A dosing strategy was selected that would 
result in a higher proportion of subjects achieving Ctrough concentrations >12.7 µg/mL at 
steady-state and be within the range of concentrations found to be safe in clinical studies, ensuring 
virtually no subjects would be expected to exceed the maximum trough concentration of 
90 µg/mL. The following 2 regimens were selected to begin at Week 6 based on Week 5 
vedolizumab concentrations: Regimen A for subjects with Week 5 vedolizumab concentration of 
≥30 µg/mL but <50 µg/mL, and Regimen B for subjects with Week 5 vedolizumab concentrations 
of <30 µg/mL.
The approved dosing regimen of vedolizumab IV 300 mg at Weeks 0, 2, 6, and then Q8W 
thereafter (through Week 22) will be tested in the Standard Dosing Arm. For all subjects 
randomized to the Dose Optimized Arm, vedolizumab IV 600 mg at Week 6 followed by either 
300 mg Q4W or 600 mg Q4W (through Week 26) will be tested. The assessment of target 
concentrations and high clearance was based on phase 3 GEMINI data [25], which identified a 
maximum dose of 600 mg to account for the variability of clearance among subjects. The 
maintenance dosing interval Q4W is necessary to achieve the derived target concentration in the 
highest clearance individuals evidenced by a Week 5 serum vedolizumab concentration 
<30 μg/mL. Subjects with Week 5 serum vedolizumab concentrations above or equal to 30 μg/mL 
and below 50 μg/mL will receive maintenance doses of 300 mg Q4W in order to achieve the steady 
state serum vedolizumab target concentration.
The primary endpoint is the proportion of subjects achieving mucosal healing (defined as Mayo 
endoscopic subscore ≤1 point) at Week 30. Assessment at Week 30, or 6 months from the Week 6 
randomization, was selected as it's a real-world time point for mucosal healing (Ulcerative Colitis 
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and Crohn’s Disease: Outcomes From the VICTORY Consortium) [34]. The presence of mucosal 
healing has been demonstrated to decrease the risk of relapse, hospitalizations, colorectal cancer, 
and colectomy. Endoscopic assessment has been demonstrated to be a feasible and more beneficial 
strategy than clinical assessment to guide treatment optimization in UC patients. Although 
different endoscopic scores have been used to define mucosal healing, the Mayo endoscopic 
subscore 0 or 1 has been one of the most used definitions. Endoscopies will be read by a central 
reader to eliminate interpretation bias and allow the study to remain open label for subject 
convenience. Additional efficacy assessments are included as part of the secondary endpoints of 
the study.
The Week 6 time point for assigning dosing regimens was selected based upon the correlation of 
Ctrough concentrations at Week 6 with clinical remission status at Week 14 [25]. The Week 14 time 
point, which is an established efficacy evaluation time point for vedolizumab, was designed as a 
check to allow for dose reduction from the initial dosing regimen in the event that the Week 13 
serum vedolizumab concentration exceeded 90 μg/mL since approximately 75% of the 
steady-state exposure will be achieved at that time.
FcRn receptor gene polymorphisms may impact vedolizumab drug clearance and, as a result, 
influence clinical outcomes. Pharmacogenomic analysis may be conducted to investigate the 
contribution of genetic variance on drug clearance in subjects identified as having a predefined 
Week 5 serum vedolizumab concentration threshold (<50 µg/mL).
Participation of study subjects in pharmacogenomics (PGx) sample collection is optional, and 
subjects will have the capability to opt in to the PGx informed consent. As PGx 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.
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.
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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, must be confirmed prior to enrollment at Baseline/Day 1.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry on Day 1 into the 
study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures.
3. The subject is male or female and between age 18 to 85 years, inclusive, at Screening.
4. The subject has a diagnosis of UC established at least 1 month prior to Screening by clinical 
and endoscopic evidence and corroborated by a histopathology report.
5. The subject has moderately to severely active UC as determined by a complete Mayo score of 
6 to 12 with an endoscopic subscore ≥2 within 28 days prior to enrollment.
6. The subject has evidence of UC proximal to the rectum (≥15 cm of involved colon) prior to 
start of vedolizumab IV dosing. 
7. The subject has been determined to be suitable for vedolizumab IV for routine management of 
UC by their physician.
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 an inadequate response with, lost response to, or intolerance of at least 1 of 
the following agents: immunomodulators, corticosteroids, or TNF-α antagonists. Subjects who 
are naïve to TNF-α antagonist therapy or who have previously failed TNF-α antagonist therapy 
(including primary and secondary nonresponders or intolerant) may be included.
10. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use barrier method of contraception (eg, condom with or without 
spermicide)* from signing of informed consent throughout the duration of the study and for 
18 weeks after last dose. The female partner of a male subject should also be advised to use a 
highly effective/effective method of contraception.* 
11. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use a highly effective/effective method of contraception* from signing of 
informed consent throughout the duration of the study and 18 weeks after the last dose.
*Definitions and highly effective methods of contraception are defined in 
Section 9.1.14 and reporting responsibilities are defined in Section 9.1.15.
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7.2
Exclusion Criteria
Subjects meeting any of the following exclusion criteria are not to be enrolled in the study.
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, ischemic 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 7.4.2 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 screening (whichever is longer).
7. The subject has had prior exposure to approved or investigational anti-integrin antibodies (eg, 
natalizumab, efalizumab, etrolizumab, AMG-181, anti-MAdCAM-1 antibodies, or rituximab).
8. The subject has previously received approved or investigational 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.
11. The subject has any evidence of an active infection during Screening (eg, sepsis, 
cytomegalovirus, or listeriosis).
12. The subject has a clinically significant infection (eg, pneumonia, pyelonephritis) within 
30 days prior to screening, or ongoing chronic infection.
13. The subject has evidence of active C. difficile as evidenced by positive C. difficile toxin or is 
having treatment for C. difficile infection or other intestinal pathogens during Screening.
14. The subject has a known history of infection with human immunodeficiency virus (HIV), 
hepatitis B (HBV)*, or chronic HBV or hepatitis C virus (HCV) infection. Subjects with 
documented successful treatment of HCV with sustained virological response (SVR) at 
26 weeks can be enrolled. 
* HBV immune subjects (ie, being hepatitis B surface antigen [HBsAg] negative and hepatitis 
B antibody positive) may, however, be included.
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15. The subject has active or latent TB as evidenced by the following:
a) A diagnostic TB test performed within 30 days of Screening or during the Screening Period 
that is positive, defined as:
1. Positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests, OR
2. A TB skin test reaction ≥5 mm.
NOTE: If subjects have received BCG vaccine then a QuantiFERON TB Gold test 
should be performed instead of the TB skin test.
OR
b) Chest X-ray within 3 months of Screening that is suspicious for pulmonary TB, and a 
positive or 2 successive indeterminate QuantiFERON tests within 30 days prior to 
Screening or during the Screening Period.
Note: subjects with documented previously treated TB with a negative QuantiFERON test 
can be included in the study.
16. The subject has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, HIV infection, organ transplantation).
17. The subject has any live vaccination within 30 days prior to Screening or is planning to receive 
any live vaccination during participation in the study.
18. The subject has used a topical (rectal) treatment with (5-ASA) or corticosteroid 
enemas/suppositories within 2 weeks prior to Screening.
19. The subject has a history of hypersensitivity or allergies to vedolizumab IV or its components.
20. The subject has received total parenteral nutrition (TPN) or albumin in the last 30 days prior to 
Screening.
21. The subject has any unstable or uncontrolled cardiovascular disorder, heart failure moderate to 
severe (New York Class Association III or IV), any 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.
22. 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.
23. The subject has a history of malignancy, except for the following: adequately-treated 
nonmetastatic basal cell skin cancer; squamous cell skin cancer that has been adequately 
treated and that has not recurred for at least 1 year prior to Screening; and history of cervical 
carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years 
prior to screening. 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.
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24. The subject has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, demyelinating, or neurodegenerative disease.
25. The subject has a positive PML subjective symptom checklist during Screening or prior to the 
administration of the first dose of study drug on Day 1.
26. Any of the following laboratory abnormalities during the Screening period:
a) Hemoglobin level <8 g/dL.
b) White blood cell (WBC) count <3×109/L.
c) Lymphocyte count <0.5×109/L.
d) Platelet count <100×109/L or >1200×109/L.
e) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3× the upper limit 
of normal (ULN).
f)
Alkaline phosphatase >3×ULN.
g) Serum creatinine >2×ULN.
27. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 1 year prior to the Screening Visit.
28. The subject has an active psychiatric problem that, in the investigator’s opinion, may interfere 
with compliance with study procedures.
29. The subject is unable to attend all the study visits or comply with study procedures.
30. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 18 weeks after last dose; or intending to donate ova during such time period.
31. If male, the subject intends to donate sperm during the course of this study or for 18 weeks 
after last dose.
32. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress. 
7.3
Week 6 Randomized Treatment Period Inclusion Criteria
At Week 6, subjects must meet both of the following inclusion criteria to be eligible for 
randomization into the Randomized Treatment Period of the study: 
1. Following Lead-in Period, the subject is assessed as having a high vedolizumab clearance, 
based on a predefined Week 5 serum vedolizumab concentration threshold (<50 µg/mL).
2. Following Lead-in Period, the subject is a nonresponder based on partial Mayo score at 
Week 6. 
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7.4
Excluded Medications, Procedures, and Treatments
7.4.1
Excluded Medications
The following medications are excluded from use during the study from the time of Screening
through the Final Visit/ET (Week 30), unless specified otherwise:
1. Any approved or nonapproved biologic or biosimilar agent for the treatment of IBD.
2. Any approved or nonapproved nonbiologic therapy for treatment of UC in an investigational 
protocol.
3. Any nonbiologic therapies (eg. cyclosporine, thalidomide) for the treatment of UC other than 
those listed in section 7.4.2.
4. Any live vaccines through 6 months after the last dose of study drug.
5. Any approved or nonapproved biologic for the treatment of non-IBD conditions other than 
localized injections (eg. Intra-ocular injections for wet macular degeneration).
6. Topical (rectal) treatment with 5-ASA or corticosteroid enemas/suppositories.
7. TPN or albumin.
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator.
7.4.2
Permitted Medications
The following medications for UC are permitted during the study:

Probiotics (eg, Culturelle, Saccharomyces boulardii) provided that the subject was receiving 
them at the Screening Visit and they remain stable throughout the study.

Oral 5-ASA compounds provided that the subject was receiving them at the Screening Visit and
that they remain stable throughout the study.

Oral corticosteroid therapy for UC total of up to 30 mg/day is permitted during Screening and 
upon enrollment. Tapering must be made at the investigator’s discretion no later than Week 14. 
See Section 7.4.2.1.

Antidiarrheals for control of chronic diarrhea.

Azathioprine, 6-mercaptopurine, or methotrexate, provided that the dose has been stable for 
8 weeks immediately prior to Screening and remain stable throughout the duration of the 
study.
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7.4.2.1
Corticosteroid Taper
The maximum dose of oral prednisone for the treatment of UC that may be coadministered with 
vedolizumab IV is 30 mg/day or 9 mg/day budesonide (or equivalent). Oral corticosteroid taper 
should be initiated by Week 10 and no later than Week 14 according to the following schedule:

For prednisone doses >10 mg/day (or equivalent), the dose will be reduced at a rate of 
5 mg/week until a 10 mg/day dose is reached.

For prednisone doses ≤10 mg/day (or equivalent) or once a 10 mg/day dose (or equivalent) is 
reached, the dose will be reduced at a rate of 2.5 mg/week until discontinuation. For subjects 
who cannot tolerate the corticosteroid taper without recurrence of clinical symptoms, 
corticosteroids could be increased up to, but not exceed, the original dose the subject was on at 
the start of the induction phase. In such cases, the tapering regimen above will be reinitiated 
within 2 weeks.

Budesonide should be reduced 3 mg every 2 weeks until discontinuation.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or permanent 
discontinuation of study medication should be recorded in the electronic case report form (eCRF) 
using the following categories. For screen failure subjects, refer to Section 9.1.24.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.

Liver Function Test 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 9.1.11), if the following circumstances occur at any 
time during study medication treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
2. Significant protocol deviation. The discovery after the first dose of study medication that the 
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health.
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3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.
4. Voluntary withdrawal. The subject (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).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.15.
7. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
8. Other.
7.6
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 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit, Final Safety Visit, and the LTFU survey. 
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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Vedolizumab IV 300 mg 
The sponsor will supply the study sites with the following study 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 for reconstitution using 4.8 mL of sterile water for 
injection. Each vial will be packaged in an appropriately labeled single vial carton.
Additional reference information and administration instructions can be found in the pharmacy 
manual.
8.1.1.2
Vedolizumab IV 600 mg 
The sponsor will supply the study sites with the following study medication in an open-label 
manner: 2 vials of vedolizumab IV 300 mg/vial, for single use, in 20 mL vials. Study medication 
will be provided in a glass vial as a lyophilized solid. Each glass vial should be reconstituted using 
4.8 mL of sterile water for injection. See pharmacy manual for further instructions. Each vial will 
be packaged in an appropriately labeled single vial carton. 
Additional reference information and administration instructions can be found in the pharmacy 
manual.
8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug must be stored under the 
conditions specified on the label, and remain in the original container until dispensed. 
Vedolizumab IV must be stored in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). A daily temperature 
log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
The dose and regimen are provided in Table 8.a. Instructions for reconstitution and administration 
will be provided in the pharmacy manual.
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Table 8.a
Vedolizumab IV Dose and Regimens
Period
Decision Visit
Group
Dose and Regimen
Dosing Schedule
Lead-in Period
Day 1 and Week 2 
All subjects
Vedolizumab IV 300 mg
Day 1 and Week 2
Lead-in failure subjects will receive the Week 6 study drug dose and thereafter appropriately treated per 
physician discretion
Randomized Treatment Period (a)
Standard Therapy Arm
Vedolizumab IV 300 mg Q8W
Weeks 6, 14, 22
Dose Optimization Arm 
Week 6 Dose Assignments for Dose Optimization Arm (b) 
At Week 6, all subjects randomized to the Dose Optimization Arm will be assigned to either Regimen A or 
Regimen B (below) based on the subject’s Week 5 serum vedolizumab concentration. Subjects with serum 
vedolizumab concentration <50 µg/mL and ≥30 µg/mL will be assigned to Regimen A, and subjects with 
serum vedolizumab concentration <30 µg/mL will be assigned to Regimen B:
Regimen A: Vedolizumab IV 600 mg (Week 6) and 300 mg Q4W (Weeks 10, 14, 18, 22, 26), OR
Regimen B: Vedolizumab IV 600 mg (Week 6) and 600 mg Q4W (Weeks 10, 14, 18, 22, 26)
Week 14: Dose Optimization Arm Safety Checkpoint
At Week 14 and beyond, dosing will continue as previously scheduled unless the subject’s most recent 
preceding serum vedolizumab is >90 µg/mL (eg, Week 13 PK sampling prior to Week 14 dosing). In the 
event that steady-state Ctrough levels exceed safety exposure limits of 90 µg/mL, the next dose will be withheld 
and another PK sample will be taken 1 week prior to the next scheduled dose. If at the next scheduled dose the 
Ctrough is still >90 µg/mL, the next dose will be similarly held and the PK repeated 1 week prior to the next 
scheduled dose. Once Ctrough is ≤90 µg/mL, the subject will move to the next lowest dose. For example:
If subject was on 300 mg Q4W, then subject goes to next lower dose or 300 mg Q8W dose.
If subject was on 600 mg Q4W, then subject goes to next lower dose or 300 mg Q4W dose.
If subject was moved from 600 mg Q4W to 300 mg Q4W and subsequent Ctrough >90 µg/mL, then subject 
goes to next lowest dose (ie, 300 mg Q8W).
(a) Subjects will be randomized in a 1:1 ratio to receive either dose-optimized or standard vedolizumab IV therapy. 
(b) Sites will use IRT to obtain the dose to be administered based on Week 5 serum vedolizumab concentration.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0, Pretreatment 
Events and Adverse Events.
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SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Investigational Drug Assignment and Dispensing Procedures
Subjects will be assigned to receive their treatment according to the Schedule of Study Procedures 
(Appendix A).
The investigator or investigator’s designee will access the interactive response technology (IRT) at 
Screening to obtain the subject study number. 
At Day 1 and Week 2, the investigator or the investigator’s designee will use the IRT to dispense 
the subject’s study drug. During this contact, the investigator or designee will provide the 
necessary subject-identifying information, including the subject number assigned at Screening. 
The medication identification number (Med ID) of the study drug to be dispensed will then be 
provided by the IRT by email notification to the site pharmacist/nurse. If sponsor-supplied study 
drug is lost or damaged, the site staff can request a replacement from the IRT.
For subjects that are lead-in failures at Week 6, the IRT will dispense 300 mg vedolizumab if 
requested per physician discretion.
At Week 6, the investigator or the investigator’s designee will use the IRT to randomize the 
subject into the Randomized Treatment Period of the study. During this contact, the investigator or 
designee will provide the necessary subject-identifying information, including the subject number 
assigned at Screening and Week 5 vedolizumab serum concentration. The subject will be 
randomized into 1 of 2 treatment arms, the Standard Dosing or the Dose Optimized arm. For 
subjects randomized to the Dose Optimization Arm, dosing regimens will be assigned by the IRT 
based on the Week 5 serum vedolizumab concentration. The Med ID of the study drug to be 
dispensed will then be provided by the IRT by email notification to the site pharmacist/nurse. If 
sponsor-supplied study drug is lost or damaged, the site staff can request a replacement from the 
IRT.
At Week 14 and beyond, for subjects in the Dose Optimization Arm, the investigator or the 
investigator’s designee will enter the subject’s most recent preceding serum vedolizumab 
concentration into IRT prior to dosing. If serum vedolizumab is >90 µg/mL, the next dose will be 
withheld and subject will be brought back the week before the next scheduled dose for repeat 
serum vedolizumab concentration. Once the subject’s serum vedolizumab is ≤90 µg/mL, dosing 
will resume at the next lower dose (see Section 6.1). 
The Med ID of the study drug to be dispensed will then be provided by the IRT by email 
notification to the site pharmacist/nurse. If sponsor-supplied study drug is lost or damaged, the site 
staff can request a replacement from the IRT.
Refer to IRT manual provided separately. At subsequent drug-dispensing visits, the investigator or 
designee will again contact the IRT to request additional study drug for a subject.
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8.3
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule and 
will provide it to the IRT Vendor prior to the start of this study. All randomization information will 
be stored in a secured area, accessible only by authorized personnel. Eligible subjects will be 
randomized to the Standard Dosing Arm or the Dose Optimization Arm of vedolizumab IV in a 
1:1 ratio as assigned by IRT. Randomization will be stratified by TNF-antagonist naïve or failure 
status.
8.4
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 site will maintain source documents in addition to entering data into the IRT.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug (vedolizumab IV), 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 IRT. If there are any discrepancies 
between the packing list versus the actual product received, Takeda must be contacted to resolve 
the issue. The packing list should be filed in the investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the Med ID used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IRT 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) 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 
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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. 
The investigator’s designee administering the study drug infusion must complete an individual 
subject accountability log to document if infusion was complete or if incomplete and study drug 
was returned to the pharmacy, including the date and amount returned to the pharmacy, and 
including the initials, seal, or signature of the person administering the infusion.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2. Informed consent must be 
obtained before any protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned per IRT as described in 
Section 8.2 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
Informed consent must be obtained prior to the collection, storage, and analysis of the PGx 
samples. Subjects will have the capability to opt in to the PGx informed consent.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, 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 9.1.10).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 30 days prior to signing of informed consent. Medication history 
should be captured on the Medication History/Concomitant Medications eCRF page.
In addition, all prior biologic and any medication history for the treatment of UC disease with 
the reason for discontinuation, that stopped at or prior to signing of informed consent, is to be 
collected at Screening for subjects where possible. Any prior UC disease treatment should be 
captured on the Prior UC Disease Treatment eCRF only, and UC treatments started after signing 
the informed consent, should be captured on the Concomitant Medications eCRF page only.
9.1.3
UC Disease History
UC history collected at Screening will include details of UC diagnosis, disease severity, surgery, 
hospitalizations, and extraintestinal manifestations. After signing of informed consent all subjects 
should have UC disease included on the Concurrent Medical Conditions eCRF page.
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9.1.4
Physical Examination Procedure
A physical examination will be performed at Screening and Baseline/Day 1 and 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 at all other visits should assess clinically significant changes from the 
Baseline/Day 1 assessment.
9.1.5
Weight, Height
A subject’s height will be measured at the Screening visit; weight will be measured at Screening, 
Day 1, and Week 30 visits. Both measurements will be collected while the subject is wearing 
indoor clothing and with shoes off. The Takeda standard for collecting height is centimeters 
without decimal places and for weight it is kilograms (kg) with 1 decimal place.
9.1.6
Vital Sign Procedure
Vital signs will include body temperature, respiratory rate, blood pressure, and pulse (bpm) and 
will be collected at every visit.
On dosing days, vital signs are taken predose.
9.1.7
Primary Efficacy Measurement 
Primary and secondary efficacy assessments during the Randomized Treatment Period will be 
based on both complete and partial Mayo scores derived from subject diary entries, physician’s 
global assessment, and flexible sigmoidoscopy. A complete Mayo score will be obtained at 
Screening to determine eligibility along with confirmation of disease location. The subject must 
have evidence of UC proximal to the rectum (≥15 cm of involved colon) prior to start of 
vedolizumab IV dosing. 
Results obtained during Screening will be the Baseline complete Mayo score. Sigmoidoscopy will 
be done during Screening and Week 30/Early Termination (ET) Visit, and complete Mayo score 
will be calculated for these visits. The investigator or designee will record the complete Mayo 
score in the subject’s source documents, with the endoscopic component subscore being provided 
by the central reader at Screening only. For Week 30, the investigator or designee will use the local 
endoscopic component subscore to calculate the complete Mayo score. Seven days of completed 
diary data prior to each study visit is required for Mayo calculation (not including the day before 
the preparation day, the day of, and the day after the flexible sigmoidoscopy is performed).
A partial Mayo score will be derived for the visits at which endoscopy will not be performed and as 
listed in Schedule of Study Procedures (Appendix A). These scores will be used to determine 
clinical response during the study.
The Mayo endoscopic subscore determination of mucosal healing (as defined in Section 3.5) will 
be based upon central readings to eliminate assessment bias. 
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Refer to Appendix E for information on the Mayo Scoring System for UC.
9.1.7.1
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. Entries 
should be reviewed and monitored by the study staff.
Because the flexible sigmoidoscopy preparation and the procedure itself can interfere with the 
assessment of other clinical parameters, diary entries used to calculate the complete Mayo score 
should not be taken from the day before (the preparation day), the day of, and the day after the 
flexible sigmoidoscopy is performed.
9.1.7.2
Flexible Sigmoidoscopy and Biopsy
Flexible sigmoidoscopy will be performed at Screening (within 28 days of first dose) and Week 30 
(or ET Visit), and the results will be used for calculation of the complete Mayo score for these 
visits. For subjects without cancer surveillance endoscopy performed in the last 12 months, the 
investigator can perform a colonoscopy at Screening. All endoscopies (Screening and Week 30) 
will be centrally read. For Week 30, the investigator or designee will use the local endoscopic 
component subscore to calculate the complete Mayo score. On the days sigmoidoscopy is done, 
biopsy samples will be collected from all subjects to possibly evaluate changes in histology. 
During screening endoscopic evaluation, 2 biopsies should be taken from the rectum, 2 from the 
sigmoid, and 2 from the descending colon (if evaluated) taken from the most severely affected 
areas. If the descending is evaluated and found to be normal, 2 biopsies should also be taken 
regardless in order to provide a means of comparison at the final visit (Week 30/ET) assessment 
from that segment. At the Week 30/ET endoscopic assessment, 2 biopsies should again be taken 
from each of the 3 segments, again from the area most severely affected if inflamed and also if 
normal (which demonstrates healing) to provide a means of comparison from Baseline. Please see 
Laboratory Manual for additional collection information.
All biopsy samples collected per protocol will be centrally stored and analyzed at the end of the 
study. Although it is permissible for the investigator to take additional biopsy samples as deemed 
necessary for standard of care management of the patient during the protocol required 
colonoscopy/sigmoidoscopy, these will be considered as occurring outside the protocol. Such 
collection, handling and analyses of the additional samples will be and remain the responsibility of 
the investigator. 
9.1.8
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication used (from signing of informed consent through the 
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last scheduled follow-up visit, 18 weeks after last dose of study drug), and all medication including 
vitamin supplements, over-the-counter medications, and oral herbal preparations, must be 
recorded in the eCRF.
9.1.9
Documentation of Concomitant Procedures
At each visit, subjects will be asked whether they have had any UC-related events since their last 
visit including hospitalizations, bowel surgeries, or UC-related procedures that are not part of the 
protocol. The timing of the event will be collected relative to the start of treatment on Day 1 of the 
study through the last clinic visit (Follow-up Visit, 18 weeks after the last dose of study drug). All 
events with timing will be recorded in the eCRFs. The underlying symptom or diagnosis should 
correspondingly be recorded as an AE as applicable.
9.1.10 Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, electrocardiogram 
(ECG), or physical examination abnormalities noted at the Screening examination. The condition 
(ie, diagnosis) should be described.
9.1.11 Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures at the time 
points specified in the Schedule of Study Procedures in Appendix A. The maximum volume of 
blood at any single visit is approximately 66 mL, and the approximate total volume of blood for the 
study is up to 252 mL for subjects with Q4W dosing (this will be less for subjects with Q8W 
dosing or the Standard Arm). Details of these procedures and required safety monitoring will be 
given in the laboratory manual.
Clinical laboratory tests to be performed in this study are summarized in Table 9.a. Refer to the 
Schedule of Study Procedures in Appendix A for timing of all assessments. See the Laboratory 
Manual for testing regimen.
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Table 9.a
Clinical Laboratory Tests 
Hematology
Serum Chemistry
Urinalysis
RBC
WBC w/differential
Hemoglobin
Hematocrit
Platelets
PT/INR (a)
ALT
Albumin
Alkaline phosphatase
Amylase
Lipase
AST
Total and direct bilirubin (b)
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Calcium 
Bicarbonate
Magnesium
Phosphorus
Uric Acid
Glucose 
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Specific Gravity
Microscopic (to be obtained 
in the event of positive 
leukocyte esterase or blood, 
will include WBCs, RBCs, 
and cast[s])
Other:
Collect per Appendix A
Serum/Plasma
Urine
Stool
CRP 
HIV test
Hepatitis panel, including HBsAg and 
anti-HCV
AVA 
PGx sample (optional)
FSH (c)
QuantiFERON for TB 
Beta hCG (female subjects of 
childbearing potential)
Urine pregnancy hCG
(female subjects of childbearing 
potential)
Fecal calprotectin
C.difficile toxin
FSH=follicle-stimulating hormone, GGT= γ-glutamyl transferase, hCG=human chronic gonadotropin, 
PT=prothrombin time, RBC=red blood cell.
(a) PT/INR to be collected at Baseline and then only if liver function tests (LFTs) are elevated at subsequent visits.
(b) Direct bilirubin is measured only if total bilirubin is elevated.
(c) FSH level will be obtained for female subjects at Screening if they are postmenopausal by history (eg, defined as at 
least 1 year since last regular menses with an FSH >40 IU/L or at least 5 years since last regular menses, confirmed 
before any study medication is implemented) and not surgically sterile. The FSH result must be >40 IU/mL for the 
subject to be permitted not to use adequate contraception. 
Central laboratories will perform laboratory tests for hematology, serum chemistries, and 
urinalysis as well as specialty testing outlined above with the exception of the urine pregnancy 
tests, which will be done on site. 
All Screening laboratory tests can be repeated once at the discretion of the principal investigator.
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The results of laboratory tests will be returned to the investigator, who is responsible for reviewing 
and filing these results. Refer to the Schedule of Study Procedures in Appendix A.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted.
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in 
conjunction with total bilirubin >2 ×ULN.)
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 10.2.3 Reporting of Abnormal Liver Function Tests for reporting requirements).
9.1.12 Fecal Calprotectin Sample Collection
A stool sample will be collected for the analysis of fecal calprotectin, a biomarker of intestinal 
inflammatory activity, as shown in the Schedule of Study Procedures in Appendix A.
9.1.13 Stool Sample for C. difficile 
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 subject becomes symptomatic, 
including worsening or return of disease activity. 
9.1.14 Contraception and Pregnancy Avoidance Procedure
9.1.14.1 Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 18 Weeks after 
last dose of study drug, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with or without 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period. Females of childbearing potential who are partners of male subjects are also advised to use 
additional contraception as shown in the list containing highly effective/effective contraception 
below.
9.1.14.2 Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 18 Weeks after 
last dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use a highly effective/effective method of contraception (from 
the list below). In addition they must be advised not to donate ova during this period.
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9.1.14.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
*A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as 
no menses for 12 months without an alternative medical cause. A high FSH level in the 
postmenopausal range (FSH >40 IU/L) may be used to confirm a post-menopausal state in 
younger women (eg, those <45 year old) or women who are not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.
**Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, the 
only acceptable methods of contraception are: 

Non-Hormonal Methods: 
Intrauterine device (IUD).
Bilateral tubal occlusion.
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success).
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the 
subject. True abstinence is defined as refraining from heterosexual intercourse during 
the entire period of the study, from 1 month prior to the first dose until 18 weeks after 
last dose.

Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method.
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study 
drug OR combined with a barrier method (male condom, female condom or 
diaphragm) if for shorter duration until she has been on contraceptive for 3 
months;
Oral.
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Intravaginal (eg, ring).
Transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months prior to the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has 
been on contraceptive for 3 months;
Oral.
Injectable.
Implantable.
2. Unacceptable methods of contraception are:
–
Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).
–
Spermicides only.
–
Withdrawal.
–
No method at all.
–
Use of female and male condoms together.
–
Cap/diaphragm/sponge without spermicide and without condom.
3. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
4. During the course of the study, regular urine hCG pregnancy tests will be performed only for 
women of childbearing potential and all subjects (male and female) will receive continued 
guidance with respect to the avoidance of pregnancy and sperm donation as part of the study 
procedures. Such guidance should include a reminder of the following:
a) contraceptive requirements of the study.
b) reasons for use of barrier methods (ie, condom) in males with pregnant partners.
c) assessment of subject compliance through questions such as
i.
Have you used the contraception consistently and correctly since the last visit?
ii.
Have you forgotten to use contraception since the last visit?
iii.
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)?
iv.
Is there a chance you could be pregnant?
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5. In addition to a negative serum hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative urine hCG pregnancy test as close as possible and prior to 
receiving any dose of Lead-in medication (ie, standard of care) and study medication and at the 
Week 30/Final Visit and Safety Follow-up Visit. 
9.1.14.4 General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the recommendations previously described in 
Section 9.1.14.3 item 4.
9.1.15 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. The subject will be withdrawn as per 
the procedures in Section 7.6. 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 study medication, eg, after 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.
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received.
All pregnancies in subjects on study drug will be followed up to final outcome, using the 
pregnancy form. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted.
9.1.16 ECG Procedure 
A standard 12-lead ECG will be recorded at Screening. 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. 
9.1.17
PGx Sample Collection
When sampling of whole blood for pharmacogenomic analysis occurs, every subject must sign 
informed consent/be consented in order to participate in the PGx part of the study. 
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Deoxyribonucleic acid (DNA) forms the basis for the genes that make the body produce proteins 
such as enzymes, drug transporters or drug targets, and 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 vedolizumab.

Finding out more information about how vedolizumab works.

Generating information needed for research, development, and regulatory approval of tests to 
predict response to vedolizumab.

Identifying variations in genes related to the biological target of vedolizumab.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of vedolizumab and other study drugs, to increase understanding of the disease/condition 
being studied, and for improving the efficiency, design and study methods of future research 
studies.
Two whole blood samples (3 mL per sample) for DNA isolation will be collected before dosing on 
Day 1 from each subject, into plastic potassium ethylenediamine-tetraacetic acid (K2EDTA) 
spray-coated tubes, and stored under frozen conditions. A portion of the DNA sample will be used 
to explore FcRn polymorphisms and its association with drug clearance. 
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. In addition, if the DNA sample was not collected at the 
designated time point described in the protocol, it can be collected at a later time point.
Two whole blood samples (2.5 mL per sample) will be collected before dosing on Day 1 for 
ribonucleic acid (RNA) pharmacogenomic analysis from each subject in the study, into a PaxGene 
tube, and stored under frozen conditions.
Each pharmacogenomic sample for a study subject should be identifiable on the requisition form 
with an 8-digit subject ID (the 5-digit site number plus the 3-digit subject identification number).
The samples will be stored for no longer than 15 years after completion of the vedolizumab study 
and/or until the drug development of vedolizumab is no longer actively pursued by Takeda or its 
collaborators. 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 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 study 
drug or related drugs.
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
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9.1.18 Immunogenicity Sample Collection
Blood specimens for the assessment of AVA will be collected as shown in the Schedule of Study 
Procedures in Appendix A. A sample will be assessed for neutralizing AVA if AVA is detected. 
Serum titers of AVA will be determined using a validated assay. Neutralizing AVA will be 
determined using a validated assay.
9.1.19 PK Sample Collection
Blood samples (one 5-mL sample per scheduled time) to measure serum vedolizumab 
concentration will be collected into red-top Vacutainers according to the Schedule of Study 
Procedures in Appendix A. The actual date and time of sample collection will be recorded on the 
source document and eCRF.
PK samples must be collected on the same day as the visit date and prior to dosing (on the days 
of vedolizumab dosing).
Serum concentrations of vedolizumab will be measured using a validated assay.
9.1.20 Pharmacodynamic and Exploratory Biomarker Assessments
Additional blood samples will be collected at Baseline (Appendix A) for measurement of cellular 
biomarkers that may correlate with response to vedolizumab.
9.1.21 Tuberculosis Screening 
All subjects will complete TB screening to determine eligibility. All subjects must complete either 
a QuantiFERON test or a tuberculin skin test within 30 days of Screening or at Screening. Chest 
X-ray should be completed if high risk for TB or indeterminate skin test or QuantiFERON.
Subjects will be excluded from the study if they have active or latent TB, regardless of treatment 
history, as defined in Section 7.2.
9.1.22 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 IV 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 Management Program for PML (RAMP) in Section 11.1.1. The symptoms from a 
positive PML checklist will be recorded as an AE. 
9.1.23 Patient Reported Outcome Measures 
Subjects will complete the IBDQ at the time points shown in the Schedule of Study Procedures in 
Appendix A.
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The IBDQ is a valid and reliable [35] instrument used to assess quality of life in adult patients with 
IBD. It includes 32 questions on 4 domains of HRQOL: Bowel Systems (10 items), Emotional 
Function (12 items), Social Function (5 items), and Systemic Function (5 items). 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 [36]. A total IBDQ score ≥170 is associated with clinical 
remission [36,37].
9.1.24 Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible during screening, the investigator should contact the IRT as 
a notification of screen failure and complete the Screen Failure eCRF. 
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria. 

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other (specify reason).
Subject numbers assigned to subjects who fail screening should not be reused.
Subjects who fail screening may be rescreened once. Subjects undergoing rescreening must be 
reconsented and assigned a new subject number by IRT.
9.1.25 Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria at 
Baseline/Day 1 are eligible for enrollment into the Lead-in Period of the study. 
At Week 6 subjects will be assessed for eligibility for randomization into the Randomized 
Treatment Period of the study based on the criteria described in Section 6.1. If the subject is found 
to be not eligible for randomization, the investigator should record the primary reason for Lead-in 
failure (Section 9.1.26) on the applicable eCRF.
9.1.26 Documentation of Lead-in Failure
Investigators must account for all subjects enrolled into the Lead-in Period.
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If the subject is found to be not eligible for randomization during the Lead-in Period or will not be 
continuing into the Randomization Period for other reasons, the investigator should contact the 
IRT as a notification of Lead-in Period failure and complete the appropriate eCRF. 
The primary reason for Lead-in Period failure is recorded in the eCRF using the following 
categories:

Subject was determined to be a responder.

Subject was a nonresponder with serum vedolizumab concentrations above a predefined 
vedolizumab concentration threshold (≥50 µg/mL)). 

PTE/AE.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other (specify reason).
Subject numbers assigned to subjects who fail the Lead-in Period should not be reused.
9.2
Monitoring Subject Treatment Compliance
A vedolizumab IV dispensing log, including records of drug received from the sponsor and 
volume of vedolizumab IV dispensed to each subject intravenously, will be maintained by the site. 
If a subject is persistently noncompliant with the study medication (ie, fails to keep scheduled 
study visits), it may be appropriate to withdraw the subject from the study. 
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Schedule of Study 
Procedures in Appendix A. Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening Period
Subjects will be screened within 28 days prior to Enrollment. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. Subjects 
can be enrolled at any time during the Screening period provided that all screening procedures 
have been completed and eligibility has been confirmed. See Section 9.1.24 for procedures for 
documenting screening failures. Procedures to be completed at Screening Visit can be found in the 
Schedule of Study Procedures in Appendix A. 
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9.3.2
Enrollment and Lead-in Period
Enrollment into the Lead-in Period will take place on Day 1. If the subject has satisfied all of the 
inclusion criteria and none of the exclusion criteria for enrollment, the subjects will be enrolled 
using the IRT as described in Section 8.2. All subjects with moderately to severely active UC who 
are eligible for treatment with vedolizumab IV will receive vedolizumab IV 300 mg for the 
Lead-in Period at Day 1 and Week 2 as described in Section 6.1. 
Subjects will return to the clinic at Weeks 5 and 6 for assessments that will determine if they are 
eligible for randomization into the Randomized Treatment Period or are lead-in failures. The 
procedures performed and documented during Day 1 and Weeks 2, 5, and 6 of the Lead-in Period 
are shown in the Schedule of Study Procedures in Appendix A.
9.3.3
Randomization (Week 6) and Randomized Treatment Period
If the subject has met the serum vedolizumab concentration threshold defined as having high 
vedolizumab clearance, based on a predefined Week 5 serum vedolizumab concentration threshold 
(<50 µg/mL), and has met the nonresponder criteria at Week 6, the subject will be randomized at 
Week 6 using the IRT as described in Section 8.2. Subjects will be administered the assigned 
regimen of study drug as described in Section 6.1. Procedures and subsequent dosing and dose 
adjustments will be performed and documented according to the Schedule of Study Procedures in 
Appendix A.
Subjects who are determined to be responders or are nonresponders at Week 6 with levels above a 
predefined serum vedolizumab concentration threshold (≥50 µg/mL) at Week 5 (ie, Lead-In 
Failures) will not be randomized and will receive the Week 6 study drug dose (300 mg) and 
thereafter appropriate treatment per physician discretion. These subjects will be followed for up to 
18 weeks and receive a LTFU safety survey by telephone call 6 months after the last dose (Week 6) 
of study drug according to the Schedule of Study Procedures in Appendix A.
9.3.3.1
Lead-in Failures
Subjects who are Lead-in Failures will perform all procedures for Week 6 as per the Schedule of 
procedures (Appendix A). No redistribution of patient diaries will be made for these subjects.
9.3.4
Randomized Treatment Period and Dose Regimen Selection
Sites will enter the subject’s Week 5 vedolizumab serum concentration into the IRT in order to 
receive their assigned dosing regimen. 
At Week 14 and beyond, for subjects randomized into the Dose Optimization Arm, the subject’s 
most recent preceding serum vedolizumab concentration (eg, Week 13 PK sampling prior to Week 
14 dosing) will be entered into the IRT in order to confirm and continue their assigned dosing 
regimen.
Subjects will follow the relevant dosing and visit schedule as per the Schedule of Study Procedures 
in Appendix A.
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9.3.5
Final Visit or Early Termination
For randomized subjects, final treatment period visit procedures will be performed at Week 30 or 
at the ET Visit, if applicable, according to the Schedule of Study Procedures in Appendix A. 
For all subjects receiving study medication, the investigator must complete the End of Study eCRF 
page.
9.3.6
Week 40 (Q8W)/Week 44 (Q4W) Follow-up (18 Weeks Post-Treatment)
For all enrolled subjects, follow-up will begin the first day after the last dose of vedolizumab IV 
and will continue for 18 weeks. This follow-up visit will be scheduled to assess safety for all 
subjects and for AVA assessments for all subjects who stopped vedolizumab IV during study as 
per the Schedule of Study Procedures in Appendix A.
9.3.7
Long-Term Follow-Up Safety Survey (6-Months Post-Treatment)
Upon completion of or ET from the study, all subjects will complete a LTFU safety survey by 
telephone. This questionnaire will be administered at 6 months from the last dose of study drug.
9.3.8
Unscheduled Visits (if applicable)
Subjects may return to the study center for unscheduled visits as needed. Unscheduled visits can be 
performed when the subject has a study-related issue in between regular visits (ie, SAE follow-up, 
additional PK samples, LFT elevations). 
At any unscheduled visits, the following procedures will be performed and documented as 
applicable:

Collection of concomitant medications and procedures.

Collection of AEs and SAEs.

Any additional procedures included in the protocol may be conducted at the judgment of the 
investigator.
Standard-of-care visits (routine check-ups) should not be captured as an unscheduled visit in 
eCRF. However, if the visit is due to disease exacerbation the procedures described in 
Section 9.3.9 should be performed.
9.3.9
Unscheduled Visits Due to Disease Exacerbation 
Subjects who are seen by the investigator or site staff at a time point not required by the protocol 
(ie, unscheduled visit) due to disease exacerbation will undergo the following: 

Physical examination. 

Vital signs assessment. 

Diary review. 
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
Collection of concomitant medications and procedures.

Collection of AEs and SAEs.

Clinical chemistry and hematology, as indicated.

Partial or complete Mayo score.

Flexible sigmoidoscopy, if indicated.

PK sample collection.

AVA sample collection.

C. difficile, if indicated.
There is no minimum time for repeat evaluation by unscheduled visit in order to determine if a 
subject has disease exacerbation. In general, however, enough time should be provided for 
clinically meaningful change to occur. 
9.4
Biological Sample Retention and Destruction 
In this study, specimens for genome/gene analysis will be collected according to the Schedule of 
Study Procedures in Appendix A. 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 blood samples will be sent to a central laboratory that processes the blood sample and serves 
as a secure storage facility. The sponsor and researchers working with the sponsor will have access 
to the samples collected and any test results. All samples collected during the study will be stored 
securely with limited access and the sponsor will require anyone who works with the samples to 
agree to hold the research information and any results in confidence.
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided pharmacogenomic samples can withdraw their consent and 
request disposal of a stored sample at any time. Notify sponsor of consent withdrawal.
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory retest and/or continued monitoring of an abnormal value are not considered an 
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intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.
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
Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
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 
An AESI, either serious or nonserious, is an AE of scientific and medical concern specific to the 
compound or program, for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. Such events may require further investigation in order 
to characterize and understand them and would be described in protocols and instructions provided 
for investigators as to how and when they should be reported to Takeda.
AESIs for this compound are serious infections (and include opportunistic infection such as PML), 
liver injury, malignancies, infusion-related or systemic reactions, and hypersensitivity, as 
described in further detail as follows:
10.1.5.1 Hypersensitivity Reactions (Including Infusion-Related Reactions)
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab IV; hence such 
premedications are unlikely to be necessary or beneficial. At the discretion of the investigator, 
however, subjects may be administered premedication prior to any study drug administration. 
Corticosteroids, if given as a premedication, should be limited to the day of administration. 
Vedolizumab IV should be administered by a health care practitioner prepared to manage 
hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and medical 
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support measure should be available for immediate use. Subjects should be observed for 2 hours 
following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion.
Subjects and caregivers will be instructed to report the development of rash, hives, pruritus, flushing, 
urticaria, injection site pain, redness and/or swelling, etc. that may represent an 
administration-related reaction (ie, infusion-related reaction) to study medication. Subjects will be 
asked to report administration-related AEs to the sites immediately as they are experienced. 
Appropriate treatment and follow-up will be determined by the investigator. If signs or symptoms of 
an administration-related reaction are observed during the administration of study medication, it 
should be immediately discontinued and the subject treated as medically appropriate. In the case of a 
mild reaction, study drug administration may be reinitiated (with appropriate premedication and 
investigator supervision) at the discretion of the investigator. Subjects with a severe or serious 
administration-related reaction (eg, shortness of breath, wheezing, stridor, angioedema,
life-threatening change in vital signs, severe injection site reactions) must be withdrawn from the 
study. 
In all cases of administration-related reaction, the medical monitor must be informed as soon as 
practical. The disposition of subjects with less severe administration-related reactions should be 
discussed with the medical monitor.
10.1.5.2 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 7.5.
10.1.5.3 Malignancy 
All cases of malignancies that are detected during the study will be reported as AEs. Local medical 
practices for the management of malignances will apply. Subjects with history of malignancy 
(except for specific cancers) or at high risk for malignancy will be excluded from the study per the 
exclusion criteria. 
10.1.5.4 Other 
Other special interest AEs include liver injury and PML, which are discussed in Sections 10.2.3
and 11.1.1, respectively.
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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.
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.
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
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.
10.1.13
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death. 

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Start of PTE collection:
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication 
(Day 1) or until screen failure before Day 1. For subjects who discontinue prior to study 
medication administration, PTEs are collected until the subject discontinues study participation.
Start of AE collection: 
AEs must be collected from the time that the subject is first administered study medication 
(Day 1). 
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End of AE collection: 
Routine collection of AEs will continue for 18 weeks following the last dose of study medication.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date (and time).
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.
The IBDQ and patient diary will not be used as a primary means to collect AEs. However, should 
the investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the patient for medical evaluation should be undertaken. 
Through this follow-up, if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied.
10.2.1.3 Special Interest AE Reporting 
If an AESI that occurs during the treatment period or the follow-up period is considered to be 
clinically significant based on the criteria in Section 10.1.5, it should be recorded in a special 
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interest AE eCRF or SAE Form. The applicable form should be completed and reported to the 
SAE reporting contact in Section 1.1 within 24 hours.
The special interest AEs have to be recorded as AEs in the eCRF. An evaluation form along with 
all other required documentation must be submitted to the sponsor.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed in the eCRF 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.
A paper SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1 in the event that the eCRF is not available.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal LFTs 
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.11 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 
copy of all expedited reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No data safety monitoring committee will be used in this study.
11.1
PML Independent Adjudication Committee 
A PML Independent Adjudication Committee (IAC) will be instituted for this study. The PML 
IAC will consist of a panel of leading PML experts, including a neurologist, neuroradiologist, and 
a virologist.
11.1.1 Risk Assessment and Management Program (RAMP) for PML
Natalizumab (TYSABRI), another integrin receptor antagonist, has been associated with PML, a 
rare and often fatal opportunistic infection of the central nervous system. PML is caused by the 
John Cunningham virus (JCV) and typically only occurs in patients who are immunocompromised 
[38,39]. Natalizumab is a pan-α4 integrin antagonist that binds to both the α4β1 and α4β7 integrins 
and inhibits cellular adhesion to vascular cell adhesion molecule-1 (VCAM-1) and MAdCAM-1 
[40,41]. In contrast, vedolizumab binds to the α4β7 integrin only [24] 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 
IV, the sponsor, with input from renowned PML experts, has developed a RAMP program. The 
complete description of the RAMP program, including materials and instructions for its 
implementation and monitoring, is included in the RAMP 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 IV clinical study will be evaluated according to a prespecified 
algorithm (the PML Case Evaluation Algorithm). The next dose of study drug will be held until the 
evaluation is complete and results are available. Subsequent doses of study drug will be 
administered only if the possibility of PML is definitively excluded, as described in the RAMP 
algorithm. An IAC has been established as part of the RAMP program to review new neurological 
signs and symptoms potentially consistent with PML, and will provide input regarding subject 
evaluation and management as defined in the IAC charter. 
To ensure success of the RAMP program, site personnel will be trained to recognize the features of 
PML, and subjects will be trained to report specific neurological signs and symptoms without 
delay. Educational materials for teaching site personnel and subjects about PML and the RAMP 
procedures will be distributed to all sites and are included in the study manual. Formal teaching 
and training will be performed for site personnel prior to the start of the study. Subjects will 
receive training and educational materials prior to receiving treatment. The informed consent form 
will contain specific information on the hypothetical risk of PML. Any documented case of PML 
will be reported as an SAE, regardless of whether hospitalization occurs.
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
Drug Dictionary(WHODRUG).
12.1
Electronic CRFs
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor or 
delegated contract research organization (CRO) will make arrangements to train appropriate site 
staff in the use of the eCRF. These forms are used to transmit the information collected in the 
performance of this study to the sponsor and regulatory authorities. eCRFs must be completed in 
English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
The principal investigator must review the data change for completeness and accuracy, and must 
sign, or sign and seal, and date.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
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and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the 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 and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
A data review will be conducted prior to database lock. This review will assess the accuracy and 
completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods.
13.1.1 Analysis Sets
The full analysis set (FAS) will include all randomized subjects who receive at least 1 
postrandomization dose of study drug (ie, in the Randomized Treatment Period). Subjects in this 
set will be analyzed according to treatment they were randomized to receive (intent-to-treat [ITT]).
The safety analysis set will include all enrolled subjects who receive at least 1 dose of study drug. 
Subjects in this set will be analyzed according to the treatment received.
The PK set will include all randomized subjects who receive at least 1 postrandomization dose of 
study drug (ie, in the Randomized Treatment Period) and have at least 1 measurable 
postrandomization concentration of vedolizumab.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for all enrolled subjects by 
treatment group (nonrandomized vedolizumab IV and randomized treatment groups) and overall. 
Additional summaries will be provided for the FAS and other analysis sets, as appropriate. For 
continuous variables, summary statistics (nonmissing 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 
name.
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 the subset of the FAS who are taking concomitant oral corticosteroids at 
Baseline. 
All proportion-based primary, secondary and additional efficacy endpoints will be summarized by 
presenting the point estimate and 95% confidence intervals for the proportion by treatment group. 
The difference in proportions between treatment groups along with the 95% confidence interval 
will be presented. The primary efficacy analyses will be based on logistic model with treatment as 
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a factor, natural logarithm of trough concentration at Week 6 and other important covariates as 
explanatory variables. Odds ratio and its 95% confidence interval for treatment effect will be 
provided. All subjects with missing data for determination of endpoint status will be considered as 
a nonresponder in the analysis.
The additional efficacy endpoints of change from Baseline in CRP and fecal calprotectin will be 
summarized descriptively by time point and treatment group. A mixed model repeated measures 
analysis with treatment, visit, treatment by visit as fixed effect and its baseline value as a covariate 
will be performed. An unstructured covariance matrix is assumed. The LS mean, p-value and 
2-sided 95% confidence interval of treatment difference will be provided.
13.1.4 PK Analysis 
PK analyses will be performed on the PK set. Measured serum vedolizumab concentrations will be 
summarized by time using descriptive statistics. Individual serum concentration versus time data 
will be presented in a data listing.
Ctrough will be derived and further details will be provided in the SAP. Ctrough will be summarized 
using descriptive statistics (nonmissing values, mean, SD, %CV, median, minimum, and 
maximum).
The additional endpoint, the proportion of subjects with Ctrough below the threshold target of 
18.4 µg/mL at Week 14 and 12.7 µg/mL at Week 30, will be presented by treatment group.
Further analysis will be performed as deemed necessary and will not be reported in the clinical 
study report (CSR). These analyses will be part of a separate report.
13.1.5 Other Analyses
The following additional endpoints will be analyzed on the FAS. 
Change from Baseline in IBDQ total score and IBDQ domain scores will be summarized 
descriptively by time point and treatment group.
The proportion of subjects with positive AVA (transient and persistent) and the proportion of 
subjects with positive neutralizing AVA during the study will be summarized by treatment group. 
The impact of AVA on PK, efficacy, and safety will be examined.
A positive AVA subject is defined as a subject who has at least 1 positive AVA result in any 
postbaseline sample, and is further categorized as:

Transiently positive: defined as subjects with confirmed positive AVA in 1 sample at a 
postdose visit.

Persistently positive: defined as subjects with confirmed positive AVA in 2 or more 
consecutive positive AVA samples at postdose visits.
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13.1.6 Safety Analysis
All safety analyses will be performed using the safety analysis set and will be split into 
prerandomization and postrandomization periods. The nonrandomized vedolizumab IV group as 
well as the randomized treatment groups will be summarized. 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), and SAEs which occur on or after the first dose date 
and up to 18 weeks after the last dose date of the study drug will be summarized by MedDRA 
system organ class, high level term, and preferred term overall, by severity, and by relationship to 
vedolizumab 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 time point 
and treatment group. Subjects with markedly abnormal values for laboratory tests and vital signs 
will be tabulated. 
Physical examination findings and PML checklist data will be presented in data listings.
13.2
Interim Analysis and Criteria for Early Termination
An interim analysis will be conducted for the purpose of publication when all subjects have 
completed the Week 30 Final Visit or ET Visit. No study decisions will be made based on the 
interim results and subjects will continue to the Follow-up Period.
All available data will be included in the interim analysis. Data which can be considered final at 
Week 30 (all data except AEs, concomitant medications, and UC-related procedures and any 
Follow-up Visit data) will be cleaned and locked prior to the analysis. 
As all efficacy endpoints are measured at Weeks 14 or 30 there is no alpha adjustment required in 
the statistical analyses. Further details on the interim analysis will be documented in the SAP.
13.3
Determination of Sample Size
The sample size was based on an estimate of precision and not on statistical power considerations. 
A total sample size of approximately 250 subjects enrolled to achieve approximately 100 subjects 
randomized at Week 6, including 50 subjects per treatment group, will be sufficient to provide 
95% confidence intervals for mucosal healing rates with a half width no wider than +/-13.9%. In 
addition, the maximum width of the 95% confidence intervals (2-sided) for the difference in 
mucosal healing rates between the 2 groups will be no wider than +/-19.6%. If there is a high rate 
of patient drop out from the study, additional patients may be added.
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
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. The deviation should be documented on the Significant Protocol Deviation eCRF by 
the site and reviewed/acknowledged 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 notification no 
protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for America’s 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
REFERENCES
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10. Remicade (infliximab) 100 mg powder for concentrate for solution for infusion. Summary of 
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14. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. 
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26. Rosario M, Dirks NL, Gastonguay MR, Fasanmade AA, Wyant T, Parikh A, et al. Population 
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27. Vaughn BP, Martinez-Vazquez M, Patwardhan VR, Moss AC, Sandborn WJ, Cheifetz AS. 
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patients with inflammatory bowel disease: results from a pilot observational study. Inflamm 
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concentrations of infliximab guide dosing for patients with inflammatory bowel disease. 
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31. Parikh A, Leach T, Wyant T, Scholz C, Sankoh S, Mould DR, et al. Vedolizumab for the 
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vedolizumab pharmacokinetics and endoscopic outcomes in patients with ulcerative colitis. 
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predicts sustained clinical remission and lack of recourse to optimisation in inflammatory 
bowel disease. 11th Congress of European Crohn's and Collitis Organisation; March 16-19, 
2016; Amsterdam.
34. Kochhar G, Parikh M, Chaudrey K, Shmidt E, Luo M, Barocas M, et al. Mucosal healing with 
vedolizumab in ulcerative colitis and Crohn’s disease: outcomes from the VICTORY 
consortium. 2016 AIBD Annual Conference Crohn's & Colitis Foundation of America; 08-10 
December 2016; Orlando, Florida. P-002.
35. Irvine EJ. Development and subsequent refinement of the inflammatory bowel disease 
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36. 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.
37. 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 
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39. Steiner I, Berger JR. Update on progressive multifocal leukoencephalopathy. Curr Neurol 
Neurosci Rep 2012;12(6):680-6.
40. 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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CONFIDENTIAL
Appendix A
Schedule of Study Procedures
Screening
Lead-in (week)
Randomized Treatment Period (week)
Follow-up 
(c)
LTFU 
Phone 
Call (d)
Week
Day 1/
BL (a)
2
5
6 (b)
Decision
10
13
14
18
22 
(EOT 
Q8wk)
26 
(EOT 
Q4wk)
30
Final 
Visit/ET 
18 wks 
from 
EOT
6-months 
from
EOT 
Study Day
-28 to -1
1
15±3
36±3
43±3
71±3
92±3
99±3
127±5
155±5
183±5
211±5
Q8 281±7
Q4 309±7 
Q8 337±7
Q4 365±7
Visit Window (Days):
1
Days 
12-18
Days 
33-39
Days 40-46
Days 
68-74
Days 
89-95
Days 96-102
Days 
122-132
Days 
150-160
Days 
178-188
Days 
206-216
Q8 Days 
274-288
Q4 Days 
302-316 
Q8 Days 
330-344
Q4 Days 
358-372
Visits that apply to 
Lead-in Failures
X
X
X
X
X
X
X
Visits that apply to 
Standard Arm 
X
X
X
X
X
X
X
X
X
X
Visits that apply to Dose 
Optimization Arm 
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
Informed consent
X
Access IRT 
X
X
X
X
X
X (e)
X (e)
X (e)
X (e)
X
Lead in Period 
inclusion/exclusion 
criteria 
X
X
Randomized Treatment 
Period inclusion criteria
X
Demographics/medical 
history/concurrent 
medical conditions
X
UC disease history
X
Medication history/Prior 
UC disease treatments
X
Footnotes are on last table page.
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CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Screening
Lead-in (week)
Randomized Treatment Period (week)
Follow-up 
(c)
LTFU 
Phone 
Call (d)
Week
Day 1/
BL (a)
2
5
6 (b)
Decision
10
13
14
18
22 
(EOT 
Q8wk)
26 
(EOT 
Q4wk)
30
Final 
Visit/ET 
18 wks 
from 
EOT
6-months 
from
EOT 
Study Day
-28 to -1
1
15±3
36±3
43±3
71±3
92±3
99±3
127±5
155±5
183±5
211±5
Q8 281±7
Q4 309±7 
Q8 337±7
Q4 365±7
Visit Window (Days):
1
Days 
12-18
Days 33-39 Days 40-46
Days 
68-74
Days 
89-95
Days 96-102
Days 
122-132
Days 
150-160
Days 
178-188
Days 
206-216
Q8 Days 
274-288
Q4 Days 
302-316 
Q8 Days 
330-344
Q4 Days 
358-372
Concomitant 
medications 
X
X
X
X
X
X
X
X
X
X
X
X
X
Collection of 
concomitant procedures
X
X
X
X
X
X
X
X
X
X
X
X
Tuberculosis 
QuantiFERON or skin 
test (f)
X
Hepatitis, HIV
X
Physical examination
X
X
X
X
X
Vital signs (g)
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and height (g)
X
X
X
Flexible sigmoidoscopy 
(h)
X
X
Complete Mayo Score
X
X (i)
Partial Mayo Score
X
X
X
X
X
X
X
X
X (i)
Footnotes are on last table page.
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CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Screening
Lead-in (week)
Randomized Treatment Period (week)
Follow-up 
(c)
LTFU 
Phone 
Call (d)
Week
Day 1/
BL (a)
2
5
6 (b)
Decision
10
13
14
18
22 
(EOT 
Q8wk)
26 
(EOT 
Q4wk)
30
Final 
Visit/ET 
18 wks 
from 
EOT
6-months 
from
EOT 
Study Day
-28 to -1
1
15±3
36±3
43±3
71±3
92±3
99±3
127±5
155±5
183±5
211±5
Q8 281±7
Q4 309±7 
Q8 337±7
Q4 365±7
Visit Window (Days):
1
Days 
12-18
Days 33-39 Days 40-46
Days 
68-74
Days 
89-95
Days 96-102
Days 
122-132
Days 
150-160
Days 
178-188
Days 
206-216
Q8 Days 
274-288
Q4 Days 
302-316 
Q8 Days 
330-344
Q4 Days 
358-372
PK samples for 
vedolizumab (j)
X
X
X
X
X
X
X
X
X
X
X
X
Dose Regimen 
Assignment (k)
X
Vedolizumab (IV) 
lead-in period (m)
X
X
X
Vedolizumab (IV) 
randomization period 
(m)
X
X
X
X
X
X
Clinical laboratory 
testing
X
X
X
X
X
X
X
X
X
X
X
PT/INR (n)
X
Exploratory biomarker 
sample
X
Urinalysis 
X
X
CRP
X
X
X
X
X
PGx samples (o)
X
AVA testing (p)
X
X
X
X
X
X
Footnotes are on last table page.
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CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Screening
Lead-in (week)
Randomized Treatment Period (week)
Follow-up 
(c)
LTFU 
Phone 
Call (d)
Week
Day 1/
BL (a)
2
5
6 (b)
Decision
10
13
14
18
22 
(EOT 
Q8wk)
26 
(EOT 
Q4wk)
30
Final 
Visit/ET 
18 wks 
from 
EOT
6-months 
from
EOT 
Study Day
-28 to -1
1
15±3
36±3
43±3
71±3
92±3
99±3
127±5
155±5
183±5
211±5
Q8 281±7
Q4 309±7 
Q8 337±7
Q4 365±7
Visit Window (Days):
1
Days 
12-18
Days 
33-39
Days 40-46
Days 
68-74
Days 
89-95
Days 
96-102
Days 
122-132
Days 
150-160
Days 
178-188
Days 
206-216
Q8 Days 
274-288
Q4 Days 
302-316 
Q8 Days 
330-344
Q4 Days 
358-372
Pregnancy test (serum 
and urine) (hCG) (q)
X
X
X
X
X
X
X
X
X
X
X
FSH (r)
X
ECG
X
PML checklist (s)
X
X
X
X
X
X
X
X
X
X
X
PML wallet card
X
X (t)
IBDQ
X
X
X
Patient diary
X
X
X
X
X (l)
X
X
X
X
X
X
X
Stool sample for C. 
difficile Test 
X
Stool sample for fecal 
calprotectin (u)
X
X
X
X
PTE assessment (v)
X
X
AEs (w)
X
X
X
X
X
X
X
X
X
X
X
X
LTFU 
questionnaire via 
phone call 
X
BL=baseline, EOT=end of treatment.
(a) Assessments to be completed predose.
(b) Confirm Week 5 PK results before the Week 6 visit.
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(c) 18 Week posttreatment follow-up is Week 40 (Q8W) and Week 44 (Q4W). If a subject in the Dose Optimization Arm dose is lowered to 300 mg Q8W dosing and the last dose is 
week 26, they should follow the Q4W schedule and windows for the 2 Follow-up Visits.
(d) LTFU telephone call to be performed 6 months after last dose of study drug for all subjects enrolled in the study and receiving at least 1 dose of study medication. This is expected 
to occur for Lead-in failures no later than Week 32 and for Randomized subjects at Week 48 for a Q8W regimen or at Week 52 for Q4W regimen. If a subject in the Dose Optimization 
Arm dose is lowered to 300 mg Q8W dosing and the last dose is week 26, they should follow the Q4W schedule and windows for the 2 Follow-up Visits.
(e) In Dose Optimization Arm, dosing may be withheld or lowered based on prior serum vedolizumab concentration. If subject switches to the 300 mg Q8W dosing due to high serum 
vedolizumab concentration, the IRT only needs to be called on dose dispensing visits.
(f) Assessed by QuantiFERON test or a TB skin test reaction at Screening, within 30 days of Screening. See section 9.1.21.
(g) Vital signs will include body temperature, respiratory rate, blood pressure, and pulse (bpm). On dosing days, vital signs are taken predose. Height will be collected only at 
Screening Visit. 
(h) Biopsies to be collected at Screening and Week 30. 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 performed by the central reader. All biopsy samples collected per protocol will be centrally stored and analyzed at the end of the 
study. Although it is permissible for the investigator to take additional biopsy samples as deemed necessary for standard of care management of the patient during the protocol 
required colonoscopy/sigmoidoscopy, these will be considered as occurring outside the protocol. Such collection, handling and analyses of the additional samples will be and remain 
the responsibility of the investigator. 
(i) Partial Mayo score to be performed if flexible sigmoidoscopy is not performed at this visit.
(j) PK samples for serum vedolizumab on dosing days must be collected predose on the same date as the infusion. If the samples are not collected prior to vedolizumab dosing or not 
collected on the same day as the infusion, it is a significant deviation. PK samples are also collected on non-dosing visits per Appendix A.
(k) For subjects randomized to the Dose Optimization Arm, dosing regimens will be assigned by the IRT based on the Week 5 serum vedolizumab concentrations. 
(l) Not applicable for Lead-in Failures. No redistribution of patient diaries to Lead-in failures.
(m) All subjects will receive treatment with vedolizumab IV per label through Week 2. Nonresponders at Week 6 with serum vedolizumab concentration <50 µg/mL based on Week 
5 PK collection will be randomized at Week 6 in a 1:1 ratio to 1 of 2 treatment arms as follows: vedolizumab IV Standard Dosing Arm or Dose Optimization Arm. At Week 6, all 
subjects who respond or are nonresponders and are above a predefined vedolizumab concentration threshold (≥50 µg/mL) at Week 5 will not be eligible to be randomized into the 
study, and will receive the Week 6 study drug infusion and thereafter continue to receive appropriate treatment per physician’s discretion.
(n) PT/INR to be collected at Baseline and then only if LFTs are elevated at subsequent visits.
(o) Blood samples (for DNA and RNA analysis) will be collected on Day 1. 
(p) On dosing days, blood samples must be taken predose. 
(q) Women of childbearing potential only. Serum pregnancy test at Screening only; urine pregnancy test should be done thereafter, including before every IV infusion.
(r) FSH level will be obtained for female subjects at Screening if they are postmenopausal by history (eg, defined as at least 1 year since last regular menses with an FSH >40 IU/L or 
at least 5 years since last regular menses, confirmed before any study medication is implemented) and not surgically sterile. The FSH result must be >40 IU/mL for the subject to be 
permitted not to use adequate contraception.
(s) PML checklist must be administered at all visits in Appendix A and on dosing days, prior to vedolizumab dosing.
(t) Long-term Follow-up Wallet card will be given to subjects at the last clinical visit.
(u) Stool sample for fecal calprotectin should be the first bowel movement on the day of collection. 
(v) PTEs will be captured immediately following the signing of the informed consent at the Screening Visit, up until the first dose of study drug. 
(w) Collection of AEs will begin following first dose of study drug and will continue through Wk 40 (for Q8W)/Final Safety Visit or Wk 44 (for Q4W)/Final Safety Visit. Collection 
of all SAEs will begin once the informed consent is signed and will continue through Week 40 (for Q8W)/Final Safety Visit or Week 44 (for Q4W)/Final Safety Visit.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by 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 by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50 ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
13. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study 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 and for 18 weeks after last dose. 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 and for 18 weeks after last dose. If the partner 
or wife of the subject is found to be pregnant during the study, the investigator will offer the 
subject the choice to receive unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix D
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix E
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity
Category(a)
Stool frequency (b)
0 = Normal no. of stools for this patient
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
Sub score, 0 to 3
Rectal bleeding (c)
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
Sub score, 0 to 3
Findings on endoscopy 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Sub score, 0 to 3; 0 = Normal or inactive disease
Physician’s global assessment (d)
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Sub score, 0 to 3
(a) The Mayo score ranges from 012, with higher scores indicating more severe disease. Partial Mayo score excludes 
endoscopy and ranges from 09.
(b) Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency.
(c) The daily bleeding score represents the most severe bleeding of the day.
(d) The physician’s global assessment acknowledges the 3 other criteria, the patient’s daily recollection of abdominal 
discomfort and general sense of well-being, and other observations, such as physical findings and the patient’s 
performance status.
Adapted from: Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 
1987; 317 (26):1625-9. 
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Appendix F
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 03 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Investigator agreement revised to remove provision of package insert.
The primary change occurs in Section 1.2 Approval.
Initial 
wording:
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:
Amended 
wording:
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:
Rationale for Change: Investigator brochure was provided to investigators.
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Change 2: Subject number to enroll was increased from 200 to 250, to randomize approximately 
100 subjects.
The primary change occurs in Section 6.1 Study Design.
Initial 
wording:
Approximately 200 subjects will be enrolled in order to randomize up to 100 
nonresponder subjects with high vedolizumab drug clearance.
Amended 
wording:
Approximately 200 250 subjects will be enrolled in order to randomize up to
approximately 100 nonresponder subjects with high vedolizumab drug clearance.
Rationale for Change: Subject number increased due to a higher than expected lead-in failure
rate.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 6.1 Study Design

Figure 6.a Schematic of Study Design

Section 13.3 Determination of Sample Size
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Change 3: Site number was increased from 70 to 80.
The primary change occurs in Section 2.0 STUDY SUMMARY.
Initial 
wording:
Estimated total: Approximately 70 in the United States and Canada
Amended 
wording:
Estimated total: Approximately 70 80 in the United States and Canada
Rationale for Change: To add additional sites to contribute to enrollment.
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Change 4: Section 5.2.2 Secondary Endpoints, Day 1 was removed from the complete Mayo 
score definition of Baseline.
The primary change occurs in Section 5.2.2 Secondary Endpoints.
Initial 
wording:
Proportion of subjects achieving clinical response, where clinical response is 
defined as a reduction in complete Mayo score of ≥3 points and ≥30% from 
Baseline (Day 1) with an accompanying decrease in rectal bleeding subscore of 
≥1 point or absolute rectal bleeding subscore of ≤1 point, at Week 30.
Amended 
wording:
Proportion of subjects achieving clinical response, where clinical response is 
defined as a reduction in complete Mayo score of ≥3 points and ≥30% from 
Baseline (Day 1) with an accompanying decrease in rectal bleeding subscore of 
≥1 point or absolute rectal bleeding subscore of ≤1 point, at Week 30.
Rationale for Change: Screening labs are used to calculate the complete Mayo score.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 3.5 Study Definitions
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Change 5: Exclusion Criteria #7, clarified subjects with prior exposure to approved or 
investigational anti-integrin antibodies are excluded.
The primary change occurs in Section 7.2 Exclusion Criteria.
Initial 
wording:
The subject has previously received natalizumab, efalizumab, etrolizumab, 
AMG-181, MAdCAM-1 antibodies, or rituximab.
Amended 
wording:
The subject has previously received had prior exposure to approved or 
investigational anti-integrin antibodies (eg, natalizumab, efalizumab, 
etrolizumab, AMG-181, anti-MAdCAM-1 antibodies, or rituximab).
Rationale for Change: Clarification of existing text.
Section 2.0 STUDY SUMMARY also contains this change. 
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Change 6: Exclusion Criteria #8, clarified subjects that previously received approved or 
investigational Vedolizumab (not just Vedolizumab IV) are excluded.
The primary change occurs in Section 7.2 Exclusion Criteria.
Initial 
wording:
The subject has previously received vedolizumab IV.
Amended 
wording:
The subject has previously received approved or investigational vedolizumab 
IV.
Rationale for Change: Clarification of existing text that any type of vedolizumab is excluded.
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Change 7: Exclusion Criteria #11, clarified timing of exclusion is during Screening.
The primary change occurs in Section 7.2 Exclusion Criteria.
Initial 
wording:
The subject has any evidence of an active infection (eg, sepsis, cytomegalovirus, 
or listeriosis).
Amended 
wording:
The subject has any evidence of an active infection during Screening (eg, sepsis, 
cytomegalovirus, or listeriosis).
Rationale for Change: Clarification of existing text.
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Change 8: Exclusion Criteria #18, clarified timing of exclusion is 2 weeks prior to Screening.
The primary change occurs in Section 7.2 Exclusion Criteria.
Initial 
wording:
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.
Amended
wording:
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 prior to Screening.
Rationale for Change: Clarification of existing text.
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Change 9: Exclusion Criteria #25, clarified timing of PML checklist administration.
The primary change occurs in Section 7.2 Exclusion Criteria.
Initial 
wording:
The subject has a positive PML subjective symptom checklist prior to the 
administration of the first dose of study drug.
Amended 
wording:
The subject has a positive PML subjective symptom checklist during Screening 
or prior to the administration of the first dose of study drug on Day 1.
Rationale for Change: Clarification of existing text.
Section 2.0 STUDY SUMMARY also contains this change. 
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Change 10: Section 7.4.1 Excluded Medications was updated.
The primary change occurs in Section 7.4.1 Excluded Medications.
Initial 
wording:
The following medications are excluded from use during the study from the time of 
Screening, unless specified otherwise:
1. TNF-α antagonist infliximab, adalimumab, certolizumab pegol, golimumab, or 
biosimilar agent.
2. Any treatment for UC other than those listed in Section 7.4.2 (either approved or 
investigational).

From randomization and throughout study, any of the following for the 
treatment of UC:
–
Nonbiologic therapies (eg, cyclosporine, thalidomide).
–
A nonbiologic investigational therapy.
–
An approved nonbiologic therapy in an investigational protocol.
3. All live vaccines within 30 days prior to randomization, throughout the study 
treatment period, and for at least 6 months after the last dose of study drug. 
4. Either approved or investigational biologic agents for the treatment of non-IBD 
conditions, other than localized injections (eg, intra-ocular injections for wet 
macular degeneration).
Amended 
or new 
wording:
The following medications are excluded from use during the study from the time of 
Screening through the Final Visit/ET (Week 30), unless specified otherwise:
1. TNF-α antagonist infliximab, adalimumab, certolizumab pegol, golimumab, or 
biosimilar agent. Any approved or nonapproved biologic or biosimilar agent 
for the treatment of IBD.
2. Any treatment for UC other than those listed in Section 7.4.2 (either approved or 
investigational).

From randomization and throughout study, any of the following for the 
treatment of UC:
–
Nonbiologic therapies (eg, cyclosporine, thalidomide).
–
A nonbiologic investigational therapy.
–
An approved nonbiologic therapy in an investigational protocol.
2. Any approved or nonapproved nonbiologic therapy for treatment of UC in 
an investigational protocol.
3. Any nonbiologic therapies (eg. cyclosporine, thalidomide) for the treatment 
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of UC other than those listed in section 7.4.2.
4. All Any live vaccines within 30 days prior to randomization, throughout the study 
treatment period, and for at least through 6 months after the last dose of study 
drug. 
5. Either Any approved or investigational nonapproved biologic agents for the 
treatment of non-IBD conditions, other than localized injections (eg, intra-ocular 
injections for wet macular degeneration).
6. Topical (rectal) treatment with 5-ASA or corticosteroid 
enemas/suppositories.
7. TPN or albumin.
Rationale for Change: The excluded medications are not allowed because the subjects may not 
remain on them throughout the study on a stable dose and any variable that can interfere with 
primary drug efficacy should be removed.
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Change 11: Section 7.4.2 Permitted Medications was updated.
The primary change occurs in Section 7.4.2 Permitted Medications.
Initial 
wording:

Probiotics (eg, Culturelle, Saccharomyces boulardii)

Oral 5-ASA compounds.

5-ASA or corticosteroid enemas/suppositories, stable for at least 2 weeks prior to 
Screening.

Oral corticosteroid therapy for UC up to 30 mg/day is permitted during Screening 
and upon enrollment. Tapering must be made at the investigator’s discretion no 
later than Week 14. See Section 7.4.2.1.

Antidiarrheals for control of chronic diarrhea.

Azathioprine, 6-mercaptopurine, or methotrexate, provided that the dose has been 
stable for 8 weeks immediately prior to Screening.
Amended 
wording:

Probiotics (eg, Culturelle, Saccharomyces boulardii) provided that the subject 
was receiving them at the Screening Visit and they remain stable throughout 
the study.

Oral 5-ASA compounds provided that the subject was receiving them at the 
Screening Visit and that they remain stable throughout the study.

5-ASA or corticosteroid enemas/suppositories, stable for at least 2 weeks prior to 
Screening.

Oral corticosteroid therapy for UC total of up to 30 mg/day is permitted during 
Screening and upon enrollment. Tapering must be made at the investigator’s 
discretion no later than Week 14. See Section 7.4.2.1.

Antidiarrheals for control of chronic diarrhea.

Azathioprine, 6-mercaptopurine, or methotrexate, provided that the dose has been 
stable for 8 weeks immediately prior to Screening and remain stable 
throughout the duration of the study.
Rationale for Change: All concomitant medications that are allowed while the subjects are in 
the study are to be administered in stable doses throughout the study. Clarification of existing 
text.
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Change 12: Section 7.4.2.1 Corticosteroid Taper, co-administration maximum dose and 
budesonide taper were added.
The primary change occurs in Section 7.4.2.1 Corticosteroid Taper.
Initial 
wording:
Oral corticosteroid taper should be initiated by Week 10 and no later than Week 14 
according to the following schedule:

For prednisone doses >10 mg/day (or equivalent), the dose will be reduced at a 
rate of 5 mg/week until a 10 mg/day dose is reached.

For prednisone doses ≤10 mg/day (or equivalent) or once a 10 mg/day dose (or 
equivalent) is reached, the dose will be reduced at a rate of 2.5 mg/week until 
discontinuation. For subjects who cannot tolerate the corticosteroid taper without 
recurrence of clinical symptoms, corticosteroids could be increased up to, but not 
exceed, the original dose the subject was on at the start of the induction phase. In 
such cases, the tapering regimen above will be reinitiated within 2 weeks.
Amended 
wording:
The maximum dose of oral prednisone for the treatment of UC that may be 
coadministered with vedolizumab IV is 30 mg/day or 9 mg/day budesonide (or 
equivalent). Oral corticosteroid taper should be initiated by Week 10 and no later 
than Week 14 according to the following schedule:

For prednisone doses >10 mg/day (or equivalent), the dose will be reduced at a 
rate of 5 mg/week until a 10 mg/day dose is reached.

For prednisone doses ≤10 mg/day (or equivalent) or once a 10 mg/day dose (or 
equivalent) is reached, the dose will be reduced at a rate of 2.5 mg/week until 
discontinuation. For subjects who cannot tolerate the corticosteroid taper without 
recurrence of clinical symptoms, corticosteroids could be increased up to, but not 
exceed, the original dose the subject was on at the start of the induction phase. In 
such cases, the tapering regimen above will be reinitiated within 2 weeks.

Budesonide should be reduced 3 mg every 2 weeks until discontinuation.
Rationale for Change: Up to 30 mg/day of oral corticosteroids is considered the standard of 
care; any doses higher than that, indicates a more severe disease progression and unlikely to taper 
the patient.
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Change 13: Section 7.6 Procedures for Discontinuation or Withdrawal of a Subject, replacement 
language was removed.
The primary change occurs in Section 7.6 Procedures for Discontinuation or Withdrawal of a 
Subject.
Initial 
wording:
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 
7.5. In addition, a subject may discontinue his or her participation without giving a 
reason at any time during the study. Should a subject’s participation be discontinued, 
the primary criterion for termination must be recorded by the investigator. In 
addition, efforts should be made to perform all procedures scheduled for the Early 
Termination Visit, Final Safety Visit, and the LTFU survey. Discontinued or 
withdrawn subjects will not be replaced.
Amended 
wording:
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 
7.5. In addition, a subject may discontinue his or her participation without giving a 
reason at any time during the study. Should a subject’s participation be discontinued, 
the primary criterion for termination must be recorded by the investigator. In 
addition, efforts should be made to perform all procedures scheduled for the Early 
Termination Visit, Final Safety Visit, and the LTFU survey. Discontinued or 
withdrawn subjects will not be replaced.
Rationale for Change: Per Section 13.1.3, if there is a high rate of patient drop out from the 
study, additional patients may be added.
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Change 14: Section 8.1.2 Storage, clarified storage requirements for Vedolizumab IV.
The primary change occurs in Section 8.1.2 Storage.
Initial 
wording:
Vedolizumab IV must be stored at 2ºC to 8ºC (36ºF to 46ºF). A daily temperature log 
of the drug storage area must be maintained every working day.
Amended 
wording:
Vedolizumab IV must be stored in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). A 
daily temperature log of the drug storage area must be maintained every working day.
Rationale for Change: Clarification of existing text.
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Change 15: Section 8.2 Investigational Drug Assignment and Dispensing Procedures, clarified 
lower dose will resume once serum Vedolizumab is ≤90 µg/mL.
The primary change occurs in Section 8.2 Investigational Drug Assignment and Dispensing 
Procedures.
Initial 
wording:
At Week 14 and beyond, for subjects in the Dose Optimization Arm, the investigator 
or the investigator’s designee will enter the subject’s most recent preceding serum 
vedolizumab concentration into IRT prior to dosing. If serum vedolizumab is 
>90 µg/mL, the next dose will be withheld and subject will be brought back the week 
before the next scheduled dose for repeat serum vedolizumab concentration. Once the 
subject’s serum vedolizumab is <90 µg/mL, dosing will resume at the next lower 
dose (see Section 6.1). 
Amended 
wording:
At Week 14 and beyond, for subjects in the Dose Optimization Arm, the investigator 
or the investigator’s designee will enter the subject’s most recent preceding serum 
vedolizumab concentration into IRT prior to dosing. If serum vedolizumab is 
>90 µg/mL, the next dose will be withheld and subject will be brought back the week 
before the next scheduled dose for repeat serum vedolizumab concentration. Once the 
subject’s serum vedolizumab is < ≤90 µg/mL, dosing will resume at the next lower 
dose (see Section 6.1). 
Rationale for Change: Clarification of existing text.
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Change 16: Section 9.1.2 Medication History and Prior UC Disease Treatment eCRF data entry
was clarified.
The primary change occurs in Section 9.1.2 Demographics, Medical History, and Medication 
History Procedure.
Initial 
wording:
Medication history information to be obtained includes any medication relevant to 
eligibility criteria stopped at or within 30 days prior to signing of informed consent. 
In addition, all prior biologic and any medication history for the treatment of UC 
disease with the reason for discontinuation is to be collected for subjects where 
possible.
Amended 
wording:
Medication history information to be obtained includes any medication relevant to 
eligibility criteria stopped at or within 30 days prior to signing of informed consent. 
Medication history should be captured on the Medication History/Concomitant 
Medications eCRF page.
In addition, all prior biologic and any medication history for the treatment of UC 
disease with the reason for discontinuation, that stopped at or prior to signing of 
informed consent, is to be collected at Screening for subjects where possible.
Any prior UC disease treatment should be captured on the Prior UC Disease 
Treatment eCRF only, and UC treatments started after signing the informed 
consent, should be captured on the Concomitant Medications eCRF page only.
Rationale for Change: Clarification of existing text.
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Change 17: Section 9.1.3 UC Disease History, clarified eCRF data entry for UC disease as 
concurrent condition.
The primary change occurs in Section 9.1.3 UC Disease History.
Initial 
wording:
UC history collected at Screening will include details of UC diagnosis, disease 
severity, surgery, hospitalizations, and extraintestinal manifestations. 
Amended 
wording:
UC history collected at Screening will include details of UC diagnosis, disease 
severity, surgery, hospitalizations, and extraintestinal manifestations. After signing 
of informed consent all subjects should have UC disease included on the 
Concurrent Medical Conditions eCRF page.
Rationale for Change: Clarification of existing text.
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Change 18: Section 9.1.6 Vital Sign Procedure, 5 minute period for vital sign collection and 
order of procedure language were removed.
The primary change occurs in Section 9.1.6 Vital Sign Procedure.
Initial 
wording:
When vital signs are scheduled at the same time as blood draws, the blood draw will 
take priority and it is recommended that vital signs be obtained within 0.5 hour before 
or after the scheduled blood draw.
Amended 
wording:
When vital signs are scheduled at the same time as blood draws, the blood draw will 
take priority and it is recommended that vital signs be obtained within 0.5 hour before 
or after the scheduled blood draw.
Rationale for Change: To allow for more flexibility in time of vital sign collection.
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Change 19: Section 9.1.9 Documentation of Concomitant Procedures, clarified last clinic visit.
The primary change occurs in Section 9.1.9 Documentation of Concomitant Procedures .
Initial 
wording:
At each visit, subjects will be asked whether they have had any UC-related events 
since their last visit including hospitalizations, bowel surgeries, or UC-related 
procedures that are not part of the protocol. The timing of the event will be collected 
relative to the start of treatment on Day 1 of the study through the last clinic visit. All 
events with timing will be recorded in the eCRFs. The underlying symptom or 
diagnosis should correspondingly be recorded as an AE as applicable.
Amended 
wording:
At each visit, subjects will be asked whether they have had any UC-related events 
since their last visit including hospitalizations, bowel surgeries, or UC-related 
procedures that are not part of the protocol. The timing of the event will be collected 
relative to the start of treatment on Day 1 of the study through the last clinic visit
(Follow-up Visit, 18 weeks after the last dose of study drug). All events with 
timing will be recorded in the eCRFs. The underlying symptom or diagnosis should 
correspondingly be recorded as an AE as applicable.
Rationale for Change: Clarification of existing text.
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Change 20: Section 9.1.10 Documentation of Concurrent Medical Conditions, clarified this 
includes lab, ECG, or physical exam abnormalities found at Screening.
The primary change occurs in Section 9.1.10 Documentation of Concurrent Medical Conditions.
Initial 
wording:
Concurrent medical conditions are those significant ongoing conditions or diseases 
that are present at signing of informed consent. This includes clinically significant 
laboratory, electrocardiogram (ECG), or physical examination abnormalities noted at 
baseline examination. The condition (ie, diagnosis) should be described.
Amended 
wording:
Concurrent medical conditions are those significant ongoing conditions or diseases 
that are present at signing of informed consent. This includes clinically significant 
laboratory, electrocardiogram (ECG), or physical examination abnormalities noted at
baseline the Screening examination. The condition (ie, diagnosis) should be 
described.
Rationale for Change: Clarification of existing text.
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Change 21: Section 9.1.11 Procedures for Clinical Laboratory Samples, added that Screening 
labs may be repeated once at investigator discretion.
The primary change occurs in Section 9.1.11 Procedures for Clinical Laboratory Samples.
Amended 
wording:
All Screening laboratory tests can be repeated once at the discretion of the 
principal investigator.
Rationale for Change: To allow for repeat testing at investigator discretion.
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Change 22: Section 9.1.19 PK Sample Collection, clarified PK samples collection timing.
The primary change occurs in Section 9.1.19 PK Sample Collection.
Initial 
wording:
Blood samples (one 5-mL sample per scheduled time) to measure serum vedolizumab 
concentration will be collected into red-top Vacutainers according to the Schedule of 
Study Procedures in Appendix A. The actual time of sample collection will be 
recorded on the source document and eCRF.
Amended 
wording:
Blood samples (one 5-mL sample per scheduled time) to measure serum vedolizumab 
concentration will be collected into red-top Vacutainers according to the Schedule of 
Study Procedures in Appendix A. The actual date and time of sample collection will 
be recorded on the source document and eCRF.
PK samples must be collected on the same day as the visit date and prior to 
dosing (on the days of vedolizumab dosing).
Rationale for Change: Clarification of existing text.
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Change 23: Section 9.1.21 Tuberculosis Screening was updated to clarify Chest X-Ray should 
only be performed if skin or QuantiFERON tests are indeterminate.
The primary change occurs in Section 9.1.21 Tuberculosis Screening.
Initial 
wording:
All subjects will complete TB screening to determine eligibility. All subjects must 
complete either a QuantiFERON test, a tuberculin skin test within 30 days of 
screening or at Screening, or chest X-ray within 3 months prior to enrollment and 
provide written confirmation. Subjects will be excluded from the study if they have 
active or latent TB, regardless of treatment history, as defined in Section 7.2.
Amended
wording:
All subjects will complete TB screening to determine eligibility. All subjects must 
complete either a QuantiFERON test or, a tuberculin skin test within 30 days of 
screening or at Screening., or cChest X-ray within 3 months prior to enrollment and 
provide written confirmation. should be completed if high risk for TB or 
indeterminate skin test or QuantiFERON. Subjects will be excluded from the 
study if they have active or latent TB, regardless of treatment history, as defined in 
Section 7.2.
Rationale for Change: Chest X-ray should not be used as the primary screening for TB. 
Clarification of existing text.
Appendix A
Schedule of Study Procedures, Footnote f also contains this change.
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Change 24: Section 9.1.24 Documentation of Screen Failure, added rescreening criteria.
The primary change occurs in Section 9.1.24 Documentation of Screen Failure.
New 
wording:
Subjects who fail screening may be rescreened once. Subjects undergoing 
rescreening must be reconsented and assigned a new subject number by IRT.
Rationale for Change: To allow for rescreening of subjects.
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Change 25: Section 9.3.1 Screening Period, period for enrollment was clarified.
The primary change occurs in Section 9.3.1 Screening Period.
Initial 
wording:
Subjects will be screened within 28 days prior to Enrollment. Subjects will be 
screened in accordance with predefined inclusion and exclusion criteria as described 
in Section 7.0. See Section 9.1.24 for procedures for documenting screening failures. 
Procedures to be completed at Screening Visit can be found in the Schedule of Study 
Procedures in Appendix A. 
Amended 
wording:
Subjects will be screened within 28 days prior to Enrollment. Subjects will be 
screened in accordance with predefined inclusion and exclusion criteria as described 
in Section 7.0. Subjects can be enrolled at any time during the Screening period 
provided that all screening procedures have been completed and eligibility has 
been confirmed. See Section 9.1.24 for procedures for documenting screening 
failures. Procedures to be completed at Screening Visit can be found in the Schedule 
of Study Procedures in Appendix A. 
Rationale for Change: Clarification of existing text.
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Change 26: Section 13.1.3 Efficacy Analysis, primary efficacy analysis was updated.
The primary change occurs in Section 13.1.3 Efficacy Analysis.
Initial 
wording:
All proportion-based primary, secondary and additional efficacy endpoints will be 
summarized by presenting the point estimate and 95% confidence intervals for the 
proportion by treatment group. The difference in proportions between treatment 
groups along with the 95% confidence interval will be presented. All subjects with 
missing data for determination of endpoint status will be considered as a 
nonresponder in the analysis.
The additional efficacy endpoints of change from Baseline in CRP and fecal 
calprotectin will be summarized descriptively by time point and treatment group. 
Amended 
wording:
All proportion-based primary, secondary and additional efficacy endpoints will be 
summarized by presenting the point estimate and 95% confidence intervals for the 
proportion by treatment group. The difference in proportions between treatment 
groups along with the 95% confidence interval will be presented. The primary 
efficacy analyses will be based on logistic model with treatment as a factor, 
natural logarithm of trough concentration at Week 6 and other important 
covariates as explanatory variables. Odds ratio and its 95% confidence interval 
for treatment effect will be provided. All subjects with missing data for 
determination of endpoint status will be considered as a nonresponder in the analysis.
The additional efficacy endpoints of change from Baseline in CRP and fecal 
calprotectin will be summarized descriptively by time point and treatment group. A 
mixed model repeated measures analysis with treatment, visit, treatment by 
visit as fixed effect and its baseline value as a covariate will be performed. An 
unstructured covariance matrix is assumed. The LS mean, p-value and 2-sided 
95% confidence interval of treatment difference will be provided.
Rationale for Change: Clarification of existing text.
Section 2.0 STUDY SUMMARY also contains this change. 
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Change 27: Section 13.3 Determination of Sample Size was updated to note that additional 
subjects may be added to account for high drop-out rates.
The primary change occurs in Section 13.3 Determination of Sample Size.
Initial 
wording:
The sample size was based on an estimate of precision and not on statistical power 
considerations. A total sample size of approximately 250 subjects enrolled to achieve 
approximately 100 subjects randomized at Week 6, including 50 subjects per 
treatment group, will be sufficient to provide 95% confidence intervals for mucosal 
healing rates with a half width no wider than +/-13.9%. In addition, the maximum 
width of the 95% confidence intervals (2-sided) for the difference in mucosal healing 
rates between the 2 groups will be no wider than +/-19.6%. 
Amended 
wording:
The sample size was based on an estimate of precision and not on statistical power 
considerations. A total sample size of approximately 250 subjects enrolled to achieve 
approximately 100 subjects randomized at Week 6, including 50 subjects per 
treatment group, will be sufficient to provide 95% confidence intervals for mucosal 
healing rates with a half width no wider than +/-13.9%. In addition, the maximum 
width of the 95% confidence intervals (2-sided) for the difference in mucosal healing 
rates between the 2 groups will be no wider than +/-19.6%. If there is a high rate of 
patient drop out from the study, additional patients may be added.
Rationale for Change: Clarification of existing text.
Section 2.0 STUDY SUMMARY also contains this change.
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Change 28: Appendix A, Prior UC disease treatment was added to the schedule of procedures.
The primary change occurs in Appendix A Schedule of Study Procedures.
Initial 
wording:
Medication history
Amended 
wording:
Medication history/Prior UC disease treatments
Rationale for Change: Clarification of existing text.
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Change 29: Appendix A, concomitant medications was checked at Screening.
The primary change occurs in Appendix A Schedule of Study Procedures.
New 
wording:
Screening
Week
Study Day
-28 to -1
Visit Window (Days):
Concomitant medications
X
Rationale for Change: Clarification of existing text.
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Change 30: Appendix A, footnote (j), PK collection was clarified.
The primary change occurs in Appendix A Schedule of Study Procedures.
Initial 
wording:
(j) PK samples for serum vedolizumab to be collected predose (30 minutes prior to start of infusion) prior to each 
dose and at Weeks 5 (all subjects) and 13 (for subjects in Dose Optimization Arm only) for determination of serum 
vedolizumab concentrations.
Amended 
wording:
(j) PK samples for serum vedolizumab on dosing days must to be collected predose on the same date as the 
infusion (30 minutes prior to start of infusion) prior to each dose and at Weeks 5 (all subjects) and 13 (for subjects 
in Dose Optimization Arm only) for determination of serum vedolizumab concentrations .If the samples are not 
collected prior to vedolizumab dosing or not collected on the same day as the infusion, it is a significant 
deviation. PK samples are also collected on nondosing visits per Appendix A.
Rationale for Change: Removed the requirement of the timing of the predose PK sample.
Clarification of existing text.
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Study No. Vedolizumab-4014
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Protocol Incorporating Amendment No. 03
19 April 2018
Change 31: Appendix A, footnote (s), PML checklist administration was clarified.
The primary change occurs in Appendix A Schedule of Study Procedures.
Initial 
wording:
(s) PML checklist must be administered prior to vedolizumab dosing at every dosing visit.
Amended 
wording:
(s) PML checklist must be administered at all visits in Appendix A and on dosing days, prior to vedolizumab 
dosing at every dosing visit.
Rationale for Change: Clarification of existing text.
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Study No. Vedolizumab-4014
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Protocol Incorporating Amendment No. 03
19 April 2018
Change 32: Appendix B Responsibilities of the Investigator, added responsibility if 
investigator/institution retains the services of any individual or party to perform trial-related 
duties and functions, the investigator/institution should ensure that this individual or party is 
qualified to perform those trial-related duties and functions and should implement procedures to 
ensure the integrity of the trial-related duties and functions performed and any data generated.
The primary change occurs in Section Appendix B Responsibilities of the Investigator.
New 
wording:
If the investigator/institution retains the services of any individual or party 
to perform trial-related duties and functions, the investigator/institution 
should ensure that this individual or party is qualified to perform those 
trial-related duties and functions and should implement procedures to 
ensure the integrity of the trial-related duties and functions performed and 
any data generated.
Rationale for Change: To add a new investigator responsibility per an update in the ICH
guideline.
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(dd-MMM-yyyy HH:mm ‘UTC’) 
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PPD

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 4 Open-Label Study to Evaluate Vedolizumab IV Dose Optimization on 
Treatment Outcomes In Nonresponders With Moderately to Severely Active Ulcerative Colitis
NCT Number: NCT03029143
SAP Approve Date: 17 March 2021
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.


STATISTICAL ANALYSIS PLAN
STUDY NUMBER: VEDOLIZUMAB-4014
A Phase 4 Open-Label Study to Evaluate Vedolizumab IV Dose Optimization on 
Treatment Outcomes in Non-responders with Moderately to Severely Active 
Ulcerative Colitis
PHASE 4
Version: Final 
Date: 17 March 2021
Prepared by:
Statistical Analyst, USMA, Takeda
Based on:
Protocol Version: Amendment 3
Protocol Date: 19 April 2018
Pr
of Takeda: For 
ommercial Use Only and Subject to the Applicable Terms of Use
mization
zatio
rely Ac
ely A
Final
inal
7 March
Marc
Sta
S
sion: Am
on:
Date:
ate: 1
PPD


Vedolizumab-4014
Page 2 of 43
Statistical Analysis Plan Final 1.0
17 March 2021
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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Statistical Analysis Plan Final 1.0
17 March 2021
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE
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.............................................................................................17
5.1
Primary Endpoint.....................................................................................................17
5.2
Secondary Endpoints ...............................................................................................17
5.3
Additional Endpoints ...............................................................................................17
5.4
Safety Endpoints:.....................................................................................................18
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................19
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................20
7.1
General Principles....................................................................................................20
7.1.1
Study Definitions ...............................................................................................20
7.1.2
Definition of Study Days....................................................................................21
7.1.3
Definition of Study Visit Windows ....................................................................22
7.1.4
Definition of Study Periods................................................................................23
7.1.5
Conventions for Missing Adverse Event Dates...................................................23
7.1.6
Conventions for Missing Concomitant Medication Dates...................................24
7.1.7
Convention for Calculation of Mayo Scores.......................................................25
7.1.8
Methods for Handling of Missing Efficacy Data ................................................26
7.1.9
Convention for Calculation of Inflammatory Bowel Disease Questionnaire
(IBDQ) ..............................................................................................................26
7.2
Analysis Sets ...........................................................................................................27
7.3
Disposition of Subjects ............................................................................................27
7.4
Demographic and Other Baseline Characteristics.....................................................28
7.5
Medical History and Concurrent Medical Conditions...............................................30
7.6
Medication History and Concomitant Medications...................................................30
7.7
Study Drug Exposure and Compliance.....................................................................31
7.8
Efficacy Analysis.....................................................................................................32
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Statistical Analysis Plan Final 1.0
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7.8.1
Primary Efficacy Endpoint(s).............................................................................32
7.8.2
Secondary Efficacy Endpoint(s).........................................................................33
7.8.3
Additional Efficacy Endpoint(s).........................................................................33
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................34
7.9.1
Pharmacokinetic Analysis ..................................................................................34
7.9.2
Pharmacodynamic Analysis ...............................................................................34
7.10
Other Outcomes.......................................................................................................35
7.11
Safety Analysis........................................................................................................35
7.11.1 Adverse Events ..................................................................................................35
7.11.2 Clinical Laboratory Evaluations .........................................................................37
7.11.3 Vital Signs .........................................................................................................38
7.11.4 12-Lead ECGs ...................................................................................................38
7.11.5 Other Observations Related to Safety.................................................................38
7.12
Interim Analysis ......................................................................................................38
7.13
Changes in the Statistical Analysis Plan...................................................................39
8.0
REFERENCES..............................................................................................................40
9.0
APPENDICES...............................................................................................................41
LIST OF IN-TEXT TABLES
Table 4.a 
The Schedule of Study Procedures .....................................................................12
Table 7.a 
Study Definitions ...............................................................................................21
Table 7.b 
Visit windows for complete Mayo score and flexible sigmoidoscopy.................22
Table 7.c 
Visit windows for partial Mayo score.................................................................22
Table 7.d 
Visit windows for other endpoints......................................................................22
Table 7.e 
Visit windows for vital signs and safety lab parameters......................................23
Table 7.f 
IBDQ domain calculations .................................................................................26
Table 7.g 
Baseline Characteristics .....................................................................................28
LIST OF IN-TEXT FIGURES 
Figure 4.a
Schematic of Study Design ................................................................................11
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Statistical Analysis Plan Final 1.0
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LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................41
Appendix B
AEs of Special Interest (AESI)...........................................................................42
Appendix C
Criteria for Identification of Markedly Abnormal Values for Vital Signs............43
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Statistical Analysis Plan Final 1.0
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
AVA
antivedolizumab antibody
CMH
Cochran-Mantel-Haenszel
CRP
C-reactive protein
Ctrough
observed concentration at the end of a dosing interval
CV
coefficient of variation
ECG
electrocardiogram
eCRF
electronic case report form 
EOT
end of treatment
ET
early termination
FAS
full analysis set
FSH
follicle-stimulating hormone
hCG
human chorionic gonadotropin
HLT
high level term
HRQOL
health-related quality of life
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire 
INR
international normalized ratio
IRT
interactive response technology
IV
intravenous
LFT
liver function tests
LLN
lower limit of normal
LTFU
long-term follow-up
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
PGA
physician’s global assessment
PGx
pharmacogenomics
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PP
per protocol
PT
preferred term
PTE
pretreatment event
Q4W
every 4 weeks
Q8W
every 8 weeks
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
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SOC
System Organ Class
TEAE
treatment-emergent adverse events
TNF
tumor necrosis factor
VDZ
vedolizumab
UC
ulcerative colitis
ULN
upper limit of normal
WBC
white blood cell
WHODrug
World Health Organization Drug Dictionary
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Vedolizumab-4014
Page 8 of 43
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4.0
OBJECTIVES
4.1
Primary Objectives
To determine the effect of vedolizumab intravenous (IV) dose optimization on endoscopic 
mucosal healing compared with the standard vedolizumab IV dosing regimen at Week 30 in 
subjects with ulcerative colitis (UC) and high vedolizumab clearance, based on a predefined 
Week 5 serum vedolizumab concentration threshold (<50 μg/mL) and who are Week 6 
non-responders.
4.2
Secondary Objectives
To determine the effect of vedolizumab IV dose optimization on clinical response and remission 
compared with the standard vedolizumab IV dosing regimen at Week 30 in subjects with UC and 
high vedolizumab clearance, based on a predefined Week 5 serum vedolizumab concentration 
threshold (<50 μg/mL) and who are Week 6 non-responders.
4.3
Additional Objectives
Safety Objectives:

To evaluate the safety of administering higher induction doses of vedolizumab IV compared 
with the standard dosing regimen over the 30-week treatment period in subjects with UC and 
high vedolizumab clearance, based on a predefined Week 5 serum vedolizumab 
concentration threshold (<50 μg/mL) and who are Week 6 non-responders.
Additional Objectives:

Additional proteomic or cellular biomarker analyses that correlate with response may be 
performed in the future and reported separately.
4.4
Study Design
This is a phase 4, open-label, multicenter study to investigate the efficacy and safety of dose 
optimization of vedolizumab IV, compared with standard dosing of vedolizumab IV, over a 
30-week treatment period (ie, a 6-week Lead in Period followed by 24-week Randomized
Treatment Period). This study will enroll adult subjects with moderately to severely active UC 
who are eligible for treatment with vedolizumab IV. Approximately 250 subjects will be enrolled 
in order to approximate 100 non-responder subjects with high vedolizumab drug clearance.
The study is comprised of a 28-day Screening Period, a 6-week Lead-in Period, and a 24-week
Randomized Treatment Period, followed by an 18-week Follow-Up Safety Visit and a long-term 
follow-up (LTFU) safety survey by telephone at 6 months after the last dose of study medication. 
The study visits schedule and assessments will be completed per the schedule of study 
procedures in Table 4.a. A schematic of the study design is included as following Figure 4.a.
On Day 1 and Week 2 (Lead-in Period), all eligible subjects will receive vedolizumab IV 300 mg. 
At Week 5, serum vedolizumab concentration will be measured. At Week 6, subjects will be 
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Vedolizumab-4014
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17 March 2021
assessed for clinical response based on partial Mayo score (a reduction in partial Mayo score of 
≥2 points and ≥25% from Baseline (Day 1) with an accompanying decrease in rectal bleeding 
subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point).
Results of both Week 5 vedolizumab concentration and Week 6 clinical response will establish 
which of the following 2 treatment pathways a subject will follow at Week 6:

Pathway 1: Subjects who are non-responders based on partial Mayo score at Week 6 and who 
are assessed as having high vedolizumab clearance, based on a predefined Week 5 serum 
vedolizumab concentration threshold (<50 µg/mL) will proceed with randomization at 
Week 6 in a 1:1 ratio to receive either dose-optimized or standard vedolizumab IV therapy as 
described below.

Pathway 2: Subjects who respond at Week 6 or have levels above a predefined Week 5 serum 
vedolizumab concentration threshold (≥50 µg/mL) (Lead-in Failure) will not be randomized 
and will receive the Week 6 study dose (300 mg) and thereafter appropriate treatment per 
physician discretion. Following the last dose of study drug (Week 6), subjects will have the 
18-week Follow-Up Safety Visit and 6 month LTFU phone call. 
At Week 6, eligible subjects will be randomized 1:1 into the Standard Treatment arm or the Dose 
Optimized arm (ie, Pathway 1), stratified by tumour necrosis factor (TNF)-antagonist naïve or 
failure status and receive the following treatments: 
Vedolizumab IV Standard Treatment Arm: 
Vedolizumab IV 300 mg Q8W (Weeks 6, 14, and 22).
Vedolizumab IV Dose Optimized Arm: 
Week 6: Dose Assignments for Dose Optimization Arm
At Week 6, all subjects randomized to the Dose Optimization Arm will be assigned to either 
Regimen A or Regimen B (below) based on the subject’s Week 5 serum vedolizumab 
concentration. Subjects with serum vedolizumab concentration <50 µg/mL and ≥30 µg/mL 
will be assigned to Regimen A, and subjects with serum vedolizumab concentration 
<30 µg/mL will be assigned to Regimen B:
Regimen A: Vedolizumab IV 600 mg (Week 6) and 300 mg every 4 weeks (Q4W)
(Weeks 10, 14, 18, 22, and 26), OR
Regimen B: Vedolizumab IV 600 mg (Week 6) and 600 mg Q4W (Weeks 10, 14, 18, 22, 
and 26).
Week 14: Dose Optimization Arm 
At Week 14 and beyond, dosing will continue as previously scheduled unless the subject’s 
most recent preceding serum vedolizumab concentration is >90 µg/mL (eg, Week 13 
pharmacokinetic (PK) sampling prior to Week 14 dosing). In the event that steady-state 
Ctrough levels exceed safety exposure limits of 90 µg/mL, the next dose will be withheld and 
another PK sample will be taken 1 week prior to the next scheduled dose. If at the next 
scheduled dose the Ctrough is still >90 µg/mL, the next dose will be similarly held and the PK 
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Vedolizumab-4014
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Statistical Analysis Plan Final 1.0
17 March 2021
repeated 1 week prior to the next scheduled dose. Once Ctrough is ≤90 µg/mL, the subject will 
move to the next lowest dose. For example:
If subject was on 300 mg Q4W, then subject goes to next lower dose or 300 mg every 
8 weeks (Q8W) dose.
If subject was on 600 mg Q4W, then subject goes to next lower dose or 300 mg Q4W 
dose.
If subject was moved from 600 mg Q4W to 300 mg Q4W and subsequent 
Ctrough >90 µg/mL, then subject goes to next lowest dose (ie, 300 mg Q8W).
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Vedolizumab-4014
Page 11 of 43
Statistical Analysis Plan Final 1.0
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Figure 4.a
Schematic of Study Design
Conc=concentration, EOT=end of treatment, VDZ=vedolizumab. 
(a) On Day 1 and Week 2 (Lead-in Period), all eligible subjects will receive vedolizumab IV 300 mg.
(b) Subjects who respond at Week 6 (by partial Mayo score) will not be randomized and will receive the Week 6 
study drug dose and thereafter receive appropriate treatment per physician discretion. Following the last dose of 
study drug (Week 6), subjects will have the 18-week Follow-Up Safety Visit and 6 month LTFU telephone call.
(c) Subjects who are nonresponders at Week 6 and have levels above a predefined serum vedolizumab concentration 
threshold (≥50 µg/mL) at Week 5 (Lead-in Failures), will not be randomized and will receive the Week 6 study drug 
dose and thereafter receive appropriate treatment per physician discretion. Following the last dose of study drug 
(Week 6), subjects will have the 18-week Follow-Up Safety Visit and 6 month LTFU telephone call.
(d) At Week 14 and beyond, dosing will continue as previously scheduled unless the subject’s most recent preceding 
serum vedolizumab concentration is >90 µg/mL. The dose will be withheld and PK will be repeated 1 week prior to 
the next scheduled dose until Ctrough is ≤90 µg/mL. Once ≤90 µg/mL, the subject will move to the next lower dose.
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Vedolizumab-4014
Page 12 of 43
Statistical Analysis Plan Final 1.0
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CONFIDENTIAL
Table 4.a
The Schedule of Study Procedures
Screening
Lead-in (week)
Randomized Treatment Period (week)
Follow-up (c)
LTFU Phone 
Call (d)
Week
Day 1/
BL (a)
2
5
6 (b)
Decision
10
13
14
18
22 
(EOT 
Q8wk)
26 
(EOT 
Q4wk)
30
Final 
Visit/ET 
18 wks from 
EOT
6-months from
EOT 
Study Day
-28 to -1
1
15±3
36±3
43±3
71±3
92±3
99±3
127±5
155±5
183±5
211±5
Q8 281±7
Q4 309±7 
Q8 337±7
Q4 365±7
Visit Window (Days):
1
Days 
12-18
Days 
33-39
Days 40-46
Days 
68-74
Days 
89-95
Days 
96-102
Days 
122-132
Days 
150-160
Days 
178-188
Days 206-
216
Q8 Days 274-
288
Q4 Days 302-
316 
Q8 Days 330-344
Q4 Days 358-372
Visits that apply to Lead-in 
Failures
X
X
X
X
X
X
X
Visits that apply to Standard 
Arm 
X
X
X
X
X
X
X
X
X
X
Visits that apply to Dose 
Optimization Arm 
X
X
X
X
X
X
X
X 
X
X
X
X
X
X
Informed consent
X
Access IRT 
X
X
X
X
X
X (e)
X (e)
X (e)
X (e)
X
Lead in Period
inclusion/exclusion criteria 
X
X
Randomized Treatment Period 
inclusion criteria
X
Demographics/medical 
history/concurrent medical 
conditions
X
UC disease history
X
Medication history/Prior UC 
disease treatments
X
Footnotes are on last table page.
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Vedolizumab-4014
Page 13 of 43
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CONFIDENTIAL
Table 4.a
The Schedule of Study Procedures (continued)
Screening
Lead-in (week)
Randomized Treatment Period (week)
Follow-up (c)
LTFU Phone 
Call (d)
Week
Day 
1/
BL 
(a)
2
5
6 (b)
Decision
10
13
14
18
22 
(EOT 
Q8wk)
26 
(EOT 
Q4wk)
30
Final 
Visit/ET 
18 wks from 
EOT
6-months from
EOT 
Study Day
-28 to -1
1
15±3
36±3
43±3
71±3
92±3
99±3
127±5
155±5
183±5
211±5
Q8 281±7
Q4 309±7 
Q8 337±7
Q4 365±7
Visit Window (Days):
1
Days 
12-18
Days 
33-39
Days 40-
46
Days 
68-74
Days 
89-95
Days 
96-
102
Days 
122-132
Days 
150-160
Days 
178-
188
Days 206-
216
Q8 Days 274-
288
Q4 Days 302-
316 
Q8 Days 330-
344
Q4 Days 358-
372
Concomitant medications 
X
X
X
X
X
X
X
X
X
X
X
X
X
Collection of concomitant 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
Tuberculosis QuantiFERON or 
skin test (f)
X
Hepatitis, HIV
X
Physical examination
X
X
X
X
X
Vital signs (g)
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and height (g)
X
X
X
Flexible sigmoidoscopy (h)
X
X
Complete Mayo Score
X
X (i)
Partial Mayo Score
X
X
X
X
X
X
X
X
X (i)
Footnotes are on last table page.
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Vedolizumab-4014
Page 14 of 43
Statistical Analysis Plan Final 1.0
17 March 2021
CONFIDENTIAL
Table 4.a
The Schedule of Study Procedures (continued)
Screening
Lead-in (week)
Randomized Treatment Period (week)
Follow-up (c)
LTFU Phone 
Call (d)
Week
Day 1/
BL (a)
2
5
6 (b)
Decision
10
13
14
18
22 
(EOT 
Q8wk)
26 
(EOT 
Q4wk)
30
Final 
Visit/ET 
18 wks from 
EOT
6-months from
EOT 
Study Day
-28 to -1
1
15±3
36±3
43±3
71±3
92±3
99±3
127±5
155±5
183±5
211±5
Q8 281±7
Q4 309±7 
Q8 337±7
Q4 365±7
Visit Window (Days):
1
Days 
12-18
Days 
33-39
Days 40-
46
Days 
68-74
Days 
89-95
Days 96-
102
Days 
122-
132
Days 
150-160
Days 
178-188
Days 206-
216
Q8 Days 274-
288
Q4 Days 302-
316 
Q8 Days 330-344
Q4 Days 358-372
PK samples for vedolizumab (j)
X
X
X
X
X
X
X
X
X
X
X
X
Dose Regimen Assignment (k)
X
Vedolizumab (IV) lead-in 
period (m)
X
X
X
Vedolizumab (IV) 
randomization period (m)
X
X
X
X
X
X
Clinical laboratory testing
X
X
X
X
X
X
X
X
X
X
X
PT/INR (n)
X
Exploratory biomarker sample
X
Urinalysis 
X
X
CRP
X
X
X
X
X
PGx samples (o)
X
AVA testing (p)
X
X
X
X
X
X
Footnotes are on last table page.
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Page 15 of 43
Statistical Analysis Plan Final 1.0
17 March 2021
CONFIDENTIAL
Table 4.a
The Schedule of Study Procedures (continued)
Screening
Lead-in (week)
Randomized Treatment Period (week)
Follow-up (c)
LTFU Phone 
Call (d)
Week
Day 
1/
BL 
(a)
2
5
6 (b)
Decision
10
13
14
18
22 
(EOT 
Q8wk)
26 
(EOT 
Q4wk)
30
Final 
Visit/ET 
18 wks from 
EOT
6-months
from
EOT 
Study Day
-28 to -1
1
15±3
36±3
43±3
71±3
92±3
99±3
127±5
155±5
183±5
211±5
Q8 281±7
Q4 309±7 
Q8 337±7
Q4 365±7
Visit Window (Days):
1
Days 
12-18
Days 
33-39
Days 40-
46
Days 
68-74
Days 
89-95
Days 96-
102
Days 
122-
132
Days 
150-160
Days 
178-188
Days 206-
216
Q8 Days 274-
288
Q4 Days 302-
316 
Q8 Days 330-344
Q4 Days 358-372
Pregnancy test (serum and 
urine) (hCG) (q)
X
X
X
X
X
X
X
X
X
X
X
FSH (r)
X
ECG
X
PML checklist (s)
X
X
X
X
X
X
X
X
X
X
X
PML wallet card
X
X (t)
IBDQ
X
X
X
Patient diary
X
X
X
X
X (l)
X
X
X
X
X
X
X
Stool sample for C. difficile
Test 
X
Stool sample for fecal 
calprotectin (u)
X
X
X
X
PTE assessment (v)
X
X
AEs (w)
X
X
X
X
X
X
X
X
X
X
X
X
LTFU questionnaire via 
phone call 
X
BL=baseline, EOT=end of treatment.
(a) Assessments to be completed predose.
(b) Confirm Week 5 PK results before the Week 6 visit.
(c) 18 Week posttreatment follow-up is Week 40 (Q8W) and Week 44 (Q4W). If a subject in the Dose Optimization Arm dose is lowered to 300 mg Q8W dosing and the last dose 
is week 26, they should follow the Q4W schedule and windows for the 2 Follow-up Visits.
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CONFIDENTIAL
(d) LTFU telephone call to be performed 6 months after last dose of study drug for all subjects enrolled in the study and receiving at least 1 dose of study medication. This is 
expected to occur for Lead-in failures no later than Week 32 and for Randomized subjects at Week 48 for a Q8W regimen or at Week 52 for Q4W regimen. If a subject in the Dose 
Optimization Arm dose is lowered to 300 mg Q8W dosing and the last dose is week 26, they should follow the Q4W schedule and windows for the 2 Follow-up Visits.
(e) In Dose Optimization Arm, dosing may be withheld or lowered based on prior serum vedolizumab concentration. If subject switches to the 300 mg Q8W dosing due to high 
serum vedolizumab concentration, the IRT only needs to be called on dose dispensing visits.
(f) Assessed by QuantiFERON test at Screening or a TB skin test reaction within 30 days of Screening.
(g) Vital signs will include body temperature, respiratory rate, blood pressure, and pulse (bpm). On dosing days, vital signs are taken predose. Height will be collected only at 
Screening Visit. 
(h) Biopsies to be collected at Screening and Week 30. 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 performed by the central reader. All biopsy samples collected per protocol will be centrally stored and analyzed 
at the end of the study. Although it is permissible for the investigator to take additional biopsy samples as deemed necessary for standard of care management of the patient during 
the protocol required colonoscopy/sigmoidoscopy, these will be considered as occurring outside the protocol. Such collection, handling and analyses of the additional samples will 
be and remain the responsibility of the investigator. 
(i) Partial Mayo score to be performed if flexible sigmoidoscopy is not performed at this visit.
(j) PK samples for serum vedolizumab on dosing days must be collected predose on the same date as the infusions. If the samples are not collected prior to vedolizumab dosing or 
not collected on the same day as the infusion, it is a significant deviation. PK samples are also collected on nondosing visits per Table 4.a.
(k) For subjects randomized to the Dose Optimization Arm, dosing regimens will be assigned by the IRT based on the Week 5 serum vedolizumab concentrations. 
(l) Not applicable for Lead-in Failures. No redistribution of patient diaries to Lead-in failures.
(m) All subjects will receive treatment with vedolizumab IV per label through Week 2. Nonresponders at Week 6 with serum vedolizumab concentration <50 µg/mL based on 
Week 5 PK collection will be randomized at Week 6 in a 1:1 ratio to 1 of 2 treatment arms as follows: vedolizumab IV Standard Dosing Arm or Dose Optimization Arm. At Week 
6, all subjects who respond or are nonresponders and are above a predefined vedolizumab concentration threshold (≥50 µg/mL) at Week 5 will not be eligible to be randomized 
into the study, and will receive the Week 6 study drug infusion and thereafter continue to receive appropriate treatment per physician’s discretion.
(n) PT/INR to be collected at Baseline and then only if liver function tests are elevated at subsequent visits.
(o) Blood samples (for deoxyribonucleic acid and ribonucleic acid analysis) will be collected on Day 1. 
(p) On dosing days, blood samples must be taken predose. 
(q) Women of childbearing potential only. Serum pregnancy test at Screening only; urine pregnancy test should be done thereafter, including before every IV infusion.
(r) FSH level will be obtained for female subjects at Screening if they are postmenopausal by history (eg, defined as at least 1 year since last regular menses with an FSH >40 IU/L 
or at least 5 years since last regular menses, confirmed before any study medication is implemented) and not surgically sterile. The FSH result must be >40 IU/mL for the subject 
to be permitted not to use adequate contraception.
(s) PML checklist must be administered at all visits in Table 4.a. and on dosing days, prior to vedolizumab dosing.
(t) Long-term Follow-up Wallet card will be given to subjects at the last clinical visit.
(u) Stool sample for fecal calprotectin should be the first bowel movement on the day of collection. 
(v) PTEs will be captured immediately following the signing of the informed consent at the Screening Visit, up until the first dose of study drug. 
(w) Collection of AEs will begin following first dose of study drug and will continue through Wk 40 (for Q8W)/Final Safety Visit or Wk 44 (for Q4W)/Final Safety Visit. 
Collection of all SAEs will begin once the informed consent is signed and will continue through Week 40 (for Q8W)/Final Safety Visit or Week 44 (for Q4W)/Final Safety Visit.
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
Proportion of subjects achieving endoscopic mucosal healing (defined as Mayo endoscopic 
subscore from central reader ≤1 point, modified so that a score of 1 does not include friability) at 
Week 30.
5.2
Secondary Endpoints
The secondary endpoints are:

Proportion of subjects achieving clinical remission, where clinical remission is defined as a 
complete Mayo score of ≤2 points and no individual subscore >1 point at Week 30.

Proportion of subjects achieving clinical response (based on complete Mayo score), where 
clinical response is defined as a reduction in complete Mayo score of ≥3 points and ≥30% 
from Baseline with an accompanying decrease in rectal bleeding subscore of ≥1 point or 
absolute rectal bleeding subscore of ≤1 point, at Week 30.

Proportion of subjects achieving clinical response (based on partial Mayo score), which is 
defined as a reduction in partial Mayo score of ≥2 points and ≥25% from Baseline with an 
accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding 
subscore of ≤1 point, at Week 14.

Proportion of subjects using oral corticosteroids at Baseline who have discontinued 
corticosteroids and are in clinical remission, at Week 30.

Proportion of subjects achieving durable clinical response, which is defined as clinical 
response based on partial Mayo score at Weeks 14 and 30.
5.3
Additional Endpoints
The exploratory/additional endpoints include:

Change in C-reactive protein (CRP) levels from Baseline to Week 6, 14, and 30.

Change in fecal calprotectin concentrations from Baseline to Weeks 6, 14, and 30.

Proportion of subjects with positive antivedolizumab antibodies (AVAs) and positive 
neutralizing AVAs.

Proportion of subjects with Ctrough values that fall below the threshold targets of 18.4 μg/mL 
at Week 14 and 12.7 μg/mL at Week 30.

Change from Baseline to Week 30 in health-related quality of life (HRQOL) based on 
inflammatory bowel disease questionnaire (IBDQ) scores.

Proportion of subjects achieving a stool frequency subscore = 0; rectal bleeding subscore = 0 
and endoscopy subscore from central reader = 0 or 1 (modified so that a score of 1 does not 
include friability).
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
Proportion of subjects achieving a stool frequency subscore = 0 or 1 and a prespecified 
specific change of 1 or more from Baseline and rectal bleeding subscore = 0; and endoscopy 
subscore from central reader = 0 or 1 (modified so that a score of 1 does not include 
friability).
5.4
Safety Endpoints:

Adverse events (AEs).

Adverse events of special interest (AESIs) (including serious infections and opportunistic 
infection such as progressive multifocal leukoencephalopathy (PML), liver injury, 
malignancies, infusion-related or injection site reactions or systemic reactions and 
hypersensitivity).

Serious adverse events (SAEs).

Vital signs.

Results of standard laboratory tests (clinical chemistry, hematology, coagulation, urinalysis).
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6.0
DETERMINATION OF SAMPLE SIZE
The sample size was based on an estimate of precision and not on statistical power 
considerations. A total sample size of approximately 250 subjects enrolled to achieve 
approximately 100 subjects randomized at Week 6, including 50 subjects per treatment group, 
will be sufficient to provide 95% confidence intervals for endoscopic mucosal healing rates with 
a half width no wider than +/-13.9%. In addition, the maximum width of the 95% confidence 
intervals (2-sided) for the difference in endoscopic mucosal healing rates between the 2 groups 
will be no wider than +/-19.6%. If there is a high rate of patient drop out from the study, 
additional patients may be added.
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.2, or higher.
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.05 significance level unless otherwise stated. P-values will be rounded to 
3 decimal places prior to assessment of statistical significance. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated. The denominator 
for the proportion will be based on the number of subjects who provided non-missing responses 
for the categorical variable. For continuous variables, the numbers of subjects with non-missing 
values, mean, median, SD, minimum, and maximum values will be tabulated. 
7.1.1
Study Definitions
Baseline values are defined as the last observed value before the first dose of study medication.
Other study definitions are described in Table 7.a.
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Table 7.a
Study Definitions
Term
Definition
High clearance
Week 5 serum vedolizumab concentration <50 µg/mL
Very high clearance
Week 5 serum vedolizumab concentration <30 µg/mL
Complete Mayo score
A composite index of 4 disease activity variables (stool 
frequency, rectal bleeding, findings on sigmoidoscopy from 
central reader, and physician’s global assessment), each scored 
on a scale from 0 to 3 (higher scores indicate greater disease 
activity).
Partial Mayo score
A composite index of 3 disease activity variables (stool 
frequency, rectal bleeding, and physician’s global assessment), 
each scored on a scale from 0 to 3 (higher scores indicate greater 
disease activity). Partial Mayo score is calculated analogously to 
the complete Mayo score but excludes the sigmoidoscopy 
subscore.
Clinical remission by complete Mayo score
A complete Mayo score of ≤2 points and no individual subscore 
>1 point.
Clinical response by complete Mayo score
A reduction in complete Mayo score of ≥3 points and ≥30% 
from Baseline with an accompanying decrease in rectal bleeding 
subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 
point.
Clinical response by partial Mayo score
A reduction in partial Mayo score of ≥2 points and ≥25% from 
Baseline (Day 1) with an accompanying decrease in rectal 
bleeding subscore of ≥1 point or absolute rectal bleeding 
subscore of ≤1 point
Corticosteroid-free remission
Subjects using oral corticosteroids at Baseline (Day 1) who have 
discontinued oral corticosteroids and are in clinical remission at 
Week 30.
Durable clinical response
A clinical response (based on partial Mayo score), which is 
defined as a reduction in partial Mayo score of ≥2 points and 
≥25% from Baseline with an accompanying decrease in rectal 
bleeding subscore of ≥1 point or absolute rectal bleeding 
subscore of ≤1 point at Weeks 14 and 30.
Endoscopic mucosal healing
A Mayo endoscopic subscore from central reader of ≤1 point
(modified so that a score of 1 does not include friability).
Vedolizumab IV standard dosing
Vedolizumab IV 300 mg infused intravenously at Weeks 0, 2, 
and 6 and then once Q8W thereafter.
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the study 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.
The study day prior to the first dose of study drug will be calculated as: 
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Date of assessment/event – date of first dose of study drug. 
The study day on or after the first dose of study drug will be calculated as: 
Date of assessment/event – date of first dose of study drug + 1.
7.1.3
Definition of Study Visit Windows
A windowing convention will be used to determine the analysis value for a given study visit 
(excluding follow-up) for observed data analyses. The visit windows are defined as follows:
Table 7.b
Visit windows for complete Mayo score and flexible sigmoidoscopy
Visit
Target Day
Day Range
Baseline
1
≤1
Week 30
211
≥2
Table 7.c
Visit windows for partial Mayo score
Visit
Target Day
Day Range
Baseline
1
≤1
Week 2
15
2-28
Week 6
43
29 – 56
Week 10 a
71
57 – 84
Week 14
99
85– 112
Week 18 a
127
113 – 140
Week 22
155
141 – 168
Week 26 a
183
169 – 196
Week 30
211
≥197
a: Not a scheduled visit for Standard Arm
Table 7.d
Visit windows for other endpoints
Visit
Target Day
IBDQ
CRP, Fecal Calprotectin
Baseline
1
≤1
≤1
Week 6
43
NA
2 – 70
Week 14
99
2 – 154
71 – 154
Week 30
211
≥155
≥155
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Table 7.e
Visit windows for vital signs and safety lab parameters
Visit
Target Day
Vital Signs
Hematology, 
Chemistry
Urinalysis
Baseline
1
≤1
≤1
≤1
Week 2
15
2 - 25
2 - 28
NA
Week 5
36
26 - 39
NA
NA
Week 6
43
40 - 56
29 - 56
NA
Week 10 a
71
57 - 81
57 - 84
NA
Week 13 a
92
82 - 95
NA
NA
Week 14
99
96 - 112
85 - 112
NA
Week 18 a
127
113 - 140
113 - 140
NA
Week 22
155
141 - 168
141 - 168
NA
Week 26 a
183
169 - 196
169 - 196
NA
Week 30
211
197 - 245
197 - 245
≥2
a: Not a scheduled visit for Standard Arm
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.
For 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.
7.1.4
Definition of Study Periods
The study periods are defined as follows:
Lead-in period = Date of first dose of study drug to (i) date of last dose of study drug for lead-in 
failures or (ii) date of first randomised dose of study drug for randomized 
subjects
Lead-in failure follow-up period = Date of last dose of study drug for lead-in failures to end of 
study
Post-randomization period = Date of first dose of randomized study drug to end of study
7.1.5
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):
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–
First study medication date
–
Consent date (for SAEs only)
2. If an onset date is incomplete, the derived onset date will be calculated as follows:
–
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 as follows:
–
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 onset date occurs after the database lock date, the imputed AE onset 
date will be imputed as the database lock date.
Missing dates for hospitalizations, colectomies and UC procedures will follow the rules defined 
for Adverse Events.
7.1.6
Conventions for Missing Concomitant Medication Dates
Start and stop dates for all concomitant medications are collected on the electronic case report 
form (eCRF). However, in case of missing or partial information in these dates, the following 
rules will be used:
If the start date is missing or partial:

If the day is missing, the start day will be the first day of the month.
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
If the month is missing, the start month will be the month corresponding to 90 days prior to 
the first study medication date.

If the year is missing, the start year will be the year of the entry visit (or consent date, for 
those missing entry visit).

If the entire date is missing, the start date will be the date of first study drug administration.
If the stop date is missing, partial or “continuing”:

If the day is missing, the stop day will be the last day of the month reported.

If the month is missing, the stop month will be the month during which the last assessment 
occurred.

If the year or the entire date is missing or if the medication is “continuing”, the stop year will 
be the year in which the last assessment occurred.
7.1.7
Convention for Calculation of Mayo Scores
The Mayo scoring system is a composite index of 4 disease activity variables:

Stool frequency.

Rectal bleeding.

Findings on sigmoidoscopy.

Physician’s global assessment.
Each subscore is scored individually on an integer scale of 0 to 3, with higher scores indicating
greater disease activity. The sigmoidoscopy is assessed by a central reader as well as the 
Investigator and an important difference to note is that a subscore of 1 from the central reader 
excludes friability. The Partial Mayo score is calculated analogously but excludes the 
sigmoidoscopy subscore.
Mayo scores will be derived from first principles and will follow the visit windows defined in
Section 7.1.3. All subscores should be integers; apply rounding as final subscores are created and 
prior to calculation of total score.
1. Identify the Mayo calculation date, ie, date of physician’s global assessment (PGA) on Mayo 
eCRF and allocate to an analysis window.
2. Identify the PGA subscore and the sigmoidoscopy subscore from the central reader data
within the analysis window.
3. Calculate rectal bleeding subscore and stool frequency subscore:
a) Select all diary data from 14 days prior to the date of PGA.
b) Merge in sigmoidoscopy dates and set diary data one day prior, on the day and one day 
after the sigmoidoscopy to missing.
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c) Sum the 7 most recent non-missing results and divide by 7. If less than 7 non-missing 
results remain:
i.
If at least 3 non-missing results remain then sum the available non-missing 
results and divide by the number of available data points.
ii.
If less than 3 non-missing results remain then a subscore cannot be calculated. 
4. 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.
7.1.8
Methods for Handling of Missing Efficacy Data
Missing efficacy data will be handled as follows:

If the sigmoidoscopy subscore from the central reader is missing then the subscore from the 
Investigator will be used as a replacement. 

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.
7.1.9
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 
inflammatory bowel disease (IBD) and 7 indicates better IBD.
Table 7.f
IBDQ domain calculations
IBDQ Subdomain
Calculation
IBDQ Bowel symptoms score
Sum of (Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26 and 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 subdomain above, if 50% or less of the component scores are missing at a visit, the mean of the 
available component scores will be imputed as the value for the missing component scores. If more than 50% of the 
component scores are missing for the subdomain, the imputed value will be set to missing.
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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 subdomain scores are missing at 
a visit, the imputed value for total score will be set to missing.
7.2
Analysis Sets
The Randomized Set will include all randomized subjects who were enrolled in the treatment 
period. 
The Full Analysis Set (FAS) will include all randomized subjects who were enrolled in the 
treatment period and received at least 1 dose of the study drug post-randomization. Patients in 
this population set will be analyzed according to the treatment they were randomized to receive, 
regardless of any errors of dosing.
The Per-Protocol (PP) Set is a subset of the FAS and consists of all subjects who do not violate 
the protocol in a way that would impact the primary efficacy results. All significant protocol 
deviations will be reviewed manually to decide which subjects will be excluded prior to database 
lock. The hierarchy of reasons for exclusion is as follows: inclusion and exclusion criteria 
violations (including randomization inclusion and exclusion criteria), study medication dosing 
errors, receiving forbidden concomitant medications such as oral corticosteroids without tapering
and refusal for final endoscopy. 
The PK Set will include all randomized subjects who receive at least 1 post-randomization dose 
of study drug (ie, in the Randomized Treatment Period) and have at least 1 measurable
post-randomization concentration of vedolizumab.
The Safety Analysis Set will include all subjects who were enrolled and received at least 1 dose 
of study medication. 
7.3
Disposition of Subjects
Subject disposition will be summarized and provided in listings. The following summaries will 
be produced:

Study Information: Including 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: Including the total number of screen failures, descriptive 
statistics for age, counts and percentages for gender, ethnicity, race and the primary reason 
for screen failure.

Summary of Eligibility for Randomization after Lead-in Period: Including reason for lead-in 
failure.
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
Number of Subjects Enrolled by Site: Performed by country and site.

Number of Subjects Randomized by Site and Treatment Group: Performed by the 
randomization stratification factor TNF-antagonist naïve or failure (according to interactive 
response technology [IRT] data), as well as by country and site.

Disposition of Subjects: Including the number of 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 study visits along with 
the primary reason for discontinuation of study visits.

Significant Protocol Deviations: As captured on the eCRF.

Reasons for Exclusion from PP Set.

Analysis Sets: According to Section 7.2.
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for the Safety Analysis Set by 
treatment group (Lead-in VDZ Only, Randomized VDZ including Standard VDZ Dosing, VDZ 
Dose Optimization (Regimen A and B separately as well as combined) and Total).
Demographic and baseline characteristics data include age (continuous and categorical [<65, ≥65 
and <35, ≥35]), gender, ethnicity, race, height, weight, body mass index, smoking classification 
and female reproductive status. Baseline UC characteristics data are described in Table 7.g.
Categorical variables will be summarized using frequencies and percentages. Continuous 
variables will be summarized using mean, SD, median, maximum and minimum. 
Table 7.g
Baseline Characteristics
Characteristics
Summarized as
Categories
Duration of Ulcerative Colitis
Categorical and Continuous
<1 years
1 - <3 years
3 - <7 years
≥7 years
Any acute exacerbations within the past 12 
months
Categorical
Yes/No
Number of Acute Exacerbations 
Continuous
Any hospitalizations for ulcerative colitis 
within the past 12 months
Categorical
Yes/No
Number of Hospitalizations
Continuous
Colonoscopy within the last 12 months
Categorical
Yes/No
Disease location
Categorical
Proctosigmoiditis
Left Sided Colitis
Extensive Colitis
Pancolitis
Surgery for ulcerative colitis
Categorical
Yes/No
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Characteristics
Summarized as
Categories
Number of surgeries
Continuous
History of Extraintestinal Manifestations
Categorical
Yes/No
Extraintestinal Manifestations
Categorical
Arthritis/Arthralgia
Iritis/Uveitis
Erythema Nodosum
Pyoderma Gangrenosum
Aphthous Stomatitis
Abscess
Fever above 38oC during the past 
week
Other
Number of weeks of corticosteroid use over the 
last 12 months
Continuous
Baseline Disease Activity assessed by complete 
Mayo Score
Categorical and Continuous
Mild <6 
Moderate = 6,7,8 
Severe= 9,10,11,12
Baseline endoscopic subscore
Categorical 
Normal or inactive disease = 0
Mild disease = 1*
Moderate disease = 2
Severe disease = 3
Baseline Partial Mayo Score
Categorical and Continuous
Mild = 2,3,4
Moderate = 5,6
Severe = 7,8,9
Baseline stool frequency subscore
Categorical 
Normal no. of stools for this patient= 0
1 to 2 stools more than normal = 1
3 to 4 stools more than normal = 2
5 or more stools more than normal = 3
Baseline rectal bleeding subscore
Categorical 
No blood seen = 0
Streaks of blood with stool less than 
half the time = 1
Obvious blood with stool most of the
time = 2
Blood alone passes = 3
Baseline physician’s global assessment
Categorical 
Normal = 0
Mild disease = 1
Moderate disease = 2
Severe disease = 3
Baseline Fecal Calprotectin
Categorical and Continuous
≤250 μg/g 
>250 to ≤500 μg/g 
>500 μg/g
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Characteristics
Summarized as
Categories
Baseline CRP (mg/dL)
Continuous
TNF-antagonist status (IRT)
Categorical
Naïve, Failure (according to IRT for 
randomized subjects only)
TNF-antagonist status (eCRF)
Categorical
Naïve, Failure, Exposed not failed
(according to prior UC treatment 
eCRF – naïve: no biologics recorded; 
failure: a biologic discontinued due to 
inadequate response, loss of response 
or intolerance; exposed not failed: a 
biologic discontinued due to other 
reasons)
* excludes friability, per FDA draft guidance [1].
7.5
Medical History and Concurrent Medical Conditions
Medical history refers to the significant conditions/diseases that stopped at or prior to signing of 
informed consent. Concurrent medical conditions are those significant ongoing 
conditions/diseases present at signing of informed consent. All medical history and concurrent 
medical conditions will be summarized and listed for the Safety Analysis Set by treatment group 
(Lead-in VDZ Only, Randomized VDZ including Standard VDZ Dosing, VDZ Dose 
Optimization (Regimen A and B separately as well as combined) and Total).
Medical history and concurrent medical conditions will be coded using the latest version of 
MedDRA and will be summarized in tables using System Organ Class (SOC) and MedDRA 
preferred term (PT). The tables will include numbers and percentages of subjects and will be 
sorted in alphabetical order by SOC and descending frequency of PT. A subject will only be 
counted once within a particular class even if he/she has multiple conditions/symptoms. 
7.6
Medication History and Concomitant Medications
Medication history, prior UC medication history and concomitant medications are defined as 
follows:

Medication history is defined as medication that the subjects stopped taking within 30 days 
prior to signing of informed consent (ie, stop date <informed consent date). 

Prior UC medication history is defined as prior medications used for the treatment of UC
stopped at or prior to signing informed consent.

Concomitant medication is defined as medication that the subjects continued taking or took 
from signing of informed consent through end of study:
–
Concomitant medication that started and stopped prior to baseline (ie, stop date 
≥informed consent date, and stop date ≤first dose date).
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–
Concomitant medication that started prior to and was ongoing at baseline or that started 
after baseline but prior to follow-up (ie, start date ≤last dose date, and stop date >first 
dose date.
–
Concomitant medication that started during the 18 week follow-up period (ie, start date 
>last dose date)
If start date and stop date are missing, medication will be assumed to occur both prior and 
concomitantly.
Medication history, prior UC medication history and concomitant medications will be coded 
using the latest version of WHODrug and summarized by giving the number and percentage of 
subjects by PT within each therapeutic class, with therapeutic class and medications within each 
class sorted in alphabetical order. If a subject reports taking 2 drugs belonging to the same class, 
he/she will only be counted once within that class. 
Concomitant procedures are defined as UC-related events including abscess drainage, bowel 
resection, colectomy, fistulotomy, MRI, CT scan or colonoscopy not scheduled in the protocol, 
occurring from first dose to Follow-Up Visit. Concomitant procedures will not be coded. The 
number of patients with each procedure and the number of procedures will be summarized 
descriptively.
Summaries of medication history, prior UC medication history, concomitant medication and 
concomitant procedures will be based on the Safety Analysis Set and summarized by treatment
group (Lead-in VDZ Only, Randomized VDZ including Standard VDZ Dosing, VDZ Dose 
Optimization (Regimen A and B separately as well as combined) and Total). All data will be 
presented in listings.
7.7
Study Drug Exposure and Compliance
The summary of study drug exposure will be based on the Safety Analysis Set by treatment 
group (Lead-in VDZ Only, Randomized VDZ including Standard VDZ Dosing, VDZ Dose 
Optimization (Regimen A and B separately as well as combined) and Total). 
Exposure will be presented as the frequency and percentage of subjects who received complete
infusions. A subject has received complete infusion if the total amount was infused as per data
collected in eCRF.
Duration of exposure will be calculated as:
(date of last dose – date of first dose) + 1 + approximately 5 times half-life of vedolizumab, 
126 days (18 weeks)
It will be summarized as a continuous variable and in addition, there will be a categorical 
summary which will not have the addition of 18 weeks which will reflect the study design more 
closely. For Standard VDZ Dosing, duration of exposure will be summarized in the following 
categories: <6 Weeks, 6–<14 Weeks, 14–<22 Weeks, and ≥22 Weeks. For VDZ Dose 
Optimization, duration of exposure will be summarized in the following categories: <6 Weeks, 
6–<10 Weeks, 10–<14 Weeks, 14–<18 Weeks, 18–<22 Weeks, 22–<26 Weeks and ≥26 Weeks. 
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Since all doses will be administered at in-clinic visits compliance will not be presented. All study 
drug administration and accountability data will be listed by site and subject number. The 
following variables will be listed: subject number, treatment, dose dates and times, dose
interruption dates and times (if applicable), and completion status of infusion and reason for
incomplete infusion.
7.8
Efficacy Analysis
All efficacy analyses will be based on the FAS and will present Standard VDZ Dosing vs VDZ 
Dose Optimization (Regimen A and B separately as well as combined).
All proportion-based primary, secondary and additional efficacy endpoints will be summarized 
by presenting the point estimate and 95% confidence intervals (based on Clopper-Pearson 
method) for the proportion by treatment group. The difference in proportions between treatment 
groups along with the 95% two-sided confidence interval will be presented. The confidence 
intervals for difference in proportions with numerators ≤5 are from exact methods, otherwise 
from the normal approximation. 
All subjects with missing data for determination of binary endpoint status will be considered as a 
value of ‘NO’ in the analysis.
A percentage bar chart for each proportion-based efficacy endpoint by treatment group will be 
provided. The listings corresponding to efficacy analyses will also be provided.
7.8.1
Primary Efficacy Endpoint(s)
The primary endpoint is the proportion of subjects achieving endoscopic mucosal healing 
(defined as Mayo endoscopic subscore from central reader ≤1 point, modified so that a score of 
1 does not include friability) at Week 30 to compare vedolizumab IV dose optimization with 
standard vedolizumab IV dosing regimen. 
The primary analysis on the primary endpoint will be based on a logistic regression model.
Endoscopic mucosal healing is the response variable and treatment and randomization 
stratification factor TNF antagonist status (naïve, failure; according to IRT data) are factors and
baseline complete Mayo score and natural logarithm of trough concentration at Week 6, are 
covariates in the model. The logistic regression model will be evaluated using the 
test at a 5% 
level of significance. If the primary logistic model does not converge, an alternative simple 
logistic model for mucosal healing will be used with treatment as a factor and no other covariates 
will be used. The summary will display the number and percent of subjects achieving endoscopic 
mucosal healing along with its 95% confidence interval by treatment group, the absolute 
treatment difference along with its 95% two-sided confidence interval, the odds ratio along with 
its 95% confidence interval and the 
p-value from the logistic regression.
The secondary analysis on the primary endpoint will be based on the Cochran-Mantel-Haenszel 
(CMH) test stratified by TNF antagonist status (naïve, failure). The CMH chi-square test will be 
performed at a 5% significance level. The summary will display the number and percent of 
subjects achieving mucosal healing and not achieving mucosal healing (with and without the 
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non-responder missing data imputation) along with the 95% confidence intervals by treatment 
group, the absolute treatment difference along with the 95% two-sided confidence interval, the 
adjusted treatment difference (risk difference) along with the 95% two-sided confidence interval 
and p-value from the CMH chi-square test. 
Both the primary and secondary analyses will also be performed on the PP Set and on observed 
cases (FAS subset to those with a Week 30 sigmoidoscopy).
A sensitivity analysis will be performed to assess endoscopic mucosal healing as assessed by the 
Investigator rather than the central reader. All analyses described above will be repeated.
7.8.2
Secondary Efficacy Endpoint(s)
The secondary endpoints are:

Proportion of subjects achieving clinical remission, where clinical remission is defined as a 
complete Mayo score of ≤2 points and no individual subscore >1 point at Week 30.

Proportion of subjects achieving clinical response, where clinical response is defined as a
reduction in complete Mayo score of ≥3 points and ≥30% from Baseline with an 
accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding 
subscore of ≤1 point, at Week 30.

Proportion of subjects achieving clinical response (based on partial Mayo score), which is 
defined as a reduction in partial Mayo score of ≥2 points and ≥25% from Baseline with an 
accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding 
subscore of ≤1 point, at Week 14.

Proportion of subjects using oral corticosteroids at Baseline who have discontinued 
corticosteroids and are in clinical remission, at Week 30.

Proportion of subjects achieving durable clinical response, which is defined as clinical 
response based on partial Mayo score at Weeks 14 and 30.
The secondary efficacy will be analyzed in the same fashion as the secondary analysis on the
primary endpoint.
All analyses will be based on the FAS, with the exception of corticosteroid-free remission which 
will be based on the subset of the FAS who are taking concomitant oral corticosteroids at 
Baseline.
7.8.3
Additional Efficacy Endpoint(s)
The additional efficacy endpoints include:

Change in CRP levels from Baseline to Week 6, 14, and 30.

Change in fecal calprotectin concentrations from Baseline to Weeks 6, 14, and 30.

Proportion of subjects achieving a stool frequency subscore = 0; rectal bleeding subscore = 0 
and endoscopy subscore from central reader = 0 or 1 (modified so that a score of 1 does not 
include friability).
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
Proportion of subjects achieving a stool frequency subscore = 0 or 1 and a prespecified 
specific change of 1 or more from Baseline and rectal bleeding subscore = 0; and endoscopy 
subscore from central reader = 0 or 1 (modified so that a score of 1 does not include 
friability).

Change in partial Mayo score from Baseline.
All proportion-based additional efficacy endpoints will be analyzed in the same fashion as the 
secondary analysis on the primary endpoint.
The additional efficacy endpoints of change from Baseline in CRP, fecal calprotectin and partial 
Mayo score will be summarized descriptively by time point and treatment group. Additionally, 
for change from Baseline in CRP and fecal calprotectin a mixed model repeated measures 
analysis with treatment, TNF antagonist status, visit, treatment by visit as fixed effect and its 
baseline value as a covariate will be performed. An unstructured covariance matrix is assumed. 
The least square mean, p-value and 2-sided 95% confidence interval of treatment difference will 
be provided.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
PK analyses will be performed on the PK Set by treatment (Total, Standard VDZ Dosing, VDZ 
Dose Optimization Regimen A, VDZ Dose Optimization Regimen B). Total will only be 
displayed up to and including Week 6 while all patients receive the same VDZ dose and regimen.
7.9.1
Pharmacokinetic Analysis
Measured serum vedolizumab concentrations will be summarized by time and treatment using 
descriptive statistics. Individual serum concentration versus time data will be presented in a data 
listing.
Ctrough, trough serum vedolizumab concentrations (measured concentration at the end of a dosing 
interval at steady state), will be derived directly before next administration. Ctrough will be 
summarized using descriptive statistics (number of non-missing values, mean, SD, %CV, median, 
minimum, and maximum).
The additional endpoint, the proportion of subjects with Ctrough below the threshold target of
18.4 μg/mL at Week 14 and 12.7 μg/mL at Week 30, will be presented by treatment group.
All PK analyses described above will be repeated excluding any PK samples taken post-dose and 
those from follow-up visits. All PK data and significant protocol deviations related to PK will be 
manually reviewed and any data points to be excluded will be documented prior to database lock. 
Further analysis will be performed as deemed necessary and will not be reported in the clinical 
study report. These analyses will be part of a separate report.
7.9.2
Pharmacodynamic Analysis
Additional proteomic or cellular biomarker analyses that correlate with response may be 
performed in the future and reported separately.
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7.10
Other Outcomes
The following additional endpoints will be analyzed on the FAS by treatment group (Standard 
VDZ Dosing, VDZ Dose Optimization (Regimen A and Regimen B separately as well as 
combined)). 
Change from Baseline in IBDQ total score and IBDQ domain scores will be summarized 
descriptively by time point and treatment group.
The proportion of subjects with positive AVA (transient and persistent) and the proportion of 
subjects with positive neutralizing AVA during the study will be summarized by treatment group. 
The impact of AVA on PK, efficacy, and safety may be examined.
A positive AVA subject is defined as a subject who has at least 1 positive AVA result in any 
postbaseline sample, and is further categorized as:

Transiently positive: defined as subjects with confirmed positive AVA in 1 sample at a 
postdose visit.

Persistently positive: defined as subjects with confirmed positive AVA in 2 or more 
consecutive positive AVA samples at postdose visits.
7.11
Safety Analysis
Safety is assessed by AEs, SAEs, AESIs, vital signs and results of standard laboratory tests 
(clinical chemistry, hematology, coagulation, urinalysis).
All safety analyses will be performed using the Safety Analysis Set by study period (Lead-in, 
Lead-in failure follow-up, Post-randomization, Total) and for the post-randomization period by 
treatment group (Standard VDZ Dosing, VDZ Dose Optimization (Regimen A and B separately 
as well as combined)).
7.11.1
Adverse Events
A TEAE is defined as an AE with an onset that occurs after receiving study drug (AE start date 
≥first dose date) and no more than 18 weeks/126 days after the last dose of study drug (AE start 
date – last dose date ≤126). All AEs will be coded using the latest version of MedDRA. At the 
AE level, the summary tables will present the number of subjects reporting each of these 
MedDRA events, ie, the number of subjects reporting 1 or more events that map to the given 
MedDRA term. At the SOC level, the summary tables will present the number of subjects 
reporting 1 or more events that map to the given SOC. That is, the number of subjects reported at 
the SOC level will be less than or equal to the sum of the subject counts across all AEs within 
that SOC.
For the summary of TEAEs by SOC, PT and maximum intensity, if a subject experiences more 
than 1 episode of a particular coded AE, the subject will be counted only once by the maximum 
intensity of the episode (PT) per period. Similarly, if a subject has more than 1 adverse event 
within a SOC, the subject will be counted only once by the maximum intensity in that SOC per 
period. AEs with missing severity will be classified as having the highest severity.
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TEAEs classified in the eCRF as possibly or probably related to the study medication will also 
be summarized by PT and SOC. If a subject experiences more than 1 episode of a particular 
coded AE, the subject will be counted only once by the most related report for the PT per period. 
Similarly, if a subject has more than 1 AE within a SOC, the subject will be counted only once 
by the most related report in that SOC per period. AEs with missing relationship will be 
classified as having the highest relationship to study drug.
SOCs will be sorted in alphabetical order. Within a SOC, adverse events will be sorted in 
descending order of total number of subjects with the PT. 
All AEs, not just those which are treatment-emergent, will be presented in listings. Special 
listings for TEAEs leading to study discontinuation, SAEs and deaths will also be presented.
7.11.1.1
Treatment-Emergent Adverse Events
An overview of TEAEs will be provided by period and treatment group summarizing relatedness, 
severity, those leading to discontinuation, SAEs including relatedness and those leading to 
discontinuation and deaths. The number of events will be displayed as well and the number and 
percentage of patients experiencing the event. 
The number and percentage of subjects experiencing TEAEs will be summarized by period and 
treatment group:

TEAEs by SOC, High Level Term (HLT) and PT.

TEAEs by severity and by SOC, HLT and PT.

TEAEs by relationship to the investigational product and by SOC, HLT and PT.

Drug-related TEAEs by SOC, HLT and PT.

TEAEs leading to study drug discontinuation 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
Treatment-Emergent Serious Adverse Events
The number and percentage of subjects experiencing SAEs will be summarized by period and
treatment group:

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.
7.11.1.3
Treatment-Emergent AESIs
AESIs are defined as serious infections, opportunistic infection such as PML, liver injury, 
malignancies, infusion-related reactions or systemic reactions and hypersensitivity); see
Appendix B for details.
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The number and percentage of subjects experiencing AESIs will be summarized by period and 
treatment group:

AESIs by SOC, HLT and PT.

AESIs by severity and by SOC, HLT and PT.

AESIs by relationship to the investigational product and by SOC, HLT and PT.
7.11.2
Clinical Laboratory Evaluations
The following laboratory parameters will be presented:

Serum chemistry: alanine aminotransferase, albumin, alkaline phosphatase, amylase, lipase,
aspartate aminotransferase, bicarbonate, blood urea nitrogen, calcium, creatine kinase, 
creatinine, γ-glutamyl transferase, glucose, magnesium,
phosphorus, potassium, sodium, total bilirubin and direct bilirubin ( only measured if total 
bilirubin is elevated and therefore will only be displayed in listings), total protein and uric 
acid.

Hematology: hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, white 
blood cell (WBC) count, WBC differentials and PT/international rationalized ratio (INR)
(measured at Baseline and only if liver function tests are elevated at subsequent visits, 
therefore post-baseline data will only be displayed in listings).

Urinalysis: bilirubin, blood, glucose, ketones, leukocyte esterase, nitrite, specific gravity, pH, 
protein, microscopic analysis (obtained if positive leukocyte esterase or blood and includes 
RBCs, WBCs and casts, therefore only displayed in listings).

Serum/Plasma: CRP, HIV test, Hepatitis panel (including HBsAg and anti-HCV), FSH, 
QuantiFERON for tuberculosis, Beta human chronic gonadotropin (hCG) (female subjects of 
childbearing potential).

Urine: Urine pregnancy hCG (female subjects of childbearing potential).

Stool: Fecal calprotectin, C.difficile.
Laboratory test results will be summarized in CV units by period and treatment group in the 
following ways: 

For continuous data, descriptive statistics for observed values and change from baseline 
values will be presented by the scheduled time point.

For categorical data, the number and percentage in each category will be presented by 
scheduled time point.

Number and percentage of subjects with at least 1 markedly abnormal value (MAV) will be 
presented by study visit.
The number and percentage of subjects with Liver Function Test (LFT) abnormalities will be 
presented by period and treatment group. LFT abnormalities are defined as follows:

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 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%).
The laboratory data will be listed in full. Laboratory data outside of the normal reference range 
will be flagged in the listing. Special listings for laboratory data for subjects with test results 
meeting marked abnormality criteria (see Appendix A for details) will also be presented.
7.11.3
Vital Signs
Descriptive statistics will be used to summarize vital signs (including blood pressure, body
temperature, pulse rate and respiration rate) by period, treatment group and study visit. Values, 
change from baseline and % change from baseline for each visit will be summarized. Vital signs 
data will also be listed in full.
The number and percentage of subjects with at least one post-baseline MAV (see Appendix C) 
will be presented for each variable over all visits. A listing of MAVs for vital signs will also be 
presented.
7.11.4
12-Lead ECGs
A standard 12-lead electrocardiogram (ECG) will be recorded at Screening. It includes the 
following categories: within normal limits, abnormal but not clinically significant, or abnormal 
and clinically significant. All the categories will be presented in data listings.
7.11.5
Other Observations Related to Safety
Physical examination findings and PML checklist data will be presented in listings.
The 6 month LTFU questionnaire data will be summarized and also presented in listings.
7.12
Interim Analysis
A data cut will be performed after the first 125 enrolled subjects reach Week 6 or early terminate, 
whichever occurs first. The purpose of the analysis on this data cut is for publication only; no 
study decisions will be made and all subjects will continue in the study. The analysis will be 
performed on this data cut excluding subjects who violate any Screening inclusion or exclusion 
criteria. The data included in the analysis will be limited to demography, baseline characteristics, 
medical history, concomitant medications, partial Mayo score, CRP, fecal calprotectin, serum 
concentrations, AEs and laboratory data up to Week 6 and will be cleaned by Data Management. 
Comparisons will be made between Week 6 responders and Week 6 non-responders, no formal 
efficacy comparisons will be made. The interim analysis will follow all methodology outlined in 
this SAP with the exception of Mayo scores (Section 7.1.7). Instead Mayo scores and subscores 
will be taken directly from the eCRF and Week 6 response status will then be derived. These 
analyses will be repeated after database lock on all enrolled subjects who do not violate any 
Screening inclusion or exclusion criteria.
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The planned interim analysis described in the protocol will not be performed due to the timing 
and impact of the COVID-19 pandemic. 
7.13
Changes in the Statistical Analysis Plan 
The following changes from the protocol have been made:

Clarifications throughout the document to elaborate that endoscopic mucosal healing is based 
on central reader subscores which are modified so that a score of 1 does not include friability, 
per draft FDA guidelines. 

The PP Set was added.

Change from baseline in partial Mayo score has been added as an additional efficacy 
endpoint.

An additional interim has been added whilst the pre-specifed interim will not be performed 
due to the impact of the COVID-19 pandemic.
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8.0
REFERENCES
1. Ulcerative Colitis: Endpoints for Clinical Trials, FDA draft guidance, August 2016.
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9.0
APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Chemistry—Criteria for Markedly Abnormal Values
Conventional Units
Takeda Preferred SI Units
Parameter
Units
Low Abnormal
High Abnormal
Units
Low Abnormal
High Abnormal
Albumin
g/dL
<3.5 
--
g/L
<35 
--
Alkaline phosphatase
U/L
--
>3 × ULN
U/L
--
>3 × ULN
ALT
U/L
--
>3 × ULN
U/L
--
>3 × ULN
Amylase
U/L
--
>3 × ULN
U/L
--
>3 × ULN
AST
U/L
--
>3 × ULN
U/L
--
>3 × ULN
Bicarbonate
mEq/L
<21
>33
mmol/L
<21
>33
Blood Urea Nitrogen
mg/dL
--
>2 × ULN
mmol/L
--
>2 × ULN
Calcium
mg/dL
<6.1
>12.9
mmol/L
<1.52
>3.22
Creatine kinase
U/L
--
>3 × ULN
U/L
--
>3 × ULN
Creatinine
mg/dL
--
>2× ULN
mmol/L
--
2× ULN
GGT*
U/L
--
>3 × ULN
U/L
--
>3 × ULN
Glucose
mg/dL
<50
>450
mmol/L
<2.5
>25
Lipase
U/L
--
>3 × ULN
U/L
--
>3 × ULN
Phosphorus
mg/dL
<2.5
--
mmol/L
<0.81
--
Potassium
mEq/L
<2.8 
>6.3 
mmol/L
<2.8 
>6.3 
Sodium
mEq/L
<117
>160
mmol/L
<117
>160
Total bilirubin
mg/dL
--
>2.2 
μmol/L
--
>37.6
Total protein
g/dL
<2.0
>9.0
g/L
<20
>90
Uric Acid
mg/dL
--
>2 × ULN
μmol/L
--
>2 × ULN
LLN=lower limit of normal, ULN=upper limit of normal. * GGT = -Glutamyl Transferase
Hematology—Criteria for Markedly Abnormal Values
Conventional Units
Takeda Preferred SI Units
Parameter
Units
Low Abnormal
High Abnormal
Units
Low Abnormal
High Abnormal
Hematocrit
%
<0.8 × LLN
>1.2 × ULN
Fraction of 1
<0.8 × LLN
>1.2 × ULN
Hemoglobin
g/dL
<8
---
g/L
<80
---
Lymphocytes
103 cells/µL
<0.5
---
109 cells/L
<0.5
---
Platelet count
103 /µL
<100
>1200
109 /L
<100
>1200
RBC count
106 cells/µL
<0.8 × LLN
>1.2 × ULN
1012 cells/L
<0.8 × LLN
>1.2 × ULN
WBC count
103 cells/µL
<3.0
---
109 cells/L
<3.0
---
PT
sec
---
>3 × ULN
sec
---
>3 × ULN
INR†
NA
---
>2.5 × ULN
NA
---
>2.5× ULN
LLN=lower limit of normal, ULN=upper limit of normal. † Values are for subjects without anticoagulation, based on the normal range 
provided above for PT.
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Vedolizumab-4014
Page 42 of 43
Statistical Analysis Plan Final 1.0
17 March 2021
Appendix B
AEs of Special Interest (AESI) 
AESI
MedDRA Terms or Definitions
Infections
SOC: INFECTIONS AND INFESTATIONS
Hypersensitivity 
Reactions
Anaphylactic/anaphylactoid shock conditions SMQ (broad).
Angioedema SMQ (broad).
Hypersensitivity SMQ (broad).
Infusion
Related 
Reaction
Analysis for these AEs will occur on two levels:

Investigator defined Infusion Related Reactions (as indicated on the AE 
eCRF).

All AEs that occur on or one calendar day after the infusion date.
Malignancies
SOC: NEOPLASMS BENIGN, 
MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS)
PML
Human polyomavirus infection PT.
JC virus infection PT.
JC virus CSF test positive PT.
JC polyomavirus test positive PT
Leukoencephalopathy PT.
Polyomavirus test positive PT.
Progressive multifocal leukoencephalopathy PT.
Liver injury
Cholestasis and jaundice of hepatic origin SMQ (Broad) 
Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions SMQ (Broad)
Hepatitis, non-infectious SMQ (Broad) 
Liver related investigations, signs and symptoms SMQ (Narrow) 
Liver infections SMQ (Broad)
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Vedolizumab-4014
Page 43 of 43
Statistical Analysis Plan Final 1.0
17 March 2021
Appendix C
Criteria for Identification of Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Systolic Arterial Pressure
mmHg
<85
>180
Diastolic Arterial Pressure
mmHg
<50
>110
Pulse
bpm
<50
>120
Body Temperature
oC
<35.6
>37.7
oF
<96.1
>99.9 
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