Clinical trial NCT02790138
Conditions: Pouchitis
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2016-10-12; Completion date: 2021-02-02
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy of vedolizumab intravenous (IV) and placebo in terms of the percentage of participants with chronic or recurrent pouchitis achieving clinically relevant remission.

Detailed description:
Vedolizumab is being tested to treat people who have chronic pouchitis. This study will look at the healing of inflammation of ileal pouch in people who take vedolizumab as compared to those receiving a matching placebo. The study will enroll approximately 110 patients. Participants will be randomly assigned to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* Vedolizumab 300 mg IV
* Placebo IV

All participants will receive an intravenous infusion at Day 1, Weeks 2, 6, 14, 22, and 30 along with concomitant antibiotic treatment with ciprofloxacin 500 mg twice daily through Week 4.

This multicenter trial will be conducted in North America and Europe. The overall time to participate in treatment and efficacy assessment of this study is 34 weeks. Participants will make multiple visits to the clinic, plus a final visit 18 weeks after the last dose of study drug for a safety follow-up assessment (up to Week 48). Participants will also participate in a long-term follow-up, by phone after the last dose of study drug up to Week 56.

Arms: arm 1: Vedolizumab placebo-matching intravenous (IV) infusion, once at Day 1, Weeks 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4. arm 2: Vedolizumab 300 mg, IV infusion, once at Day 1, Weeks 2, 6, 14, 22, and 30 along with ciprofloxacin 500 mg, tablet, orally twice daily up to Week 4.
Interventions: intervention 1: Vedolizumab Placebo intervention 2: Ciprofloxacin intervention 3: Vedolizumab
Intervention descriptions: intervention 1: Vedolizumab placebo-matching IV infusion intervention 2: Ciprofloxacin tablets intervention 3: Vedolizumab IV infusion

Protocol documents:
Prot_000.pdf: 



Title: A Randomized, Double-Blind, Placebo-Controlled Phase 4 Study to Evaluate the Efficacy 
and Safety of Entyvio (Vedolizumab IV) in the Treatment of Chronic Pouchitis (EARNEST)
NCT Number: NCT02790138
Protocol Approve Date: 14 September 2020
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL AMENDMENT
A Randomized, Double-Blind, Placebo-Controlled Phase 4 Study to Evaluate the Efficacy 
and Safety of Entyvio (Vedolizumab IV) in the Treatment of Chronic Pouchitis (EARNEST)
Vedolizumab IV 300 mg in the Treatment of Chronic Pouchitis
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
Takeda Development Centre Europe, Ltd.
61 Aldwych
London, WC2B 4AE
United Kingdom
Study Number:
Vedolizumab-4004
IND Number: 
009125
EudraCT Number:
2015-003472-78
Compound:
Vedolizumab IV
Date:
14 September 2020
Amendment Number: 
04
Amendment History: 
Date
Amendment Number
Amendment Type
Region
12 February 2016
Initial Protocol
Not applicable
Global
01 June 2016
01
Non-substantial
Global
20 October 2016
02
Substantial
Global
21 April 2017
03
Substantial
Global
14 September 2020
04
Non-substantial
Global
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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 (TDC) sponsored investigators per individual country requirements 
will be provided with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
United States/Canada
Contact
Europe/Rest of World
Contact
Serious adverse event and 
pregnancy reporting
Medical Monitor
(medical advice on protoco
and compound)
Responsible Medical 
Officer 
(carries overall 
responsibility for the 
conduct of the study)
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
uiuiremen
reme
i
each sub
each s
ssigne
signed
nt guide
t guid
Europe/R
Europe
A
cial Use Only and Subject to 


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


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1.3
Protocol Amendment 04 Summary of Changes
Rationale for Amendment 04
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 04.
The primary reason for this amendment is to add exploratory objectives and endpoints for the 
Minor grammatical, editorial and formatting changes, for clarification purposes only, are not listed
below nor in Appendix J. For specific description of text changes and where the changes are 
located, see Appendix J.
Changes in Amendment 04
3. Added centrally read endoscopic assessments of the pouch.
7. Clarified that prior medication history includes all prior medications for the treatment of 
UC/pouchitis.
8. Corrected acute histologic inflammation descriptors for score of 0 in Appendix E for 
clarification of PDAI scoring.
9. Deleted duplicated text describing analysis set for primary analysis. 
CCI
CCI
CCI
Property of Takeda: 
fied that
ed tha
C/
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pouc
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Co
Corre
clcla
9.9
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ommercial Use Only
Com
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, the 
vedolizumab IV (Entyvio) package insert and any other product information provided by the 
sponsor. I agree to conduct this study in accordance with the requirements of this protocol and also 
to protect the rights, safety, privacy, and well-being of study subjects in accordance with the 
following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 04 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Principal Investigator/Coordinating Investigator ......................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.1.1
Disease and Current Treatments for Chronic or Recurrent Pouchitis...................20
4.1.2
Vedolizumab......................................................................................................21
4.1.2.1 Nonclinical...................................................................................................22
4.1.2.2 Human Experience .......................................................................................22
4.2
Rationale for the Proposed Study.............................................................................23
4.3
Benefit-Risk Assessment .........................................................................................23
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................25
5.1
Objectives................................................................................................................25
5.1.1
Primary Objective ..............................................................................................25
5.1.2
Secondary Objectives.........................................................................................25
5.1.3
Exploratory Objectives.......................................................................................25
5.1.4
Safety Objective.................................................................................................26
5.2
Endpoints.................................................................................................................26
5.2.1
Primary Endpoint...............................................................................................26
5.2.2
Secondary Endpoints..........................................................................................26
5.2.3
Exploratory Endpoints .......................................................................................26
5.2.4
Safety Endpoints................................................................................................27
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................28
6.1
Study Design ...........................................................................................................28
6.2
Justification for Study Design, Dose, and Endpoints ................................................29
6.3
Premature Termination or Suspension of Study or Study Site...................................29
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................29
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6.3.2
Criteria for Premature Termination or Suspension of Study Sites .......................30
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)..............................................................................30
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............31
7.1
Inclusion Criteria .....................................................................................................31
7.2
Exclusion Criteria ....................................................................................................31
7.2.1
Gastrointestinal Exclusion Criteria.....................................................................32
7.2.2
Infectious Disease Exclusion Criteria .................................................................32
7.2.3
General Exclusion Criteria .................................................................................33
7.3
Excluded Medications..............................................................................................34
7.3.1
Permitted Medications and Treatments...............................................................35
7.3.1.1 Oral Corticosteroid Dosing and Tapering .....................................................36
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................36
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................37
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................38
8.1
Study Drug and Materials ........................................................................................38
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................38
8.1.1.1 Vedolizumab IV and Placebo .......................................................................38
8.1.1.2 Companion Medication ................................................................................38
8.1.2
Storage...............................................................................................................38
8.1.3
Dose and Regimen .............................................................................................38
8.1.4
Overdose............................................................................................................39
8.2
Study Drug Assignment and Dispensing Procedures ................................................39
8.3
Randomization Code Creation and Storage..............................................................40
8.4
Drug Blind Maintenance..........................................................................................40
8.5
Unblinding Procedure..............................................................................................40
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................40
9.0
STUDY PLAN ..............................................................................................................42
9.1
Study Procedures.....................................................................................................42
9.1.1
Informed Consent Procedure..............................................................................42
9.1.2
Demographics, Medical History, and Medication History Procedure..................42
9.1.3
Ulcerative Colitis and Pouchitis History.............................................................42
9.1.4
Physical Examination Procedure ........................................................................42
9.1.5
Weight, Height...................................................................................................43
9.1.6
Vital Sign Procedure..........................................................................................43
9.1.7
PML Checklist...................................................................................................43
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9.1.8
ECG Procedure..................................................................................................43
9.1.9
Primary Efficacy Measurement ..........................................................................43
9.1.10 Pouchitis Endoscopy..........................................................................................43
9.1.11 PDAI .................................................................................................................44
9.1.12
9.1.13
9.1.14 Patient Reported Outcome Measures..................................................................45
9.1.14.1
IBDQ .....................................................................................................45
9.1.14.2
Cleveland Global Quality of Life (CGQL) instrument (Fazio Score).......45
9.1.15 Documentation of Concomitant Medications......................................................45
9.1.16 Documentation of Concurrent Medical Conditions.............................................45
9.1.17 Procedures for Clinical Laboratory Samples.......................................................46
9.1.18
9.1.19 Clostridium Difficile Sample Collection.............................................................47
9.1.20 Tuberculosis Screening ......................................................................................47
9.1.21 Contraception and Pregnancy Avoidance Procedure...........................................47
9.1.21.1
Male Subjects and Their Female Partners ...............................................47
9.1.21.2
Female Subjects and Their Male Partners ...............................................47
9.1.21.3
Definitions and Procedures for Contraception and Pregnancy 
Avoidance....................................................................................................48
9.1.21.4
General Guidance With Respect to the Avoidance of Pregnancy.............50
9.1.22 Pregnancy ..........................................................................................................50
9.1.23 Documentation of Screen Failure .......................................................................50
9.1.24 Documentation of Randomization......................................................................51
9.2
Monitoring Subject Treatment Compliance..............................................................51
9.3
Schedule of Observations and Procedures................................................................51
9.3.1
Screening...........................................................................................................51
9.3.2
Rescreening .......................................................................................................51
9.3.3
Study Randomization.........................................................................................52
9.3.4
End of Treatment Visit.......................................................................................52
9.3.5
Final Endoscopy Visit or Early Termination.......................................................52
9.3.6
Safety Follow-Up Visit ......................................................................................52
9.3.7
Post-Study Follow-Up........................................................................................52
9.3.8
Unscheduled Visits Due to Exacerbation/Relapse of Pouchitis ...........................52
9.3.9
Post-Study Care .................................................................................................53
10.0
PRETREATMENT EVENTS (PTE) AND ADVERSE EVENTS (AE) .........................54
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10.1
Definitions...............................................................................................................54
10.1.1 PTEs..................................................................................................................54
10.1.2 AEs....................................................................................................................54
10.1.3 Product Complaints............................................................................................54
10.1.4 Additional Points to Consider for PTEs and AEs................................................54
10.1.5 SAEs..................................................................................................................56
10.1.6 AEs of Special Interest.......................................................................................57
10.1.7 Intensity of PTEs and AEs .................................................................................59
10.1.8 Causality of AEs ................................................................................................59
10.1.9 Relationship to Study Procedures.......................................................................59
10.1.10
Start Date.....................................................................................................59
10.1.11
Stop Date .....................................................................................................59
10.1.12
Frequency ....................................................................................................59
10.1.13
Action Concerning Study Drug ....................................................................59
10.1.14
Outcome.......................................................................................................60
10.2
Procedures...............................................................................................................60
10.2.1 Collection and Reporting of AEs........................................................................60
10.2.1.1
PTE and AE Collection Period ...............................................................60
10.2.1.2
PTE and AE Reporting ...........................................................................61
10.2.1.3
AEs of Special Interest ...........................................................................61
10.2.2 Collection and Reporting of SAEs......................................................................61
10.2.3 Reporting of Abnormal Liver Function Tests .....................................................62
10.3
Follow-Up of SAEs .................................................................................................62
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....62
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................64
11.1
Steering Committee .................................................................................................64
11.2
Adjudication Committee..........................................................................................64
11.2.1 Risk Assessment and Minimization Action Plan for PML (RAMP) Program......64
12.0
DATA HANDLING AND RECORDKEEPING............................................................66
12.1
eCRFs......................................................................................................................66
12.2
Record Retention .....................................................................................................66
13.0
STATISTICAL METHODS..........................................................................................68
13.1
Statistical and Analytical Plans ................................................................................68
13.1.1 Analysis Sets......................................................................................................68
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................68
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13.1.3 Efficacy Analysis...............................................................................................68
13.1.4 Safety Analysis ..................................................................................................69
13.2
Futility Analysis and Criteria for Early Termination ................................................69
13.3
Determination of Sample Size..................................................................................70
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................71
14.1
Study-Site Monitoring Visits ...................................................................................71
14.2
Protocol Deviations..................................................................................................71
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................71
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................72
15.1
IRB and/or IEC Approval ........................................................................................72
15.2
Subject Information, Informed Consent, and Subject Authorization .........................73
15.3
Subject Confidentiality ............................................................................................74
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................74
15.4.1 Publication and Disclosure.................................................................................74
15.4.2 Clinical Trial Registration..................................................................................75
15.4.3 Clinical Trial Results Disclosure ........................................................................75
15.5
Insurance and Compensation for Injury....................................................................75
16.0
REFERENCES..............................................................................................................76
LIST OF IN-TEXT TABLES
Table 8.a
Dose and Regimen .............................................................................................39
Table 9.a
Clinical Laboratory Tests...................................................................................46
Table 10.a
Takeda Medically Significant AE List................................................................57
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................29
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................80
Appendix B
Responsibilities of the Investigator.....................................................................82
Appendix C
Elements of the Subject Informed Consent.........................................................84
Appendix D
Investigator Consent to Use of Personal Information..........................................87
Appendix E
The Pouchitis Disease Activity Index (PDAI) ....................................................88
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Appendix F
The Modified Pouchitis Disease Activity Index (mPDAI) ..................................89
Appendix G
Appendix H
Appendix I
Inflammatory Bowel Disease Questionnaire (IBDQ)..........................................92
Appendix J
Detailed Description of Amendments to Text...................................................102
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Takeda Development Centre Europe, Ltd
Compound:
Vedolizumab IV
Title of Protocol: A Randomized, Double-Blind,
Placebo-Controlled Phase 4 Study to Evaluate the Efficacy 
and Safety of Entyvio (Vedolizumab IV) in the Treatment 
of Chronic Pouchitis (EARNEST)
IND No.: 009125
EudraCT No.:
2015-003472-78
Study Number: Vedolizumab-4004
Phase: 4
Study Design:
Phase 4, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of vedolizumab
300 mg intravenous (IV) infusion during a 34-week treatment period (with last dose at Week 30) using pouch 
endoscopy. Approximately 110 subjects with a proctocolectomy and ileal pouch anal anastomosis (IPAA) for 
ulcerative colitis (UC) who have developed chronic or recurrent pouchitis will be enrolled. 
Chronic or recurrent pouchitis is defined as a modified Pouchitis Disease Activity Index (mPDAI) score ≥5 assessed 
as the average from 3 days immediately prior to the Baseline endoscopy and a minimum endoscopic subscore of 2 
(outside the staple or suture line) with either:
(a) ≥3 recurrent episodes within 1 year prior to the Screening visit, each treated with ≥2 weeks of antibiotic or other 
prescription therapy, or 
(b) requiring maintenance antibiotic therapy taken continuously for ≥4 weeks immediately prior to the Baseline 
Endoscopy Visit.
Subjects will be randomized in a 1:1 ratio to either the approved UC vedolizumab dose regimen or placebo treatment 
at Day 1, Weeks 2, 6, 14, 22, and 30. All subjects will receive concomitant antibiotic treatment with ciprofloxacin 
500 mg twice daily from randomization through Week 4. Efficacy will be assessed at Week 14 and Week 34. 
Primary Objective:
To compare the efficacy of vedolizumab IV and placebo in terms of the percentage of subjects with chronic or 
recurrent pouchitis achieving clinically relevant remission.
Secondary Objectives:
To assess the efficacy of vedolizumab IV by:
!
Percentage of subjects achieving mPDAI <5 and a reduction of overall score by ≥2 points from Baseline.
!
Percentage of subjects achieving PDAI <7 and a reduction of overall score by ≥3 points from Baseline.
!
Time to remission (defined as a PDAI score <7 and a decrease in PDAI score of ≥3 points from Baseline).
!
Percentage of subjects achieving a partial response (defined as reduction of mPDAI score by ≥2 points from 
Baseline).
!
Change in PDAI endoscopic subscore.
!
Change in PDAI histologic subscore.
!
Change in total PDAI.
!
Change in Inflammatory Bowel Disease Questionnaire (IBDQ), and Cleveland Global Quality of Life (CGQL, 
Fazio Score, 3 items).
Exploratory Objectives:
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Safety Objective:
To assess the safety of vedolizumab IV in chronic or recurrent pouchitis.
Subject Population: Adult subjects with a proctocolectomy and IPAA for UC, that was completed at least 1 year 
before the Day 1 (Randomization) Visit, who have developed chronic or recurrent pouchitis, defined as a mPDAI
score ≥5 assessed as the average from 3 days immediately prior to the Baseline endoscopy and a minimum endoscopic 
subscore of 2 (outside the staple or suture line) with either:
(a) ≥3 recurrent episodes within 1 year prior to the Screening visit, each treated with ≥2 weeks of antibiotic or other 
prescription therapy, or
(b) requiring maintenance antibiotic therapy taken continuously for ≥4 weeks immediately prior to the Baseline 
Endoscopy Visit
Number of Subjects:
Approximately 110 subjects will be randomly assigned in a 
1:1 ratio to receive vedolizumab IV (n=55) or placebo 
(n=55).
Number of Sites: 
Approximately 40 sites in North America and Europe.
Dose Level(s):
Group 1: Vedolizumab IV 300 mg at Day 1, Weeks 2, 6, 14, 
22, and 30.
Group 2: Placebo IV at Day 1, Weeks 2, 6, 14, 22, and 30. 
All subjects will receive ciprofloxacin 500 mg twice daily 
through Week 4.
Route of Administration:
Intravenous
Duration of Treatment:
34 weeks (with last dose at Week 30)
Period of Evaluation:
The study includes up to a 4-week Screening Period, a 
34-week Treatment Period (with last dose at Week 30), 
and an 18-week Follow-up Period following last dose. 
The duration of the study from the start of screening to 
18 weeks post last dose at Week 30 will be 
approximately 52 weeks. All subjects will participate 
in a long-term follow-up (LTFU) safety survey by 
telephone 26 weeks after their last dose.
Main Criteria for Inclusion:
!
Male or female subjects aged 18 to 80 years, inclusive.
!
History of IPAA for UC completed at least 1 year prior to the Day 1 (Randomization) Visit.
!
Pouchitis that is chronic or recurrent, defined by an mPDAI score ≥5 assessed as the average from 3 days 
immediately prior to the Baseline endoscopy and a minimum endoscopic subscore of 2 (outside the staple or 
suture line) with either (a) ≥3 recurrent episodes within 1 year prior to the Screening Period treated with ≥2 weeks 
of antibiotic or other prescription therapy, or (b) requiring maintenance antibiotic therapy taken continuously for
≥4 weeks immediately prior to the Baseline Endoscopy Visit.
Main Criteria for Exclusion:
!
Crohn’s disease (CD), CD of the pouch, irritable pouch syndrome (IPS), isolated or predominant cuffitis, 
diverting stoma, or mechanical complications of the pouch. 
!
Previous treatment with vedolizumab, natalizumab, efalizumab, rituximab, etrolizumab, or anti-mucosal 
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addressin cell adhesion molecule-1 (MAdCAM-1) therapy.
!
Any investigational or approved biologic or biosimilar agent within 60 days of randomization.
!
Nonbiologic investigational therapy within 30 days prior to randomization. 
!
Active or latent tuberculosis.
!
Chronic hepatitis B virus (HBV) infection or chronic hepatitis C virus (HCV) infection or a known history of 
human immunodeficiency virus (HIV) infection (or is found to be seropositive at Screening) or subject is 
immunodeficient.
!
Active, severe infection.
!
Positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist at Screening.
Main Criteria for Evaluation and Analyses:
The primary efficacy endpoint is the percentage of subjects with chronic or recurrent pouchitis achieving clinically 
relevant remission after 14 weeks of treatment. Clinically relevant remission will be defined as an mPDAI score <5 
and a reduction in overall score by ≥2 points from Baseline.
Secondary efficacy endpoints are:
!
Percentage of subjects achieving mPDAI score <5 and a reduction of overall score by ≥2 points from Baseline 
after 34 weeks of treatment (last dosing at week 30).
!
Percentage of subjects achieving PDAI score <7 and a reduction of overall score by ≥3 points from Baseline 
PDAI score after 14 weeks of treatment and after 34 weeks of treatment (last dosing at Week 30).
!
Time to remission (defined as a PDAI score <7 and a decrease in PDAI score of ≥3 points from Baseline).
!
Percentage of subjects achieving a partial response (defined as a reduction in mPDAI score by ≥2 points from 
Baseline) after 14 and after 34 weeks of treatment (last dosing at week 30).
!
Change in PDAI endoscopic subscore at Weeks 14 and 34 compared to Baseline.
!
Change in PDAI histologic subscore at Weeks 14 and 34 compared to Baseline.
!
Change in total PDAI score at Weeks 14 and 34 compared to Baseline.
!
Change in IBDQ, and CGQL (Fazio Score, 3 items) at Weeks 14, 22, and 34 compared to Baseline.
CCI
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Safety will be assessed by adverse events (AEs), adverse events of special interest (AESIs), serious adverse events 
(SAEs), vital signs, and results of standard laboratory tests (clinical chemistry, hematology, coagulation, and
urinalysis).
Statistical Considerations:
The primary efficacy endpoint is the percentage of subjects who achieve clinically relevant remission at Week 14 
(defined as an mPDAI score <5 and a decrease in mPDAI score of ≥2 points from Baseline). Subjects who withdraw 
early for any reasons will be included in the denominator for the estimation of this percentage. At the final analysis, the 
difference between the percentages of subjects achieving remission at Week 14 in each treatment group will be 
assessed by the chi-squared test. The null hypothesis, that the percentage of subjects achieving remission at Week 14 
in each treatment group is the same, will be tested against the alternative hypothesis that the 2 percentages are not the 
same.
The primary efficacy analysis will be based on the full analysis set (FAS) including all randomized subjects. Analysis 
will also be performed on the PP population for confirmatory purposes. 
The secondary endpoint of time to remission (defined as a PDAI score <7 and a decrease in PDAI score of ≥3 points 
from Baseline), will be analyzed by survival analysis procedures. Remission rates from the time of randomization over 
the 34-week study period will be estimated by Kaplan-Meier product limit methods. The log-rank test will be applied 
to compare the 2 treatment groups. Cox proportional hazards regression will be performed to explore the effect of
prognostic factors. Adjustments for baseline imbalances on key prognostic factors will be made using Cox regression. 
As this is a multicenter clinical study, heterogeneity of treatment effect across the participating centers will be 
explored. 
Statistical tests will be 2-sided and performed at the 0.05 level of significance.
A single futility analysis will be performed when 25 patients per treatment arm have been recruited and completed 
their Week 14 assessment for primary efficacy. The purpose of this analysis will be to assess for futility, and at this 
point simulations will be performed to determine the posterior probability of achieving a treatment difference of at 
least 25% between the active and placebo treatment arms. On the basis of the posterior probability of success, a 
decision will be made to continue or terminate the study on the grounds of futility. It is not intended to stop the study 
on the grounds of efficacy; hence, no adjustment to the statistical significance level used for testing at the final analysis 
is necessary.
Safety analyses will be based on the safety (SAF) analysis set. All subjects who received at least 1 dose of study drug 
will be included in the safety analysis set. No formal statistical tests will be performed for safety analyses.
Sample Size Justification: 
The sample size is calculated on the basis of remission rate at 14 weeks. The remission rate in subjects treated with 
placebo is estimated to be 15%. An effect size of at least 25% would be considered clinically meaningful (ie, a 
remission rate of 40% in subjects maintained on vedolizumab IV). Therefore, a total of 98 evaluable subjects (49 per 
treatment group) will be required to detect a 25% difference in the remission rate at the 2-sided 0.05 level of 
significance with 80% power. To account for attrition, 110 subjects will be randomized (55 per treatment group).
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the
Study-Related Responsibilities document. The vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical research 
as well as study participation. The Signatory Coordinating Investigator will be required to review 
and sign the clinical study report and by doing so agrees that it accurately describes the results of 
the study.
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3.3
List of Abbreviations
5-ASA
5-aminosalicylate
6-MP
6-mercaptopurine
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATZ
anal transitional zone
eCRF
electronic case report form
CD
Crohn’s disease
CGQL
Cleveland Global Quality of Life
CIMS
Central Image Management Solutions
CRA
clinical research associate
CRO
contract research organization
ECG
electrocardiogram
EMA
European Medicines Agency
EOS
end of study
EOT
end of treatment 
ET
early termination
FAP
familial adenomatous polyposis
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
G6PD
glucose-6-phosphate dehydrogenase
GALT
gut-associated lymphoid tissue
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HBsAg
hepatitis B virus surface antigen
hCG
human chorionic gonadotropin
HBV
hepatitis B virus
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
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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IEC
independent ethics committee
IgG1
immunoglobulin G1
INR
international normalized ratio
IPAA
ileal pouch anal anastomosis
IPS
irritable pouch syndrome
IRB
institutional review board
IRR
infusion-related reaction
IV
intravenous
IWRS
interactive web response system
JCV
John Cunningham virus
LFT
liver function tests
LTFU
long-term follow-up
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
Med ID
medication identification number
MedDRA
Medical Dictionary for Regulatory Activities
mPDAI
modified Pouchitis Disease Activity Index
PC
product complaint
PD
pharmacodynamics
PDAI
Pouchitis Disease Activity Index
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PP
per-protocol 
PTE
pretreatment event
Q8W
once every 8 weeks
RAMP
Risk Minimization Action Plan for PML
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reactions
TB
Tuberculosis
TEAE
treatment-emergent adverse event
TNF-α
tumor necrosis factor-alpha
UC
ulcerative colitis
ULN
upper limit of normal
WBC
white blood cell
WHODRUG
World Health Organization Drug Dictionary
CCI
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3.4
Corporate Identification
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Europe and/or TDC Americas, as applicable
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Vedolizumab IV
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4.0
INTRODUCTION
4.1
Background
4.1.1
Disease and Current Treatments for Chronic or Recurrent Pouchitis
The surgical treatment of choice for patients with ulcerative colitis (UC) is removal of the colon 
followed by construction of an ileal pouch anal anastomosis (IPAA). Inflammation of the “pouch,” 
commonly called pouchitis, is the most common long-term complication in these patients and is 
characterized by watery, sometimes bloody stool associated with urgency, incontinence, 
abdominal cramps, malaise, and fever. In addition to these abnormalities, biopsy of the pouch 
shows chronic inflammatory changes with intense infiltration of both acute and chronic 
inflammatory cells. 
Pouchitis is a poorly understood condition, with a reported cumulative frequency of 23% to 46% 
over 10 to 11 years in patients who underwent an ileoanal pouch procedure [1, 2]. The etiology of 
pouchitis is likely multi-factorial. Pouchitis may be due in part to exposure of the ileal mucosa of 
the pouch to noxious components of feces, such as short chain fatty acids and bile acids, to which 
it may never be completely adapted. Altered immunoregulation, previously undiagnosed Crohn’s 
disease (CD) affecting the ileum, and ischemia caused by decreased mucosal blood flow may also
be involved in the etiology of pouchitis [3]. 
The clinical response of pouchitis to treatment with antibiotics such as metronidazole or 
ciprofloxacin, as well as probiotics including Lactobacilli, suggests that fecal stasis, C difficile 
infection, bacterial overgrowth, or dysbiosis (altered proportions among fecal bacterial 
populations) may be triggers. Other therapeutic agents tested for the treatment of pouchitis with 
mixed success include mesalamine, corticosteroids, nutritional agents (short-chain fatty acids, 
glutamine, or soluble fiber administered per suppository or enema), immunomodifying agents, 
cigarettes and transdermal nicotine, bisthmus-containing agents, and allopurinol [3]. Importantly, 
none of these therapies have been shown to be effective in clinical trials. Furthermore, due to their 
nonspecific mechanism of action, use of some of these therapies may place patients at risk for 
infection complications. 
Results from 3 clinical trials of the probiotic agent VSL#3 for the primary and secondary 
prophylaxis of pouchitis have been published [4-6] and showed efficacy around 85% to 90%. 
However, long-term efficacy in routine care could not be reproduced in another study [7]. 
While pouchitis usually responds to short-term antibiotic therapy, some patients experience 
recurrent pouchitis and require chronic antibiotic therapy to sustain remission or the more drastic 
option of surgical removal of the pouch. Chronic or recurrent pouchitis is often managed with 
long-term antibiotic administration, with metronidazole and ciprofloxacin being the antibiotics 
most often prescribed [8]. There are presently no approved drugs for the treatment or prevention of 
pouchitis in the United States or Europe. Thus, a large unmet medical need exists in the 
management of refractory pouchitis.
Although many patients respond to antibiotic therapy, there is also evidence to suggest that 
aberrant regulation of the mucosal immune system might play a part in the pathogenesis of 
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Vedolizumab IV
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pouchitis arising from an abnormal mucosal immune response to a dysbiosis of the pouch 
microbiota [9]. For example, pouchitis rarely occurs in patients with familial adenomatous 
polyposis (FAP) who have undergone a colectomy with creation of IPAA [10]. There are known 
genetic risk factors for the development of pouchitis associated with a dysregulation of the 
mucosal immune system [11]. The interleukin-1 receptor antagonist gene allele 2, tumor necrosis 
factor gene allele 2, and NOD2/CARD15 polymorphisms have all been associated with pouchitis 
[12-15].
Herfarth et al conducted a systematic review of the use of biologics in the treatment of pouchitis 
[16]. Well-controlled clinical studies of tumor necrosis factor-alpha (TNF-α) antagonist therapy in 
the treatment of pouchitis were not available. However, the available data for infliximab suggests 
potential clinical effectiveness in the treatment of antibiotic refractory or fistulizing pouchitis. The 
data for adalimumab are more limited and sufficient long-term outcomes were lacking. There are 
no published data available related to the efficacy of certolizumab, golimumab, natalizumab, or 
vedolizumab in patients with antibiotic refractory pouchitis or fistulizing and/or pouch 
complications [16]. Subjects with pouchitis were excluded from the pivotal phase 3 clinical studies 
for vedolizumab.
4.1.2
Vedolizumab
Vedolizumab (also called MLN0002) is a humanized immunoglobulin G1 (IgG1) monoclonal 
antibody (mAb) directed against the human lymphocyte integrin α4β7. The α4β7 integrin 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 
[17-20]. Vedolizumab binds the α4β7 integrin, antagonizing its adherence to MAdCAM-1 and as 
such, impairs the migration of gut homing lymphocytes into GI mucosa. As a result, vedolizumab 
acts as a gut-selective immunomodulator [21].
Vedolizumab IV (also known as ENTYVIO; KYNTELES; or MLN0002 IV) has been granted 
marketing approval in several regions, including the United States, European Union, and several 
other countries worldwide. Vedolizumab IV is approved for the treatment of adult patients with 
moderately to severely active UC or CD, who have had an inadequate response with, lost response 
to, or were intolerant to either conventional therapy (corticosteroids, immunomodulators) or a 
TNF-α antagonist. The approved dosing regimen is 300 mg vedolizumab IV infused intravenously 
at Weeks 0, 2, and 6, then once every 8 weeks (Q8W) thereafter. 
pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of vedolizumab in healthy 
subjects and subjects with UC or CD.
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4.1.2.1
Nonclinical
No nonclinical studies have been conducted to evaluate vedolizumab specifically for chronic 
pouchitis in UC.
Nonclinical in vitro and in vivo studies have been conducted with vedolizumab and its murine 
homologue, Act-1. Act-1 has demonstrated clinical and histomorphologic evidence of efficacy in a 
cotton-top tamarin model of inflammatory bowel disease (IBD). Extensive nonclinical evaluations 
of the cardiovascular, acute, local, subchronic, chronic, immunologic, and reproductive toxicity of 
vedolizumab in pharmacologically responsive species (New Zealand white rabbits and 
cynomolgus monkeys) have been conducted and support its clinical development. Nonclinical 
studies also show that vedolizumab does not antagonize α4β1 integrin [21].
4.1.2.2
Human Experience
As of 19 November 2016, approximately 4200 subjects (309 healthy subjects, 1811 subjects with 
UC, 2138 subjects with CD, 3 subjects undergoing allo-HSCT, 1 subject with pouchitis, and 2 
subjects with melanoma) have received at least 1 dose of vedolizumab across completed and 
ongoing company-sponsored interventional clinical studies (see Investigator’s Brochure [IB], 
Edition 19). Vedolizumab exposure has extended for ≥12 months in 1832 subjects, ≥24 months in 
1379 subjects, ≥36 months in 1169 subjects, ≥48 months in 862 subjects, ≥60 months in 
645 subjects, ≥72 months in 308 subjects, ≥84 months in 32 subjects, and ≥96 months in 22 
subjects. Based on drug shipment data, the global cumulative postmarketing patient exposure to 
vedolizumab IV globally is estimated to be approximately 77,382 patient-years.
In the 52-week pivotal phase 3 studies (C13006 and C13007), the most common (≥5% and at a 
higher incidence than placebo) adverse events in subjects administered vedolizumab IV were 
nausea, nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, fatigue, headache, 
and cough. Most serious adverse events (SAEs) were 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 correlate 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%). Concomitant use of 
corticosteroids and/or conventional immunomodulators did not appear to be associated with any 
increased rate of infections based on the comparative rates of infections in the phase 3 clinical 
studies among subjects. One death occurred in a vedolizumab-treated subject during Study 
C13006 and 5 deaths occurred during Study C13007, including 1 death in a placebo-treated 
subject. Results from the clinical program to date do not suggest an increased risk for malignancy 
with vedolizumab treatment. No cases of progressive multifocal leukoencephalopathy (PML) 
were reported in these studies.
Overall, 4% of subjects treated with vedolizumab IV and 3% of subjects treated with placebo 
experienced a treatment-emergent adverse event (TEAE) defined by the investigator as an 
infusion-related reaction (IRR). The most frequently observed IRR events in the subjects treated 
with vedolizumab (by preferred term and reported more than twice) were nausea, headache, 
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Vedolizumab IV
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pruritus, dizziness, fatigue, IRR, pyrexia, urticaria, and vomiting. The majority of IRRs were mild 
or moderate in intensity, and few resulted in discontinuation of study treatment. Observed IRRs 
generally resolved with no or minimal intervention following the infusion. 
Overall, vedolizumab was well tolerated in clinical studies. For additional safety related 
information from the clinical trials experience, see the current edition of the IB.
4.2
Rationale for the Proposed Study
There are presently no approved drugs for the treatment or prevention of pouchitis in the United 
States or Europe. Thus, a large unmet medical need exists in the management of pouchitis.
While pouchitis usually responds to short-term antibiotic therapy, approximately 5% to 19% of 
patients with acute pouchitis develop refractory or rapidly relapsing forms of the disease [22, 23]. 
Chronic or recurrent pouchitis is often managed with long-term antibiotic administration, with 
metronidazole and ciprofloxacin being the antibiotics most often prescribed [8]. The disease 
course of antibiotic-responsive pouchitis may evolve into antibiotic-dependent pouchitis and then 
antibiotic-refractory pouchitis. In cases where chronic or recurrent pouchitis does not respond to 
therapy, this may necessitate the drastic option of surgical removal of the pouch.
Although many patients respond to antibiotic therapy, there is also evidence to suggest that 
aberrant regulation of the mucosal immune system might play a part in the pathogenesis of 
pouchitis arising from an abnormal mucosal immune response to a dysbiosis of the pouch 
microbiota [9].
The humanized mAb vedolizumab is effective for induction and maintenance therapy of UC and 
CD [24-28]. Vedolizumab abrogates the interaction of α4β7 integrin on memory T and B cells with 
MAdCAM-1 expressed on the vascular endothelium in the gut [19, 20]. MAdCAM-1 levels are 
elevated in IBD [19]. This mechanism of action suggests that vedolizumab may be effective in the 
treatment of other chronic inflammatory diseases of the GI tract, such as chronic or recurrent 
pouchitis. It is hypothesized that vedolizumab IV will effectively and safely achieve clinically 
relevant remission in subjects with chronic or recurrent pouchitis. This study will establish 
whether vedolizumab IV may be an effective therapy for chronic or recurrent pouchitis. 
4.3
Benefit-Risk Assessment
The proposed study (Vedolizumab-4004) is designed to evaluate the efficacy and safety of 
vedolizumab IV in the treatment of adult subjects with chronic or recurrent pouchitis. Currently, 
no drugs have been approved in the United States or Europe for the treatment or prevention of 
pouchitis, indicating that a high unmet medical need exists for this patient population.
Inhibition of the interaction of the α4β7 integrin on memory T and B cells with MAdCAM-1 
expressed on the vascular endothelium in the gut may be effective in the treatment of chronic 
inflammatory diseases of the GI tract, such as chronic or recurrent pouchitis. All subjects will 
receive concomitant antibiotic treatment with ciprofloxacin 500 mg twice daily through Week 4. 
Additional courses of antibiotics will be allowed, as needed, for flares after Week 14.
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Vedolizumab IV
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The dosing and administration regimen of vedolizumab are consistent with the approved 
vedolizumab IV label. The proposed protocol will include safety measures similar to those 
conducted in the vedolizumab IV UC and CD clinical programs, including sufficient safety 
measures, evaluations, and discontinuation criteria to assure safety in the individual subjects in the 
planned study.
Overall, vedolizumab IV has been well tolerated in clinical studies and the benefit-risk profile is 
positive.
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Vedolizumab IV
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to compare the efficacy of vedolizumab IV to placebo in terms of the 
percentage of subjects with chronic or recurrent pouchitis achieving clinically relevant remission 
5.1.2
Secondary Objectives
The secondary objectives are to assess the efficacy of vedolizumab IV by:
!
Percentage of subjects achieving mPDAI <5 and a reduction of overall score by ≥2 points from 
Baseline mPDAI.
!
Percentage of subjects achieving PDAI <7 and a reduction of overall score by ≥3 points from 
Baseline PDAI. 
!
Time to remission (defined as a PDAI score <7 and a decrease in PDAI score of ≥3 points from 
Baseline).
!
Percentage of subjects achieving a partial response (defined as reduction mPDAI score by ≥2 
points from Baseline). 
!
Change in PDAI endoscopic subscore. 
!
Change in PDAI histologic subscore. 
!
Change in total PDAI.
!
Change in Inflammatory Bowel Disease Questionnaire (IBDQ), and Cleveland Global Quality 
of Life (CGQL, Fazio Score, 3 items). 
5.1.3
Exploratory Objectives
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5.1.4
Safety Objective
The safety objective is to assess the safety of vedolizumab IV in chronic or recurrent pouchitis.
5.2
Endpoints
5.2.1
Primary Endpoint 
The primary efficacy endpoint is the percentage of subjects with chronic or recurrent pouchitis 
achieving clinically relevant remission after 14 weeks of treatment. Clinically relevant remission 
is defined as an mPDAI score <5 and a reduction of overall score by ≥2 points from Baseline.
5.2.2
Secondary Endpoints
Secondary efficacy endpoints are:
!
Percentage of subjects achieving an mPDAI score <5 and a reduction of overall score by ≥2 
points from Baseline after 34 weeks of treatment (last dosing at Week 30).
!
Percentage of subjects achieving PDAI score <7 and a reduction of overall score by ≥3 points 
from Baseline PDAI score after 14 weeks of treatment and after 34 weeks of treatment (last 
dosing at Week 30).
!
Time to remission (defined as a PDAI score <7 and a decrease in PDAI score of ≥3 points from 
Baseline).
!
Percentage of subjects achieving a partial response (defined as reduction in mPDAI score by 
≥2 points from Baseline) after 14 and after 34 weeks of treatment (last dosing at Week 30).
!
Change in PDAI endoscopic subscore at Weeks 14 and 34 compared to Baseline.
!
Change in PDAI histologic subscore at Weeks 14 and 34 compared to Baseline.
!
Change in total PDAI score at Weeks 14 and 34 compared to Baseline.
!
Change in IBDQ, and CGQL (Fazio Score, 3 items) at Weeks 14, 22, and 34 compared to 
Baseline.
5.2.3
Exploratory Endpoints
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5.2.4
Safety Endpoints
Safety will be assessed by adverse events (AEs), adverse events of special interest (AESIs), SAEs, 
vital signs, and results of standard laboratory tests (clinical chemistry, hematology, coagulation, 
and urinalysis).
CCI
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 4, randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of vedolizumab IV 300 mg over a 34-week treatment period (with the last dose 
at Week 30) in subjects with a proctocolectomy and IPAA for UC who have developed chronic or 
recurrent pouchitis. 
Approximately 110 adult subjects with chronic or recurrent pouchitis will be randomized to this 
study. Subjects must have developed chronic or recurrent pouchitis, defined as a modified 
Pouchitis Disease Activity Index (mPDAI) score ≥5 assessed as the average from 3 days 
immediately prior to the Baseline endoscopy and a minimum endoscopic subscore of 2 (outside 
the staple or suture line) with either (a) ≥3 recurrent episodes within 1 year prior to the Screening 
visit, each treated with ≥2 weeks of antibiotic or other prescription therapy, or (b) requiring 
maintenance antibiotic therapy taken continuously for ≥4 weeks immediately prior to the Baseline 
Endoscopy Visit.
After the Screening Period of up to 28 days, subjects will be randomized at Day 1 in a 1:1 ratio to 
either vedolizumab IV or placebo treatment. Subjects will receive their assigned infusion 
(vedolizumab or placebo) at Day 1, Weeks 2, 6, 14, 22, and 30 (final dose). All subjects will 
receive concomitant antibiotic treatment with ciprofloxacin 500 mg twice daily through Week 4. 
Additional courses of antibiotics will be allowed, as needed, for flares after Week 14. Final 
efficacy assessments will be measured 4 weeks after the last study dose (Week 34). Additional 
safety follow-ups will occur 18 weeks after the last study dose (Week 48) and subjects will be 
required to participate in a long-term follow-up (LTFU) safety survey by telephone, 26 weeks after 
the last dose of study drug (Week 56).
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
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Figure 6.a
Schematic of Study Design
6.2
Justification for Study Design, Dose, and Endpoints
In 1310 patients who had an IPAA for chronic UC, 559 patients had at least 1 episode of pouchitis. 
Approximately 70% of those patients who had at least 1 attack of pouchitis had a second episode 
[29]. There are currently no approved drugs for the treatment of chronic or recurrent pouchitis. 
Chronic pouchitis is often managed with long-term antibiotic administration; however, long-term 
antibiotic use can lead to antibiotic resistance. The treatment of antibiotic refractory pouchitis is 
also often challenging. While a prolonged course of combined antibiotic agents is often used,
maintenance of remission in this group of patients after induction treatment with combined 
antibiotics remains challenging and represents an unmet need [30]. Existing data suggests 
infliximab may be clinically effective for antibiotic-refractory pouchitis, but well-controlled 
studies are not presently available for any TNF-α antagonist therapies [16]. The mechanism of 
action of vedolizumab suggests that it may be effective in the treatment of chronic inflammatory 
diseases of the GI tract, such as pouchitis. Based on these considerations it is proposed that 
vedolizumab IV may be efficacious in achieving disease remission in the study population 
defined. 
Since there are no approved drugs for chronic or recurrent pouchitis, the placebo-controlled design 
was selected. The dose and administration regimen selected for the vedolizumab IV treatment 
group is consistent with the approved label for UC [31, 32].
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination (ET) of the study.
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
New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for vedolizumab, such that the risk/benefit 
is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.

At the futility analysis, if the probability of success does not meet the pre-determined futility 
threshold and the study is stopped for futility at this point.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
study site, a study-specific procedure for ET or suspension will be provided by the sponsor; the 
procedure will be followed by applicable study sites during the course of termination or study 
suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization and first dose.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures.
3. The subject is male or female and aged 18 to 80 years, inclusive.
4. The subject has a history of IPAA for UC completed at least 1 year prior to the Day 1 
(Randomization) Visit.
5. The subject has pouchitis that is chronic or recurrent, defined by an mPDAI score ≥5 assessed 
as the average from 3 days immediately prior to the Baseline endoscopy and a minimum 
endoscopic subscore of 2 (outside the staple or suture line) with either (a) ≥3 recurrent episodes 
within 1 year prior to the Screening Period treated with ≥2 weeks of antibiotic or other 
prescription therapy, or (b) requiring maintenance antibiotic therapy taken continuously for ≥4 
weeks immediately prior to the Baseline Endoscopy Visit
6. The subject agrees to take ciprofloxacin (500 mg twice daily) on Day 1 and through Week 4, 
regardless of the previous treatment and to stop any previous antibiotic therapy on Day 1 of the 
study. (Additional courses of antibiotics will be allowed, as needed, for flares after Week 14.)
7. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use a barrier method of contraception (eg, condom with spermicide)* from 
signing of informed consent throughout the duration of the study and for 18 weeks after last 
dose. The female partner of a male subject should also be advised to use a highly effective 
method of contraception*.
8. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use a highly effective method of contraception* from signing of informed 
consent throughout the duration of the study and for 18 weeks after last dose. 
*Definitions and highly effective methods of contraception are defined in 
Section 9.1.21 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.22 Pregnancy.
7.2
Exclusion Criteria
The exclusion criteria are divided into 3 categories: GI exclusion criteria, infectious disease 
exclusion criteria, and general exclusion criteria. Subjects meeting any of the following criteria 
will not qualify for entry into the study: 
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7.2.1
Gastrointestinal Exclusion Criteria
1. The subject has CD or CD of the pouch. Subjects will be excluded if the investigator suspects, 
on the basis of the screening endoscopy, that the pattern of inflammation may be due to CD.
2. The subject has irritable pouch syndrome (IPS).
3. The subject has isolated or predominant cuffitis.
4. The subject has mechanical complications of the pouch (eg, pouch stricture or pouch fistula).
5. The subject currently requires or has a planned surgical intervention for UC during the study.
6. The subject has diverting stoma.
7.2.2
Infectious Disease Exclusion Criteria
1. The subject has evidence of an active infection (eg, sepsis, cytomegalovirus, or listeriosis) 
during Screening.
2. The subject has active or latent tuberculosis (TB), regardless of treatment history, as 
evidenced by any of the following:
a) A diagnostic TB test performed within 30 days of Screening or during the Screening Period 
that is positive, as defined by:
i.
A positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests OR
ii.
A tuberculin skin test reaction ≥10 mm (≥5 mm in subjects receiving the equivalent of 
>15 mg/day prednisone) OR
b) Chest X-ray within 3 months prior to Day 1 that is suspicious for pulmonary TB, and a 
positive or 2 successive indeterminate QuantiFERON test within 30 days prior to 
Screening or during the Screening Period.
Note: if the subject has a negative diagnostic TB test documented in the previous 3 months, 
screening testing does not need to be repeated provided subject has no risk factors for 
exposure.
3. The subject has chronic hepatitis B virus (HBV) infection* or chronic hepatitis C virus 
(HCV) infection** or a known history of human immunodeficiency virus (HIV) infection 
(or is found to be seropositive at Screening) or subject is immunodeficient (eg, due to organ 
transplantation, history of common variable immunodeficiency, etc). 
* Subjects who are positive for hepatitis B virus surface antigen (HBsAg) will be excluded. 
For subjects who are negative for HBsAg but are positive for either surface antibodies 
and/or core antibodies, HBV DNA polymerase chain reaction will be performed and if any 
test result meets or exceeds detection sensitivity, the subject will be excluded.
** If subject is HCV antibody positive, then a viral load test will be performed. If the viral 
load test is positive, then the subject will be excluded.
4. The subject has evidence of active infection with C difficile during Screening (to be confirmed 
by laboratory test). 
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7.2.3
General Exclusion Criteria
1. The subject has any prior exposure to vedolizumab, natalizumab, efalizumab, rituximab, 
etrolizumab, or anti-MAdCAM-1 therapy.
2. The subject has a history of hypersensitivity or allergies to vedolizumab or its components.
3. The subject has allergies to and/or contraindications for ciprofloxacin, a history of tendon 
disorders related to quinolone administration and/or glucose-6-phosphate dehydrogenase 
(G6PD) deficiency. Further conditions requiring precautions for use of ciprofloxacin have to 
be considered based on local prescribing information. 
4. The subject is taking, has taken, or is required to take any excluded medications (as listed in 
Section 22).
5. The subject has received any investigational or approved biologic or biosimilar agent within 
60 days prior to Randomization
6. The subject has received an investigational nonbiologic therapy within 30 days prior to 
Randomization.
7. The subject has received an approved nonbiologic therapy (including 5-aminosalicylate 
[5-ASA], corticosteroid, azathioprine, 6-mercaptopurine [6-MP], etc.) in an investigational 
protocol within 30 days prior to Randomization.
8. The subject has received any live vaccinations within 30 days prior to randomization.
9. The subject has a positive PML subjective symptom checklist at Screening.
10. [Previous criterion #10 incorporated into criterion #3 in amendment number 3].
11. The subject has had a kidney, heart, or lung transplant.
12. [Previous criterion #12 deleted in amendment number 3].
13. 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 the Screening visit; and history of 
cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 
3 years prior to Screening. Subjects with a remote history of malignancy (eg, >10 years since 
completion of curative therapy without recurrence) will be considered based on the nature of 
the malignancy and the therapy received and must be discussed with the sponsor on a 
case-by-case basis prior to enrollment.
14. The subject has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, demyelinating, or neurodegenerative disease.
15. The subject has conditions which, in the opinion of the investigator, may interfere with the 
subject’s ability to comply with the study procedures.
16. The subject has any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, 
genitourinary, hematological, coagulation, immunological, endocrine/metabolic, neurologic, 
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or other medical disorder that, in the opinion of the investigator, would confound the study 
results or compromise subject safety.
17. The subject has any of the following laboratory abnormalities during the Screening Period:
i.
Hemoglobin level <8 g/dL.
ii.
White blood cell (WBC) count <3 × 109/L.
iii.
Lymphocyte count <0.5 × 109/L.
iv.
Platelet count <100 × 109/L or >1200 × 109/L.
v.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 
× the upper limit of normal (ULN).
vi.
Alkaline phosphatase >3 × ULN.
vii.
Serum creatinine >2 × ULN.
18. If female, the subject is pregnant or lactating or intending to become pregnant or nurse before, 
during, or within 18 weeks after the last dose of study drug; or intending to donate ova during 
such time period.
19. If male, the subject intends to donate sperm or father a child during the course of this study or 
for 18 weeks after the last dose of study drug.
20. 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. 
21. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 1 year prior to Screening.
22. [Previous criterion #22 incorporated into criterion #3 in amendment number 3].
7.3
Excluded Medications
The following medications are excluded from use during the study until Week 34 unless specified 
otherwise:
1. Any treatment for pouchitis other than those listed below in Section 7.3.1 (either approved or 
investigational). 
2. Antibiotic therapy for pouchitis from Week 4 through Week 14 of the study. (Antibiotics will 
be allowed after Week 14, as needed, for flares.)
3. Tizanidine, methotrexate, and zolpidem from Randomization to Week 4 (contraindication to 
ciprofloxacin)
–
Several drugs might interfere with ciprofloxacin when administered concomitantly. Use 
with caution or monitoring (especially drugs metabolized by CYP1A2) may be required 
(as detailed in local prescribing information). 
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4. Oral corticosteroids for pouchitis, except as described in Section 7.3.1.1.
5. Within 30 days prior to Randomization and throughout study until Week 34, any of the 
following for the treatment of pouchitis:
–
Nonbiologic therapies (eg, cyclosporine, thalidomide) other than those specifically listed 
in Section 7.3.1.
–
An investigational nonbiologic therapy.
–
An approved nonbiologic therapy in an investigational protocol.
6. NSAIDS (if used continuously for ≥2 weeks) within 30 days prior to Randomization (Day 1) 
and throughout the study until Week 34
–
Note: occasional use of NSAIDs and acetaminophen for headache, arthritis, myalgia, 
menstrual cramps etc. and daily use of low dose (≤100 mg acetylsalicylic acid for 
cardiovascular prophylaxis are permitted).
7. Any investigational or approved biologic or biosimilar agent within 60 days prior to 
Randomization (Day 1) and throughout the study until Week 34. 
8. 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.
9. 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).
10. Rectal products (enemas and suppositories including 5-ASA and corticosteroids) within 15 
days prior to Randomization (Day 1) and throughout the study until Week 34. 
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator. 
7.3.1
Permitted Medications and Treatments
The following medications for pouchitis are permitted during the study:
1. Ciprofloxacin (500 mg twice daily for 4 weeks, starting at Randomization) is mandatory 
therapy in this study. If subjects are receiving other antibiotics at Randomization, they will be 
switched to ciprofloxacin and continue on this for the first 4 weeks of the study. 
2. Additional antibiotics will be allowed, as needed, for flares after Week 14.
3. Oral 5-ASA if taken at a stable dose for at least 2 weeks prior to randomization and throughout 
the study until Week 34.
4. Anti-diarrheals for control of chronic diarrhea, with stable dose for at least 2 weeks prior to 
Randomization and throughout the study until Week 34.
5. Antibiotic therapy for pouchitis if taken before Screening should be kept at a stable dose for 2 
weeks prior to Randomization.
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6. Oral corticosteroid therapy for pouchitis if taken at a stable dose for at least 4 weeks prior to 
Randomization and with mandatory tapering after Week 4 (Visit 4) of the study as described 
in Section 7.3.1.1.
7. Probiotics (eg, Saccharomyces boulardii) and/or immunomodulators (azathioprine, 6-MP), if 
taken at a stable dose for at least 8 weeks prior to Randomization and throughout the study 
until Week 34.
7.3.1.1
Oral Corticosteroid Dosing and Tapering
The maximum dose of oral corticosteroids for the treatment of pouchitis that may be 
co-administered with vedolizumab IV is 20 mg/day prednisone or 9 mg/day budesonide or 5 
mg/day beclomethasone dipropionate (or equivalent) as long as they have been used at a stable 
dose for at least 4 weeks prior to Randomization.
It is required that subjects receiving oral corticosteroids begin a tapering regimen by Week 4 
(Visit 4) of the study. Tapering should be finished by Week 8, if possible.
7.4
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.23.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires ET 
because continued participation imposes an unacceptable risk to the subject’s health or the 
subject is unwilling to continue because of the PTE or AE.

Liver Function Test (LFT) Abnormalities.
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.17), if the following circumstances occur at any 
time during study drug treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).

Leukopenia or lymphopenia: WBC and lymphocyte counts will be monitored for all 
subjects. Azathioprine, 6-MP, if applicable, should be discontinued and the dose of 
vedolizumab held for an absolute lymphocyte count <0.5×109/L at any point in the study. 
The absolute lymphocyte count must be repeated at appropriate intervals as determined by 
the investigator. The next dose of vedolizumab can be administered only if the absolute 
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lymphocyte count is ≥0.5×109/L. If the absolute lymphocyte count remains <0.5×109/L, 
study drug should be discontinued and the subject withdrawn from the study.
2. Significant protocol deviation. The discovery post-randomization that the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the voluntary withdrawal category. Similarly, lack of efficacy 
should not be recorded in the voluntary withdrawal category).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.22.
7. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject. 
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.5
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.4. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the ET 
Visit and post-treatment follow-up visit and safety phone call (18 and 26 weeks post-treatment). 
Discontinued or withdrawn subjects will not be replaced. Refer to Section 9.3.9 for appropriate 
Post-Study Care procedures.
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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling 
8.1.1.1
Vedolizumab IV and Placebo
The study sites will be supplied by the sponsor with the following medication in an open-label 
manner: vedolizumab IV 300 mg/vial, for single use, in 20 mL vials. The study drug will be 
provided in a glass vial as a lyophilized solid for reconstitution using 4.8 mL of sterile water for 
injection and further dilution (5.0 mL) in 250 mL of sterile 0.9% sodium chloride. Each vial will be 
packaged in an appropriately labeled single vial carton. 
The placebo infusion will be 250 mL of commercially available sterile 0.9% sodium chloride 
provided by the clinical study center. For both active vedolizumab and placebo infusions, the 
unblinded investigational pharmacist or designee will mask the IV bags after preparation in order 
to maintain the study blind.
Additional reference information and administration instructions can be found in the pharmacy 
manual.
8.1.1.2
Companion Medication
Treatment with ciprofloxacin is required per protocol from Day 1 until Week 4 (Visit 4). 
Ciprofloxacin 500 mg twice daily must be prescribed by the investigator as per the local label. 
Ciprofloxacin will not be provided by the sponsor but will be reimbursed.
8.1.2
Storage
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study drug must be stored under the conditions 
specified on the label, and remain in the original container until dispensed. 
Vedolizumab IV must be stored at 2ºC to 8ºC (36ºF to 46ºF). A daily temperature log of the drug 
storage area must be maintained.
8.1.3
Dose and Regimen
The study drug regimen for both randomized groups is provided in Table 8.a. The vedolizumab IV
or placebo/sodium chloride infusion will be administered intravenously over 30 minutes. 
Instructions for reconstitution and blinded administration will be provided in the pharmacy 
manual. Subjects should be observed for 2 hours following the first 2 infusions, at a minimum, and 
1 hour after each subsequent infusion.
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All subjects will receive the antibiotic ciprofloxacin from Day 1 through Week 4 (Visit 4).
Table 8.a
Dose and Regimen
Treatment Group
Dose
Treatment Description
1
300 mg vedolizumab IV
IV infusion with vedolizumab at Weeks 0, 2, 6, 14, 22, 30
2
0.9% sodium chloride 
(250 mL)
IV infusion with placebo at Weeks 0, 2, 6, 14, 22, 30
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will in addition be documented on AE CRF(s) according to Section 10.0, 
Pretreatment Events and Adverse Events.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
The investigator or the investigator’s designee will access the interactive web response system 
(IWRS) at Screening to obtain the study-specific subject identification number (subject number). 
The investigator or the investigator’s designee will utilize the IWRS to randomize the subject into 
the study. During this contact, the investigator or designee will provide the necessary 
subject-identifying information, including the subject number assigned at Screening. At 
drug-dispensing visits, the investigator or designee will again contact the IWRS to register the 
visits. At Day 1, Weeks 2, 6, 14, 22, and 30 for all subjects in both treatment groups, the IWRS will
provide email notification to the unblinded site pharmacist/nurse. If the subject is randomized to 
vedolizumab IV, a medication identification number (Med ID) will be assigned by IWRS and 
provided to the unblinded site pharmacist/nurse by email notification. If the subject was 
randomized to receive placebo, the IWRS will provide email notification to the unblinded site 
pharmacist/nurse, but no Med ID will be assigned. To maintain the blind the IWRS will ensure the 
investigator or designee is unaware if a Med ID has been assigned or not. If sponsor-supplied drug 
(active vials) is lost or damaged, the site can request a replacement from IWRS by the unblinded 
site pharmacist/nurse. Refer to IWRS manual provided separately.
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8.3
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. Subjects will be randomized in a 1:1 ratio to either vedolizumab or placebo treatment 
using an IWRS. Randomization will be stratified to achieve equal distribution of patients using 
maintenance antibiotic therapy at a stable dose for at least 4 weeks prior to randomization and 
those having had at least 3 episodes of pouchitis despite treatment (with pulse antibiotics or other 
prescription therapy) during the 1 year prior to baseline endoscopy. 
8.4
Drug Blind Maintenance 
The study drug blind will be maintained using the IWRS. All subjects and study personnel except 
for those directly involved with study drug preparation will be blinded to study drug assignment 
for the entire study. In order to maintain the blind, unblinded individuals preparing study drug will 
cover the product in a blinding bag prior to dispensing. All unblinded dosing information must be 
maintained in a secured area, accessible only by unblinded personnel, and separate from blinded 
information.
8.5
Unblinding Procedure
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In the 
event of a medical emergency, if possible, the medical monitor should be contacted before the 
investigational drug blind is broken to discuss the need for unblinding.
The investigator can perform emergency unblinding using the IWRS, if medically necessary. In all 
scenarios, the sponsor must be notified as soon as possible if the investigational drug blind is 
broken. The date, time, and reason the blind is broken must be recorded in the source documents 
and the same information (except the time) must be recorded on the eCRF.
If any site personnel (with the exception of the dispensing pharmacist or unblinded site pharmacy 
personnel/nurse) are unblinded, study drug must be stopped immediately, and the subject must be 
withdrawn from the study. 
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator and investigator’s designated site pharmacy must ensure that the 
sponsor-supplied drug is used in accordance with the protocol and is dispensed only to subjects 
enrolled in the study. To document appropriate use of sponsor-supplied drug (vedolizumab IV),
the investigator pharmacy must maintain records of all sponsor-supplied drug delivery to the site, 
site inventory, dispensation and use by each subject, and return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the designated site pharmacy must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, designated site 
pharmacy personnel should acknowledge the receipt of the shipment by signing bottom half of the 
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packing list and by recording in IWRS. If there are any discrepancies between the packing list 
versus the actual product received, Takeda must be contacted to resolve the issue. The packing list 
should be filed in the investigator’s essential document file.
The investigator’s designated site pharmacy must maintain 100% accountability for all 
sponsor-supplied drugs received and dispensed during his or her entire participation in the study. 
Proper drug accountability includes, but is not limited to:

Monitoring expiration dates (monitored via IWRS).

Frequently verifying that actual inventory matches documented inventory.

Verifying that the drug accountability log is completed for the Medication ID used to prepare 
each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IWRS will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator’s designated site pharmacy must record the current inventory of all 
sponsor-supplied drugs (vedolizumab IV) on a sponsor-approved drug accountability log. The 
following information will be recorded at a minimum: protocol number and title, name of 
investigator, site identifier and number, description of sponsor-supplied drugs, expiry date and 
amount dispensed, and amount returned to the pharmacy (if applicable) including initials, seal, or
signature of the person dispensing the drug. The log should include all required information as a 
separate entry for each subject (by subject identifier) to whom sponsor-supplied drug is dispensed. 
The investigator’s designated site pharmacy staff must complete an individual subject 
accountability log to document if infusion was complete or if incomplete and study drug was 
returned to the pharmacy, including the date and amount returned to the pharmacy, including the 
initials, seal, or signature of the person administering the infusion. Only unblinded designated site 
pharmacy personnel and unblinded clinical research associates (CRAs) can perform drug 
accountability and only unblinded designated site pharmacy staff and unblinded clinical CRAs can 
process drug returns in order to preserve blinding.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent process are described in Section 15.2 and Appendix C.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject through 
the IWRS system at the time that informed consent is obtained; this subject number will be used 
throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth or age, sex, Hispanic 
ethnicity (as applicable), race as described by the subject, height, weight, and smoking/nicotine 
usage status of the subject at Screening.
Medical history to be obtained will include determining whether the subject has any 
significant conditions or diseases relevant to the disease under study that resolved at or prior to 
signing of informed consent. Ongoing conditions are considered concurrent medical 
conditions (see Section 9.1.16).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 60 days prior to signing of informed consent.
In addition, all prior medication history for the treatment of UC/pouchitis, with the reason for 
discontinuation, is to be collected for subjects where possible.
9.1.3
Ulcerative Colitis and Pouchitis History
UC history will include details of UC diagnosis, disease severity, surgery including IPAA date, 
hospitalizations, and extraintestinal manifestations.
9.1.4
Physical Examination Procedure
A Visit 1 (Screening) physical examination will consist of the following body systems: (1) eyes; 
(2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal 
system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other. All subsequent physical examinations should assess clinically 
significant changes from the assessment performed prior to first dose of study drug. 
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9.1.5
Weight, Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters without decimal places and for 
weight it is kilograms (kg) with 1 decimal place.
9.1.6
Vital Sign Procedure
Vital signs will include body temperature, respiratory rate, supine blood pressure (systolic and 
diastolic, resting more than 5 minutes), and pulse (resting more than 5 minutes).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained at least 0.5 hours before or after the scheduled blood draw.
9.1.7
PML Checklist
Site staff will administer the subjective PML checklist during Screening to exclude subjects with 
positive responses from enrolling into the study. The subjective PML checklist will be 
administered prior to dosing at each visit, as shown in Appendix A, to evaluate symptoms 
suggestive of PML. Any subjects reporting signs or symptoms of PML will undergo objective 
testing and may be referred to a neurologist for a full evaluation. The symptoms from a positive 
PML checklist obtained after randomization will be recorded as an AE. Additional information 
and tools will be found in the Investigator Site File.
9.1.8
ECG Procedure
A standard 12-lead electrocardiogram (ECG) will be recorded. The investigator (or a qualified 
observer at the study site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. A copy of the 
ECG trace should be kept with the subject’s notes.
9.1.9
Primary Efficacy Measurement 
The primary efficacy measure is having achieved clinically relevant remission after 14 weeks of 
treatment. Clinically relevant remission will be defined as a mPDAI score <5 and a decrease in 
mPDAI score of ≥2 points from Baseline.
9.1.10 Pouchitis Endoscopy
Endoscopy will be performed at Screening (baseline endoscopy), Week 14, and Week 34. 
All study endoscopies will be video-recorded using the Robarts Central Image Management 
Solutions (CIMS). All study videos will be subject to central review to ensure consistent grading. 
Central reviewer’s assessment will stand as final assessment for eligibility, if different from the 
site’s.
Central reviewers will score endoscopic findings by using a defined list of descriptors defined in 
the Endoscopy Image Review Charter. These include the mPDAI/PDAI descriptors. Additionally,
, number of ulcers (total, aphthous, and non-aphthous), and proportion of surface area 
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ulcerated (excluding aphthous ulcers) in the pouch will be scored for Screening, Week 14, and 
Week 34/Early Termination videos. 
At each endoscopy, a total of 4 to 5 pieces of biopsy will be obtained from the distal, mid, and 
proximal pouch body. Biopsies will be assessed for the presence of inflammation by trained, 
central histopathologists. Work Instructions will detail the requirements for study endoscopy, 
biopsy and histopathology. Subject preparation for endoscopy should follow the site’s usual 
clinical practice (such as phosphate enema or polyethylene glycol). 
9.1.11 PDAI
The PDAI was developed as an objective, and quantitative criteria for pouch inflammation after 
IPAA. The 18-point overall score is calculated from 3 separate 6-point scales based on clinical 
symptoms (0 to 6), endoscopic findings (0 to 6) and histologic changes (0 to 6). The PDAI 
incorporates histologic features of acute inflammation, along with symptom and inflammation on 
endoscopy, and establishes a cutoff of 7 for differentiation between ‘pouchitis’ (≥7 points) and ‘no 
pouchitis’ (<7 points) [33]. See Appendix E. 
Clinically relevant remission in this study is defined as a PDAI score <7 and a reduction of ≥3 
points compared to Baseline. 
Although the standard PDAI remains an optimal way to diagnose pouchitis, the mPDAI, 
consisting of symptom and endoscopy scores from the PDAI but omitting histology scores, offers 
similar sensitivity and specificity in diagnosing patients with acute or acute relapsing pouchitis. A 
cutoff of 5 differentiates patients with pouchitis (mPDAI ≥5) from patients without pouchitis 
(mPDAI <5) [34]. See Appendix F.
Clinically relevant remission in this study is defined as an mPDAI score <5 and a reduction of ≥2 
points from Baseline.
A partial response is defined as a reduction of mPDAI score of ≥2 points from Baseline.
The clinical part of the PDAI score (patient reported symptoms) will be assessed as the average 
from the 3 days immediately prior to Baseline endoscopy (or bowel preparation for endoscopy). 
Recording will be facilitated by a paper diary.
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9.1.14 Patient Reported Outcome Measures
Subjects will complete the IBDQ and the CGQL quality of life questionnaires at the time points 
specified in the schedule of events (Appendix A). 
9.1.14.1 IBDQ
The IBDQ is a valid and reliable [37-39] instrument used to assess quality of life in adult patients 
with IBD. It includes 32 questions on 4 domains of Health-Related Quality-of-Life (HRQOL): 
Bowel Systems (10 items), Emotional Function (12 items), Social Function (5 items), and
Systemic Function (5 items). Subjects are asked to recall symptoms and quality of life from the last
2 weeks and rate each item on a 7-point Likert scale (higher scores equate to higher quality of life). 
A total IBDQ score is calculated by summing the scores from each domain; the total IBDQ score 
ranges from 32 to 224. See Appendix I.
9.1.14.2 Cleveland Global Quality of Life (CGQL) Instrument (Fazio Score)
The CGQL (Fazio Score) was developed as a quality-of-life indicator specifically for patients with 
ileal pouch-anal anastomosis [40]. Subjects rate 3 items (current quality of life, current quality of 
health, and current energy level), each on a scale of 0 to 10 (0, worst; 10, best). The scores are 
added, and the final CGQL utility score is obtained by dividing this result by 30 [40].
Fazio score will be assessed as the average from 3 days immediately prior to endoscopy (or bowel
preparation for endoscopy). Recording will be facilitated by a paper diary.
9.1.15 Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the sponsor (including ciprofloxacin). At each study visit, subjects will be asked whether they 
have taken any medication other than the study drug (used from signing of informed consent 
through Week 48), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF.
9.1.16 Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at Screening/baseline examination, according to the judgement 
of the investigator. The condition (ie, diagnosis) should be described as current on the Medical 
History eCRF.
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9.1.17 Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 20 mL, and the approximate total volume of 
blood for the study is 75 mL. Details of these procedures, specimen handling and required safety 
monitoring will be given in the laboratory manual. 
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBC
WBC with differential*
Hemoglobin
Hematocrit
Platelets
PT/INR
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Calcium
Chloride
Magnesium
Phosphorus
Uric Acid
Glucose
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Specific Gravity
Other:
HIV
Hepatitis panel, including HBsAg and anti-HCV
Serum
Urine
Stool
QuantiFERON for TB
CRP 
hCG (for pregnancy in female 
subjects of childbearing potential only)
Fecal 
calprotectin 
beta hCG (for pregnancy in female subjects of 
childbearing potential only)
FSH, if menopause is suspected (Screening visit only)
C difficile
*WBC differential to include lymphocytes, monocytes, basophils, eosinophils, and neutrophils.
FSH =follicle-stimulating hormone, GGT= γ-Glutamyl transferase, hCG =human chorionic gonadotropin, 
PT=prothrombin time, RBC=red blood cells.
The central laboratory will perform laboratory tests for hematology, serum chemistries, stool, 
urinalysis, and QuantiFERON for TB. The results of laboratory tests will be returned to the 
investigator, who is responsible for reviewing and filing these results.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48-72 hours after the abnormality was noted.
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(Please refer to Section 7.4 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal 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 drug, discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3
Reporting of Abnormal Liver Function Tests for reporting requirements).
9.1.19 Clostridium Difficile Sample Collection
A stool sample will be collected during Screening for the analysis of C difficile.
9.1.20 Tuberculosis Screening
All subjects will complete TB screening to determine eligibility as described in Section 7.2.2, 
unless a negative test result is available from within 3 months prior to Screening and subject has no 
risk factors for exposure. All subjects must complete a diagnostic test during Screening either a 
QuantiFERON test or a tuberculin skin test. Subjects will be excluded from the study if they have 
active or latent TB, regardless of treatment history.
9.1.21 Contraception and Pregnancy Avoidance Procedure
9.1.21.1 Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study drug, nonsterilized** male subjects who are sexually active with a female partner of 
childbearing potential* must use barrier contraception (eg, condom with spermicidal cream or 
jelly). In addition, they must be advised not to donate sperm during this period. 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 contraception below.
9.1.21.2 Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study drug, female subjects of childbearing potential* who are sexually active with a
nonsterilized male partner** must use a highly effective method of contraception (from the list 
below). 
In addition, they must be advised not to donate ova during this period.
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9.1.21.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential (ie, fertile) following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high follicle stimulating hormone 
(FSH) level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a 
post-menopausal state in younger women (ie, younger than age 45) or women who are not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those that, alone or in combination, 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, the 
only acceptable methods of contraception are: 

Non-hormonal methods:

Intrauterine device (IUD). 

Bilateral tubal occlusion. 

Vasectomised partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomised partner has received medical assessment of 
the surgical success).

Hormonal methods:

Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study 
drug OR combined with a barrier method (male condom, female condom or 
diaphragm) if for shorter duration until she has been on contraceptive for 3 months;

Oral.

Intravaginal (eg, ring).

Transdermal.

Progestogen-only hormonal contraception associated with inhibition of 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 until she 
has been on contraceptive for 3 months;
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
Oral. 

Injectable.

Implantable.
2. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
3. Subjects will be provided with information on highly effective methods of contraception as 
part of the subject informed consent process and will be asked to sign a consent form stating 
that they understand the requirements for avoidance of pregnancy, donation of ova, and sperm 
donation during the course of the study.
4. During the course of the study, regular urine human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women of childbearing potential and all subjects (male and 
female) will receive continued guidance with respect to the avoidance of pregnancy and sperm 
donation as part of the study procedures. Such guidance should include a reminder of the
following:
a.
Contraceptive requirements of the study.
b. Reasons for use of barrier methods (ie, condom) in males with pregnant partners.
c.
Assessment of subject compliance through questions such as:
i. Have you used the contraception consistently and correctly since the last 
visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual 
cycles a pregnancy test must be performed if the answer is “yes”)?
iv. Is there a chance you could be pregnant?
5. In addition to a negative serum hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses) and a negative urine hCG pregnancy test prior to receiving each IV dosing.
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9.1.21.4 General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:

Contraceptive requirements of the study.

Reasons for use of barrier methods (ie, condom) in males with pregnant partners.

Assessment of subject compliance through questions such as:
o
Have you used the contraception consistently and correctly since the last visit?
o
Have you forgotten to use contraception since the last visit? 
o
Are your menses late (even in women with irregular or infrequent menstrual cycles 
a pregnancy test must be performed if the answer is “yes”)
o
Is there a chance you could be pregnant?
9.1.22 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and 
sponsor-supplied treatment should be immediately discontinued. In addition, any pregnancies in 
the partner of a male subject during the study or for 18 weeks after the last dose, should also be 
recorded following authorization from the subject’s partner.
If the pregnancy occurs during administration of active study drug, eg, after Visit 1 or within 18 
weeks of the last dose of active study drug, the pregnancy should be reported immediately, using a 
pregnancy notification form, to the contact listed in Section 1.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of the study drug the subject received (blinded or unblinded, as applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug 
including placebo will be followed up to final outcome, using the pregnancy form. Pregnancies 
will remain blinded to the study team. The outcome, including any premature termination, must be 
reported to the sponsor. An evaluation after the birth of the child will also be conducted.
9.1.23 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible, the investigator should complete the eCRF. The IWRS
should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:
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1. PTE/AE.
2. Did not meet inclusion criteria or did meet exclusion criteria (specify reason).
3. Significant protocol deviation.
4. Lost to follow-up.
5. Voluntary withdrawal (specify reason).
6. Study termination.
7. Other, specify.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.24 Documentation of Randomization
Randomization will be performed through the IWRS system. Only subjects who meet all of the 
inclusion criteria and none of the exclusion criteria are eligible for randomization into the 
treatment phase.
9.2
Monitoring Subject Treatment Compliance
A study drug dispensing log, including records of drug received from the sponsor and volume of 
vedolizumab dispensed to each subject intravenously, will be maintained by the site. 
If a subject is persistently noncompliant with the study drug, it may be appropriate to withdraw the 
subject from the study. 
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A.
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening 
Subjects will be screened within 28 days prior to randomization. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.23 for procedures for documenting screening failures.
Procedures to be completed at Screening (Visit 1) can be found in the Schedule of Study 
Procedures (Appendix A). 
9.3.2
Rescreening
Automatic rescreening of a subject is not allowed. If the principal investigator believes in the 
appropriateness of the subject for the study and considers a rescreen, permission for the same must 
be obtained from the medical monitor. Rescreening at the investigator’s discretion without prior 
approval from the medical monitor is not permitted. Rescreening can be done only once for a 
patient.
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There is a minimum of 28 days from initial screening before rescreening can be done.
If C difficile eradication is done, a minimum of 28 days after end of therapy is required before 
rescreening. 
All inclusion and exclusion criteria must be met again at Randomization. 
If a patient was randomized, no rescreening or re-enrollment is possible.
9.3.3
Study Randomization 
Randomization will take place on Day 1. The Day 1 procedures are documented in Appendix A.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IWRS as described in Section 8.2. 
Subjects will be instructed on when the first dose of study drug will be given as described in 
Section 8.1.3. The procedure for documenting Screening failures is provided in Section 9.1.23. 
9.3.4
End of Treatment Visit
The End of Treatment (EOT) Visit will be performed at Week 30.
9.3.5
Final Endoscopy Visit or Early Termination
The Final Endoscopy Visit will be performed at Week 34 or at ET.
For all subjects receiving study drug, the investigator must complete the End of Study (EOS) 
eCRF page.
9.3.6
Safety Follow-Up Visit
Follow-up will begin the first day after the Final Endoscopy Visit or Early Termination Visit and 
will continue for 18 weeks post-treatment until Week 48. If subject is male or subject is 
postmenopausal and cannot attend the site for this visit, the visit may be conducted via phone.
9.3.7
Post-Study Follow-Up
Upon completion of or early termination from the study, all subjects will complete a LTFU safety 
survey by telephone. This questionnaire will be administered at 26 weeks after the last dose of 
study drug.
9.3.8
Unscheduled Visits Due to Exacerbation/Relapse of Pouchitis
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:
1. Physical examination.
2. Urine pregnancy test (for females of childbearing potential).
3. Clinical chemistry and hematology, if indicated.
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4. Concomitant medications.
5. AE/SAE assessment.
9.3.9
Post-Study Care
Vedolizumab IV will not be supplied upon completion of the subject’s participation in the study. 
The subject should be returned to the care of a physician and standard therapies as required.
Subject to applicable laws and feasibility and Takeda’s decision, access to the study drug may be 
available to individual subjects for whom no standard therapy exists, and the subject is at risk of 
significant morbidity or mortality.
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10.0
PRETREATMENT EVENTS (PTE) AND ADVERSE EVENTS (AE)
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study drug; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with the use of a drug whether or not 
it is considered related to the drug.
10.1.3 Product Complaints
A product complaint (PC) is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product and/or device 
(eg, prefilled syringe).
An investigator who is made aware of or identifies a potential PC should immediately report the 
event to Takeda in accordance with the contact list provided to the site. Whenever possible, the 
associated product should be maintained in accordance with the instructions pending further 
guidance from a Takeda representative.
10.1.4 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 preexisting conditions or underlying disease should not be considered PTEs or 
AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
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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 findings are only considered to be PTEs or AEs if they
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory or ECG re-test and/or continued monitoring of an abnormal value or finding are not 
considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent medical condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study drug) or an AE 
(worsening or complication occurs after start of study drug). Investigators should ensure that 
the event term recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) 
any occurrence of an episode should only be captured as a PTE/AE if the condition becomes 
more frequent, serious or severe in nature. Investigators should ensure that the AE term 
recorded captures the change in the condition from Baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if occurring to a 
greater extent to that which would be expected. 
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration 
of the study drug, the worsening or complication should be recorded appropriately as an AE. 
Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).
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
If the subject experiences a worsening or complication of an AE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”).
Changes in intensity of AEs /Serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions)

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be recorded as a PTE or an AE. Complications resulting
from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page 
of the eCRF.
10.1.5 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.
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5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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).
10.1.6 AEs of Special Interest
An AESI (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 including opportunistic infection such as PML, 
liver injury, malignancies, infusion-related or systemic reactions and hypersensitivity, as 
described in further detail below.
Injection and/or Infusion Site Reactions and Hypersensitivity 
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence such 
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premedications are unlikely to be necessary or beneficial. At the discretion of the investigator, 
however, subjects may be administered premedication prior to any study drug administration. 
Corticosteroids, if given as a premedication, should be limited to the day of administration. 
Vedolizumab IV should be administered by a health care practitioner prepared to manage 
hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and medical 
support measure should be available for immediate use. Subjects should be observed for 2 hours
following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion.
Subjects and caregivers will be instructed to report the development of rash, hives, pruritus, flushing, 
urticaria, injections site pain, redness, and/or swelling, etc. that may represent an 
administration-related reaction (ie, infusion-related reaction) to study drug. Subjects will be asked to 
report administration-related AEs to the sites immediately as they are experienced. Appropriate 
treatment and follow-up will be determined by the investigator. If signs or symptoms of an 
administration-related reaction are observed during the administration of study drug, it should be 
immediately discontinued and the subject treated as medically appropriate. In the case of a mild 
reaction, study drug administration may be reinitiated (with appropriate premedication and 
investigator supervision) at the discretion of the investigator. Subjects with a severe or serious 
administration-related reaction (eg, shortness of breath, wheezing, stridor, angioedema, 
life-threatening change in vital signs, severe injection site reactions) must be withdrawn from the 
study (see Investigator Site File). 
In all cases of administration-related reaction, the medical monitor must be informed as soon as
practical. The disposition of subjects with less severe administration-related reactions should be 
discussed with the medical monitor.
Serious Infections
Subjects will be monitored for signs and symptoms of infection and for lymphopenia during the 
study. Subjects with signs and symptoms suggestive of infections, including GI infections, will be 
treated as clinically indicated. Interventions may include antibiotic treatment, if appropriate and/or 
discontinuation of concomitant immunomodulators. Blood, sputum, urine, and/or stool cultures 
should be obtained as appropriate for the detection and diagnosis of infection. Withholding or 
terminating study drug administration may be considered as described in Section 7.4.
Malignancies
All cases of malignancies that are detected during the study will be reported as AEs. Local medical 
practices for the management of malignances will apply. Subjects with history of malignancy 
(except for specific cancers) or at high risk for malignancy will be excluded from the study per the 
exclusion criteria. 
Other 
Other special interest AEs include liver injury and PML, which are discussed in Sections 10.2.3
and 11.2.1, respectively.
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10.1.7 Intensity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.8 Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications 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 medications and concurrent treatments.
10.1.9 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. 
10.1.10
Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator, and the time, if available.
10.1.11
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died, and the time, if available.
10.1.12
Frequency
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.13
Action Concerning Study Drug

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.
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
Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped 
before the onset of the AE.

Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.14
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with
some persisting paresis).

Fatal – the AEs/PTEs which are considered as the cause of death. 

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Start of PTE collection:
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study drug (Day 1; Visit 
2) or until screen failure. For subjects who discontinue prior to study drug administration, PTEs are 
collected until the subject discontinues study participation.
Start of AE collection: 
AEs must be collected from the time that the subject is first administered study drug (Day 1; 
Visit 2). Any drugs provided by the sponsor are considered study drugs, including placebo.
Routine collection of AEs will continue until Week 48 (Visit 10).
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10.2.1.2 PTE and AE Reporting
1. Event term.
2. Start and stop date, and time (if available).
3. Frequency
4. Intensity
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
PDAI and QOL instruments will not be used as a primary means to collect AEs. However, should 
the investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied.
10.2.1.3 AEs of Special Interest
If an AE of special interest, which occurs during the treatment period or the follow-up period, is 
considered to be clinically significant based on the criteria in Section 10.1.6, it should be recorded 
in an AE of special interest eCRF or SAE Form. The applicable form should be completed and 
reported to the SAE reporting contact in Section 1.1 within 24 hours.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE eCRF or form must be completed, in English and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s).

Causality assessment.
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The SAE eCRF should be completed within 24 hours of first onset or notification of the event. 
However, as a back-up, if required, the SAE form should be completed and reported to Takeda 
Pharmacovigilance or designee within 24 hours to the attention of the contact listed in Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.17 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-Up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first awareness
of the event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be 
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 a study drug/sponsor supplied drug or 
that would be sufficient to consider changes in the study drug/sponsor supplied drug 
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administration or in the overall conduct of the trial. The study site also will forward a copy of all
expedited reports to his or her IRB or IEC in accordance with local regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No data safety monitoring committee will be used in this study.
11.1
Steering Committee 
The Steering Committee will comprise medical experts involved in the study, the sponsor, and an 
independent statistician. The Steering Committee will remain blinded to treatment assignments 
throughout the conduct of the study. The Steering Committee will oversee the conduct and 
reporting of the study, ensuring expert clinical guidance and a high standard of scientific quality, 
and making any necessary modifications to the protocol. The Steering Committee charter will 
define the responsibilities of the committee.
11.2
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. Adjudication will be done on blinded data.
11.2.1 Risk Assessment and Minimization Action Plan for PML (RAMP) Program
Natalizumab (TYSABRI), another integrin receptor antagonist, has been associated with PML, a 
rare and often fatal opportunistic infection of the central nervous system. PML is caused by the 
John Cunningham virus (JCV) and typically only occurs in subjects who are immunocompromised 
[41, 42]. Natalizumab is a pan- α4 integrin antagonist that binds to both the α4β1 and α4β7 
integrins and inhibits cellular adhesion to VCAM-1 and MAdCAM-1 [43, 44]. In contrast, 
vedolizumab binds to the α4β7 integrin only [21] and inhibits adhesion to MAdCAM-1, but not
VCAM-1. Although no cases of PML have been reported in clinical trials with vedolizumab to 
date, a risk of PML cannot be ruled out.
To address the theoretical risk of the development of PML in subjects treated with vedolizumab, 
the sponsor, with input from renowned PML experts, has developed a Risk Minimization Action 
Plan for PML, the RAMP. The complete description of the RAMP program, including materials 
and instructions for its implementation and monitoring, is included in the Investigator Site File.
The RAMP is focused on early clinical detection and management of that specific safety risk, 
including the discontinuation of study drug, if applicable. Subjects are assessed for signs and 
symptoms of PML prior to the administration of each dose of study drug using a PML subjective 
symptom checklist. Subjects with a positive PML subjective symptom checklist at any time after 
enrollment in a vedolizumab clinical study will be evaluated according to a prespecified algorithm 
(the PML Case Evaluation Algorithm). The next dose of study drug will be held until the 
evaluation is complete and results are available. Subsequent doses of study drug will be 
administered only if the possibility of PML is definitively excluded, as described in the RAMP 
algorithm. An IAC has been established as part of the RAMP program to review new neurological 
signs and symptoms potentially consistent with PML, and will provide input regarding subject 
evaluation and management as defined in the IAC charter.
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To ensure success of the RAMP program, site personnel will be trained to recognize the features of 
PML, and subjects will be trained to report specific neurological signs and symptoms without 
delay. Educational materials for teaching site personnel and subjects about PML and the RAMP 
procedures will be distributed to all sites and are included in the Investigator Site File. Formal 
teaching and training will be performed for site personnel prior to the start of the study. Subjects 
will receive training and educational materials prior to receiving treatment. The informed consent 
form will contain specific information on the hypothetical risk of PML. Any documented case of 
PML will be reported as an SAE, regardless of whether hospitalization occurs.
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent medical 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
eCRFs 
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply study 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 the sponsor or its designee. 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 study site agreement between the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
A blinded data review will be conducted prior to 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
All randomized subjects will contribute to the full analysis set (FAS) and be used for the primary 
analysis population for efficacy. Subjects in the FAS will be analyzed according to the treatment 
they were randomized to receive.
All FAS subjects who do not have any major protocol violations will be included in the 
per-protocol (PP) population. Major protocol violations will be specified in the SAP. 
All subjects who received at least 1 dose of study drug will be included in the safety analysis set 
(SAF).
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Baseline and demographic information will be listed and summarized. For continuous variables, 
the summary will consist of descriptive statistics (number of subjects, mean, standard deviation, 
minimum, median, and maximum). For categorical variables, the summary will consist of number 
and percentage of subjects in each category.
Medical history and concurrent medical conditions will be summarized by system organ class and 
preferred term. Medication history and concomitant medications will be summarized by preferred 
term.
13.1.3 Efficacy Analysis
The primary efficacy endpoint is the percentage of subjects who achieve remission after 14 weeks 
of treatment (defined as a mPDAI score <5 and a reduction of overall score by ≥2 points from 
Baseline). Subjects who withdraw early for any reasons will be included in the denominator for the 
estimation of this percentage. At the final analysis, the difference between the percentages of 
subjects achieving remission at Week 14 in each treatment group will be assessed by the 
chi-squared test. The null hypothesis, that the percentage of subjects achieving remission at 
Week 14 in each treatment group is the same, will be tested against the alternative hypothesis that 
the 2 percentages are not the same.
The secondary endpoint, the time to symptomatic remission (defined as a PDAI score <7 and a 
decrease in PDAI score of ≥3 points from Baseline), will be analyzed by survival analysis 
procedures. Remission rates from the time of randomization over the 34-week study period will be 
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estimated by Kaplan-Meier product limit methods. The log-rank test will be applied to compare 
the 2 treatment groups. Cox proportional hazards regression will be performed to explore the effect 
of prognostic factors. Adjustments for baseline imbalances on key prognostic factors will be made 
using Cox regression. As this is a multicenter clinical study, heterogeneity of treatment effect 
across the participating centers will be explored. 
Other dichotomous secondary endpoints will be analyzed by calculating rates and corresponding 
95% confidence intervals, which will be reported by treatment group; rate differences between 
treatment groups and their 95% confidence intervals will also be reported.
Change from baseline in mPDAI, PDAI, 
 IBDQ, and CGQL scores will be analyzed 
using Wilcoxon rank-sum tests; the Wilcoxon-Mann-Whitney odds estimator and its 95% CI will 
also be presented.
The primary efficacy analysis will be based on the FAS population including all randomized 
subjects. Analysis will also be performed on the PP population for confirmatory purposes.
Statistical tests will be 2-sided and performed at the 0.05 level of significance.
13.1.4 Safety Analysis
Safety analyses will be based on the SAF set. All subjects who received at least 1 dose of study 
drug will be included in the safety analysis set. No formal statistical tests or inference will be 
performed for safety analyses. Safety data will be presented by treatment group.
The number and percentage of subjects with AEs (regardless of relationship to study drug), AEs of 
special interest (ie, serious infections including opportunistic infection such as PML, liver injury, 
malignancies, infusion-related or systemic reactions, and hypersensitivity), AEs leading to 
discontinuation, and SAEs that occur on or after the first dose date and up to 18 weeks after the last 
dose date of the study drug will be summarized by MedDRA system organ class, high level term, 
and preferred term overall, by severity, and by relationship to study drug. If a subject experienced 
more than 1 AE for a given preferred term, intensity is defined as the intensity of the most severe 
event and relationship to study drug is the relationship of the most related event. 
Change from Baseline in clinical laboratory tests, vital signs and weight will be summarized by 
treatment group. Subjects with markedly abnormal values for laboratory tests and vital signs will 
be tabulated.
Physical examination findings and PML checklist data will be presented in data listings.
Data from the long-term follow-up survey will be summarized descriptively.
13.2
Futility Analysis and Criteria for Early Termination
A single futility analysis will be performed when 25 patients per treatment arm have been recruited 
and completed their Week 14 assessment of primary efficacy. The purpose of this analysis will be 
to assess futility, and at this point simulations will be performed to determine the posterior 
probability of achieving a treatment difference of at least 25% between the active and placebo 
treatment arms. On the basis of the posterior probability of success, a decision will be made to 
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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continue or terminate the study on the grounds of futility or to continue the study to completion. It 
is not intended to stop the study on the grounds of efficacy; hence, no adjustment to the statistical 
significance level used for testing at the final analysis is necessary.
13.3
Determination of Sample Size
The sample size is calculated based on the remission rate at 14 weeks. The previous sample size 
was based on the observed remission rate in GEMINI 1 in patients with moderate to severe 
ulcerative colitis: the placebo group remission rate was 8%, the vedolizumab group rate was 23%;
an effect size of 15%. 
However, pouchitis is different from UC and a new assessment using published data was made to 
evaluate what would be a significant treatment effect. On the basis of 2 recent papers using the 
mPDAI as the primary endpoint [45, 46], a placebo rate of 15% was estimated. A clinically
significant effect was estimated to be of 25%, an average of the remission (complete response)
observed in the 2 aforementioned papers (32% and 21% post-induction response, respectively) 
evaluating the effect of infliximab using the mPDAI.
An effect size of at least 25% would be considered clinically meaningful (ie, a remission rate of 
40% in subjects maintained on vedolizumab IV). Therefore, a total of 98 evaluable subjects (49 per 
treatment group) will be required to detect a 25% difference in the remission rate at the 2-sided 
0.05 level of significance with 80% power. To account for attrition, 110 subjects will be 
randomized (55 per treatment group). 
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study drug, subject medical records, informed consent documentation, documentation of subject 
authorization to use personal health information (if separate from the informed consent forms), 
and review of eCRFs and associated source documents. It is important that the investigator and 
other study personnel are available during the monitoring visits and that sufficient time is devoted 
to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (prospectively approved deviations) 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 IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor
should be notified immediately. The investigator and institution guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, the 
vedolizumab IV (Entyvio) package insert, a copy of the informed consent form, and, if applicable, 
subject recruitment materials and/or advertisements and other documents required by all 
applicable laws and regulations, must be submitted to a central or local IRB or IEC for approval. 
The IRB’s or IEC’s written approval of the protocol and subject informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study (ie, before 
shipment of the sponsor-supplied drug or study specific screening activity). The IRB or IEC 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, informed consent form) reviewed; and state the approval date. The 
sponsor will 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.
Study 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 trial 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 and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for American investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor
or sponsor’s designee.
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16.0
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21.
Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and 
selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in 
development for inflammatory bowel diseases. J Pharmacol Exp Ther 
2009;330(3):864-75.
22.
Hurst RD, Chung TP, Rubin M, Michelassi F. The implications of acute pouchitis on the 
long-term functional results after restorative proctocolectomy. Inflamm Bowel Dis 
1998;4(4):280-4.
23.
Madiba TE, Bartolo DC. Pouchitis following restorative proctocolectomy for ulcerative 
colitis: incidence and therapeutic outcome. J R Coll Surg Edinb 2001;46(6):334-7.
24.
Feagan BG, Greenberg GR, Wild G, Fedorak RN, Pare P, McDonald JW, et al. Treatment 
of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med 
2005;352(24):2499-507.
25.
Parikh A, Fox I, Leach T, Xu J, Scholz C, Patella M, et al. Long-term clinical experience 
with vedolizumab in patients with inflammatory bowel disease. Inflamm Bowel Dis 
2013;19(8):1691-9.
26.
Feagan BG, Greenberg GR, Wild G, Fedorak RN, Pare P, McDonald JW, et al. Treatment 
of active Crohn's disease with MLN0002, a humanized antibody to the alpha4beta7 
integrin. Clin Gastroenterol Hepatol 2008;6(12):1370-7.
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27.
Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. 
Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 
2013;369(8):699-710.
28.
Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. 
Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 
2013;369(8):711-21.
29.
Meagher AP, Farouk R, Dozois RR, Kelly KA, Pemberton JH. J ileal pouch-anal 
anastomosis for chronic ulcerative colitis: complications and long-term outcome in 1310 
patients. Br J Surg 1998;85(6):800-3.
30.
Shen B, Lashner BA. Diagnosis and treatment of pouchitis. Gastroenterol Hepatol (N Y) 
2008;4(5):355-61.
31.
Entyvio (vedolizumab) for injection, for intravenous use. Full Prescribing Information. 
Deerfield, IL: Takeda Pharmaceuticals America, Inc., Issued May 2014.
32.
Entyvio (vedolizumab) 300 mg powder for concentrate for solution for infusion. Summary 
of Product Characteristics. Denmark: Takeda Pharma A/S, Issued 25 September 2015.
33.
Sandborn WJ, Tremaine WJ, Batts KP, Pemberton JH, Phillips SF. Pouchitis after ileal 
pouch-anal anastomosis: a Pouchitis Disease Activity Index. Mayo Clin Proc 
1994;69(5):409-15.
34.
Shen B, Achkar JP, Connor JT, Ormsby AH, Remzi FH, Bevins CL, et al. Modified 
pouchitis disease activity index: a simplified approach to the diagnosis of pouchitis. Dis 
Colon Rectum 2003;46(6):748-53.
35.
Daperno M, D'Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. 
Development and validation of a new, simplified endoscopic activity score for Crohn's 
disease: the SES-CD. Gastrointest Endosc 2004;60(4):505-12.
36.
Mosli MH, Feagan BG, Zou G, Sandborn WJ, D'Haens G, Khanna R, et al. Reproducibility 
of histological assessments of disease activity in UC. Gut 2015;64(11):1765-73.
37.
Irvine EJ. Development and subsequent refinement of the inflammatory bowel disease 
questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel 
disease. J Pediatr Gastroenterol Nutr 1999;28(4):S23-7.
38.
Guyatt G, Mitchell A, Irvine EJ, Singer J, Williams N, Goodacre R, et al. A new measure 
of health status for clinical trials in inflammatory bowel disease. Gastroenterology 
1989;96(3):804-10.
39.
Guyatt GH, Deyo RA, Charlson M, Levine MN, Mitchell A. Responsiveness and validity 
in health status measurement: a clarification. J Clin Epidemiol 1989;42(5):403-8.
40.
Fazio VW, O'Riordain MG, Lavery IC, Church JM, Lau P, Strong SA, et al. Long-term 
functional outcome and quality of life after stapled restorative proctocolectomy. Ann Surg 
1999;230(4):575-84; discussion 84-6.
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41.
Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory 
therapies. Annu Rev Med 2010;61:35-47.
42.
Steiner I, Berger JR. Update on progressive multifocal leukoencephalopathy. Curr Neurol 
Neurosci Rep 2012;12(6):680-6.
43.
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 
2005;353(18):1912-25.
44.
TYSABRI (natalizumab) injection. Full Prescribing Information. Cambridge, MA: Biogen 
Idec Inc., Revised May 2015.
45.
Ferrante M, D'Haens G, Dewit O, Baert F, Holvoet J, Geboes K, et al. Efficacy of 
infliximab in refractory pouchitis and Crohn's disease-related complications of the pouch: 
a Belgian case series. Inflammatory Bowel Disease 2010;16(2):243-9.
46.
Barreiro-de Acosta M, Garcia-Bosch O, Souto R, Manosa M, Miranda J, Garcia-Sanchez 
V, et al. Efficacy of infliximab rescue therapy in patients with chronic refractory pouchitis: 
a multicenter study. Inflammatory bowel diseases 2012;18(5):812-7.
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Appendix A
Schedule of Study Procedures
Screening
Treatment
Final 
Endosc
opy 
Visit
or ET
Safety 
Follow-Up
(a)
Post-Study
Study Day/Week:
Days
-28 to -1
Wk0/ 
Day 1
Wk 
2
Wk 
4
Wk 
6
Wk 
14
Wk 
22
Wk 30 
(EOT)
Wk 34
(EOS)
Wk 48
(or 18 
weeks 
post-tx if 
ET)
Phone Wk 
56
(or 26 
weeks 
post-tx if 
ET)
Visit Windows (Days):
±2
±2
±2
±3
±7
±7
±7
±7
±7
Visit Number:
1 (b)
2
3
4
5
6
7
8
9 (c) 
/ET
10
11
Informed Consent (d)
X
Inclusion/Exclusion Criteria
X
X
Demographics
X
Medical/Surgical History
X (e)
UC/Pouchitis Disease 
History
X
Concomitant
Medications/Procedures (f)
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
Weight & Height
X (g)
X
X
X
X
X
X
X
X
Vital Signs 
X 
X
X
X
X
X
X
X
X
ECG
X
IBDQ
X
X
X
X
CGQL
X
X
X
X
mPDAI
X (h)
X
X
PDAI 
X (h)(i)
X
X
Pouch Endoscopy with 
Biopsy
X
X
X
Hematology
X
X
X
X
X
Serum Chemistry and Other 
Laboratory Tests
X
X
X
X
X
HIV/Hepatitis panel
X (j)
Urinalysis
X
X
X
X
X
CRP
X
X
X
X
X
FSH (k)
X
Tuberculosis 
QuantiFERON or Skin Test
X
C difficile test
X
Serum Pregnancy Test (l)
X
X
Urine Pregnancy Test (l)
X (m) X (m)
X
X (m) X (m) X (m) X (m)
X
Fecal Calprotectin Assay
X
X (m)
X
X
X
X
Study Drug Dosing (IV) (n)
X
X
X
X
X
X
Ciprofloxacin 
X
X
X (o)
X(o)
X(o)
X(o)
Footnotes are on last table page.
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Appendix A
Schedule of Study Procedures (continued)
Screening
Treatment
Final 
Endosc
opy 
Visit 
or ET
Safety 
Follow-Up 
(a)
Post-Study
Study Day/Week:
Days
-28 to -1
Wk0/ 
Day 1
Wk 
2
Wk 
4
Wk 
6
Wk 
14
Wk 
22
Wk 30 
(EOT)
Wk 34
(EOS)
Wk 48
(or 18 
weeks 
post-tx if 
ET)
Phone Wk 
56
(or 26 
weeks 
post-tx if 
ET)
Visit Windows (Days):
±2
±2
±2
±3
±7
±7
±7
±7
±7
Visit Number:
1 (a)
2
3
4
5
6
7
8
9 (b) 
/ET
10
11
PML Checklist
X
X (m) X (m)
X
X (m) X (m) X (m) X (m)
X
X
Provide PML Wallet Card
X
X
PTE Assessment (f)
X
X
AE/SAE Assessment (f)
X
X
X
X
X
X
X
X
X
Long-Term Follow-Up 
Questionnaire
X
Access IWRS to Obtain 
Subject ID
X
Access IWRS for 
Randomization
X
Access IWRS to Register 
Visit
X
X
X
X
X
X
X
X
Wk=Week.
(a) If subject is male or subject is postmenopausal and cannot attend the site for the safety follow-up visit, the safety 
follow-up visit may be conducted via phone.
(b) Once informed consent is obtained, listed procedures may be performed at any time during the screening period.
(c) Perform Visit 9 procedures if subject withdraws before Week 34.
(d) Informed consent process can begin prior to Visit 1, for example, if washout from medications is required. 
(e) Smoking/nicotine usage status will be captured as part of medical history.
(f) Record adverse events, PTEs, and medications from the time of signing the Informed Consent Form. 
(g) Height collected only at Visit 1.
(h) Clinical mPDAI and PDAI scores (patient reported symptoms) will be assessed as average from 3 days immediately prior to 
baseline endoscopy (or bowel preparation for endoscopy). Recording will be facilitated by a paper diary.
(i) Clinical and endoscopic PDAI scores for Visit 2 will be the scores obtained during Screening, and the histologic score will be 
added when available to complete the full PDAI score.
(j) Hepatitis and HIV testing only done at the Screening Visit.
(k) Only if menopause is suspected.
(l) Only required for women of child bearing potential.
(m) To be performed before dosing.
(n) Subjects should be observed for 2 hours following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion 
for monitoring hypersensitivity reactions.
(o) All subjects will receive ciprofloxacin 500 mg twice daily through Week 4. Additional antibiotics will be allowed, as needed, 
for flares after Week 14.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on Investigators from the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572) which must be completed and 
signed before the Investigator may participate in this study.
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard 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/Secure prior 
approval of the study and any changes by an appropriate IRB/IEC that conform to 21 Code of 
Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
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.
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10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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.
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 
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participation at any time without penalty or loss of benefits to which the subject is otherwise
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients,
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from Screening throughout the duration of the study. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study drug will be discontinued and the investigator will 
offer the subject the choice to receive unblinded treatment information.
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study. If the partner or wife
of the subject is found to be pregnant during the study, the investigator will offer the subject the 
choice to receive unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name,
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix E
The Pouchitis Disease Activity Index (PDAI)
The Pouchitis Disease Activity Index (PDAI)[33]
Criteria
Score
Subtotal
Clinical
Stool frequency
Usual postoperative stool frequency
1-2 stools/day > postoperative usual
3 or more stools/day > postoperative usual
Rectal bleeding
None or rare
Present daily
Fecal urgency or abdominal cramps
None
Occasional
Usual
Fever (temperature >37.8 ◦C)
Absent 
Present
0
1
2
0
1
0
1
2
0
1
Endoscopic inflammation
Edema
Granularity
Friability
Loss of vascular pattern
Mucus exudates
Ulceration
1
1
1
1
1
1
Acute histologic 
inflammation
Polymorphic nuclear leukocyte infiltration 
None
Mild
Moderate + crypt abscess
Severe + crypt abscess
Ulceration per low power field (mean)
0%
<25%
25-50%
>50%
0
1
2
3
0
1
2
3
Total PDAI
Based on Sandborn et al. Mayo Clin Proc. 1994; 69(5);409-15.
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Appendix F
The Modified Pouchitis Disease Activity Index (mPDAI) 
The Modified Pouchitis Disease Activity Index (mPDAI)
Criteria
Score
Subtotal
Clinical
Stool frequency
Usual postoperative stool frequency
1-2 stools/day > postoperative usual
3 or more stools/day > postoperative usual
Rectal bleeding
None or rare
Present daily
Fecal urgency or abdominal cramps
None
Occasional
Usual
Fever (temperature >37.8 ◦C)
Absent 
Present
0
1
2
0
1
0
1
2
0
1
Endoscopic inflammation
Edema
Granularity
Friability
Loss of vascular pattern
Mucus exudates
Ulceration
1
1
1
1
1
1
Total mPDAI
Based on Shen et al. Dis Colon Rectum 2003:46(6):748-53 [34]. 
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CCI
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mercial Use Only and Subject to the Applicable Terms of Use


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CCI
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ial Use Only and Subject to the Applicable Terms of Use


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Appendix I
Inflammatory Bowel Disease Questionnaire (IBDQ)
INSTRUCTIONS FOR SELF-ADMINISTERED IBDQ
This questionnaire is designed to measure the effects of your inflammatory bowel disease on your 
daily function and quality of life. You will be asked about symptoms you have been having as a 
result of your bowel disease, the way you have been feeling in general, and how your mood has 
been.
On this questionnaire there are 32 questions. Each question has a graded response numbered from 
I through 7. Please read each question carefully and circle/mark the number which best describes 
how you have been feeling in the past 2 weeks.
EXAMPLE
How often have you felt unwell as a result of your bowel problem in the past 2 weeks?
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
If you are having trouble understanding a question, STOP for a moment! Think about what the 
question means to you. How is it affected by your bowel problem? Then answer the question as 
best you can. You will have the chance to ask the research assistant questions after completing the 
questionnaire. This takes only a few minutes to complete.
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QUALITY OF LIFE IN INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE 
(IBDQ)
This questionnaire is designed to find out how you have been feeling during the last 2 weeks. 
You will be asked about symptoms you have been having as a result of your inflammatory 
bowel disease, the way you have been feeling in general, and how your mood has been.
1. How frequent have your bowel movements been during the last two weeks? Please indicate 
how frequent your bowel movements have been during the last two weeks by picking one of 
the options from
1
BOWEL MOVEMENTS AS OR MORE FREQUENT THAN THEY HAVE EVER 
BEEN
2
EXTREMELY FREQUENT
3
VERY FREQUENT
4
MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
5
SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
6
SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
7
NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
2. How often has the feeling of fatigue or of being tired and worn out been a problem for you 
during the last 2 weeks? Please indicate how often the feeling of fatigue or tiredness has been a 
problem for you during the last 2 weeks by picking one of the options from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
3. How often during the last 2 weeks have you felt frustrated, impatient, or restless? Please 
choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
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Vedolizumab IV
Study No. Vedolizumab-4004
Page 94 of 107
Protocol Incorporating Amendment No. 04
14 September 2020
4. How often during the last 2 weeks have you been unable to attend school or do your work 
because of your bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
5. How much of the time during the last 2 weeks have your bowel movements been loose? Please 
choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
6. How much energy have you had during the last 2 weeks? Please choose an option from
1
NO ENERGY AT ALL
2
VERY LITTLE ENERGY
3
A LITTLE ENERGY
4
SOME ENERGY
5
A MODERATE AMOUNT OF ENERGY
6
A LOT OF ENERGY
7
FULL OF ENERGY
7. How often during the last 2 weeks did you feel worried about the possibility of needing to have 
surgery because of your bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
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Vedolizumab IV
Study No. Vedolizumab-4004
Page 95 of 107
Protocol Incorporating Amendment No. 04
14 September 2020
8. How often during the last 2 weeks have you had to delay or cancel a social engagement 
because of your bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
9. How often during the last 2 weeks have you been troubled by cramps in your abdomen? Please 
choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
10. How often during the last 2 weeks have you felt generally unwell? Please choose an option 
from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
11. How often during the last 2 weeks have you been troubled because of fear of not finding a 
washroom? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
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Vedolizumab IV
Study No. Vedolizumab-4004
Page 96 of 107
Protocol Incorporating Amendment No. 04
14 September 2020
12. How much difficulty have you had, as a result of your bowel problems, doing leisure or sports 
activities you would have liked to have done during the last 2 weeks? Please choose an option 
from
1
A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE
2
A LOT OF DIFFICULTY
3
A FAIR BIT OF DIFFICULTY
4
SOME DIFFICULTY
5
A LITTLE DIFFICULTY
6
HARDLY ANY DIFFICULTY
7
NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS OR 
LEISURE ACTIVITIES
13. How often during the last 2 weeks have you been troubled by pain in the abdomen? Please 
choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
14. How often during the last 2 weeks have you had problems getting a good night’s sleep, or been 
troubled by waking up during the night? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
NONE OF THE TIME
15. How often during the last 2 weeks have you felt depressed or discouraged? Please choose an 
option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
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Vedolizumab IV
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Protocol Incorporating Amendment No. 04
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6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
16. How often during the last 2 weeks have you had to avoid attending events where there was no 
washroom close at hand? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
17. Overall, in the last 2 weeks, how much of a problem have you had with passing large amounts 
of gas? Please choose an option from
1
A MAJOR PROBLEM
2
A BIG PROBLEM
3
A SIGNIFICANT PROBLEM
4
SOME TROUBLE
5
A LITTLE TROUBLE
6
HARDLY ANY TROUBLE
7
NO TROUBLE
18. Overall, in the last 2 weeks, how much of a problem have you had maintaining or getting to, 
the weight you would like to be at? Please choose an option from
1
A MAJOR PROBLEM
2
A BIG PROBLEM
3
A SIGNIFICANT PROBLEM
4
SOME TROUBLE
5
A LITTLE TROUBLE
6
HARDLY ANY TROUBLE
7
NO TROUBLE
19. Many patients with bowel problems often have worries and anxieties related to their illness. 
These include worries about getting cancer, worries about never feeling any better, and worries 
about having a relapse. In general, how often during the last 2 weeks have you felt worried or 
anxious? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
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Vedolizumab IV
Study No. Vedolizumab-4004
Page 98 of 107
Protocol Incorporating Amendment No. 04
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4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
20. How much of the time during the last 2 weeks have you been troubled by a feeling of 
abdominal bloating? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
21. How often during the last 2 weeks have you felt relaxed and free of tension? Please choose an 
option from
1
NONE OF THE TIME
2
A LITTLE OF THE TIME
3
SOME OF THE TIME
4
A GOOD BIT OF THE TIME
5
MOST OF THE TIME
6
ALMOST ALL OF THE TIME
7
ALL OF THE TIME
22. How much of the time during the last 2 weeks have you had a problem with rectal bleeding 
with your bowel movements? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
23. How much of the time during the last 2 weeks have you felt embarrassed as a result of your 
bowel problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
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Study No. Vedolizumab-4004
Page 99 of 107
Protocol Incorporating Amendment No. 04
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4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
24. How much of the time during the last 2 weeks have you been troubled by a feeling of having to 
go to the bathroom even though your bowels were empty? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
25. How much of the time during the last 2 weeks have you felt tearful or upset? Please choose an 
option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
26. How much of the time during the last 2 weeks have you been troubled by accidental soiling of 
your underpants? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
27. How much of the time during the last 2 weeks have you felt angry as a result of your bowel 
problem? Please choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
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Vedolizumab IV
Study No. Vedolizumab-4004
Page 100 of 107
Protocol Incorporating Amendment No. 04
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4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
28. To what extent has your bowel problem limited sexual activity during the last 2 weeks? Please 
choose an option from
1
NO SEX AS A RESULT OF BOWEL DISEASE
2
MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE
3
MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE
4
SOME LIMITATION AS A RESULT OF BOWEL DISEASE
5
A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE
6
HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE
7
NO LIMITATION AS A RESULT OF BOWEL DISEASE
29. How much of the time during the last 2 weeks have you been troubled by nausea or feeling sick 
to your stomach? Please choose an option. from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
30. How much of the time during the last 2 weeks have you felt irritable? Please choose an option 
from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
31. How often during the past 2 weeks have you felt a lack of understanding from others? Please 
choose an option from
1
ALL OF THE TIME
2
MOST OF THE TIME
3
A GOOD BIT OF THE TIME
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Vedolizumab IV
Study No. Vedolizumab-4004
Page 101 of 107
Protocol Incorporating Amendment No. 04
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4
SOME OF THE TIME
5
A LITTLE OF THE TIME
6
HARDLY ANY OF THE TIME
7
NONE OF THE TIME
32. How satisfied, happy, or pleased have you been with your personal life during the past 2 
weeks? Please choose one of the following options from
1
VERY DISSATISFIED, UNHAPPY MOST OF THE TIME
2
GENERALLY DISSATISFIED, UNHAPPY
3
SOMEWHAT DISSATISFIED, UNHAPPY
4
GENERALLY SATISFIED, PLEASED
5
SATISFIED MOST OF THE TIME, HAPPY
6
VERY SATISFIED MOST OF THE TIME, HAPPY
7
EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY OR PLEASED
Copyright © 1989 McMaster University, Hamilton, Ontario, Canada.
The Inflammatory Bowel Disease Questionnaire (IBDQ), authored by Dr. Jan Irvine et al, is the copyright of 
McMaster University (Copyright ©1989, McMaster University). The IBDQ has been provided under license from
McMaster University and must not be copied, distributed or used in any way without the prior written consent of 
McMaster University. 
Contact the McMaster Industry Liaison Office at McMaster University, email: milo@mcmaster.ca for licensing 
details.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Vedolizumab IV
Study No. Vedolizumab-4004
Page 102 of 107
Protocol Incorporating Amendment No. 04
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Appendix J
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 04 are indicated. 
The corresponding text has been revised throughout the protocol. 
This protocol amendment is considered as non-substantial as the changes made do not 
significantly or negatively impact the safety or physical or mental integrity of the clinical trial
participants nor the scientific value of the trial. 
Change 1:
 
The primary change occurs in Section 5.1.3 Exploratory Objectives:
Initial 
wording:
Exploratory objectives are:
Amended 
or new
wording:
Exploratory objectives are:
Rationale for Change:
The addition of these exploratory objectives is considered to be non-substantial and does not 
require new subject procedures nor does it alter the main objectives of this trial.
CCI
CCI
CCI
CCI
Property of Takeda: For Non-Commercial Use Only
On
ct to the Ap
he
to
able Terms of Use
d. 
calal trial
tria
l
ab
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Applic
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da: For Non-Commercial Use
Takeda
ale f
ale for
o
f
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perty of Ta


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Page 103 of 107
Protocol Incorporating Amendment No. 04
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Section 2.0 STUDY SUMMARY also contains this change. 
Change 2: Added exploratory endpoints corresponding to new objectives 
The primary change occurs in Section 5.2.3 Exploratory Endpoints:
Initial 
wording:
The exploratory endpoints are:
Amended 
or new 
wording:
The exploratory endpoints are:
CCI
CCI
CCI
Property of Takeda: For Non-Commercial Use Only and Subje
bje
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Ter
ble
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Vedolizumab IV
Study No. Vedolizumab-4004
Page 104 of 107
Protocol Incorporating Amendment No. 04
14 September 2020
Rationale for Change:
To add new exploratory endpoints corresponding to new objectives.
The addition of exploratory endpoints is consistent with changes to the exploratory objectives and 
is considered to be a non-substantial change; the additional endpoints do not require new subject
procedures nor do they alter the main objectives of this trial.
Section 2.0 STUDY SUMMARY also contains this change.
Change 3:
The primary change occurs in Section 9.1.10: Pouchitis Endoscopy:
Initial 
wording:
Amended 
or new 
wording:
Rationale for Change:
To clarify centrally read assessments that correspond to the new exploratory endpoints. This 
change is considered non-substantial because the additional exploratory endpoints do not require 
new subject procedures nor do they alter the main objectives of this trial.
CCI
CCI
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
and
and
subject
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Study No. Vedolizumab-4004
Page 105 of 107
Protocol Incorporating Amendment No. 04
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Added tex
Rationale for Change:
 
.
Change 5:
The primary change occurs in Section 13.1.3 Efficacy Analysis:
Initial 
wording:
Change from baseline in mPDAI, PDAI, IBDQ, and CGQL scores will be analyzed 
using Wilcoxon rank sum tests; the Wilcoxon-Mann-Whitney odds estimator and its 
95% CI will also be presented.
Amended 
or new 
wording:
Change from baseline in mPDAI, PDAI, 
IBDQ, and CGQL scores will be 
analyzed using Wilcoxon rank sum tests; the Wilcoxon-Mann-Whitney odds 
estimator and its 95% CI will also be presented.
Rationale for Change:
CCI
CCI
CCI
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Property of Takeda: For Non-Commercial U
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Vedolizumab IV
Study No. Vedolizumab-4004
Page 106 of 107
Protocol Incorporating Amendment No. 04
14 September 2020
Rationale for Change:
Change 7: Clarified that prior medication history includes all prior medications for the treatment 
of UC/pouchitis.
The primary change occurs in Section 9.1.2: Demographics, Medical History, and Medication 
History Procedure:
Initial 
wording:
In addition, all prior biologic medication history for the treatment of UC/pouchitis, 
with the reason for discontinuation is to be collected for subjects where possible.
Amended 
or new 
wording:
In addition, all prior biologic medication history for the treatment of UC/pouchitis, 
with the reason for discontinuation, is to be collected for subjects where possible.
Rationale for Change:
This change clarifies the intent of the study to collect all prior medication for the treatment of 
UC/pouchitis and not just biologics. This clarification is considered to be a non-substantial change.
10. Change 8: Corrected acute histologic inflammation descriptors for score of 0 in Appendix E
The primary change occurs in Appendix E The Pouchitis Disease Activity Index (PDAI)Appendix 
EAppendix EAppendix EAppendix EAppendix EAppendix EAppendix E .
Description 
of change:
[Added response 0 = None for polymorphic nuclear leukocyte infiltration. Added 
response 0 = 0% added for ulceration per low power field (mean).]
CCI
CCI
CCI
Property of Takeda: For Non-Com
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Study No. Vedolizumab-4004
Page 107 of 107
Protocol Incorporating Amendment No. 04
14 September 2020
Rationale for Change:
Corrected table to align with histology scoring used in this study and to be consistent with other 
text in the protocol.  
Change 9: Deleted duplicated text describing analysis set for primary analysis.
The primary change occurs in Section 13.1.3 Efficacy Analysis: 
Deleted 
text:
The primary efficacy analysis will be based on the full analysis set (FAS) including all 
randomized subjects. Analysis will also be performed on the PP population for 
confirmatory purposes.
Rationale for Change:
The same information was written twice within the same section of the protocol. Deleted one of the 
duplicated statements. This is an editorial correction that does not impact the analysis methods and 
is a non-substantial change.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Double-Blind, Placebo-Controlled Phase 4 Study to Evaluate the Efficacy 
and Safety of Entyvio (Vedolizumab IV) in the Treatment of Chronic Pouchitis (EARNEST)
NCT Number: NCT02790138
SAP Approve Date: 12 February 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.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Vedolizumab-4004
A Randomized, Double-Blind, Placebo-Controlled Phase 4 Study to Evaluate the Efficacy 
and Safety of Entyvio (Vedolizumab IV) in the Treatment of Chronic Pouchitis (EARNEST)
Vedolizumab IV 300 mg in the Treatment of Chronic Pouchitis
PHASE 4
Version: Final V2.0 (Amendment 01)
Date: 12 February 2021
Prepared by:
Based on:
Protocol Version: Amendment 04
Protocol Date: 14 September 2020
Original SAP Date: 29 June 2020
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Statistical Analysis Plan
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1.1
Signatures
Study Number:
Vedolizumab-4004
Study Title:
A Randomized, Double-Blind, Placebo-Controlled Phase 4 Study to 
Evaluate the Efficacy and Safety of Entyvio (Vedolizumab IV) in the 
Treatment of Chronic Pouchitis (EARNEST)
Version / Date:
Final V2.0 / 12 February 2021
Approvals:
This document is signed electronically.
Electronic signatures can be found on the last page of this document.
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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Signatures..................................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objective......................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Exploratory Objectives ..............................................................................................8
4.4
Safety Objective ........................................................................................................8
4.5
Study Design .............................................................................................................9
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Exploratory Endpoints .............................................................................................11
5.4
Safety Endpoints......................................................................................................11
5.5
Other Data and Variables Collected .........................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Study Definitions.............................................................................................13
7.1.2
Definition of Study Days .................................................................................16
7.1.3
Definition of Baseline Values ..........................................................................16
7.1.4
Definition of Last Visit ....................................................................................16
7.1.5
Definition of Screen Failure.............................................................................16
7.1.6
Covariates and Subgroups................................................................................17
7.1.7
Definition of Study Visit Windows..................................................................17
7.1.8
Handling of Missing Data................................................................................19
7.1.9
Convention for Calculation of Time since IPAA..............................................22
7.1.10
Conventions for Calculation of PDAI and mPDAI Scores................................22
7.1.11
Multiple Comparisons/Multiplicity ..................................................................24
7.2
Analysis Sets ...........................................................................................................24
7.3
General Study Information and Disposition of Subjects ...........................................25
7.4
Significant Protocol Deviations and Major Protocol Violations................................26
7.4.1
Significant Protocol Deviations........................................................................26
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7.4.2
Major Protocol Violations................................................................................27
7.5
Demographic and Other Baseline Characteristics.....................................................27
7.6
Medical History and Concurrent Medical Conditions...............................................30
7.7
Medication History and Concomitant Medications...................................................30
7.8
Study Drug Exposure...............................................................................................32
7.9
Efficacy Analysis.....................................................................................................33
7.9.1
General Consideration for the Efficacy Data Analysis......................................33
7.9.2
Overall PDAI and mPDAI Summaries.............................................................35
7.9.3
Primary Efficacy Endpoint...............................................................................37
7.9.4
Secondary Efficacy Endpoints .........................................................................38
7.9.5
Exploratory Efficacy Endpoints .......................................................................40
7.9.6
Sensitivity Analyses and Additional Analyses..................................................44
7.10
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................45
7.11
Other Outcomes.......................................................................................................46
7.12
Safety Analysis........................................................................................................46
7.12.1
Adverse Events................................................................................................46
7.12.2
Clinical Laboratory Evaluations.......................................................................50
7.12.3
Vital Signs.......................................................................................................51
7.12.4
12-Lead ECGs.................................................................................................51
7.12.5
Other Observations Related to Safety...............................................................52
7.13
Futility Analysis ......................................................................................................52
7.14
Changes in the Statistical Analysis Plan...................................................................52
7.15
Sample Code............................................................................................................53
8.0
REFERENCES..............................................................................................................56
9.0
APPENDICES...............................................................................................................57
LIST OF IN-TEXT TABLES
Table 7.a
Visit Windows for Efficacy and Safety Variables...............................................18
Table 7.b
Demographic and Baseline Characteristics.........................................................28
Table 7.c
Pouchitis Related Baseline Characteristics .........................................................29
Table 7.d
Clinical Laboratory Tests...................................................................................50
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LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ................................................................................10
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................57
Appendix B
The Pouchitis Disease Activity Index (PDAI) ....................................................59
Appendix C
The Modified Pouchitis Disease Activity Index (mPDAI) ..................................60
Appendix F
The Cleveland Global Quality of Life (CGQL) Instrument (Fazio Score)...........63
Appendix G
Quality of Life Questionnaires: IBDQ................................................................64
Appendix H
Criteria for Identification of Markedly Abnormal Laboratory Values .................65
Appendix I
Criteria for Identification of Markedly Abnormal Values for Vital Signs............67
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
anti-TNF
tumor necrosis factor-alpha antagonist
BMI
body mass index
CGQL
Cleveland Global Quality of Life
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CS
corticosteroids
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FC
fecal calprotectin
HLT
high level term
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
informed consent form
IPAA
ileal pouch anal anastomosis
IV
intravenous
LOCF
last observation carried forward
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
mPDAI
Modified Pouchitis Disease Activity Index
PML
progressive multifocal leukoencephalopathy
PMNL
polymorphic nuclear leukocyte infiltration
PDAI
Pouchitis Disease Activity Index
p.p.
percent points
PPS
per protocol set
PT
preferred term
PTE
pretreatment event
RB
rectal bleeding
SAF
safety analysis set
SAP
statistical analysis plan
SD
standard deviation
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SF
stool frequency
SI
International System of Units
SMQ
Standard MedDRA Query
SOC
system organ class
TEAE
treatment-emergent adverse event
UC
ulcerative colitis
WHODrug
World Health Organization Drug
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4.0
OBJECTIVES
4.1
Primary Objective
The primary objective is to compare the efficacy of vedolizumab IV to placebo in terms of the 
percentage of subjects with chronic or recurrent pouchitis achieving clinically relevant remission.
4.2
Secondary Objectives
The secondary objectives are to assess the efficacy of vedolizumab IV by:
!
Percentage of subjects achieving modified Pouchitis Disease Activity Index (mPDAI) <5 and 
a reduction of overall score by ≥2 points from baseline mPDAI.
!
Percentage of subjects achieving Pouchitis Disease Activity Index (PDAI) <7 and a reduction 
of overall score by ≥3 points from baseline PDAI.
!
Time to remission (defined as a PDAI score <7 and a decrease in PDAI score of ≥3 points 
from baseline).
!
Percentage of subjects achieving a partial response (defined as reduction mPDAI score by ≥2 
points from baseline).
!
Change in PDAI endoscopic subscore.
!
Change in PDAI histologic subscore.
!
Change in total PDAI.
!
Change in Inflammatory Bowel Disease Questionnaire (IBDQ) and Cleveland Global Quality 
of Life (CGQL).
4.3
Exploratory Objectives
4.4
Safety Objective
The safety objective is to assess the safety of vedolizumab IV in chronic or recurrent pouchitis.
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Statistical Analysis Plan
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4.5
Study Design
This is a phase 4, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy and safety of vedolizumab IV 300 mg over a 34-week treatment period (with the last 
dose at Week 30) in subjects with a proctocolectomy and ileal pouch anal anastomosis (IPAA) 
for ulcerative colitis (UC) who have developed chronic or recurrent pouchitis. 
Approximately 110 adult subjects with chronic or recurrent pouchitis were to be randomized to 
this study. Subjects must have developed chronic or recurrent pouchitis, defined as an mPDAI 
score ≥5 assessed as the average from 3 days immediately prior to the baseline endoscopy and a 
minimum endoscopic subscore of 2 (outside the staple or suture line) with either (a) ≥3 recurrent 
episodes within 1 year prior to the Screening visit, each treated with ≥2 weeks of antibiotic or 
other prescription therapy, or (b) requiring maintenance antibiotic therapy taken continuously for 
≥4 weeks immediately prior to the baseline Endoscopy Visit.
Eligible subjects were randomized at Day 1 in a 1:1 ratio to the following 2 treatment arms; 
subjects enrolled under protocol amendment 03 (or later) were randomized stratified by type of 
pouchitis (chronic or recurrent):

Arm 1: Vedolizumab IV 300 mg dose at Week 0, 2, 6, 14, 22 and 30, administered as a 
30-minute infusion;

Arm 2: Placebo IV dose at Week 0, 2, 6, 14, 22 and 30, administered as a 30-minute 
infusion.
All subjects received concomitant antibiotic treatment with ciprofloxacin 500 mg twice daily 
through Week 4. Additional courses of antibiotics were allowed, as needed, for flares after Week 
14. Final efficacy assessments were to be performed 4 weeks after the last study dose (Week 34). 
Additional safety follow-ups occurred 18 weeks after the last study dose (Week 48) and subjects 
were required to participate in a long-term follow-up safety survey by telephone, 26 weeks after 
the last dose of study drug (Week 56).
A schematic of the study design is included as Figure 4.a. A schedule of assessments is listed in 
Appendix A.
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Statistical Analysis Plan
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Figure 4.a
Schematic of Study Design
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary efficacy endpoint is clinically relevant remission after 14 weeks of treatment.
Clinically relevant remission is defined as an mPDAI score < 5 and a reduction of overall score 
by ≥2 points from baseline.
5.2
Secondary Endpoints
Secondary endpoints include:

Clinically relevant remission at Week 34 (last dosing at Week 30).

PDAI remission (defined as PDAI score < 7 and a decrease in PDAI score by ≥3 points 
from baseline) at Week 14 and at Week 34.

Time to PDAI remission (defined as a PDAI score < 7 and a decrease in PDAI score of 
≥3 points from baseline).

Partial mPDAI response (defined as decrease in mPDAI score by ≥2 points from 
baseline) at Week 14 and at Week 34.

Change from baseline in PDAI endoscopic subscore at Weeks 14 and 34.

Change from baseline in PDAI histologic subscore at Weeks 14 and 34.

Change from baseline in Total PDAI score at Weeks 14 and 34.

Change from baseline in IBDQ and CGQL at Weeks 14, 22 and 34.
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5.3
Exploratory Endpoints
5.4
Safety Endpoints
Safety will be assessed by adverse events (AEs), adverse events of special interest (AESIs), 
serious adverse events (SAEs), vital signs and results of standard laboratory tests (clinical 
chemistry, hematology, coagulation and urinalysis).
5.5
Other Data and Variables Collected
Other data and variables collected and mapped to the study database include:
!
Demographic data (see details in section 7.5)
!
Baseline disease characteristics (see details in section 7.5)
!
Medical history (see details in section 7.6)
!
Prior and concomitant medications (see details in section 7.7)
!
Study drug exposure (see details in section 7.8)
!
Significant protocol deviations (see details in section 7.4.1)
6.0
DETERMINATION OF SAMPLE SIZE
The sample size was calculated based on the remission rate at 14 weeks. 
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Statistical Analysis Plan
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Initially, the sample size was based on the observed remission rate in GEMINI 1 (MLN0002-
C13006) in subjects with moderate to severe UC: the placebo group remission rate was 8%, the 
vedolizumab group rate was 23%; an effect size of 15%.
However, pouchitis is different from UC and a new assessment using published data was made to 
evaluate what would be a significant treatment effect. Based on 2 recent papers using the mPDAI 
as the primary endpoint [2,3], a placebo rate of 15% was estimated. A clinically significant effect 
was estimated to be of 25%, an average of the remission (complete response) observed in the 2 
aforementioned papers (32% and 21% post-induction response, respectively) evaluating the 
effect of infliximab using the mPDAI.
An effect size of at least 25% would be considered clinically meaningful (i.e., a remission rate of 
40% in subjects maintained on vedolizumab IV). Therefore, a total of 98 evaluable subjects (49 
per treatment arm) is required to detect a 25% difference in the remission rate at the 2-sided 
significance level of 0.05 with 80% power. To account for attrition, 110 subjects were planned to 
be randomized (55 per treatment arm).
7.0
METHODS OF ANALYSIS AND PRESENTATION
This statistical analysis plan (SAP) version is an amendment to the SAP Version 1.0 (dated 
29 June 2020) and is based on the study protocol, amendment 04, dated 14 September 2020 [1].
A blinded 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.
7.1
General Principles
In general, unless stated otherwise below, all descriptive data summaries will be provided by 
treatment arm for the applicable analysis set. Where appropriate, variables will be further 
summarized by study visit and/or subgroups defined in section 7.1.6. 
For continuous variables, the number of subjects with non-missing values, mean, median, 
standard deviation (SD), minimum and maximum values will be tabulated. Means and medians 
will be presented to 1 more decimal place than the recorded data. The SDs will be presented to 2 
more decimal places than the recorded data. Confidence intervals (CIs) about a parameter 
estimate will be presented using the same number of decimal places as the parameter estimate.
For categorical variables, the number (and %) of subjects falling into each category will be 
presented. Percentages will be calculated based only on non-missing observations in the 
respective analysis set and will, in general, be displayed with 1 decimal place. The number of 
missing observations will be reported in category “Missing” (no percentage shown for this 
category). The same handling applies to similar categories like “not collected”, “not applicable”.
All CIs, statistical tests and resulting p-values will be reported as 2-sided unless otherwise stated; 
p-values will be displayed with 3 decimal places (p-values < 0.001 will be displayed as 
“< 0.001”).
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Statistical Analysis Plan
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All study-related raw data and relevant derived data, as specified below, will be presented in data 
listings. The listings will be sorted by treatment arm and by subject. In general, listings will be 
done for all subjects randomized. Screen failure data will be grouped and presented at the end of 
data listings, where appropriate. When no data are available for a table or appendix, an empty 
page with the title will be produced with suitable text (e.g., “There were no subjects with 
markedly abnormal values of laboratory parameters.”).
All statistical analyses will be conducted using SAS System® Version 9.4, or higher.
7.1.1
Study Definitions
The following treatment arm labels will be used in the outputs:

Vedolizumab IV 

Placebo IV
Type of pouchitis:
The study protocol defines the type of pouchitis as follows:

Chronic pouchitis is defined as pouchitis requiring maintenance antibiotic therapy taken 
continuously for ≥4 weeks immediately prior to the baseline endoscopy visit.

Recurrent pouchitis is defined as ≥3 recurrent episodes of pouchitis within 1 year prior to 
screening, each treated with ≥2 weeks of antibiotic or other prescription therapy.
For the purpose of the analysis, the type of pouchitis will be determined based on the following 
criteria:
a) If the subject received a maintenance antibiotic therapy continuously for ≥26 days, that 
was started at least 26 days prior to start of study medication (Day 1, see section 7.1.2) 
and was continued until at least 7 days before screening (date of informed consent 
considered here), then the type of pouchitis is chronic.
Note: For the calculation of duration of immediate prior antibiotic use, the following 
should be applied:

only prior antibiotics for UC/pouchitis as defined below will be considered;

records of prior antibiotics with reported end date completely missing and not flagged 
as ongoing or as ended after the screening/informed consent date will be ignored (i.e. 
imputed end dates of those records not to be considered);

for prior antibiotics reported with a partial end date, that would be imputed as being 
after Day 1 (see section 7.1.2), the end date will be assumed as Day 1-1 (assume that 
antibiotic stopped before Day 1 as per protocol), unless the partial end date clearly 
indicates continuation after Day 1 (see details for end date imputations in section 
7.1.8.2).
b) If the number of pouchitis episodes in the last 1 year prior to screening reported in the 
eCRF is ≥3, then the type of pouchitis is recurrent;
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Statistical Analysis Plan
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since the onset/end dates of the episodes within the last year are not recorded, it will be 
assumed they were treated appropriately.
c) If based on available data, both the criteria for chronic and recurrent pouchitis are met, 
then the type of pouchitis is set to chronic.
d) If neither of the criteria a) and b) above is met, recurrent pouchitis is assumed.
This definition will be revisited during blind data review.
Clinically relevant remission (mPDAI remission) is defined as mPDAI score < 5 and decrease of 
mPDAI score by ≥2 points from baseline.
PDAI remission is defined as PDAI score < 7 and decrease of PDAI score of ≥3 points from 
baseline.
Partial (mPDAI) response is defined as decrease of mPDAI score by ≥2 points from baseline. 
Relapse of pouchitis is defined as a worsening in the pouchitis symptoms after previous
(documented) clinically relevant remission (mPDAI remission), identified by any of the 
following events:
!
an adverse event with preferred term “Pouchitis” (MedDRA code 10036463), e.g. 
worsening of pouchitis, pouchitis flare (or similar)
!
an adverse event flagged on the AE CRF page as related to flare
!
worsening of pouchitis symptoms reported on the Flare CRF page
!
start or change in concomitant medication flagged as for treatment of flare.
The corresponding date of relapse is the start/onset date of the respective event. The 
corresponding date of the (first) relapse (daterelapse) is the minimum of the start/onset dates of the 
aforementioned events after clinically relevant remission was achieved (datemPDAI remission); the 
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IBDQ remission is defined as a total IBDQ score of ≥170.
IBDQ (clinically meaningful) improvement, hereafter referred to as IBDQ improvement, is 
defined as a change from baseline by ≥16 points.
Corticosteroids (CS) for UC/pouchitis-related treatment will be identified by ATC codes
A07EA, C05AA, H02AB, H02 with the following exception:

CS with indication “asthma” and with route of administration reported as nasal or by 
inhalation are not considered UC/pouchitis-related treatment.
Antibiotics for UC/pouchitis-related treatment will be identified by ATC codes A07AA, J01--
(i.e., all ATC codes starting with J01) with the following exceptions:

J01C, J01CA, J01CF, J01XE are not considered UC/pouchitis-related treatment;

J01AA, J01FA, J01CR are only considered UC/pouchitis-related treatment if flagged in 
the eCRF as given for pouchitis or for a flare of pouchitis.
Prior anti-TNF treatment:

Prior tumor necrosis factor-alpha antagonist (anti-TNF) treatment will be identified by 
the ATC 4th level (chemical) subgroup “TUMOR NECROSIS FACTOR ALPHA (TNF-) 
INHIBITORS” (ATC code L04AB).

Discontinuation of prior anti-TNF treatments for reasons “inadequate response”, “loss of 
response”, and “intolerance” will be considered failure of prior anti-TNF treatment. 
A subject with multiple prior anti-TNF therapies may have multiple reasons for failure.
Other relevant UC/pouchitis treatments:
Other relevant UC/pouchitis treatments will be identified by the following ATC codes
A07DA, A07E, A07EC, A07FA, A16--, L01BB, L04AA, L04AC, L04AD, L04AX 
(L04-- are immunosuppressants).
Prior treatments started pre-/post-colectomy:
Classification of prior treatments will be done relative to the (imputed) date of colectomy 
(=IPAA).
a) A prior treatment that started on or after the date of the IPAA, and before Day 1, is 
considered “started post-colectomy”.
Note: this applies also to treatments that were started prior to IPAA, then stopped and 
started again on or after the date of the IPAA.
b) A prior treatment that was started before the IPAA is considered “started pre-colectomy”.
Note: this applies also to treatments that were started prior to IPAA and continued after 
IPAA.
Discontinuation of prior treatments for UC/pouchitis:
Discontinuation of prior treatments for UC/pouchitis for reasons “inadequate response”, “loss of 
response”, and “intolerance” will be considered failure of the prior treatment. 
For prior UC/pouchitis treatments recorded on the “Medication History/Concomitant 
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Medications” eCRF form, the reason for discontinuation will be identified as “not recorded”.
A subject with multiple prior treatments may have multiple reasons for failure.
Note: This is a generalization of the definition for prior anti-TNF treatments above.
7.1.2
Definition of Study Days
Study Day 1 (Day 1) is defined as the date on which a subject is administered the first dose of 
study medication. Other study days are defined relative to the Study Day 1 with Day -1 being the 
day prior to Study Day 1. Typically, the study day of an assessment (or event) is derived as:
study day = date of assessment/event – date of first dose of study medication + 1.
7.1.3
Definition of Baseline Values
Unless otherwise specified, baseline values are defined as the last observed value before the first 
dose/administration of study medication.
For procedures performed on the same day as the first dose of study medication (Day 1) that as 
per protocol were to be performed prior to the first dose of study medication, it is assumed that 
the procedures are performed prior to the administration of the study medication (and data is 
considered pre-treatment, baseline). If there is more than one baseline score, then the one closer 
to the date of randomization will be used for analyses.
7.1.4
Definition of Last Visit
In general, “last visit” is defined as the last available observation of a subject after the first dose 
of study medication until either Week 34 or the date of early discontinuation, whichever comes 
first. 
7.1.5
Definition of Screen Failure
Screen failure subjects are subjects who signed the informed consent form (ICF) and were not 
enrolled in the study. The primary reason for screen failure is collected in the eCRF using the 
following categories:

Pretreatment Event (PTE)/AE

Did Not Meet Entrance Criteria

Significant Protocol Deviation

Lost to Follow-Up

Voluntary Withdrawal

Study Termination

Other
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7.1.6
Covariates and Subgroups
The following subgroups may be used in the data summaries, adaptations of the subgroup 
categories specified below might be applied as deemed necessary to achieve subgroups of 
reasonable size:

Type of pouchitis: 
chronic pouchitis vs recurrent pouchitis (see definitions in section 7.1.1)

Prior anti-TNF treatment started post-colectomy(a): 
anti-TNF failure, anti-TNF used/no failure, anti-TNF not used (see definitions in section 
7.1.1).
(a) Note: this includes on prior treatments collected on the CRF form “UC Disease Last 
Antibiotic Medication and All Prior Biologics”.
A subject with multiple prior anti-TNF treatment courses post-colectomy who 
experienced at least one failure will be categorized as “anti-TNF failure”.

Prior anti-TNF exposure (for UC or pouchitis): 
anti-TNF naïve vs anti-TNF experienced

baseline severity based on mPDAI(b):
5 to 8 (moderately active)
9 to 12 (severely active)
(b) Note: If there are < 8 subjects with a baseline mPDAI<5 after adjudication of the 
PDAI endoscopy ulceration score, they will be excluded from this subgroup analyses; 
otherwise they will be analyzed as a separate subgroup.

baseline severity based on PDAI(c):
< 7 (quiescent)
7 to 12 (moderately active)
13 to 18 (severely active)
(c) Note: if there are < 8 subjects in a subgroup, analysis of this subgroup will be omitted; 
subjects with missing PDAI at baseline will be excluded from this subgroup analyses.

baseline polymorphic nuclear leukocyte infiltration (PMNL) based on PDAI:
0 - 1 = none/mild
≥2 = moderate/severe + crypt abscess

time from IPAA to start of treatment: < 7 years vs ≥ 7 years

baseline FC: ≤ 250 µg/g vs > 250 µg/g

baseline CRP: ≤ 5 mg/L vs > 5 mg/L
7.1.7
Definition of Study Visit Windows
The visit windows to be used in the data analysis are shown in Table 7.a. However, these 
windows will be reviewed (and adapted as deemed necessary) during the blind data review.
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Unless otherwise specified, data will be allocated to and summarized for the respective study 
visits according to the actual assessment date and the analysis visit windows below. Furthermore, 
the following additional ordered rules will be applied to identify an analysis record/value to be 
used in the analysis and summaries:

Data recorded within one of the analysis visit windows below will be used in the analysis 
for the respective scheduled visit; data recorded at days outside the defined visit windows 
will not be included in the by-visit summaries. 

Data identified on the eCRF as coming from an “unscheduled” visit will be eligible for 
windowing.

If a subject has more than one measurement within an analysis window, the assessment 
closest to the target day will be used. In case of ties between observations located on 
different sides of the target day, the later assessment will be used in analyses. In case of 
ties located on the same side of the target day (e.g., more than one value for the same 
day), the mean of the values will be used for continuous parameters and the worst result 
will be chosen over a more positive one for categorical parameters (e.g., an abnormal 
vital signs value will be chosen over a normal vital sign value). 
Table 7.a
Visit Windows for Efficacy and Safety Variables
Visit
Target Day
Visit Window (days)
per Protocol
Analysis Visit Window 
(days)
Baselinea
1
--
-42 – 1
Week 2
15
±2
±4 (11 – 19)
Week 4
29
±2
±4 (25 – 33)
Week 6
43
±2
±7 (36 – 50)
Week 14
99
±3
±14 (85 – 113)
Week 22
155
±7
±14 (141 – 169)
Week 30b
211
±7
±14 (197 – 224)
Week 34c
239
±7
±14 (225 – 253)
(m)PDAI: ±28 (211 – 267)
Week 48
337
±7
±21 (316 – 358)
Week 56
393
±7
±21 (372 – 414)
a The formal lower boundary of the Baseline visit is Day -28 consistent with the protocol defined screening period; 
however, screening assessment done up to 14 days earlier (Day -42) will be considered for the determination of a 
baseline value.
b The formal upper boundary of Week 30 window would be Day 225; data reported on Day 225 will be allocated to 
Week 34.
c mPDAI/PDAI assessments performed on/between days 211 to 267 will be considered for the analysis of Week 34.
Note: Baseline, Week 14 and Week 34 are planned visits for pouchitis assessments (PDAI).
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The following additional rule(s) do(es) apply:

All assessments, including the assessments that do not fit within any defined analysis 
visit window, will be listed. Data recorded at days outside the above visit windows will 
be shown in the data listings as “unscheduled” visit; data recorded at early 
discontinuation will be shown as “early termination”.
7.1.8
Handling of Missing Data
In general, missing data will not be imputed. Exceptions and rules for these exceptions are 
summarized hereafter:

The general handling of missing (m)PDAI data is described in section 7.1.10; additional 
handling missing (m)PDAI data is described in the respective subsections of section 7.9.

The general handling of subjects with missing efficacy data for (determination of) a 
response-type endpoints described in section 7.9.1.1; additional handling of those cases in 
sensitivity analyses is described in section 7.9.6.1. 

Missing data for AE onset and end dates will be imputed as described in section 7.1.8.1.

Missing data for concomitant medication start and stop dates will be imputed as 
described in section 7.1.8.2.

A (partially) missing IPAA date will be imputed as described in section 7.1.9.
Further missing data handling rules are described in the respective sections as applicable.
7.1.8.1
Conventions for Missing or Incomplete Adverse Event Dates
A missing or incomplete AE onset date will be imputed according to the following conventions:
1. If an onset date is missing, the imputed onset date will be imputed as the first non-
missing valid date from the following list (in order of precedence):

First study medication date 

Informed consent date.
2. If an onset date is incomplete, the derived onset date will be calculated following:

Missing day, but month and year present: the day will be imputed as the 15th of the 
month. If the month and year are equal to the month and year of the first study 
medication dose and the first study medication dose occurs after the imputed date, the 
derived onset date will be set equal to the first study medication date. If the AE end 
date occurs prior to the imputed date, the derived onset date will be set equal to the 
AE end date.

Missing day and month, but year present: the day and month will be imputed as the 
30th June of the year. If the year is equal to the year of the first study medication dose 
and the first study medication dose occurs after the imputed date, the derived onset 
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date will be set equal to the first study medication date. If the AE end date occurs 
prior to the imputed date, the derived onset date will be set equal to the AE end date.
A missing or incomplete AE end date will be imputed according to the following conventions:
1. If an end date is missing (and AE not flagged as ongoing), the end date will be imputed 
as the last study assessment date. If the AE start date is after the last study assessment, 
the end date will be imputed as the AE start date.
2. If an end date is incomplete, the derived end date will be calculated following: 

Missing day, but month and year present: the day will be imputed as the last date of 
the month (for example, February 2019 will be imputed as 28th February 2019).

Missing day and month, but year present: the day and month will be imputed as the 
31st December of the year.
7.1.8.2
Conventions for Missing Concomitant Medication Dates
Start and stop dates for all concomitant medications are collected on the eCRF. However, in case 
of missing or partial information in these dates, the following rules will be used:
If the medication start date is (partially) missing:

If the day is missing, the start day will be the first day of the month.

If the day and month are missing, and year is the same as in the date of first dose of study 
medication, the start day will be the first day of the month corresponding to 90 days prior 
to the date of first dose of study medication (if the month of first dose is Jan, Feb, or Mar, 
the start day will be 1 Jan of that year instead). 

If the day and month are missing, and the year is not the same as the year of first dose of 
study medication, the start day will be 1st Jan of that year.

If the year is missing, the start year will be the minimum of year of the first site visit and 
the year of the ICF date.

If the entire date is missing:
–
If the eCRF indicates that the medication ended prior to the ICF date, then the 
medication start date will be imputed as ICF date - 1.
–
Otherwise the start date will be imputed as minimum of the date of first dose of study 
medication (Day 1) and the medication end date.
If the medication end date is (partially) missing and medication is not flagged as "ongoing":

If the day is missing:
–
In general, the end date will be the last day of the month reported. If the eCRF 
indicates the medication ended prior to ICF date, and month is the month of ICF, the 
end date will be imputed as ICF date - 1. 
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
If the day and month are missing:
–
If the year is the same as the date of last assessment, then the end date day will be 
imputed by the last day of the month during which the last assessment occurred.
–
If the year is not the same as the year of the last assessment, then the end date will be 
imputed as 31st December of that year.

If the year is missing or the entire date is unknown, the end year will be the year in which 
the last assessment occurred (further imputation according to the rules for partial dates 
above). If information collected on the CRF indicates that the medication ended prior to 
the ICF date, the medication end date will be imputed as ICF date - 1.
Special handling of (partially) missing medication end dates for antibiotics given for 
UC/pouchitis started before Day 1 will be applied; the general imputation rules defined above 
will be used with the following exceptions:

If the exact end date is unknown and available information does indicate that the 
antibiotic is continued after the ICF date but does not indicate that the antibiotic is 
continued after Day 1, it will be assumed that the antibiotic was stopped prior to Day 1 as 
per protocol, and the end date will be imputed as Day 1 – 1 as described below.

If the day is missing:
–
In principle, the general rule for that case defined above will be applied.
–
However, if month/year of the partial medication end date are the same as of Day 1, 
the end date will be imputed as Day 1 – 1 (if Day 1 is the 1st of a month, the end date 
will be imputed as Day 1).

If the day and month are missing (i.e. only year is reported):
–
In principle, the general rule for that case defined above will be applied.
–
However, if the year of the partial end date is the same as of Day 1, and
a) end of medication is not flagged as ongoing after ICF, then assume as ended prior 
to ICF and the end date will be imputed as ICF date – 1;
b) end of medication is flagged as ongoing after ICF or as ended after ICF, then the 
end date will be imputed as Day 1 – 1.

If the entire end date is unknown:
–
If the start date is before the ICF date and end of medication is not flagged as 
ongoing/ended after ICF, then assume the medication ended prior to ICF and impute 
the end date as ICF date – 1.
–
If the start date is before the ICF date and end of medication is flagged as continued 
after ICF date (ongoing at ICF or ended after ICF), the end date will be imputed as 
Day 1 – 1. 
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–
If the start date is after the ICF date (but before Day 1), an there is no indication that 
the medication was continued after Day 1, the end date will be imputed as Day 1 – 1.
7.1.9
Convention for Calculation of Time since IPAA
Time since IPAA is calculated as the number of years from IPAA date to first dose date (Day 1):
date	
  −date + 1
365.25
If the IPAA date is partially missing, the following rules will take effect:

Missing day, but month and year are present: the day will be imputed as the 15th day of 
the month.

Missing day and month, but year is present: the day and month will be imputed as 
30th June of the year.
7.1.10
Conventions for Calculation of PDAI and mPDAI Scores
The Pouchitis Disease Activity Index (PDAI) is an objective and quantitative criterion for pouch 
inflammation after IPAA, consisting of the 3 subdomains clinical symptoms, endoscopic 
inflammation and acute histologic inflammation. Each subdomain is scored from 0 to 6, the total 
PDAI score is the sum of the 3 subscores and has a range of 0 to 18. The clinical symptoms are 
based on a patient diary completed for 3 days prior to endoscopy or bowel preparation for 
endoscopy. The average of the completed diary entries is taken for PDAI calculation, where at 
least one non-missing day needs to exist. A cutoff of 7 for differentiation between ‘pouchitis’ (≥7 
points) and ‘no pouchitis’ (<7 points) is established. See Appendix B for more details.
The modified Pouchitis Disease Activity Index (mPDAI) consists of PDAI subdomains clinical 
symptoms and endoscopic inflammation; the mPDAI score has a range of 0 to 12. A cutoff of 5 
differentiates subjects with pouchitis (mPDAI ≥5) from subjects without pouchitis (mPDAI <5).
See Appendix C for more information.
The PDAI (and so the mPDAI) was to be assessed at baseline (Screening/ Visit 1), Week 14 and 
Week 34. Scores for all individual PDAI components were to be entered in the eCRF and the 
original mPDAI and PDAI total scores were derived based on these eCRF entries. In addition, 
the original central reader assessments of the 6 endoscopic inflammation components and the 2 
acute histologic inflammation components will be captured in the study database.
For the purpose of the data analysis, the following rules will be applied used:

Clinical symptoms:
For the 4 clinical symptoms, generally, the scores entered in the eCRF will be used for 
the calculation of the clinical symptoms subscore. If the score of a clinical symptom is 
missing in the eCRF, it should be attempted to derive the symptom score from the 
corresponding patient diary entries.
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
Endoscopic inflammation:
For the 6 PDAI endoscopy components, the central reader data will be used to derive the 
endoscopic inflammation subscore (i.e., eCRF data will not be used). 
In case adjudication of the endoscopy ulceration score was done in context of the 
endoscopy additional (re-assessment) introduced in protocol amendment no. 4, the 
adjudicated ulceration score will be used in the calculation of the endoscopic 
inflammation subscore.
However, the original ulceration score will be kept and reported/listed as well.

Acute histologic inflammation:
For the 2 PDAI histology components, the central reader data will be used to derive the 
acute histologic inflammation subscore (i.e., eCRF data will not be used).

mPDAI total score:
The mPDAI total score will be calculated as the sum of the clinical symptoms subscore 
and endoscopic inflammation subscore which are derived according to the rules above.

PDAI total score:
The PDAI total score will be calculated as the sum of all 3 subscores (clinical symptoms, 
endoscopic inflammation, acute histologic inflammation) which are derived according to 
the rules above.

Where multiple assessments for a PDAI component are available for a visit (i.e., within 
the defined analysis window), the latest assessment will be used for the calculation of the 
respective subscores and total scores. Consequently, the assessment date of the last 
component/domain included in the calculation of a domain subscore or the total scores 
will be used as the analysis date for the domain subscore and total scores.
For the endoscopic and the histologic items, the date the endoscopy was performed or 
histology biopsy taken, respectively, will be considered the date of assessment.

PDAI assessments performed at early discontinuation (of study drug) that fall into the 
respective analysis window will be considered for analysis.

Handling of missing data for these calculations is described below.
Missing data handling for PDAI:

For the “as observed” summaries described in section 7.9.2, no missing (m)PDAI data 
will be imputed and only reported data will be summarized. For other data summaries 
and analyses imputation methods described below are to be applied.

Imputation of completely missing mPDAI and PDAI assessments:
Imputation of completely missing mPDAI and PDAI assessments will be done as 
described in the respective subsection of section 7.9.

Imputation of partially missing mPDAI and PDAI assessments:
Individual (m)PDAI components at baseline will not be imputed; thus, the respective 
PDAI domain subscore and the total PDAI score (and total mPDAI score, if applicable) 
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are missing for baseline.
Individual (m)PDAI components at post-baseline time points will be imputed using last-
observation carried forward (LOCF); for this baseline data and unscheduled data (e.g. 
reported at early discontinuation) will be considered. Consequently, the respective PDAI 
domain subscore and the total PDAI score (and total mPDAI score, if applicable) will be 
derived using the imputed individual components.
Note:
In context of the blind data review the PDAI component scores need to be reviewed and verified 
against the source data; potential inconsistencies will need to be identified and their handling will 
be defined prior to database lock. This includes but is not limited to the following:

Verification of scoring of clinical symptoms as per eCRF (supposed to be the average 
over 3 last diary days) against patient reported diary data.

Verification of presence/absence of endoscopic findings as per eCRF against central 
reader raw data (the eCRF does not distinguish between absence and missing as only 
symptoms present are reported).

In case of early termination, PDAI results might be reported on Early Termination page 
but not on Week 14 or Week 34, allocation of the Early Termination records to the 
respective target visits Week 14 and Week 34 to be defined.
7.1.11
Multiple Comparisons/Multiplicity
No adjustment of the statistical significance level is necessary to account for the futility analysis 
(see details in section 7.13).
Inferential comparisons between the two treatment arms are planned for multiple endpoints and 
two analysis populations. The study was powered for the difference in the primary endpoint and 
the analysis of the two populations for the primary efficacy endpoint is considered sensitivity 
analysis, therefore no multiplicity adjustment is needed. 
No multiplicity adjustment for inferential testing of the secondary and exploratory endpoints is 
considered; therefore, p-values from those tests will be presented as nominal p-values only and 
have to be interpreted as such.
7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data:

The safety analysis set (SAF) will consist of all randomized subjects who received at 
least 1 dose of study medication. Subjects will be analyzed according to the treatment 
actually received.

The full analysis set (FAS) will consist of all randomized subjects who receive at least 1 
dose of study drug. The FAS will be used as the primary analysis population for efficacy.
Subjects will be analyzed according to the treatment they were randomized to.
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
The per protocol set (PPS) will include all subjects in the FAS who do not have any 
major protocol violations. Major protocol violations that lead to exclusion of a subject 
from the PPS are listed in Section 7.4.2.
In addition, the populations “all screened subjects”, “screening failures” and “all randomized 
subjects” may be used for particular data summaries. 
If any subjects are found to be noncompliant in dosing schedule or with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the analysis prior to data 
base lock but all randomized subjects will be presented in the subject listings.
7.3
General Study Information and Disposition of Subjects
General study information and subject eligibility will be summarized as follows:

Study information, including the date first subject signed the ICF, date of first and last 
study drug dose, date of last subject’s last visit/contact, date of last subject’s last 
procedure for collection of data for primary endpoint, Medical Dictionary for Regulatory 
Activities (MedDRA) version used, World Health Organization Drug (WHODrug) 
dictionary version used and SAS® version used for the data analysis.

Demographic data for screen failures, showing age, gender, race, ethnicity. 

Eligibility for randomization, including number of subjects screened, number of subjects 
eligible/not eligible for randomization, and primary reason for subjects not eligible for 
randomization.
Subject disposition will be summarized for all randomized subjects as follows:

Subjects randomized by geographical region (Western Europe, North America), country 
and site.

Number (and %) of subjects who were randomized but not treated, if applicable 

Number (and %) of subjects who received study drug (at least once)

Number (and %) of subjects who completed the study drug

Number (and %) of subjects who prematurely discontinued (permanently) study drug and 
the reason for discontinuation. The reasons for discontinuation include PTE/AE, 
significant protocol deviation, lost to follow-up, voluntary withdrawal, study termination, 
pregnancy, lack of efficacy and other. 

Number (and %) of subjects who completed Week 14*.

Number (and %) of subjects who completed Week 34*.

Number (and %) of subjects who completed all planned study visits.

Number (and %) of subjects who prematurely discontinued the study and the reason for 
discontinuation.
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* Week 14/Week 34 visits are considered completed when a subject's last visit with pouchitis 
assessment (at least one mPDAI subdomain assessed) was done in the respective visit window or 
thereafter.
In addition, incidence of protocol deviations and subject eligibility for the analysis sets will be 
summarized:

Incidence of significant protocol deviations by category (see also section 7.4.1).

Incidence of major protocol violations by category (see also section 7.4.2).

Number (and %) of subjects eligible for each analysis set;
Reasons for exclusion from analysis sets will be listed.
Corresponding subject data listings to be provided:

All subjects: inclusion/exclusion criteria responses by subject

Screen failures: screening and demographic data captured for screen failures

Randomized subjects: date of ICF date, date of screening, date of randomization, further 
randomization information, date of first dose, last dose and last study visit.

Randomized subjects who did not meet at least one inclusion criteria or who did meet at 
least one exclusion criteria will be listed.

Subjects excluded from analysis sets will be listed including the reason for exclusion.
7.4
Significant Protocol Deviations and Major Protocol Violations
7.4.1
Significant Protocol Deviations
Significant protocol deviations were to be collected on the eCRF throughout the study conduct.
Significant protocol deviations will be summarized for all randomized subjects using the 
following categories:

Entry Criteria

Concomitant Medication

Procedures Not Performed Per Protocol (Primary Endpoint or Safety Related)

Study Medication

Withdrawal Criteria
A corresponding subject data listing, grouped by study site, will be provided.
Note: Study monitors informed that also several non-significant deviations had been reported in 
the study database (via the eCRF). Therefore, all deviations reported in the study database will 
be reviewed and re-assessed regarding their significance in context of the blind data review.
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7.4.2
Major Protocol Violations
Major protocol violations that lead to exclusion from the PPS include the following categories:

Randomized, but not treated

Received wrong study medication (at least once)

Missing baseline mPDAI score

mPDAI score < 5 at baseline (considering the adjudicated endoscopy ulceration score)

Missing Week 14 mPDAI score
Further major protocol violations might be identified in context of the blind data review. 
Major protocol violations will be summarized by means of a frequency table. A corresponding 
subject data listing, grouped by study site, will be provided.
7.5
Demographic and Other Baseline Characteristics
Generally, demographic and baseline characteristics will be summarized for all subjects 
randomized and for all analysis sets (SAF, FAS and PPS). If all subjects randomized and the 
SAF are identical, only one (combined) summary will be provided (with population title All 
randomized subjects / Safety Analysis Set). If two or all sets of SAF, FAS or PPS are identical, 
summaries can be combined accordingly. All summaries will be done by treatment arm and 
overall (in the respective analysis set).
Table 7.b lists the demographic and general baseline variables that will be tabulated. 
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Table 7.b
Demographic and Baseline Characteristics
Demography (unit)
Summarized as
Categories
Age (years)
Continuous and
Categorical
< 35 years
35 to < 65 years
≥ 65 years
Gender
Categorical
Male
Female
Ethnicity
Categorical
Hispanic or Latino
Non-Hispanic and Latino
Not Collected
Racea
Categorical
American Indian or Alaska Native
Asian
Black or African American
Native Hawaiian or Other Pacific Islander
White
Multiracial
Height (cm)
Continuous
Weight (kg)
Continuous
Body Mass Index (BMI) (kg/m2)
Continuous and
Categorical
Underweight (BMI< 18.5)
Normal (BMI 18.5 to < 25.0)
Overweight (BMI 25.0 to < 30.0)
Obesity (BMI ≥ 30.0)
Smoking Classification
Categorical
Never-smoker
Current smoker
Ex-smoker
Female Reproductive Status
Categorical
Postmenopausal
Surgically Sterile
Female of Childbearing Potential
N/A (Subject is male)b
a recorded on the eCRF. Subjects who identify themselves as more than one race on the eCRF will be classified as 
Multiracial for tabulation and will be included only in the multiracial category.
b Category “N/A” will be excluded from calculations of percentages for the other categories.
The BMI will be derived as body weight (kg) / height (m)2 using the last body weight 
measurement prior to first dose of study medication (usually at Day 1) and the height measured 
at Visit 1 (Screening). 
Table 7.c lists the pouchitis related baseline variables that will be tabulated.
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Table 7.c
Pouchitis Related Baseline Characteristics
Characteristics (unit)
Summarized as
Categories
Type of pouchitis
Categorical
Chronic pouchitis
Recurrent pouchitis
Time since IPAAa
Continuous and 
Categorical
< 1 year
1 to < 3 years
3 to < 7 years
≥ 7 years
Baseline mPDAIb
Continuous and 
Categorical
< 5 (quiescent)
5 to 8 (moderately active)
9 to 12 (severely active)
Baseline PDAIc
Continuous and 
Categorical
< 7 (quiescent)
7 to 12 (moderately active)
13 to 18 (severely active)
Baseline stool frequency
(from PDAI)
Categorical
0 = Usual postoperative stool frequency
1 = 1-2 stools/day > postoperative usual
2= 3 or more stools/day > postoperative usual
Baseline polymorphic nuclear 
leukocyte infiltration (PMNL; from 
PDAI)
Categorical
0 = none
1 = mild
2 = moderate + crypt abscess
3 = severe + crypt abscess
Prior anti-TNF exposure
(for UC or pouchitis)e
Categorical
anti-TNF naïve
anti-TNF experienced
Prior anti-TNF started post-
colectomyf
Categorical
anti-TNF failure
by reason: inadequate response, loss of response, 
intolerance
anti-TNF used/no failure
anti-TNF not used
Concomitant use of corticosteroids 
(for UC or pouchitis) at baseline
Categorical
Yes
No
Baseline CRP (mg/L)
Continuous and 
Categorical
≤ 2.87 mg/L
> 2.87 mg/L to ≤ 5 mg/L
> 5 mg/L to ≤ 10mg/L
> 10 mg/L
Baseline FC (μg/g)
Continuous and 
Categorical
≤ 250 μg/g
> 250 μg/g to ≤ 500 μg/g
> 500 μg/g
a See section 7.1.9 for calculation rule.
b See Appendix C for details on score derivation.
c See Appendix B for details on score derivation.
d See Appendix E for details on score derivation.
e Considering any prior use of anti-TNF for UC or pouchitis as recorded on the “UC Disease Last Antibiotic Medication and All 
Prior Biologics” or “Medication History/Concomitant Medications” CRF pages. See also section 7.1.1.
f Considering prior use of anti-TNF started post IPAA as recorded on the “UC Disease Last Antibiotic Medication and All Prior 
Biologics”; reasons for discontinuation “inadequate response”, “loss of response”, and “intolerance” are considered anti-TNF 
treatment failure. See also section 7.1.1 and section 7.1.6 for further details.
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7.6
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that stopped at or prior to the time 
of ICF. Concurrent medical conditions are defined as significant ongoing conditions or diseases 
present at signing of ICF; the investigated disease “pouchitis” is not considered a concurrent 
medical condition. Both medical history and concurrent medical conditions will be summarized 
using the SAF (by treatment arm and overall).
Medical history and concurrent medical conditions will be coded using the MedDRA dictionary 
(MedDRA 23.0 Mixed). Medical history and concurrent medical conditions will be summarized 
by system organ class (SOC) and preferred term (PT), showing the number (and %) of subjects 
with medical history or condition (by SOC and PT); the tables will be sorted in alphabetic order 
by SOC and in decreasing frequency based on the total number of reports by PTs within each 
SOC. The denominator used for calculating the percentages will be the total number of subjects 
in the SAF (within treatment arm and overall, respectively). A subject having multiple reports 
the same PT will be counted only once for that PT. Similarly, a subject with multiple reports 
within the same SOC (even with different PTs) will be counted only once for that SOC.
The listings for medical history and concurrent medical condition data will contain at least one 
record per subject indicating if there was any medical history or concurrent condition reported, 
and, where applicable, showing the details of the medical history or concurrent medical 
condition (e.g., SOC, PT, start and end dates).
In addition, surgical and disease history related to UC (recorded separately in the eCRF) will be 
listed. 
7.7
Medication History and Concomitant Medications
Medication history and concomitant medications were to be recorded in the eCRF. Reported 
medications will be grouped as follows:

Prior medications: medications started prior to Day 1

Concomitant medications: medications ongoing at Day 1 or started on or after Day 1 and 
before the end of study participation/early discontinuation
All medications will be coded using the WHODrug dictionary (01 March 2016 Expanded 
version).
Summaries of prior medications and concomitant medications will be provided based on the SAF 
and will present the number and percentage of subjects (using the total number of subjects in the 
treatment arm as the denominator) by therapeutic classification, subclassification, and preferred 
medication name. Therapeutic classification and subclassification terms will be sorted 
alphabetically; preferred medication names will be sorted using decreasing frequency across 
treatment arms.
Medications for treatment of UC or pouchitis (including worsening and flares) will primarily 
include antibiotics, corticosteroids, anti-TNFs and other relevant UC/pouchitis treatment (see 
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definitions in section 7.1.1); in addition, other medications flagged on the respective eCRF pages 
as “specifically for pouchitis” or “for treatment of flare” will be included.
Failure of prior treatment for UC or pouchitis will be identified as specified for prior anti-TNF 
treatments (see section 7.1.1), namely discontinuation reasons “inadequate response”, “loss of 
response”, and “intolerance” will be considered failure.
For the first 4 weeks, ciprofloxacin is given as companion antibiotic according to protocol; this 
companion antibiotic will not be considered as concomitant treatment as such. Ciprofloxacin will 
be considered as concomitant treatment in the following cases:

Ciprofloxacin taken prior to the Week 4 visit (i.e. on or after Day 1) in addition to the 
companion antibiotic (i.e. total daily dose is higher than as per protocol).

Ciprofloxacin taken after the later of Day 29 / actual Week 4 visit date.
(e.g., if Week 4 visit was one Day 23, all ciprofloxacin up to Day 29 will be considered 
as companion antibiotic; if Week 4 visit was on Day 35, all ciprofloxacin up to Day 35 
will be considered as companion antibiotic).
The following additional medication summaries will be provided for the FAS and PPS 
populations:
Prior UC/Pouchitis Medications

Prior medications for UC and prior biologics (for UC/pouchitis) grouped by therapeutic 
classification, subclassification.
(as collected on eCRF form “UC Disease Last Antibiotic Medication and All Prior 
Biologics”, complemented by any such medication recorded as prior medication on the 
“Medication History/Concomitant Medications” eCRF form)

Prior medications for UC/pouchitis started post-colectomy (= after IPAA) grouped by 
therapeutic classification, subclassification.
(as collected on eCRF form “UC Disease Last Antibiotic Medication and All Prior 
Biologics”, complemented by any such medication recorded as prior medication on the 
“Medication History/Concomitant Medications” eCRF form)

Summary of reasons for failure/discontinuation and primary reason of intolerance of prior 
medications for UC/pouchitis started post-colectomy (= after IPAA) grouped by 
therapeutic classification, subclassification.
(as collected on eCRF form “UC Disease Last Antibiotic Medication and All Prior
Biologics”, complemented by any such medication recorded as prior medication on the 
“Medication History/Concomitant Medications” eCRF form; for prior medications for 
UC or pouchitis recorded on the “Medication History/Concomitant Medications” eCRF 
form, the reason for discontinuation will be identified as “not recorded”).
A subject with multiple prior treatment courses within the same treatment class 
(therapeutic classification or subclassification) who experienced at least one failure in the 
treatment class will be counted as “failure” for the respective treatment class.
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Concomitant Pouchitis Medications

Concomitant medications for the treatment of pouchitis/worsening of pouchitis/flares 
grouped by therapeutic classification, subclassification.
Intake of the companion antibiotic medication (ciprofloxacin 500 mg twice daily) during 
the first 4 weeks as per protocol will not be included in this summary. However, if this 
medication was continued after 4 weeks* or re-started after Week 4* or given for a 
flare/worsening, it will be included and counted in the summary.
*Note: 4 weeks and Week 4 here refer to the later of the actual Week 4 visit date and 
Day 29 (see above).

Use of concomitant corticosteroids (CS) for pouchitis using frequency tables showing 
number (and %) of subjects with/without CS use by visit (baseline/Day 1, Week 14, 
Week 34), where the reference day for baseline is Day 1 and for Week 14/34 is the day of 
the corresponding mPDAI assessment.

Use of concomitant antibiotics for pouchitis (excluding the companion antibiotic 
medication given per protocol up to Week 4) using frequency tables showing number 
(and %) of subjects with/without antibiotics use by visit (baseline/Day 1, Week 14, 
Week 34), where the reference day for baseline is Day 1 and for Week 14/34 is the day of 
the corresponding mPDAI assessment.
Separate listings for medication history and concomitant medications will be produced by site 
and subject number. In addition, antibiotic medications and/or prior biologics related to UC 
(recorded separately in the eCRF) will be listed.
7.8
Study Drug Exposure
Study drug exposure will be summarized based on the SAF, FAS and PPS.
The following exposure data summaries will be provided (by treatment arm):

Number (and %) of subjects by total number of intravenous infusions received

Number (and %) of subjects who received any incomplete infusion (a subject has 
received complete infusion if the total amount was infused as per data collected in eCRF)

Descriptive statistics for the total vedolizumab dose (mg) received in the study

Descriptive statistics for duration of exposure (days)

Frequency table for duration of exposure, showing the number (and %) of subjects 
according to the following categories: <20 weeks, 20 to <24 weeks, 24 to <32 weeks, 32 
to <40 weeks, 40 to <48 weeks and ≥48 weeks.
For subjects randomized to vedolizumab IV, the duration of exposure will be calculated as: 
date of last dose – date of first dose + 1 + 126,
where adding 126 days accounts for 5 times the half-life of vedolizumab IV. For subjects 
randomized to the placebo arm, the duration of exposure will be calculated as: 
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date of last dose – date of first dose + 1.
All study drug administration and accountability data will be listed. 
7.9
Efficacy Analysis
This section describes the analyses to be conducted on the primary, secondary and additional 
endpoints related to efficacy. 
7.9.1
General Consideration for the Efficacy Data Analysis
The primary efficacy analyses will be done based on the FAS, i.e., in general, all efficacy 
endpoints will primarily be summarized and analyzed for the FAS. Analyses of selected mPDAI 
and PDAI based endpoints (e.g., clinically relevant [mPDAI] remission, PDAI remission, partial 
mPDAI response, sustained mPDAI remission, sustained PDAI remission) will be repeated for 
the PPS. Further sensitivity analyses are described in section 7.9.6.1. The PDAI was to be 
assessed at baseline (Screening/ Visit 1), Week 14 and Week 34. All summaries will be provided 
by treatment arm and visit, if applicable.
Subjects for whom the total PDAI score at baseline cannot be calculated due to missing PDAI 
component or subscore will be excluded from the response analyses for PDAI remission, 
sustained PDAI remission, 
 and analysis of time to PDAI remission and 
summaries of changes in the respective PDAI subscore(s) and changes in the respective PDAI 
component(s). However, data from such subjects will be included in the descriptive PDAI 
summaries by visit.
All efficacy data (originally reported data and derived outcomes) will be listed.
7.9.1.1
Analysis of Response-type Endpoints
For response-type efficacy endpoints (such as the primary endpoint), frequency tables will be 
provided, showing 
!
the number and proportion (%) of subjects achieving and not achieving the response (by 
treatment arm, visit)
!
corresponding 2-sided 95% CIs for the response rate (by treatment arm, visit)
!
difference in response rates (expressed in percent points [p.p]) between treatment arms
(vedolizumab – placebo) and corresponding 95% CI
If not stated otherwise, the 95% CIs will be calculated using the exact method. Visit here 
typically refers to post-baseline visits (i.e., if not specifically mentioned those tables will be 
provided only for post-baseline visits).
The difference in response rate between the treatments will be tested using a chi-squared test and 
the (2-sided) p-value reported. If the number of responders or non-responders in either of the two 
treatment arms is too small (i.e., ≤5), the exact method (i.e., Fisher’s Exact test) will be 
performed instead. 
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In order to account for the stratified randomization, response rates will be additionally analyzed 
stratified by type of pouchitis using the Cochran-Mantel-Haenszel (CMH) test, showing the 
relative risks (of response, relative to placebo) and 95% confidence limits overall (common) and 
for the two levels of type of pouchitis, and the p-value for association between treatment and 
response from the CMH statistics. This additional analysis will only be done for the endpoints 
mPDAI remission and PDAI remission (at Week 14 and Week 34) for the FAS and PPS, and 
only if the number of responders and non-responders in both treatment arms is sufficiently large
(i.e., >5); this analysis will not be done for any subgroup analyses.
In these analyses, all subjects with missing data for determination of response status at a time 
point will be considered as a non-responder (non-response imputation). 
This applies, in particular, to the following endpoints: clinically relevant remission (mPDAI 
remission), PDAI remission, partial mPDAI response.
7.9.1.2
Analysis of Other Categorical/Ordinal Endpoints
For categorical and ordinal efficacy endpoints other than response-type efficacy endpoints, 
frequency tables will be provided, showing the number and proportion (%) of subjects per 
category by treatment arm and visit (see details for standard frequency tables in in section 7.1).
7.9.1.3
Analysis of Continuous Endpoints
Continuous efficacy endpoints (observed values) and their change from baseline will be 
summarized descriptively by treatment arm and visit (see details for descriptive statistics in 
section 7.1).
Where required, e.g. for secondary efficacy endpoints, changes from baseline to relevant visits in 
both treatment arms will be compared using the Wilcoxon rank-sum tests; the (Wilcoxon-Mann-
Whitney) odds estimator and its 95% CI and the Hodges-Lehmann estimate for difference 
(location shift) with its 95% CI will be presented.
7.9.1.4
Analysis of Time-To-Event Endpoints
For time-to-event endpoints, the time to event (in days) from first dose of study medication 
(Day 1) will be derived as
time (days) = date of event – date of Day 1 + 1.
The time to event will be analyzed using Kaplan-Meier product limit methods, with subjects that 
do not experience the event during the study being censored at the time of the last corresponding 
assessment or date of last record (week 34 or early discontinuation), as applicable. Summaries 
will present the total number (and %) of subjects with event, total number of cases censored; the 
time to event will be summarized by estimates of 25th, 50th (median), and 75th percentiles with 95% 
CIs, and the range (min, max); in addition, cumulated number of subjects with event by 
appropriate time points and corresponding Kaplan-Meier estimates (with 95% CI) and number of 
subjects at risk by time point will also be summarized.
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The survival analysis will be supplemented with a corresponding Kaplan-Meier plot (by 
treatment arm, using an appropriate time scale) to illustrate the time to event, showing also the 
number of subjects at risk at the time points (at baseline and at the time points corresponding to 
the summary table).
7.9.2
Overall PDAI and mPDAI Summaries
The primary and most of the secondary efficacy are based on the PDAI and mPDAI, assessed at 
baseline/screening, Week 14 and Week 34. The PDAI (and mPDAI) scores and components and 
their changes from baseline will be summarized as described below for the FAS and the PPS. In 
general, all scores are integer scores and therefore, minimum and maximum values will be 
displayed without decimals. Details for response-type frequency tables, (standard) frequency 
tables and descriptive statistics can be found in sections 7.9.1.1, 7.9.1.2 and 7.9.1.3, respectively.
mPDAI total score (summaries for overall populations and subgroups specified in section 7.9.3)
a) descriptive statistics, as observed
(for FAS and PPS overall, including inferential statistics as described in section 7.9.1.3)
b) descriptive statistics, LOCF applied (only for the FAS);
(for FAS overall, including inferential statistics as described in section 7.9.1.3)
c) frequency table with categories < 5 (quiescent), 5 to 8 (moderately active), 9 to 12 
(severely active), as observed
d) response-type frequency table with categories < 5 (remission), ≥5 (active), non-response 
imputation applied as described in section 7.9.1.1
PDAI total score (summaries for overall populations and subgroups specified in section 7.9.4)
a) descriptive statistics, as observed
(for FAS and PPS overall, including inferential statistics as described in section 7.9.1.3)
b) descriptive statistics, LOCF applied (only for the FAS)
(for FAS overall, including inferential statistics as described in section 7.9.1.3)
c) frequency table with categories < 7 (quiescent), 7 to 12 (moderately active), 13 to 18 
(severely active), as observed
d) response-type frequency table with categories < 7 (remission), ≥7 (active), non-response 
imputation applied as described in section 7.9.1.1
PDAI domains and components
Clinical symptoms

Clinical symptoms subscore
a) descriptive statistics, as observed
(for FAS and PPS overall, including inferential statistics as described in section 
7.9.1.3)
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b) descriptive statistics, LOCF applied (only for the FAS)
(for FAS overall, including inferential statistics as described in section 7.9.1.3)

Stool frequency (SF)
a) frequency table with categories 0 = “usual postoperative frequency”, 1 = “1-2 
stools/day more than usual”, 2 = ”≥3 stools/day more than usual” (observed data, no 
imputation applied)
b) response-type frequency table with categories 0 = “usual postoperative frequency”, 
≥1 = “more than usual”
c) response-type frequency table with categories 0 = “usual postoperative frequency”, 
≥1 = “more than usual”, for the subpopulation having an SF score > 0 at baseline
d) response-type frequency table with categories ≤1 = “≤2 stools/day more than usual 
postoperative frequency”, 2 = “≥3 stools/day more than usual” (without inferential 
statistics)
e) response-type frequency table with categories ≤1 = “≤2 stools/day more than usual 
postoperative frequency”, 2 = “≥3 stools/day more than usual”, for the subpopulation 
having an SF score > 1 at baseline (without inferential statistics)

Rectal bleeding (RB)
a) frequency table with categories 0 = “none or rare”, 1 = “present daily” (observed data, 
no imputation applied)
b) response-type frequency table with categories 0 = “none or rare”, 1 = “present daily”
(without inferential statistics)
c) response-type frequency table with categories 0 = “none or rare”, 1 = “present daily”, 
for the subpopulation having an RB score > 0 (i.e. rectal bleeding present daily) at 
baseline (without inferential statistics)

Clinical components fecal urgency or abdominal cramps, fever:
frequency tables with categories as per PDAI (see Appendix B)
Endoscopic inflammation

Endoscopic inflammation subscore
a) descriptive statistics, as observed
(for FAS and PPS overall, including inferential statistics as described in section 
7.9.1.3)
b) descriptive statistics, LOCF applied (only for the FAS)
(for FAS overall, including inferential statistics as described in section 7.9.1.3)
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
Endoscopic component ulceration
a) frequency table with categories 0 = “absent”, 1 = “present” (observed data, no 
imputation applied)
b) response-type frequency table with categories 0 = “absent”, 1 = “present”
(without inferential statistics)
c) response-type frequency table with categories 0 = “absent”, 1 = “present”,
for the subpopulation having an ulceration score > 0 (i.e. ulceration present) at 
baseline (without inferential statistics)

Endoscopic components friability, loss of vascular pattern, edema:
frequency tables with categories 0 = “absent”, 1 = “present”

Note: no specific summaries for components granularity and mucus exudates
Note: For the components of endoscopic inflammation, the central reader data should be 
used and not the eCRF data (the eCRF only captured presence, thus missing and absence 
cannot be distinguished).
Acute histologic inflammation

Acute histologic inflammation subscore
a) descriptive statistics, as observed
(for FAS and PPS overall, including inferential statistics as described in section 
7.9.1.3)
b) descriptive statistics, LOCF applied (only for the FAS)
(for FAS overall, including inferential statistics as described in section 7.9.1.3)

Histologic inflammation components polymorphic nuclear leukocyte infiltration and 
ulceration per low power field:
frequency tables with categories as per PDAI (see Appendix B)
Further summaries and analyses of the primary and secondary efficacy endpoints related to the 
PDAI are described in sections 7.9.3 and 7.9.4. Further summaries and analyses of individual 
PDAI components are described in section 7.9.6. In general, the summaries and analyses of and 
outcome/endpoint or component described in this section and the later section should be grouped 
together and, where possible, be shown in the same table.
7.9.3
Primary Efficacy Endpoint
The primary endpoint is clinically relevant (mPDAI) remission (defined as an mPDAI score < 5 
and a reduction of mPDAI score by ≥2 points from baseline) at Week 14.
Let pv and pp describe the proportion of subjects achieving the primary endpoint (i.e., of Week 
14 mPDAI remitters) in the vedolizumab and placebo arms, respectively. The null and 
alternative hypotheses for the primary efficacy endpoint are:
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H0: pv = pp
H1: pv ≠ pp
The primary endpoint (a response-type endpoint) will be summarized and analyzed as described 
in section 7.9.1.1 based on the FAS (primary analysis) and the PPS (sensitivity analysis). The 
primary inferential analysis for testing the hypothesis is the chi-squared test described in section 
7.9.1.1. Related descriptive summaries are described in section 7.9.2. 
Corresponding subgroup analyses will be done for subgroups by type of pouchitis, prior anti-
TNF failure for pouchitis (started post-colectomy), prior anti-TNF exposure, baseline severity 
based on mPDAI, baseline PMNL, time from IPAA to start of treatment, baseline FC, baseline 
CRP (see definitions in section 7.1.6). Results from those subgroup analyses will be illustrated 
by means of forest plots for the treatment difference in response rates with corresponding 95% 
CI by subgroup.
7.9.4
Secondary Efficacy Endpoints
The secondary efficacy endpoints will be summarized and analyzed as described below based on 
the FAS (primary analysis); analyses will be repeated for the PPS (sensitivity analysis) as 
indicated below. Related descriptive summaries for PDAI-based endpoints are already described 
in section 7.9.2. 
Corresponding subgroup analyses for subgroups by type of pouchitis, prior anti-TNF failure for 
pouchitis (started post-colectomy), prior anti-TNF exposure, baseline severity based on mPDAI, 
baseline PMNL, time from IPAA to start of treatment, baseline FC, baseline CRP (see 
definitions in section 7.1.6) will be done for the endpoints mPDAI remission at Week 34, PDAI 
remission at Week 14 and Week 34, and partial mPDAI response at Week 14 and Week 34. 
Analyses for PDAI remission at Week 14 and Week 34 will also be repeated for subgroups by 
baseline severity based on PDAI. Results from those subgroup analyses will be illustrated by 
means of forest plots for the treatment difference in response rates with corresponding 95% CI
by subgroup.
Clinically relevant (mPDAI) Remission at Week 34
The secondary endpoint clinically relevant (mPDAI) remission at Week 34 will be summarized 
and analyzed as described in section 7.9.1.1 based on the FAS and the PPS.
PDAI Remission at Week 14 and at Week 34
PDAI remission (defined as a PDAI score < 7 and a decrease in PDAI score of ≥3 points from 
baseline) at Week 14 and at Week 34 will be summarized and analyzed as described in section 
7.9.1.1 based on the FAS and the PPS.
Time to PDAI Remission
The time point of PDAI remission is defined as the first visit on which the PDAI score is < 7 and 
a decrease in the PDAI score of ≥3 points from baseline occurred (=Visitremission). The time to 
PDAI remission is then derived using the date of Visitremission and summarized and analyzed as 
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described in section 7.9.1.4 based on the FAS. Subjects who did not achieve PDAI remission, 
will be censored at the time of their last PDAI assessment; if a subject’s last PDAI assessment is 
the baseline assessment, the subject will be censored at Day 1. Cumulated event counts, KM 
estimates and number at risk will be shown for the Week 14 and Week 34 visits (considering the 
last day of the respective analysis windows defined in section 7.1.7). 
Cox proportional hazards regression will be performed to explore the effect of prognostic factors. 
Prognostics factors include type of pouchitis, prior anti-TNF failure for pouchitis (started post-
colectomy), prior anti-TNF exposure, time from IPAA, baseline severity based on mPDAI, 
baseline severity based on PDAI, baseline PMNL, baseline FC, baseline CRP (for all factors use 
same categories as for subgroup analyses of the primary endpoint, see also section 7.1.6), age 
(< 35 years vs ≥35 years), gender, BMI (< 30 vs ≥30 kg/m2). This regression analysis will be 
done for the FAS and the PPS.
Adjustments for baseline imbalances on key prognostic factors (listed above) will be made using 
Cox regression. 
Partial mPDAI Response at Week 14 and at Week 34
Partial mPDAI response (defined as a reduction in mPDAI score by ≥2 points from baseline) at 
Week 14 and at Week 34 will be summarized and analyzed as described in section 7.9.1.1 based 
on the FAS and the PPS.
Changes in PDAI Subscores
Total PDAI and PDAI subscores (mPDAI score, clinical symptoms, endoscopic inflammation 
and histologic inflammation) and their changes will be summarized as described in section 7.9.2. 
In addition, the changes in these scores from baseline to Week 14 and to Week 34 will be 
analyzed as described in section 7.9.1.3 (including inferential statistics for the FAS and PPS 
overall populations).
All summaries and analyses will be done for the FAS and the PPS based on observed data; for 
the FAS analyses will be repeated with missing data imputed using the last observation carried 
forward (LOCF) approach applied (thereby considering data from unscheduled visits or early 
termination).
IBDQ
The IBDQ is an instrument used to assess quality of life in adult subjects with IBD. It includes 
32 questions on 4 domains: bowel systems (10 items), emotional function (12 items), social 
function (5 items) and systemic function (5 items). Subjects are asked to recall symptoms and 
quality of life from the last 2 weeks and rate each item on a 7-point Likert scale (higher scores 
equate to higher quality of life). A total IBDQ score is calculated by summing the scores from 
each domain; the total IBDQ score ranges from 32 to 224 (see calculation rules in Appendix G).
The IBDQ was to be assessed at Day 1 (baseline), Week 14, Week 22 and Week 34. 
The total IBDQ score and domain scores and their respective changes from baseline to Week 14, 
Week 22 and Week 34 will be summarized descriptively as described in section 7.9.1.3
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(including inferential statistics for the FAS and PPS overall populations, only for the total IBDQ 
score).
In addition, IBDQ remission and IBDQ improvement will be summarized by visit, by means of 
response-type frequency tables as described in section 7.9.1.1 (without inferential statistics).
All IBDQ summaries will be provided once based on observed data (FAS and PPS) and once 
with missing data imputed using LOCF (FAS only).
CGQL
The CGQL was developed as a quality-of-life indicator specifically for subjects with IPAA. It 
includes three components (current quality of life, current quality of health and current energy 
level), each scored on a scale of 0 (worst) to 10 (best). The CGQL utility score will be derived as 
the sum of the component scores divided by 30; the CGQL is recorded with a patient diary which 
is completed for 3 days prior to endoscopy or bowel preparation for endoscopy. The Fazio score 
is assessed as the average of the completed CGQL utility scores, where at least one non-missing 
day needs to exist (see further details in Appendix F). The CGQL was to be assessed at Day 1 
(baseline), Week 14, Week 22 and Week 34. 
The Fazio score and change from baseline to Week 14, Week 22 and Week 34 will be 
summarized descriptively as described in section 7.9.1.3 (including inferential statistics), once 
based on observed data (FAS and PPS) and once with missing data imputed using LOCF (FAS 
only).
7.9.5
Exploratory Efficacy Endpoints
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7.9.6
Sensitivity Analyses and Additional Analyses 
7.9.6.1
Sensitivity Analyses
Sensitivity analyses are considered for the following endpoints:
!
Clinically relevant (mPDAI) remission at Week 14 and Week 34
!
PDAI remission at Week 14 and Week 34
!
Partial mPDAI response at Week 14 and at Week 34
!
Sustained mPDAI remission
!
Sustained PDAI remission
At first, the analyses for the aforementioned endpoints as described in sections 7.9.3, 7.9.4 and 
7.9.5. will be repeated based on the PPS. In case, major differences between the results for the 
FAS and the PPS are detected for these endpoints, analysis of further efficacy endpoints based on 
the PPS might be warranted.
To assess the impact of dropouts and missing data for response-type efficacy endpoints listed 
above, further sensitivity analysis will be performed in addition to the initial non-response 
imputation approach described in section 7.9.1.1. and applied to the respective response-type 
frequency tables and analyses: 
1) Impute all missing data using LOCF
2) Hybrid approach: 
a.
Interim missing data (e.g. Week 14 missing, but Week 34 data present) will be 
imputed using LOCF.
b. Missing data after study drug discontinuation will be imputed based on the 
primary reason for study drug discontinuation:
missing data after study drug discontinuations due to AE or lack of efficacy will 
be imputed using the non-response imputation (as done in the initial approach);
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missing data after study discontinuations for other reasons will be imputed using 
LOCF. 
3) Non-response imputation for use of concomitant antibiotics prior to Week 14:
In addition to the general non-response imputation for missing data in the initial analysis, 
subjects with use of concomitant antibiotics relevant for UC/pouchitis (see section 7.1.1), 
other than the companion antibiotic given per protocol up to Week 4, prior to Week 14 
(date of Week 14 endoscopy) will be imputed as non-responders at Week 14 and Week 
34 for the aforementioned efficacy endpoints.
Independently from the three approaches described above, missing individual PDAI components 
will be imputed as described in section 7.1.10. Those analyses will be done initially based on the 
FAS. If large deviations from the results of the initial analyses are identified, they might be 
repeated based on the PPS and further sensitivity analyses with different missing data imputation 
methods might be considered.
7.9.6.2
Additional Analyses
Due to large number of centers with small number of patients recruited, appropriate pooling of 
centers by the following geographical regions will be done:
!
Europe (all European countries)
–
Central Europe (UK, Belgium, Germany, the Netherlands)
–
Southern Europe (France, Italy, Spain)
!
North America (US/Canada)
–
USA
–
Canada
Appropriate summaries for the aforementioned response-type endpoints by region will be 
provided and corresponding forest plots for the treatment difference in response rates with 
corresponding 95% CI by region will be plotted (for the FAS population only).
If the graphical exploration yields substantial differences between the region/centers, the 
exploration will be repeated for the PPS and corresponding summary statistics will be produced 
for both populations. Additionally, these endpoints might be analyzed additionally accounting 
for region/center (regions/centers with alike effects might be grouped accordingly).
7.10
Pharmacokinetic/Pharmacodynamic Analysis
Not applicable.
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7.11
Other Outcomes
Not applicable.
7.12
Safety Analysis
Safety analyses include AEs, clinical laboratory values, vital signs and electrocardiograms 
(ECGs). All safety summaries will be based on the SAF, and if not mentioned otherwise will 
show results by treatment arm. 
7.12.1
Adverse Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed ICF to participate in a study, but prior to administration of 
any study medication. An adverse event (AE) is defined as any untoward medical occurrence in a 
clinical investigation subject administered a study medication. Treatment-emergent adverse 
events (TEAEs) will be defined as any AE that occurs after the first dose of study medication (on 
or after Day 1) and up to the last dose of study medication plus applicable follow up (18 weeks = 
126 days from the date of last dose).
Adverse events were to be recorded throughout the study with assessment of intensity (mild, 
moderate, severe), relationship to study medication (related, not related) and seriousness (SAE or 
not). Further AE information collected include onset and end of AE, type (pretreatment or AE), 
relationship to study procedure, actions taken concerning study medication, and outcome. PTEs 
and AEs will be coded using MedDRA, Version 23.0 Mixed.
The overview of TEAEs will be summarized using the number of events as well as the number 
and percentage of subjects with TEAEs. All other TEAE summaries provide the number and 
percentage of subjects with event, with events grouped by MedDRA system organ class (SOC), 
high level term (HLT), and preferred term (PT). 
Most frequent TEAEs are defined as events that occur in at least 5% of subjects within either 
treatment arm. Exposure adjusted incidence rates will be derived as incidence per 100 subject 
years.
The following outputs will be produced for TEAEs overall:

Overview of TEAEs, showing the number (and %) of subjects with and number of 
TEAEs (number of events) overall, TEAEs overall by intensity, TEAEs overall by drug 
relationship, TEAEs leading to study drug discontinuation, serious TEAEs overall, 
serious TEAEs by drug relationship, serious TEAEs leading to study drug discontinuation, 
and the number of deaths.

Number (and %) of subjects with and number of TEAEs by SOC, HLT and PT

Exposure-adjusted* TEAEs by SOC, HLT, and PT

Subject mapping of TEAEs by SOC, HLT, and PT
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
Number (and %) of subjects with and number of TEAEs leading to study drug 
discontinuation by SOC, HLT and PT

Subject mapping of TEAEs leading to study drug discontinuation by SOC, HLT, and PT

Number (and %) of subjects with and number of serious TEAEs by SOC, HLT and PT

Exposure-adjusted* serious TEAEs by SOC, HLT, and PT

Subject mapping of serious TEAEs by SOC, HLT, and PT

Number (and %) of subjects with and number of most frequent TEAEs by SOC, HLT and 
PT

Number (and %) of subjects with and number of most frequent non-serious TEAEs by 
SOC, HLT and by PT

Number (and %) of subjects with and number of drug-related TEAEs by SOC, HLT and 
PT

Intensity of TEAEs by SOC, HLT and PT

Intensity of drug-related TEAEs by SOC, HLT and PT
* For the expose-adjusted TEAE tables the exposure-adjusted incidence rate (incidence per 100 
subject years) will be summarized. For the purpose of this analysis, 

the exposure-adjusted incidence rate is defined as the number of subjects with AEs (with 
onset during the exposure interval) divided by the total exposure time of the subjects (in a 
treatment arm)

for both treatment arms, 
a subject’s exposure interval is defined as [date of first dose; date of last dose + 126 days] 
and the corresponding exposure time as date of last dose – date of first dose + 1 + 126.
The following summaries will be provided for TEAEs related to a flare:

Overview of TEAEs related to a flare, showing the number (and %) of subjects with and 
number of TEAEs related to a flare overall, TEAEs related to a flare overall by intensity, 
TEAEs related to a flare overall by drug relationship, TEAEs related to a flare leading to 
study drug discontinuation, serious TEAEs related to a flare overall, serious TEAEs 
related to a flare by drug relationship, serious TEAEs related to a flare leading to study 
drug discontinuation.

Number (and %) of subjects with and number of TEAEs related to a flare by SOC, HLT
and PT

Number (and %) of subjects with and number of TEAEs related to a flare leading to study 
drug discontinuation by SOC, HLT and PT

Number (and %) of subjects with and number of serious TEAEs related to a flare by SOC, 
HLT and PT
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
Number (and %) of subjects with and number of drug-related TEAEs related to a flare by 
SOC, HLT and PT

Intensity of TEAEs related to a flare by SOC, HLT and PT
The following pretreatment event summaries will be provided:

Number (and %) of subjects with and number of pretreatment events by SOC, HLT and 
PT

Number (and %) of subjects with and number of serious pretreatment events by SOC, 
HLT and PT
For the number (and %) of subjects with TEAEs in above summaries, subjects who reported the 
same TEAE multiple times will be counted only once per PT; similarly, subjects who reported 
multiple TEAEs falling in the same HLT or SOC will be counted only once per HLT or SOC, 
respectively. For the intensity summaries, if a subject reported multiple TEAEs coded to the 
same SOC or HLT or PT then the maximum intensity reported will be considered. If the intensity 
for a TEAE is missing, it will be counted as “severe” in the summaries, but in listings will be 
shown as missing. Similarly, for the summary of drug-related TEAEs, for subjects with multiple 
reports of the same PT (or within HLT or SOC), the worst case reported for the PT (within HLT 
or SOC) will be considered. If the drug-relationship for a TEAE is missing, it will be counted as 
“related” in the summaries, but in listings will be shown as missing. 
Data listings will be provided for pretreatment events, TEAEs overall*, TEAEs related to a flare, 
TEAEs leading to study drug discontinuation*, serious TEAEs*, and AEs resulting in death*. 
*In those listings, TEAEs related to a flare will be flagged.
7.12.1.1
Adverse Events of Special Interest
Based on the mechanism of action of vedolizumab, the following 5 AEs of special interest 
(AESIs) have been predefined with corresponding MedDRA search criteria. Standard MedDRA 
Query (SMQ) below refer to MedDRA V23.0 SMQ.
Hypersensitivity Reactions including Infusion-Related Reactions (IRRs) 
Possible IRRs will be identified using the following MedDRA search criteria:

Anaphylactic/anaphylactoid shock conditions SMQ (broad)

Angioedema SMQ (broad) 

Hypersensitivity SMQ (broad)

Infusion related reaction HLT
An AE that is indicated as an infusion site reaction in the eCRF will also be considered an 
IRR AESI.
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Suspected Progressive Multifocal Leukoencephalopathy (PML)
Suspected PMLs will be identified within the Infection and Infestation SOC using the following 
MedDRA search criteria: 

Human polyomavirus infection PT

JC virus infection PT

JC virus CSF test positive PT

Leukoencephalopathy PT

Polyomavirus test positive PT

JC polyomavirus test positive PT

Progressive multifocal leukoencephalopathy PT
Liver Injury
Reports of liver injury will be identified using the following MedDRA search criteria:

Cholestasis and jaundice of hepatic origin SMQ (broad) 

Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions SMQ 
(broad)

Hepatitis, non-infectious SMQ (broad) 

Liver related investigations, signs and symptoms SMQ (narrow) 

Liver infections SMQ (broad)
Malignancies
Reports of malignancy will be identified using the following MedDRA criterion: 

Neoplasms benign, malignant and unspecified (incl. cysts and polyps) SOC.

An AE that is indicated as malignancy in the eCRF will also be considered an AESI.
Serious Infections
Reports of infection, flagged as serious TEAE, will be identified using the following MedDRA 
criterion: 

Infections and infestations SOC.
Incidence of the 5 AESIs will be summarized showing the number (and %) of subjects with and 
the number of events by SOC, HLT and PT.
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7.12.2
Clinical Laboratory Evaluations
The laboratory parameters for serum chemistries, hematology, stool and urinalysis shown in 
Table 7.d were recorded in this study. Refer to Appendix A for scheduled measurements for 
clinical laboratory tests.
Table 7.d
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBC
WBC with differential*
Hemoglobin
Hematocrit
Platelets
PT/INR
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Calcium
Chloride
Magnesium
Phosphorus
Uric Acid
Glucose
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Specific Gravity
Other:
HIV
Hepatitis panel, including HBsAg and anti-HCV
Serum
Urine
Stool
QuantiFERON for TB
CRP 
hCG (for pregnancy in female 
subjects of childbearing potential only)
Fecal 
calprotectin 
beta hCG (for pregnancy in female subjects of 
childbearing potential only)
FSH, if menopause is suspected (Screening visit only)
C difficile
*WBC differential to include lymphocytes, monocytes, basophils, eosinophils, and neutrophils.
FSH =follicle-stimulating hormone, GGT= γ-Glutamyl transferase, hCG =human chorionic gonadotropin, 
PT=prothrombin time, RBC=red blood cells.
In general, clinical laboratory parameters will be presented using the International System of 
Units (SI) unless otherwise stated. For test results not reported in SI units, the conversion to SI 
units will be done in the derived analysis data sets using the known conversion factors. If 
necessary, SI units from the central laboratory may be converted to Takeda’s preferred SI units 
in the derived dataset. All data summaries will be based on the values using these preferred SI 
units. If a lab test with quantitative results has a value that is reported using a non-numeric 
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qualifier (e.g., less than (<) a certain value, or greater than (>) a certain value), the given numeric 
value will be used in the summary statistics, ignoring the non-numeric qualifier.
Continuous laboratory parameters tabulated using summary statistics for observed values and 
change from baseline by visit (baseline, each post baseline visit and last visit). Categorical 
laboratory parameters (e.g. urinalysis) will only be listed.
Criteria for markedly abnormal values (MAV) of laboratory parameters are listed in Appendix H.
For laboratory parameters with available criteria, incidence of MAVs will be summarized as 
follows:

Overview table with number (and %) of subjects with any MAV reported overall and by 
visit

For each laboratory parameter for which at least one MAV was reported:
a summary table for number (and %) of subjects with MAV by visit.
If both the baseline and on-treatment values of a parameter are beyond the MAV limit for that 
parameter, then the on-treatment value will be considered a MAV only if it is more extreme than 
was the baseline value.
In addition, the number (and %) of subjects with elevated liver function tests Alanine 
Aminotransferase, Aspartate Aminotransferase and Alkaline Phosphatase will be summarized 
separately.
All laboratory parameters will be listed, with values outside the normal ranges flagged as above 
“(H)” or below “(L)”; additionally, MAV values will be flagged (either as “(H#)” or “(L#)”).
7.12.3
Vital Signs
Systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse, body temperature (in °C), 
weight (in kg), and respiration rate were measured at the time points indicated in the schedule of 
study procedures (refer to Appendix A).
For each vital sign parameter, the observed values and change from baseline will be summarized 
by visit (including last visit) using descriptive statistics.
Criteria for MAV of vital signs (SBP, DBP, pulse and body temperature) are listed in Appendix I. 
For these vital signs parameters, incidence of MAV the number (and %) of subjects with MAV 
will be summarized by visit.
Vital signs data will be listed with markedly abnormal values (MAVs) flagged, either as “(H#)” 
for values exceeding the upper criterion or as “(L#)” for values exceeding the lower criterion.
7.12.4
12-Lead ECGs
Overall ECG interpretation category (within normal limits, abnormal but not clinically 
significant and abnormal clinically significant) are collected by the eCRF at Screening and 
occasional post-baseline unscheduled visits. ECG interpretations will be listed only. 
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7.12.5
Other Observations Related to Safety
Other safety related data recorded include the following data. The following additional safety 
data will only be collected by the eCRF when triggered by an adverse event. For those data 
appropriate data listings will be provided:

Physical examinations 

Liver function tests (increase, sign and symptoms, event history and test results) 

Infections (details of infection, their diagnostic tests, cause/origin, history preceding 
events and associated symptoms) will also be listed.

Malignancy (status based on diagnostic tests, stage, the risk factors and additional details)

Results from the PML checklist that includes the PML criteria, their response, symptoms, 
result and abnormality; data will be listed (by visit) only for subjects with any 
abnormality reported.

Results from the PML algorithm; data will be listed (by visit) only for subjects with any 
abnormality reported
7.13
Futility Analysis
A futility analysis was planned to be performed after a total of 50 subjects (25 subjects per 
treatment arm) have been randomized and completed Week 14 assessment of the primary 
efficacy endpoint (mPDAI remission). 
Since it was not intended stop the study early on the grounds of efficacy based on the results 
from this futility analysis, no adjustment to the statistical significance level is necessary for the 
final analysis.
This futility analysis is described in a separate analysis plan (dated 12 October 2018).
7.14
Changes in the Statistical Analysis Plan 
The following changes from protocol concerning the statistical analysis were applied:

The wording “Percentage of subjects with…” or “Percentage of subjects achieving…” in the 
definition of response-type primary and secondary efficacy endpoints was removed to clarify 
that the respective event itself is considered the endpoint. 

The wording of some study endpoints was slightly altered for purpose of clarification; these 
alterations do not have an impact on the analysis of the endpoints.

In order to be consistent and to not include any subjects that didn’t receive any dose of study 
drug the definition of the FAS is adapted to ‘all randomized subjects who receive at least 1 
dose of study drug’.
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!
In the protocol, further analysis of time to PDAI remission in both treatment arms using the 
log-rank test was specified. This analysis has been removed due to the lack of accuracy of
this endpoint (PDAI remission only assessed at Week 14 and Week 34).
!
For the purpose of the analysis, the definition of type of pouchitis was refined and adapted to 
be determined based on data/information captured in the eCRF (see section 7.1.1).
!
During blind data review two subjects were identified that were reported with total mPDAI 
baseline scores ≥ 5 as per the initial endoscopy reading but having a total mPDAI baseline 
score < 5 based on the adjudicated PDAI ulceration score. Those subjects will be included in 
the FAS population but excluded from the PPS and from subgroup analyses by baseline 
severity based on mPDAI.
!
During blind data review it was identified that several subjects have used concomitant 
antibiotics other than the companion antibiotic given per protocol prior to Week 14.
Therefore, a sensitivity analysis of the key response-type efficacy endpoints has been added 
in which subjects for those the concomitant use of antibiotics prior to Week 14 is 
reported/identified will be considered as non-responder (see section 7.9.6.1).
!
The initially planned subgroup analysis by failure of prior anti-TNF treatment for pouchitis 
was refined to a subgroup analysis by failure of prior anti-TNF treatment started post-
colectomy (see section 7.1.6).
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8.0
REFERENCES
1. A Randomized, Double-Blind, Placebo-Controlled Phase 4 Study to Evaluate the Efficacy 
and Safety of Entyvio (Vedolizumab IV) in the Treatment of Chronic Pouchitis (EARNEST), 
Amendment 03, Takeda Development Center Americas, Inc., Protocol Vedolizumab-4004, 
Protocol Amendment 04, 14 September 2020.
2. Ferrante M, D'Haens G, Dewit O, Baert F, Holvoet J, Geboes K, et al. Efficacy of infliximab 
in refractory pouchitis and Crohn's disease-related complications of the pouch: a Belgian 
case series. Inflammatory Bowel Disease 2010;16(2):243-9.
3. Barreiro-de Acosta M, Garcia-Bosch O, Souto R, Manosa M, Miranda J, Garcia-Sanchez V, 
et al. Efficacy of infliximab rescue therapy in patients with chronic refractory pouchitis: a 
multicenter study. Inflammatory bowel diseases 2012;18(5):812-7.
4. A Randomized, Double-Blind, Placebo-Controlled Phase 4 Study to Evaluate the Efficacy 
and Safety of Entyvio (Vedolizumab IV) in the Treatment of Chronic Pouchitis (EARNEST), 
Futility Analysis Plan, Final, 12 October 2018.
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9.0
APPENDICES
Appendix A
Schedule of Study Procedures
Screening
Treatment
Final 
Endosc
opy 
Visit or 
ET
Safety 
Follow-Up 
(a)
Post-Study
Study Day/Week:
Days
-28 to -1
Wk0/ 
Day 1
Wk 
2
Wk 
4
Wk 
6
Wk 14 Wk 22
Wk 30 
(EOT)
Wk 34
(EOS)
Wk 48
(or 18 
weeks post-
tx if ET)
Phone Wk 
56
(or 26 
weeks post-
tx if ET)
Visit Windows (Days):
±2
±2
±2
±3
±7
±7
±7
±7
±7
Visit Number:
1 (b)
2
3
4
5
6
7
8
9 (c) 
/ET
10
11
Informed Consent (d)
X
Inclusion/Exclusion Criteria
X
X
Demographics
X
Medical/Surgical History
X (e)
UC/Pouchitis Disease 
History
X
Concomitant 
Medications/Procedures (f)
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
Weight & Height
X (g)
X
X
X
X
X
X
X
X
Vital Signs 
X 
X
X
X
X
X
X
X
X
ECG
X
IBDQ
X
X
X
X
CGQL
X
X
X
X
mPDAI
X (h)
X
X
PDAI 
X (h)(i)
X
X
Pouch Endoscopy with 
Biopsy
X
X
X
Hematology
X
X
X
X
X
Serum Chemistry and Other 
Laboratory Tests
X
X
X
X
X
HIV/Hepatitis panel
X (j)
Urinalysis
X
X
X
X
X
CRP
X
X
X
X
X
FSH (k)
X
Tuberculosis QuantiFERON 
or Skin Test
X
C difficile test
X
Serum Pregnancy Test (l)
X
X
Urine Pregnancy Test (l)
X (m) X (m)
X
X (m) X (m) X (m) X (m)
X
Fecal Calprotectin Assay
X
X (m)
X
X
X
X
Study Drug Dosing (IV) (n)
X
X
X
X
X
X
Ciprofloxacin 
X
X
X (o)
X(o)
X(o)
X(o)
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Screening
Treatment
Final 
Endosc
opy 
Visit or 
ET
Safety 
Follow-Up 
(a)
Post-Study
Study Day/Week:
Days
-28 to -1
Wk0/ 
Day 1
Wk 
2
Wk 
4
Wk 
6
Wk 14 Wk 22
Wk 30 
(EOT)
Wk 34
(EOS)
Wk 48
(or 18 
weeks post-
tx if ET)
Phone Wk 
56
(or 26 
weeks post-
tx if ET)
Visit Windows (Days):
±2
±2
±2
±3
±7
±7
±7
±7
±7
Visit Number:
1 (b)
2
3
4
5
6
7
8
9 (c) 
/ET
10
11
PML Checklist
X
X (m) X (m)
X
X (m) X (m) X (m) X (m)
X
X
Provide PML Wallet Card
X
X
PTE Assessment (f)
X
X
AE/SAE Assessment (f)
X
X
X
X
X
X
X
X
X
Long-Term Follow-Up 
Questionnaire
X
Access IWRS to Obtain 
Subject ID
X
Access IWRS for 
Randomization
X
Access IWRS to Register 
Visit
X
X
X
X
X
X
X
X
Wk=Week.
(a) If subject is male or subject is postmenopausal and cannot attend the site for the safety follow-up visit, the safety follow-up 
visit may be conducted via phone.
(b) Once informed consent is obtained, listed procedures may be performed at any time during the screening period.
(c) Perform Visit 9 procedures if subject withdraws before Week 34.
(d) Informed consent process can begin prior to Visit 1, for example, if washout from medications is required.
(e) Smoking/nicotine usage status will be captured as part of medical history.
(f) Record adverse events, PTEs and medications from the time of signing the ICF.
(g) Height collected only at Visit 1.
(h) Clinical mPDAI and PDAI scores (patient reported symptoms) will be assessed as average from 3 days immediately prior to 
baseline endoscopy (or bowel preparation for endoscopy). Recording will be facilitated by a paper diary.
(i) Clinical and endoscopic PDAI scores for Visit 2 will be the scores obtained during Screening and the histologic score will be 
added when available to complete the full PDAI score.
(j) Hepatitis and HIV testing only done at the Screening Visit.
(k) Only if menopause is suspected.
(l) Only required for women of child bearing potential.
(m) To be performed before dosing.
(n) Subjects should be observed for 2 hours following the first 2 infusions, at a minimum and 1 hour after each subsequent 
infusion for monitoring hypersensitivity reactions.
(o) All subjects will receive ciprofloxacin 500 mg twice daily through Week 4. Additional antibiotics will be allowed, as needed, 
for flares after Week 14.
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Vedolizumab-4004
Page 59 of 67
Statistical Analysis Plan
Final V2.0 / 12 February 2021
Appendix B
The Pouchitis Disease Activity Index (PDAI)
Criteria
Score
Subtotal
Clinicala
Stool Frequency
Usual postoperative stool frequency
1-2 stools/day > postoperative usual
3 or more stools/day > postoperative usual
Rectal Bleeding
None or rare
Present daily
Fecal urgency or abdominal cramps
None
Occasional
Usual
Fever (temperature >37.8°C)
Absent
Present
0
1
2
0
1
0
1
2
0
1
Endoscopic inflammation
Edema
Granularity
Friability
Loss of vascular pattern
Mucus exudates
Ulceration
1
1
1
1
1
1
Acute histologic 
inflammation
Polymorphic nuclear leukocyte 
infiltration
None
Mild
Moderate + crypt abscess
Severe + crypt abscess
Ulceration per low power field (mean)
0%
<25%
25-50%
>50%
0
1
2
3
0
1
2
3
PDAI Score
a The clinical symptoms are based on a patient diary completed 3 days prior to endoscopy or bowel preparation for 
endoscopy. The average of the completed diary entries is taken for PDAI calculation, where at least one non-missing 
day need to exist.
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Vedolizumab-4004
Page 60 of 67
Statistical Analysis Plan
Final V2.0 / 12 February 2021
Appendix C
The Modified Pouchitis Disease Activity Index (mPDAI)
Criteria
Score
Subtotal
Clinicala
Stool Frequency
Usual postoperative stool frequency
1-2 stools/day > postoperative usual
3 or more stools/day > postoperative usual
Rectal Bleeding
None or rare
Present daily
Fecal urgency or abdominal cramps
None
Occasional
Usual
Fever (temperature >37.8°C)
Absent
Present
0
1
2
0
1
0
1
2
0
1
Endoscopic inflammation
Edema
Granularity
Friability
Loss of vascular pattern
Mucus exudates
Ulceration
1
1
1
1
1
1
mPDAI Score
a The clinical symptoms are based on a patient diary completed 3 days prior to endoscopy or bowel preparation for 
endoscopy. The average of the completed diary entries is taken for mPDAI calculation, where at least one non-
missing day need to exist.
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Vedolizumab-4004
Page 61 of 67
Statistical Analysis Plan
Final V2.0 / 12 February 2021
Property of Takeda: For Non-Com
CCI


Vedolizumab-4004
Page 62 of 67
Statistical Analysis Plan
Final V2.0 / 12 February 2021
CCI
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Vedolizumab-4004
Page 63 of 67
Statistical Analysis Plan
Final V2.0 / 12 February 2021
Appendix F
The Cleveland Global Quality of Life (CGQL) Instrument (Fazio Score)
Component
Scale
    Current Quality of Life
0 (worst) to 10 (best)
    Current Quality of Health 
0 (worst) to 10 (best)
    Current Energy Level
0 (worst) to 10 (best)
CGQL Utility Scorea
(sum of components)/30
Fazio Scoreb
Average of utility scores from 3 days prior to endoscopy
a If there are any missing components the CGQL utility will also be missing.
b The Fazio score is assessed as the average of the completed CGQL utility scores, where at least one non-missing 
day need to exist.
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Vedolizumab-4004
Page 64 of 67
Statistical Analysis Plan
Final V2.0 / 12 February 2021
Appendix G
Quality of Life Questionnaires: IBDQ
Sub-score
Calculation
IBDQ Bowel symptoms score
Sum of (Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, Q29), 
Ranging from 10 to 70, 10 questions
IBDQ Emotional function score
Sum of (Q3, Q7, Q11, Q15, Q19, Q21, Q23, Q25, Q27, Q30, 
Q31, Q32), 
Ranging from 12 to 84, 12 questions
IBDQ Social function score
Sum of (Q4, Q8, Q12, Q16, Q28), 
Ranging from 5 to 35, 5 questions
IBDQ Systemic symptoms score
Sum of (Q2, Q6, Q10, Q14, Q18), 
Ranging from 5 to 35, 5 questions
Note: For each component score above, if 50% or less of the component score is missing at a visit, the MEAN 
of the remaining component score will be imputed as the value for the missing component score. If more than
50% of the component score is missing for the item, the imputed value will be set to missing.
IBDQ score
Sum of (bowel, emotion, social, system)
Note: If any of the component score is missing at a visit, the imputed value will be set to missing.
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Vedolizumab-4004
Page 65 of 67
Statistical Analysis Plan
Final V2.0 / 12 February 2021
Appendix H
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology
Parameter
Gender
Age
Conventional Units
Takeda Preferred SI Units
Units
Markedly
Abnormal
Value
Units
Markedly
Abnormal
Value
Red Blood 
Cells
Both
Adult
×106 cells/µL
< 0.8 × LLN, 
> 1.2 × ULN
×1012 cells/L < 0.8 × LLN, 
> 1.2 × ULN
White Blood 
Cells
Both 
Adult
×103 cells/µL <2.0,
> 1.5 × ULN
×109 cells/L
< 2.0, 
> 1.5 × ULN
Hemoglobin
Both
Adult
g/dL
< 0.8 × LLN, 
> 1.2 × ULN
g/L
< 0.8 × LLN, 
> 1.2 × ULN
Hematocrit
Both
Adult
%
< 0.8 × LLN, 
> 1.2 × ULN
Fraction of 1
< 0.8 × LLN, > 1.2 × 
ULN
Platelets
Both
Adult
×103/µL
< 70, > 600
×109 /L
< 70, > 600
Segmented 
Neutrophils 
(Absolute)
Both
Adult
×103 cells/µL < 0.5 × LLN, 
> 1.5 × ULN
× 109 cells/L
< 0.5 × LLN, > 1.5 × 
ULN
Segmented 
Neutrophils 
(Relative)
Both
Adult
%
< 0.5 × LLN, 
> 1.5 × ULN
Fraction of 1
< 0.5 × LLN, > 1.5 × 
ULN
Lymphocytes 
(Absolute)
Both
Adult
×103 cells/µL < 0.5 × LLN, 
> 1.5 × ULN
× 109 cells/L
< 0.5× LLN, > 1.5 × 
ULN
Lymphocytes 
(Relative)
Both
Adult
%
< 0.5 × LLN, 
> 1.5 × ULN
Fraction of 1
< 0.5 × LLN, > 1.5 × 
ULN
Monocytes 
(Absolute)
Both
Adult
×103 cells/µL > 2 × ULN
× 109 cells/L
> 2 × ULN
Monocytes 
(Relative)
Both
Adult
%
> 2 × ULN
Fraction of 1
> 2 × ULN
Eosinophils 
(Absolute)
Both
Adult
×103 cells/µL > 2 × ULN
× 109 cells/L
> 2 × ULN
Eosinophils 
(Relative)
Both
Adult
%
> 2 × ULN
Fraction of 1
> 2 × ULN
Basophils 
(Absolute)
Both
Adult
×103 cells/µL > 3 × ULN
× 109 cells/L
> 3 × ULN
Basophils 
(Relative)
Both
Adult
%
> 3 × ULN
Fraction of 1
> 3 × ULN
PT
Both
Adult
Sec
> 1.5 × ULN
Sec
> 1.5 × ULN
INR†
Both
Adult
NA
> 1.5
NA
> 1.5
LLN=lower limit of normal or lower reference limit; ULN=upper limit of normal or upper reference limit
† Values are for subjects without anticoagulation, based on the normal range provided above for PT.
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Vedolizumab-4004
Page 66 of 67
Statistical Analysis Plan
Final V2.0 / 12 February 2021
Serum Chemistry
Parameter
Gender
Age
(years)
Conventional Units
Takeda Preferred SI Units
Units
Markedly 
Abnormal
Values
Units
Markedly
Abnormal
Value
Alanine 
Aminotransferase
Both
Adult
U/L
>3 × ULN
U/L
>3 × ULN
Albumin
Both
Adult
g/dL
< 2.5
g/L 
< 25
Alkaline 
Phosphatase
Both
>20
U/L
>3 × ULN
U/L
>3 × ULN
Aspartate 
Aminotransferase
Both
Adult
U/L
>3 × ULN
U/L
> 3 × ULN
Total Bilirubin
Both
Adult
mg/dL
> 2.0
µmol/L
> 34.2
Total Protein
Both
Adult
g/dL
< 0.8 × LLN, 
> 1.2 × ULN
g/L
< 0.8 × LLN, 
> 1.2 × ULN
Creatinine
Both
Adult
mg/dL
> 2
µmol/L
> 177 
Blood Urea 
Nitrogen
Both
Adult
mg/dL
> 30
mmol/L
> 10.7   
Creatine Kinase
Both
Adult
U/L
>5 × ULN
U/L
>5 × ULN
-Glutamyl 
Transferase
Both
Adult
U/L
>3 × ULN
U/L
>3 × ULN
Potassium (serum)
Both
Adult
mEq/L
< 3.0, > 6.0
mmol/L
< 3.0, > 6.0
Sodium
Both
Adult
mEq/L
< 130, > 150
mmol/L
< 130, > 150
Direct Bilirubin 
Both
Adult
mg/dL
>2 × ULN
µmol/L
>2 × ULN
Calcium
Both
Adult
mg/dL
< 27, > 58.6
mmol/L
< 1.50, > 3.25
Uric Acid
Both
Adult
mg/dL
> 13.0
µmol/L
> 773
Glucose
Both
Adult 
mg/dL
< 50, > 350
mmol/L
< 2.8, > 19.4
Magnesium
Both
Adult
mg/dL
< 1.2, > 3.0
mmol/L
< 0.5, > 1.2
Phosphorus
Both
Adult
mg/dL
< 1.6, > 6.2
mmol/L
< 0.52, > 2.000
Chloride
Both
Adult
mEq/L
< 75, > 126
mmol/L
< 75, > 126
LLN=lower limit of normal or lower reference limit; ULN=upper limit of normal or upper reference limit 
†Any abnormal values should be interpreted with the ratio progesterone/estrogen and SHBP values: Higher levels of 
SHBP lower levels of free progesterone.
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Vedolizumab-4004
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Statistical Analysis Plan
Final V2.0 / 12 February 2021
Appendix I
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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