Conditions: Ulcerative Colitis Crohn's Disease
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 89
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate vedolizumab pharmacokinetics (PK), safety and tolerability in pediatric participants with moderately to severely active UC or CD.

Detailed description:
The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat pediatric participants who have moderately to severely active UC or CD. This study will look at the PK, efficacy, immunogenicity, safety, and tolerability in participants who take vedolizumab.

The study will enroll approximately 80 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two dose regimens (high or low) per weight group \>=30 kg and 10 kg to \<30 kg in ratio 1:1-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Vedolizumab high dose group - Vedolizumab 300 mg or 200 mg
* Vedolizumab low dose group - Vedolizumab 150 mg or 100 mg

All participants will be administered vedolizumab via IV infusion. Participants assigned to the low dose group who do not achieve clinical response (based on pediatric UC/CDAI) at Week 14 will receive the high dose (that is, 300 mg for participants \>=30 kg baseline weight and 200 mg for participants 10 kg to \<30 kg baseline weight) of vedolizumab IV at Week 14. Participants assigned to the high dose group who had not achieved clinical response continued on the same blinded high dose at Week 14.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is up to 36 weeks. After completing the Week 22 Visit procedures, eligible participants may enter a blinded extension study. Participants will make multiple visits to the clinic, and those who do not enter extension study will have a final visit 18 weeks after last dose of study drug for a follow-up assessment. Participants who do not enter the extension study will also participate in a long-term safety follow-up, by telephone, 6 months after the last dose of study drug.

Arms:
arm 1: Participants with UC having baseline weight of \<30 kg were randomized to this low dose group and received vedolizumab 100 mg IV infusion on Day 1 and at Weeks 2, 6 and 14. arm 2: Participants with UC having baseline weight of \<30 kg were randomized to this high dose group and received vedolizumab 200 mg IV infusion on Day 1 and at Weeks 2, 6 and 14. arm 3: Participants with CD having baseline weight of \<30 kg were randomized to this low dose group and received vedolizumab 100 mg IV infusion on Day 1 and at Weeks 2, 6 and 14. arm 4: Participants with CD having baseline weight of \<30 kg were randomized to this high dose group and received vedolizumab 200 mg IV infusion on Day 1 and at Weeks 2, 6 and 14. arm 5: Participants with UC having baseline weight of \>=30 kg were randomized to this low dose group and received vedolizumab 150 mg IV infusion on Day 1 and at Weeks 2, 6 and 14. arm 6: Participants with UC having baseline weight of \>=30 kg were randomized to this high dose group and received vedolizumab 300 mg IV infusion on Day 1 and at Weeks 2, 6 and 14. arm 7: Participants with CD having baseline weight of \>=30 kg were randomized to this low dose group and received vedolizumab 150 mg IV infusion on Day 1 and at Weeks 2, 6 and 14. arm 8: Participants with CD having baseline weight of \>=30 kg were randomized to this low dose group and received vedolizumab 300 mg IV infusion on Day 1 and at Weeks 2, 6 and 14.

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

Protocol document:
Prot_000.pdf: 



Title: A Phase 2, Randomized, Double-Blind, Dose-Ranging Study to Determine the 
Pharmacokinetics, Safety and Tolerability of Vedolizumab IV in Pediatric Subjects With 
Ulcerative Colitis or Crohn’s Disease
NCT Number: NCT03138655
Protocol Approve Date: 30 August 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


PROTOCOL AMENDMENT
A Phase 2, Randomized, Double-Blind, Dose-Ranging Study to Determine the 
Pharmacokinetics, Safety and Tolerability of Vedolizumab IV in Pediatric Subjects With 
Ulcerative Colitis or Crohn’s Disease
A Phase 2, Randomized, Double-Blind, Dose-Ranging Study With Vedolizumab IV in 
Pediatric Subjects With Ulcerative Colitis or Crohn’s Disease
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway, Deerfield, IL 60015, USA
Takeda Development Centre Europe, Ltd.
61 Aldwych, London, WC2B 4AE, United Kingdom
Study Number:
MLN0002-2003
IND Number:
009125
EudraCT Number:
2017-002231-41
Compound:
Vedolizumab IV
Date:
30 August 2019
Amendment Number:
04
Amendment History
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
07 October 2016
Initial
NA
Global
07 April 2017
01
Substantial
Global
30 May 2017
02
Nonsubstantial
Global
17 January 2018
03
Substantial
Global
30 August 2019
04
Nonsubstantial 
Global
Prope
eda: For non-commercial use only and subject to the applicable Terms of Use


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts 
A separate contact information list will be provided to each site.
Takeda Development Center (TDC) sponsored investigators per individual country requirements 
will be provided with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Americas and Europe 
TDC Contact
Serious adverse event and pregnancy reporting
Medical Monitor
(medical advice on protocol and compound)
Responsible Medical Officer 
(carries overall responsibility for the conduct of
the study)
Property of Takeda: For non-commerci
uct o
ct o
m
 the
nd Europ
d Euro
he applicable Terms of Use
uirement
remen
i
each sub
ach su
ssigned 
signed
nt guide
t guid
ontact
ac
he 
PPD


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


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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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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 purpose of this amendment is to clarify procedures for completion and review 
of entries to diaries, and to define the minimum number of completed subjects in either weight 
group before interim analysis is undertaken.
Study personnel and corresponding contact details have been updated. Minor grammatical, 
editorial, and formatting changes are included for clarification purposes only.
For specific descriptions of text changes, the rationale for the changes, and where the changes are 
located, see Appendix J.
Changes in Amendment 04
1. Clarified procedures for completion and review of entries to diaries.
2. Clarification of criteria for interim analysis.
3. Amended the concomitant oral corticosteroid dosing information.
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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 ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Principal Investigator/Coordinating Investigator ......................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................16
3.5
Study Definitions.....................................................................................................17
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.1.1
Epidemiology of UC and CD in the Pediatric Population ...................................18
4.1.2
Clinical Manifestations and Prognosis of UC and CD in Pediatric Patients.........19
4.1.3
Vedolizumab IV.................................................................................................20
4.1.3.1 Nonclinical...................................................................................................20
4.1.3.2 Clinical ........................................................................................................21
4.2
Rationale for the Proposed Study.............................................................................23
4.3
Benefit/Risk Assessment..........................................................................................24
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
Additional Objectives.........................................................................................25
5.2
Endpoints.................................................................................................................25
5.2.1
Primary Endpoints .............................................................................................25
5.2.2
Secondary Endpoints..........................................................................................25
5.2.3
Additional Endpoints .........................................................................................25
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................28
6.1
Study Design ...........................................................................................................28
6.1.1
Extension Study Vedolizumab-2005 ..................................................................30
6.2
Justification for Study Design, Dose, and Endpoints ................................................30
6.2.1
Justification for Study Design and Endpoints .....................................................30
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6.2.2
Dose Justification...............................................................................................31
6.3
Premature Termination or Suspension of Study or Investigational Site.....................32
6.3.1
Criteria for Premature Termination or Suspension of the Study..........................32
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .........32
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)................................................................32
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............33
7.1
Inclusion Criteria .....................................................................................................33
7.2
Exclusion Criteria ....................................................................................................35
7.3
Excluded Medications and/or Procedures, and Treatments.......................................38
7.3.1
Permitted Medications and Treatments...............................................................39
7.3.1.1 Oral Corticosteroid Dosing...........................................................................39
7.4
Diet and Fluid Control .............................................................................................40
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................40
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................41
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................43
8.1
Study Medication and Materials...............................................................................43
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.....................................43
8.1.1.1 Vedolizumab IV...........................................................................................43
8.1.2
Storage...............................................................................................................43
8.1.3
Dose and Regimen .............................................................................................43
8.1.4
Overdose............................................................................................................44
8.2
Study Drug Assignment and Dispensing Procedures ................................................44
8.3
Investigational Drug Blind Maintenance ..................................................................45
8.4
Unblinding Procedure..............................................................................................45
8.5
Accountability and Destruction of Sponsor-Supplied Drugs.....................................45
9.0
STUDY PLAN ..............................................................................................................47
9.1
Study Procedures.....................................................................................................47
9.1.1
Informed Consent Procedure..............................................................................47
9.1.2
Demographics, Medical History, and Medication History Procedure..................47
9.1.3
Physical Examination Procedure ........................................................................47
9.1.4
Weight, Height...................................................................................................48
9.1.5
Vital Signs Procedure.........................................................................................48
9.1.6
Efficacy Measurements......................................................................................48
9.1.6.1 Completion and Review of Entries to Diaries ...............................................48
9.1.7
Documentation of Concomitant Medications and Procedures.............................49
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9.1.8
Use of Local Anesthetic .....................................................................................50
9.1.9
Procedures for Clinical Laboratory Samples.......................................................50
9.1.10 Contraception and Pregnancy Avoidance Procedure...........................................51
9.1.10.1
Male Subjects and Their Female Partners ...............................................51
9.1.10.2
Female Subjects and Their Male Partners ...............................................52
9.1.10.3
Definitions and Procedures for Contraception and Pregnancy 
Avoidance....................................................................................................52
9.1.11 Pregnancy ..........................................................................................................54
9.1.12 PK Sample Collection and Analysis ...................................................................55
9.1.13 Immunogenicity Sample Collection ...................................................................56
9.1.14 TB Screening .....................................................................................................56
9.1.15 Fecal Calprotectin Sample Collection.................................................................56
9.1.16 Stool Sample for Culture, Ova and Parasite Evaluation, and C difficile Assay ....56
9.1.17 PML Checklist...................................................................................................56
9.1.18 IMPACT-III Questionnaire (Subjects 9 to 17 Years of Age)...............................57
9.1.19 Endoscopies.......................................................................................................57
9.1.20 Documentation of Screen Failure .......................................................................57
9.1.21 Documentation of Randomization......................................................................58
9.1.22 Monitoring Subject Treatment Compliance ........................................................58
9.2
Schedule of Observations and Procedures................................................................58
9.2.1
Screening...........................................................................................................58
9.2.2
Randomization and Stratification .......................................................................58
9.2.3
End-of-Study or ET Visit ...................................................................................59
9.2.4
Final Safety Follow-up Visit ..............................................................................59
9.2.5
Long-term Follow-up Safety Survey ..................................................................59
9.2.6
Poststudy Care ...................................................................................................59
9.2.7
Unscheduled Visits Due to Disease Exacerbation...............................................59
9.2.8
Other Unscheduled Visits (if Applicable)...........................................................60
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................61
10.1
Definitions...............................................................................................................61
10.1.1 PTEs..................................................................................................................61
10.1.2 AEs....................................................................................................................61
10.1.3 Additional Points to Consider for PTEs and AEs................................................61
10.1.4 SAEs..................................................................................................................63
10.1.5 AESIs ................................................................................................................64
10.1.6 Severity of PTEs and AEs..................................................................................64
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10.1.7 Causality of AEs ................................................................................................64
10.1.8 Relationship to Study Procedures.......................................................................65
10.1.9 Start Date...........................................................................................................65
10.1.10
Stop Date .....................................................................................................65
10.1.11
Frequency ....................................................................................................65
10.1.12
Action Concerning Study Drug ....................................................................65
10.1.13
Outcome.......................................................................................................65
10.2
Procedures...............................................................................................................66
10.2.1 Collection and Reporting of AEs........................................................................66
10.2.1.1
PTE and AE Collection Period ...............................................................66
10.2.1.2
PTE and AE Reporting ...........................................................................66
10.2.1.3
AE Collection Involving Medically Anticipated Clinical Events.............67
10.2.1.4
Reporting Special Interest AEs...............................................................67
10.2.2 Collection and Reporting of SAEs......................................................................69
10.2.3 Reporting of Abnormal LFTs.............................................................................69
10.2.4 Product Complaints............................................................................................69
10.3
Follow-up of SAEs ..................................................................................................70
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.....70
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................71
11.1
Data Safety Monitoring Board .................................................................................71
11.2
Adjudication Committee..........................................................................................71
11.2.1 Risk Assessment and Management Program for PML (RAMP Program)............71
12.0
DATA HANDLING AND RECORD KEEPING...........................................................73
12.1
eCRFs......................................................................................................................73
12.2
Record Retention .....................................................................................................73
13.0
STATISTICAL METHODS..........................................................................................75
13.1
Statistical and Analytical Plans ................................................................................75
13.1.1 Analysis Sets......................................................................................................75
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................75
13.1.3 Efficacy Analysis...............................................................................................75
13.1.4 PK Analysis .......................................................................................................76
13.1.5 Other Analyses...................................................................................................76
13.1.6 Safety Analysis ..................................................................................................76
13.2
Interim Analysis ......................................................................................................77
13.3
Determination of Sample Size..................................................................................77
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................78
14.1
Study-Site Monitoring Visits ...................................................................................78
14.2
Protocol Deviations..................................................................................................78
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................78
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................80
15.1
IRB and/or IEC Approval ........................................................................................80
15.2
Subject Information, Informed Consent, and Subject Authorization .........................81
15.3
Subject Confidentiality ............................................................................................82
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................82
15.4.1 Publication and Disclosure.................................................................................82
15.4.2 Clinical Trial Registration..................................................................................83
15.4.3 Clinical Trial Results Disclosure ........................................................................83
15.5
Insurance and Compensation for Injury....................................................................83
16.0
REFERENCES..............................................................................................................84
LIST OF IN-TEXT TABLES
Table 8.a
Dose and Regimen .............................................................................................44
Table 9.a
Clinical Laboratory Tests...................................................................................51
Table 10.a
Takeda Medically Significant AE List................................................................64
LIST OF IN-TEXT FIGURES
Figure 6.a 
Schematic of Study Design ................................................................................29
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................87
Appendix B
Responsibilities of the Investigator.....................................................................90
Appendix C
Elements of the Subject Informed Consent.........................................................92
Appendix D
Investigator Consent to Use of Personal Information..........................................95
Appendix E
PUCAI...............................................................................................................96
Appendix F
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity............97
Appendix G
PCDAI...............................................................................................................98
Appendix H
CDAI Scoring System for the Assessment of CD Activity................................100
Appendix I
SES-CD...........................................................................................................101
Appendix J
Summary of Changes .......................................................................................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 Phase 2, Randomized, Double-Blind, 
Dose-Ranging Study to Determine the Pharmacokinetics, 
Safety, and Tolerability of Vedolizumab IV in Pediatric 
Subjects With Ulcerative Colitis or Crohn’s Disease
IND No.: 009125
EudraCT No.:
2017-002231-41
Study Number: MLN0002-2003
Phase: 2
Study Design:
This is a phase 2, randomized, double-blind, dose-ranging study enrolling male and female pediatric subjects (2 to 
17 years, inclusive) who weigh ≥10 kg with moderately to severely active ulcerative colitis (UC) or Crohn’s disease 
(CD) and who have demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the 
following agents: corticosteroids, immunomodulators, and/or tumor necrosis factor-alpha (TNF-α) antagonist therapy. 
The study will evaluate the pharmacokinetics (PK), efficacy, immunogenicity, safety, and tolerability of vedolizumab 
IV administered by intravenous (IV) infusion. Approximately 80 pediatric subjects will be enrolled to ensure that 
40 subjects weighing ≥30 kg and 40 subjects weighing 10 kg to <30 kg, as well as a minimum of 36 subjects with UC 
and a minimum of 36 subjects with CD, will be enrolled in the study.
Eligible subjects will receive vedolizumab infusions at Day 1 and Weeks 2, 6, and 14. The study will allow 
characterization of Week 14 PK and efficacy and the study will continue to Week 22. After completing the Week 22
Visit procedures, eligible subjects may enter an extension study. Those subjects who do not enter the extension study 
will have a Final Safety Visit 18 weeks after their last dose of study drug and participate in a long-term follow-up 
safety survey by telephone 6 months after their last dose of study drug. 
Primary Objective:
To evaluate vedolizumab PK in pediatric subjects with UC or CD.
Secondary Objectives:

To assess the efficacy of vedolizumab IV in pediatric subjects with UC or CD.

To characterize the dose-response relationship of vedolizumab IV in pediatric subjects with UC or CD. 
Subject Population: Male and female pediatric subjects 2 to 17 years, inclusive, who weigh ≥10 kg and who have 
moderately to severely active UC or CD.
Number of Subjects:
Approximately 80 subjects (subjects who 
discontinue may be replaced as determined 
by the sponsor).
Number of Sites: 
Estimated total: 72 sites in North America, Europe, and Middle East.
Dose Level(s) (at Study Entry):
Subjects weighing ≥30 kg before the first 
dose in the study will be randomly assigned 
to receive 300 mg (high dose) or 150 mg 
(low dose) vedolizumab IV.
Subjects weighing <30 kg before the first 
dose in the study will be randomly assigned 
to receive 200 mg (high dose) or 100 mg 
(low dose) vedolizumab IV.
Route of Administration:
IV
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Duration of Treatment:
22 weeks
Period of Evaluation:
This phase 2 study includes a 4-week Screening Period, a 22-week 
Treatment Period (with last dose at Week 14). Subjects who do not 
enter the extension study will have an 18-week Follow-up Period 
starting from their last dose of study drug and a long-term follow-up 
safety survey by telephone 6 months after their last dose of study 
drug.
Main Criteria for Inclusion:

The subject:
a)
is male or female; and
b)
weighs ≥10 kg at the time of randomization; and
c)
is 2 to 17 years, inclusive, at the time of randomization, with moderately to severely active UC or CD 
diagnosed at least 3 months prior to Screening by clinical and endoscopic evidence and corroborated by a 
histopathology report.

The subject has demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the 
following agents: corticosteroids, immunomodulators, and/or TNF-α antagonist therapy.

The subject has a medical history of moderately to severely active UC during Screening defined as a complete 
Mayo score of 6 to 12, and a total of Mayo subscores of stool frequency and rectal bleeding ≥4 and an endoscopy
subscore ≥2; or has moderately to severely active CD defined as simple endoscopic score for Crohn’s disease 
(SES-CD) ≥7, and the Crohn’s Disease Activity Index (CDAI) components of average daily Abdominal Pain 
Score of >1 for the 7 days prior, and total number of liquid/very soft stools >10 for the 7 days prior to the first dose 
of study drug.

The subject has evidence of UC extending proximal to the rectum (ie, not limited to proctitis) or evidence of CD 
involving the ileum and/or colon, at a minimum.

Subjects with extensive colitis or pancolitis of >8 years duration or left-sided colitis of >12 years duration must 
have documented evidence that a surveillance colonoscopy was performed within 12 months prior to their first 
dose of study drug.
Main Criteria for Exclusion:

The subject has had previous exposure to approved or investigational anti-integrins including, but not limited to, 
natalizumab, efalizumab, etrolizumab, or AMG 181, or mucosal addressin cell adhesion molecule-1
(MAdCAM-1) antagonists, or rituximab.

The subject has had prior exposure to vedolizumab.

The subject has had hypersensitivity or allergies to any of the vedolizumab excipients.

The subject has received:
a)
any investigational biologic (other than those listed in Exclusion Criterion #1) within 60 days or 5 half-lives 
prior to Screening (whichever is longer).
b)
an approved biologic or biosimilar agent within 2 weeks prior to the first dose of the study drug or at any time 
during the Screening period.

The subject has a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist prior 
to the administration of the first dose of study drug. 

The subject currently requires surgical intervention for UC or CD, or is anticipated to require surgical intervention 
for UC or CD during this study.

The subject has other serious comorbidities that will limit his or her ability to complete the study.
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Main Criteria for Evaluation and Analyses:
The primary endpoints for this study are PK parameters at Week 14 (area under the serum concentration-time curve at
Week 14 [AUCWk 14], average serum concentration during a dosing interval at Week 14 [Cav,Wk 14], and observed serum 
concentration at the end of Week 14 [Ctrough,Wk 14]). 
The secondary endpoints for this study are:

Percentage of UC subjects who achieve clinical response based on complete Mayo score at Week 14.

Percentage of CD subjects who achieve clinical response based on CDAI, as defined by a ≥70 point decrease from 
baseline in CDAI score at Week 14.
Statistical Considerations:
The PK parameters will be derived by compartmental and/or noncompartmental approaches, data permitting. All PK 
parameters will be summarized using descriptive statistics (nonmissing values, mean, SD, percent coefficient of 
variation [%CV], median, minimum, maximum) by dose and weight group. 
All proportion-based efficacy endpoints will be summarized by presenting the point estimate and 95% CIs for the 
proportion by indication (UC or CD) and dose group. Subject with any component of a scale missing will be 
considered as a nonresponder/nonremitter for that particular endpoint, scale, or time point in the analysis.
Sample Size Justification: 
The planned sample size is approximately 80 subjects including 40 subjects who weigh ≥30 kg and 40 subjects who 
weigh <30 kg. Subjects will be randomly assigned in a 1:1 ratio to receive 1 of 2 dose regimens (high or low) per 
weight group (≥30 kg or <30 kg). The randomization will be stratified by previous exposure/failure to TNF-α 
antagonist therapy or naive to TNF-α antagonist therapy and by indication (UC or CD) and by weight group (≥30 kg or 
<30 kg). Randomization caps will be implemented to ensure that the sample size for each dose regimen will be a 
minimum of 9 subjects with UC and 9 subjects with CD per weight group. A sample size of 9 subjects is expected to 
have at least 80% power to establish 95% CIs that are within 60% and 140% of the geometric mean estimates for total 
clearance after IV administration (CL) for each dose (high or low), indication (UC or CD), and weight group (≥30 kg 
or <30 kg), assuming the intersubject variability for CL in the pediatric population is similar to that in the adult 
population (%CV ≤36.6%). The sample size is based on industry guidance; CL is used because it controls overall drug 
exposure (area under the serum concentration-time curve [AUC] and average serum concentration during a dosing 
interval) and it is the parameter that allows computation of the dosage required to maintain an average steady-state 
concentration. The proposed sample size will also allow for descriptive analysis of efficacy for each indication and 
characterization of the dose-response relationship in pediatric subjects.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Clinical Study Supplier template. The identified vendors in the template for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
Term
Definition
5-ASA
5-aminosalicylic acid
6-MP
6-mercaptopurine 
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the serum concentration-time curve 
AUCWk 14
area under the serum concentration-time curve at Week 14
AZA
azathioprine
bpm
beats per minute
Cav,Wk 14
average serum concentration during a dosing interval at Week 14
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
C difficile
Clostridium difficile
CFR
Code of Federal Regulations
CLL
linear total clearance
CL
total clearance after IV administration
CMV
cytomegalovirus
Ctrough
serum concentration at the end of a dosing interval
Ctrough,Wk 14
serum concentration at the end of Week 14
Ctrough,Wk 22
serum concentration at the end of Week 22
DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form
ELISA
enzyme-linked immunosorbent assay
ESR
erythrocyte sedimentation rate
ET
Early Termination
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
GI
gastrointestinal(ly)
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IAC
Independent Adjudication Committee
IBD
inflammatory bowel disease
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terva
erval ata W
ministratio
nistratio
at the end
t the e
on at the
n at th
tration at 
ation a
y monitori
monit
cardiogra
ardiog
ctronic ca
ronic c
enzy
zyme
me
y
-l
ery
erythr
ty
Ea
E
T
GI
GI
HBsAg
HBs
HB
CCI


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Term
Definition
IBDU
inflammatory bowel disease unclassified
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IRR
infusion-related reaction
IV
intravenous(ly)
IRT
interactive web response technology
LFT
liver function test
LLN
lower limit of normal
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
MLN0002
vedolizumab
MTX
methotrexate
NOAEL
no-observed-adverse-effect level
NSAID
nonsteroidal anti-inflammatory drug
OTC
over-the-counter
PCDAI
Pediatric Crohn’s Disease Activity Index
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PTE
pretreatment event
PUCAI
Pediatric Ulcerative Colitis Activity Index
Q2W
once every 2 weeks
Q4W
once every 4 weeks
Q8W
once every 8 weeks
RAMP
Risk Assessment and Minimization for PML
SAE
serious adverse event
SAP
statistical analysis plan
SES-CD
simple endoscopic score for Crohn’s disease
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TEAE
treatment-emergent adverse event
TNF-α
tumor necrosis factor-alpha
UC
ulcerative colitis
ULN
upper limit of normal
VCAM-1
vascular cell adhesion molecule-1
WBC
white blood cell
3.4
Corporate Identification
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
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TDC
TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Asia, TDC Europe and/or TDC Americas, as applicable
3.5
Study Definitions
Term
Definition
Ulcerative Colitis (UC) Subjects:
Clinical response based on complete 
Mayo score or partial Mayo score
A reduction in complete Mayo score of ≥3 points and ≥30% from Baseline (or a 
partial Mayo score of ≥2 points and ≥25% from Baseline, if the complete Mayo 
score was not performed at the visit) with an accompanying decrease in rectal 
bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point.
Clinical remission based on complete 
Mayo score
A complete Mayo score of ≤2 points with no individual subscore >1.
Clinical response based on PUCAI 
A ≥20-point decrease from Baseline in Pediatric Ulcerative Colitis Activity 
Index (PUCAI) score.
Clinical remission based on PUCAI
PUCAI score <10.
Disease worsening
An increase in the PUCAI of >20 points at 2 consecutive visits at least 7 days 
apart, or the PUCAI was >35 points at any scheduled or unscheduled visit. 
Crohn’s Disease (CD) Subjects:
Clinical response based on CDAI
A ≥70-point decrease from Baseline in Crohn’s Disease Activity Index (CDAI) 
score.
Clinical remission based on CDAI
CDAI score ≤150.
Clinical response based on PCDAI
A ≥15-point decrease from Baseline in PCDAI score with total PCDAI ≤30.
Clinical response based on SES-CD
A ≥50% reduction in simple endoscopic score for Crohn’s disease (SES-CD) 
score from Baseline endoscopy (or meets criteria for clinical remission based 
on SES-CD score 0 to 2) with accompanying decrease in average daily 
abdominal pain score (CDAI component) by >0.25.
Clinical remission based on PCDAI
PCDAI score ≤10.
Enhanced clinical response based on 
CDAI
A ≥100-point decrease from Baseline in CDAI score.
Disease worsening
An increase in the PCDAI of >15 points at 2 consecutive visits at least 7 days 
apart, or the PCDAI was>30 points at any scheduled or unscheduled visit.
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4.0
INTRODUCTION
4.1
Background
4.1.1
Epidemiology of UC and CD in the Pediatric Population
The overall prevalence of UC in the adult and pediatric population is approximately 
200 cases/100,000 persons in the United States and about 150 cases/100,000 persons in Western 
Europe [1-4]. As of 2009, the prevalence rate of UC in the pediatric population was 
34/100,000 persons, with the lowest prevalence rate being observed in children younger than 
5 years [5]. Although in recent years the UC incidence has increased in the age group of 11 to 
15 years, this rate has remained stable in children younger than 10 years [6]. No significant 
differences in prevalence by sex have been reported for pediatric UC [5]. However, a family 
history of UC does not seem to be a negative prognostic factor in UC patients [6].
In the United States, the overall prevalence of CD is approximately 125 cases/100,000 of the 
population and 150 cases/100,000 in Western Europe [1-4]. As of 2009, the prevalence rate of CD 
in children was 58/100,000 persons, with the lowest prevalence rate being observed in children 
younger than 5 years. Approximately 20% of all cases of CD occur in the pediatric population 
younger than 15 years, and a male preponderance is reported in pediatric CD [5], while a female 
preponderance is seen only among patients diagnosed during adolescence (13 to 19 years) [7]. 
A large study in the United States demonstrated that UC, CD, and indeterminate colitis (otherwise 
known as inflammatory bowel disease unclassified [IBDU]) were equally prevalent in the 
pediatric population up to 2 years of age and that definitive diagnoses were made in only 1% of 
patients before 1 year of age [8]. UC was the most prevalent disease type (47%) among those in the 
3- to 5-year age group compared with CD (35%). The prevalence of indeterminate colitis 
decreased as children aged. A family history of inflammatory bowel disease (IBD) was noted in 
3% of siblings, 9% of parents, and 22% of second-degree relatives, with the strongest family 
histories noted in the younger pediatric population and those with UC (44%). Although there are 
fewer studies of childhood IBD compared with adult-onset IBD, the pediatric population is unique 
in that there are fewer environmental confounders, such as smoking or contraceptive use, 
compared with adults. It is therefore possible that genetics and microbiology play a stronger role in 
the development of pediatric IBD. Compared with adult CD, pediatric CD appears to be associated 
with a higher frequency of mutation in the NOD2/CARD15 gene[7].
The incidence of pediatric IBD appears to be increasing. A large study in Finland showed a near 
doubling of the pediatric IBD incidence over a 15-year period [9,10]. In 1987, the incidence was 
3.9 cases/100,000 of the population and increased to 7.0 cases/100,000 of the population in 2003. 
The highest frequency of new-onset cases in the pediatric population (33%) occurred in patients 
between age 12 and 15 years; however, 5% of cases occurred in children younger than 3 years. 
According to the Crohn’s and Colitis Foundation of America, approximately 1 million Americans 
have either UC or CD, of which approximately 100,000 are younger than 21 years. 
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4.1.2
Clinical Manifestations and Prognosis of UC and CD in Pediatric Patients
Although UC and CD are separate illnesses, they share many common signs and symptoms. In 
both the pediatric and adult populations, clinical manifestations include diarrhea, abdominal pain, 
fecal urgency, and incontinence. Fever, weight loss, malaise, and fatigue are indicators of more 
extensive disease. There are a number of extraintestinal manifestations of IBD, including 
arthropathy, primary sclerosing cholangitis, and uveitis. For approximately 25% of IBD patients, 
the onset of disease occurs during childhood or adolescence. The diagnosis of UC or CD is usually 
established histopathologically via endoscopic mucosal biopsies in both adult and pediatric 
populations.
Disease localization appears to be affected by age. In CD, the most commonly affected sites in the 
pediatric population are the terminal ileum (71% of patients at diagnosis) and right colon (71%) 
[11]. Upper gastrointestinal (GI) involvement also is commonly seen in pediatric CD, although 
this may be a function of routine upper GI endoscopy with biopsies being routinely performed 
based upon consensus diagnostic recommendations [12]. In pediatric CD, simple inflammatory 
disease, which is predominant at diagnosis, appears to give way to complex stricturing and 
penetrating behavior over time. 
In UC, the extent of disease at diagnosis is more widespread in the pediatric population compared 
with adults; pancolitis occurs in up to 90% and proctitis in only a minority of patients (4% to 13%). 
Rectal sparing may occur in only 30% of pediatric patients with UC and, therefore, unlike adults, 
sigmoidoscopy alone may be sufficient to establish the diagnosis in the pediatric population [7].
While the symptoms of UC are similar in both the pediatric and adult populations, pediatric 
patients usually present with more extensive disease. Less is known about the clinical course of 
long-term disease [13]. Whether the course differs in children, adolescents, and adults is unknown 
at present [7]. Antineutrophil cytoplasmic antibody and anti-Saccharomyces cerevisiae antibody 
serologies have been associated with a greater risk of developing earlier and more frequent 
complications in pediatric CD [14] and may serve as a useful stratification variable in therapeutic 
trials of CD.
Although growth failure is a common sequela of UC and CD in the pediatric population, pediatric 
patients with CD appear to be at twice the risk of growth failure compared with those with UC 
[15]. Nutritional therapy and surgical resection have been shown to improve growth, but there 
remains a clear need for more effective and less morbid treatment options. As with adults, 
long-term complications of UC and CD in pediatric patients include malignancy (eg, colorectal 
cancer), which may be attributable at least in part to the underlying inflammatory disease and also 
possibly to treatment with systemic immunosuppressants.
Treatment options for adult and pediatric patients are similar. Pharmacological treatments for 
these diseases include the 5-aminosalicylic acid (5-ASA) and its derivatives, corticosteroids, and 
immunomodulators (thiopurines, such as azathioprine [AZA] and 6-mercaptopurine [6-MP]) for 
both UC and CD, along with methotrexate (MTX) for CD. AZA and 6-MP are often used in 
conjunction with corticosteroids or other therapy to induce remission. AZA and 6-MP show 
efficacy in maintaining remission in pediatric CD [16] and also in moderate to severe pediatric UC 
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[17]. MTX has a rapid onset of action and has been shown to be effective in induction and 
maintenance of remission in pediatric patients with CD [18-20]. Over the past decade, tumor 
necrosis factor-alpha (TNF-α) antagonist therapies have been studied and approved for use in the 
pediatric population. Infliximab is approved for use in pediatric patients with moderately to 
severely active UC or CD in the United States and European Union [21], and adalimumab is 
approved in the United States and European Union for moderately to severely active CD [22]. 
4.1.3
Vedolizumab IV
Vedolizumab (also known as MLN0002) is a recombinant humanized monoclonal antibody
composed of 2 light chains of the subclass and 2 immunoglobulin G1 heavy chains. 
Vedolizumab binds specifically to the human lymphocyte integrin 47. The α4β7 integrin 
mediates lymphocyte trafficking to GI mucosa and gut-associated lymphoid tissue through 
adhesive interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is 
expressed on the endothelium of mesenteric lymph nodes and GI mucosa [23-26]. As a result, 
vedolizumab impairs the migration of gut-homing leukocytes into GI mucosa [27] and acts as a 
gut-selective immunomodulator.
Vedolizumab IV (also known as ENTYVIO; KYNTELES; Vedolizumab for Injection, for 
Intravenous Use; Vedolizumab Powder for Concentrate for Solution for Infusion, or MLN0002 
IV) has been granted marketing approval in over 50 countries, including the United States and 
European Union, for the treatment of adult patients with moderately to severely active UC or CD 
who have failed conventional treatment, including immunomodulators, corticosteroids, or TNF-α 
antagonists. The approved initial dose and administration regimen consists of 300 mg 
vedolizumab IV infused intravenously (IV), over approximately 30 minutes, at Day 1 and 
Weeks 2, 6, and then once every 8 weeks (Q8W) thereafter. 
4.1.3.1
Nonclinical
Extensive nonclinical evaluations of the cardiovascular, acute, local tolerance, subchronic, 
chronic, immunologic, and reproductive toxicity in pharmacologically responsive species (New 
Zealand white rabbits and cynomolgus monkeys) have been conducted with vedolizumab. In local 
tolerance studies in rabbits, no evidence of significant adverse local effects was seen following 
administration of vedolizumab IV or vedolizumab subcutaneous. No evidence of effects on 
electrocardiogram (ECG), heart rate, or mean arterial pressure was seen in cynomolgus monkeys 
at vedolizumab doses up to 100 mg/kg. In addition, there was no evidence of embryo-fetal toxicity 
(gravid rabbits) or prenatal and postnatal toxicity (cynomolgus monkeys), or immunotoxicity 
(cynomolgus monkeys) at these doses. The no-observed-adverse-effect level (NOAEL) in both 
pharmacologically responsive species (monkeys and rabbits) was vedolizumab 100 mg/kg. This 
dose was associated with an exposure 26 times (rabbits) and 18 times (cynomolgus monkeys) 
higher than the geometric mean clinical area under the serum concentration-time curve (AUC) 
after a single dose of vedolizumab 300 mg IV by 30-minute infusion.
A 13-week toxicity study of vedolizumab IV in juvenile cynomolgus monkeys (11 to 15 months 
old at study start) supports studies in the pediatric population. Monkeys of this species typically 
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are weaned at around 9 months old, making the specified ages of the monkeys equivalent to young 
children, although an exact age correspondence cannot be defined. Juvenile monkeys were dosed 
with the same dose regimen as previously studied in adult monkeys (approximately 3 to 7 years 
old): 0 (vehicle control), 10, 30, or 100 mg/kg administered by 30 minute IV infusion once every 
2 weeks (Q2W). There were no test article-related clinical observations, or effects on body 
weights, food consumption, ophthalmology, electrocardiology, clinical pathology parameters 
(hematology, coagulation, clinical chemistry, and urinalysis), T-cell–dependent antibody 
response, flow cytometry analyses (peripheral blood and cerebrospinal fluid), macroscopic and 
microscopic findings, and organ weights. Thus, 100 mg/kg was considered to be the NOAEL in 
this study.
4.1.3.2
Clinical
No studies have been completed in pediatric subjects. Data are not yet available for studies being 
conducted in Japan that will include subjects ≥15 years. Single- and multiple-dose 
pharmacokinetics (PK) of vedolizumab IV have been studied in healthy adult subjects and in 
subjects with moderately to severely active UC or CD. Similar vedolizumab PK was observed in 
healthy subjects and subjects with UC or CD. In adults, vedolizumab serum concentrations 
generally fell in a biexponential fashion until approximately 1 to 10 µg/mL, with a total clearance 
after IV administration (CL) of approximately 0.157 L/day and a serum half-life of around 
25 days. Thereafter, the serum concentrations fell in a nonlinear fashion. The volume of 
distribution for vedolizumab IV is approximately 5 L.
Vedolizumab IV has demonstrated statistically significant and clinically relevant evidence of 
effectiveness in multiple completed clinical studies in adult subjects with moderately to severely 
active UC or CD. 
In subjects with moderately to severely active UC (C13006; GEMINI I), vedolizumab IV 300 mg 
administered as an IV infusion at Day 1 and Week 2 (induction) followed by either Q8W or once 
every 4 weeks (Q4W) administration from Week 6 through Week 52 (maintenance) induced a 
statistically significant increase in rates of clinical response at Week 6 and clinical remission at 
Week 52 (primary endpoint for the induction phase and maintenance phase, respectively) 
compared with placebo [28]. The study also met important secondary endpoints, including clinical 
remission at Week 6, durable clinical response, durable clinical remission, and mucosal healing at 
Weeks 6 and 52, and corticosteroid-free clinical remission at Week 52. Given the significant 
morbidity associated with chronic corticosteroid treatment, the corticosteroid-sparing effects of 
vedolizumab provide an important benefit to patients with UC.
In subjects with moderately to severely active CD (C13007; GEMINI II), vedolizumab IV 300 mg 
administered as an IV infusion at Day 1 and Week 2 (induction) followed by either Q4W or Q8W 
administration from Week 6 through Week 52 (maintenance) demonstrated statistically significant 
differences in efficacy compared with placebo for both the induction phase and maintenance phase 
[29]. The study met its first primary endpoint for the induction phase, clinical remission at Week 6, 
but did not meet the second primary endpoint of enhanced clinical response (Crohn’s Disease 
Activity Index [CDAI]-100) at Week 6 in the overall population, although the treatment difference 
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favored vedolizumab. The study met its primary endpoint for the maintenance phase (clinical 
remission at Week 52), as well as important secondary endpoints, including enhanced clinical 
response at Week 52 and corticosteroid-free clinical remission at Week 52. 
In C13011 (GEMINI III), vedolizumab (300 mg IV at Day 1 and Weeks 2 and 6) was administered 
as induction therapy to subjects with moderately or severely active CD who had failed 
conventional therapies, including TNF-α antagonists. The primary endpoint of clinical remission 
at Week 6 in the TNF-α antagonist failure intent-to-treat population was not met; however, a 
treatment difference was observed at Week 10 in this population [30]. Similar treatment 
differences favoring vedolizumab were also demonstrated for the overall population and in the 
subgroup of subjects who were TNF-α antagonist naïve.
Vedolizumab has shown an acceptable safety profile based on an analysis of safety data from both 
completed and ongoing studies, as well as from postmarketing experience (see current version of 
Investigator’s Brochure). Vedolizumab was well-tolerated in phase 1 and 2 clinical studies. The 
majority of the safety data is from 3 well-controlled, phase 3 clinical studies that evaluated the 
safety of vedolizumab for up to 12 months in subjects with UC (Study C13006 [52 weeks]) or CD 
(Studies C13007 [52 weeks] and C13011 [10 weeks]). Subgroup analyses based on weight did not 
show any clinically relevant differences from the overall safety population. In addition, an interim 
safety assessment is available for an ongoing, uncontrolled long-term extension study 
(Study C13008), in which subjects are administered vedolizumab Q4W. 
As of 19 November 2016, more than 4200 subjects have received at least 1 dose of vedolizumab 
across all studies in the clinical development program. 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 the most recent drug shipment data 
(19 November 2016), the cumulative patient exposure to vedolizumab IV since its marketing 
approval in May 2014 is estimated to be approximately 77,382 patient-years.
In the pivotal phase 3 studies (Studies C13006 and C13007), the most common (≥5% and at a 
higher incidence than placebo) adverse reactions in subjects administered vedolizumab IV were 
nausea, nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, fatigue, headache, 
and cough. Most serious adverse events (SAEs) 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. Results from the clinical program to date do not suggest an increased risk 
of malignancy with vedolizumab IV treatment. No cases of progressive multifocal 
leukoencephalopathy (PML) were reported in these studies or during postmarketing experience to 
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date. A similar safety profile was observed in adult subjects who received vedolizumab IV Q8W or 
Q4W.
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, 
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. 
One death occurred in a vedolizumab-treated subject during Study C13006 and 5 deaths occurred 
during Study C13007, including 1 death in a placebo-treated subject. As of 19 May 2016, a total of 
27 deaths from multiple causes were reported in the vedolizumab clinical development program, 
including the ongoing long-term Study C13008. Twenty-six of the 27 subjects were randomized to 
the vedolizumab treatment group. Of these deaths, 14 occurred within 18 weeks of the last dose of 
vedolizumab in phase 3 clinical studies and 12 occurred more than 18 weeks after the last dose of 
vedolizumab was administered. The cause of the deaths varied, with the majority considered not to 
be related to vedolizumab therapy.
Overall, vedolizumab was well tolerated in clinical studies and postmarketing safety data are 
consistent with the safety profile observed in the clinical studies. The benefit/risk profile continues 
to be positive.
4.2
Rationale for the Proposed Study
A safe and effective dose for vedolizumab in children has yet to be determined. The aim of this 
phase 2 dose-ranging study is to evaluate vedolizumab PK in male and female pediatric subjects 
with moderately to severely active UC or CD. In addition, the dose-response at Week 14 in these 
subjects will be characterized to aid in dose selection for the pediatric phase 3 studies. PK, efficacy 
(including endoscopic assessment at Week 14), and safety assessments will be performed during 
the 22-week study. 
Eligible subjects will be randomized to receive doses of vedolizumab IV by infusion at Day 1 and 
Weeks 2, 6, and 14 as follows:

Subjects weighing ≥30 kg:
–
Vedolizumab IV 300 mg (high dose).
–
Vedolizumab IV 150 mg (low dose).

Subjects weighing 10 kg to <30 kg:
–
Vedolizumab IV 200 mg (high dose). 
–
Vedolizumab IV 100 mg (low dose).
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4.3
Benefit/Risk Assessment
Since vedolizumab has not yet been formally evaluated in pediatric subjects, the benefit/risk 
profile in pediatric patients with UC or CD has not been determined. Ongoing studies being 
conducted in Japan will include subjects ≥15 years of age; however, data are not yet available in 
these adolescent subjects. 
There remains an unmet medical need in pediatric patients who fail to respond, or who lose 
response to, all existing therapy (including conventional therapy or TNF-α antagonists), or in 
whom side effects of these agents are intolerable or life threatening. Vedolizumab IV may provide 
an alternative therapy for this patient population. 
Vedolizumab IV has demonstrated statistically significant and clinically relevant evidence of 
effectiveness in multiple completed clinical studies in adult subjects with moderately to severely 
active UC or CD.
In clinical studies, vedolizumab has shown an acceptable and consistent safety profile in adults
(≥18 years of age) with body weights ranging from 28.7 kg to 170 kg. In the pivotal phase 3 
studies in adult UC and CD subjects (C13006 and C13007), the most common (≥5% and at a 
higher incidence than placebo) adverse reactions in subjects administered vedolizumab IV were 
nausea, nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, fatigue, headache, 
and cough. Most SAEs have been related to exacerbations or complications of the underlying UC 
or CD. For those infections that were reported more frequently in vedolizumab-treated subjects, 
the sites of these infections correlated with the known tissue distribution of MAdCAM-1 binding 
sites. No additive risk of infection was identified among subjects who received a concomitant 
immunosuppressant. A similar safety profile was observed in adult subjects who received 
vedolizumab IV Q8W or Q4W. Postmarketing safety has been consistent with the safety profile 
observed during clinical development. 
In addition, results from a 13-week juvenile monkey toxicity study showed that vedolizumab was 
safe and well tolerated at doses up to 100 mg/kg, which was the highest dose tested. Thus, based on
the clinical and postmarketing data in adults, combined with nonclinical data in juvenile monkeys, 
the benefit/risk profile in pediatric subjects with UC or CD is expected to be positive.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
!
To evaluate vedolizumab PK in pediatric subjects with UC or CD.
5.1.2
Secondary Objectives
!
To assess the efficacy of vedolizumab IV in pediatric subjects with UC or CD.
!
To characterize the dose-response relationships of vedolizumab IV in pediatric subjects with 
UC or CD. 
5.1.3
Additional Objectives
!
To assess the safety and tolerability of vedolizumab IV in pediatric subjects with UC or CD.
5.2
Endpoints
5.2.1
Primary Endpoints 
PK parameters:
!
Area under the serum concentration-time curve at Week 14 (AUCWk 14).
!
Average serum concentration during a dosing interval at Week 14 (Cav,Wk 14).
!
Observed serum concentration at the end of a dosing interval at Week 14 (Ctrough,Wk 14).
5.2.2
Secondary Endpoints
!
Percentage of UC subjects who achieve clinical response based on complete Mayo score, as 
defined by a reduction in complete Mayo score of ≥3-points and ≥30% from Baseline with an 
accompanying decrease in rectal bleeding subscore of ≥1-point or absolute rectal bleeding 
subscore of ≤1-point at Week 14.
!
Percentage of CD subjects who achieve clinical response based on CDAI, as defined by a 
≥70-point decrease from Baseline in CDAI score at Week 14.
5.2.3
Additional Endpoints
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bject to the applicable Terms of Use
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 2, randomized, double-blind, dose-ranging study involving pediatric subjects with 
moderately to severely active UC or CD who have demonstrated an inadequate response to, loss of 
response to, or intolerance of at least 1 of the following agents: corticosteroids, 
immunomodulators, and/or TNF-α antagonist therapy. The study will evaluate the PK, efficacy, 
immunogenicity, safety, and tolerability of vedolizumab IV. Approximately 80 pediatric subjects 
will be enrolled to ensure that 40 subjects weighing ≥30 kg and 40 subjects weighing 10 kg to 
<30 kg, as well as a minimum of 36 subjects with UC and a minimum of 36 subjects with CD, will 
be enrolled in the study. Subjects who discontinue may be replaced as determined by the sponsor. 
This study includes a 4-week Screening Period, a 22-week Double-Blind Treatment Period (with 
last dose at Week 14) for all subjects. Eligible subjects may exit the study at Week 22 and continue 
to receive study drug in an extension study. Subjects who do not enter the extension study will 
participate in an 18-week Follow-up Period starting from the last dose of study drug and complete
a long-term follow-up safety survey by telephone 6 months after their last dose of study drug. A 
schematic of the study design is included in Figure 6.a. 
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Figure 6.a
Schematic of Study Design
Screening
Period
Double-Blind Treatment Period
Follow-up 
Period
Additional
Follow-up
Dosing at Day 1, and Weeks 2, 6, and 14:
UC subjects who weigh ≥30 kg
300 mg (N=10)
150 mg (N=10)
UC subjects who weigh 10 kg to <30 kg
200 mg (N=10)
100 mg (N=10)
CD subjects who weigh ≥30 kg 
300 mg (N=10)
150 mg (N=10)
CD subjects who weigh 10 kg to <30 kg
200 mg (N=10)
100 mg (N=10)
Final Safety Visit 
(b) 
(18 weeks after 
the last dose of 
study drug)
Long-Term 
Follow-Up
Safety Survey 
by Telephone
(c)
(6 months 
after the last 
dose of study 
drug)
End-of-Study 
(a)/ ET
Procedures
Extension Study 
Vedolizumab-
2005 (d)
Days
Day
Wk Wk
Wk
Wk
Wk
Wk
Wk
Wk
-28 to -1
1
1
2
2-6
6
10
14
22
32 (b)
Randomization
Visit: 1
2
3
4
5
6
7
8
9
10 (e)
ET=Early Termination, Wk 2-6=nondosing visit scheduled anytime between Days 16 and 42 for PK collection.
(a) Subjects who consent to participate in the extension study (Vedolizumab-2005) may be eligible for the extension study dosing 
after procedures have been completed at Week 22 (Visit 9).
(b) Subjects who do not enter the extension study or withdraw before Week 22 will also complete ET Visit (Week 22) procedures 
and a Final Safety Visit 18 weeks after their last dose of study drug.
(c) Subjects who withdraw before Week 22 will also participate in a long-term follow-up safety survey by telephone 6 months after 
the last dose of study drug.
(d) Subjects will provide informed consent/pediatric assent for participation in extension Study Vedolizumab-2005 on or after 
Week 14 through Week 22 of Study MLN0002-2003.Visit 1 of extension Study Vedolizumab-2005 is within 1 week of completing 
Week 22 (Visit 9) procedures.
(e) Subjects who do not enter the extension study (Vedolizumab-2005) will complete the Final Safety Visit 18 weeks after their last 
dose of study drug and participate in a long-term follow-up safety survey by telephone 6 months after the last dose of study drug.
The total duration of the study will be approximately 36 weeks from start of the Screening Period
to the posttreatment Final Safety Visit. Study drug will be administered on Day 1 and Weeks 2, 6,
and 14 as described in Section 8.1.3. Clinical response will be assessed at Week 14 based on 
PUCAI/PCDAI and recorded in the interactive web response technology (IRT) system. Subjects 
randomized to the low dose group who have not achieved clinical response will be escalated to 
receive the high dose of vedolizumab IV (300 mg for subjects ≥30 kg and 200 mg for subjects 
<30 kg) at Week 14. This blinded dose escalation will be done via IRT. Subjects randomized to the 
high dose group who have not achieved clinical response will continue on the same blinded dose at 
Week 14. At the Week 22 Visit, subjects may be eligible to enter an extension study 
(Vedolizumab-2005) to continue receiving study drug. Subjects who do not enter the extension 
study will complete an End-of-Study/ET Visit at Week 22 and then attend the Final Safety Visit 18 
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weeks after their last dose of study drug. Subjects who withdraw prior to Week 22 (ET) will 
complete the Week 22 assessments (and an endoscopy if prior to the Week 14 Visit) at their ET 
Visit and then attend the Final Safety Visit 18 weeks after their last dose of study drug. An ET 
endoscopy is not required for subjects who withdraw prior to Week 6. All subjects who do not 
participate in the extension study will also be required to participate in a long-term follow-up
safety survey by telephone, 6 months after their last dose of study drug.
Eligible subjects will be randomly assigned in a 1:1 ratio to receive 1 of 2 dose regimens (high or 
low) per weight group on Day 1. The randomization will be stratified by previous exposure/failure 
to TNF-α antagonist therapy or naive to TNF-α antagonist therapy, by indication (UC or CD), and
by weight group (≥30 kg or <30 kg). Randomization caps will be implemented to ensure the 
sample size for each dose regimen will be a minimum of 9 UC subjects and 9 CD subjects per 
weight group (≥30 kg or <30 kg). 
A Schedule of Study Procedures is provided in Appendix A. Safety and efficacy assessments will
be made throughout the study, at the Week 22 End-of-Study/ET Visit, and at the Final Safety Visit
18 weeks after the last dose of study drug (for subjects who do not enroll in the Vedolizumab-2005 
extension study). SAEs and AEs will be collected throughout the study. Subjects will receive their 
last dose of study drug at Week 14 and have an endoscopy at the Week 14 Visit for efficacy 
evaluation. 
Blood samples to evaluate PK will be collected (predose and/or postdose) over the course of the 
study as described in Section 9.1.12. 
 
).
6.1.1
Extension Study Vedolizumab-2005
Subjects who are eligible to enroll in Study Vedolizumab-2005 include those who, at Week 22 of 
Study MLN0002-2003, achieved clinical response as defined by a reduction of partial Mayo score 
of ≥2 points and ≥25% from Baseline, or a reduction of the PUCAI of ≥20 points from Baseline for 
subjects with UC; or a reduction of the CDAI as defined by a ≥70 point decrease from Baseline or 
a decrease of the PCDAI of ≥15 points for subjects with CD.
Subjects who elect to participate in Study Vedolizumab-2005 will provide informed 
consent/pediatric assent for participation on or after Week 14 through Week 22 of Study 
MLN0002-2003. Relevant assessments from the Week 22 Visits of Study MLN0002-2003 will be 
used as the predose assessments for the extension study.
6.2
Justification for Study Design, Dose, and Endpoints
6.2.1
Justification for Study Design and Endpoints
This is a phase 2, dose-ranging study enrolling male and female pediatric subjects (2 to 17 years, 
inclusive) with moderately to severely active UC or CD who have failed at least 1 conventional 
therapy and/or TNF-α antagonist therapy. The study will evaluate the PK, efficacy, 
immunogenicity, safety, and tolerability of vedolizumab IV in pediatric subjects.
Property of Takeda: 
2
: For non-commercial u
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The primary endpoints of AUCWk 14, Ctrough,Wk 14, and Cav,Wk 14 were selected to obtain pediatric PK 
data, as it is expected that all subjects will have achieved steady-state drug concentrations. The 
secondary endpoint is the percentage of UC subjects who achieve clinical response at Week 14 
based on Mayo score and percentage of CD subjects who achieve clinical response at Week 14 
based on CDAI score, which are commonly used to evaluate patients with UC and CD, 
respectively. The 14-week time point is expected to be sufficient for the purpose of characterizing 
PK and the dose-response relationship. The secondary endpoints will allow characterization of 
efficacy to explore the dose-response relationship in pediatric subjects to aid dose selection for the 
phase 3 studies. This study will continue to Week 22 to explore steady-state serum vedolizumab 
concentration observed at the end of the dosing interval (Ctrough,Wk 22). 
6.2.2
Dose Justification
The approved dose and administration regimen of vedolizumab IV in adult subjects is 300 mg 
administered at Day 1 and Weeks 2, 6, and Q8W thereafter. Vedolizumab IV has demonstrated an 
adequate safety profile in adults over a wide range of single or multiple doses up to 10 mg/kg.
In this study, eligible pediatric subjects will be randomly assigned to receive 1 of 2 dose regimens 
at Day 1 and Weeks 2, 6, and 14 as follows:

Subjects weighing ≥30 kg:
–
Vedolizumab IV 300 mg (high dose). 
–
Vedolizumab IV 150 mg (low dose).

Subjects weighing 10 kg to <30 kg:
–
Vedolizumab IV 200 mg (high dose). 
–
Vedolizumab IV 100 mg (low dose). 
The high and low doses in subjects who weigh ≥30 kg or 10 kg to <30 kg proposed for this study 
were selected based on simulations performed using a population PK model developed from phase 
3 data in adult subjects with UC or CD. Population PK analyses suggest that while body weight is 
a predictor of linear total clearance (CLL) and volume of the central compartment (Vc), the 
magnitude of the effect is not considered to be clinically relevant. Population PK analyses suggest 
that CLL of vedolizumab is not affected by subject age. The doses selected provide estimated 
serum concentration at the end of a dosing interval (Ctrough) values in pediatric subjects that are 
between the 5th and 95th percentiles of Ctrough values observed in adults administered vedolizumab 
IV 300 mg at Weeks 0, 2, 6 and Q8W or Q4W in phase 3 studies. Body weights in the adult pivotal 
phase 3 studies ranged from 28.7 to 170 kg. No clinically meaningful differences in safety were 
observed in adult subjects across quartiles of body weight.
The high and low doses to be tested in this study differ 2-fold and are expected to characterize 
dose-response in pediatric subjects. This information will be used to select doses for the phase 3 
studies in pediatric subjects with UC or CD. Subjects assigned to the low dose group who do not 
achieve clinical response (based on PUCAI/PCDAI) at Week 14 will receive the high dose of 
vedolizumab IV (300 mg if ≥30 kg or 200 mg if 10 kg to <30 kg) at Week 14. 
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6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the product, such that the risk /benefit is 
no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.

The data safety monitoring board (DSMB) recommends that the study should be suspended or 
terminated.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to first dose. Subjects who are 
screen failures may be rescreened, but will need prior approval by the sponsor. 
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, parent, or legal guardian is capable of 
understanding and complying with protocol requirements.
2. The subject and/or the parent or legal guardian gives voluntary informed consent/assent and 
signs and dates a written informed consent/assent form and any required privacy authorization 
prior to the initiation of any study procedures. 
3. The subject:
a) is male or female; and
b) weighs ≥10 kg at the time of randomization; and
c) is 2 to 17 years, inclusive, at the time of randomization, with moderately to severely active 
UC or CD diagnosed at least 3 months prior to Screening by clinical and endoscopic 
evidence and corroborated by a histopathology report.
4. The subject has a medical history of moderately to severely active UC during Screening 
defined as a complete Mayo score of 6 to 12, and a total of Mayo subscores of stool frequency 
and rectal bleeding ≥4 and an endoscopy subscore ≥2; or has moderately to severely active CD 
defined as simple endoscopic score for Crohn’s disease (SES-CD) ≥7, and the CDAI 
components of average daily Abdominal Pain Score of >1 for the 7 days prior, and total 
number of liquid/very soft stools >10 for the 7 days prior to the first dose of study drug.
5. The subject has evidence of UC extending proximal to the rectum (ie, not limited to proctitis) 
or evidence of CD involving the ileum and/or colon, at a minimum.
6. Subjects with extensive colitis or pancolitis of >8 years duration or left-sided colitis of 
>12 years duration must have documented evidence that a surveillance colonoscopy was 
performed within 12 months prior to their first dose of study drug.
7. A male subject who is sexually active with a female partner of childbearing potential* agrees 
to use adequate contraception* from signing of informed consent/assent throughout the 
duration of the study and for 18 weeks after last dose or agree to completely abstain from 
heterosexual intercourse.
8. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed 
consent/assent throughout the duration of the study and for 18 weeks after last dose or agree to 
completely abstain from heterosexual intercourse. 
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*Definitions and acceptable methods of contraception are defined in 
Section 9.1.10 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.11 Pregnancy.
9. Subjects with a family history of colorectal cancer (ie, first-degree relative), personal history of 
increased colorectal cancer risk, or other known risk factor must be up-to-date on colorectal 
cancer surveillance.
10. The subject’s vaccinations are up to date.
11. The subject has demonstrated an inadequate response to, loss of response to, or intolerance of 
at least 1 of the following agents as defined below:
Corticosteroids:

Signs and/or symptoms of persistently active disease despite a history of at least one 
4-week induction regimen that included a dose equivalent to or more than prednisone 
1 mg/kg daily orally for 2 weeks or IV for 1 week. 
OR

Two failed attempts to taper corticosteroids to below a dose equivalent to prednisone 
10 mg daily orally on 2 separate occasions. 
OR

History of significant intolerance to corticosteroids (including, but not limited to, 
Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and infection).
Immunomodulators

Signs and symptoms of persistently active disease despite a history of at least one 8-week 
regimen of oral AZA (≥1.5 mg/kg/day) or 6-MP mg/kg (≥1.0 mg/kg/day) or MTX 
(≥10 mg/m2 once a week). 
OR

History of intolerance of at least 1 immunomodulator (including, but not limited to, 
nausea/vomiting, abdominal pain, pancreatitis, liver function test (LFT) abnormalities, 
lymphopenia, thiopurine methyltransferase genetic mutation, infection). 
TNF-α antagonists

Signs and symptoms of persistently active disease despite a history of at least 1 induction 
regimen of infliximab 5 mg/kg IV at Week 0 and Weeks 2 and 6 or adalimumab 2-week 
regimen of 160 mg on Day 1 and 80 mg on Day 15 if ≥40 kg or 80 mg on Day 1 and 40 mg 
on Day 15 if <40 kg. For any other TNF-α antagonist, the subject must demonstrate signs 
and symptoms of persistently active disease despite a history of at least 1 induction 
regimen, as determined by the investigator.
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OR

Recurrence of symptoms during maintenance dosing following prior clinical benefit, ie, 
fitting clinically with secondary loss of response (discontinuation despite clinical benefit 
does not qualify). 
OR

History of intolerance of infliximab or adalimumab (including, but not limited to, 
infusion-related reaction, demyelination, congestive heart failure, infection). 
12. The subject may be receiving a therapeutic dose of the following drugs: 
a) Oral 5-ASA compounds, providing the dose has been stable for the 2 weeks prior to first 
dose of study drug.
b) Oral corticosteroid therapy (prednisone at a stable dose ≤50 mg/day, or equivalent steroid), 
provided that the dose has been stable for the 4 weeks prior to first dose of study drug if 
corticosteroids have been initiated, or for the 2 weeks prior to first dose of study drug if 
corticosteroids are being tapered.
c) Probiotics (eg, Saccharomyces boulardii), provided the dose has been stable for the 2 
weeks prior to first dose of study drug.
d) Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic 
diarrhea.
e) Antibiotics used for the treatment of CD (eg, ciprofloxacin, metronidazole), providing the 
dose has been stable for the 2 weeks prior to first dose of study drug.
f)
Azathioprine or 6-MP, provided the dose has been stable for the 8 weeks prior to first dose 
of study drug.
g) MTX, provided the dose has been stable for the 8 weeks prior to first dose of study drug.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has had previous exposure to approved or investigational anti-integrins including, 
but not limited to, natalizumab, efalizumab, etrolizumab, or AMG 181, or MAdCAM-1 
antagonists, or rituximab.
2. The subject has had prior exposure to vedolizumab.
3. The subject has had hypersensitivity or allergies to any of the vedolizumab excipients.
4. The subject has received:
a) any investigational biologic (other than those listed in Exclusion Criterion #1) within 
60 days or 5 half-lives prior to Screening (whichever is longer).
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b) an approved biologic or biosimilar agent within 2 weeks prior to the first dose of the study 
drug or at any time during the Screening period.
5. The subject has a positive PML subjective symptom checklist prior to the administration of the 
first dose of study drug.
6. The subject currently requires surgical intervention for UC or CD, or is anticipated to require 
surgical intervention for UC or CD during this study.
7. Within 30 days prior to first dose of study drug, the subject received any of the following for 
the treatment of underlying disease:
a) Nonbiologic therapies (eg, cyclosporine, thalidomide) other than those specifically listed 
in Section 7.3.
b) A nonbiologic investigational therapy.
8. Use of topical (rectal) treatment with 5-ASA or corticosteroid within 2 weeks of the
administration of the first dose of study drug.
9. The subject has, in the judgment of the investigator, clinically significant abnormal 
hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening.
10. The subject has any of the following laboratory abnormalities during the Screening Period:
a) Lymphocyte count <1.0×109/L or investigator concern regarding underlying 
lymphocytopenia.
b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3× the upper limit 
of normal (ULN).
c) Alkaline phosphatase >3×ULN.
d) Serum creatinine >2×ULN.
11. The subject has any unstable or uncontrolled cardiovascular, heart failure moderate to severe 
(New York Class Association III or IV), pulmonary, hepatic, renal, GI, genitourinary, 
hematological, coagulation, immunological, endocrine/metabolic, neurological, or other 
medical disorder that, in the opinion of the investigator, would confound the study results or 
compromise subject safety.
12. Active or latent tuberculosis (TB), as evidenced by a diagnostic TB test performed within 30 
days of Screening or during the Screening Period that is positive, defined as:

Positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests, OR

A TB skin test reaction ≥5 mm.
NOTE: If subjects have received BCG vaccine then a QuantiFERON TB Gold test should 
be performed instead of the TB skin test.
Note: subjects with documented previously treated TB with a negative QuantiFERON test can 
be included in the study.
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13. Clinically significant current or recent history (within 1 year prior to signing of informed 
consent/assent) of alcohol dependence or illicit drug use.
14. The subject is required to take excluded medications listed in Section 7.3.
15. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 18 weeks after the last dose of study drug, or intending to donate ova during such 
time period. If male, the subject intends to donate sperm during the course of this study or for 
18 weeks after the last dose of study drug. 
16. The subject has a current diagnosis of indeterminate colitis (IBDU). For subjects less than 
6 years of age, any findings that suggest monogenic very early onset inflammatory bowel 
disease should be excluded.
17. The subject has evidence of abdominal abscess or toxic megacolon at the Screening Visit.
18. The subject has ileostomy, colostomy, ileo-anal pouch, or known fixed symptomatic stenosis 
of the intestine.
19. The subject has extensive colonic resection, eg, subtotal or total colectomy.
20. The subject has a history or evidence of adenomatous colonic polyps that have not been 
removed.
21. The subject has a history or evidence of colonic mucosal dysplasia.
22. The subject has chronic hepatitis B virus (HBV) infection* or chronic hepatitis C virus (HCV) 
infection.
* HBV immune subjects (ie, being hepatitis B surface antigen [HBsAg] negative and hepatitis 
B antibody positive) may be included, however.
23. The subject has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
24. The subject has evidence of or treatment for Clostridium difficile (C difficile) infection within 
60 days or other intestinal pathogen within 30 days prior to first dose of study drug.
25. The subject has other serious comorbidities that will limit his or her ability to complete the 
study.
26. The subject has any history of malignancy, except for the following: (a) adequately treated 
nonmetastatic basal cell skin cancer; (b) squamous cell skin cancer that has been adequately 
treated and that has not recurred for at least 1 year prior to enrollment; and (c) history of 
cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 
3 years prior to first dose of study drug. Subjects with remote history of malignancy 
(eg, >10 years since completion of curative therapy without recurrence) will be considered 
based on the nature of the malignancy and the therapy received, and inclusion must be 
discussed with the sponsor on a case-by-case basis prior to enrollment.
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27. The subject has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, or neurodegenerative disease.
28. The subject has active psychiatric problems that, in the investigator’s opinion, may interfere 
with compliance with the study procedures. This includes affective disorders that may 
confound the interpretation of subject reporting of gastrointestinal symptoms (eg, abdominal 
pain) in the opinion of the investigator.
29. The subject had a clinically significant infection (eg, pneumonia, pyelonephritis) within 
30 days prior to first dose of study drug.
30. The subject has received any live vaccinations within 30 days prior to first dose of study drug.
31. The subject has history of lupus.
32. The subject has had a surgical procedure requiring general anesthesia within 30 days prior to 
screening or is planning to undergo major surgery during the study period.
33. The subject is unable to comply with all study assessments.
34. The subject is an immediate family member or study-site employee, or is in a dependent 
relationship with a study-site employee who is involved in the conduct of this study (eg, 
spouse, parent, child, sibling) or may consent under duress. 
7.3
Excluded Medications and/or Procedures, and Treatments
The following medications are excluded from use during the study: 

Any treatment for UC or CD other than those listed in Section 7.3.1 (either approved or 
investigational).

All live vaccines during the study treatment period and for at least 6 months after the last dose 
of study drug. 

Either approved or investigational biological agents for the treatment of non-IBD conditions, 
other than localized injections (eg, intraocular injections for wet macular degeneration).

Chronic nonsteroidal anti-inflammatory drug (NSAID) use defined as daily use for 
>2 consecutive weeks (Note: occasional use of NSAIDs and acetaminophen for headache, 
arthritis, myalgias, menstrual cramps are permitted).

TNF-α antagonists may not be administered after subject signs informed consent/assent to 
participate in the study.
Subjects must be instructed not to take any medications, including over-the-counter (OTC) 
products, without first consulting with the investigator.
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7.3.1
Permitted Medications and Treatments 
The following medications are permitted during the study: 

Immunomodulators (such as MTX, AZA, 6-MP), stable for at least 8 weeks prior to first dose 
of study drug.

Oral 5-ASAs, probiotics, enteral nutrition, or antibiotics stable for at least 2 weeks prior to first 
dose of study drug.

Antidiarrheals for control of chronic diarrhea. Any significant increase in the subject’s use in 
the 2 weeks prior to first dose of study drug must be considered by the investigator.
Concomitant medications, with the exception of corticosteroids, must be maintained at a constant 
dose throughout the first 14 weeks of the study. Any new medication or any increase in dose of a 
baseline medication required to treat new or unresolved UC or CD symptoms (other than 
antidiarrheals for control of chronic diarrhea) will need to be discussed with the medical monitor. 
Initiation of corticosteroids, immunosuppressants, or other therapies is not permitted during the 
study. Initiation of these therapies after the first dose of study drug will result in the subject being 
withdrawn from the study as a failure to respond to study drug. However, medications should not 
be withheld if, in the opinion of the investigator, failure to prescribe them would compromise 
subject safety.
7.3.1.1
Oral Corticosteroid Dosing
For subjects on corticosteroids whose dose is not being tapered during Screening, their dose must 
remain stable for at least the first 2 weeks after their initial dose of study drug.
Corticosteroid doses may be tapered during the screening period up until the final 2 weeks prior to 
the first dose of study drug when a stable dose must be maintained. The corticosteroid dose must 
also remain stable during the first 2 weeks of vedolizumab treatment during the study, for a total of 
4 weeks of stable corticosteroid dosing. 
After the Week 2 dose of study drug, tapering of the corticosteroid dose may be initiated at the 
discretion of the investigator:

For subjects entering the study at a corticosteroid dose of ≥20 mg/day, tapering may resume by 
5 mg/week down to 20 mg/day for subjects weighing ≥40 kg, and down to 0.5 mg/kg/day for 
those <40 kg.

For subjects entering the study at a corticosteroid dose of <20 mg/day, tapering may resume by 
5 mg/week down to 10 mg/day for those who weigh ≥40 kg or more and down to 
0.25 mg/kg/day for those weighing <40 kg.
Once these thresholds are reached, the corticosteroid dose will be held stable until the third dose of
study drug is given at Week 6. Thereafter, between Weeks 6 and 14, corticosteroid tapering may 
resume at the discretion of the investigator by 5 mg/week down to 10 mg/day, and thereafter by 
2.5 mg/week until zero.
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If the investigator decides not to taper corticosteroids, the maximum dose of oral corticosteroids 
for the treatment of UC or CD that may be coadministered with vedolizumab IV is ≤50 mg/day of 
prednisone (or equivalent steroid) as long as that dose has been stable for 2 weeks prior to the first 
dose of study drug. Subjects who require higher doses should be withdrawn from the study.
7.4
Diet and Fluid Control 
There are no diet or fluid restrictions and subjects do not need to fast prior to study drug infusions 
or blood draws.
7.5
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 9.1.20.
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.

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 9.1.9), 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: White blood cell (WBC) and lymphocyte counts will be 
monitored for all subjects. AZA, 6-MP, or MTX, if applicable, should be discontinued and 
the dose of vedolizumab held for an absolute lymphocyte count <1.0×109/L at any point in 
the study. The absolute lymphocyte count must be repeated at appropriate intervals as 
determined by the investigator. The next dose of vedolizumab can be administered only if 
the absolute lymphocyte count is ≥1.0×109/L. If the absolute lymphocyte count remains 
<1.0×109/L, study drug should be discontinued and the subject withdrawn from the study.
2. PML:
a) As described in Section 11.2.1 Risk Assessment and Management Program for PML 
(RAMP Program), vedolizumab will be held in subjects with a positive subjective PML 
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checklist. Subsequent doses of vedolizumab will be administered only if the possibility of 
PML is definitively excluded, as described in the RAMP algorithm.
b) Subjects with confirmed PML, as adjudicated by the PML Independent Adjudication 
Committee (IAC), will be withdrawn from the study.
3. Any serious infection that meets the following criteria:
a) Life threatening as defined in Section 10.1.4.
b) Requires intensive care unit admission.
c) Systemic opportunistic infection including tuberculosis (including pulmonary), 
cytomegalovirus (CMV) (including CMV colitis), and listeriosis.
4. Significant protocol deviation. The discovery after the first dose of study drug 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.
5. 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. 
6. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (eg, withdrawal due to an 
AE).
7. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
8. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.11.
9. Death.
10. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5 or if the investigator 
determines that discontinuation of the study drug is in the subject’s best interest. In addition, a 
subject or subject’s parent/legal guardian 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 
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to perform all procedures scheduled for the Final Visit/ET Visit, the Final Safety Visit, and the 
6 month long-term follow-up safety survey. Discontinued or withdrawn subjects may be replaced.
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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Vedolizumab IV
The sponsor will supply the study sites with the following study drug: vedolizumab IV 
300 mg/vial, for single use in a 20 mL vial.
 
. Each vial will be packaged in 
an appropriately labeled single-vial carton. The sponsor will only provide the study drug 
(vedolizumab). Sites will provide all other materials for infusion.
Each carton will have a single-panel or multilingual booklet label that will contain, but will not be 
limited to the following: sponsor’s name and address, protocol number, packaging job/lot number, 
name and strength of the product, medication identification number, subject information, caution 
statement, directions for use, and storage conditions.
Additional reference information and administration instructions can be found in the pharmacy 
manual. 
8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug must be 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 every working day.
8.1.3
Dose and Regimen
The dose and dosing regimen for subjects in this study is provided in Table 8.a. All subjects will 
receive double-blind treatment of study drug by IV infusion on Day 1 and Weeks 2, 6, and 14. 
Subjects should remain on the doses assigned for their weight category at randomization on Day 1
(300 or 150 mg for subjects ≥30 kg; 200 or 100 mg for subjects 10 kg to <30 kg) even if their 
weight category changes during the study.
The infusion will be administered intravenously over approximately 30 minutes for all subjects 
weighing ≥20 kg (longer infusion times up to 60 minutes may be used). For subjects weighing 
<20 kg, the infusion will be administered over approximately 2 hours. Instructions for 
reconstitution and administration will be provided in the pharmacy manual. Subjects should be 
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e applicable Terms of Use
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observed for 2 hours following the first 2 infusions, at a minimum, and 1 hour after each 
subsequent infusion.
Subjects assigned to the low dose group who do not achieve clinical response (based on 
PUCAI/PCDAI) at Week 14 will receive the high dose (ie, 300 mg for subjects ≥30 kg and 200 mg 
for subjects <30 kg) of vedolizumab IV at Week 14. 
Table 8.a
Dose and Regimen
Indication
Baseline
Weight
Vedolizumab IV Dose
Treatment Description
UC 
≥30 kg
300 mg (high dose) 
150 mg (low dose)
IV infusion at Day 1 and Weeks 2, 6, and 14
10 kg to <30 kg
200 mg (high dose)
100 mg (low dose)
CD 
≥30 kg
300 mg (high dose) 
150 mg (low dose)
IV infusion at Day 1 and Weeks 2, 6, and 14
10 kg to <30 kg
200 mg (high dose)
100 mg (low dose)
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug 
to 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, to capture this important safety information consistently in the database. Cases of 
overdose without manifested signs or symptoms are not considered AEs. AEs associated with an 
overdose will be documented on AE eCRF(s) according to Section 10.0, Pretreatment Events and 
Adverse Events.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
Subjects will receive treatment according to the appropriate regimen as described in Section 8.1.3.
The investigator or investigator’s designee will access the IRT system at Screening to obtain the 
subject study number. The investigator or the investigator’s designee will use the IRT to 
randomize the subject into the study. During this contact, the investigator or designee will provide 
the necessary subject-identifying information, including the subject number assigned at Screening. 
The medication identification (ID) number of the investigational drug to be dispensed will then be 
provided by the IRT. If sponsor-supplied drug is lost or damaged, the site can request a 
replacement from IRT. Refer to the IRT manual provided separately. At subsequent 
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drug-dispensing visits, the investigator or designee will again contact the IRT to request additional 
investigational drug for a subject. The medication ID number of the investigational drug to be 
dispensed will be provided by the IRT.
8.3
Investigational Drug Blind Maintenance
The investigational drug blind will be maintained using the IRT.
8.4
Unblinding Procedure
The investigational drug blind may be broken by the investigator if information concerning the 
investigational drug is essential for the medical treatment of the subject. The medical monitor must 
be informed of the unblinding at the earliest possible opportunity. In nonurgent cases, the medical 
monitor must be contacted before the subject is unblinded.
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by 
accessing the IRT.
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents, and the same 
information (except the time) must be recorded on the eCRF.
8.5
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee or destroyed at the site. The site will maintain source documents in addition to entering 
data into the IRT.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug, the investigator or designee must maintain records of all 
sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each subject, and 
return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment in the IRT. If there are any discrepancies between 
the packing list versus the actual product received, Takeda must be contacted to resolve the issue. 
The packing list should be filed in the investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the medication ID used to prepare each dose.
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
Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs in the 
IRT. The following information will be recorded at a minimum: protocol number and title, name of 
investigator, site identifier and number, description of sponsor-supplied drugs, date and amount 
dispensed, and the initials, seal, or signature of the person dispensing the drug.
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 or destroyed at the site. 
Accountability for clinical trial material being destroyed at the site must be documented using a 
Study Accountability Tracking Document or equivalent document. In addition, a Certificate of 
Destruction document must be provided by the sites that can identify or allow traceability to the 
batches, and/or medication ID numbers involved, and actual quantities destroyed. 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/pediatric assent are described in Section 15.2.
Informed consent/pediatric assent must be obtained prior to the subject entering into the study, and 
before any protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time of Screening; this subject number will be used throughout the study.
Subjects reaching an age that is not covered by their pediatric assent must provide consent for their 
appropriate age group to remain in the study. Subjects who reach the age of consent must provide 
consent with a signed informed consent form to remain in the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained may include (depending on local regulations) date of 
birth or age, sex, Hispanic ethnicity (United States only), race as described by the subject or 
parent/guardian, and smoking status of the subject at Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered ongoing medical history.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 1 month prior to signing of informed consent. Vaccination history 
does not need to be documented as medication history, and vaccination status will be recorded as 
part of the inclusion and exclusion criteria.
In addition, all prior biologic medication history for the treatment of UC or CD with the reason for 
discontinuation is to be collected for subjects where possible.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of investigational 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) GI system; (6) dermatologic system; (7) extremities; 
(8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other. All subsequent
physical examinations should assess clinically significant changes from the assessment prior to 
first dose examination.
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9.1.4
Weight, Height
A subject should have weight and height measured while wearing indoor clothing and without 
shoes, socks, or hats. The Takeda standard for collecting weight is kilograms (kg) with 1 decimal 
place. Height should be recorded to the nearest tenth of a centimeter (if possible). Height may be 
measured using a wall-mounted stadiometer using replicated measurements (average of 3 
measurements).
9.1.5
Vital Signs Procedure
Vital signs will include body temperature, respiratory rate, blood pressure, and pulse (beats per 
minute). On dosing days, vital signs are taken predose. Vital signs should be measured prior to any 
venesection/cannulation procedures. 
9.1.6
Efficacy Measurements
9.1.6.1
Completion and Review of Entries to Diaries
During Screening, subjects and parents or legal guardians will be instructed on how to 
appropriately complete entries into the diary. Three days (UC) or 5 days (CD) of completed diary 
data prior to the Day 1 visit is required for disease activity index calculation. Data on disease 
activity collected during screening will be reviewed on Day 1, before administering the first dose 
of study drug to ensure that the subject is still eligible for inclusion. Scores between initial 
screening and Day 1 before dosing should not change substantially.
During the rest of the study, 7 days (UC) or 10 days (CD) of completed diary data prior to each 
visit is required for disease activity index calculation. Therefore, subject symptoms must be 
recorded daily throughout the study, including the Screening Period. Diary entries will be 
reviewed by site personnel during Screening and (prior to dosing, if applicable) at Day 1 and
Weeks 1, 2, 6, 10, 14, and 22 (or ET Visit), and at any unscheduled visit(s) due to disease 
exacerbation. Subjects who enter the extension study (Vedolizumab-2005) will return their diaries 
to the site at the Week 22 Visit.
Entries should be reviewed and monitored by the study staff while the subject/parent or legal 
guardian is in the clinic, and any changes should be made directly onto the diary by the 
subject/parent or legal guardian. Diary entries will be transcribed by site personnel into the eCRF.
UC Activity 
A PUCAI score (see Appendix E) will be evaluated using the subject’s/parent’s or legal guardian’s 
paper diary entries collected during Screening and then at every scheduled visit during the study as 
per the Schedule of Study Procedures (Appendix A).
A complete Mayo score will be evaluated during Screening, using subject diary entries and 
flexible sigmoidoscopy results prior to randomization. A complete Mayo score will also be 
evaluated at Week 14 (prior to dosing) or an ET Visit (if appropriate). Subjects/parents or legal 
guardians will make daily entries into the diary, which will be used for Mayo score calculation. 
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During Screening, subjects/parents or legal guardians will be instructed on how to appropriately 
complete the daily diary entry. The symptoms of UC must be recorded throughout the study, 
including the Screening Period. Entries should be reviewed and monitored by the study staff while 
the subject/parent or legal guardian is in the clinic, and any changes should be made directly onto 
the diary by the subject/parent or legal guardian.
Diary entries preceding each study visit will be used to calculate the Mayo score. Because the 
flexible sigmoidoscopy preparation can interfere with the assessment of other clinical parameters, 
diary entries used to calculate the complete Mayo score should not be from days during which the 
flexible sigmoidoscopy preparation is administered. 
A partial Mayo score will be derived at Day 1, Weeks 2, 6, 10, and 22, and at any unscheduled 
visit(s) due to disease exacerbation (see Appendix F).
CD Activity 
A PCDAI score (see Appendix G) will be evaluated using the subject’s/parent’s or legal 
guardian’s paper diary entries and laboratory results collected during Screening and then at every 
scheduled visit during the study as per the Schedule of Study Procedures (Appendix A). 
A CDAI score (see Appendix H) evaluated during Screening using the subject/parent’s or legal 
guardian’s paper diary entries will also be derived at Day 1, Weeks 2, 6, 10, 14, and 22, and at any 
unscheduled visit(s) due to disease exacerbation. On all dosing days, the CDAI score components 
are to be performed prior to dosing; the total CDAI score will be calculated once results are 
available for all components. Entries should be reviewed and monitored by the study staff while 
the subject/parent is in the clinic, and any changes should be made directly onto the diary by the 
subject/parent.
Diary entries preceding each study visit will be used to calculate the CDAI score. Because the 
colonoscopy preparation can interfere with the assessment of other clinical parameters, diary 
entries used to calculate the complete CDAI score should not be from days during which the 
colonoscopy preparation is administered. 
Further efficacy measurements will be made based on endoscopy using SES-CD score (see 
Appendix I).
9.1.7
Documentation of Concomitant Medications and Procedures
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject, parent, or legal guardian OTC. Concomitant medication 
is not provided by Takeda. A concomitant procedure is any nonpharmacological medical 
intervention to treat their UC or CD.
At each study visit (from signing of informed consent through the end of the study), subjects or 
parents/legal guardians will be asked whether they have taken any medication other than the study 
drug or undergone any procedures to treat their UC or CD. All medication (including vitamin 
supplements, OTC medications, and oral herbal preparations) and concomitant procedures must be 
recorded in the eCRF.
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9.1.8
Use of Local Anesthetic
It is recommended to use local anesthetic patches (eg, Synera) or creams (eg, EMLA) for blood 
draws or IV insertions for the comfort of the subject. This will not be recorded as a concomitant 
medication.
9.1.9
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood collected at any single visit (including blood collection for PK analysis) is 
approximately 13 mL for subjects weighing ≥30 kg and 8 mL for subjects weighing 10 to <30 kg. 
The approximate total volume of blood for the study is 86 mL for subjects ≥30 kg and 55 mL for 
subjects weighing 10 to <30 kg. Details of these procedures and required safety monitoring will be 
given in the laboratory manual. Clinical laboratory tests to be conducted are summarized in 
Table 9.a.
The central laboratory will perform laboratory tests for hematology and serum chemistries, with 
the exception of the urine pregnancy test, which will be performed at the study site, and the 
erythrocyte sedimentation rate (ESR), which may be performed at a local laboratory. The results of 
laboratory tests will be returned to the investigator, who is responsible for reviewing and filing 
these results.
Blood samples should be taken in the following order, so that PK samples are collected as close as 
possible to the scheduled nominal time point: PK, safety samples, 
If subjects experience ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. 
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on reporting of abnormal liver function tests in relation to ALT or AST >3×ULN in 
conjunction with total bilirubin >2×ULN.)
If the ALT or AST remains elevated >3×ULN on 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).
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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
RBC
WBC with differential
Hemoglobin
Hematocrit
Platelets
INR (if required)
ESR
ALT
Albumin
Alkaline phosphatase
AST
Direct bilirubin
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Glucose
Chloride
Bicarbonate
Calcium
Amylase 
CRP
Other:
Serum
Urine
HIV test
Hepatitis panel, including HBsAg and anti-HCV
QuantiFERON test 
Female subjects only: hCG (urine pregnancy test) 
(female subjects of childbearing potential; only
collected at each scheduled visit for females who 
reach menarche prior to or during the study) (a)
Female subjects only: Beta hCG (for pregnancy test; only
collected at each scheduled visit for females who reach 
menarche prior to or during the study) (a)
Stool:
C difficile testing and toxin A and B
Fecal calprotectin
Ova and parasite evaluation
CRP=C-reactive protein, ESR=erythrocyte sedimentation rate, GGT=γ-glutamyl transferase, hCG=human chorionic 
gonadotropin, RBC=red blood cell. 
(a) Serum pregnancy analysis is performed at Screening Visit and Week 22/ET Visit. Urine pregnancy analysis is 
performed at all other scheduled visits as specified in Appendix A.
9.1.10 Contraception and Pregnancy Avoidance Procedure
9.1.10.1
Male Subjects and Their Female Partners
From signing of parental informed consent/assent form, throughout the duration of the study, and 
for 18 weeks after last dose of study drug, 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 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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contraception as shown in the list containing highly effective/effective contraception 
(Section 9.1.10.3).
9.1.10.2
Female Subjects and Their Male Partners
From signing of parental informed consent/assent form, throughout the duration of the study, and 
for 18 weeks after last dose of study drug, female subjects of childbearing potential* who are 
sexually active with a nonsterilized male partner** must use a highly effective/effective method of 
contraception (from the list below). In addition, they must be advised not to donate ova during this 
period. This will apply to female subjects of childbearing potential who have reached 
menarche prior to or during the study.
9.1.10.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A female subject is considered a female subject of childbearing potential, that is, fertile, 
following menarche and until becoming postmenopausal 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 postmenopausal state in younger women (eg, those <45 years old) or women 
who are not using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
** Sterilized males should be at least 1 year post–bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, the 
only acceptable methods of contraception are:

Nonhormonal Methods: 
–
Intrauterine device. 
–
Bilateral tubal occlusion. 
–
Vasectomized partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success). 
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the 
subject. True abstinence is defined as refraining from heterosexual intercourse during 
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the entire period of the study, from 1 month prior to the first dose until 18 weeks after 
last dose.

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 till she has been 
on contraceptive for 3 months;

Oral.

Injectable.

Implantable.
2. Standard-of-care medications and effective methods of contraception are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom).

Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action PLUS condom with or without spermicide.
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
4. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent/assent process and will be asked to sign a 
consent/assent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
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5. During the course of the study, regular urine hCG pregnancy tests will be performed only for 
female subjects 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 male subjects 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 female subjects 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?
6. 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 any dose of study 
drug (as close as possible and prior to first dose of study drug, preferably on the same day).
9.1.11 Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition to the procedures
summarized below, the ET and follow-up procedures (ie, Final Safety Visit [18 weeks after the last 
dose of study drug] and the long-term follow-up safety survey by telephone [6 months after the last 
dose of study drug]) should be completed. Any pregnancies in the partner of a male subject during 
the study or for 18 weeks after the last dose of study drug should also be recorded, following 
authorization from the subject’s partner. 
If the pregnancy occurs during administration of active study drug 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 1.1. The investigator must inform the subject of 
their right to receive treatment dose information. If the subject chooses to receive treatment dose 
information, the individual blind for dose should be broken by the investigator.
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment dose the subject received (if applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug 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.
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9.1.12 PK Sample Collection and Analysis
Blood samples for the assessment of PK will be collected as shown in the Schedule of Study 
Procedures (Appendix A). Blood samples (11 to 12 samples total) will be collected during the 
course of the study as follows:

Day 1 (1 sample: postdose). 

Day 8 (Week 1) (1 sample; nondosing visit). 

Day 15 (Week 2) (2 samples: 1 predose and 1 postdose). 

Between Days 16 and 42 (Weeks 2 to 6) (1 sample; nondosing visit).

Day 43 (Week 6) (2 samples: 1 predose and 1 postdose). 

Day 71 (Week 10) (1 sample; nondosing visit). 

Day 99 (Week 14) (2 samples: 1 predose and 1 postdose). 

Day 155 (Week 22) (1 sample).
For subjects who continue to the extension study, the Day 155 (Week 22) PK sample should be 
predose to first dose of the extension study. For subjects who do not enroll into the extension 
study, the Day 155 (Week 22) PK sample should be collected anytime during the visit.

Final Safety Visit 18 weeks after the last dose of study drug (for subjects who do not continue 
into the extension study).
Blood samples should be obtained within 30 minutes prior to dosing, where applicable, at 
Weeks 2, 6, and 14, and at any unscheduled visit for a subject who experiences a SAE or disease 
exacerbation. The exact dosing (start and end of infusion) and sampling times must be recorded 
accurately in the eCRF for all doses and PK samples. Samples collected outside the protocol times 
will not be considered to be protocol deviations as long as dosing (start and end of infusion) and 
PK sampling dates and time are accurately collected in the eCRF. If the infusion is stopped 
prematurely, this should be recorded in the eCRF and PK samples should be taken 5 minutes after 
the end of the infusion. The postdose samples collected on dosing days should be collected as close 
to the end of infusion as feasible (must be obtained within 60 minutes after the end of the infusion) 
from the opposite arm in which the study drug infusion was given. If blood collection from the 
opposite arm in which the study drug infusion was given is not feasible, the postdose sample may 
be collected from the infusion arm 30 to 60 minutes after the end of infusion and after the IV saline 
flush has been completed. Each blood sample will be aliquotted to provide 1 serum sample per 
time point. Detailed instructions on collection and processing of PK samples are included in the 
laboratory manual. 
Serum concentrations of vedolizumab will be determined using validated sandwich enzyme-linked 
immunosorbent assay (ELISA).
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9.1.13 Immunogenicity Sample Collection 
9.1.14 TB Screening 
All subjects will complete TB screening to determine eligibility. Subjects will be excluded from 
the study if they have active or latent TB, regardless of treatment history, as defined in Section 7.2.
9.1.15 Fecal Calprotectin Sample Collection
9.1.16 Stool Sample for Culture, Ova and Parasite Evaluation, and C difficile Assay
A stool sample will be obtained for culture, ova and parasite evaluation, and C difficile assay. A 
sample will be collected and cultured during Screening and at any point in the study when a subject
becomes symptomatic, including worsening of UC or CD. 
9.1.17 PML Checklist 
Clinic staff will administer an age-appropriate version of 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, if applicable) at each visit, as shown in 
Appendix A, to evaluate symptoms suggestive of PML. 
Any subjects reporting signs or symptoms of PML will undergo objective testing and may be 
referred to a neurologist for a full evaluation, as described in the Risk Assessment and 
Minimization for PML (RAMP) algorithm referenced in Section 11.2.1. Vedolizumab will be held 
in subjects with a positive subjective PML checklist. Subsequent doses of vedolizumab will be 
administered only if the possibility of PML is definitively excluded, as described in the RAMP 
algorithm. Subjects with confirmed PML, as adjudicated by the PML IAC, will be withdrawn from 
the study.
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The signs and/or symptoms from a positive PML checklist will be recorded as an AE. Additional 
information and tools for the RAMP can be found in the Study Manual. 
9.1.18 IMPACT-III Questionnaire (Subjects 9 to 17 Years of Age)
The IMPACT-III questionnaire is a self-reported measure with 35 closed questions encompassing 
6 domains: Bowel Symptoms (7 items), Systemic Symptoms (3 items), Social Functioning 
(12 items), Body Image (3 items), Treatment/Interventions (3 items), and Emotional Functioning 
(7 items). The IMPACT-III uses a 5-point Likert scale ranging from 1 to 5 for all answers. The 
outcome score ranges from 35 to 175, with higher scores suggesting better quality of life. 
IMPACT-III (where translations are available) will be administered to subjects aged 9 to 17 years 
at the time of first dose of study drug. Entries should be reviewed and monitored by the study staff 
while the subject/parent or legal guardian is in the clinic, and any changes should be made directly 
onto the questionnaire by the subject/parent or legal guardian. Questionnaire entries will be 
transcribed by site personnel into the eCRF.
After obtaining permission from the original authors to use the IMPACT-III questionnaire, the 
current version will be provided in the study manual.
9.1.19 Endoscopies
Endoscopy will be performed during Screening (unless 1 has already been performed within 
28 days prior to signing of informed consent/assent) and at Week 14 (or ET Visit). This will 
involve a flexible sigmoidoscopy (sigmoidoscope) or a colonoscopy, performed with a 
videoendoscope following a cleansing preparation (oral or rectal cathartic). Endoscopies will be 
read centrally for the efficacy analysis, for the screening endoscopy, and for the Week 14 Visit 
endoscopy (or ET Visit if appropriate), wherever possible, through use of video recordings. An ET 
endoscopy is not required if a subject withdraws prior to Week 6. On the days that endoscopies are 
performed, all other study procedures for that visit should be performed either prior to the 
endoscopy or on another day within the visit window.
9.1.20 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent/assent.
If the subject is found to be not eligible at this visit, the investigator should complete the eCRF. 
The IRT should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE.

Did not meet inclusion criteria or did meet exclusion criteria. 

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal.
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
Study termination.

Other.
Subject numbers assigned to subjects who fail screening should not be reused even if the subject is 
eligible to be rescreened. Subjects who are screen failures may be rescreened but need prior 
approval by the sponsor.
9.1.21 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.1.22 Monitoring Subject Treatment Compliance
Study drug will be administered in the clinic and treatment compliance will be monitored. If a 
subject is persistently noncompliant with the study drug (eg, fails to keep scheduled study visits), it 
may be appropriate to withdraw the subject from the study.
9.2
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.2.1
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 9.1.20 for procedures for documenting screening failures.
Procedures to be completed at Screening can be found in Appendix A (Schedule of Study
Procedures). 
9.2.2
Randomization and Stratification
Randomization will take place after confirmation of eligibility. Randomized subjects who do not 
complete the study may be replaced depending on emerging data from the ongoing study.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for the 
study, the subject should be randomized in the IRT, as described in Section 8.2. The randomization 
will be stratified by previous exposure/failure to TNF-α antagonists therapy or naive to TNF-α 
antagonists therapy, and by indication (UC or CD), and by weight group (≥30 kg or 10 kg to 
<30 kg). Subjects will be given the first dose of study drug as described in Section 6.1. The 
procedure for documenting screening failures is provided in Section 9.1.20.
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9.2.3
End-of-Study or ET Visit
The End-of-Study Visit will be performed at Week 22 or at the ET Visit. The procedures listed in 
Schedule of Study Procedures (Appendix A) at Week 22 will be performed and documented. This 
is the End-of-Study for subjects entering the Vedolizumab-2005 extension study.
For all subjects that received study drug, the investigator must complete the End-of-Study eCRF 
page.
9.2.4
Final Safety Follow-up Visit
For subjects not participating in the Vedolizumab-2005 extension study, a Final Safety Follow-up 
Visit will be performed 18 weeks after the last dose of study drug. Assessments will be completed 
per the Schedule of Study Procedures (Appendix A) at the Final Safety Visit. 
9.2.5
Long-term Follow-up Safety Survey
Upon completion or ET from the study, all subjects not entering the Vedolizumab-2005 extension 
study will be required to participate in a long-term follow-up safety survey by telephone 6 months 
after the last dose of study drug. This is the End-of-Study for subjects not entering the 
Vedolizumab-2005 extension study.
9.2.6
Poststudy Care
The study drug will not be available upon completion of the subject’s participation in the study. 
The subject should be returned to the care of a physician and use standard therapies as required.
Subjects who complete the study through Week 22 may be eligible to enroll in an extension study 
and continue to receive vedolizumab IV.
9.2.7
Unscheduled Visits Due to Disease Exacerbation 
Subjects who are seen by the investigator or site staff at a time point not required by the protocol 
(ie, unscheduled visit) due to disease exacerbation will undergo the following: 

Physical examination (including height and weight). 

Vital signs assessment. 

Diary review. 

PML checklist.

Collection of concomitant medications and procedures.

Collection of AEs and SAEs.

Clinical chemistry and hematology, as indicated.

Stool sample for culture.

Stool sample for fecal calprotectin.
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!
Urine hCG for female subjects of childbearing potential.
!
PUCAI/PCDAI. 
!
CDAI score.
!
Partial Mayo score.
!
 
!
PK assessment.
There is no minimum time for repeat evaluation by unscheduled visit to determine if a subject 
meets the criteria for disease worsening (Section 3.5). In general, however, enough time should be 
provided for clinically meaningful change to occur (eg, 1 week). 
9.2.8
Other Unscheduled Visits (if Applicable)
Subjects may return to the study center for unscheduled visits as needed. Unscheduled visits can be 
performed when the subject has a study-related issue in between regular visits (eg, SAE follow-up, 
LFT elevations). The following procedures may be done during these visits: concomitant 
medications, clinical laboratory blood draws, urine sample and AE collection, as appropriate. 
Standard-of-care visits (routine check-ups) should not be captured as an unscheduled visit in 
eCRF. However, if the visit is due to disease exacerbation, the procedures described in 
Section 9.2.7 should be performed. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 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 finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values) 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 or as 
an AE.
Laboratory values:

Changes in laboratory values are only considered to be PTEs or AEs if they are judged to be 
clinically significant (ie, if some action or intervention is required or if the investigator judges 
the change to be beyond the range of normal physiologic fluctuation). A laboratory retest 
and/or continued monitoring of an abnormal value are not considered an intervention. In 
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addition, repeated or additional noninvasive testing for verification, evaluation, or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values 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 
ongoing medical history and should NOT be recorded as PTEs or AEs. Baseline evaluations 
(eg, laboratory tests) should NOT be recorded as PTEs unless related to study procedures. 
However, if the subject experiences a worsening or complication of such an ongoing medical 
history, 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 condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg, “worsening of…”).

If a subject has a degenerative ongoing medical history (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study drug, the worsening or complication should be recorded appropriately as an AE. 
Investigators should ensure that the AE term recorded captures the change in the condition (eg, 
“worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs/serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
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worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action should NOT be recorded as an 
AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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Table 10.a
Takeda Medically Significant AE List 
Term
Acute liver failure 
Hepatic necrosis
Acute renal failure 
Malignant hypertension
Acute respiratory failure/acute respiratory distress 
syndrome
Neuroleptic malignant syndrome/malignant hyperthermia
Agranulocytosis
Pulmonary fibrosis 
Anaphylactic shock
Pulmonary hypertension
Aplastic anemia
Spontaneous abortion/stillbirth and fetal death
Confirmed or suspected endotoxin shock
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Confirmed or suspected transmission of infectious 
agent by a medicinal product
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Convulsive seizure
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 AESIs
An AESI (serious or nonserious) is one of scientific and medical concern specific to the compound 
or program, for which ongoing monitoring and rapid communication by the investigator to Takeda 
may be appropriate. Such events may require further investigation to characterize and understand 
them and would be described in protocols and instructions provided for investigators as to how and 
when they should be reported to Takeda. 
10.1.6 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.7 Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs, and concurrent treatments, may also be responsible.
Not related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs, and concurrent treatments.
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10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related. 
10.1.9 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator.
10.1.10
Stop Date
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.11
Frequency 
Episodic AEs/PTEs (eg, vomiting) or those that occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous.
10.1.12
Action Concerning Study Drug 

Drug withdrawn – study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – 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 reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Dose interrupted – the dose was interrupted due to the particular AE.
10.1.13
Outcome

Recovered/resolved – the 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.”
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
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 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
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 or until 
screen failure. For subjects who discontinue prior to study drug administration, PTEs are collected 
until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study drug. 
Routine collection of AEs will continue until Week 22 (for subjects who enroll in the extension 
study) or until the Final Safety Visit, which is 18 weeks after the last dose of study drug (for 
subjects who do not enroll in the extension study). 
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects or parents/legal guardians may report AEs occurring at any other time during the study. 
Subjects experiencing a serious PTE must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or there is a satisfactory 
explanation for the change. Nonserious PTEs, related or unrelated to the study procedure, need not 
be followed up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
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a) Event term.
b) Start and stop date.
c) Severity.
d) Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related) (not completed for PTEs).
e) Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
f)
Action concerning study drug (not applicable for PTEs).
g) Outcome of event.
h) Seriousness.
10.2.1.3 AE Collection Involving Medically Anticipated Clinical Events 
UC and CD are associated with certain characteristic signs and symptoms, including diarrhea, 
rectal bleeding, and abdominal pain, that may be present at Baseline and persist or fluctuate based 
on the individual subject’s disease history during the course of the study. These signs and 
symptoms will not be collected as AEs. These characteristics of disease activity will be regularly 
captured in the disease severity scores used for UC and CD. 
Exacerbations of disease activity (eg, increase in the daily amount of rectal bleeding or abdominal 
pain beyond the subject’s normal fluctuation, new signs and symptoms of UC and CD) will be 
collected as AEs and reported according to regulatory reporting requirements. 
 
 
10.2.1.4 Reporting Special Interest AEs
If a special interest AE that occurs during the treatment period or the follow-up period is
considered to be clinically significant based on the criteria below, it should be recorded in the 
Special Interest AE eCRF or an SAE Form. The eCRF or SAE Form should be completed and 
reported to the SAE reporting contact in Section 1.1 within 24 hours.
Infusion-Related Reactions and Hypersensitivity
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence, such 
premedications are unlikely to be necessary or beneficial. At the discretion of the investigator, 
however, subjects may be administered premedication prior to any study drug administration. 
Corticosteroids, if given as a premedication, should be limited to the day of administration. 
Vedolizumab should be administered by a health care professional prepared to manage 
hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and
medical support measures should be available for immediate use. Subjects should be observed for 
2 hours following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion. 
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Subjects and parents/legal guardians should be instructed to report symptoms, such as the 
development of rash, hives, pruritus, flushing, urticaria, that may represent an infusion-related 
reaction to study drug. If signs or symptoms of an infusion-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) at the discretion of the investigator. Subjects with severe or 
serious infusion-related reactions (eg, stridor, angioedema, life-threatening change in vital signs) 
must be withdrawn from the study. 
In all cases of administration-related reactions, the medical monitor must be informed as soon as 
practical. The disposition of subjects with less severe infusion-related reactions should be 
discussed with the medical monitor. 
Serious Infection 
Subjects will be monitored for signs and symptoms of infection and for lymphopenia during the 
study. Subjects with signs and symptoms suggestive of infections, including GI infections, will be 
treated as clinically indicated. Interventions may include antibiotic treatment, if appropriate and/or 
discontinuation of concomitant immunomodulators. Blood, sputum, urine, and/or stool cultures 
should be obtained as appropriate for the detection and diagnosis of infection. Withholding or 
terminating study drug administration may be considered, as described in Section 7.5.
Subjects and caregivers will be advised to seek medical attention for potential serious infection if 
they have signs and/or symptoms including, but not limited to, acute change in level of 
consciousness, high or low temperature (>38.5°C or <36°C), fast heart beat (tachycardia 
>140 beats per minutes [bpm] for ages 2 to 5 years, >130 bpm for ages 6 to 12 years, >110 bpm for 
ages 13 to 18 years), difficult or rapid breathing (respiratory rate >22/min for ages 2 to 5 years, 
>18 for ages 6 to 12 years, >14 for ages 13 to 18 years), passing out/faintness, drowsiness/difficult 
to rouse, unusual irritability, poor feeding/eating/drinking, seizure, and acute or dramatic increase 
in pain.
Malignancy 
All cases of malignancies that are detected during the study will be reported as AEs. Local medical 
practices for the management of malignancies 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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10.2.2 Collection and Reporting of SAEs
When an SAE occurs during the AE collection period, it should be reported according to the 
following procedure:
A Takeda SAE eCRF or SAE Form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s).

Causality assessment.
The SAE eCRF should be transmitted 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 the 
attention of the contact listed in Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal LFTs 
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms, and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3×ULN and total bilirubin >2×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B, or 
other acute liver disease or medical history. Follow-up laboratory tests as described in 
Section 9.1.9 must also be performed. In addition, an LFT Increases eCRF must be completed and 
transmitted with the Takeda SAE form (as per Section 10.2.2).
10.2.4 Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. An investigator who 
is made aware of or identifies a potential product complaint should immediately report the event to 
Takeda in accordance with the contact list provided to the site. Whenever possible, the associated 
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product should be maintained in accordance with the instructions pending further guidance from a 
Takeda representative.
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, 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 reports within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit/risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations. 
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11.0
STUDY-SPECIFIC COMMITTEES
11.1
Data Safety Monitoring Board 
An independent DSMB has been established to review safety, PK, and other relevant data, and to 
monitor the general safety of subjects who participate in the study. 
The DSMB will have scheduled regular meetings performing a full safety assessment to ensure 
monitoring of the overall safety of the study subjects. In addition, ad hoc meetings can be 
requested at any time by Takeda and the DSMB. 
The composition of, and working procedures for the DSMB are defined in the DSMB Charter and 
will be provided to the DSMB members. The DSMB charter is not included in this protocol.
11.2
Adjudication Committee
A PML IAC will be instituted for this study. The PML IAC will consist of a panel of leading PML 
experts, including a neurologist, neuroradiologist, and a virologist. 
11.2.1 Risk Assessment and Management Program 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 and typically only occurs in patients who are immunocompromised 
[31,32]. Natalizumab is a pan-4 integrin antagonist that binds to both the α4β1 and α4β7 integrins 
and inhibits cellular adhesion to vascular cell adhesion molecule-1(VCAM-1) and MAdCAM-1 
[33,34]. In contrast, vedolizumab binds to the α4β7 integrin only [27] and inhibits adhesion to
MAdCAM-1, but not VCAM-1. Although no cases of PML have been reported in clinical studies 
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 Assessment and 
Management Program for PML (RAMP) for PML. The complete description of the RAMP 
program, including materials and instructions for its implementation and monitoring, is included 
in the study manual. 
The RAMP is focused on early clinical detection and management of that specific safety risk, 
including the discontinuation of study drug, if applicable. Subjects are assessed for signs and 
symptoms of PML prior to the administration of each dose of study drug using a PML subjective 
symptom checklist. Subjects with a positive PML subjective symptom checklist at any time after 
enrollment in a vedolizumab clinical study will be evaluated according to a prespecified algorithm 
(the PML Case Evaluation Algorithm), which may include evaluation by a neurologist as 
appropriate. 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 
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PML, and will provide input regarding subject evaluation and management as defined in the IAC 
charter. 
To ensure success of the RAMP program, site personnel will be trained to recognize the features of 
PML, and subjects/parents/legal guardians will be trained to report specific neurological signs and 
symptoms without delay. Educational materials for teaching site personnel and subjects/parents or 
legal guardians about PML and the RAMP procedures will be distributed to all sites and are 
included in the study manual. Formal teaching and training will be performed for site personnel 
prior to the start of the study. Subjects will receive age-appropriate 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 RECORD KEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concomitant procedures will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an informed consent/assent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. All eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
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 into the eCRFs.
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by the study 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/assent forms, subject authorization 
forms regarding the use of personal health information (if separate from the informed consent 
forms), electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition 
to enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any 
source documentation printed on degradable thermal sensitive paper should be photocopied by the 
site and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
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 
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should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to receiving unblinding of 
subject’s treatment assignment from IRT after 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 meeting will be conducted prior to unblinding of subject’s treatment 
assignment. This review will assess the accuracy and completeness of the study database, subject 
evaluability, and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
The full analysis set (FAS) will include all randomized subjects who receive at least 1 dose of 
study drug. Subjects in this set will be analyzed according to treatment they were randomized to 
receive.
The safety analysis set will include all subjects who receive at least 1 dose of study drug. Subjects 
in this set will be analyzed according to the treatment they actually received.
The PK set is defined as all subjects who receive at least 1 dose of study drug and have at least 
1 measurable concentration of vedolizumab. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by dose group and overall based on 
all randomized subjects. Additional summaries will be provided for the FAS and other analysis 
sets, as appropriate. For continuous variables, summary statistics (nonmissing values, mean, 
median, SD, minimum and maximum) will be generated. For categorical variables, the counts and 
percentages of each possible value will be generated.
Medical history will be summarized by system organ class and preferred term. Medication history 
and concomitant medications will be summarized by preferred name.
13.1.3 Efficacy Analysis
All proportion-based efficacy endpoints will be summarized by presenting the point estimate and 
95% CIs for the proportion by indication (UC or CD) and weight groups. For all subjects with 
missing Mayo, CDAI, PUCAI, or PCDAI data for determination of endpoint at any time point, to 
ensure all subjects in the FAS are included in the analysis, a subject with any component of a scale 
missing will be considered to be a nonresponder/nonremitter for that particular endpoint, scale, 
and time point. Change from Baseline in fecal calprotectin results will be summarized by weight 
group.
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13.1.4 PK Analysis 
Measured serum concentrations of vedolizumab by time will be summarized by dose and weight 
groups using descriptive statistics. Individual serum concentration data versus time will be 
presented by dose group in a data listing.
The PK parameters will be derived by compartmental and/or noncompartmental approaches, data 
permitting. The Clinical Pharmacology Data Analysis Plan and SAP will provide further details of 
derivations. All PK parameters will be summarized using descriptive statistics (nonmissing values, 
mean, SD, percent coefficient of variation, median, minimum, maximum) by dose and weight 
group. In addition, Ctrough,Wk 14 will be summarized using descriptive statistics by dose, weight 
group, and by response status based on complete Mayo score or CDAI. 
Further analysis will be performed as deemed necessary and will not be reported in the clinical 
study report. These analyses will be part of a separate report.
13.1.5 Other Analyses
The dose-response relationship at Week 14 will be explored. Further details will be provided in the 
SAP.
Change from Baseline in IMPACT-III total and subscale scores will be summarized descriptively 
by dose group.
13.1.6 Safety Analysis
Safety analyses will be performed using the safety analysis set. Safety data will be summarized by 
dose group and various subgroups including by indication (UC or CD) and weight group. No 
statistical inference will be made for safety analyses.
The number and percentage of subjects with TEAEs (defined as any AE, regardless of relationship 
to study drug), AESIs (ie, malignancies, infusion reactions, serious infections, liver injury, PML), 
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. 
Separate summaries will also be generated for TEAEs overall and by severity.
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CCI


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Change from Baseline in clinical laboratory tests and vital signs will be summarized by dose 
group. Subjects with markedly abnormal values for laboratory tests and vital signs will be 
tabulated.
Physical examination findings and PML checklist data will be presented in data listings.
13.2
Interim Analysis 
Several interim analyses will be conducted to support future pediatric studies. These interim 
analyses may occur 1) when at least 20 patients in either weight group have completed Week 22 or 
withdrawn from the study or 2) when all subjects per indication and weight group (ie, UC 10 kg to 
<30 kg, CD 10 kg to <30 kg, UC ≥30 kg, CD ≥30 kg) have completed the study. Interim analyses
will be carried out by an independent statistical group not involved in daily activities of the study.
13.3
Determination of Sample Size
The planned sample size is 80 subjects including 40 subjects who weigh ≥30 kg and 40 subjects 
who weigh 10 kg to <30 kg. Subjects will be randomly assigned in a 1:1 ratio to receive 1 of 2 dose
regimens (high or low) per weight group per weight group (≥30 kg or 10 kg to <30 kg). The 
randomization will be stratified by previous exposure/failure to TNF-α antagonist therapy or naive 
to TNF-α antagonist therapy and by indication (UC or CD) and by weight group (≥30 kg or 10 kg 
to <30 kg). Randomization caps will be implemented to ensure that the sample size for each dose 
regimen will be a minimum of 9 subjects with UC and 9 subjects with CD per weight group. A 
sample size of 9 subjects is expected to have at least 80% power to establish 95% CIs that are 
within 60% and 140% of the geometric mean estimates for CL for each dose (high or low), 
indication (UC or CD), and weight group (≥30 kg or 10 kg to <30 kg), assuming the intersubject 
variability for CL in the pediatric population is similar to that in the adult population (%CV 
≤36.6%). The sample size is based on industry guidance [35,36]; CL is used because it controls 
overall drug exposure (AUC and average serum concentration during a dosing interval) and it is 
the parameter that allows computation of the dosage required to maintain an average steady-state 
concentration. The proposed sample size will also allow for descriptive analysis of efficacy for 
each indication and characterization of the dose-response relationship in pediatric subjects.
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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 in the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study drug, subject medical records, informed consent documentation, documentation of subject 
authorization to use personal health information (if separate from the informed consent forms), 
and review of eCRFs and associated source documents. It is important that the investigator and 
other study personnel are available during the monitoring visits and that sufficient time is devoted 
to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the
safety and rights of a subject or the reliability and robustness of the data generated, it will be 
reported to regulatory authorities as a serious breach of GCP and 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 
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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 requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of members 
who make up the respective IRB or IEC. If any member of the IRB or IEC has direct participation 
in this study, written notification regarding his or her abstinence from voting must also be 
obtained. Those Americas sites unwilling to provide names and titles of all members due to 
privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study-specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will notify the 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 study. Until the site receives 
notification from the sponsor or designee, no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent/assent 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/assent 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/assent 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/assent is given. The informed consent/assent 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/assent form and if applicable, the subject authorization form. The informed 
consent/assent 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/assent 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/assent 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/assent, then the 
subject’s legally acceptable representative may provide such consent/assent 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/assent 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/assent form and subject authorization (if applicable) at the time of consent/assent 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/assent 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 or the subject’s legally acceptable representative 
signs the informed consent/assent in the subject’s medical record. Copies of the signed informed 
consent/assent form, the signed subject authorization form (if applicable), and subject information 
sheet (if applicable) shall be given to the subject or the subject’s legally acceptable representative.
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All revised informed consent/assent 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/assent was obtained should be recorded in the subject’s 
medical record, and the subject or the subject’s legally acceptable representative should receive a 
copy of the revised informed consent/assent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, 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
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum, register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites before start of study, as defined in Takeda Policy/Standard. Takeda contact information, 
along with the investigators’ city, state (for investigators in the United States), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws, and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1. Loftus CG, Loftus EV, Jr., Harmsen WS, Zinsmeister AR, Tremaine WJ, Melton LJ, 3rd, et al. 
Update on the incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted 
County, Minnesota, 1940-2000. Inflamm Bowel Dis 2007;13(3):254-61.
2. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing 
incidence and prevalence of the inflammatory bowel diseases with time, based on systematic 
review. Gastroenterology 2012;142(1):46-54 e42; quiz e30.
3. Shivananda S, Lennard-Jones J, Logan R, Fear N, Price A, Carpenter L, et al. Incidence of 
inflammatory bowel disease across Europe: is there a difference between north and south? 
Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut 
1996;39(5):690-7.
4. Trallori G, Palli D, Saieva C, Bardazzi G, Bonanomi AG, d'Albasio G, et al. A 
population-based study of inflammatory bowel disease in Florence over 15 years (1978-92). 
Scand J Gastroenterol 1996;31(9):892-9.
5. Kappelman MD, Moore KR, Allen JK, Cook SF. Recent trends in the prevalence of Crohn's 
disease and ulcerative colitis in a commercially insured US population. Dig Dis Sci 
2013;58(2):519-25.
6. da Silva BC, Lyra AC, Rocha R, Santana GO. Epidemiology, demographic characteristics and 
prognostic predictors of ulcerative colitis. World J Gastroenterol 2014;20(28):9458-67.
7. Nieuwenhuis EE, Escher JC. Early onset IBD: what's the difference? Dig Liver Dis 
2008;40(1):12-5.
8. Heyman MB, Kirschner BS, Gold BD, Ferry G, Baldassano R, Cohen SA, et al. Children with 
early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium 
registry. J Pediatr 2005;146(1):35-40.
9. Turunen P, Kolho KL, Auvinen A, Iltanen S, Huhtala H, Ashorn M. Incidence of inflammatory 
bowel disease in Finnish children, 1987-2003. Inflamm Bowel Dis 2006;12(8):677-83.
10. Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM. 
Epidemiology of pediatric inflammatory bowel disease: a systematic review of international 
trends. Inflamm Bowel Dis 2011;17(1):423-39.
11. IBD Working Group of the European Society for Paediatric Gastroenterology HaN. 
Inflammatory bowel disease in children and adolescents: recommendations for diagnosis--the 
Porto criteria. J Pediatr Gastroenterol Nutr 2005;41(1):1-7.
12. Kugathasan S, Judd RH, Hoffmann RG, Heikenen J, Telega G, Khan F, et al. Epidemiologic 
and clinical characteristics of children with newly diagnosed inflammatory bowel disease in 
Wisconsin: a statewide population-based study. J Pediatr 2003;143(4):525-31.
13. Higuchi L, Bousvaros A. Ulcerative Colitis. In: Guandalini S, editor. Textbook of Pediatric 
Gastroenterology and Nutrition. London: Taylor & Francis; 2004, p. 385-409.
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14. Amre DK, Lu SE, Costea F, Seidman EG. Utility of serological markers in predicting the early 
occurrence of complications and surgery in pediatric Crohn's disease patients. Am J 
Gastroenterol 2006;101(3):645-52.
15. Motil KJ, Grand RJ, Davis-Kraft L, Ferlic LL, Smith EO. Growth failure in children with 
inflammatory bowel disease: a prospective study. Gastroenterology 1993;105(3):681-91.
16. Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M. Azathioprine or 6-mercaptopurine 
for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 
2009(1):CD000067.
17. Kader HA, Mascarenhas MR, Piccoli DA, Stouffer NO, Baldassano RN. Experiences with 
6-mercaptopurine and azathioprine therapy in pediatric patients with severe ulcerative colitis. J 
Pediatr Gastroenterol Nutr 1999;28(1):54-8.
18. Weiss B, Lerner A, Shapiro R, Broide E, Levine A, Fradkin A, et al. Methotrexate treatment in 
pediatric Crohn disease patients intolerant or resistant to purine analogues. J Pediatr 
Gastroenterol Nutr 2009;48(5):526-30.
19. Chande N, MacDonald JK, McDonald JW. Methotrexate for induction of remission in 
ulcerative colitis. Cochrane Database Syst Rev 2007(4):CD006618.
20. El-Matary W, Vandermeer B, Griffiths AM. Methotrexate for maintenance of remission in 
ulcerative colitis. Cochrane Database Syst Rev 2009(3):CD007560.
21. National Institutes of Health. Office of Rare Diseases Research: National Center for 
Advancing Translational Sciences (NCATS). Genetic and Rare Diseases Information Center 
(GARD): Pediatric Crohn's disease. Accessed 18 August 2014. Available at: 
http://rarediseases.info.nih.gov/gard/9856/pediatric-crohns-disease/resources/8.
22. Abbott Laboratories. Humira (adalimumab) for Ulcerative Colitis. Gastrointestinal Drugs 
Advisory Committee, Food and Drug Administration, Center for Drug Evaluation and 
Research; 28 August 2012; Silver Spring, MD.
23. Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking and 
regional immunity. Adv Immunol 1999;72:209-53.
24. Salmi M, Jalkanen S. Lymphocyte homing to the gut: attraction, adhesion, and commitment. 
Immunol Rev 2005;206:100-13.
25. Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, et al. Human mucosal 
addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated 
lymphoid tissue. Am J Pathol 1997;151(1):97-110.
26. Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. Expression and 
function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. Immuno 
1994;153(2):517-28.
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27. 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.
28. 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.
29. 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:Supplementary Appendix 
(http://www.nejm.org/doi/suppl/10.1056/NEJMoa1215739/suppl_file/nejmoa_appendix.pdf).
30. Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, et al. Effects of 
vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis 
factor antagonist treatment failed. Gastroenterology 2014;147(3):618-27 e3.
31. Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory 
therapies. Annu Rev Med 2010;61:35-47.
32. Steiner I, Berger JR. Update on progressive multifocal leukoencephalopathy. Curr Neurol 
Neurosci Rep 2012;12(6):680-6.
33. 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.
34. Tysabri (natalizumab) injection. Full Prescribing Information. Cambridge, MA: Biogen Idec 
Inc., Revised March 2014.
35. Guidance for Industry: General Clinical Pharmacology Considerations for Pediatric Studies 
for Drugs and Biological Products. US Dept of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER). December 2014.
36. Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive sample 
size when designing pediatric pharmacokinetic studies. J Clin Pharmacol 2012;52(10):1601-6.
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Appendix A
Schedule of Study Procedures 
Days
-28 to -1
Day
1
Wk
1
Wk
2
Wk
2-6*
Wk
6
Wk
10
Wk
14
Wk 22
End-of-Study/ ET 
Visit (a)
Unscheduled Visit
(UC/CD 
Exacerbation or 
Other) (b)
Wk 32
(or last dose day 
+18 weeks)
Final Safety Visit 
(a)
Visit Windows:
NA
NA
2
days
2
days
NA
3
days
3
days
3
days
3
days
1
wk
Visit Day
1
8
15
16-42
43
71
99
155
Visit Number:
1
2
3
4
5
6
7
8
9
10
Informed consent/pediatric assent 
X
PML wallet card
X
Allergy reaction card
X
Demographics
X
Medical history 
X
Medication history
X
UC/CD prior biologics history
X
Dosing (see Figure 6.a)
X
X
X
X
Physical examination (c)
X
X
X
X
X
X
X
X
X
Weight and height (d)
X
X
X
X
X
X
X
X
X
Vital signs (e)
X
X
X
X
X
X
X
X
X
PML checklist (f)
X
X
X
X
X
X
X
X
Concomitant medications
X (g)
X
X
X
X
X
X
X
X
X
X
Concomitant procedures
X (g)
X
X
X
X
X
X
X
X
X
X
IRT Randomization/drug dispensing
X
X
X
X
PUCAI/PCDAI (h)
X
X
X
X
X
X
X
X
Complete Mayo 
(UC subjects only) (i)
X
X
X
Partial Mayo (UC subjects only) (i)
X
X
X
X
X
X
CDAI score 
X (j)
X
X
X
X
X
X
X
Endoscopy (k)
X
X
X
Subject diary dispensed (l)
X
X
X
X
X
X
X
X
TB screening
X
Footnotes on next page.
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Appendix A
Schedule of Study Procedures (continued)
Days
-28 to -1
Day
1
Wk
1
Wk
2
Wk
2-6*
Wk
6
Wk
10
Wk
14
Wk 22
End-of-Study/ ET 
Visit (a)
Unscheduled Visit
(UC/CD 
Exacerbation or 
Other) (b)
Wk 32
(or last dose day 
+18 weeks)
Final Safety Visit 
(a)
Visit Windows:
NA
NA
% 2
days
% 2
days
NA
%3
days
%3
days
%3
days
%3
days
%1
wk
Visit Day
1
8
15
16-42
43
71
99
155
Visit Number:
1
2
3
4
5
6
7
8
9
10
Stool sample for culture (m)
X
X
Fecal calprotectin (n)
X
X
X
X
PTE assessment (o)
X
X
AE assessment (p)
X
X
X
X
X
X
X
X
X
X
Sample collection for:
Serum pregnancy test (q)
X
X
Urine pregnancy test (q)
X
X
X
X
X
HBV, HCV, HIV screening
X
Clinical chemistry 
(including CRP)
X
X
X
X
X
X
X
X
X
Hematology (r)
X
X
X
X
X
X
X
X
X
PK assessment (s)
X
X
X
X
X
X
X
X
X
X
IMPACT-III (u)
X
X
* Wk 2-6=nondosing visit scheduled anytime between Days 16 and 42 for PK collection. 
CRP=C-reactive protein, NA=not applicable.
(a) Subjects discontinued from the study for any reason will complete procedures for Week 22/ET assessments (plus fecal calprotectin sample, and endoscopy and Complete Mayo 
Score if before Week 14 Visit), the Final Safety Visit (18 weeks after the last dose of study drug), and will also be contacted by telephone 6 months after the last dose of study drug to 
complete a long-term follow-up safety survey. Subjects who complete the study but do not enter the extension study will complete procedures for Week 22 assessments (but will not 
repeat fecal calprotectin sample, or endoscopy and Complete Mayo Score performed at the Week 14 Visit), the Final Safety Visit (18 weeks after the last dose of study drug [Week 
32]), and will also be contacted by telephone 6 months after the last dose of study drug to complete a long-term follow-up safety survey.
(b) Subjects seen at an unscheduled visit for disease exacerbation will complete all of the Unscheduled Visit assessments. Other unscheduled visits may include concomitant 
medications, vital signs, clinical laboratory blood draws, urine sample, and AE collection, as appropriate.
(c) Physical examination: clinically significant findings will be recorded as Medical History if start is prior to signing the informed consent/pediatric assent, as PTEs if start is after 
signing of the informed consent/pediatric assent, or as AEs if start is after the first dose of study drug.
(d) Weight (kg; without shoes, socks, or hats) and height (cm) will be measured during Screening and study visits per table above. Weight should be measured prior to dosing on Day 
1 and Weeks 2, 6, and 14.
(e) Vital signs should be measured prior to dosing on Day 1 and Weeks 2, 6, and 14 or at any time at visits when study drug is not administered per table above.
(f) Must be performed at Screening and prior to dosing on Day 1 and Weeks 2, 6, and 14.
Property of Takeda: For non-comm
ial use only and subject to the applicable Terms of Use
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Vedolizumab IV
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Page 89 of 104
Protocol Incorporating Amendment No. 04
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(g) Monitoring of concomitant medications and concomitant procedures will begin at signing of the informed consent/pediatric assent.
(h) The components of the PUCAI/PCDAI scores may be completed within 7 days prior to receiving study drug.
(i) A complete Mayo score is required when endoscopy is performed. A complete Mayo score will be obtained within 28 days prior to randomization to determine eligibility (an 
endoscopy performed prior to consent/pediatric assent if within 28 days prior to signing of informed consent/assent is also acceptable). A baseline complete Mayo score, calculated by
adding the screening endoscopy subscore to the partial Mayo score obtained on Day 1 (or within 28 days prior to signing of informed consent/assent if applicable), will be used for the 
comparison with the Week 14 complete Mayo score to determine response at Week 14. A complete Mayo score will be obtained for subjects who withdraw prior to Week 14 if they 
undergo endoscopy at the ET Visit. 
(j) The subcomponents of the CDAI score will be completed within 7 days prior to randomization using hematocrit results collected during Screening.
(k) Endoscopy will be performed during Screening unless 1 has already been performed within 28 days prior to signing of informed consent/assent. The endoscopy at Week 22/ET is 
only required for ET visits that occur prior to Week 14. An ET endoscopy is not required if a subject withdraws prior to Week 6.
(l) The subject diaries will be dispensed at each visit and completed daily for CD subjects and UC subjects. Three days (UC) or 5 days (CD) of completed diary data prior to the Day 
1 visit is required for disease activity index calculation. Diary entries preceding each subsequent study visit (7 day for UC and 10 days for CD) will be used to calculate the Mayo or 
CDAI score. Because the flexible sigmoidoscopy/colonoscopy preparation can interfere with the assessment of other clinical parameters, diary entries used to calculate the complete 
Mayo or CDAI score should not be from days during which the flexible sigmoidoscopy/colonoscopy preparation is administered.
(m) A stool sample will be obtained for culture, ova and parasite evaluation, and C difficile assay. A sample will be collected and cultured during Screening and at any point in the 
study when a subject becomes symptomatic, including worsening of UC or CD.
(n) A stool sample will be collected during Screening, Week 14, and at unscheduled visits due to disease exacerbations for the analysis of fecal calprotectin. The stool sample for the 
analysis of fecal calprotectin must be collected before any bowel preparation is given and before dosing. A stool sample should be collected at the ET Visit for subjects who withdraw 
before Week 14, but is not to be collected at the Week 22/End-of-Study Visit for subjects who completed the procedure at Week 14. 
(o) PTEs will be captured immediately following the signing of the informed consent/pediatric assent at Screening, up until the first dose of study drug.
(p) Collection of all AEs will commence from the time that the subject is first administered study drug and will continue through Week 22 for subjects who enter the extension study 
or the Final Safety Visit (18 weeks after the last dose of study drug) for subjects who do not enter the extension study.
(q) All female subjects of childbearing potential (females who reach menarche prior to or during the study) (as per Section 9.1.11) must have a serum pregnancy test at Screening and 
Week 22/ET visit. A urine pregnancy test will be completed for all females of childbearing potential prior to each dose of study drug (Day 1 and Weeks 2, 6, and 14), and at any 
unscheduled visit. 
(r) The ESR may be performed at a local laboratory.
(s) The exact time of blood draw must be accurately registered in the eCRF. PK samples will be collected on Day 1 (1 sample: postdose); Day 8 [Wk 1] (1 sample); Days 15 [Wk 2], 
43 [Wk 6], and 99 [Wk 14] (2 samples predose and postdose); any time between Days 16 and 42 [Wks 2-6] (1 sample); Day 71 [Wk 10] (1 sample), Day 155 [Wk 22] (1 sample), and 
Final Safety Visit 18 weeks after the last dose of study drug (1 sample postdose of final administration for subjects who ET or for subjects who do not enroll in the extension study). 
The postdose samples collected on dosing days should be collected as close to the end of infusion as feasible (and must be obtained within 60 minutes after the end of the infusion) 
from the opposite arm in which the study drug infusion was given. If blood collection from the opposite arm in which the study drug infusion was given is not feasible, the postdose 
sample may be collected from the infusion arm 30 to 60 minutes after the end of infusion and after the IV saline flush has been completed.
(t)
 
(u) IMPACT-III (where translations are available) will be administered to subjects aged 9 to 17 years.
Property of Takeda: 
n-commercial use only and subject to the applicable Terms of Use
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CCI


Vedolizumab IV
Study No. MLN0002-2003
Page 90 of 104
Protocol Incorporating Amendment No. 04
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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. If the investigator/institution retains the services of any individual or party to perform study 
related duties and functions, the investigator/institution should ensure that this individual or 
party is qualified to perform those study related duties and functions and should implement 
procedures to ensure the integrity of the study related duties and functions performed and any 
data generated.
4. 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.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. 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.
7. 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.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. 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.
10. 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 
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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.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Study No. MLN0002-2003
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Protocol Incorporating Amendment No. 04
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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 or 
subject’s legal representative:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject or the subject’s legally acceptable representative otherwise 
is entitled, and that the subject may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. 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.
24. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
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from Screening throughout the duration of the study and for 18 weeks after the last dose of 
study drug. 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.
25. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening throughout the duration of the study and for 18 weeks after the last dose of study 
drug. 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.
26. 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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Vedolizumab IV
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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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Study No. MLN0002-2003
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Appendix E
PUCAI
The PUCAI is composed of 6 clinical items. Weights of the included items were assigned 
according to a multivariate regression analysis of 157 children with UC, in which rectal bleeding 
assumed the highest weight. 
The historical parameters should reflect a daily average of the patient’s last 48 hours. However, if 
the patient’s condition is changing rapidly, the last 24 hours may be used. The PUCAI score ranges 
from 0 to 85; a score of <10 denotes remission, 10 to 34 mild disease, 35 to 64 moderate disease, 
and 65 to 85 severe disease. A clinically significant response is defined as a PUCAI change of ≥20.
Item
Points
1
Abdominal pain
no pain
0
pain can be ignored
5
pain cannot be ignored
10
2
Rectal bleeding
none
0
small amount only, in <50% of stools
10
small amount with most stools
20
Large amount
30
3
Stool consistency of most stools
Formed
0
Partially formed
5
Completely unformed
10
4
Number of stools per 24 hours
0-2
0
3-5
5
6-8
10
>8
15
5
Nocturnal stools (any episode causing wakening)
No
0
Yes
10
6
Activity level
No limitation of activity
0
Occasional limitation of activity
5
Severe restricted activity
10
SCORE
Total Max 85
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Appendix F
Mayo Scoring System for the Assessment of Ulcerative Colitis Activity
Category (a)
Stool frequency (b)
0=Normal no. of stools for this patient
1=1 to 2 stools more than normal
2=3 to 4 stools more than normal
3=5 or more stools more than normal
Subscore, 0 to 3
Rectal bleeding (c)
0=No blood seen
1=Streaks of blood with stool less than half the time
2=Obvious blood with stool most of the time
3=Blood alone passes
Subscore, 0 to 3
Findings on endoscopy
0=Normal or inactive disease
1=Mild disease (erythema, decreased vascular pattern, mild friability)
2=Moderate disease (marked erythema, lack of vascular pattern, friability, erosions)
3=Severe disease (spontaneous bleeding, ulceration)
Subscore, 0 to 3; 0=Normal or inactive disease
Physician’s global assessment (d)
0=Normal
1=Mild disease
2=Moderate disease
3=Severe disease
Subscore, 0 to 3
Source: Adapted from Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly 
to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317(26):1625-9.
(a) The Mayo score ranges from 0-12, with higher scores indicating more severe disease. Partial Mayo score excludes 
endoscopy and ranges from 0-9.
(b) Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency.
(c) The daily bleeding score represents the most severe bleeding of the day.
(d) The physician’s global assessment acknowledges the 3 other criteria, the patient’s daily recollection of abdominal 
discomfort and general sense of well-being, and other observations, such as physical findings and the patient’s 
performance status.
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Appendix G
PCDAI
The PCDAI was specifically designed for use in children. The PCDAI includes a child-specific 
item: the height velocity variable as well as 3 laboratory parameters: hematocrit (adjusted for age 
and sex), ESR, and albumin level.
The limitation of activity should be based on the most significant limitation during the past week, 
even if it is only for 1 day. However, if the activity limitation is due to another illness (eg, upper 
respiratory infection), the illness period should be excluded from the patient’s PCDAI score.
The PCDAI score can range from 0-100, with higher scores signifying more active disease. A 
score of <10 is consistent with inactive disease, 11 to 30 indicates mild disease, and >30 is 
moderate-to-severe disease. A decrease of 12.5 points is taken as evidence of improvement.
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History (recall 1 week)
Abdominal pain
None
0
Mild (brief episodes, not interfering with activities)
5
Moderate/severe (frequent or persistent, affecting activities)
10
Stools
0-1 liquid stools, no blood
0
2-5 liquid or up to 2 semi-formed with small blood
5
Gross bleeding, >6 liquid stools or nocturnal diarrhoea
10
Patient functioning, general well-being (Recall, 1 week)
No limitation of activities, well
0
Occasional difficulties in maintaining age appropriate activities, below par
5
Frequent limitation of activities, very poor
10
EXAMINATION
Weight
Weight gain or voluntary weight loss
0
Involuntary weight loss 1-9%
5
Weight loss >10%
10
Height
<1 channel decrease (or height velocity >-SD)
0
>1<2 channel decrease (or height velocity <-1SD>-2SD)
5
>2 channel decrease (or height velocity <-2SD)
10
Abdomen
No tenderness, no mass
0
Tenderness, or mass without tenderness
5
Tenderness, involuntary guarding, definite mass
10
Peri-rectal disease
None, asymptomatic tags
0
1-2 indolent fistula, scant drainage, tenderness of abscess
5
Active fistula, drainage, tenderness or abscess
10
Extra-intestinal manifestations
(Fever >38.5 x 3 days in week, arthritis, uveitis, erythema nodosum, or pyoderma gangrenosum)
none
0
one
5
two
10
LABORATORY
Hematocrit (%)
<10 years
11-14 (male)
11-19 (female)
15-19 (male)
>33
>35
>34
>37
0
28-33
30-34
29-33
32-36
2.5
<28
<30
<29
<32
5
ESR (mm/hr)
<20
0
20-50
2.5
>50
5
Albumin (g/L)
>35
0
31-34
5
<30
10
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Appendix H
CDAI Scoring System for the Assessment of CD Activity
Category
Count
Initial
Total
Multiplication
Factor
Total
Number of liquid or very 
soft stools
7-day total number of liquid or very soft 
stools (reported on the 7 days immediately 
prior to the study visit)
×2
Abdominal pain
7-day total of daily abdominal pain scores 
on a 3-point scale: 0=none, 1=mild, 
2=moderate, 3=severe (reported on the 7 
days immediately prior to the study visit)
×5
General well-being
7-day total of daily general well-being 
scores on a 4-point scale: 0=generally well, 
1=slightly under par, 2=poor, 3=very poor, 
4=terrible (reported on the 7 days 
immediately prior to the study visit)
×7
Extra-intestinal 
manifestations of CD
Total number of checked boxes (check all 
that apply):
□ Arthritis/arthralgia
□ Iritis/uveitis
□ Erythema nodosum/pyoderma
gangrenosum/aphthous stomatitis
□ Anal fissure, fistula, or abscess
□ Other fistula
□ Fever over 37.8°C during past week
×20
Lomotil/Imodium/ 
opiates for diarrhea
Yes=1
No=0
×30
Abdominal mass
None=0
Questionable=2
Definite=5
×10
Hematocrit (%)(a)
Males: subtract value from 47
Females: subtract value from 42
×6
Body weight (b)
(1 – (body weight/
standard weight))×100
×1
Final score
Add totals:
Source: Adapted from: Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s disease activity 
index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70 (3):439-44. 
(a) If hematocrit subtotal <0, enter 0.
(b) If body weight subtotal <-10, enter -10.
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Appendix I
SES-CD
SES Score
Variable
0
1
2
3
Size of ulcers (cm)
None
Aphthous ulcers
(diameter 0.1-0.5)
Large ulcers
(diameter 0.5-2)
Very large ulcers
(diameter >2)
Ulcerated surface
None
<10%
10-30%
>30%
Affected surface
Unaffected
segment
<50%
50-75%
>75%
Presence of narrowings
None
Single, can be
passed
Multiple, can be
passed
Cannot be passed
SES-CD=sum of all variables for the 5 bowel segments.
Values are given to each variable for every examined bowel segment.
Source: Adapted from 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.
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Vedolizumab IV
Study No. MLN0002-2003
Page 102 of 104
Protocol Incorporating Amendment No. 04
30 August 2019
Appendix J
Summary of Changes
Change 1: Clarified procedures for completion and review of entries to diaries.
The primary change occurs in Section 9.1.6.1 Completion and Review of Entries to Diaries
Initial 
wording:
9.1.6.1 Completion and Review of Entries to Diaries
During Screening, subjects and parents or legal guardians will be instructed on how to 
appropriately complete entries into the diary. Three days (UC) or 5 days (CD) of 
completed diary data prior to the Day 1 visit is required for disease activity index 
calculation.
Amended 
or new 
wording:
9.1.6.1 Completion and Review of Entries to Diaries
During Screening, subjects and parents or legal guardians will be instructed on how to 
appropriately complete entries into the diary. Three days (UC) or 5 days (CD) of 
completed diary data prior to the Day 1 visit is required for disease activity index 
calculation. Data on disease activity collected during screening will be reviewed 
on Day 1, before administering the first dose of study drug to ensure that the 
subject is still eligible for inclusion. Scores between initial screening and Day 1 
before dosing should not change substantially.
Rationale for Change:
Amended to ensure that eligibility for the study is maintained at the end of the screening period.
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Vedolizumab IV
Study No. MLN0002-2003
Page 103 of 104
Protocol Incorporating Amendment No. 04
30 August 2019
Change 2 Clarification of criteria for interim analysis.
The primary change occurs in Section 13.2 Interim Analysis:
Initial 
wording:
Several interim analyses will be conducted to support future pediatric studies. These 
will occur 1) when 20 patients in the ≥30 kg weight group have completed Week 22 or 
withdrawn from the study and 2) when all subjects per indication and weight group 
(ie, UC 10 kg to <30 kg, CD 10 kg to <30 kg, UC ≥30 kg, CD ≥30 kg) have completed 
the study. Interim analyses will be carried out by an independent statistical group not 
involved in daily activities of the study.
Amended 
or new 
wording:
Several interim analyses will be conducted to support future pediatric studies. These
will interim analyses may occur 1) when at least 20 patients in the ≥30 kg either
weight group have completed Week 22 or withdrawn from the study and or 2) when 
all subjects per indication and weight group (ie, UC 10 kg to <30 kg, CD 10 kg to <30 
kg, UC ≥30 kg, CD ≥30 kg) have completed the study. Interim analyses will be carried 
out by an independent statistical group not involved in daily activities of the study.
Rationale for Change:
Amended to make provision for interim analyses in both weight groups (ie, the <30 kg group as 
well as the previously planned ≥30 kg group) before all subjects have completed Week 22 or were 
withdrawn from the study.
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Vedolizumab IV
Study No. MLN0002-2003
Page 104 of 104
Protocol Incorporating Amendment No. 04
30 August 2019
Change 3: Amended the concomitant oral corticosteroid dosing information.
The primary change occurs in Section 7.3.1.1 Oral Corticosteroid Dosing: 
Initial 
wording:
…

For subjects entering the study at a corticosteroid dose of <20 mg/day, tapering 
may resume by 5 mg/week down to 10 mg/day for those who weigh ≥40 kg or 
more and down to 0.25 mg/day for those weighing <40 kg.
Once these thresholds are reached, the corticosteroid dose will be held stable until the 
third dose of study drug is given at Week 6. Thereafter, between Weeks 6 and 14, 
corticosteroid tapering may resume at the discretion of the investigator by 5 mg/week 
down to 10 mg/day, and thereafter by 2.5 mg/wk until zero.
Amended 
or new 
wording:
…

For subjects entering the study at a corticosteroid dose of <20 mg/day, tapering 
may resume by 5 mg/week down to 10 mg/day for those who weigh ≥40 kg or 
more and down to 0.25 mg/kg/day for those weighing <40 kg.
Once these thresholds are reached, the corticosteroid dose will be held stable until the 
third dose of study drug is given at Week 6. Thereafter, between Weeks 6 and 14, 
corticosteroid tapering may resume at the discretion of the investigator by 5 mg/week 
down to 10 mg/day, and thereafter by 2.5 mg/week until zero.
Rationale for Change:
To correct dosages for corticosteroid tapering in subjects entering the study at a dose of 
<20 mg/day.
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PPD

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 2, Randomized, Double-Blind, Dose-Ranging Study to Determine the 
Pharmacokinetics, Safety and Tolerability of Vedolizumab IV in Pediatric Subjects With 
Ulcerative Colitis or Crohn’s Disease
NCT Number: NCT03138655
SAP Approve Date: 1 May 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: MLN0002-2003
A Phase 2, Randomized, Double-Blind, Dose-Ranging Study to Determine the 
Pharmacokinetics, Safety and Tolerability of Vedolizumab IV in Pediatric Subjects With 
Ulcerative Colitis or Crohn’s Disease
PHASE 2
Version: Final 4.0
Date: 1 May 2019
Prepared by:
Based on:
Protocol Version: Amendment 03
Protocol Date: 17 January 2018
Property of Taked
d on:
d on:
Pr
P
e only and subject to the applicable Terms of Use
Determi
Determi
ediatric 
diatric
al 4.0.0
May
May 201
2
PPD


MLN0002-2003
Page 2 of 49
Statistical Analysis Plan Final 4.0
1 May 2019
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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s of Use
PPD


MLN0002-2003
Page 3 of 49
Statistical Analysis Plan Final 4.0
1 May 2019
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Additional Objectives ................................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoints ...................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Additional Endpoints ...............................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Definition of Study Days....................................................................................13
7.1.2
Visit Windows for Statistical Analysis ...............................................................13
7.1.3
Methods for Handling of Missing Efficacy Data ................................................15
7.1.4
Conventions for Missing Adverse Event Dates...................................................15
7.1.5
Conventions for Missing Concomitant Medication Dates...................................16
7.1.6
Conventions for Calculation of Mayo Score.......................................................17
7.1.7
Conventions for Calculation of CDAI Scores.....................................................20
7.1.8
Conventions for Calculation of SES-CD ............................................................22
7.1.9
Conventions for Calculation of PUCAI ..............................................................23
7.1.10 Conventions for Calculation of PCDAI ..............................................................23
7.2
Analysis Sets ...........................................................................................................23
7.2.1
Full Analysis Set (FAS) .....................................................................................23
7.2.2
Safety Analysis Set ............................................................................................24
7.2.3
PK Analysis Set .................................................................................................24
7.2.4
Randomized Set.................................................................................................25
7.3
Disposition of Subjects ............................................................................................25
7.4
Demographic and Other Baseline Characteristics.....................................................26
7.5
Medical History and Concurrent Medical Conditions...............................................28
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MLN0002-2003
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Statistical Analysis Plan Final 4.0
1 May 2019
7.6
Medication History and Concomitant Medications...................................................28
7.7
Study Drug Exposure and Compliance.....................................................................28
7.8
Efficacy Analysis.....................................................................................................29
7.8.1
Secondary Efficacy Endpoints............................................................................30
7.8.2
...........................................................................31
7.8.3
.............................................................................................32
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................32
7.9.1
Pharmacokinetic Analysis ..................................................................................32
7.9.2
Pharmacodynamic Analysis ...............................................................................33
7.10
Other Outcomes.......................................................................................................33
7.10.1
.....................................................................................33
7.10.2 Health-Related Quality-of-Life ..........................................................................33
7.10.3 Immunogenicity.................................................................................................33
7.11
Safety Analysis........................................................................................................34
7.11.1 Adverse Events ..................................................................................................34
7.11.2 Clinical Laboratory Evaluations .........................................................................36
7.11.3 Vital Signs .........................................................................................................36
7.11.4 Other Observations Related to Safety.................................................................37
7.12
Interim Analysis ......................................................................................................37
7.13
Changes in the Statistical Analysis Plan...................................................................37
7.13.1 Revision History ................................................................................................37
8.0
REFERENCES..............................................................................................................39
LIST OF IN-TEXT TABLES
Table 7.a
Analysis Visit Windows for Safety Data ............................................................14
Table 7.b
Analysis Visit Windows for Efficacy Data .........................................................14
Table 7.c
Examples of Diary Subscore Entries and Corresponding Subscore Derivation 
per GEMINI Approach.......................................................................................19
Table 7.d
Examples of Diary Subscore Entries and Corresponding Subscore Derivation 
per draft FDA UC guidance ...............................................................................20
Table 7.e
Examples of Diary Subscore Entries and Corresponding Subscore (Stool) 
Derivation..........................................................................................................22
Table 7.f
Baseline Disease Characteristics ........................................................................27
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29
29
......
......30
30
.........
......
.........
......
..........
......
.........
......
..........
...
.........
....
.........
.......
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.........
......
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.........
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......
T TABL
T TA
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Table 7.d
able 7.
Tab
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CCI
CCI
CCI


MLN0002-2003
Page 5 of 49
Statistical Analysis Plan Final 4.0
1 May 2019
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ..................................................................................9
LIST OF APPENDICES
Appendix A
Mayo Score Calculation Worksheet ...................................................................40
Appendix B
Crohn's Disease Activity Index (CDAI) .............................................................42
Appendix C 
Simple Endoscopic Score for Crohn's Disease (SES-CD)...................................44
Appendix D
PUCAI..............................................................................................................45
Appendix E
PCDAI...............................................................................................................46
Appendix F
AEs of Special Interest.......................................................................................47
Appendix G
Criteria for Identification of Markedly Abnormal Laboratory Values and Vital 
Sign Values........................................................................................................48
Appendix H
Criteria for Markedly Abnormal Values for Vital Signs......................................49
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MLN0002-2003
Page 6 of 49
Statistical Analysis Plan Final 4.0
1 May 2019
3.0
LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse events of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the serum concentration-time curve at Week 14
Cav,Wk 14
average serum concentration during a dosing interval at Week 14
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CI
confidence interval
CL
total clearance after IV administration
Ctrough,Wk 14
serum concentration at the end of Week 14
Ctrough,Wk 22
serum concentration at the end of Week 22
CV
coefficient of variation
ET
Early Termination
FAS
full analysis set
IV
intravenous(ly)
MedDRA
Medical Dictionary for Regulatory Activities
PCDAI
Pediatric Crohn’s Disease Activity Index
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PTE
pretreatment event
PUCAI
Pediatric Ulcerative Colitis Activity Index
SAP
statistical analysis plan
SD
standard deviation
SES-CD
simple endoscopic score for Crohn’s disease
TEAE
treatment-emergent adverse event
TNF-α
tumor necrosis factor-alpha
UC
ulcerative colitis
WHODrug
World Health Organization Drug Dictionary
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
14
22
r Regulato
Regulat
Disease A
sease 
c(s)
(s)
multifoca
multifo
ment even
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tatistical 
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s
CCI


MLN0002-2003
Page 7 of 49
Statistical Analysis Plan Final 4.0
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4.0
OBJECTIVES
4.1
Primary Objectives
!
To evaluate vedolizumab pharmacokinetics (PK) in pediatric subjects with ulcerative colitis 
(UC) or Crohn’s disease (CD).
4.2
Secondary Objectives
!
To assess the efficacy of vedolizumab intravenous (IV) in pediatric subjects with UC or CD.
!
To characterize the dose-response relationships of vedolizumab IV in pediatric subjects with 
UC or CD.
4.3
Additional Objectives
!
To assess the safety and tolerability of vedolizumab IV in pediatric subjects with UC or CD.
4.4
Study Design
This is a phase 2, randomized, double-blind, dose-ranging study involving pediatric subjects with 
moderately to severely active UC or CD who have demonstrated an inadequate response to, loss 
of response to, or intolerance of at least 1 of the following agents: corticosteroids, 
immunomodulators, and/or tumor necrosis factor-alpha (TNF-α) antagonist therapy. The study 
will evaluate the PK, efficacy, immunogenicity, safety, and tolerability of vedolizumab IV 
administered as a 30-minute infusion. Approximately 80 pediatric subjects will be enrolled to 
ensure that 40 subjects weighing ≥30 kg and 40 subjects weighing <30 kg, as well as a minimum 
of 36 subjects with UC and a minimum of 36 subjects with CD, will be enrolled in the study. 
Subjects who discontinue may be replaced as determined by the sponsor. 
This study includes a 4-week Screening Period, a 22-week Double-Blind Treatment Period (with 
last dose at Week 14) for all subjects. Eligible subjects may exit the study at Week 22 and 
continue to receive study drug in an extension study. Subjects who do not enter the extension 
study will participate in an 18-week Follow-up Period starting from the last dose of study drug 
and complete a long-term follow-up safety survey by telephone 6 months after their last dose of 
study drug. 
The total duration of the study will be approximately 36 weeks from start of the Screening Period 
to the posttreatment Final Safety Visit. Study drug will be administered on Day 1 and Weeks 2, 
6, and 14. Subjects in the low dose group who do not achieve clinical response based on 
Pediatric Ulcerative Colitis Activity Index (PUCAI)/Pediatric Crohn’s Disease Activity Index 
(PCDAI) at Week 14 will receive a high dose of vedolizumab IV (300 mg for subjects ≥30 kg 
and 200 mg for subjects <30 kg) at Week 14. At the Week 22 Visit, subjects may be eligible to 
Property of Takeda: For non-commercial use on
ect to the applicable Terms of Use
lit
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s with U
with U
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CCI


MLN0002-2003
Page 8 of 49
Statistical Analysis Plan Final 4.0
1 May 2019
enter an extension study (Vedolizumab-2005) to continue receiving study drug. Subjects who do 
not enter the extension study will complete an End-of-Study/Early Termination (ET) Visit at 
Week 22 and then attend the Final Safety Visit 18 weeks after their last dose of study drug. 
Subjects who withdraw prior to Week 22 (ET) will complete the Week 22 assessments (and an 
optional endoscopy if prior to the Week 14 Visit) at their ET Visit and then attend the Final 
Safety Visit 18 weeks after their last dose of study drug. All subjects who do not participate in 
the extension study will also be required to participate in a long-term follow-up safety survey by 
telephone, 6 months after their last dose of study drug. 
Eligible subjects will be randomly assigned in a 1:1 ratio to receive 1 of 2 dose regimens (high or 
low) per weight group on Day 1. The randomization will be stratified by previous 
exposure/failure of TNF-α antagonists therapy or naive to TNF-α antagonist therapy, by 
indication (UC or CD), and by weight group (≥30 kg or <30 kg). Randomization caps will be 
implemented to ensure the sample size for each dose regimen will be a minimum of 9 UC 
subjects and 9 CD subjects per weight group (≥30 kg or <30 kg). 
Safety and efficacy assessments will be made throughout the study, at the Week 22 End-of-
Study/ET Visit, and at the Final Safety Visit 18 weeks after the last dose of study drug (for 
subjects who do not enroll in the Vedolizumab-2005 extension study). Serious adverse events 
and AEs will be collected throughout the study. Subjects will receive their last dose of study 
drug at Week 14 and have an endoscopy at the Week 14 Visit for efficacy evaluation. 
Approximately 11 blood samples to evaluate PK will be collected (predose and/or postdose) over 
the course of the study.
Property of Takeda: For non-commerci
 only and subject to the applicable Terms of Use
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CCI


MLN0002-2003
Page 9 of 49
Statistical Analysis Plan Final 4.0
1 May 2019
Figure 4.a
Schematic of Study Design
Screening
Period
Double-Blind Treatment Period
Follow-up 
Period
Additional
Follow-up
Dosing at Day 1, and Weeks 2, 6, and 14:
UC subjects who weigh ≥30 kg
300 mg (N=10)
150 mg (N=10)
UC subjects who weigh 10 kg to <30 kg
200 mg (N=10)
100 mg (N=10)
CD subjects who weigh ≥30 kg
300 mg (N=10)
150 mg (N=10)
CD subjects who weigh 10 kg to <30 kg
200 mg (N=10)
100 mg (N=10)
Final Safety Visit 
(b) 
(18 weeks after 
the last dose of 
study drug)
Long-Term 
Follow-Up
Safety Survey 
by Telephone
(c)
(6 months 
after the last 
dose of study 
drug)
End-of-Study 
(a)/ ET
Procedures
Extension Study 
Vedolizumab-
2005 (d)
Days
Day
Wk Wk
Wk
Wk
Wk
Wk
Wk
Wk
-28 to -1
1
1
2
2-6
6
10
14
22
32 (b)
Randomization
Visit: 1
2
3
4
5
6
7
8
9
10 (e)
ET=Early Termination, Wk 2-6=nondosing visit scheduled anytime between Days 16 and 42 for PK collection.
(a) Subjects who consent to participate in the extension study (Vedolizumab-2005) may be eligible for the extension study dosing 
after procedures have been completed at Week 22 (Visit 9).
(b) Subjects who do not enter the extension study or withdraw before Week 22 will also complete ET Visit (Week 22) procedures 
and a Final Safety Visit 18 weeks after their last dose of study drug.
(c) Subjects who withdraw before Week 22 will also participate in a long-term follow-up safety survey by telephone 6 months 
after the last dose of study drug.
(d) Subjects will provide informed consent/pediatric assent for participation in extension Study Vedolizumab-2005 on or after 
Week 14 through Week 22 of Study MLN0002-2003.Visit 1 of extension Study Vedolizumab-2005 is within 1 week of 
completing Week 22 (Visit 9) procedures.
(e) Subjects who do not enter the extension study (Vedolizumab-2005) will complete the Final Safety Visit 18 weeks after their 
last dose of study drug and participate in a long-term follow-up safety survey by telephone 6 months after the last dose of study 
drug.
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MLN0002-2003
Page 10 of 49
Statistical Analysis Plan Final 4.0
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints 
PK parameters:
!
Area under the serum concentration-time curve at Week 14 (AUCWk 14). 
!
Average serum concentration during a dosing interval at Week 14 (Cav,Wk 14). 
!
Observed serum concentration at the end of a dosing interval at Week 14 (Ctrough,Wk 14).
5.2
Secondary Endpoints
!
Percentage of UC subjects who achieve clinical response based on complete Mayo score, as 
defined by a reduction in complete Mayo score of ≥3-points and ≥30% from Baseline with an 
accompanying decrease in rectal bleeding subscore of ≥1-point or absolute rectal bleeding 
subscore of ≤1-point at Week 14.
!
Percentage of CD subjects who achieve clinical response based on Crohn’s Disease Activity 
Index (CDAI), as defined by a ≥70-point decrease from Baseline in CDAI score at Week 14.
5.3
Additional Endpoints
Prop
ly and subject to the applicable Terms of Use
).
Ctrough,
rough
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CCI


MLN0002-2003
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Statistical Analysis Plan Final 4.0
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Prop
se
CCI


MLN0002-2003
Page 12 of 49
Statistical Analysis Plan Final 4.0
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6.0
DETERMINATION OF SAMPLE SIZE
The planned sample size is 80 subjects including 40 subjects who weigh ≥30 kg and 40 subjects 
who weigh <30 kg. Subjects will be randomly assigned in a 1:1 ratio to receive 1 of 2 dose 
regimens (high or low) per weight group (≥30 kg or <30 kg). The randomization will be 
stratified by previous exposure/failure of TNF-α antagonist therapy or naive to TNF-α antagonist 
therapy and by indication (UC or CD) and by weight group (≥30 kg or <30 kg). Randomization 
caps will be implemented to ensure that the sample size for each dose regimen will be a 
minimum of 9 subjects with UC and 9 subjects with CD per weight group. A sample size of 9 
subjects is expected to have at least 80% power to establish 95% confidence intervals (CIs) that 
are within 60% and 140% of the geometric mean estimates for clearance (CL) for each dose 
(high or low), indication (UC or CD) and weight group (≥30 kg or <30 kg), assuming the 
intersubject variability for CL in the pediatric population is similar to that in the adult population 
(%CV ≤36.6%). The sample size is based on industry guidance [FDA, 2014; Wang et al, 2012]; 
CL is used because it controls overall drug exposure (area under the serum concentration-time 
curve and average serum concentration during a dosing interval) and it is the parameter that 
allows computation of the dosage required to maintain an average steady-state concentration. 
The proposed sample size will also allow for descriptive analysis of efficacy for each indication 
and characterization of the dose-response relationship in pediatric subjects.
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MLN0002-2003
Page 13 of 49
Statistical Analysis Plan Final 4.0
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All statistical analyses will be conducted using SAS® version 9.2 or higher.
Unless otherwise specified, baseline is defined as the last observed non-missing value before the 
first dose of study medication. Values measured on Day 1 must be prior to administration of 
study drug to be classified as baseline. Change from baseline will be calculated by subtracting 
the baseline values from the individual post-baseline values. If either the baseline or post-
baseline value is missing, the change from baseline is set to missing.
Where appropriate, variables will be summarized descriptively by study visit. For categorical 
variables, the count and proportions of each possible value will be tabulated by treatment group. 
Percentages will be calculated out of the total number of subjects in the analysis set and by 
subgroups, when applicable. 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. 
Two-sided confidence intervals (CI) about a point estimate will be computed using Jeffreys prior 
interval due to the small sample sizes expected and will be presented using the same number of 
decimal places as the point estimate. The exact 95% CI (e.g., Clopper-Pearson interval) will be 
presented as well.
Analysis windowing convention will be used to determine the analysis values for a given study 
visit for observed data analyses. Details are provided in Section 7.1.2.
In the event that a subject is randomized to the wrong disease indication, that subject will be 
analyzed based on the correct disease indication. 
7.1.1
Definition of Study Days
Day 1 will be defined as the day of first study drug administration, as recorded on the electronic 
case report form (eCRF) dosing page. 
Study day will be calculated relative to the date of the first dose of study drug. Study days prior 
to the first dose of study drug will be calculated as:
Date of assessment/event – Date of first dose of study drug.
Study days on or after the first dose of study drug will be calculated as:
Date of assessment/event – Date of first dose of study drug + 1.
7.1.2
Visit Windows for Statistical Analysis
Subjects do not always adhere strictly to the visit timing stated in the protocol. Therefore, the 
designation of visits will be based on the day of evaluation relative to the start of study drug 
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rather than the nominal visit recorded in the data. Accordingly, the study is divided into 
continuous, mutually exclusive analysis windows.
The rules provided in the Table 7.a and Table 7.b below will be used for safety and efficacy data. 
The lower and upper bounds of each window are the approximate midpoints between the 
scheduled days for the current visit and its adjacent scheduled visits. The value used in analysis 
for by-visit summaries is the value within the specified window. If a patient 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 (i.e., more than 
one value for the same day), the mean of the values will be used for continuous parameters and 
the worst result will be chosen over a more positive one for categorical parameters. 
Table 7.a
Analysis Visit Windows for Safety Data 
Visit 
Target Day
Laboratory, Vital Sign 
Baseline
1
≤ 1
Week 2
15
2 – 28
Week 6
43
29 – 56
Week 10
71
57 – 84
Week 14
99
85 – 126
Week 22a
155
127 – 189
Week 32 (FU)b
225
≥ 190
a For subjects who complete Week 22 and enter the Extension Study 2005, Week 22 will end on Day 189 or the day 
prior to or on the first dosing of the extension study whichever comes first. 
b Only for subjects who do not enter the Extension Study 2005.
Table 7.b
Analysis Visit Windows for Efficacy Data 
Visit
Target Day
Partial Mayo Score, CDAI, 
PUCAI, PCDAI
Endoscopy, Complete Mayo Score, 
fecal calprotectin
Baseline
1
1
1
Week 2
15
2 – 28
Week 6
43
29 – 56
Week 10
71
57 – 84 
Week 14
99
85 – 126 
2 – 126 
Week 22a
155
≥ 127 
≥ 127 
a For subjects who complete Week 22 and enter the Extension Study 2005, Week 22 will end on Day 189 or the day 
prior to or on the first dosing of the Extension Study whichever comes first. 
Given the study design, the end of Study MLN0002-2003 is defined separately given subjects’ 
eligibility to enter the Extension Study Vedolizumab-2005: 
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
Subjects who will roll over to the Extension Study will exit Study MLN0002-2003 at Week 
22 and continue to receive study drug in the Extension Study. Therefore, the end of Study 
MLN0002-2003 for these subjects occurs on the calendar day prior to the date of the first 
dose of study drug in the Extension Study 2005.

Subjects who do not enter the Extension Study will participate in an 18-week Follow-up 
Period starting from the last of dose of study drug in Study MLN0002-2003 and complete a 
long-term follow-up safety survey by telephone 6 months after their last dose of study drug
in Study MLN0002-2003. Note that the 6-month follow-up safety survey by telephone will 
be analysed separately and is not in scope of this SAP.
7.1.3
Methods for Handling of Missing Efficacy Data
Through the end of the treatment period, the missing efficacy data will be handled as follows:

Missing data for dichotomous (i.e., proportion-based) endpoints will be handled using the 
non-responder imputation method, i.e. any subject with missing information for 
determination of endpoint status will be considered as a non-responder in the analysis. 

Missing data for continuous endpoints will be imputed using last available post-baseline 
observation carried forward (LOCF) method.
Other missing data handling methods may be explored to assess the impact of dropouts for 
different missing mechanisms.
7.1.4
Conventions for Missing Adverse Event Dates
Every effort will be made to determine the actual onset date for the event or to obtain a reliable 
estimate for the onset date from the investigator.
For AEs or SAEs, a missing or incomplete onset date will be imputed according to the following 
conventions:
1. If an onset date is missing, the derived onset date will be calculated as the first non-missing 
valid date from the following list (in order of precedence):

First study medication date.

Consent date (for SAEs only).
2. If an onset date is incomplete, the derived onset date will be calculated following:

Missing day, but month and year present: the day will be imputed as the 15th of the month. 
If the month and year are equal to the month and year of the first study medication dose 
and the first study medication dose occurs after the imputed date, the derived onset date 
will be set equal to the first study medication date. If the AE end date occurs prior to the 
imputed date, the derived onset date will be set equal to the AE end date.

Missing day and month, but year present: the day and month will be imputed as the 30th
June of the year. If the year is equal to the year of the first study medication dose and the 
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first study medication dose occurs after the imputed date, the derived onset date will be 
set equal to the first study medication date. If the AE end date occurs prior to the imputed 
date, the derived onset date will be set equal to the AE end date.

If the imputed AE onset date occurs after the database lock date, the imputed AE onset 
date will be imputed as the database lock date. 
For AEs or SAEs, a missing or incomplete end date will be imputed according to the following 
conventions:
3. If an end date is missing, the derived end date will be imputed as the last assessment date, 
assuming that the last assessment occurs after the AE start. If the last assessment occurs prior 
to the AE start date, the derived end date will be imputed as the AE start date.
4. If an end date is incomplete, the derived end date will be calculated following:

Missing day, but month and year present: the day will be imputed as the last date (for 
example February 2009 will be imputed as 28 February 2009) of the month.

Missing day and month, but year present: the day and month will be imputed as the 31st 
December of the year. 

If the imputed AE end date occurs after the database lock date, the imputed AE end date 
will be imputed as the database lock date. 
7.1.5
Conventions for Missing Concomitant Medication Dates
Start and stop dates for medication history and concomitant medications are collected on the 
eCRF. Definitions of medication history and concomitant medications are defined in Section 7.6. 
In case of missing or partial dates for concomitant medications, or medication history, the 
following rules will be used:
If the start date is partial or unknown:
–
If the day is missing, the start day will be the first day of the month.
–
If the month is missing:

If the year is the same as the year of first dose of study drug, the start month will be 
the month corresponding to 90 days prior to the date of first dose of study drug with 
exception that the month of first dose is Jan, Feb, or Mar. 

If the year is the same as the year of first dose of study drug and the month of first 
dose is Jan, Feb, or Mar, the start month will be Jan.

If the year is not the same as the year of first dose of study drug, the start month will 
be Jan.
–
If the entire date is unknown (e.g. the year is missing)

If CRF indicates that the medication ended prior to the informed consent date, then the 
medication start date will be imputed to the informed consent date minus one day.
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
Otherwise the start date will be minimum of the date of first dose of study drug and 
the medication end date.
If the stop date is partial, unknown or “ongoing”:
–
If the day is missing, the stop day will be the last day of the month reported.
–
If the month is missing: 

If the year is the same as the year of last assessment, then the stop month will be to 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 month will 
be Dec.
–
If the entire date is unknown (e.g. the year is missing) or if the medication is “ongoing”, 
the stop year will be the year in which the last assessment occurred. If information 
collected on the CRF indicate that the medication ended prior to the informed consent 
date, then the medication stop date will be imputed as the informed consent date minus 
one day.
If both start date and end date are imputed and the imputed start date is greater than the imputed 
end date, then the imputed start date will be set to the imputed end date.
No dates will be imputed for previous medications.
7.1.6
Conventions for Calculation of Mayo Score
The Mayo scoring system is a composite index of 4 disease activity variables (see Appendix A 
for details): 
–
Stool frequency.
–
Rectal bleeding.
–
Findings on endoscopy.
–
Physician’s global assessment (PGA).
Each variable is scored individually on an integer scale of 0 to 3, with higher scores indicating 
greater disease activity. The Partial Mayo score is calculated analogously but excludes the 
endoscopy subscore. The Modified Mayo score is calculated analogously but excludes the PGA 
subscore.
Mayo scores will be derived from first principles. All subscores should be rounded to the nearest 
integers. Apply rounding as final subscores are created and prior to calculation of total score. 
The day prior, day of and day after endoscopy cannot be used for patient Diary entry because of 
the required bowel prep for the procedure. The Day of endoscopy must be entered into IVR (not 
applicable at all study visits), and Day of Visit must be confirmed in IVR.
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7.1.6.1
GEMINI Approach
For the purpose of comparing the efficacy results with GEMINI studies, the Complete Mayo 
score, Partial, and Modified Mayo score for each subject will be calculated using the conventions 
of calculating Mayo score in GEMINI studies. The GEMINI approach will serve as the primary 
method to calculate Mayo score and derive all Mayo score-based efficacy endpoints. 
1. Use the date of the visit where PGA was performed to identify analysis visit using the 
analysis visit windowing rules defined in Section 7.1.2.
2. Identify PGA result (subscore).
3. Identify the endoscopy subscore (based on adjudicated data) using the analysis visit windows.
4. Calculate rectal bleeding subscore and stool frequency subscore:
a) Select the Diary data completed by the patient from 7 days prior to the visit date 
identified in (1).
b) Merge in endoscopy dates (including dates of attempted endoscopy) and set diary data 
one day prior, on the day and one day after the endoscopy to missing.
c) For Baseline, if less than 3 days of data remain then a subscore cannot be calculated. 
Otherwise, sum the 3 most recent non-missing results and divide by 3. Patients who have 
less than 3 days of Diary data at Baseline are not eligible for enrollment and the subscore 
will be considered missing.
d) For post-Baseline visits, sum the 3 most recent non-missing results and divide by 3. If 
only 2 non-missing results remain, then sum the 2 most recent non-missing results and 
divide by 2. If less than 2 days of diary data are available, the patient will be categorized 
as a non-responder and the subscore will be considered missing. 
5. Calculate total score:
a) For complete Mayo, sum the PGA subscore, endoscopy subscore, rectal bleeding 
subscore and stool frequency subscore. All 4 subscores must be available.
b) For partial Mayo, sum the PGA subscore, rectal bleeding subscore and stool frequency 
subscore. All 3 subscores must be available.
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Table 7.c provides examples of calculated Mayo scores using various Diary scenarios (Excluding 
Baseline):
Table 7.c
Examples of Diary Subscore Entries and Corresponding Subscore Derivation 
per GEMINI Approach
Example
Diary Daya
Valid Days for 
Calculation of 
Subscore
Average 
Subscore
Final 
Subscore
-7
-6
-5
-4
-3
-2
-1
Diary #1
X
Sb
X
2
3
0
1
-1, -2, -3
1.33
1
Diary #2
3
X
Sb
X
1
Mc
2
-1, -3, -7
2
2
Diary #3
Sb
X
3
Mc
Mc
Mc
0
-1, -5
1.5
2
Diary #4
4
4
X
Sb
X
3
3
-1, -2, -6
3.33
3
Diary #5
2
3
4
4
X
Sb
X
-4, -5, -6
3.67
4
Diary #6
2
Mc
Mc
X
Sb
X
2
-1, -7
2
2
Diary #7
Mc
3
X
Sb
X
Mc
Mc
Missing
N/A
Missing
a Days are named relative to Day 1, which is the Day of the Study Visit; b Endoscopy; c Missing.
7.1.6.2
Draft FDA UC Guidance Approach
The Complete Mayo and Partial Mayo will also be calculated per draft FDA UC Guidance 
(August, 2016). The efficacy endpoints based on Complete, Partial, or Modified Mayo scores at 
Week 6, Week 14, and Week 22 will be derived using this approach as sensitivity analysis. 
1. Use the date of the visit where PGA was performed to identify analysis visit using the 
analysis visit windowing rules.
2. Identify PGA result (subscore).
3. Identify the endoscopy subscore (based on adjudicated data) using the visit windows.
4. Calculate rectal bleeding subscore and stool frequency subscore:
a) Select the Diary data completed by the patient from 7 days prior to the visit date 
identified in (1).
b) Merge in endoscopy dates (including dates of attempted endoscopy) and set diary data 
one day prior, on the day and one day after the endoscopy to missing.
c) For Baseline, if less than 3 days of data remain then a subscore cannot be calculated. 
Otherwise, sum the 3 most recent non-missing results and divide by 3. Patients who have 
less than 3 days of Diary data at Baseline are not eligible for enrollment and the subscore 
will be considered missing.
d) For post-Baseline visits, sum the 3 most recent consecutive non-missing results and 
divide by 3. For patients who do not have 3 consecutive days of non-missing Diary data 
but have at least 4 days of data available in the last 7-day period prior to the visit, the 
non-missing scores from the total number of available days in the last 7-day period will 
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be averaged. If less than 3 consecutive days or 4 days of Diary data in the last 7-day 
period are available, the patient will be categorized as a non-responder and the subscore 
will be considered missing. 
5. Calculate total score:
a) For complete Mayo, sum the PGA subscore, endoscopy subscore, rectal bleeding 
subscore and stool frequency subscore. All 4 subscores must be available.
b) For partial Mayo, sum the PGA subscore, rectal bleeding subscore and stool frequency 
subscore. All 3 subscores must be available.
Table 7.d provides examples of calculated Mayo scores using various Diary scenarios 
(Excluding Baseline) per draft FDA UC guidance:
Table 7.d
Examples of Diary Subscore Entries and Corresponding Subscore Derivation 
per draft FDA UC guidance 
Example
Diary Daya
Valid Days for 
Calculation of 
Subscore
Average 
Subscore
Final 
Subscore
-7
-6
-5
-4
-3
-2
-1
Diary #1
X
Sb
X
2
3
0
1
-1, -2, -3
1.33
1
Diary #2
3
X
Sb
X
1
Mc
2
Missing
N/A
Missing
Diary #3
Sb
X
3
Mc
Mc
Mc
0
Missing
N/A
Missing
Diary #4
4
4
X
Sb
X
3
3
-1, -2, -6, -7
3.5
4
Diary #5
2
3
4
4
X
Sb
X
-4, -5, -6, -7
3.25
3
Diary #6
2
Mc
Mc
X
Sb
X
2
Missing
N/A
Missing
Diary #7
Mc
3
X
Sb
X
Mc
Mc
Missing
N/A
Missing
a Days are named relative to Day 1, which is the Day of the Study Visit; b Endoscopy; c Missing.
7.1.7
Conventions for Calculation of CDAI Scores
The CDAI score is the summation of 8 components, including number of liquid or very soft 
stools, abdominal pain, general well-being, extra-intestinal manifestations of Crohn’s Disease, 
Lomotil/Imodium/opiates for diarrhea usage, abdominal mass, hematocrit level, and body weight 
(see Appendix B for details). Minor modifications to allow for weights below those of adults are 
made to the CDAI to facilitate its use in children, e.g., replacing “standard weight” by “ideal 
weight for height” (Griffiths et al, 2005).
7.1.7.1
GEMINI Approach
Number of liquid or very soft stools, abdominal pain, and general well-being are self-reported 
via subject electronic diary entries. To calculate subscores at each visit, the diary data from the 
10 days prior to the date of CDAI calculation were used and the following rules were applied:
1. Identify the date of the Clinician CDAI completion date from the Diary system.
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2. Calculate the 3 Diary subscores (liquid/soft stool frequency, abdominal pain and general 
wellbeing) as follows. 
a.
Select the diary data from 10 days prior to the CDAI completion date identified in (1).
b. Merge in endoscopy video dates (including dates of attempted endoscopy video) and set 
diary data one day prior, on the day and one day after the endoscopy to missing.
c.
For number of liquid or very soft stools only, if any of the 7 most recent days of diary 
data have stool frequency values greater than 24, set the value for the stool record for that 
day to missing.
d. Calculate the 3 Diary components:
i.
If less than 4 days of diary data is non-missing, then a subscore cannot be calculated.
ii.
If 4, 5 or 6 days of diary is non-missing, the subscore is calculated as {average of 
non-missing diary from available days ×7} rounding to the nearest integer.
iii.
If 7 or more days of diary is non-missing, the subscore is calculated as sum of the 
most recent 7 days of non-missing diary.
Table 7.e provides examples of calculated CDAI scores using various Diary 
scenarios. Any on-study colonoscopies and/or MREn are taken into account such that 
the diary data from the day prior, day of, and day after are excluded from the visit’s 
CDAI calculation.
e.
The subscore is calculated by multiplying the factor appropriate for the item.

For stool, the factor is 2.

For abdominal pain, the factor is 5.

For general well-being, the factor is 7.
3. Extra-intestinal manifestations of Crohn’s Disease Subscore: total number of checked items 
from Diary data, and multiply by a factor of 20.
4. Lomotil/Imodium/opiates for diarrhea Subscore: Subscore is 1 if “Yes” is selected; subscore 
is 0 if “No” is selected. Multiply by a factor of 30.
5. Abdominal Mass Subscore: subscore is 0 if “None” is selected, subscore is 2 if 
“Questionable” is selected, and subscore is 5 if “Definite” is selected. Multiply by a factor of 
10.
6. Calculate Hematocrit Subscore as follows:
a.
For the Baseline Visit, identify the most recent non-missing Hematocrit (%) results with 
the sample collection date prior to the CDAI completion date in (1)
b. For post-Baseline visits, identify the Hematocrit (%) results using the visit windows 
defined in Section 7.1.2.
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c.
For male subjects, the subscore is calculated as the maximum of {47- Hematocrit (%), 0} 
rounding to the nearest integer. For female subjects, the subscore is calculated as the 
maximum of {42- Hematocrit (%), 0} rounding to the nearest integer. 
d. The haematocrit subtotal is then multiplied by a factor of 6 to determine the haematocrit 
subscore. If the haematocrit subtotal is 0, the haematocrit subscore is set to 0. 
7. Body Weight Subscore
a.
Identify the weight in kilogram (kg) using the visit windows defined in Section 7.1.2.
b. Identify the standard weight using subject’s gender, age and height according to
Appendix B. Minor modifications are made to the CDAI by replacing “Standard Weight” 
by “Ideal Weight for Height”. See Appendix B for details.
c.
Calculate the subscore using the formula below, rounding to the nearest integer. If the 
body weight subscore is < -10, the body weight subscore is set to -10. 
1 −
Body Weight
Ideal Weight for Height × 100
8. Calculate total CDAI score for a study visit as the sum of the 8 subscores at that particular 
study visit. If any of the 8 subscores is missing, the total CDAI score cannot be calculated 
and the total CDAI score for that study visit will be set to missing. 
Table 7.e
Examples of Diary Subscore Entries and Corresponding Subscore (Stool) 
Derivation
Day -
14
Day -
13
Day -
12
Day -
11
Day -
10
Day -9
Day -
8
Day -7
Day -6 Day -5
Day -4
Day -3
Day -2 Day -1
Raw 
Sum
Final Subtotal 
(factor = x 2)
1
2
M
2
2
2
2
1
1
1
1
1
1
1
7
14
1
X
MRE
X
3
X
C
X
1
1
1
1
1
1
9
18
1
2
M
2
M
3
M
3
M
3
M
3
3
3
21
42
1
2
M
2
M
2
M
M
M
1
3
2
2
M
14
28
1
M
M
2
3
X
MRE
X
X
C
X
3
3
3
21
42
1
M
X
MRE
X
C
X
M
2
M
M
M
2
0
N/A
Missing
M = Missing data. C = Colonoscopy. N/A = Not Available. Used days are highlighted.
7.1.8
Conventions for Calculation of SES-CD
The SES-CD has been shown to be comparable to the Crohn’s Disease Endoscopic Index of 
Severity and a straightforward scoring system for Crohn’s disease (see Appendix C for details). 
The overall SES-CD score ranges from 0 to 56 and is the sum of 4 variables (i.e., size of ulcers 
[cm], ulcerated surface [%], affected surface [%], and presence of narrowing) across 5 bowel 
segments (i.e., rectum, descending and sigmoid colon, transverse colon, ascending colon, and 
ileum). Each variable is coded from 0 to 3 based on severity, where 0 is none or not severe and 3 
is the most severe case, with the sum of the scores for each variable ranging from 0 to 15, except 
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for presence of narrowing. Presence of narrowing ranges from 0 to 11 since a severity of 3 
represents a narrowing which a colonoscope cannot be passed and, thus, can only be observed 
once among the bowel segments. The segmental SES-CD score is the sum of the 4 variables for 
each bowel segment and can range from 0 to 12, where each individual variable score ranges 
from 0 to 3.
7.1.9
Conventions for Calculation of PUCAI
The PUCAI is composed of 6 clinical items (see Appendix E for details) for a daily average of 
last two days (Turner, 2007). 
To calculate the PUCAI total score for a study visit, sum the 6 subscores at that particular study 
visit. If any of the 6 subscores is missing, the PUCAI total score cannot be calculated and the 
PUCAI total score for that study visit will be set to missing. 
The PUCAI score ranges from 0 to 85; a score of <10 denotes remission, 10 to 34 mild disease, 
35 to 64 moderate disease, and 65 to 85 severe disease. A clinically significant response is 
defined as a PUCAI change of ≥20.
7.1.10 Conventions for Calculation of PCDAI
The PCDAI was specifically designed for use in children based upon a one-week (7 day) history 
recall of symptoms. The PCDAI includes a child-specific item: the height velocity variable as 
well as 3 laboratory parameters: hematocrit (adjusted for age and sex), ESR, and albumin level 
(see Appendix E for details).
The limitation of activity should be based on the most significant limitation during the past week, 
even if it is only for 1 day. However, if the activity limitation is due to another illness (eg, upper 
respiratory infection), the illness period should be excluded from the patient’s PCDAI score.
To calculate the PCDAI total score for a study visit, sum of the 11 subscores at that particular 
study visit. If any of the 11 subscores is missing, the PCDAI total score cannot be calculated and 
the PCDAI total score for that study visit will be set to missing. 
The PCDAI score can range from 0-100, with higher scores signifying more active disease. A 
score of ≤10 is consistent with inactive disease, 11 to 30 indicates mild disease, and >30 is 
moderate-to-severe disease. 
7.2
Analysis Sets
7.2.1
Full Analysis Set (FAS)
The full analysis set (FAS) will include all randomized subjects who receive at least 1 dose of 
study drug. Subjects in this set will be analyzed according to treatment they were randomized to 
receive. This population will be used for efficacy analysis.

The treatment groups for efficacy data collected on or prior to Week 14 will be presented 
for each weight group as follows:
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< 30 kg
≥ 30 kg
100mg
200mg
150mg
300mg

The treatment groups for efficacy data collected after Week 14 will be presented for each 
weight group as follows:
< 30 kg
≥ 30 kg
100mg only
200mg only
100mg200mg
150mg only
300mg only
150mg300mg
7.2.2
Safety Analysis Set
The safety analysis set will include all subjects who receive at least 1 dose of study drug. 
Subjects in this set will be analyzed according to the treatment regimen they actually received,
i.e. according to the following 6 mutually exclusive subject groups. This population will be used 
for safety analysis.
For subjects who remain on their original treatment throughout the study:

100mg only.

200mg only.

150mg only.

300mg only.
and for subjects who escalate from low to high dose at Week 14:

100 200mg.

150 300mg.
The treatment groups for safety data will be presented for each weight group as follows when 
applicable:
< 30 kg
≥ 30 kg
100mg only
200mg only
100mg200mg
Total
150mg only
300mg only
150mg300mg
Total
7.2.3
PK Analysis Set
The PK analysis set is defined as all subjects who receive at least 1 dose of study drug and have 
at least 1 measurable concentration of vedolizumab. Subjects in this set will be analyzed 
according to the treatment regimen they received. This population will be used for PK analysis.

The treatment groups for PK data collected on or prior to Week 14 will be presented as
follows:
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< 30 kg
≥ 30 kg
100mg
200mg
150mg
300mg

The treatment groups for PK data collected after Week 14 will be presented as follows:
< 30 kg
≥ 30 kg
100mg only
200mg only
100mg200mg
150mg only
300mg only
150mg300mg
7.2.4
Randomized Set
The Randomized set will include all subjects who are randomized into the study regardless 
whether they receive any dose of study drug or not. Subjects will be analyzed according to their 
randomized treatment group. 
7.3
Disposition of Subjects
The following summaries of subject disposition will be produced by indication and randomized 
treatment group for each weight group, as appropriate. The data may be pooled across weight 
groups, treatment groups, and/or indications for additional analysis.

Study Information
This summary will include details of the date that the first subject signed the informed 
consent form, the date of the last subject’s last visit/contact, the date of the last subject’s last 
procedure for collection of data for the primary endpoint and the Medical Dictionary for 
Regulatory Activities (MedDRA), World Health Organization Drug Dictionary (WHODrug) 
and SAS® Versions used for reporting.

Summary of Screen Failures
This summary will include the total number of screen failures, descriptive statistics for age, 
counts and percentages for gender, ethnicity, race and the primary reason for screen failure. 

Number of Subjects Randomized by Site and Treatment Group
This summary will be performed by the randomization stratification factors: previous 
exposure/failure of TNF-α antagonist therapy or naïve to TNF-α antagonist therapy, 
indication (UC, CD) and weight group (≥30 kg, <30 kg), as well as by geographic region, 
country and site.

Disposition of Subjects
This summary will be performed on the Randomized Set and will summarize subjects 
randomized but not treated, subjects completing or prematurely discontinuing study drug 
along with the primary reason for study drug discontinuation, subjects completing or not 
completing all study visits along with the primary reason for discontinuation of study visits, 
and subjects enrolling into the Extension Study 2005. This table will be presented by
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indication and randomized treatment group for each weight group separately. The data may 
be pooled across weight groups, treatment groups, and/or indications for additional analysis.

Significant Protocol Deviations
This summary will be performed on the Randomized Set and will summarize the significant 
protocol deviations captured on the electronic case report form by indication and randomized 
treatment group and overall for each weight group separately.

Analysis Sets
The analysis sets defined in Section 7.2 will be summarized, including randomized but not 
treated if necessary.
All subject disposition information will be listed.
7.4
Demographic and Other Baseline Characteristics
The Randomized Set will be used for all summaries in this section. Additional summaries may 
be performed on other analysis sets if required.
Demographic and baseline characteristics will be summarized by indication, and treatment group 
and overall for each weight group. The summary will include descriptive statistics for age, age 
category (children vs adolescent), height, weight and body mass index and counts and 
percentages for gender, ethnicity, race, substance use and geographical region. 
Baseline disease characteristics will be summarized for each indication separately by weight 
group, treatment group and overall. The summaries will include descriptive statistics for disease 
duration, baseline disease activity (based on complete Mayo, partial Mayo and PUCAI for UC 
and CDAI, PCDAI and SES-CD for CD), baseline number of liquid or very soft stools subscore 
and abdominal pain subscore from CDAI for CD, baseline fecal calprotectin and baseline C-
reactive protein. Counts and percentages will also be presented for baseline stool frequency 
subscore, rectal bleeding subscore, endoscopic subscore and physician’s global assessment 
subscore from Mayo for UC (0, 1, 2, 3 for all subscores) and anti-TNF history (naïve, 
exposed/failed).
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Table 7.f
Baseline Disease Characteristics 
Indication
Baseline Characteristics
Summarized as
Categories
UC and CD
Disease duration
Continuous and 
Categorical
< 1 year
≥ 1 to < 3 years
≥ 3 to < 7 years
≥ 7 years
Baseline fecal calprotectin (µg/g)
Continuous and 
Categorical
≤ 250 µg/g
> 250 µg/g and ≤ 500 µg/g
> 500 µg/g
Baseline CRP (mg/L)
Continuous and 
Categorical
≤ 1 mg/L
> 1 mg/L and ≤ 3 mg/L
> 3 mg/L and ≤ 10 mg/L
> 10 mg/L
Prior TNF History
Categorical
Naïve, Exposure/Failure
UC only
Baseline Mayo score
Continuous
Baseline disease activity based on complete 
Mayo
Categorical
Mild (<6), Moderate (6 to 
8), Severe (9 to 12)
Baseline partial Mayo score
Continuous
Baseline disease activity based on partial Mayo
Categorical
Mild (2-4), Moderate (5-6), 
Severe (7-9)
Baseline PUCAI
Continuous 
Baseline disease activity based on PUCAI
Categorical
Mild (10-34), Moderate 
(35-64), Severe (65-85) 
Baseline stool frequency subscore from Mayo
Categorical
0, 1, 2, 3
Baseline rectal bleeding subscore from Mayo
Categorical
0, 1, 2, 3
Baseline endoscopic subscore from Mayo
Categorical
0, 1, 2, 3
Baseline physician’s global assessment subscore 
from Mayo
Categorical
0, 1, 2, 3
CD only
Baseline CDAI score
Continuous
Baseline disease activity based on CDAI
Categorical
>330, ≤330
Baseline PCDAI
Continuous
Baseline disease activity based on PCDAI
Categorical
Mild (11-30), Moderate to 
Severe (>30)
Baseline SES-CD
Continuous
Baseline disease activity based on SES-CD
Categorical
Moderate (7-15), Severe 
(>15)
Baseline number of liquid or very soft stools 
subscore from CDAI
Continuous
Baseline abdominal pain subscore from CDAI
Continuous
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All demographic, baseline characteristics and baseline disease characteristics will be listed.
7.5
Medical History and Concurrent Medical Conditions
The safety analysis set will be used for all summaries in this section.
Medical history is defined as any significant conditions or diseases relevant to the disease under 
study that stopped at or prior to signing of informed consent. Medical history will be coded using 
MedDRA and will be summarized by system organ class and preferred term, by treatment group 
and overall.
Concurrent medical conditions are defined as any significant conditions or diseases relevant to 
the disease under study that were ongoing at signing of informed consent. Concurrent medical 
conditions will be coded using MedDRA and will be summarized by system organ class and 
preferred term, by treatment group and overall. 
Medical history and concurrent medical conditions will be presented in data listings.
7.6
Medication History and Concomitant Medications
The safety analysis set will be used for all summaries in this section.
Medication history is defined as any medication relevant to eligibility criteria stopped at or 
within 1 month prior to signing of informed consent. Medication history will be coded using 
WHODrug and will be summarized by preferred medication name, by treatment group and 
overall.
Prior biologic history for the treatment of UC or CD is defined as prior biologic medications 
stopped at or prior to signing of informed consent. Prior biologic history will be coded using 
WHODrug and will be summarized for each indication separately by preferred medication name, 
by treatment group and overall.
Concomitant medications are defined as any drugs used in addition to the study medication from 
signing of informed consent through the end of the study. Concomitant medications will be 
coded using WHODrug and categorized as follows:

Concomitant medications that started and stopped prior to baseline.

Concomitant medications that started prior to and were ongoing at baseline.

Concomitant medications that started after baseline.

Concomitant medications that were ongoing at baseline and those that started after baseline.
Each category of concomitant medications will be summarized by preferred medication name, by 
treatment group and overall.
Medication history, prior biologic history and concomitant medications will be listed.
7.7
Study Drug Exposure and Compliance
The safety analysis set will be used for all summaries in this section.
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Completed infusions are defined as infusions where the total amount of study drug is infused. 
The number of completed infusions will be summarized by treatment group and overall. 
The extent of exposure will be calculated by the duration between the first and last dose of study 
drug plus 18 weeks in order to account for the known duration of detectable vedolizumab serum 
concentration after the last dose, i.e.
Date of last dose of Vedolizumab – Date of first dose of Vedolizumab + 1 + 126 days.
Extent of exposure will be summarized using descriptive statistics by treatment group and 
overall. 
Compliance will be calculated as the percentage of completed infusions out of the total number 
of planned infusions, and as the percentage of completed and partial infusions out of the total 
number of planned infusions, respectively. 
Study drug administration data will be presented in data listings.
7.8
Efficacy Analysis
The efficacy analysis will be based on the FAS. 
The following definitions apply to efficacy endpoints:
Term
Definition
UC Subjects:
Complete Mayo Score
The Complete Mayo score is a composite index of 4 disease activity variables 
(stool frequency, rectal bleeding, endoscopy, and physician’s global 
assessment, which ranges from 0-12.
Partial Mayo Score
The Partial Mayo score is a composite index of 3 disease activity variables 
(stool frequency, rectal bleeding, and physician’s global assessment), which 
ranges from 0-9.
Modified Mayo score
The Modified Mayo comprises 3 disease activity variables from the complete 
Mayo assessment (stool frequency, rectal bleeding, and endoscopy), which 
ranges from 0-9.
Clinical response based on complete 
Mayo score or partial Mayo score
A reduction in complete Mayo score of ≥3 points and ≥30% from Baseline (or 
a partial Mayo score of ≥2 points and ≥25% from Baseline, if the complete 
Mayo score was not performed at the visit) with an accompanying decrease in 
rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 
point.
Clinical response based on modified 
Mayo score
Defined as a reduction in total score of ≥2 points and ≥25% from Baseline 
with an accompanying decrease in rectal bleeding subscore of ≥1 point or 
absolute rectal bleeding subscore of ≤1 point.
Clinical remission based on complete 
Mayo score
A complete Mayo score of ≤2 points with no individual subscore >1.
Clinical remission based upon 
modified Mayo
Defined as Stool Frequency subscore=0 or 1 and a decrease of 1 or more from 
Baseline; Rectal Bleeding subscore=0; and Endoscopy subscore=0 or 1 
(modified so that a score of 1 does not include friability)
Clinical response based on PUCAI 
A ≥20-point decrease from Baseline in PUCAI score.
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Term
Definition
Clinical remission based on PUCAI
PUCAI score <10.
Disease Worsening by PUCAI
An increase in the PUCAI of >20 points at 2 consecutive visits at least 7 days 
apart, or the PUCAI was >35 points at any scheduled or unscheduled visit.
CD Subjects:
Clinical response based on CDAI
A ≥70-point decrease from Baseline in CDAI score.
Clinical remission based on CDAI
CDAI score ≤150.
Clinical response based on PCDAI
A ≥15-point decrease from Baseline in PCDAI score with total PCDAI ≤30.
Clinical response based on SES-CD
and CDAI 
A ≥50% reduction in SES-CD score from Baseline endoscopy (or meets 
criteria for clinical remission based on SES-CD score 0 to 2) with 
accompanying decrease in average daily abdominal pain score (CDAI 
component) by >0.25.
Clinical remission based on PCDAI
PCDAI score ≤10.
Clinical remission based on SES-CD
and CDAI 
A daily abdominal pain score of ≤1 for the 7 days prior to the visit. A total 
number of liquid/very soft stools of ≤10 for the 7 days prior to the visit. SES-
CD ≤4 and at least a 2-point reduction versus Baseline and no subscore >1 in 
any individual variable.
Enhanced clinical response based on 
CDAI
A ≥100-point decrease from Baseline in CDAI score.
Disease Worsening by PCDAI
An increase in the PCDAI of >15 points at 2 consecutive visits at least 7 days 
apart, or the PCDAI was >30 points at any scheduled or unscheduled visit.
For all subjects with missing Mayo, CDAI, PUCAI, or PCDAI data for determination of 
endpoint at any time point, to ensure all subjects in the FAS are included in the analysis, a 
subject with any component of a scale missing will be considered as a non-responder/non-
remitter for that particular endpoint, scale, and time point.
All proportion-based efficacy endpoints will be summarized for each indication separately by 
weight group and treatment group on the FAS. Both 95% Jeffrey interval and exact 95% CI (e.g., 
Clopper-Pearson interval) will be presented. 
All efficacy data will be listed for each indication separately, sorted by weight group, treatment 
group and subject ID.
7.8.1
Secondary Efficacy Endpoints
The secondary efficacy endpoints are clinical response at Week 14 based on complete Mayo for 
UC subjects or CDAI for CD subjects. These binary variables will be summarized by presenting 
the count and percentage of subjects meeting the endpoint at Week 14 along with the 95% CI for 
the proportion using the FAS for each indication separately. All subjects with missing data for 
determination of response will be considered as non-responders in the primary analyses. 
7.8.1.1
Sensitivity Analysis
For UC, sensitivity analysis will be performed for secondary efficacy endpoints using the 
conventions of calculating Mayo score per draft FDA UC guidance described in Section 7.1.6.2. 
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Additional sensitivity analyses may be conducted to ensure the robustness of the final analysis. 
Methods to deal with missing data may include, but not limited to, observed data only and last 
observation carried forward.
7.8.2.1
Sensitivity Analysis
For UC, sensitivity analysis will be performed for Complete, Partial, or Modified Mayo score-
derived endpoints using the conventions of calculating Mayo score per draft FDA UC guidance 
described in Section 7.1.6.2. 
The relationship between CDAI and PCDAI and that between Mayo and PUCAI may be 
explored, respectively.
7.8.2
7.8
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7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
The PK analysis set will be used for all PK analyses. Treatment groups will be presented as 
defined in Section 7.2. Missing PK data will not be imputed. More details on the PK analysis
will be described in a separate document, i.e., CPAP. 
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Measured serum concentrations of vedolizumab will be summarized by weight group, treatment 
group and visit/time for each indication separately using descriptive statistics. 
The PK parameters AUCWk 14, Cav,Wk 14 and Ctrough,Wk 14 (primary endpoint) and Ctrough,Wk 22 
(additional endpoint) will be summarized by weight group and treatment group for each 
indication separately using descriptive statistics (e.g., non-missing values, mean, SD, geometric 
mean, geometric mean %CV, median, minimum and maximum) as appropriate. 
Serum concentration data and PK parameters will also be listed.
Additional analysis may be performed by combining the PK data across the indications.
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
7.10.2 Health-Related Quality-of-Life
The change from Baseline in IMPACT-III total and subscale scores (additional endpoint) at 
Week 22 will be summarized as observed and as imputed by LOCF method using descriptive 
statistics by weight group and treatment group for each indication separately on the FAS.
7.10.3 Immunogenicity
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7.11
Safety Analysis
The safety analysis set will be used for all summaries in this section. Treatment groups will be 
presented as defined in section 7.2. In addition to the analyses described, subgroup analyses will 
be performed by indication (UC, CD), and anti-TNF history (naïve, exposed/failed) for selected 
AE tables. No statistical inference will be made.
7.11.1 Adverse Events
A treatment-emergent adverse event (TEAE) is defined as an AE whose date of onset occurs on 
or after the first dose of study drug through Week 22 for subjects entering the extension study or 
the Final Safety Visit 18 weeks after their last dose of study drug for those who do not enter the 
extension study.
A Pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
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administration of any study drug; it does not necessarily have to have a causal relationship with 
study participation.
An overview of TEAEs will be provided by treatment group and overall, summarizing the 
number of events and the number and percentage of subjects with the following:

TEAEs and serious TEAEs.

TEAEs and serious TEAEs by relationship to study drug.

TEAEs by severity.

TEAEs and serious TEAEs leading to study drug discontinuation.

Deaths.
The number and percentage of subjects with the following categories of TEAEs will be 
summarized by MedDRA system organ class, high level term and preferred term, by treatment 
group and overall:

TEAEs.

Drug-related TEAEs.

TEAEs leading to study drug discontinuation.

Serious TEAEs.

Drug-related serious TEAEs

Pretreatment events (PTEs).

AESI (malignancies, infections, infusion related reactions, hypersensitivity reactions, liver 
injury, PML).
The details of AESIs are described in Appendix F.
The number and percentage of subjects with the most frequent TEAEs occurring in at least 5% of 
subjects in any treatment group will be summarized by preferred term, by treatment group and 
overall.
The number and percentage of subjects with the most frequent non-serious TEAEs occurring in 
at least 5% of subjects in any treatment group will be summarized by system organ class and 
preferred term, by treatment group and overall.
The number and percentage of subjects with the following categories of TEAEs will be 
summarized by MedDRA system organ class, high level term and preferred term, by severity, 
treatment group and overall:

TEAEs.

Drug-related TEAEs.
The following AE data will be summarized by indication and by anti-TNF history respectivrly:
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
Overview of TEAEs.

TEAEs.

Related TEAEs.

SAEs.
The following AE data will be listed:

AEs.

AESI

AEs leading to study discontinuation.

Serious TEAEs.

AEs resulting in death.

PTEs.
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory evaluations will be analyzed from the first dose of study drug throughout the 
study (i.e. Week 22 for subjects who enrolled into the extension study 2005, or 18-week safety 
follow-up period for subjects who did not enroll into the extension study 2005).
Laboratory test results will be summarized by visit, including the change from baseline, by 
treatment group.
The number and percentage of subjects in categories of urine laboratory parameters will be 
summarized by visit and treatment group.
Shifts of laboratory test results (low, normal, high) from baseline will be summarized by visit 
and treatment group.
The number and percentage of subjects with markedly abnormal laboratory values (see Appendix 
G for details) will be summarized by visit and treatment group. 
The number and percentage of subjects with elevated liver enzyme laboratory parameters 
(including ALT, AST, alkaline phosphatase and bilirubin) will be summarized by treatment 
group.
All laboratory results will be presented in data listings.
7.11.3 Vital Signs
Vital signs including weight and height will be summarized by visit, including the change from 
baseline, by treatment group. 
The number and percentage of subjects with markedly abnormal values of vital signs (see 
Appendix H for details) will be summarized by visit and treatment group. 
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All vital signs data will also be listed.
7.11.4 Other Observations Related to Safety
PML checklist findings will be presented in data listings.
7.12
Interim Analysis
Several interim analyses will be conducted to support future pediatric studies. These will occur 
1) when 20 subjects in the ≥30 kg weight group have completed week 22 or withdrawn 
from the study, and 
2) when all subjects per indication and weight group (ie, UC ≥30 kg, CD ≥30 kg, UC 10 kg 
to <30 kg, CD 10 kg to <30 kg) have completed the study. 
Depending on the timing of data availability, the first analysis may be performed together with 
the later analysis/analyses. A separate clinical study report may be written for ≥30 kg weight 
group if all the patients in this weight group finish their study before those in <30 kg.
The interim analyses will be performed by a separate set of unblinded statisticians and 
programmers at the contract research organization (CRO) who are not involved in daily activities 
of the study. To maintain the blind of MLN0002-2003 throughout Week 32 of the extension 
study Vedolizumab-2005 and ensure the unbiased study conduct, results of the interim analyses 
will not be shared with any personnel directly involved in the conduct of the study. They will 
remain blinded to the treatment assignments of individual subjects and the results of the interim 
analyses until unblinding of study Vedolizumab-2005. Details of handling of unblinding data 
will be provided in a separate data access management plan document.
The statistical methodologies to be used in the interim analyses are as described in this SAP, 
with the exception that only data/cohort(s) through the time of the interim data cut will be 
included. 
7.13
Changes in the Statistical Analysis Plan 
The analyses described in the SAP do not differ from those specified in the protocol.
7.13.1 Revision History
Version 
Date 
Description of Revision
1.0
28Sept2015
N/A
2.0 
31May2016

Added analysis of fecal calprotectin endpoint.

For <12 years, dose-response analyses may also be presented by baseline 
weight.
3.0 
07Oct2016

Updated using the latest SAP template.

Updated in line with Protocol Amendment 1, 07 Oct 2016. 

Age subgroup analyses replaced with weight subgroup analyses.

Analyses by anti-TNF history (naive, failed) updated to anti-TNF history 
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Version 
Date 
Description of Revision
(naive, exposed/failed).
!
Added sensitivity analyses of secondary efficacy endpoints.
!
IMPACT III analyses added.
4.0
1May2019
!
Updated in line with Protocol Amendment 3, 17 Jan 2018.
!
Removed HBI endpoint, Peripheral blood lymphocyte binding endpoint, ECG 
endpoint, and PD analysis set.
!
Added analysis visit windowing rules for safety and efficacy data analysis in 
Section 7.1.2.
!
Added methods for missing data handling for efficacy data in Section 7.1.3.
!
Added conventions for handling missing or incomplete dates for AE and 
concomitant medications in Sections 7.1.4 and 7.1.5.
!
Added the definition for Randomized Set in Section 7.2.
!
Added conventions to calculate SES-CD, CDAI, Mayo score, PUCAI, 
PCDAI in Section 7.1 and Appendices A to E.
!
Added compliance calculation text in Section 7.7
!
Clarified the definition of efficacy endpoints in Section 7.8.
!
Added the exact 95% CI (e.g. Clopper-Pearson method) to the analysis of
proportion-based efficacy endpoints in Section 7.8.
!
Added additional analysis to certain subgroups of subjects of interest in 
Section 7.8.2.
!
Refined the PK analysis and concentration-response analysis in Sections 7.9 
and 7.10.
!
Added details of AESIs in Appendix F.
!
Added criteria to identify markedly abnormal values for laboratory data and
vital sign data in Appendices G and H.
!
Described how treatment groups will be presented for PK, efficacy, and 
safety data.
!
 
!
Clarified the subgroup safety analysis will be performed for selected AE 
tables in Section 7.11.1.
!
Removed serious PTE from safety analysis in Section 7.11.1.
!
Removed the AE data listing of AEs occurring more than 30 days post 
treatment in Section 7.11.1
!
Removed physical examination data listing from Section 7.11.4, because 
physical examination data will be reported as part of MH and/or AE.
Simplified PML data presentation in Section 7.11.4.
!
Added details for the interim analyses in Section 7.12. 
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8.0
REFERENCES
1. Draft FDA Ulcerative Colitis Guidance. US Dept of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER). August 2016. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidanc
es/UCM515143.pdf.
2. Guidance for Industry: General Clinical Pharmacology Considerations for Pediatric Studies 
for Drugs and Biological Products. US Dept of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER). December 2014.
3. Turner D, Otley AR, Mack D, et al. Development and evaluation of a Pediatric Ulcerative 
Colitis Activity Index (PUCAI): a prospective multicenter study. Gastroenterology. 2007; 
133: 423.
4. Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive 
sample size when designing pediatric pharmacokinetic studies. J Clin Pharmacol 
2012;52(10):1601-6.
5. Griffiths, A., et al. A Review of Activity Indices and End Points for Clinical Trials in 
Children with Crohn’s Disease. Inflamm Bowel Dis 2005;11:185–196.
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Statistical Analysis Plan Final 4.0
1 May 2019
Appendix A
Mayo Score Calculation Worksheet
Complete and Partial Mayo Scoring “Points to Remember”
The Mayo Score is widely used in clinical trials to assess Ulcerative Colitis disease activity. It is a combination of
two patient-reported and two physician-determined components. The Partial Mayo Score includes only the Stool 
Frequency, Rectal Bleeding, and PGA subscores. (Does not include endoscopy) 
Sub Scores
Stool Frequency
(Patient)
0 = Normal number of stools for this 
patient
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than 
normal
Stool frequency WILL:
Be derived from patient reported diary data in IVRS and 
will be the average of 3 days prior to visit

Be variable from patient to patient. Instruct patients to set the 
baseline of “normal” to whatever is “normal” for them. (eg, A 
patient normally has 1 stool per day and today has had 4 
stools. Therefore the patient has had 3 more than “normal”, 
which yields a value of 2 for that day)

Be defined as the passage of solid or liquid fecal material. 
Episodes of incontinence count. A non-productive trip to the 
bathroom or the simple passage of gas DO NOT COUNT as a 
stool.
Rectal Bleeding
(Patient)
0 = No blood seen 
1 = Streaks of blood with stool less 
than half the time 
2 = Obvious blood with stool most of 
the time 
3 = Blood alone passes
Rectal bleeding WILL:

Be derived from patient reported diary data in IVRS and will 
be the average of 3 days prior to visit

Represent the most severe bleeding of the day. Hemorrhoidal 
bleeding DOES NOT COUNT.
Findings on Endoscopy
(Physician)
0 = Normal or inactive disease 
1 = Mild disease (erythema, 
decreased vascular pattern, 
mild friability)
2 = Moderate disease (marked 
erythema, lack of vascular 
pattern, friability, erosions)
3 = Severe disease (spontaneous 
bleeding, ulceration)
Findings on Endoscopy WILL:

Be documented by photographic evidence

Be classified by the worst affected segment if mucosal 
appearance varies

Be characterized as follows
Moderate: Bleeds to touch (forceps applied to colonic 
mucosa for 1 second)
Severe: Bleeds spontaneously 

Endoscopy should be performed by the same endoscopist for 
any given patient
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Statistical Analysis Plan Final 4.0
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Physician’s Global Assessment
(Physician)
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Physician’s Global Assessment WILL:

Be based on the patient’s overall status on the day of visit

Reflect how the patient is doing at present. Assessment 
SHOULD NOT reflect past disease severity or complexity or 
the number/kinds of medications the patient is receiving.

Be based on the
Other 3 components of the Mayo score
Patient’s recollection of abdominal discomfort and general 
sense of well-being
Patient’s performance status, fecal incontinence, and mood
Physician's observations and physical exam findings

Reflect disease activity, NOT disease severity (eg. Do not 
automatically give a high PGA to patients with pancolitis or 
severe/complicated disease, or patients requiring multiple 
medications.)

Subscores representing the average of 3 days of patient diary data can be obtained from the IVRS subscore 
report. If calculated manually, subscores should be rounded to the nearest integer.

The Mayo score is equal to the sum of the subscores.
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MLN0002-2003
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Statistical Analysis Plan Final 4.0
1 May 2019
Appendix B
Crohn's Disease Activity Index (CDAI)
Category
Count
Initial
Total
Multiplication
Factor
Total
Number of liquid or very 
soft stools
7-day total number of liquid or very soft stools 
(reported on the 7 days immediately prior to the 
study visit)
×2
Abdominal pain
7-day total of daily abdominal pain scores on a 3-
point scale: 
  0=none, 
  1=mild, 
  2=moderate, 
  3=severe (reported on the 7 days immediately prior 
to the study visit)
×5
General well-being
7-day total of daily general well-being scores on a 4-
point scale: 
  0=generally well, 
  1=slightly under par, 
  2=poor, 
  3=very poor, 
  4=terrible (reported on the 7 days immediately prior 
to the study visit)
×7
Extra-intestinal 
manifestations of CD
Total number of checked boxes (check all that 
apply):
□ Arthritis/arthralgia
□ Iritis/uveitis
□ Erythema nodosum/pyoderma
gangrenosum/aphthous stomatitis
□ Anal fissure, fistula, or abscess
□ Other fistula
□ Fever over 37.8°C during past week
×20
Lomotil/Imodium/ 
opiates for diarrhea
Yes=1
No=0
×30
Abdominal mass
None=0
Questionable=2
Definite=5
×10
Hematocrit (%)(a)
Males: subtract value from 47
Females: subtract value from 42
×6
Body weight (b)
(1 – (body weight/
ideal weight for height))×100
×1
Final score
Add totals:
Source: Adapted from: Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s disease activity 
index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70 (3):439-44. 
(a) If hematocrit subtotal <0, enter 0.
(b) If body weight subtotal <-10, enter -10.
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Statistical Analysis Plan Final 4.0
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To facilitate the use of CDAI in children, “Standard Weight” is replaced by “Ideal Weight for 
Height” (Griffiths et al, 2005). Ideal Weight for Height is calculated as follows:
(1) Find the child’s measured height to determine the percentile for that height by gender 
and age, using Centers for Disease Control and Prevention Stature-for-Age growth 
chart. 
https://www.cdc.gov/growthcharts/html_charts/statage.htm
(2) The child’s Ideal Weight for Height is the weight on the same percentile in (1) for the 
child’s gender and age, using Centers for Disease Control and Prevention Weight-for-
Age growth chart. For example, for a boy’s height at the 25th percentile for his age, 
his ideal weight will be considered to also be the 25th percentile weight for his age. 
https://www.cdc.gov/growthcharts/html_charts/wtage.htm
Numeric example: for a 2-year old boy with measured height of 84cm and measured weight of 
11kg, his height of 84cm is at the 25th percentile for his age per CDC Stature-for-Age chart. His 
ideal weight will be the 25th percentile for 2-year old boys per CDC Weight-for-Age chart, which 
is 11.78 kg. This boy’s body weight subscore of CDAI will be ( 1 −

. ) × 100 = 7.
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MLN0002-2003
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Statistical Analysis Plan Final 4.0
1 May 2019
Appendix C
Simple Endoscopic Score for Crohn's Disease (SES-CD)
The SES-CD is a validated endoscopic activity score used to assess the status and change of mucosal 
lesions in patients with CD (Daperno et al, 2004). The score assesses 4 variables in up to 5 segments 
to yield its final result.
Simple Endoscopic Score for Crohn’s Disease values
Variable
0
1
2
3
Size of ulcers
None
Aphthous ulcers
(Ø 0.1 to 0.5 cm)
Large ulcers
(Ø 0.5 to 2 cm)
Very large ulcers
(Ø >2 cm)
Ulcerated surface (%)
None
<10%
10-30%
>30%
Affected surface (%)
Unaffected 
segment
<50%
50-75%
>75%
Presence of narrowings
None
Single, can be 
passed
Multiple, can be 
passed
Cannot be passed
Ø, Diameter.
Source: Adapted from 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.
The SES-CD score chart permits assessment of each variable by segment and across the entire 
ileum plus colon, as well as calculation of a total score. 
Variable
Ileum
Right 
Colon
Transverse 
Colon
Left 
Colon
Rectum
Total
Presence and size of ulcers (0-3)
Extent of ulcerated surface (0-3)
Extent of affected surface (0-3)
Presence and type of narrowings
Total SES-CD =
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MLN0002-2003
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Statistical Analysis Plan Final 4.0
1 May 2019
Appendix D
PUCAI
Time period for evaluation: 

Answers should reflect a daily average of the last 2 days; 

however, if clinical conditions are changing rapidly (eg, during intense intravenous therapy), 
the most recent 24 hours should be considered; and 

for patients undergoing colonoscopy, answers should reflect the 2 days before bowel clean 
out was started.
Item
Points
1
Abdominal pain
no pain
0
pain can be ignored
5
pain cannot be ignored
10
2
Rectal bleeding
none
0
small amount only, in <50% of stools
10
small amount with most stools
20
Large amount
30
3
Stool consistency of most stools
Formed
0
Partially formed
5
Completely unformed
10
4
Number of stools per 24 hours
0-2
0
3-5
5
6-8
10
>8
15
5
Nocturnal stools (any episode causing wakening)
No
0
Yes
10
6
Activity level
No limitation of activity
0
Occasional limitation of activity
5
Severe restricted activity
10
SCORE
Total Max 85
Source: Turner D, Otley AR, Mack D, et al. Development and evaluation of a Pediatric Ulcerative Colitis Activity 
Index (PUCAI): a prospective multicenter study. Gastroenterology. 2007; 133: 423.
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Statistical Analysis Plan Final 4.0
1 May 2019
Appendix E
PCDAI
History (recall 1 week)
Abdominal pain
None
0
Mild (brief episodes, not interfering with activities)
5
Moderate/severe (frequent or persistent, affecting activities)
10
Stools
0-1 liquid stools, no blood
0
2-5 liquid or up to 2 semi-formed with small blood
5
Gross bleeding, >6 liquid stools or nocturnal diarrhoea
10
Patient functioning, general well-being (Recall, 1 week)
No limitation of activities, well
0
Occasional difficulties in maintaining age appropriate activities, below par
5
Frequent limitation of activities, very poor
10
EXAMINATION
Weight
Weight gain or voluntary weight loss
0
Involuntary weight loss 1-9%
5
Weight loss >10%
10
Height
<1 channel decrease (or height velocity >-SD)
0
>1<2 channel decrease (or height velocity <-1SD>-2SD)
5
>2 channel decrease (or height velocity <-2SD)
10
Abdomen
No tenderness, no mass
0
Tenderness, or mass without tenderness
5
Tenderness, involuntary guarding, definite mass
10
Peri-rectal disease
None, asymptomatic tags
0
1-2 indolent fistula, scant drainage, tenderness of abscess
5
Active fistula, drainage, tenderness or abscess
10
Extra-intestinal manifestations
(Fever >38.5 x 3 days in week, arthritis, uveitis, erythema nodosum, or pyoderma gangrenosum)
none
0
one
5
two
10
LABORATORY
Hematocrit (%)
<10 years
11-14 (male)
11-19 (female)
15-19 (male)
>33
>35
>34
>37
0
28-33
30-34
29-33
32-36
2.5
<28
<30
<29
<32
5
ESR (mm/hr)
<20
0
20-50
2.5
>50
5
Albumin (g/L)
>35
0
31-34
5
<30
10
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Statistical Analysis Plan Final 4.0
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Appendix F
AEs of Special Interest
Based on the mechanism of action of vedolizumab, certain adverse events of special interest 
(AESIs) have been predefined. The categories of adverse events of special interest, and other 
planned analyses, are described below. 
Events
MedDRA Terms or definitions
Malignancies
SOC: NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS)
Infections
SOC: INFECTIONS AND INFESTATIONS
Infusion Related Reactions
Investigator defined Infusion Related Reactions (as indicated on the AE CRF).
Hypersensitivity Reactions
Anaphylactic/anaphylactoid shock conditions SMQ (broad).
Angioedema SMQ (broad).
Hypersensitivity SMQ (broad).
PML
Human polyomavirus infection PT
JC virus infection PT
Leukoencephalopathy PT
Progressive multifocal leukoencephalopathy PT
JC virus CSF test positive PT
Polyomavirus test positive PT
JC polyomavirus test positive PT
Liver injury
Cholestasis and jaundice of hepatic origin SMQ (Broad) 
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions SMQ 
(Broad)
Hepatitis, non-infectious SMQ (Broad) 
Liver related investigations, signs and symptoms SMQ (Narrow) 
Liver infections SMQ (Broad)
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Statistical Analysis Plan Final 4.0
1 May 2019
Appendix G
Criteria for Identification of Markedly Abnormal Laboratory Values and 
Vital Sign Values.
Hematology—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
Hemoglobin
<0.8 × LLN,
>1.2 × ULN
Hematocrit
<0.8 × LLN,
>1.2 × ULN
RBC count 
<0.8 × LLN, 
>1.2 × ULN
WBC count 
<2.0 ×103/L
>1.5 × ULN
Platelet count
<70 ×103/L
>600 × 103/L
RBC=red blood cell, WBC=white blood cell. LLN=lower limit of normal, ULN=upper limit of normal.
Chemistry—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
ALT
--
>3x ULN
AST
--
>3x ULN
GGT
--
>3x ULN
Alkaline phosphatase
--
>3x ULN
Total bilirubin
--
>34.2 umol/L
Albumin
<25 g/L
--
Total protein
<0.8x LLN
>1.2x ULN
Creatinine
--
>176.8 umol/L
Sodium
<130 mmol/L
>150 mmol/L
Potassium
<3.0 mmol/L
>6.0 mmol/L
Bicarbonate
<8.0 mmol/L
--
Chloride
<75 mmol/L
>126 mmol/L
Calcium
<1.50 mmol/L
>3.25 mmol/L
Glucose
≤2.8 mmol/L
≥20 mmol/L
Phosphorous
<0.52 mmol/L
>2.10 mmol/L
CPK
--
>5x ULN
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, CPK=creatine 
phosphokinase, LLN=lower limit of normal, ULN=upper limit of normal.
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Statistical Analysis Plan Final 4.0
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Appendix H
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85 
>180 
Diastolic blood pressure
mm Hg
<50 
>110
Body temperature
oC
< 35.6
>37.7
oF
<96.1
>99.9
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