Entyvio (Vedolizumab IV) Extended Access Program in Ulcerative Colitis and Crohn's Disease
Phase: PHASE4
Conditions: Colitis, Ulcerative, Crohn Disease
Sponsor: Takeda

For non-commercial use only

PROTOCOL 
Entyvio (Vedolizumab IV) Extended Access Program in Ulcerative Colitis and 
Crohn’s Disease 
Sponsor: 
Takeda Development Center Americas, Inc. (TDC Americas) 
95 Hayden Avenue 
Lexington, MA 02421 
617-349-0200
Takeda Development Centre Asia, Pte. Limited 
8 Marina Boulevard #15-01, Marina Bay 
Financial Centre, Singapore 018981 
Study Number: 
Vedolizumab-4013 
IND Number: 
Not applicable 
EudraCT Number: 
2016-000678-40 
Compound: 
Vedolizumab IV 
Date: 
19 October 2021 
Amendment 
Number: 
7 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
17 March 2016 
Initial Protocol 
Not applicable 
Global 
22 April 2016 
Amendment 1 
Nonsubstantial 
South Africa 
12 August 2016 
Amendment 2 
Substantial 
Global 
10 October 2016 
Amendment 3 
Nonsubstantial 
Global 
21 November 2016 
Amendment 4 
Nonsubstantial 
Global 
07 February 2017 
Amendment 5 
Nonsubstantial 
Global 
25 June 2018 
Amendment 6 
Nonsubstantial 
Global 
19 October 2021 
Amendment 7 
Substantial 
Global 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study. 
For non-commercial use only

For non-commercial use only

For non-commercial use only

 
  
 
Vedolizumab IV 
 
Study No. Vedolizumab-4013  
Page 4 of 108 
Protocol Incorporating Amendment 7 
19 October 2021 
 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, the 
vedolizumab intravenous (IV) (Entyvio) package insert and any other product information 
provided by the sponsor. I agree to conduct this study in accordance with the requirements of this 
protocol and also to protect the life, dignity, integrity, confidentiality of personal information, 
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 Council for 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 A– Schedule of Study Procedures for Main XAP Study. 
• Appendix B– Responsibilities of the Investigator. 
• Appendix F– Schedule of Study Procedures for XAP-PK Substudy (if applicable). 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Provence) 
Location of Facility (Country) 
 
 
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Vedolizumab IV 
 
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Protocol Incorporating Amendment 7 
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CONFIDENTIAL 
Change in Protocol 
Rationale/Justification 
Version of amendment (s) in which 
change was made effective 
Included additional text related to 
study design text and study 
completion. 
duration of the XAP study. 
6.4 Justification for Study Design, 
Dose, and Endpoints 
Date was updated 
Date updated as per the details in the 
latest IB. 
Amendment 7 (Global) 
8.1.3. Dose and Regimen 
8.2 Drug Dosing and Dispensing 
Procedures 
Included additional text related to 
dose regimen. 
Text has been added to clarify the 
dose schedule and regimen along with 
window period of ±7 days with every 
dose. 
Amendment 6 (Global) 
8.4 Accountability and Destruction of 
Sponsor-Supplied Drugs 
Included additional text related to 
remote drug reconciliation and 
destruction 
Text has been added to clarify that the 
drug reconciliation will be completed 
remotely and destruction can be 
carried out locally or by a contracted 
third party as per local regulations. 
Amendment 6 (Global) 
9.1 Study Procedures 
Included a statement to cross-refer 
details of COVID-19. 
Text has been added to cross-refer 
details of COVID-19-related study 
procedural changes. 
Amendment 7 (Global) 
9.1.5 Documentation of Concurrent 
Medical Conditions 
Included text regarding the recording 
of ongoing AEs from qualifying 
study. 
Added clarification that “ongoing 
AEs” from qualifying study, at the 
time of signing informed consent to 
participate in this XAP study, will be 
captured as a concurrent medical 
condition. 
Amendment 6 (Global) 
9.1.7 Physical Examination 
Included text regarding procedures 
that have been conducted within last 
24 hours. 
Added clarification that if physical 
examination has been conducted 
within the last 24 hours at the 
enrollment visit, the results of that test 
can be used and the procedure does 
not need to be redone. 
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK substudy) 
9.1.8 Vital Sign Procedure 
Included text regarding procedures 
that have been conducted within last 
24 hours. 
Added clarification that if vital sign 
measurements have been conducted 
within the last 24 hours at the 
enrollment visit, the results of that test 
can be used and the procedure does 
not need to be redone. 
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK substudy) 
9.1.9 Weight, Height, and BMI 
Included text regarding procedures 
that have been conducted within last 
24 hours. 
In addition, BMI calculation details 
have been added. 
Added clarification that if weight and 
height have been conducted within the 
last 24 hours at the enrollment visit, 
the results of that test can be used and 
the procedure does not need to be 
redone. 
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK substudy) 
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Protocol Incorporating Amendment 7 
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CONFIDENTIAL 
Change in Protocol 
Rationale/Justification 
Version of amendment (s) in which 
change was made effective 
9.1.11 Contraception & Pregnancy 
Avoidance Procedure 
Clarification that spermicides are not 
commercially available in South 
Africa. South African subjects will be 
counselled to use other double-barrier 
methods. 
Clarification to support applicable 
double-barrier contraception and 
pregnancy avoidance procedures in 
South African trial sites. 
 
Amendment 1 (Local- South Africa 
only); Amendment 2 (Global – sites 
participating in XAP-PK substudy) 
9.1.11 Contraception & Pregnancy 
Avoidance Procedure 
Included text regarding procedures 
that have been conducted within last 
24 hours. 
 
Deleted text related to sperm donation 
period for male subjects 
Added clarification that if pregnancy 
test result has been recorded within 
the last 24 hours at screening, the 
results of that test can be used and the 
procedure does not need to be redone. 
 
This information has already been 
clarified at the beginning of the 
sentence. 
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK substudy) 
 
Amendment 7 (Global) 
9.1.15 Collection of AEs and SAEs 
Included text related to the time of 
collection of AEs and SAEs during 
the study. 
Added clarification that AEs and 
SAEs will be collected from the time 
when the subject signs the informed 
consent to participate in the study 
through to follow-up visit. 
Amendment 6 (Global) 
9.3.2 Treatment Period 
Included text to clarify study 
treatment and completion period. 
Included a statement to cross-refer 
details of COVID-19. 
Text has been added to clarify the 
dose schedule and regimen. 
Text has been added to cross-refer 
details of COVID-19-related visit 
window changes. 
Amendment 6 (Global) 
 
Amendment 7 (Global) 
9.3.6 Follow-up Period 
Included text to clarify study 
procedure to be followed at follow-up 
period. 
Added clarification over the follow-up 
period and procedure to be followed. 
Amendment 6 (Global) 
9.3.7 COVID-19-Related Protocol 
Considerations/Mitigations 
Included a section to clarify 
procedures/risk mitigation approaches 
during the COVID-19 pandemic. 
Text has been added to update details 
of COVID-19-related study 
procedural changes. 
Amendment 7 (Global) 
10.1.3 Additional Points to Consider 
for AEs 
10.1.5 Severity of AEs 
10.2.1.2 AE Reporting 
13.1.4 Safety Analysis 
The term ‘severity’ of AEs changed to 
‘intensity’ of AEs recorded during the 
study. 
Added to reduce the ambiguity 
between the terminologies. 
 
Amendment 6 (Global) 
For non-commercial use only

Vedolizumab IV 
 
Study No. Vedolizumab-4013  
Page 9 of 108 
Protocol Incorporating Amendment 7 
19 October 2021 
 
CONFIDENTIAL 
Change in Protocol 
Rationale/Justification 
Version of amendment (s) in which 
change was made effective 
Included text related to the time of 
collection of AEs and SAEs during 
the study. 
10.1.11 Action Concerning Study 
Medication 
Every 8-week changed to Q8W 
Editorial change added for 
consistency and defining dosing 
schedule technically. 
Amendment 6 (Global) 
10.2.1.1 AE collection period 
Included text regarding the collection 
of ongoing AEs from qualifying 
study, and AEs during the study and 
safety follow-up.  
13.1.4 Safety Analysis 
Added clarification that ongoing AEs 
from qualifying study at the time of 
signing informed consent to 
participate in this study will be 
captured as a concurrent medical 
condition and AEs/SAEs will be 
collected from the time when the 
subject signs the informed consent to 
participate in the study, through study 
till safety follow-up visit. 
Amendment 6 (Global) 
13.2 Interim Analysis and Criteria for 
Early Termination 
Text has been updated to clarify that 
interim looks at study data to review 
safety and treatment persistence of 
study subjects might be done. 
Amendment 7 (Global) 
14.2 Protocol Deviations 
Included a statement to cross-refer 
details of COVID-19. 
Text has been added to cross-refer the 
details of how to document 
COVID-19-related protocol 
deviations. 
Amendment 7 (Global) 
15.0 Ethical Aspects of the Study 
Re-emphasized the objective of the 
global Extended Access Program 
(XAP). 
Clarification to satisfy Declaration of 
Helsinki requirements. 
Amendment 1 (Local- South Africa 
only); Amendment 2 (Global – sites 
participating in XAP-PK substudy)  
15.1 IRB and/or IEC Approval  
Added clarifications for funding, 
sponsors, institutional affiliations and 
potential conflicts of interest. 
Clarification to satisfy Declaration of 
Helsinki requirements. 
Amendment 1 (Local- South Africa 
only); Amendment 2 (Global – sites 
participating in XAP-PK substudy)  
15.2 Subject Information, Informed 
Consent, Subject Authorization 
Added references to the “assent form” 
for use if applicable, eg, mentally 
incapacitated persons or subjects 
deemed otherwise incapable of 
providing informed consent. 
Clarification to satisfy Declaration of 
Helsinki requirements. 
Amendment 1 (Local- South Africa 
only); Amendment 2 (Global – sites 
participating in XAP-PK substudy)  
16.0 References 
Added 2 new references. 
Amendment 7 (Global) 
Appendix A Schedule of Study 
Procedures for Main XAP Study 
Included footnote to the procedures 
that are not required to be repeated if 
To include the timing of the initial 
study visit for MLN0002-3028 and to 
clarify that the results of procedures 
that have been conducted in last 24 
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK substudy) 
For non-commercial use only

Vedolizumab IV 
 
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Protocol Incorporating Amendment 7 
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CONFIDENTIAL 
Change in Protocol 
Rationale/Justification 
Version of amendment (s) in which 
change was made effective 
performed within 24 hours of the 
screening/enrollment visit and 
clarified the timing of the initial study 
visit for additional qualifying study. 
Included a statement in footnote to 
cross-refer details of COVID-19. 
hours at enrollment visit can be used 
and the procedure does not need to be 
redone. 
Added list of abbreviations and 
footnote text to cross-refer details of 
COVID-19-related protocol 
considerations/mitigations. 
Amendment 7 (Global) 
Appendix A Schedule of Study 
Procedures for Main XAP Study 
Footnotes were shortened to remove 
repetitive details. 
Footnotes have been reduced to 
remove redundancy. 
Details of XAP-PK substudy 
procedures moved to a separate 
Appendix F 
Amendment 6 (Global) 
2.0 Summary 
Included details about XAP-PK 
substudy. 
4.2.1 Rationale for XAP-PK Substudy 
5.1.2 Exploratory Objectives for 
XAP-PK Substudy  
5.2.2 Exploratory Endpoints for XAP-
PK Substudy 
6.1.1 Study Design of the XAP-PK 
Substudy 
6.2 Number of Subjects  
6.3 Duration of Study  
6.4 Justification for Study Design, 
Dose, and Endpoints 
6.5.1 Criteria for Premature 
Termination or Suspension of the 
Study 
7.1 Inclusion Criteria 
7.6 Criteria for Discontinuation or 
Withdrawal of a Subject 
7.7 Procedures for Discontinuation or 
Withdrawal of a Subject 
9.1.1.1 XAP-PK Substudy Informed 
Consent Procedure 
9.1.9 Weight, Height, and BMI 
9.1.16 Partial Mayo Score 
9.1.17 Harvey-Bradshaw Index Score  
9.1.18 Sample Collection and 
Analysis 
9.3.1 Enrollment Visit 1 
Details related to rationale, objectives, 
endpoints, study design, subjects, 
inclusion and withdrawal criteria, 
study procedures, and statistical 
considerations were added to explain 
XAP-PK substudy. 
All these changes are now described 
separately as XAP-PK substudy in 
Appendix E and schedule of study 
procedures for XAP-PK substudy are 
summarized in Appendix F. 
 
 
 
For XAP-PK substudy additional 
clarifications have been included to 
specify that end of substudy and 
Week 56 are same ie, end of substudy 
visit/Week 56. Clarification that End 
of Sub-study/Week 56 visit should be 
scheduled in conjunction with a 
regular infusion visit of the Main 
study has been added. 
 
Mention of predictive models for 
XAP-PK substudy have been removed 
as they were added inadvertently 
Amendment 2 (Global) and 
Amendment 6 (moved to separate 
Appendix)  
Amendment 5 (Global): Removed 
MLN0002-3028 from eligibility to 
participate in the XAP-PK substudy. 
It was added in error in Amendment 
4. Subjects in MLN0002-3028 are not 
switching from Q4W to Q8W dosing 
and are therefore an inappropriate 
population for the substudy. 
 
Amendment 6 (Global) 
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Protocol Incorporating Amendment 7 
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CONFIDENTIAL 
Change in Protocol 
Rationale/Justification 
Version of amendment (s) in which 
change was made effective 
9.3.2 Treatment Period 
9.3.6 Follow-up Period 
13.1.1 Analysis Sets 
13.3 Determination of Sample Size 
13.4 XAP-PK Substudy Analysis 
Appendix E Details Specific to 
XAP-PK Substudy 
Appendix F Schedule of Study 
Procedures for XAP-PK Substudy 
Appendix C Elements of the Subject 
Informed Consent 
To include a statement to cover the 
requirements for the XAP-PK 
substudy 
Amendment 2 (Global) 
Appendix G Partial Mayo Score 
Scale copy has been added for 
reference 
Amendment 6 (Global) 
Appendix H Harvey-Bradshaw Index Scale copy has been added for 
reference 
Amendment 6 (Global) 
For non-commercial use only

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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 7 Summary of Changes ...............................................................5 
2.0 
STUDY SUMMARY.........................................................................................................17 
3.0 
STUDY REFERENCE INFORMATION .........................................................................20 
3.1 
Study-Related Responsibilities ....................................................................................20 
3.2 
Principal Investigator/Coordinating Investigator .........................................................20 
3.3 
List of Abbreviations ...................................................................................................21 
3.4 
Corporate Identification ...............................................................................................22 
4.0 
INTRODUCTION .............................................................................................................23 
4.1 
Background ..................................................................................................................23 
4.1.1 The Inflammatory Bowel Diseases: Ulcerative Colitis and Crohn’s Disease 
and Current Treatments..........................................................................................23 
4.1.2 Vedolizumab IV .....................................................................................................24 
4.2 
Rationale for the Proposed Study ................................................................................25 
4.3 
Risk: Benefit Assessment ............................................................................................26 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................27 
5.1 
Objective ......................................................................................................................27 
5.1.1 Primary Objectives for the Main XAP Study ........................................................27 
5.2 
Endpoints .....................................................................................................................27 
5.2.1 Primary Endpoints for the Main XAP Study .........................................................27 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................28 
6.1 
Study Design of the Main XAP Study .........................................................................28 
6.2 
Number of Subjects......................................................................................................29 
6.3 
Duration of Study .........................................................................................................29 
6.4 
Justification for Study Design, Dose, and Endpoints ..................................................30 
6.5 
Premature Termination or Suspension of Study or Investigational Site ......................30 
6.5.1 Criteria for Premature Termination or Suspension of the Study ...........................30 
6.5.2 Criteria for Premature Termination or Suspension of Investigational Sites ..........31 
6.5.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)...................................................................31 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............32 
7.1 
Inclusion Criteria .........................................................................................................32 
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7.2 
Exclusion Criteria ........................................................................................................32 
7.3 
Concomitant Procedures and Medications ...................................................................33 
7.3.1 Excluded Medications ............................................................................................33 
7.4 
Diet, Fluid, Activity Control ........................................................................................33 
7.5 
Management of Clinical Events ...................................................................................33 
7.5.1 AEs of Special Interest...........................................................................................33 
7.5.2 Infusion-Related Hypersensitivity Reactions ........................................................33 
7.5.3 Serious Infection ....................................................................................................34 
7.5.4 Malignancy ............................................................................................................34 
7.5.5 Liver Injury ............................................................................................................34 
7.6 
Criteria for Discontinuation or Withdrawal of a Subject .............................................35 
7.7 
Procedures for Discontinuation or Withdrawal of a Subject .......................................35 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT.........................................................36 
8.1 
Study Medication and Materials ..................................................................................36 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ......................................36 
8.1.1.1 Vedolizumab IV ...............................................................................................36 
8.1.1.2 Other Protocol-Specified Materials .................................................................36 
8.1.2 Storage ...................................................................................................................36 
8.1.3 Dose and Regimen .................................................................................................36 
8.1.4 Overdose ................................................................................................................37 
8.2 
Drug Dosing and Dispensing Procedures ....................................................................37 
8.3 
Blinding and Unblinding..............................................................................................38 
8.4 
Accountability and Destruction of Sponsor-Supplied Drugs .......................................38 
9.0 
STUDY PLAN ...................................................................................................................40 
9.1 
Study Procedures .........................................................................................................40 
9.1.1 Informed Consent Procedure .................................................................................40 
9.1.2 Alert Card...............................................................................................................40 
9.1.3 Assessment for Continued Eligibility ....................................................................40 
9.1.4 Demographics, Medical History, and Prior Therapies ...........................................40 
9.1.5 Documentation of Concurrent Medical Conditions ...............................................41 
9.1.6 Disease History ......................................................................................................41 
9.1.7 Physical Examination Procedure ...........................................................................41 
9.1.8 Vital Sign Procedure ..............................................................................................41 
9.1.9 Weight, Height, and Body Mass Index ..................................................................41 
9.1.10 Documentation of Concomitant Medications ........................................................42 
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CONFIDENTIAL 
9.1.11 Contraception and Pregnancy Avoidance Procedure .............................................42 
9.1.12 Pregnancy ...............................................................................................................43 
9.1.13 Documentation of Baseline/Enrollment Failure ....................................................44 
9.1.14 Documentation of Study Entrance .........................................................................44 
9.1.15 Collection of AEs and SAEs ..................................................................................44 
9.2 
Monitoring Subject Treatment Compliance .................................................................45 
9.3 
Schedule of Observations and Procedures ...................................................................45 
9.3.1 Enrollment Visit 1 ..................................................................................................45 
9.3.2 Treatment Period ....................................................................................................45 
9.3.3 Final Infusion Visit ................................................................................................46 
9.3.4 Routine or Unscheduled Office Visits ...................................................................46 
9.3.5 Post Study Care ......................................................................................................46 
9.3.6 Follow-up Period ...................................................................................................46 
9.3.7 COVID-19-Related Protocol Considerations/Mitigations .....................................46 
10.0 
ADVERSE EVENTS .........................................................................................................49 
10.1 
Definitions....................................................................................................................49 
10.1.1 AEs .........................................................................................................................49 
10.1.2 Product Complaint .................................................................................................49 
10.1.3 Additional Points to Consider for AEs ..................................................................49 
10.1.4 SAEs ......................................................................................................................51 
10.1.5 Intensity of AEs .....................................................................................................52 
10.1.6 Causality of AEs ....................................................................................................52 
10.1.7 Relationship to Study Procedures ..........................................................................53 
10.1.8 Start Date ...............................................................................................................53 
10.1.9 Stop Date ................................................................................................................53 
10.1.10 
Frequency .........................................................................................................53 
10.1.11 
Action Concerning Study Medication .............................................................53 
10.1.12 
Outcome ...........................................................................................................54 
10.2 
Procedures ....................................................................................................................54 
10.2.1 Collection and Reporting of AEs ...........................................................................54 
10.2.1.1 
AE Collection Period .................................................................................54 
10.2.1.2 
AE Reporting .............................................................................................54 
10.2.1.3 
Special Interest AE Reporting ...................................................................55 
10.2.2 Collection and Reporting of SAEs .........................................................................55 
10.2.3 Reporting of Abnormal LFT ..................................................................................56 
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CONFIDENTIAL 
10.3 
Follow-up of SAEs ......................................................................................................56 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....57 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................58 
12.0 
DATA HANDLING AND RECORD KEEPING .............................................................59 
12.1 
eCRFs ...........................................................................................................................59 
12.2 
Record Retention .........................................................................................................59 
13.0 
STATISTICAL METHODS ..............................................................................................61 
13.1 
Statistical and Analytical Plans ....................................................................................61 
13.1.1 Analysis Sets ..........................................................................................................61 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................61 
13.1.3 Efficacy Analysis ...................................................................................................61 
13.1.4 Safety Analysis ......................................................................................................61 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................62 
13.3 
Determination of Sample Size .....................................................................................62 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................63 
14.1 
Study-Site Monitoring .................................................................................................63 
14.2 
Protocol Deviations ......................................................................................................63 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................63 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................64 
15.1 
IRB and/or IEC Approval ............................................................................................64 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................65 
15.3 
Subject Confidentiality ................................................................................................66 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................67 
15.4.1 Publication and Disclosure ....................................................................................67 
15.4.2 Clinical Trial Registration ......................................................................................67 
15.4.3 Clinical Trial Results Disclosure ...........................................................................68 
15.5 
Insurance and Compensation for Injury .......................................................................68 
16.0 
REFERENCES ..................................................................................................................69 
 
LIST OF IN-TEXT TABLES 
Table 10.a 
Takeda Medically Significant AE List ..................................................................52 
 
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CONFIDENTIAL 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures for Main XAP Study .............................................72 
Appendix B 
Responsibilities of the Investigator ........................................................................74 
Appendix C 
Elements of the Subject Informed Consent ...........................................................76 
Appendix D 
Investigator Consent to Use of Personal Information ............................................79 
Appendix E 
Details Specific to XAP-PK Substudy ...................................................................80 
Appendix F 
Schedule of Study Procedures for XAP-PK Substudy ..........................................92 
Appendix G 
Partial Mayo Score .................................................................................................93 
Appendix H 
Harvey-Bradshaw Index ........................................................................................94 
Appendix I 
Detailed Description of Amendments to Text .......................................................96 
 
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CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Development Center Americas, Inc. (TDC 
Americas) 
Takeda Development Centre Asia, Pte. Limited, 
Singapore  
Compound: 
Vedolizumab IV 
Title of Protocol: Entyvio (Vedolizumab IV) Extended 
Access Program in Ulcerative Colitis and Crohn’s 
Disease 
IND No.: Not 
Applicable 
EudraCT No.: 
2016-000678-40 
Study Number: Vedolizumab-4013 
Phase: 3b/4 
Study Design: 
This is a multinational, multicenter, phase 3b/4, open-label extended access program (XAP) study to monitor 
ongoing safety (eg, adverse events [AEs], serious AEs [SAEs], and AEs of special interest [AESIs]) and provide 
access to vedolizumab for qualifying subjects who have successfully completed participation in qualifying 
vedolizumab clinical studies. 
Subjects entering the XAP study from C13008 and who are switching from every 4-week (Q4W) to every 
8-week (Q8W) dosing at the time of enrollment, will be eligible to enroll in an optional pharmacokinetic (PK) 
substudy. Details related to rationale for the XAP-PK substudy are provided in Appendix E. 
Objective 
Primary Objectives for the Main XAP Study: 
To monitor ongoing safety in subjects with ulcerative colitis (UC) and Crohn’s disease (CD) and to provide 
access to vedolizumab for qualifying subjects who, in the opinion of the investigator, continue to derive benefit 
from vedolizumab and for whom continued treatment with vedolizumab is desired because there is no other 
comparable product available or the subject may be expected to develop worsening of disease if they were to 
modify treatment. 
Subject Population:  
Subjects who have successfully completed participation (having received the final dose of vedolizumab but not 
yet having completed the safety follow-up period) in qualifying vedolizumab clinical studies and meet the 
inclusion/exclusion criteria. At this time, qualified studies include C13008 and MLN0002-3028. Additional 
qualifying studies may be included at a later date as specified within the protocol for the qualifying vedolizumab 
study. They will not be specifically called out in this protocol, unless the roll-over requires a change to the 
conduct of the main XAP study. 
Number of Subjects: 
The number of subjects will be determined based upon 
the qualifying subjects who have received treatment with 
vedolizumab, completed participation in qualifying 
vedolizumab clinical studies, meet the 
inclusion/exclusion criteria, and agree to enroll in the 
XAP study. 
Number of Sites:  
The number of countries and number of sites will be 
determined based upon the number and location of 
sites with qualifying subjects completing qualifying 
vedolizumab clinical studies.  
Dose Level: 
300 mg of vedolizumab administered every 8 weeks 
(±7 days). 
The first dose of vedolizumab in this study should occur 
8 weeks (±7 days) after the last dose of study medication 
Route of Administration: 
Intravenous (IV) 
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in the qualifying study. If indicated, the time to the first 
dose of vedolizumab in this study may be extended, but 
will be performed no later than the safety follow-up visit 
in the qualifying study. 
If the subject experiences reduction in efficacy on Q8W 
dosing, the dosing frequency, based on the investigator’s 
judgment of subject’s clinical status and acknowledged 
by the medical monitor, may be changed to Q4W dosing. 
It will be at the investigator’s discretion when Q8W 
dosing will be reintroduced again. 
Subjects entering from a qualifying study in which the 
subject was on a more frequent dose can stay on at the 
dose provided in the qualifying study, if medically 
indicated based on the investigator’s clinical judgment 
and acknowledged by the medical monitor. 
Duration of Treatment: 
Subjects will remain in the study until vedolizumab is 
available to the subject through commercial channels, 
including reimbursement, for the subject’s clinical 
scenario or until subject withdrawal, whichever is 
sooner. 
Period of Evaluation: 
The subject will be evaluated until the time at which 
they leave the study. The subject is expected to 
return for a safety follow-up visit 18 weeks after the 
final study dose. 
Main Criteria for Inclusion: 
Received vedolizumab (excluding comparator or placebo subjects) during participation in a qualifying 
vedolizumab study. 
In the opinion of the investigator, the subject is continuing to derive benefit from vedolizumab and continued 
treatment with vedolizumab is desired because there is no other comparable product available or the subject may 
be expected to develop worsening of disease if they were to modify treatment. 
A male subject who is nonsterilized and sexually active with a female partner of childbearing potential agrees to 
use adequate contraception from signing of informed consent throughout the duration of the study and for 
18 weeks after last dose.  
A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to use 
routinely adequate contraception from signing of informed consent throughout the duration of the study and for 
18 weeks after last dose.  
Main Criteria for Exclusion: 
For the subject’s particular clinical scenario, vedolizumab is currently available to the subject through 
commercial channels, including reimbursement.  
Subject has any clinical condition or prior therapy that, in the opinion of the investigator, would make the subject 
unsuitable for the study or unable to comply with the dosing requirements or poses a risk to the subject being in 
the study. 
If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 18 weeks 
after participating in this study; or intending to donate ova during such time period. 
If male, the subject intends to donate sperm during the course of this study or for 18 weeks thereafter. 
Subject has received a live vaccine in the last 18 weeks or is in need of a live vaccine during the study or up to 
18 weeks after the last study dose. 
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Main Criteria for Evaluation and Analyses: 
The primary endpoints for the XAP study are: 
• 
Number and percentage of subjects with AEs and SAEs. 
• 
Number and percentage of subjects with AESIs. 
Statistical Considerations: 
This XAP study is not sized based on power considerations. All analyses will be descriptive. No formal 
statistical hypothesis testing is to be performed. 
Safety evaluations will be based on incidence, intensity and type of AEs, and vital signs. Descriptive statistics 
will be calculated.  
The number and percentage of subjects with treatment-emergent adverse events (TEAEs), defined as any AEs, 
regardless of relationship to study medication), AESIs (ie, serious infections, including opportunistic infections 
such as progressive multifocal leukoencephalopathy, malignancies, liver injury, infusion-related hypersensitivity 
reactions and injection site reactions), AEs leading to discontinuation, and SAEs that occur from the time of 
signing informed consent form and up to the safety follow-up visit will be summarized by Medical Dictionary 
for Regulatory Activities (MedDRA) system organ class (SOC), high-level term (HLT), and preferred term (PT) 
overall, by intensity, and by relationship to study medication for each treatment group. Separate summaries will 
also be generated for TEAEs overall and by intensity.  
To summarize the number of subjects with AEs, subjects reporting the same event more than once will have that 
event counted only once within each SOC, HLT, and PT. All AEs will be presented in separate data listings. 
Exposure-adjusted AEs will also be presented. 
Absolute values and change from baseline in vital sign measurements will be summarized. Vital sign data will be 
presented in data listings. 
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3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities  
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities document. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor. 
3.2 
Principal Investigator/Coordinating Investigator  
Takeda will select a Signatory Coordinating Investigator from the investigators who participate 
in the study. Selection criteria for this investigator will include significant knowledge of the 
study protocol, the study medication, their expertise in the therapeutic area, and the conduct of 
clinical research as well as study participation. The Signatory Coordinating Investigator will be 
required to review and sign the clinical study report and by doing so agrees that it accurately 
describes the results of the study. 
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3.3 
List of Abbreviations 
5-ASAs 
5-aminosalicylic acid 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AVA 
anti-vedolizumab antibodies 
BMI 
body mass index 
CD 
Crohn’s disease 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CRP 
C-reactive protein 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
ePIP 
electronic Protocol Inquiry Platform 
EU 
European Union 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBI 
Harvey-Bradshaw Index 
hCG 
human chorionic gonadotropin 
HLT 
high-level term 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
identification 
IEC 
independent ethics committee 
IRB 
institutional review board 
IV 
intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LFT 
liver function test 
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MAdCAM-1 
mucosal addressin cell adhesion molecule-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
PC 
product complaint 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PT 
preferred term 
PVC 
polyvinyl chloride 
Q4W 
every 4-week 
Q8W 
every 8-week 
SAE 
serious adverse event 
SC 
subcutaneous 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reactions 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event  
TNF-α 
tumor necrosis factor-alpha 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cells 
WHODRUG 
World Health Organization Drug Dictionary 
XAP 
extended access program 
3.4 
Corporate Identification  
TDC Asia 
Takeda Development Centre Asia, Pte. Limited 
TDC Americas 
Takeda Development Center Americas, Inc. 
TDC 
TDC Asia and/or TDC Americas, as applicable 
Takeda 
TDC Asia and/or TDC Americas, as applicable 
 
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4.0 
INTRODUCTION 
4.1 
Background 
4.1.1 The Inflammatory Bowel Diseases: Ulcerative Colitis and Crohn’s Disease and 
Current Treatments 
Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder of the 
gastrointestinal (GI) tract that includes 2 entities, namely ulcerative colitis (UC) and Crohn’s 
disease (CD). 
UC is a relapsing, remitting inflammatory disease of the colonic mucosa and submucosa. The 
prevalence of UC (in adults and pediatric population) is approximately 200 cases/100,000 of 
population in the United States (US), 150 cases/100,000 of the population in Western Europe 
[1-4]. Among first-degree relatives of subjects with UC, the incidence of UC is 30 to 100 times 
higher than the general population, indicating a significant genetic component to the disease [5]. 
CD is a relapsing, remitting inflammatory disease that may involve any portion of the length of 
the GI tract from mouth to anus in a transmural fashion from mucosa to serosa. The prevalence 
of CD is approximately 125 cases/100,000 of population in the US and approximately 
150 cases/100,000 of population in Western Europe [1-4]. Approximately 20% of all cases of 
CD occur in the pediatric population under the age of 15 years. A male preponderance is 
reported in pediatric CD, while a female preponderance is seen only among subjects diagnosed 
during adolescence (13 to19 years) [6]. 
In both the adult and pediatric populations, clinical manifestations of both diseases include 
diarrhea (typically bloody in subjects with UC), as well as abdominal pain, fecal urgency, and 
incontinence. Systemic features such as fever, weight loss, malaise, and fatigue are indicators of 
more extensive disease. The characteristic pathology of UC is one of chronic inflammation 
characterized by large numbers of lymphocytes and histiocytes in the diseased mucosa and 
submucosa with an acute inflammatory infiltrate composed of neutrophils variably present, while 
CD involves a chronic inflammatory infiltrate consisting of neutrophils and macrophages. 
Hallmarks of CD include granulomatous inflammation and aphthous ulceration. 
Conventional pharmacological treatments for both UC and CD include the 5-aminosalicylic 
acids (5-ASAs), corticosteroids, and immunomodulators (thiopurines, such as azathioprine and 
6-mercaptopurine), along with methotrexate for CD. In addition, standard practice often involves 
using these treatments in combination. Tumor necrosis factor-alpha (TNF-α) antagonists 
approved for treatment of UC and CD in the US, European Union (EU), and in other regions 
include infliximab (Remicade) [7] administered by intravenous (IV) infusion, adalimumab 
(Humira) [8] administered by subcutaneous (SC) injection, and golimumab (Simponi) [9] 
administered by SC injection for the treatment of UC only. In the US, 2 additional treatments are 
approved for CD: certolizumab (Cimzia) [10], a SC administered TNF-α antagonist, and 
natalizumab (TYSABRI) [11], a pan α4 integrin antagonist administered by IV infusion. 
Natalizumab is also approved in the EU with limited reimbursement. Current treatments have 
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been effective for many subjects with IBD but have numerous limitations for subjects with 
moderately to severely active disease. 5-aminosalicylates are the main stay of UC 
pharmacotherapy for induction and maintenance of remission for subjects with mild to moderate 
disease, but are less effective in severe disease. The National Cooperative Crohn’s Disease Study 
demonstrated a role for sulfasalazine (a 5-ASA–containing molecule) in moderate to severe CD 
[12]. Despite its use, the benefit is debatable in moderate to severely active UC [13]. 
Corticosteroids are often required for the one-third of subjects who fail to respond to 5-ASAs. 
While highly effective for induction of remission, corticosteroids are not recommended for the 
maintenance of remission in CD because they carry significant undesirable side effects, 
including osteoporosis, glucose intolerance, and increased risk of infection [14]. 
Immunomodulatory agents have relatively slow onset of action, which precludes their use during 
flares of disease, and the use of these agents has been reported to potentially increase the risk of 
lymphoma in subjects with IBD [15].  
Methotrexate, while ineffective in UC, has a role in the management of refractory CD; however, 
it also demonstrates a number of dose-limiting toxicities. Antibiotics have marginal efficacy in 
maintenance of remission in CD. TNF-α antagonists are effective in only a subset of subjects, 
with roughly two-thirds of subjects in controlled trials not in remission at the end of the first year 
of therapy [16,17]. The TNF-α antagonists are also associated with a number of serious safety 
concerns based on their suppression of systemic immunity, including reactivation of tuberculosis 
(TB); various bacterial, viral, fungal, and opportunistic infections; and malignancies such as 
hepatosplenic T-cell lymphoma [7,8]. Natalizumab is cautiously prescribed for treatment of CD 
due to the increased risk of developing rare but often fatal neurodegenerative disorder, 
progressive multifocal leukoencephalopathy (PML), which is a mechanism-based side effect 
[11].  
Failure of pharmacological therapy leads to colectomy in 9% to 35% of subjects with UC within 
5 years. Colectomy is considered to be an important adjunct treatment for refractory UC; 
however, colectomy with ileal pouch anal anastomosis (the standard surgical therapy) has many 
limitations and is associated with its own set of complications, including high stool frequency 
[18], female infertility [19], and a cumulative incidence of pouchitis of 50% at 10 years [20]. The 
limitations of current therapies for IBD indicate that there is a significant need for safer and more 
effective therapies. 
4.1.2 Vedolizumab IV 
Vedolizumab (also called MLN0002) is a humanized immunoglobulin G1 monoclonal antibody 
directed against the human lymphocyte integrin α4β7. 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 [21-24]. Vedolizumab binds to the α4β7 
integrin, antagonizing its adherence to MAdCAM-1 and as such, impairs the migration of gut 
homing leukocytes into GI mucosa. As a result, vedolizumab acts as a gut-selective 
immunomodulator [25]. 
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Vedolizumab IV (also known as ENTYVIO; KYNTELES; Vedolizumab for Injection, for 
Intravenous Use; Vedolizumab Powder for Concentrate for Solution for Infusion; or MLN0002 
IV) is approved in the US, EU and multiple other countries worldwide for the treatment of adult 
subjects with moderately to severely active UC or CD who have failed conventional treatment, 
that include corticosteroids, immunomodulators, or TNF-α antagonists [26,27]. The approved 
dosing and administration regimen consists of 300 mg vedolizumab infused IV, over 
approximately 30 minutes, at Weeks 0, 2 and 6, then once every 8 weeks thereafter.  
Detailed information regarding the nonclinical pharmacology and toxicology of vedolizumab 
along with previously conducted clinical studies which have characterized the efficacy, safety, 
tolerability, pharmacokinetic (PK), pharmacodynamic, and immunogenicity of vedolizumab can 
be found in the current version of the Investigator’s Brochure (IB). 
As of 19 May 2021, approximately 6949 subjects (869 healthy subjects, 2782 subjects with UC, 
and 3022 subjects with CD, 213 subjects undergoing allogeneic-hematopoietic stem cell 
transplantation or with acute graft-versus-host disease involving the intestinal tract, 51 subjects 
with pouchitis, and 12 subjects with melanoma) have received at least 1 dose of vedolizumab 
across completed and ongoing company-sponsored interventional clinical studies (see current 
version of IB). Vedolizumab exposure in clinical studies has extended for ≥12 months in 
2957 subjects, ≥24 months in 1906 subjects, ≥36 months in 1474 subjects, ≥48 months in 
965 subjects, ≥60 months in 717 subjects, ≥72 months in 477 subjects, ≥84 months in 
308 subjects, ≥96 months in 271 subjects, and ≥108 months in 201 subjects. 
Vedolizumab has shown an acceptable safety based on an analysis of safety data from both 
completed and ongoing studies. The integrated summary of safety for the completed studies, as 
well as a summary of safety from the ongoing phase 3/3b and 3b/4 programs (based on a data cut 
off of 19 May 2021), are detailed in the current version of the IB. As of 19 May 2021, a total of 
103 subjects who participated in vedolizumab clinical studies have died during the study or up to 
2 years following the last dose of study drug. Eight of the 103 subjects were being treated for UC 
and 14 subjects for CD (Studies C13006, C13007, C13008, C13011, MLN0002-3026, 
MLN0002SC-3027, MLN0002SC-3031, Vedolizumab-3034, Vedolizumab-4013, and 
Vedolizumab-4014). The causes of death varied and additional information can be found in the 
current version of the IB. No cases of PML have been reported to date. Overall, vedolizumab IV 
was well tolerated in clinical studies. 
4.2 
Rationale for the Proposed Study 
Establishing the safety and tolerability of vedolizumab is a key component of the pivotal 
development programs in both UC and CD. The benefit-to-risk of vedolizumab is favorable to 
date (see current version of the IB) and suggests that the drug has the potential to address an 
important unmet medical need in the treatment of UC and CD. Vedolizumab efficacy has been 
established in the registrational trials.  
The primary aim of the currently planned study is to monitor ongoing safety in subjects with UC 
and CD and to provide access to vedolizumab for qualifying subjects who have received 
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vedolizumab during participation in a qualifying vedolizumab study and who, in the opinion of 
the investigator, are continuing to derive benefit from vedolizumab and for whom continued 
treatment with vedolizumab is desired because there is no other commercial product available or 
the subject may be expected to develop worsening of disease if they were to modify treatment.  
The study will facilitate collection of additional safety information on important clinical events 
for a larger subject population. Qualifying subjects will be provided access to vedolizumab from 
the end of the qualifying vedolizumab study until vedolizumab is available to the subject through 
commercial channels, including reimbursement, for the subject’s clinical scenario or until subject 
withdrawal, whichever is sooner. 
Subjects entering the extended access program (XAP) study from C13008 and who are switching 
from every 4-week (Q4W) to every 8-week (Q8W) dosing at the time of enrollment, will be 
eligible to enroll in an optional XAP-PK substudy. Details related to rationale for the XAP-PK 
substudy are provided in Appendix E. 
4.3 
Risk: Benefit Assessment 
An integrated safety analysis was conducted using data from completed vedolizumab clinical 
studies with a cut-off of 14 March 2013. This analysis of 237 healthy subjects and 2216 subjects 
with UC or CD demonstrated an acceptable safety for vedolizumab. The safety profile of 
vedolizumab through 19 May 2021 remains consistent with this integrated analysis and no new 
safety signals have been identified. Thus, vedolizumab has a favorable risk to benefit to date. 
The risks (identified and potential) have been assessed in the clinical and nonclinical studies and 
are detailed in the current version of IB. The benefits will be continued access to vedolizumab 
for qualified subjects who have completed participation in qualifying vedolizumab clinical 
studies until vedolizumab is available to the subject through commercial channels, including 
reimbursement, for the subject’s clinical scenario or until subject withdrawal, whichever is 
sooner. 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objective 
5.1.1 Primary Objectives for the Main XAP Study 
• To monitor ongoing safety in subjects with UC and CD and to provide access to vedolizumab 
for qualifying subjects who, in the opinion of the investigator, continue to derive benefit from 
vedolizumab and for whom continued treatment with vedolizumab is desired because there is 
no other comparable product available or the subject may be expected to develop worsening 
of disease if they were to modify treatment. 
Details related to exploratory objectives for the XAP-PK substudy are provided in Appendix E. 
5.2 
Endpoints 
5.2.1 Primary Endpoints for the Main XAP Study 
• Number and percentage of subjects with adverse events (AEs) and serious AEs (SAEs). 
• Number and percentage of subjects with adverse events of special interest (AESIs). 
Details related to exploratory endpoints for the XAP-PK substudy are provided in Appendix E. 
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design of the Main XAP Study 
This is a multinational, multicenter, phase 3b/4, open-label XAP study to monitor ongoing safety 
(eg, AEs, SAEs, and AESIs) and provide access to vedolizumab for qualifying subjects who 
have successfully completed participation in qualifying vedolizumab clinical studies. At this 
time, qualified studies include C13008 and MLN0002-3028. Additional qualifying studies may 
be included at a later date as specified within the protocol for the qualifying vedolizumab study. 
They will not be specifically called out in this protocol, unless the roll-over requires a change to 
the conduct of the main XAP study. The XAP study will start in a staggered manner depending 
on the start-up timelines of the countries where the XAP will be conducted. Eligible subjects will 
be enrolled into the study upon the approval of local sites. 
In this XAP study, subjects will have an enrollment visit at which they will be consented. This 
visit should be in conjunction with the final visit of the qualifying study. Baseline data for the 
subject (eg, medical history, disease history, demographics, and prior therapies) will be obtained 
at the enrollment visit. In addition to the enrollment visit, the subject will have vedolizumab 
dosing visits every 8 weeks (±7 days). The first dose of vedolizumab in this study should occur 
8 weeks (±7 days) after the last dose of study medication in the qualifying study. If indicated, the 
time to the first dose of vedolizumab in this study may be extended, but will be performed no 
later than the safety follow-up visit in the qualifying study. 
If the subject experiences reduction in efficacy on Q8W dosing, the dosing frequency, based on 
the investigator’s judgment of subject’s clinical status and acknowledged by the medical 
monitor, may be changed to Q4W dosing. It will be at the investigator’s discretion when Q8W 
dosing will be reintroduced again.  
Subjects entering from a qualifying study in which the subject was on a more frequent dose can 
stay on at the dose provided in the qualifying study, if medically indicated based on the 
investigator’s clinical judgment and acknowledged by the medical monitor. 
Subjects will remain in the XAP study until vedolizumab is available to the subject through 
commercial channels, including reimbursement, for the subject’s clinical scenario or until subject 
withdrawal, whichever is sooner. If vedolizumab is available to the subject through commercial 
channels, including reimbursement, for Q8W dosing but the subject has not been stable on that 
regimen for the previous 6 months, the subject will only exit the XAP study if vedolizumab will 
be available to the subject through commercial channels at the previous, more frequent dosing 
regimen. If it will not be commercially available at the previous dosing regimen, the subject will 
remain in the XAP study until they are stable for 6 months and can move to commercially 
available Q8W dosing of vedolizumab. 
Within 60 days of the subject having access to vedolizumab through commercial channels, 
including reimbursement, for the subject’s clinical scenario, the subject should have the final 
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study infusion visit. Subjects will return 18 weeks after their final study infusion for a safety 
follow-up visit. 
Safety assessments will be made throughout the treatment period at the infusion visits. 
Physicians will follow the local standard of care guidelines for disease monitoring. Any safety 
information discovered during the routine treatment of a subject should be reported. All SAEs 
and AEs regardless of study medication attribution will be recorded on the electronic case report 
form (eCRF) and analyzed. 
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
the applicable regulatory requirements (including International Council for Harmonisation [ICH] 
guidelines). 
A schedule of assessments is listed in Appendix A. 
The MLN0002-3028 parent protocol is applicable only in sites from Czech Republic, Hungary, 
Italy, and Poland.  
In the event a subject is unable to report to the site for required study visits or procedures in a 
timely manner (ie, within permitted visit windows), due to the coronavirus disease 2019 
(COVID-19) pandemic, alternative procedural considerations or mitigation approaches may be 
followed to maintain subject safety and to ensure data quality and integrity (Section 9.3.7). 
Subjects entering the XAP study from C13008 and who are switching from Q4W to Q8W dosing 
at the time of enrollment, will be eligible to enroll in an optional XAP-PK substudy applicable 
only sites in Australia, Czech Republic, Hungary, New Zealand, Korea (South), Poland, and 
Russia. Details related to study design of the XAP-PK substudy are provided in Appendix E. 
6.2 
Number of Subjects 
The number of subjects will be determined based upon the qualifying subjects who have received 
treatment with vedolizumab, completed participation (having received the final dose of 
vedolizumab but not yet having completed the safety follow-up period) in qualifying 
vedolizumab clinical studies, meet the inclusion/exclusion criteria, and agree to enroll in the 
XAP study. 
Details related to number of subjects for the XAP-PK substudy are provided in Appendix E. 
6.3 
Duration of Study 
Subjects will remain in the XAP study until vedolizumab is available to the subject through 
commercial channels, including reimbursement, for the subject’s clinical scenario or until subject 
withdrawal, whichever is sooner. If vedolizumab is available to the subject through commercial 
channels, including reimbursement, for Q8W dosing but the subject has not been stable on that 
regimen for the previous 6 months, the subject will only exit the XAP study if vedolizumab will 
be available to the subject through commercial channels at the previous, more frequent dosing 
regimen. If it will not be commercially available at the previous dosing regimen, the subject will 
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remain in the XAP study until they are stable for 6 months and can move to commercially 
available Q8W dosing of vedolizumab. Subjects will return 18 weeks after their final study 
infusion for a safety follow-up visit. Subjects will be considered to have completed the XAP 
study once transitioned to commercially available and reimbursed product. 
If a subject exits the XAP study prior to Week 56 because they are moving on to commercially 
available and reimbursed product, the subject will also exit the XAP-PK substudy. The end of 
substudy visit will be conducted at the time of the final XAP dosing visit. Details related to 
duration of study of the XAP-PK substudy are provided in Appendix E. 
6.4 
Justification for Study Design, Dose, and Endpoints 
The benefit-to-risk of vedolizumab is favorable to date (as summarized in the IB, Edition 25 
[Dated 14 July 2021]) in the treatment of UC and CD. The proposed vedolizumab IV dose 
(300 mg every 8 weeks) is consistent with pivotal study data and the approved label information 
[26]. In subjects with moderately to severely active CD or UC, vedolizumab IV 300 mg 
administered as an IV infusion at Weeks 0 and 2 (induction) followed by every 8 weeks or every 
4 weeks 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 and demonstrated an acceptable safety. 
The current XAP study will provide access to vedolizumab for qualifying subjects who, in the 
opinion of the investigator, continue to derive benefit from vedolizumab and for whom continued 
treatment with vedolizumab is desired because there is no other comparable product available or 
the subject may be expected to develop worsening of disease if they were to modify treatment. 
Safety will be monitored through the collection of AEs, SAEs, and AESIs during this study. 
Details related to justification for study design, dose, and endpoints of the XAP-PK substudy are 
provided in Appendix E. 
6.5 
Premature Termination or Suspension of Study or Investigational Site 
6.5.1 Criteria for Premature Termination or Suspension of the Study 
The XAP study will be completed when the last subject completes the study unless one or more 
of the following criteria are satisfied that may require temporary suspension or early termination 
of the study: 
• New information or other evaluation regarding the safety or efficacy of vedolizumab 
indicates a change in the known risk/benefit for vedolizumab, such that the risk/benefit is no 
longer acceptable for subjects participating in the study. 
• Significant violation of GCP that compromises the study objective or subject safety. 
• Prior to the product becoming commercially available, another access program becomes 
available in the country of residence that will provide access to subjects outside of the study.  
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• The study is terminated at a site. 
• The study is terminated by the sponsor. 
Details related to criteria for premature termination or suspension of the XAP-PK substudy are 
provided in Appendix E. 
6.5.2 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 or the site is unable 
to ensure adequate performance of the study. 
6.5.3 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. 
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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria need to be confirmed prior to entry into the treatment period. 
7.1 
Inclusion Criteria 
Any subject who meets the inclusion criteria for the qualifying vedolizumab clinical studies and 
meets any of the following criteria will qualify for entry into the study: 
1. Received vedolizumab (excluding comparator or placebo subjects) during participation in a 
qualifying vedolizumab study. 
2. In the opinion of the investigator, the subject is continuing to derive benefit from 
vedolizumab and continued treatment with vedolizumab is desired because there is no other 
comparable product available or the subject may be expected to develop worsening of 
disease if they were to modify treatment. 
3. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential* agrees to use adequate contraception* from signing of informed 
consent throughout the duration of the study and for 18 weeks after last dose.  
4. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 18 weeks after last dose. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.11, Contraception and Pregnancy Avoidance Procedure, and 
reporting responsibilities are defined in Section 9.1.12, Pregnancy. 
Details related to additional inclusion criteria of the XAP-PK substudy are provided in 
Appendix E. 
7.2 
Exclusion Criteria 
Any subject who meets any of the exclusion following criteria will not qualify for entry into the 
study:  
1. For the subject’s particular clinical scenario, vedolizumab is currently available to the subject 
through commercial channels, including reimbursement.  
2. Subject has any clinical condition or prior therapy that, in the opinion of the investigator, 
would make the subject unsuitable for the study or unable to comply with the dosing 
requirements or poses a risk to the subject being in the study. 
3. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 18 weeks after participating in this study; or intending to donate ova during such 
time period. 
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4. If male, the subject intends to donate sperm during the course of this study or for 18 weeks 
thereafter. 
5. Subject has received a live vaccine in the last 18 weeks or is in need of a live vaccine during 
the study or up to 18 weeks after the last study dose. 
7.3 
Concomitant Procedures and Medications 
During the course of this study, physicians are expected to follow their subjects according to 
acceptable medical practice with regards to disease monitoring and treatment. All medications 
that are administered and all procedures that are performed during the study must be recorded in 
the subject’s eCRF and in the source documents. Concomitant medications for medical 
conditions other than UC or CD are permitted as clinically indicated, subject to specific protocol 
requirements outlined in Section 7.3.1 for excluded medications. Subjects should be up to date 
on TB testing per local requirements. 
7.3.1 Excluded Medications  
The following medications are excluded from the study: 
• Either approved or investigational biological agents for the treatment of non-IBD conditions, 
other than localized injections (eg, intra-ocular injections for wet macular degeneration). 
• All live vaccines during study treatment and for at least 18 weeks after the last dose of study 
medication. 
7.4 
Diet, Fluid, Activity Control 
There are no restrictions on diet or fluid during the study. 
The requirements for the contraception for female subjects of childbearing potential and male 
subjects who are nonsterilized are detailed in the contraception and pregnancy avoidance 
procedures (Section 9.1.11). 
7.5 
Management of Clinical Events 
7.5.1 AEs of Special Interest 
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 in order to 
characterize and understand them and would be described in protocols and instructions provided 
for investigators as to how and when they should be reported to Takeda. 
7.5.2 Infusion-Related Hypersensitivity Reactions 
Currently, there is no evidence to support the routine prophylactic administration of 
premedication (eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence, 
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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 medication 
infusion. Corticosteroids, if given as premedication, should be limited to the day of infusion. 
Subjects will be monitored for acute infusion-related hypersensitivity reactions during infusion 
and for at least 1 hour after the completion of each administration of vedolizumab. Epinephrine 
and parenteral diphenhydramine must be readily available for immediate use in case an 
infusion-related reaction occurs. Site personnel must be able to detect and treat infusion-related 
reactions. 
Subjects should be instructed to report the development of rash, hives, pruritus, flushing, 
urticaria, etc. that may represent an infusion-related reaction to vedolizumab. If any signs or 
symptoms of infusion-related reactions are observed during the infusion, administration of 
vedolizumab must be immediately discontinued and the subject treated as medically appropriate. 
In the case of a mild reaction, vedolizumab infusion may be reinitiated (with appropriate 
premedication) at the discretion of the investigator. Subjects with a severe or serious 
infusion-related reaction (eg, stridor, angioedema, life-threatening change in vital signs) must be 
withdrawn from the study. 
In all cases of infusion-related reactions, the medical monitor must be informed as soon as is 
practical. The disposition of subjects with less severe infusion-related reactions should be 
discussed with the medical monitor. All cases of infusion-related reactions that do not meet SAE 
definitions as specified in Section 10.1.4 will be collected as AEs. The intensity, relationship to 
study medication, action taken and outcome for all cases of infusion-related reactions, regardless 
of seriousness, will be recorded on the AE eCRF. 
7.5.3 Serious Infection 
Subjects will be monitored for signs and symptoms of serious infection during the study. 
Subjects with signs and symptoms suggestive of infection, including GI infections, opportunistic 
infections (such as PML) will be treated as clinically indicated; interventions may include 
antibiotic treatment, if appropriate, and/or discontinuation of concomitant immunomodulatory 
medications. Blood, sputum, urine, and/or stool cultures will be obtained as appropriate for 
detection and diagnosis of infection per local guidelines. Withholding or terminating 
vedolizumab administration may be considered as described in Section 7.6. Failure to respond to 
standard therapies for infection will be recorded as part of AE collection.  
7.5.4 Malignancy 
All cases of malignancies that are detected during the study will be reported as AEs or SAEs as 
defined in Section 10.1. Local medical practices will apply. Monitoring for colorectal mucosal 
dysplasia and cancer will be performed per local guidelines. 
7.5.5 Liver Injury 
Liver injury is defined in Section 10.2.3. 
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7.6 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study, or study 
medication should be recorded in the eCRF using the following categories. For 
baseline/enrollment failure subjects, see Section 9.1.13. 
1. AE. The subject has experienced an AE that requires the subject to discontinue vedolizumab 
or the subject elects to discontinue vedolizumab. 
2. Significant protocol deviation. The discovery after the first dose of study medication that the 
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health. 
3. Lost to follow-up. The subject did not return to the clinic or for infusion visits.  
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
5. Clinical study. The subject consents to participation in another clinical study. 
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
7. Pregnancy. The subject is found to be pregnant.  
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.12. 
8. The investigator or subject feels there is no longer an adequate benefit being derived from 
vedolizumab, or 
9. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.7 
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 7.6. In addition, a 
subject may discontinue their 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, subjects should return 18 weeks after their final study 
infusion for a safety follow-up visit. 
Details related to procedures for discontinuation or withdrawal of a subject in the XAP-PK 
substudy are provided in Appendix E. 
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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 study sites will be supplied by the sponsor with the following medication in an open-label 
manner: vedolizumab IV 300 mg/vial, for single use, in 20 mL vials. The study medication will 
be provided in a glass vial as a lyophilized solid for reconstitution using 4.8 mL of sterile water 
for injection and dilution in 250 mL of sterile 0.9% sodium chloride. Each vial will be packaged 
in an appropriately labeled single vial carton. Both the primary and secondary label information 
will fulfill all requirements specified by local governing regulations.  
Additional reference information and administration instructions can be found in the Pharmacy 
Manual. 
8.1.1.2 Other Protocol-Specified Materials 
The following supplies will also be required for study treatment administration and are to be 
provided by the clinical study site: 
Bottled sterile water for injection (for vedolizumab reconstitution). 
250 mL 0.9% sodium chloride for injection in polyvinyl chloride (PVC) IV bag(s) or 250 mL 
0.9% sodium chloride in alternative IV bags or bottles listed in the Pharmacy Manual. 
PVC infusion line or alternative infusion line listed in the Pharmacy Manual. 
8.1.2 Storage 
Study medication must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or its designee for destruction. Study medication 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 
Subjects will receive a 300 mg dose of vedolizumab by IV infusion over approximately 
30 minutes at every 8 weeks (±7 days) until vedolizumab is available to the subject through 
commercial channels, including reimbursement, for the subject’s clinical scenario or until subject 
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withdrawal, whichever is sooner. Longer infusion times of up to 60 minutes may be used based 
on study observations. All subjects will be observed at the clinical site for at least 1 hour after the 
completion of each dose in a room where appropriate treatment for infusion-related reactions is 
available. The subject should be considered clinically stable by the investigator or designee prior 
to discharge. The first dose of vedolizumab in this study should occur 8 weeks (±7 days) after the 
last dose of study medication in the qualifying study. If indicated, the time to the first dose of 
vedolizumab in this study may be extended, but will be performed no later than the safety 
follow-up visit in the qualifying study. 
If the subject experiences reduction in efficacy on Q8W dosing, the dosing frequency, based on 
the investigator’s judgment of subject’s clinical status and acknowledged by the medical 
monitor, may be changed to Q4W dosing. It will be at the investigator’s discretion when Q8W 
dosing will be reintroduced again. 
Subjects entering from a qualifying study in which the subject was on a more frequent dose can 
stay on at the dose provided in the qualifying study, if medically indicated based on the 
investigator’s clinical judgment and acknowledged by the medical monitor. 
8.1.4 Overdose 
An overdose is defined as a known deliberate or accidental administration of study medication, 
to or by a study subject, at a dose above that is assigned to that individual subject according to 
the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on an AE eCRF according to Section 10.0. 
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2. 
In the event of drug overdose, the subject should be treated symptomatically. 
8.2 
Drug Dosing and Dispensing Procedures 
Subjects will be assigned to receive their treatment every 8 weeks (±7 days) unless the medical 
monitor provides approval for the subject to enter the study at the dosing regimen in their 
qualifying study. The investigator or designee will access the interactive voice/web response 
system (IVRS/IWRS) at enrollment visit to obtain the study-specific subject identification (ID) 
number (subject number). Study medication will be prepared according to the procedures 
outlined in the Pharmacy Manual.  
During this contact, the investigator or designee will provide the necessary subject-identifying 
information, including the subject number assigned at enrollment visit. The Medication ID 
Number of the study medication to be dispensed will then be provided by the IVRS/IWRS. If 
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sponsor-supplied drug is lost or damaged, the site can request a replacement from IVRS/IWRS 
(Refer to IVRS/IWRS Manual provided separately). The Medication ID Number will be entered 
into the eCRF. At subsequent infusion visits, the investigator or designee will again contact the 
IVRS/IWRS to request additional study medication for a subject. The Medication ID Number of 
the study medication to be dispensed will be provided by the IVRS/IWRS. The Medication ID 
Number will be entered into the eCRF.  
Subjects will be assigned to receive the next available Medication ID Number allocated to each 
study site. The Medication ID Number will be entered into the eCRF. 
8.3 
Blinding and Unblinding  
This is an open-label study; there is no blinding. 
8.4 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
its designee. 
The investigator or designee must ensure that the sponsor-supplied drug (vedolizumab IV) 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 its designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and faxing per instructions provided on the form/by recording in IVRS/IWRS. If there are 
any discrepancies between the packing list versus the actual product received, Takeda must be 
contacted to resolve the issue. The packing list should be filed in the investigator’s essential 
document file. 
The investigator 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: 
• Monitoring expiration dates (monitored via IVRS/IWRS). 
• Verifying that the log is completed for the Medication ID used to prepare each dose. 
• Verifying that all containers used are documented accurately on the log. 
• Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
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The IVRS/IWRS will include all required information as a separate entry for each subject to 
whom sponsor-supplied drug is dispensed. 
The investigator or designee must record the current inventory of all sponsor-supplied drugs 
(vedolizumab IV) on a sponsor-approved drug accountability log. The following information will 
be recorded at a minimum: protocol number and title, name of the investigator, site identifier and 
number, description of sponsor-supplied drugs, expiry or re-test date and amount dispensed, 
including initials, seal, or signature of the person dispensing the drug, and the date and amount 
returned to the site by the subject, including the initials, seal, or signature of the person receiving 
the sponsor-supplied drug. The log should include all required information as a separate entry for 
each subject (by subject identifier) to whom sponsor-supplied drug is dispensed. 
The investigator’s designated site staff administering the study medication infusion must 
complete an individual subject accountability log to document if infusion was complete or if 
incomplete and study medication was returned to the pharmacy, including the date and amount 
returned to the pharmacy, including the initials, seal, or signature of the person administering the 
infusion. 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform remote sponsor-supplied drug accountability and reconciliation before 
sponsor-supplied drugs are returned to the sponsor or its designee for destruction. If required by 
local regulations and the process is reviewed and approved by sponsor, destruction can be 
performed locally or by a contracted third party (for details refer to Section 6 of Pharmacy 
Manual). 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 its 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. The subjects enrolling in 
this study will have participated in a qualifying vedolizumab study and will receive a dosing 
regimen as detailed in Section 6.1 and Section 8.1.3. Details of COVID-19-related study 
procedural changes are provided in Section 9.3.7. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2 and Appendix C. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. During the consent process, subjects will be made 
aware of the known and potential risks of vedolizumab IV treatment, infusion visits, and what to 
report to their health care professional in case of AEs. All subjects will be given an opportunity 
to ask questions. 
A unique subject ID number (subject number) will be assigned to each subject at the time that 
informed consent is obtained through the IWRS/IVRS system; this subject number will be used 
throughout the study. 
Details related to the informed consent procedure of the XAP-PK substudy are provided in 
Appendix E. 
9.1.2 Alert Card 
An alert card specifically for this study that denotes key study information will be distributed at 
the enrollment visit and 18-week safety follow-up visit. 
9.1.3 Assessment for Continued Eligibility 
At each visit, the investigator should assess the subject for continued eligibility (see Section 7.6) 
and determine if vedolizumab is available to the subject through commercial channels, including 
reimbursement, for the subject’s clinical scenario. 
9.1.4 Demographics, Medical History, and Prior Therapies 
Demographics information, medical history, and prior therapies will be obtained for all subjects 
at the enrollment visit. 
For this XAP study, medical history refers to any significant conditions or diseases relevant to 
the disease under study that stopped at or prior to signing of informed consent for the XAP study, 
and may include resolved AEs from the qualifying study. AEs that resolved during the qualifying 
study but were significant, that is, represented a new diagnosis (eg, myocardial infarction) and/or 
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resulted in unplanned surgery or procedure (eg, coronary artery bypass graft surgery) or met any 
of the seriousness criteria should be recorded into the medical history. All moderate, severe, and 
serious AEs which resolved during the qualifying study will be captured into the medical history 
of the XAP study. 
Where possible, all prior medications for the treatment of UC or CD, including date of diagnosis, 
with the reason for discontinuation, are to be collected for all subjects at the enrollment visit. 
Ongoing conditions are considered concurrent medical conditions (see Section 9.1.5). 
9.1.5 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. Concurrent medical conditions include clinically 
significant laboratory, ECG, or physical examination abnormalities. This will be obtained for all 
subjects at the enrollment visit. The condition (ie, diagnosis) should be described. AEs from the 
qualifying study which are ongoing at the time of signing informed consent to participate in this 
XAP study will be captured as concurrent medical conditions. 
9.1.6 Disease History 
The disease (UC or CD) history information will be confirmed for all subjects at the enrollment 
visit. 
9.1.7 Physical Examination Procedure 
A symptom-directed physical examination will be performed at baseline. Any clinically 
significant findings on the physical examination will be recorded as AEs. If a physical 
examination has been conducted in the previous 24 hours, the results of that examination can be 
used, but clinically significant results will be captured and considered as concurrent medical 
conditions. 
9.1.8 Vital Sign Procedure 
Vital signs, including body temperature, respiratory rate, supine blood pressure (resting more 
than 5 minutes), and pulse (beats per minute), will be obtained at every visit. At infusion visits, 
vital sign measurements will be recorded prior to dosing. At the enrollment visit, if vital sign 
measurements have been conducted in the previous 24 hours, the results of those measurements 
can be used. 
9.1.9 Weight, Height, and Body Mass Index  
A subject should have weight measured at each visit while wearing indoor clothing and with 
shoes off. At infusion visits, weight will be recorded prior to dosing. Height will be measured 
only at enrollment. At the enrollment visit, if height and/or weight have been recorded in the 
previous 24 hours, the results of those measurements can be used. The Takeda standard for 
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collecting height is centimeters without decimal places and for weight it is kilograms with 
1 decimal place. 
The body mass index (BMI) should be derived as follows:  
Metric:  
BMI = weight (kg) / [height (m2)] 
The values should be reported to 1 decimal place by rounding. 
Details related to weight, height, and BMI for the XAP-PK substudy are provided in 
Appendix E. 
9.1.10 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over-the-counter. Concomitant medication is 
not provided by Takeda. The information on concomitant medications will be collected for all 
subjects at the enrollment visit. At each study visit, subjects will be asked whether they have 
taken any medication other than the study medication (used from signing of informed consent 
through the end of the study), and all medications, including vitamin supplements, 
over-the-counter products, and oral herbal preparations, must be recorded in the eCRF. 
Subjects must be instructed to consult the investigator before taking any medications, including 
over-the-counter products. 
Any medications that are ongoing at the time of enrollment into the current study will be 
reviewed at each visit and recorded in the eCRF. 
9.1.11 Contraception and Pregnancy Avoidance Procedure 
For male subjects: 
From signing of informed consent, throughout the duration of the study, and for 18 weeks after 
last dose of study medication, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (eg, condom with 
spermicidal cream or jelly; or vaginal ring plus male condom). (Protocol Amendment No. 1: the 
use of spermicides does not apply for South Africa. See footnotes below.) In addition, they must 
be advised not to donate sperm during this period. 
For female subjects of childbearing potential: 
From signing of informed consent, throughout the duration of the study, and for 18 weeks after 
last dose of study medication, female subjects of childbearing potential* who are sexually active 
with a nonsterilized male partner** must use adequate contraception. In addition, they must be 
advised not to donate ova during this period. 
*Females NOT of childbearing potential are defined as those who have been surgically 
sterilized (hysterectomy, bilateral oophorectomy, or tubal ligation) or who are postmenopausal 
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(eg, defined as at least 1 year since last regular menses with a follicle-stimulating hormone 
>40 IU/L or at least 5 years since last regular menses, confirmed before any study medication 
is implemented). 
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate. 
An acceptable method of contraception is defined as one that has no higher than a 1% failure 
rate. In this study, where medications and devices containing hormones are included, the only 
acceptable methods of contraception are:  
Barrier Methods (Each Time 
the Subject has Intercourse): 
Intrauterine Devices: 
Hormonal Contraceptives: 
Male condom PLUS 
spermicide. 
Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide. 
Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide. 
Copper T PLUS condom 
or spermicide. 
Progesterone T PLUS 
condom or spermicide. 
Implants. 
Hormone shot/injection. 
Combined pill. 
Minipill. 
Patch. 
Vaginal ring PLUS male condom 
and spermicide. 
Protocol Amendment No. 1 (South Africa): The use of spermicides does not apply for South Africa since these 
products have been removed from the list of Health Authority–approved medications and are therefore not 
commercially available. South African subjects will be counselled to use one of the alternative double-barrier 
methods specified above, and this will also be specified in the country-specific informed consent form. 
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study. 
During the course of the study, regular urine human chorionic gonadotropin (hCG) pregnancy 
tests will be performed via dipstick test only for women of childbearing potential before dosing 
at each infusion visit and subjects will receive continued guidance with respect to the avoidance 
of pregnancy and sperm donation as part of the study procedures (Appendix A). In addition to a 
negative urine hCG pregnancy test at screening, female subjects also must have a negative urine 
hCG pregnancy test prior to receiving each IV dosing. If at screening, a subject has had a 
pregnancy test in the last 24 hours, the results of that test can be used and the test does not need 
to be readministered. 
9.1.12 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and vedolizumab 
should be immediately discontinued. In addition, any pregnancies in the partner of a male subject 
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during the study or for 18 weeks after the last dose of study medication should also be recorded 
following authorization from the subject’s partner. 
If the pregnancy occurs during administration of study medication (after enrollment visit) or 
within18 weeks of the last dose of study medication, a pregnancy notification form should be 
completed and the pregnancy should be reported immediately to the contact listed in Section 1.0. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received. 
All pregnancies in subjects will be followed up to final outcome, using the pregnancy 
notification form. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted. 
9.1.13 Documentation of Baseline/Enrollment Failure 
Investigators must account for all subjects who sign an informed consent. 
If the subject is found to be not eligible at the enrollment visit, the investigator should complete 
the eCRF. The IVRS/IWRS should be contacted as a notification of baseline/enrollment failure. 
The primary reason for baseline/enrollment failure is recorded in the eCRF using the following 
categories: 
• AE. 
• Did not meet inclusion criteria or did meet exclusion criteria (specify reason). 
• Significant protocol deviation. 
• Other, specify. 
Subject numbers assigned to subjects who fail baseline/enrollment should not be reused. 
9.1.14 Documentation of Study Entrance 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria specified in 
Section 7.1 and Section 7.2, respectively, are eligible for entrance into the treatment period. 
If the subject is found to be not eligible for the treatment period, the investigator should record 
the primary reason for failure on the applicable eCRF. 
9.1.15 Collection of AEs and SAEs 
AEs and SAEs will be collected from the time the subject signs the informed consent to 
participate in the study through to the final safety follow-up visit. 
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SAEs that occur after the end of study and are considered to be related to vedolizumab will be 
collected and forwarded to Takeda Pharmacovigilance (see Section 10.2). Definitions, 
documentation, and reporting of SAEs are described in detail in Section 10.0. 
Details related to sample collection and analysis and collection of serum for PK sampling for the 
XAP-PK substudy are provided in Appendix E. 
Details related to partial Mayo score and Harvey-Bradshaw Index Score for the XAP-PK 
substudy are provided in Appendix G and Appendix H, respectively. 
9.2 
Monitoring Subject Treatment Compliance 
A vedolizumab dispensing log, including records of drug received from the sponsor and volume 
of vedolizumab dispensed to each subject intravenously, will be maintained by the site. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time points. 
9.3.1 Enrollment Visit 1 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0. If the subject has satisfied all of the inclusion criteria and none of the 
exclusion criteria, the subject should be enrolled using the IVRS/IWRS as described in 
Section 8.2. See Section 9.1.13 for procedures for documenting baseline/enrollment failures. 
Procedures to be completed at the enrollment visit for the XAP study can be found in the 
Schedule of Study Procedures (Appendix A). Subjects will be given infusion instructions for the 
first dose of study medication as described in Section 8.1.3. 
Details related to enrollment visit 1 for the XAP-PK substudy are provided in Appendix E and 
study procedures for XAP-PK substudy are provided in Appendix F. 
9.3.2 Treatment Period 
Subjects entering the XAP study will receive Q8W dosing. 
The first dose of vedolizumab in this study should occur 8 weeks (±7 days) after the last dose of 
study medication in the qualifying study. Further details related to dosing and regimen have been 
provided in Section 8.1.3.  
Subjects entering from a qualifying study in which the subject was on a more frequent dose can 
stay on at the dose provided in the qualifying study, if medically indicated based on the 
investigator’s clinical judgment and acknowledged by the medical monitor. 
The subjects will visit an infusion center for their infusion as per the dosing regimen. Procedures 
to be completed at infusion visits can be found in the Schedule of Study Procedures 
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(Appendix A). AEs will be collected at each visit. Details of COVID-19-related visit window 
changes are provided in Section 9.3.7. 
Subjects will continue in the XAP study until vedolizumab is available to the subject through 
commercial channels, including reimbursement, for the subject’s clinical scenario or until subject 
withdrawal, whichever is sooner. Subjects will return 18 weeks after their final study infusion for 
a safety follow-up visit. 
Details related to treatment period for the XAP-PK substudy are provided in Appendix E. 
9.3.3 Final Infusion Visit 
Within 60 days of the subject having access to vedolizumab through commercial channels, 
including reimbursement, for the subject’s clinical scenario, the subject should have the final 
study infusion visit.  
9.3.4 Routine or Unscheduled Office Visits  
During the course of the study, subjects will continue to be treated by their physician. Any AEs 
discovered during routine or unscheduled office visits must be reported.  
The visit details will be captured in the eCRF. 
9.3.5 Post Study Care 
Subjects will remain in the study until vedolizumab is available to the subject through 
commercial channels, including reimbursement, for the subject’s clinical scenario or until subject 
withdrawal, whichever is sooner. There will be a follow-up safety visit for the subjects 18 weeks 
after the subject’s final study dose. Subjects should return for the follow-up visit regardless of 
whether they remain on vedolizumab after the study (ie, they left the study due to the availability 
of vedolizumab or they withdrew from the study for other reasons). Procedures to be completed 
at the safety follow-up visit can be found in the Schedule of Study Procedures (Appendix A). 
9.3.6 Follow-up Period 
Procedures to be completed during the follow-up period in the main XAP study can be found in 
the Schedule of Study Procedures (Appendix A). 
Details related to follow-up period for the XAP-PK substudy are provided in Appendix E. 
9.3.7 COVID-19-Related Protocol Considerations/Mitigations 
On a temporary basis, in order to maintain subject safety, confidentiality, and study integrity in 
the context of healthcare delivery challenges presented by the COVID-19 pandemic, subjects 
who may be impacted should contact the principal investigator to determine the best course of 
action. Depending on the impact, in some cases it may be possible to arrange for alternative 
solutions as permitted by local regulations [28,29]. Any decision on procedural changes should 
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be made on a case-by-case basis by the principal investigator in consultation with the study team 
and the medical monitor, while maintaining subject safety and confidentiality as the priority. 
Missing data, remote visits, changes to assessment approaches, and altered visit windows during 
the COVID-19 public health emergency may affect the study results. Thus, it is important to 
identify all protocol deviations and altered data collection (ie, remote data collection or missing 
data points) or assessment methods. It is crucial that any deviations related to COVID-19 be 
clearly identified as such in the eCRF. 
The following procedural changes may be considered: 
• Scheduling of study visits: If modifications to the study visits schedule are necessary, the 
investigator must submit notification via the PPD electronic Protocol Inquiry Platform (ePIP) 
system for medical monitor’s review. Each modification will be evaluated on a case-by-case 
basis to assess safety concerns/risk to the subject, as well as study impact. The medical 
monitor’s review will be documented within the ePIP system. The investigator’s clinical 
expertise and discretion as it pertains to the health and wellbeing of the subject, as well as 
familiarity with local conditions, will ultimately determine the best course of action for the 
subject, including whether the subject can safely remain in the study to complete the study 
procedures per protocol. 
– The acceptable windows for study visits and study drug dosing may be expanded as 
follows: 
i) 
Q4W regimen: from every 4 weeks (±7 days) to every 4 weeks (±10 days). 
ii) 
Q8W regimen: from every 8 weeks (±7 days) to every 8 weeks (±14 days). 
• If a subject is unable to physically report to the site for required study visits (to complete any 
of the study procedures in whole or in part), remote visits/checks (if appropriate) may be 
performed by the investigator via phone contacts and missing procedures will be captured as 
protocol deviations. Two or more consecutive missed infusion visits/checks, or a missed 
safety follow-up visit, will be considered as significant deviations. In the event of 2 
consecutive missed infusion visits, the subject’s further study participation will be based on 
the investigator’s opinion that the subject would derive benefit from vedolizumab if 
continued in the study and there were no safety concerns. The investigator must submit 
notification via the PPD ePIP system for medical monitor’s approval before the subject could 
restart study medication. All collected data will be recorded in the subject’s medical record 
and captured within the eCRF, as applicable. As a check on subject’s safety and wellbeing, at 
minimum, sites will attempt to collect the following data per the protocol: 
– Assessment for continued eligibility (Section 9.1.3). 
– Documentation of concomitant medications (Section 9.1.10). 
– Confirm contraception and pregnancy avoidance procedures (Section 9.1.11) and 
pregnancy reporting responsibilities (Section 9.1.12). 
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– Collection of AEs, SAEs, and AESIs (Section 9.1.15 and Section 7.5.1). (Note: If a 
subject has a known infection of COVID-19 and was deemed serious (based on the SAE 
criteria [Section 10.1.4]), then the event will be recorded as an AESI. If the subject is 
asymptomatic or having mild symptoms, then the event will be recorded only as an AE.) 
• In the event a subject misses the site visit(s), the following scenarios may be considered 
while rescheduling missed visits: 
– If a subject misses 1 site visit: The subject should be brought back within the acceptable 
window and as close to their originally planned dose regimen as possible. 
– If a subject misses ≥2 site visits: The subject should be brought back as soon as possible 
and their originally planned dose regimen will resume from that point forward. 
 In all cases, the investigator’s judgment and knowledge about the subject’s individual 
scenario will be relied upon. The investigator must submit notification via the PPD 
ePIP system for medical monitor’s review once the visit date has been rescheduled. 
• If sites are unable to adhere to the planned infusion schedule, subjects may be transferred to 
investigational sites away from risk zones to complete required visits, provided that the 
mitigation plan has been reviewed in advance by Takeda and the following criteria are met: 
– Study drug accountability, preparation, handling, and administration is performed, and 
documented, in accordance with the study protocol and approved Pharmacy Manual. 
– All study related activities are conducted only by qualified study staff who have been 
trained on the protocol and have been delegated by the investigator to perform specific 
study tasks. 
– Any deviations are documented and reported to PPD (and captured within the eCRF, as 
appropriate), as well as notified to the regulatory authorities as locally applicable. 
– All relevant data are reported in the subject’s medical record and captured within the 
eCRF. 
Note: Reversal of COVID-19-related allowances may be permitted in countries where measures 
are in place to maintain subject safety and to ensure study integrity and within the timelines 
specified per country regulations.  
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 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. 
10.1.2 Product Complaint 
A product complaint (PC) is a verbal, written, or electronic expression that implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug product 
and/or device (eg, prefilled syringe). 
An investigator who is made aware of or identifies a potential PC should immediately report the 
event to Takeda in accordance with the contact list provided to the site. Whenever possible, the 
associated product should be maintained in accordance with the instructions pending further 
guidance from a Takeda representative. 
10.1.3 Additional Points to Consider for AEs 
An untoward finding generally may: 
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions of underlying disease should not be considered AEs.) 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
• Be considered unfavorable by the investigator for any reason. 
• AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as an 
AE. 
Diagnoses versus signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
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recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s). 
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters are only considered to be AEs if they are 
judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation, or monitoring of an abnormality is not considered an intervention. 
• If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE. 
Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as AEs. Baseline evaluations 
(eg, laboratory tests, ECG, X-rays, etc.) should NOT be recorded as AEs unless related to 
study procedures. However, if the subject experiences a worsening or complication of such a 
concurrent condition, the worsening or complication should be recorded appropriately as an 
AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”). 
• If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from baseline (eg “worsening of…”). 
• If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an 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 AEs: 
• If the subject experiences a worsening or complication of an ongoing AE after starting 
administration of the study medication, the worsening or complication should be recorded 
appropriately as an AE. Investigators should ensure that the AE term recorded captures the 
change in the condition (eg, “worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
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should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”). 
Changes in intensity of AEs: 
• If the subject experiences changes in intensity of an AE, the event should be captured once 
with the maximum intensity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening 
of the condition should be captured appropriately as 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 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 
AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested side 
effects will be considered 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 subject HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
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6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
• Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a). 
Table 10.a 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Hepatic necrosis 
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia 
Acute liver failure 
Anaphylactic shock 
Malignant hypertension 
Acute renal failure 
Convulsive seizure 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis  
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome 
Confirmed or suspected transmission of infectious agent 
by a medicinal product 
 
Neuroleptic malignant syndrome/malignant hyperthermia 
 
Spontaneous abortion/stillbirth and fetal death 
AE: adverse event. 
AEs 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 Section 10.2.2 and Section 10.3). 
10.1.5 Intensity of 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. 
10.1.6 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
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Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug 
cannot be ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs, and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs, and concurrent treatments. 
10.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all 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.  
10.1.8 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
physician. 
10.1.9 Stop Date  
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
10.1.10 Frequency  
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous. 
10.1.11 Action Concerning Study Medication 
• Drug withdrawn – a study medication is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study medication. 
• Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
• Not Applicable – a study medication was stopped for a reason other than the particular AE; 
eg, the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE. 
• Dose Interrupted – the dose was interrupted due to the particular AE. 
• Dosing Frequency – the dosing frequency could be increased to qualifying study dosing 
regimen as agreed between the medical monitor and investigator on clinical justification, 
such as AEs, including flares or if the subject loses efficacy on Q8W dosing. The dosing 
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frequency will be decreased to every 8 weeks for subjects who were on prior study dosing 
regimen other than Q8W dosing in the qualifying studies or for subjects whose dosing 
frequency was changed to qualifying study dosing due to AEs, including flares as per 
investigator’s discretion. 
10.1.12 Outcome 
• Recovered/Resolved – Subject returned to first assessment status with respect to the AE. 
• Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE with the condition remaining “recovering/resolving.” 
• Not recovered/not resolved – there is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, signs/ symptoms, or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE state remaining “Not 
recovered/not resolved.” 
• Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis). 
• Fatal – the AEs which are considered as the cause of death.  
• Unknown – the course of the AE 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 AE Collection Period 
AEs from the qualifying study which are ongoing at the time of signing informed consent to 
participate in this study will not be collected as AEs in this study but will be captured as 
concurrent medical conditions (see Section 9.1.5). 
Collection of AEs will commence from the time that the subject signs the informed consent to 
participate in the study. Routine collection of AEs will continue until the final safety follow-up 
visit. 
10.2.1.2 AE Reporting 
At each infusion 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. 
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Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious ongoing AE 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 ongoing AEs, related or unrelated to the study procedure, need not to be 
followed-up for the purposes of the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline or until there is a satisfactory explanation 
for the changes observed. All AEs will be documented in the AE page of the eCRF, whether or 
not the investigator concludes that the event is related to study drug. The following information 
will be documented for each event: 
1. Event term. 
2. Start and stop date and time (if available). 
3. Intensity. 
4. Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (related or not related) (not completed for ongoing AEs). 
5. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
6. Action concerning study medication (not applicable for ongoing AEs). 
7. Outcome of event. 
8. Seriousness. 
10.2.1.3 Special Interest AE Reporting 
If an AESI, which occurs during the treatment period or the follow-up period, is considered to be 
clinically significant based on the criteria in Section 7.5, it should be recorded in a special 
interest AE eCRF or SAE form. The applicable form should be completed and reported to the 
SAE reporting contact in Section 1.1 within 24 hours. 
The special interest AEs have to be recorded as AEs in the eCRF. An evaluation form along with 
all other required documentation must be submitted to the sponsor/the clinical contract research 
organization (CRO) within 24 hours. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period, it should be reported according to the 
following procedure: 
A Takeda SAE eCRF or 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: 
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• A short description of the event and the reason why the event is categorized as serious. 
• Subject ID number. 
• Investigator’s name. 
• Name of the study medication(s). 
• Causality assessment. 
The SAE eCRF should be completed within 24 hours of first onset or notification of the event. 
However, as a back-up, if required, the SAE form should be completed and reported to Takeda 
Pharmacovigilance or designee within 24 hours to the attention of the contact listed in 
Section 1.1. 
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
10.2.3 Reporting of Abnormal LFT 
If a subject is noted to have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
elevated >3 × upper limit of normal (ULN) on 2 consecutive occasions during routine blood 
collection by the attending physician, the abnormality should be recorded as an AE. In addition, 
if LFT increases, eCRF must be completed providing additional information on relevant recent 
history, risk factors, clinical signs and symptoms, and results of any additional diagnostic tests 
performed. 
If a subject is noted to have ALT or AST >3 × ULN and total bilirubin >2 × ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the medical monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. In addition, if LFT 
increases, eCRF must be completed and transmitted with the Takeda SAE form. 
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 to the sponsor (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. 
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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 its designee, SUSARs will be submitted to the 
regulatory authorities as an expedited report within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to their IRB or IEC in accordance with national regulations. 
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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, adjudication committee, or clinical 
endpoint committee will be used in this study. 
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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, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary (WHODRUG). 
12.1 
eCRFs  
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor or 
delegated CRO will make arrangements to train appropriate site staff in the use of the eCRF. 
These forms are used to transmit the information collected in the performance of this study to the 
sponsor and regulatory authorities. eCRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.  
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
The principal investigator must review the data change for completeness and accuracy, and must 
sign, or sign and seal, and date. 
The eCRFs will be remotely reviewed for completeness and acceptability by study monitors 
periodically. 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 ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), 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, 
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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, ICH E6 Section 4.9.5 requires the 
investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years 
after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Site Agreement between the 
investigator and sponsor. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. 
The investigator should contact and receive written approval from the sponsor before disposing 
of any such documents as follows: 
1. The day on which marketing approval of the study medication is obtained (or the day 3 years 
after the date of notification in the case that the investigation is discontinued). 
2. The day 3 years after the date of early termination or completion of the clinical study.  
In addition, the investigator and the head of the institution should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan will be prepared and finalized prior to database lock. This document 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
A data review will be conducted prior to database lock. This review will assess the accuracy and 
completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods. 
13.1.1 Analysis Sets 
The full analysis set (FAS) will include all enrolled subjects who receive at least 1 dose of study 
medication and will be used for the safety analyses. 
Details related to analysis set for the XAP-PK substudy are provided in Appendix E. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized. For continuous variables, 
summary statistics (nonmissing values, mean, median, standard deviation, minimum, and 
maximum) will be generated. For categorical variables, the counts and percentages of each 
possible value will be generated.  
Medical history and concurrent medical conditions will be summarized by system organ class 
(SOC) and preferred term (PT). Medication history and concomitant medications will be 
summarized by PT.  
13.1.3 Efficacy Analysis 
No efficacy analyses are planned for this XAP study. 
13.1.4 Safety Analysis 
Safety analysis will be summarized using the FAS. 
All analyses will be descriptive, and no formal statistical hypothesis testing is to be performed. 
Safety evaluations will be based on incidence, intensity and type of AEs, and vital signs. 
Descriptive statistics will be calculated.  
The number and percentage of subjects with treatment-emergent adverse events (TEAEs, defined 
as any AEs, regardless of relationship to study medication), AESIs (ie, serious infections, 
including opportunistic infections, such as PML, malignancies, liver injury, infusion-related 
hypersensitivity reactions, and injection site reactions), AEs leading to discontinuation, and 
SAEs that occur from the time of signing informed consent form and up to the safety follow-up 
visit will be summarized by MedDRA SOC, high-level term (HLT), and PT overall, by intensity, 
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and by relationship to study medication. Separate summaries will also be generated for TEAEs 
overall and by intensity.  
To summarize the number of subjects with AEs, subjects reporting the same event more than 
once will have that event counted only once within each SOC, HLT, and PT. All AEs will be 
presented in separate data listings. Exposure-adjusted AEs will also be presented. 
Absolute values and change from baseline in vital sign measurements will be summarized. Vital 
sign data will be presented in data listings. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned for this XAP study. 
However, interim looks at study data to review safety and treatment persistence of study subjects 
might be done. 
13.3 
Determination of Sample Size 
The main XAP study is not sized based on power considerations. The number of subjects will be 
determined as discussed in Section 6.2. 
Details related to substudy analysis for the XAP-PK substudy are provided in Appendix E. 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring  
The study site will be monitored remotely by the CRO periodically during the study to ensure 
that all aspects of the protocol are followed and will include an electronic data capture system, 
which has a set of automatic data checks with data queries for programmed data collection. 
There will be monitoring of study site by telephone to ensure that the study drug supplies have 
been provided and protocol instructions are well understood and applied. 
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 its 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 IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the 
sponsor or its designee for any significant deviation from the protocol. 
Details of how to document COVID-19-related protocol deviations are provided in Section 9.3.7. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or its 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 US Food and Drug Administration [FDA], the 
United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in 
Section 14.1. 
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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. The primary objective of the 
study is to monitor ongoing safety in subjects with UC and CD and to provide access to 
vedolizumab for qualifying subjects who, in the opinion of the investigator, continue to derive 
benefit from vedolizumab and for whom continued treatment with vedolizumab is desired 
because there is no other comparable product available or the subject may be expected to 
develop worsening of disease if they were to modify treatment. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align their 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or its 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 their 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 its designee will supply relevant documents for submission to the respective IRB 
or IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, 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 its designee before commencement of the study 
(ie, before shipment of the sponsor-supplied study 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, ICF) reviewed; and state the approval date. The 
sponsor will notify site once the sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor has received permission from competent 
authority to begin the study. Until the site receives notification no protocol activities, including 
screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, 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 
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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. The study is being funded by Takeda. Payments for 
the conduct of the study that will be made to each study site and/or investigator will be specified 
in the Clinical Study Site Agreement. 
All investigators and sub-investigators must declare potential conflicts of interests to the sponsor. 
The sponsor will provide a financial disclosure form that must be signed by each investigator and 
sub-investigator before the study starts at their study site; in addition, any potential conflicts of 
interest that are not covered by this financial disclosure form should be disclosed separately to 
the sponsor prior to the start of the study at their site. 
All institutional affiliations of the investigator and sub-investigator should be declared on their 
curriculum vitae, which must be provided to the sponsor prior to the start of the study. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), assent form 
(if applicable, eg, mentally incapacitated persons), 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 ICF 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 are given. The ICF will detail 
the requirements of the subject and the fact that they are free to withdraw at any time without 
giving a reason and without prejudice to their further medical care. For a potential research 
subject who is deemed incapable of giving informed consent, but is able to give assent to 
decisions about participation in research, the principal investigator will be required to seek that 
assent in addition to the consent of the legally acceptable representative. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF, 
the assent form (if applicable), and the subject authorization form (if applicable). The ICF, 
subject authorization form (if applicable), assent 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 ICF, subject authorization form (if applicable), assent 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 ICF, subject authorization form (if applicable), assent 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 
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event the subject is not capable of rendering adequate written informed consent, then the 
subject’s legally acceptable representative may provide such consent or assent to decisions about 
participation in research 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 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 ICF, assent form (if applicable), 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 ICF, 
assent form (if applicable), and subject authorization form (if applicable) at the time of consent 
and prior to the 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 ICF, subject authorization form (if applicable), assent form (if 
applicable), and subject information sheet (if applicable) will be stored in the investigator’s site 
file. The investigator must document the date the subject signs the informed consent in the 
subject’s medical record. Copies of the signed ICF, the signed subject authorization form (if 
applicable), assent form (if applicable), and subject information sheet (if applicable) shall be 
given to the subject. 
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s 
legally acceptable representative in the same manner as the original informed consent. The date 
the revised consent was obtained should be recorded in the subject’s medical record, and the 
subject should receive a copy of the revised ICF. 
15.3 
Subject Confidentiality 
The sponsor and its 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 ID 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 ID 
number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its medical monitor or designee’s monitor, 
representatives from any regulatory authority (eg, FDA, Medicines and Healthcare products 
Regulatory Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated 
auditors, and the appropriate IRBs and IECs to review the subject’s original medical records 
(source data or documents), including, but not limited to, laboratory test result reports, ECG 
reports, admission and discharge summaries for hospital admissions occurring during a subject’s 
study participation, and autopsy reports. Access to a subject’s original medical records requires 
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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. 
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for America’s investigators), country, 
and recruiting status will be registered and available for public viewing.  
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator’s name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator’s 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.  
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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 its 
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, 
they should contact the sponsor or its designee. 
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16.0 
REFERENCES 
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incidence and prevalence of the inflammatory bowel diseases with time, based on systematic 
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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). 
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5. Stenson WF, MacDermott RP. Inflammatory Bowel Disease. In: Yamada T, editor. Textbook 
of Gastroenterology Lippincott Williams & Wilkins 1991:Vol. 2; Chapter 77, p. 1588-644. 
6. Nieuwenhuis EE, Escher JC. Early onset IBD: what's the difference? Digestive & Liver 
Disease 2008;40(1):12-5. 
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Product Characteristics. Leiden, The Netherlands: Janssen Biologics B.V., 06 October 2015.  
8. Humira (adalimumab) injection, for subcutaneous use. Full Prescribing Information. North 
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9. Simponi (golimumab) injection, for subcutaneous use. Full Prescribing Information. 
Horsham, PA: Janssen Biotech, Inc., Revised January 2016.  
10. Cimzia (certolizumab pegol) for injection, for subcutaneous use. Full Prescribing 
Information. Smyrna, GA: UCB, Revised February 2016.  
11. Tysabri (natalizumab) injection. Full Prescribing Information. Cambridge, MA: Biogen Idec 
Inc., Revised May 2015.  
12. Summers RW, Switz DM, Sessions JT, Jr., Becktel JM, Best WR, Kern F, Jr., et al. National 
Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology 
1979;77(4 Pt 2):847-69. 
13. Akobeng AK, Gardener E. Oral 5-aminosalicylic acid for maintenance of medically-induced 
remission in Crohn's Disease. Cochrane Database Syst Rev 2005(1):CD003715. 
14. Xu CT, Meng SY, Pan BR. Drug therapy for ulcerative colitis. World J Gastroenterol 
2004;10(16):2311-7. 
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15. Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD. Increased risk of lymphoma 
among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. 
Gut 2005;54(8):1121-5. 
16. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. 
Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 
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17. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. 
Adalimumab for maintenance of clinical response and remission in subjects with Crohn’s 
disease: the CHARM trial. Gastroenterology 2007;132(1):52-65. 
18. McIntyre PB, Pemberton JH, Wolff BG, Beart RW, Dozois RR. Comparing functional 
results one year and ten years after ileal pouch-anal anastomosis for chronic ulcerative colitis. 
Dis Colon Rectum 1994;37(4):303-07. 
19. Ording Olsen K, Juul S, Berndtsson I, Oresland T, Laurberg S. Ulcerative colitis: female 
fecundity before diagnosis, during disease, and after surgery compared with a population 
sample. Gastroenterology 2002;122(1):15-9. 
20. Penna C, Dozois R, Tremaine W, Sandborn W, LaRusso N, Schleck C, et al. Pouchitis after 
ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients 
with associated primary sclerosing cholangitis. Gut 1996;38(2):234-9. 
21. Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking and 
regional immunity. Adv Immunol 1999;72:209-53. 
22. Salmi M, Jalkanen S. Lymphocyte homing to the gut: attraction, adhesion, and commitment. 
Immunol Rev 2005;206:100-13. 
23. 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. 
24. 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. J 
Immunol 1994;153(2):517-28. 
25. 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 
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26. Entyvio (vedolizumab) for injection, for intravenous use. Full Prescribing Information. 
Deerfield, IL: Takeda Pharmaceuticals America, Inc., Issued May 2014. 
27. Entyvio (vedolizumab) 300 mg powder for concentrate for solution for infusion. Summary of 
Product Characteristics. Denmark: Takeda Pharma A/S, Issued 25 September 2015. 
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28. European Commission, EMA, and Head of Medicines Agencies. Guidance on the 
management of clinical trials during the covid-19 (coronavirus) pandemic. Updated 
4 February 2021. Accessed 13 September 2021. Available at: 
https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. 
29. US FDA. Conduct of clinical trials of medical products during the covid-19 public health 
emergency: Guidance for industry, investigators, and institutional review boards. Updated 
30 August 2021. Accessed 13 September 2021. Available at: 
https://www.fda.gov/media/136238/download.  
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Appendix A 
Schedule of Study Procedures for Main XAP Study 
 
XAP Procedures a 
 
Enrollment Visit 
(Final Visit of Qualifying Study) 
Infusion Visit b 
Safety Follow-up Visit c 
(Final Study Infusion 
+18 Weeks) 
Visit Number: 
1 
2 onwards 
– 
Informed consent 
X 
– 
– 
Alert card 
X 
– 
X 
Assess inclusion/exclusion criteria 
X 
– 
– 
Assessment for continued eligibility 
– 
X d 
– 
Demographics/medical and prior 
therapies/concurrent medical conditions 
X 
– 
– 
UC/CD history 
X 
– 
– 
Physical examination e 
X f 
– 
– 
Vital signs g 
X f 
X 
X 
Weight and BMI g 
X f 
X 
X 
Height 
X f 
– 
– 
Concomitant medications h 
X 
X 
X 
Pregnancy testing i 
X f 
X 
X 
Pregnancy avoidance 
X 
X 
– 
Call IVRS/IWRS for Subject ID/Medication 
ID/subject status 
X 
X 
X 
Administer vedolizumab 
– 
X 
– 
AE/SAE assessment j 
X 
X 
X 
AE: adverse event; AESI: adverse event of special interest; BMI: body mass index; CD: Crohn’s disease; 
COVID-19: coronavirus disease 2019; hCG: human chorionic gonadotropin; IBD: inflammatory bowel disease; 
ID: identification; IV: intravenous; IVRS: interactive voice response system; IWRS: interactive web response system; 
PML: progressive multifocal leukoencephalopathy; SAE: serious adverse event; UC: ulcerative colitis; XAP: extended 
access program. 
a At the time of this protocol amendment, the COVID-19 pandemic continues to affect the way clinical studies are being 
conducted such that alternative measures are being implemented to maintain subject safety and to ensure data quality and 
integrity. A detailed description of COVID-19-related protocol considerations/mitigations is provided in Section 9.3.7. 
b The first infusion visit should be no more than 8 weeks (± 7 days) after the last dose in the subject’s qualifying study. Infusion 
visits should occur every 8 weeks (± 7 days). A detailed description is provided in Section 6.1. 
c Subjects will return 18 weeks after their final study infusion visit for a safety follow-up visit. Subjects should return for the 
follow-up visit regardless of whether they remain on vedolizumab after the study (ie, they left the study due to commercial 
availability of vedolizumab, or they withdrew from the study for other reasons). 
d At each visit, the investigator should assess the subject for continued eligibility (see Section 7.6) and determine if vedolizumab 
is available to the subject through commercial channels, including reimbursement, for the subject’s clinical scenario.  
e A symptom-directed physical examination will be performed at baseline. Any clinically significant findings on the physical 
examination will be recorded as AEs. 
f At screening, if the procedure has been conducted within the last 24 hours, the results of that test can be used and the procedure 
does not need to be redone. 
g Should occur prior to dosing at infusion visits. 
h Concomitant medication is any drug given in addition to the study medication. The information will be collected for all subjects 
at the enrollment visit and subsequent visits as detailed in Section 9.1.10. 
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i Urine pregnancy test will be performed via dipstick test for all female subjects of childbearing potential prior to dose of 
vedolizumab at infusion visits. In addition to a negative urine hCG pregnancy test at screening, female subjects must also have a 
negative urine hCG pregnancy test prior to receiving each IV dose. Subjects will receive continued guidance with respect to the 
avoidance of pregnancy and sperm/ova donation as part of the study procedures. 
j This will include collection of AEs, SAEs, and AESIs and will include collection of additional safety information on important 
clinical events (eg, PML-related AEs, IBD-related hospitalizations, malignancies, hypersensitivity, hepatic events, and serious 
infections). AE assessment includes review of the subject’s alert card. AEs from the qualifying study which are ongoing at the 
time of signing informed consent to participate in this study will not be as AEs collected in this study but will be captured as 
concurrent medical conditions. 
 
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Appendix B 
Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572) that 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 that will assist in the protocol. 
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met. 
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF 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 ICF does not 
include such a subject authorization, then the investigator must obtain a separate subject 
authorization form from each subject or the subject’s legally acceptable representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.  
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 
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Appendix C 
Elements of the Subject Informed Consent  
In seeking informed consent, the following information shall be provided to each subject: 
1. A statement that the study involves research. 
2. An explanation of the purposes of the research. 
3. The expected duration of the subject’s participation. 
4. A description of the procedures to be followed, including invasive procedures. 
5. The identification of any procedures that are experimental. 
6. The estimated number of subjects involved in the study. 
7. A description of the subject’s responsibilities. 
8. A description of the conduct of the study. 
9. A statement describing the treatment(s). 
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 medical monitor may inspect the records. By signing a written ICF, the 
subject or the subject’s legally acceptable representative is authorizing such access. 
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained. 
16. The anticipated prorated payment(s), if any, to the subject for participating in the study. 
17. The anticipated expenses, if any, to the subject for participating in the study. 
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject. 
19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the subject otherwise is entitled, and that the subject may 
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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 ICF or provided as a separate 
document) describing to the subject the contemplated and permissible uses and disclosures of 
the subject’s personal information (including personal health information) for purposes of 
conducting the study. The subject authorization must contain the following statements 
regarding the uses and disclosures of the subject’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for subjects, 
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) 
from screening throughout the duration of the study. Regular pregnancy tests will be 
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performed throughout the study for all female subjects of childbearing potential. If a subject 
is found to be pregnant during study, study medication will be discontinued and the 
investigator will offer the subject the choice to receive unblinded treatment information. 
25. Male subjects must use adequate contraception (as defined in the informed consent) from 
screening throughout the duration of the study. If the partner or wife of the subject is found to 
be pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information. 
26. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov. 
27. For the XAP-PK substudy, a statement that results of the XAP-PK substudy will not be 
disclosed to an individual, unless prevailing laws require the sponsor to do so. 
 
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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, US, and Japan), including the following: 
• Takeda, its affiliates, and licensing partners. 
• Business partners assisting Takeda, its affiliates, and licensing partners. 
• Regulatory agencies and other health authorities. 
• IRBs and IECs. 
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following: 
• Assessment of the suitability of investigator for the study and/or other clinical studies. 
• Management, monitoring, inspection, and audit of the study. 
• Analysis, review, and verification of the study results. 
• Safety reporting and pharmacovigilance relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication. 
• Inspections and investigations by regulatory authorities relating to the study. 
• Self-inspection and internal audit within Takeda, its affiliates, and licensing partners. 
• Archiving and audit of study records. 
• Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s 
own country. 
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix E 
Details Specific to XAP-PK Substudy 
I. 
STUDY SUMMARY of XAP-PK SUBSTUDY 
Name of Sponsor(s): 
Takeda Development Center Americas, Inc. USA 
Takeda Development Centre Europe Ltd., UK 
Takeda Development Centre Asia, Pte Ltd., Singapore  
Compound: 
Vedolizumab IV 
Title of Protocol: Entyvio (Vedolizumab IV) Extended 
Access Program in Ulcerative Colitis and Crohn’s 
Disease 
IND No.: Not 
Applicable 
EudraCT No.: 
2016-000678-40 
Study Number: Vedolizumab-4013 
Phase: 3b/4 
Study Design: 
Subjects entering the XAP from the C13008 clinical study will undergo a decrease in dosing frequency from 
every 4 week (Q4W) dosing to an every 8 week (Q8W) dosing regimen. Subjects making the transition between 
the 2 studies and moving to Q8W dosing may consent to take part in a pharmacokinetic (PK) substudy (XAP-
PK). The XAP-PK substudy will assess the PK of vedolizumab (serum vedolizumab concentration and anti-
vedolizumab antibodies [AVAs]) in subjects who move from Q4W dosing to Q8W dosing. Trough PK samples 
will be drawn immediately before the last dose in the C13008 study (T0), and in addition, before the first Q8W 
dose at Week 8 (T+1) and the second Q8W dose (T+2) at Week 16 (see Appendix F) to quantify PK at the new 
steady state for Q8W dosing. Should the subject lose clinical response to vedolizumab over time after the 
transition to Q8W dosing, further trough blood samples will be drawn for PK immediately prior to first dose after 
decision to return to Q4W dosing (T’0) and in addition before the next 2 doses (T’+1, T’+2), to quantify PK at 
the new steady state for Q4W dosing. The XAP-PK substudy will also assess the proportion of subjects who 
move from Q4W dosing to Q8W dosing and remain on Q8W dosing through to Week 56/End of Substudy Visit. 
Vedolizumab PK will also be described based on trough concentrations by baseline subject factors influencing 
variability in subjects who remain on Q8W dosing, as well as those who return to Q4W dosing, either regaining 
response or not. 
Objectives: 
XAP-PK Substudy Exploratory Objectives: 
To assess drug concentration during changes in dosing regimens in subjects who stay on Q8W dosing through 
Week 56/End of Substudy Visit, subjects who return to Q4W dosing and regain clinical response, and subjects 
who return to Q4W dosing and do not regain clinical response. 
To understand the effects of AVAs on a subject’s ability to maintain or regain clinical response during changes 
in dosing regimens in subjects who stay on Q8W dosing through Week 56/End of Substudy Visit, subjects who 
return to Q4W dosing and regain clinical response, and subjects who return to Q4W dosing and do not regain 
clinical response. 
To understand the proportion of subjects who maintain clinical response during a change in dosing regimen from 
Q4W dosing to Q8W dosing in subjects who stay on Q8W dosing through Week 56/End of Substudy Visit. 
To describe vedolizumab PK based on trough concentrations by baseline subject characteristics influencing 
variability. 
To assess predose serum drug concentration and AVA in relation to efficacy and safety. 
Number of Subjects: 
Subjects who consent and qualify for the XAP study and are transitioning off the C13008 study will be offered 
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the opportunity to participate in the XAP-PK substudy (applicable for countries in which the XAP-PK substudy 
is available). No statistical assumption was used to estimate the sample size for the XAP-PK substudy. The 
number will be based on the number of subjects who consent and qualify for the XAP-PK substudy.  
Period of Evaluation: 
In the XAP-PK substudy, the subjects will be followed until Week 56 or a decision is made to change the 
subjects’ dosing regimen, the subject stops vedolizumab, or the subject withdraws from the study, whichever 
comes first. If at Week 56, the subject is still awaiting a T’+1 and/or a T’+2 sample, the subject will be followed 
until the T’+2 sample is collected and T‘ +2 will become the End of Substudy Visit and no additional samples 
will be collected. 
The End of Substudy/Week 56 visit should be scheduled in conjunction with a regular infusion visit of the Main 
XAP study (may or may not be exactly at Week 56 of the substudy but at the infusion visit closest to Week 56 
from T0). 
If a subject exits the XAP study prior to Week 56 because they are moving on to commercially available and 
reimbursed product, the subject will also exit the XAP-PK substudy. The end of substudy visit will be conducted 
at the time of the final XAP dosing visit.  
Trough PK draws for the initial Q4W dosing to Q8W dosing transition occur prior to dosing at T0, T+1, and 
T+2: 
T0 = Week 0 – Last Q4W dose in C13008 
T+1 = Week 8 – 1st Q8W dose 
T+2 = Week 16 – 2nd Q8W dose  
Trough PK draws for change in dosing regimen from Q8W to Q4W dosing occur predose at T’0, T’+,1 and 
T’+2: 
T’0 = First dose after decision to return to Q4W dosing 
T’+1 = 1st Q4W dose (4 weeks after T’0) 
T’+2 = 2nd Q4W dose (8 weeks after T’0) 
Main Criteria for Inclusion: 
Additional XAP-PK Substudy Inclusion Criteria: 
Received vedolizumab during participation in the C13008 study. 
The subject will start the main XAP study on Q8W dosing. 
The subject or, when applicable, the subject’s legally acceptable representative, has signed and dated a written 
informed consent form for the procedures related to the XAP-PK substudy. 
Main Criteria for Evaluation and Analyses: 
XAP-PK Substudy Exploratory Endpoints: 
• 
Summary statistics of predose serum drug concentration between T0 (immediately prior to last dose in 
C13008) and T+2 (Week 16: immediately prior to second Q8W dose) for those who remain on Q8W dosing 
through Week 56/End of Substudy Visit. 
• 
Summary statistics of predose serum drug concentration between T’0 (immediately prior to first dose after 
decision to return to Q4W dosing) and T’+2 (8 weeks after T’0 and immediately prior to the second Q4W 
dose) for those who return to Q4W dosing and regain clinical response through Week 56/End of Substudy 
Visit.  
• 
Summary statistics of predose serum drug concentration between T’0 (immediately prior to first dose after 
decision to return to Q4W dosing) and T’+2 (8 weeks after T’0 and immediately prior to the second Q4W 
dose) for those who return to Q4W dosing and do not regain clinical response through Week 56/End of 
Substudy Visit.  
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• 
Summary statistics of predose serum drug concentration at available on-treatment time points and at time at 
which decision is made to stop vedolizumab for subjects who stop taking vedolizumab prior to Week 56/End 
of Substudy Visit.  
• 
The maximum AVA titer and proportion of subjects with each AVA status at T0 (immediately prior to last 
dose in C13008), T+1 (Week 8), and at T+2 (Week 16: immediately prior to second Q8W dose) for those 
who remain on Q8W dosing through Week 56/End of Substudy Visit. 
• 
The maximum AVA titer and proportion of subjects with each AVA status at T’0 (immediately prior to first 
dose after decision to return to Q4W dosing), T’+1 (4 weeks after T’0 and immediately prior to first Q4W 
dose), and at T’+2 (8 weeks after T’0 and immediately prior to the second Q4W dose) for those who return 
to Q4W dosing and regain clinical response through Week 56/End of Substudy Visit.  
• 
The maximum AVA titer and proportion of subjects with each AVA status at T’0 (immediately prior to first 
dose after decision to return to Q4W dosing), T’+1 (4 weeks after T0 and immediately prior to first Q4W 
dose), and at T’+2 (8 weeks after T’0 and immediately prior to the second Q4W dose) for those who return 
to Q4W dosing and do not regain clinical response through Week 56/End of Substudy Visit.  
• 
The maximum AVA titer and proportion of subjects with each AVA status at available on-treatment time 
points and at time at which decision is made to stop vedolizumab for subjects who stop taking vedolizumab 
prior to Week 56/End of Substudy Visit. 
• 
Proportion of subjects who, after moving to Q8W dosing from Q4W dosing, remain on Q8W dosing through 
Week 56/End of Substudy Visit. 
• 
Describe vedolizumab PK based on trough concentrations by baseline subject characteristics influencing 
variability.  
• 
Summary statistics of predose serum drug concentration and AVA status in relation to efficacy and safety. 
Statistical Considerations: 
XAP-PK Substudy: 
This XAP-PK substudy is not sized based on power considerations. As for the main study, all analyses will be 
descriptive and no formal statistical hypothesis testing is to be performed. Predose serum concentrations of 
vedolizumab and maximum AVA titer will be summarized descriptively by collection time points. All 
proportion-based endpoints will be summarized by presenting the point estimate and 95% confidence intervals 
for the proportion. Partial Mayo score, Harvey-Bradshaw Index score, C-reactive protein assessment, albumin 
levels, and white blood cells will be also summarized descriptively by collection time points. 
 
RATIONALE FOR THE XAP-PK SUBSTUDY 
Subjects entering the extended access program (XAP) from the C13008 clinical study will 
undergo a decrease in dosing frequency from every 4 week (Q4W) dosing to every 8 week 
(Q8W) dosing. Subjects making the transition between the 2 studies and moving to Q8W dosing 
may consent to take part in a pharmacokinetic (PK) substudy (XAP-PK). 
The XAP-PK substudy will assess the PK of vedolizumab (serum vedolizumab concentration 
and anti-vedolizumab antibodies [AVAs]) in subjects who move from Q4W dosing to Q8W 
dosing. Trough PK samples will be drawn immediately before the last dose in the C13008 study 
(T0), and in addition before the first Q8W dose at Week 8 (T+1) and the second Q8W dose 
(T+2) at Week 16 (see Appendix F) to quantify PK at the new steady state for Q8W dosing. 
Should the subject lose clinical response to vedolizumab over time after the transition to Q8W 
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dosing, further trough blood samples will be drawn for PK (T0) immediately prior to first dose 
after decision to return to Q4W dosing (T’0) and in addition before the next 2 doses (T’+1, 
T’+2), to quantify PK at the new steady state for Q4W dosing. Vedolizumab PK will also be 
described based on trough concentrations by baseline subject factors influencing variability in 
subjects who remain on Q8W dosing, as well as those who return to Q4W dosing, either 
regaining response or not. 
The XAP-PK substudy will also assess the proportion of subjects who move from Q4W dosing 
to Q8W dosing and remain on Q8W dosing through to Week 56/End of Substudy Visit. During 
the development program, information regarding the outcome of switching subjects from Q4W 
dosing to Q8W dosing after they achieved clinical remission was not available. This information 
is considered critical for the understanding of PK-efficacy relationship of vedolizumab. 
EXPLORATORY OBJECTIVES FOR XAP-PK SUBSTUDY 
• To assess drug concentration during changes in dosing regimens in subjects who stay on 
Q8W dosing through Week 56/End of Substudy Visit, subjects who return to Q4W dosing 
and regain clinical response, and subjects who return to Q4W dosing and do not regain 
clinical response. 
• To understand the effects of AVAs on a subject’s ability to maintain or regain clinical 
response during changes in dosing regimens in subjects who stay on Q8W dosing through 
Week 56/End of Substudy Visit, subjects who return to Q4W dosing and regain clinical 
response, and subjects who return to Q4W dosing and do not regain clinical response. 
• To understand the proportion of subjects who maintain clinical response during a change in 
dosing regimen from Q4W dosing to Q8W dosing in subjects who stay on Q8W dosing 
through Week 56/End of Substudy Visit. 
• To describe vedolizumab PK based on trough concentrations by baseline subject 
characteristics influencing variability. 
• To assess predose serum drug concentration and AVA in relation to efficacy and safety. 
EXPLORATORY ENDPOINTS FOR XAP-PK SUBSTUDY 
• Summary statistics of predose serum drug concentration between T0 (immediately prior to 
last dose in C13008) and T+2 (Week 16: immediately prior to second Q8W dose) for those 
who remain on Q8W dosing through Week 56/End of Substudy Visit. 
• Summary statistics of predose serum drug concentration between T’0 (immediately prior to 
first dose after decision to return to Q4W dosing) and T’+2 (8 weeks after T’0 and 
immediately prior to the second Q4W dose) for those who return to Q4W dosing and regain 
clinical response through Week 56/End of Substudy Visit.  
• Summary statistics of predose serum drug concentration between T’0 (immediately prior to 
first dose after decision to return to Q4W dosing) and T’+2 (8 weeks after T’0 and 
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immediately prior to the second Q4W dose) for those who return to Q4W dosing and do not 
regain clinical response through Week 56/End of Substudy Visit.  
• Summary statistics of predose serum drug concentration at available on-treatment time points 
and at time at which decision is made to stop vedolizumab for subjects who stop taking 
vedolizumab prior to Week 56/End of Substudy Visit.  
• The maximum AVA titer and proportion of subjects with each AVA status at T0 
(immediately prior to last dose in C13008), T+1 (Week 8), and at T+2 (Week 16: 
immediately prior to second Q8W dose) for those who remain on Q8W dosing through Week 
56/End of Substudy Visit. 
• The maximum AVA titer and proportion of subjects with each AVA status at T’0 
(immediately prior to first dose after decision to return to Q4W dosing), T’+1 (4 weeks after 
T’0 and immediately prior to first Q4W dose), and at T’+2 (8 weeks after T’0 and 
immediately prior to the second Q4W dose) for those who return to Q4W dosing and regain 
clinical response through Week 56/End of Substudy Visit.  
• The maximum AVA titer and proportion of subjects with each AVA status at T’0 
(immediately prior to first dose after decision to return to Q4W dosing), T’+1 (4 weeks after 
T’0 and immediately prior to first Q4W dose), and at T’+2 (8 weeks after T’0 and 
immediately prior to the second Q4W dose) for those who return to Q4W dosing and do not 
regain clinical response through Week 56/End of Substudy Visit. 
• The maximum AVA titer and proportion of subjects with each AVA status at available on-
treatment time points and at time at which decision is made to stop vedolizumab for subjects 
who stop taking vedolizumab prior to Week 56/End of Substudy Visit. 
• Proportion of subjects who, after moving to Q8W dosing from Q4W dosing, remain on Q8W 
dosing through Week 56/End of Substudy Visit. 
• Describe vedolizumab PK based on trough concentrations by baseline subject characteristics 
influencing variability.  
• Summary statistics of predose serum drug concentration and AVA status in relation to 
efficacy and safety. 
STUDY DESIGN AND DESCRIPTION OF XAP-PK SUBSTUDY 
i. 
Study Design of the XAP-PK Substudy 
Subjects entering the XAP from the C13008 clinical study will undergo a decrease in dosing 
frequency from Q4W dosing to an Q8W dosing regimen. Subjects making the transition between 
the 2 studies and moving to Q8W dosing may consent to take part in a PK substudy (XAP-PK). 
The XAP-PK substudy will assess the PK of vedolizumab (serum vedolizumab concentration 
and AVAs) in subjects who move from Q4W dosing to Q8W dosing. Trough PK samples will be 
drawn immediately before the last dose in the C13008 study (T0), and in addition, before the first 
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Q8W dose at Week 8 (T+1) and the second Q8W dose (T+2) at Week 16 (see Appendix F) and 
at Week 56/End of Substudy to quantify PK at the new steady state for Q8W dosing. Should the 
subject lose clinical response to vedolizumab over time after the transition to Q8W dosing, 
further trough blood samples will be drawn for PK immediately prior to first dose after decision 
to return to Q4W dosing (T’0) and in addition before the next 2 doses (T’+1, T’+2), to quantify 
PK at the new steady state for Q4W dosing. The XAP-PK substudy will also assess the 
proportion of subjects who move from Q4W dosing to Q8W dosing and remain on Q8W dosing 
through to Week 56/End of Substudy. Vedolizumab PK will also be described based on trough 
concentrations by baseline subject factors influencing variability in subjects who remain on Q8W 
dosing, as well as those who return to Q4W dosing, either regaining response or not consenting 
subjects who meet the eligibility criteria will have blood drawn and assessments taken (body 
mass index [BMI], partial Mayo score; Appendix G, Harvey-Bradshaw Index [HBI] score; 
Appendix H) prior to the final C13008 study dose (Day 1). Subjects remaining on Q8W dosing 
at Week 8 will have their blood drawn and assessments completed (BMI, partial Mayo score, 
HBI score) prior to their first Q8W dose (T+1). Subjects remaining on Q8W dosing through 
Week 16 will have their blood drawn and assessments completed (BMI, partial Mayo score, HBI 
score) prior to their second Q8W dose (T+2) (see below for details). 
If at any time during the 56 weeks of the XAP-PK substudy, the subject changes dosing 
regimens from Q8W dosing to Q4W dosing, the subject will have their blood drawn and 
assessments completed (BMI, partial Mayo score, HBI score) immediately prior to the first dose 
after the decision to return to Q4W (T’0). Four weeks later at the first dose of the new dosing 
schedule (T’+1), the subject will have their blood drawn and assessments completed (BMI, 
partial Mayo score, HBI score) prior to the dose. If they remain on the new dosing schedule, they 
will have their blood drawn and assessments completed (BMI, partial Mayo score, HBI score) 
immediately prior to the second dose of the new dosing schedule (T’+2).  
At any time during the course of the XAP-PK substudy (56 weeks), if a subject stops taking 
vedolizumab, the subject, at the time the decision is made, will have an end of substudy visit. At 
the end of the substudy visit, the subject will have their blood drawn and assessments completed 
(BMI, partial Mayo score, HBI score). Additionally, every effort should be made to conduct an 
end of substudy visit on subjects who withdraw from the study. 
Subjects who remain on vedolizumab at Week 56 will have an end of substudy visit at which 
they will have their blood drawn and assessments completed (BMI, partial Mayo score, HBI 
score), or if, by Week 56, the subject has had a T’0 draw due to a dose change and is awaiting a 
T’+1 and/or a T’+2 draw, the subject’s last visit will be the visit at which the T’+2 draw is 
completed, a decision is made to change the subject’s dosing regimen, the subject stops 
vedolizumab, or the subject withdraws from the study, whichever comes first.  
If a subject exits the XAP study prior to Week 56 because they are moving on to commercially 
available and reimbursed product, the subject will also exit the XAP-PK substudy. The end of 
substudy visit will be conducted at the time of the final XAP dosing visit.  
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The XAP-PK substudy will be conducted in compliance with the protocol, Good Clinical 
Practice (GCP), and the applicable regulatory requirements (including International Council for 
Harmonisation [ICH] guidelines). 
A schedule of assessments is listed in Appendix F. 
ii. 
Number of Subjects in XAP-PK Substudy 
Subjects who consent and qualify for the XAP study and are transitioning off the C13008 study 
will be offered the opportunity to participate in the XAP-PK substudy (applicable for countries in 
which the XAP-PK substudy is available). No statistical assumption was used to estimate the 
sample size for the XAP-PK substudy. The number will be based on the number of subjects who 
consent and qualify for the XAP-PK substudy. 
iii. 
Duration of Study of XAP-PK Substudy 
In the XAP-PK substudy, the subjects will be followed until Week 56 or a decision is made to 
change the subjects’ dosing regimen, the subject stops vedolizumab, or the subject withdraws 
from the study, whichever comes first. If at Week 56, the subject is still awaiting a T’+1 and/or a 
T’+2 sample, the subject will be followed until the T’+2 sample is collected. 
The End of Substudy/Week 56 visit should be scheduled in conjunction with a regular infusion 
visit of the Main XAP study (may or may not be exactly at Week 56 of the substudy but at the 
infusion visit closest to Week 56 from T0). 
If a subject exits the XAP study prior to Week 56 because they are moving on to commercially 
available and reimbursed product, the subject will also exit the XAP-PK substudy. The end of 
substudy visit will be conducted at the time of the final XAP dosing visit. 
iv. 
Justification for Study Design, Dose, and Endpoints of XAP-PK Substudy 
The XAP-PK substudy will evaluate the effect of decreasing the dosing frequency on the serum 
drug concentrations of vedolizumab, AVA titers, and maintenance of clinical response in 
subjects with UC or CD. The study will assess relationship between serum drug concentrations 
by subject characteristics influencing variability (BMI, disease type [UC or CD], C-reactive 
protein [CRP], white blood cell count [WBC], and albumin).  
During the XAP-PK substudy, relevant information will be collected to help the characterization 
of the PK-efficacy relationship and factors that can potentially affect this relationship. Data from 
the pivotal vedolizumab GEMINI studies showed that median vedolizumab trough 
concentrations for subjects at steady state were around 10 µg/mL for Q8W dosing and 31 µg/mL 
for Q4W dosing. This substudy aims to identify if changing the dose frequency from every 4 
weeks to every 8 weeks will have an impact on efficacy, and what factors might have an impact 
on clearance and clinical response 
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PREMATURE TERMINATION OR SUSPENSION OF STUDY OR INVESTIGATIONAL 
SITE OF XAP-PK SUBSTUDY 
i. 
Criteria for Premature Termination or Suspension of XAP-PK Substudy 
The XAP-PK substudy will be completed when the last subject completes the end of substudy 
visit. If one or more of the following criteria are satisfied, it may require temporary suspension or 
early termination the study: 
• New information or other evaluation regarding the safety or efficacy of vedolizumab 
indicates a change in the known risk/benefit for vedolizumab, such that the risk/benefit is no 
longer acceptable for subjects participating in the study. 
• Significant violation of GCP that compromises the study objective or subject safety. 
• Prior to the product becoming commercially available, another access program becomes 
available in the country of residence that will provide access to subjects outside of the study.  
• The study is terminated at a site. 
• The study is terminated by the sponsor. 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS FOR XAP-PK 
SUBSTUDY 
i. 
Additional Inclusion Criteria of XAP-PK Substudy 
1. Received vedolizumab during participation in the C13008 study. 
2. The subject will start the main XAP study on Q8W dosing. 
3. The subject or, when applicable, the subject’s legally acceptable representative, has signed 
and dated a written ICF for the procedures related to the XAP-PK substudy. 
ii. 
Procedures for Discontinuation or Withdrawal of a Subject of XAP-PK Substudy 
Subjects in the XAP-PK substudy may discontinue study participation at any time during the 
substudy when the subject meets the study termination criteria described in Section 7.6. In 
addition, a subject may discontinue his or her participation without giving a reason at any time 
during the substudy. Should a subject’s participation be discontinued, the primary criterion for 
termination must be recorded by the investigator. In addition, every effort should be made to 
conduct an end of substudy visit for subjects who are discontinued or who withdraw their 
participation. 
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STUDY PROCEDURES FOR XAP-PK SUBSTUDY 
i. 
XAP-PK Substudy Informed Consent Procedure 
A separate ICF pertaining to collection of blood for analysis, the storage of samples, and the 
assessments conducted must be obtained prior to performing any procedures related to the 
XAP-PK substudy. The provision of consent to collect and analyze the samples is independent of 
consent to the other aspects of the main XAP study. The signed ICF for the XAP-PK substudy 
will be taken at the enrollment visit along with the informed consent procedures for the XAP 
study. 
ii. 
Weight, Height, and BMI Measurement in XAP-PK Substudy 
Subjects in the XAP-PK substudy will have height measured at enrollment visit and weight 
measured at each of the visits for the calculation of BMI. The BMI should be derived as follows:  
Metric: 
BMI = weight (kg) / [height (m2)] 
The values should be reported to 1 decimal place by rounding. 
iii. 
Partial Mayo Score in XAP-PK Substudy 
For subjects in the XAP-PK substudy with a diagnosis of UC, the partial Mayo score will be 
evaluated at the enrollment visit, at time points in which blood is drawn as is specified in 
Appendix G, and at the end of substudy visit. The partial Mayo score will be evaluated prior to 
the blood draw. 
iv. 
Harvey-Bradshaw Index Score in XAP-PK Substudy 
For subjects in the XAP-PK substudy with a diagnosis of CD, the HBI score will be evaluated at 
the enrollment visit, at time points in which blood is drawn as is specified in Appendix H and at 
the end of substudy visit. The data used to derive the HBI score (ie, clinical symptoms and 
physical examination findings) will be obtained prior to the blood draw. 
v. 
Sample Collection and Analysis in XAP-PK Substudy 
Subjects in the XAP-PK substudy will have samples taken at the enrollment visit (the last dosing 
visit of the C13008 study, prior to dosing), and in addition before the first Q8W dose at Week 8 
and the second Q8W dose at Week 16. If, at any time during the XAP-PK substudy, the subject 
changes to Q4W dosing, the subject will have their blood drawn immediately prior to first dose 
after the decision to return to Q4W dosing (T’0). If they remain on the new dosing schedule for 2 
doses, they will have samples taken immediately prior to the next 2 doses (T’+1 and T’+2). At 
Week 56 and if, at any time during the course of the XAP-PK substudy, a subject stops taking 
vedolizumab or withdraws from the study, an end of substudy visit should be conducted that 
includes sample collection. If the subject has had a T’0 draw due to a dose change prior to Week 
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56 and is awaiting a T’+1 or T’+2 draw, the subject’s end of substudy visit will be the visit at 
which the T’+2 draw is completed. 
Trough PK draws for the initial Q4W dosing to Q8W dosing transition occur prior to dosing at 
T0, T+1, and T+2: 
T0 = Week 0 – Last Q4W dose in C13008 
T+1 = Week 8 – 1st Q8W dose 
T+2 = Week 16 – 2nd Q8W dose  
Trough PK draws for change in dosing regimen from Q8W to Q4W dosing occur predose at T’0, 
T’+1, and T'+2: 
T’0 = First dose after decision to return to Q4W dosing 
T’+1 = 1st Q4W dose (4 weeks after T’0)  
T’+2 = 2nd Q4W dose (8 weeks after T’0) 
vi. 
Collection of Serum for Pharmacokinetic Sampling in XAP-PK Substudy 
Bioanalytical methods: 
Trough serum concentrations of vedolizumab will be measured by a validated sandwich 
enzyme-linked immunosorbent assay. 
C-reactive protein assessment, albumin levels, and WBC: 
Levels of CRP and albumin and WBC counts will be measured at all XAP-PK substudy visits 
specified in Appendix F. The samples for CRP and albumin level assessments and WBC will be 
obtained from the same blood draw done for the PK assessments. 
Anti-vedolizumab antibodies: 
Blood specimens for the assessment of AVAs will be collected as shown in the Schedule of 
Study Procedures (Appendix F). A sample will be assessed for neutralizing AVAs, if AVAs are 
detected. 
Serum titers of AVA will be determined using a validated assay. Neutralizing AVAs will be 
determined using a validated assay. Please refer to the Study Manual for information on sample 
collection and preparation. 
SCHEDULE OF OBSERVATIONS AND PROCEDURES OF XAP-PK SUBSTUDY 
i. 
Enrollment Visit 1 in XAP-PK Substudy 
Procedures to be completed at the enrollment visit for the XAP-PK substudy can be found in the 
Schedule of Study Procedures (Appendix F). 
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ii. 
Treatment Period in XAP-PK Substudy 
Subjects in the XAP-PK substudy will visit the site/infusion center for blood draws and other 
assessments as detailed in Appendix F. Procedures to be completed at XAP-PK substudy visits 
can be found in the Schedule of Study Procedures (Appendix F). 
If a subject exits the XAP study prior to Week 56 because they are moving on to commercially 
available and reimbursed product, the subject will also exit the XAP-PK substudy. The end of 
substudy visit will be conducted at the time of the final XAP dosing visit. 
iii. 
Follow-up Period in XAP-PK Substudy 
Procedures to be completed during the follow-up period can be found in the Schedule of Study 
Procedures (Appendix F). 
In the XAP-PK substudy, the subjects will be followed until Week 56, or a decision is made to 
change the subjects’ dosing regimen, the subject stops vedolizumab, or the subject withdraws 
from the study, whichever comes first. If at Week 56, the subject is still awaiting a T’+1 and/or a 
T’+2 sample, the subject will be followed until the T’+2 sample is collected. 
The end of substudy/Week 56 visit should be scheduled in conjunction with a regular infusion 
visit of the Main XAP study (may or may not be exactly at Week 56 of the substudy but at the 
infusion visit closest to Week 56 from T0). 
If a subject exits the XAP study prior to Week 56 because they are moving on to commercially 
available and reimbursed product, the subject will also exit the XAP-PK substudy. The end of 
substudy visit will be conducted at the time of the final XAP dosing visit. 
STATISTICAL METHODS IN XAP-PK SUBSTUDY 
i. 
Statistical and Analytical Plans in XAP-PK Substudy 
Analysis set 
The FAS-PK is the FAS within the XAP-PK substudy. 
ii. 
Determination of Sample Size in XAP-PK Substudy 
The XAP-PK substudy is not sized based on power considerations. The number of subjects will 
be determined as discussed earlier in Section ii. 
iii. 
XAP-PK Substudy Analysis 
Predose serum concentrations of vedolizumab and maximum AVA titer will be summarized 
descriptively by collection time points, and by whether the subject: 
• Remains on Q8W dosing through Week 56/End of Substudy Visit. 
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• Returns to Q4W dosing and regains clinical response through Week 56/End of Substudy 
Visit. 
• Returns to Q4W dosing and does not regain clinical response through Week 56/End of 
Substudy Visit. 
• Stops taking vedolizumab prior to Week 56/End of Substudy Visit. 
For all dichotomous endpoints, corresponding rates and 95% confidence intervals will be 
reported using the same analysis groups described above. All proportion-based endpoints will be 
summarized by presenting the point estimate and 95% confidence intervals for the proportion. 
Partial Mayo score, HBI score, CRP assessment, albumin levels, and WBC will be also 
summarized descriptively by collection time points.
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Appendix F 
Schedule of Study Procedures for XAP-PK Substudy 
 
XAP-PK Procedures 
 
Enrollment Visit 
(Final Visit of Qualifying 
Study) 
XAP-PK Blood Draw Visit (b) 
Week 56/End of 
Substudy visit (c) 
Visit Number: 
1 
– 
– 
Informed consent 
X(d) 
– 
– 
Assess inclusion/exclusion criteria 
X(e) 
– 
– 
Partial Mayo score (a) 
X 
X 
X 
HBI score (a) 
X 
X 
X 
C-reactive protein (a) (f) 
X 
X 
X 
Albumin (a) (f) 
X 
X 
X 
WBC (a) (f) 
X 
X 
X 
Trough vedolizumab 
concentration (a) (g) 
X 
X 
X 
AVA (a) (g) 
X 
X 
X 
(a) Should occur prior to dosing at infusion visits.  
(b) During the course of the substudy, samples will be drawn at the following times: 
1. 
Trough PK draws for the initial Q4W dosing to Q8W dosing transition occur prior to dosing at T0, T+1, 
and T+2: 
T0 = Week 0 – Last Q4W dose in C13008 
T+1 = Week 8 – 1st Q8W dose 
T+2 = Week 16 – 2nd Q8W dose  
2. 
Trough PK draws for change in dosing regimen from Q8W to Q4W dosing occur predose at T’0, T’+1, 
and T’+2: 
T’0 = First dose after decision to return to Q4W  
T’+1 = 1st Q4W dose (4 weeks after T’0)  
T’+2 = 2nd Q4W dose (8 weeks after T’0) 
(c) The XAP-PK end of substudy visit will be at the infusion visit closest to Week 56 unless: 
1. 
The subject stops vedolizumab prior to Week 56 in which case the last end of substudy visit should 
coincide with the time at which it was decided to stop vedolizumab. 
2. 
At Week 56, the subject has had a T’0 draw due to a dose change and is awaiting a T’+1 or T’+2 draw. 
In which case, the subject’s end of substudy visit will be the visit at which the T’+2 draw is completed, 
the time point at which the subject stops vedolizumab, the time at which a decision is made to change 
the dosing regimen, or the subject withdraws from the study, whichever comes first. 
3. 
If a subject exits the XAP study prior to Week 56 because they are moving on to commercially available 
and reimbursed product, the subject will also exit the XAP-PK substudy. The end of substudy visit will 
be conducted at the time of the final XAP dosing visit.  
(d) The subjects interested in participating in the XAP-PK substudy will sign an additional informed consent at the XAP 
enrollment visit (last visit of C13008). 
(e) Subjects consenting to the XAP-PK substudy will need to meet additional inclusion criteria as detailed in Appendix E.  
(f) Obtained from the same blood draw sample done for the PK assessments (trough vedolizumab concentration).  
(g) See laboratory manual for blood draw volume.
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Appendix G 
Partial Mayo Score 
Partial Mayo Scoring System for the Assessment of Ulcerative Colitis Activity a 
Category 
Stool frequency b 
0 = Normal no. of stools for this patient 
1 = 1 to 2 stools more than normal 
2 = 3 to 4 stools more than normal 
3 = 5 or more stools more than normal 
Sub score, 0 to 3 
Rectal bleeding c 
0 = No blood seen  
1 = Streaks of blood with stool less than half the time  
2 = Obvious blood with stool most of the time  
3 = Blood alone passes  
Sub score, 0 to 3 
Physician’s global assessment d 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
Sub score, 0 to 3 
a Partial Mayo score ranges from 0−9 with higher scores indicating more severe disease.  
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 wellbeing, and other observations, such as physical 
findings and the patient’s performance status. 
 
Adapted from: Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for 
mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317(26):1625-9.  
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Appendix H 
Harvey-Bradshaw Index 
Harvey-Bradshaw Scoring System for the Assessment of Crohn’s Disease Activity 
Category 
Total 
General Wellbeing 
0 = Very Well 
1 = Slightly Below Par 
2 = Poor 
3 = Very Poor 
4 = Terrible 
 
Abdominal Pain 
0 = None 
1 = Mild 
2 = Moderate 
3 = Severe 
 
Number of Liquid Stools Per Day 
 
Abdominal Mass 
0 = None 
1 = Dubious 
2 = Definite 
3 = Definite and Tender 
 
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Category 
Total 
Complications (score 1 per item) 
  Arthralgia/Arthritis 
  Uveitis/Iritis 
  Erythema nodosum 
  Apthous ulcers 
  Pyoderma gangrenosum 
  Anal fissure 
  Draining fistula (eg, perianal, enterocutaneous, rectovaginal) 
  Perianal Abscess 
 
Final Score (add totals)              
 
Adapted from: Harvey RF, Bradshaw JM. A simple index of Crohn's-disease activity. Lancet 
1980;1(8167):514.
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Appendix I 
Detailed Description of Amendments to Text 
This document describes changes in reference to Protocol Incorporating Amendment 7. Italicized 
text represents the existing text from original protocol (dated 17 March 2016) that is being 
replaced or moved. Bold text represents the addition of the text. Minor grammatical changes (if 
any) are not shown. 
Page 1, Sponsor 
Existing Text  
Takeda Development Center Americas, Inc. 
One Takeda Parkway 
Deerfield, IL 60015 
United States of America 
Takeda Development Centre Europe Limited 
61 Aldwych, London WC2B 4AE 
United Kingdom 
Takeda Development Centre Asia, Pte Limited 
21 Biopolis Road, Nucleos North Tower, Level 4 
Singapore 138567 
Revised Text 
Takeda Development Center Americas, Inc. (TDC Americas) 
95 Hayden Avenue 
Lexington, MA 02421 
617-349-0200 
Takeda Development Centre Asia, Pte. Limited 
8 Marina Boulevard #15-01, Marina Bay 
Financial Centre, Singapore 018981 
Rationale for Amendment 
.  
To update current corporate addresses of TDC Americas and TDC Asia, Takeda sponsor 
companies. 
 
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Revised Text 
Name of Sponsor(s): 
Takeda Development Center Americas, Inc. (TDC Americas) 
Takeda Development Centre Asia, Pte. Limited, Singapore 
Rationale for Amendment 
. 
 
Page 22, Section 3.4 
Existing Text 
TDC Asia 
Takeda Development Center Asia, Pte Ltd. 
TDC Europe 
Takeda Development Centre Europe Ltd. 
TDC Americas 
Takeda Development Center Americas, Inc. 
TDC 
TDC Asia, TDC Europe and/or TDC Americas, as applicable 
Takeda 
TDC Asia, TDC Europe and/or TDC Americas, as applicable 
Revised Text 
TDC Asia 
Takeda Development Centre Asia, Pte. Limited 
TDC Americas 
Takeda Development Center Americas, Inc. 
TDC 
TDC Asia and/or TDC Americas, as applicable 
Takeda 
TDC Asia and/or TDC Americas, as applicable 
Rationale for Amendment 
. 
 
Page 25, Section 4.1.2 
Existing Text 
As of 19 Nov 2016, approximately 4200 subjects (309 healthy subjects, 1811 subjects with UC, 
and 2138 subjects with CD, 3 subjects undergoing allogeneic-hematopoietic stem cell 
transplantation, 1 subject with pouchitis, and 2 subjects with melanoma) have received at least 
1 dose of vedolizumab across completed and ongoing company-sponsored interventional clinical 
studies (see current version of IB). Vedolizumab exposure in clinical studies 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. 
Vedolizumab has shown an acceptable safety based on an analysis of safety data from both 
completed and ongoing studies. The integrated summary of safety for the completed studies, as 
well as a summary of safety from the ongoing phase 3 programs (based on a data cut off of 
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19 Nov 2016), are detailed in the current version of the IB. As of 19 Nov 2016, a total of 
30 subjects who participated in vedolizumab clinical studies have died during the study or up to 
2 years following the last dose of study drug (Studies C13004, C13006, C13007, C13008, 
CCT-101, and Vedolizumab-1015). The causes of death varied and additional information can be 
found in the current version of the IB. No cases of PML have been reported to date. Overall, 
vedolizumab IV was well tolerated in clinical studies. 
Revised Text 
As of 19 May 2021, approximately 6949 subjects (869 healthy subjects, 2782 subjects with UC, 
and 3022 subjects with CD, 213 subjects undergoing allogeneic-hematopoietic stem cell 
transplantation or with acute graft-versus-host disease involving the intestinal tract, 
51 subjects with pouchitis, and 12 subjects with melanoma) have received at least 1 dose of 
vedolizumab across completed and ongoing company-sponsored interventional clinical studies 
(see current version of IB). Vedolizumab exposure in clinical studies has extended for 
≥12 months in 2957 subjects, ≥24 months in 1906 subjects, ≥36 months in 1474 subjects, 
≥48 months in 965 subjects, ≥60 months in 717 subjects, ≥72 months in 477 subjects, 
≥84 months in 308 subjects, ≥96 months in 271 subjects, and ≥108 months in 201 subjects. 
Vedolizumab has shown an acceptable safety based on an analysis of safety data from both 
completed and ongoing studies. The integrated summary of safety for the completed studies, as 
well as a summary of safety from the ongoing phase 3/3b and 3b/4 programs (based on a data 
cut off of 19 May 2021), are detailed in the current version of the IB. As of 19 May 2021, a total 
of 103 subjects who participated in vedolizumab clinical studies have died during the study or up 
to 2 years following the last dose of study drug. Eight of the 103 subjects were being treated 
for UC and 14 subjects for CD (Studies C13006, C13007, C13008, C13011, MLN0002-3026, 
MLN0002SC-3027, MLN0002SC-3031, Vedolizumab-3034, Vedolizumab-4013, and 
Vedolizumab-4014). The causes of death varied and additional information can be found in the 
current version of the IB. No cases of PML have been reported to date. Overall, vedolizumab IV 
was well tolerated in clinical studies. 
Rationale for Amendment 
Text updated as per the details in the latest IB. This change has been incorporated in 
Amendment 7. 
 
Page 26, Section 4.3 
Existing Text 
An integrated safety analysis was conducted using data from completed and unblinded clinical 
studies as of 14 March 2013. This analysis of 237 healthy subjects and 2216 subjects with UC or 
CD demonstrated an acceptable safety for vedolizumab. The safety of vedolizumab through 
19 November 2016 remains consistent with this integrated analysis and no new safety signals 
have been identified. Thus, vedolizumab has a favorable risk to benefit to date. 
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Revised Text 
An integrated safety analysis was conducted using data from completed vedolizumab clinical 
studies with a cut-off of 14 March 2013. This analysis of 237 healthy subjects and 2216 subjects 
with UC or CD demonstrated an acceptable safety for vedolizumab. The safety profile of 
vedolizumab through 19 May 2021 remains consistent with this integrated analysis and no new 
safety signals have been identified. Thus, vedolizumab has a favorable risk to benefit to date. 
Rationale for Amendment 
Text updated as per the details in the latest IB. This change has been incorporated in 
Amendment 7. 
 
Page 29, Section 6.1 
Existing Text 
6.1 
Study Design 
Remain same 
Revised Text 
In the event a subject is unable to visit the site for required study visits in a timely manner 
(ie, within permitted visit windows), due to the coronavirus disease 2019 (COVID-19) 
pandemic, alternative procedural considerations or mitigation approaches may be followed 
to maintain subject safety and to ensure data quality and integrity (Section 9.3.7). 
Rationale for Amendment 
Due to the interruption from the COVID-19 pandemic, a risk and mitigation approach was 
finalized and provided in the protocol to maintain subject safety and to ensure data quality and 
integrity. 
 
Page 30, Section 6.4 
Existing Text 
The benefit-to-risk of vedolizumab is favorable to date (as summarized in the IB, Edition 19 
[Dated Feb 2017]) in the treatment of UC and CD. The proposed vedolizumab IV dose (300 mg 
every 8 weeks) is consistent with pivotal study data and the approved label information [26]. 
Revised Text 
The benefit-to-risk of vedolizumab is favorable to date (as summarized in the IB, Edition 25 
[Dated 14 July 2021]) in the treatment of UC and CD. The proposed vedolizumab IV dose 
(300 mg every 8 weeks) is consistent with pivotal study data and the approved label information 
[26]. 
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Rationale for Amendment 
Date has been updated as per the latest IB.  
Page 40, Section 9.1 
Existing Text 
Remain same 
Revised Text 
Details of COVID-19-related study procedural changes are provided in Section 9.3.7. 
Rationale for Amendment 
Text has been added to cross-refer details of COVID-19-related study procedural changes. 
 
Page 42, Section 9.1.11 
Existing Text 
For male subjects: 
From signing of informed consent, throughout the duration of the study, and for 18 weeks after 
last dose of study medication, nonsterilized** male subjects who are sexually active with a 
female partner of childbearing potential* must use barrier contraception (eg, condom with 
spermicidal cream or jelly; or vaginal ring plus male condom). (Protocol Amendment No. 1: the 
use of spermicides does not apply for South Africa. See footnotes below.) In addition, they must 
be advised not to donate sperm during this period from signing of informed consent to 18 weeks 
after the last dose of study medication. 
Revised Text 
For male subjects: 
From signing of informed consent, throughout the duration of the study, and for 18 weeks 
after last dose of study medication, nonsterilized** male subjects who are sexually active 
with a female partner of childbearing potential* must use barrier contraception (eg, 
condom with spermicidal cream or jelly; or vaginal ring plus male condom). (Protocol 
Amendment No. 1: the use of spermicides does not apply for South Africa. See footnotes 
below.) In addition, they must be advised not to donate sperm during this period. 
Rationale for Amendment 
Deleted text related to sperm donation period for male subjects. This information has already 
been clarified at the beginning of the sentence. 
 
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Page 46, Section 9.3.2 
Existing Text 
Remain same 
Revised Text 
Details of COVID-19-related visit window changes are provided in Section 9.3.7. 
Rationale for Amendment 
Text has been added to cross-refer details of COVID-19-related visit window changes. 
 
Page 46 through 48, Section 9.3.7 
Existing Text 
None (a new section was added in revised text) 
Revised Text 
9.3.7 COVID-19-Related Protocol Considerations/Mitigations 
On a temporary basis, in order to maintain subject safety, confidentiality, and study 
integrity in the context of healthcare delivery challenges presented by the COVID-19 
pandemic, subjects who may be impacted should contact and the principal investigator to 
determine the best course of action. Depending on the impact, in some cases it may be 
possible to arrange for alternative solutions as permitted by local regulations [28,29]. Any 
decision on procedural changes should be made on a case-by-case basis by the principal 
investigator in consultation with the study team and the medical monitor, while 
maintaining subject safety and confidentiality as the priority. 
Missing data, remote visits, changes to assessment approaches, and altered visit windows 
during the COVID-19 public health emergency may affect the study results. Thus, it is 
important to identify all protocol deviations and altered data collection (ie, remote data 
collection or missing data points) or assessment methods. It is crucial that any deviations 
related to COVID-19 be clearly identified as such in the eCRF. 
The following procedural changes may be considered: 
• Scheduling of study visits: If modifications to the study visits schedule are necessary, 
the investigator must submit notification via the PPD electronic Protocol Inquiry 
Platform (ePIP) system for medical monitor’s review. Each modification will be 
evaluated on a case-by-case basis to assess safety concerns/risk to the subject, as well as 
study impact. The medical monitor’s review will be documented within the ePIP 
system. The investigator’s clinical expertise and discretion as it pertains to the health 
and wellbeing of the subject, as well as familiarity with local conditions, will ultimately 
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determine the best course of action for the subject, including whether the subject can 
safely remain in the study to complete the study procedures per protocol. 
– The acceptable windows for study visits and study drug dosing may be expanded as 
follows:  
i) 
Q4W regimen: from every 4 weeks (±7 days) to every 4 weeks (±10 days). 
ii) 
Q8W regimen: from every 8 weeks (±7 days) to every 8 weeks (±14 days). 
• If a subject is unable to physically report to the site for required study visits (to 
complete any of the study procedures in whole or in part), remote visits/checks (if 
appropriate) may be performed by the investigator via phone contacts and missing 
procedures will be captured as protocol deviations. Two or more consecutive missed 
infusion visits/checks, or a missed safety follow-up visit, will be considered as significant 
deviations. In the event of 2 consecutive missed infusion visits, the subject’s further 
study participation will be based on the investigator’s opinion that the subject would 
derive benefit from vedolizumab if continued in the study and there were no safety 
concerns. The investigator must submit notification via the PPD ePIP system for 
medical monitor’s approval before the subject could restart study medication. All 
collected data will be recorded in the subject’s medical record and captured within the 
eCRF, as applicable. As a check on subject’s safety and wellbeing, at minimum, sites 
will attempt to collect the following data per the protocol: 
– Assessment for continued eligibility (Section 9.1.3). 
– Documentation of concomitant medications (Section 9.1.10). 
– Confirm contraception and pregnancy avoidance procedures (Section 9.1.11) and 
pregnancy reporting responsibilities (Section 9.1.12). 
– Collection of AEs, SAEs, and AESIs (Section 9.1.15 and Section 7.5.1). (Note: If a 
subject has a known infection of COVID-19 and was deemed serious (based on the 
SAE criteria [Section 10.1.4]), then the event will be recorded as an AESI. If the 
subject is asymptomatic or having mild symptoms, then the event will be recorded 
only as an AE.) 
• In the event a subject misses the site visit(s), the following scenarios may be considered 
while rescheduling missed visits: 
– If a subject misses 1 site visit: The subject should be brought back within the 
acceptable window and as close to their originally planned dose regimen as possible. 
– If a subject misses ≥2 site visits: The subject should be brought back as soon as 
possible and their originally planned dose regimen will resume from that point 
forward. 
 In all cases, the investigator’s judgment and knowledge about the subject’s 
individual scenario will be relied upon. The investigator must submit notification 
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via the PPD ePIP system for medical monitor’s review once the visit date has 
been rescheduled. 
• If sites are unable to adhere to the planned infusion schedule, subjects may be 
transferred to investigational sites away from risk zones to complete required visits, 
provided that the mitigation plan has been reviewed in advance by Takeda and the 
following criteria are met: 
– Study drug accountability, preparation, handling, and administration is performed, 
and documented, in accordance with the study protocol and approved Pharmacy 
Manual. 
– All study related activities are conducted only by qualified study staff who have 
been trained on the protocol and have been delegated by the investigator to perform 
specific study tasks. 
– Any deviations are documented and reported to PPD (and captured within the 
eCRF, as appropriate), as well as notified to the regulatory authorities as locally 
applicable. 
– All relevant data are reported in the subject’s medical record and captured within 
the eCRF. 
Note: Reversal of COVID-19-related allowances may be permitted in countries where 
measures are in place to maintain subject safety and to ensure study integrity and within 
the timelines specified per country regulations.  
Rationale for Amendment 
Text has been added to update details of COVID-19-related study procedural changes. 
 
Page 62, Section 13.2 
Existing Text 
No interim analysis is planned.  
Revised Text 
No interim analysis is planned for this XAP study. 
However, interim looks at study data to review safety and treatment persistence of study 
subjects might be done. 
Rationale for Amendment 
Text has been updated to clarify that interim looks at study data to review safety and treatment 
persistence of study subjects might be done. 
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Page 63, Section 14.2 
Existing Text 
Remain same  
Revised Text 
Details of how to document COVID-19-related protocol deviations are provided in 
Section 9.3.7. 
Rationale for Amendment 
Text has been added to cross-refer details of COVID-19-related protocol deviations. 
 
Page 71, Section 16 
Existing Text 
Remain same  
Revised Text 
28. European Commission, EMA, and Head of Medicines Agencies. Guidance on the 
management of clinical trials during the covid-19 (coronavirus) pandemic. Updated 
4 February 2021. Accessed 13 September 2021. Available at: 
https://ec.europa.eu/health/sites/default/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf. 
29. US FDA. Conduct of clinical trials of medical products during the covid-19 public 
health emergency: Guidance for industry, investigators, and institutional review 
boards. Updated 30 August 2021. Accessed 13 September 2021. Available at: 
https://www.fda.gov/media/136238/download.  
Rationale for Amendment 
Added 2 new references. 
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Page 72 and 73, Appendix A 
Existing Text 
Appendix A 
Schedule of Study Procedures 
 
XAP Procedures 
 
Enrollment Visit 
(Final Visit of Qualifying Study) 
Infusion Visit (a) 
Safety Follow-up Visit 
(b) 
(Final Study Infusion 
+18 Weeks) 
Visit Number: 
1 
2 onwards 
– 
Informed consent 
X 
– 
– 
Alert card 
X 
– 
X 
Assess inclusion/exclusion criteria 
X 
– 
– 
Assessment for continued eligibility 
– 
X (c) 
– 
Demographics/medical and prior therapies/ 
concurrent medical conditions 
X 
– 
– 
UC/CD history 
X 
– 
– 
Physical examination (d) 
X (i) 
– 
– 
Vital signs (e) 
X (i) 
X 
X 
Weight and BMI (e) 
X (i) 
X 
X 
Height 
X (i) 
– 
– 
Concomitant medications (f) 
X 
X 
X 
Pregnancy testing (g) 
X (i) 
X 
X 
Pregnancy avoidance 
X 
X 
– 
Call IVRS/IWRS for Subject ID/Medication 
ID/subject status 
X 
X 
X 
Administer vedolizumab 
– 
X 
– 
AE/SAE assessment (h) 
X 
X 
X 
(a) The first infusion visit should be no more than 8 weeks (± 7 days) after the last dose in the subject’s qualifying study. Infusion 
visits should occur every 8 weeks (± 7 days). A detailed description is provided in Section 6.1. 
(b) Subjects will return 18 weeks after their final study infusion visit for a safety follow-up visit. Subjects should return for the 
follow-up visit regardless of whether they remain on vedolizumab after the study (ie, they left the study due to commercial 
availability of vedolizumab, or they withdrew from the study for other reasons). 
(c) At each visit, the investigator should assess the subject for continued eligibility (see Section 7.6) and determine if 
vedolizumab is available to the subject through commercial channels, including reimbursement, for the subject’s clinical 
scenario.  
(d) A symptom-directed physical examination will be performed at baseline. Any clinically significant findings on the physical 
examination will be recorded as AEs. 
(e) Should occur prior to dosing at infusion visits. 
(f) Concomitant medication is any drug given in addition to the study medication. The information will be collected for all 
subjects at the enrollment visit and subsequent visits as detailed in Section 9.1.10. 
(g) Urine pregnancy test will be performed via dipstick test for all female subjects of childbearing potential prior to dose of 
vedolizumab at infusion visits. In addition to a negative urine hCG pregnancy test at screening, female subjects must also have a 
negative urine hCG pregnancy test prior to receiving each IV dose. Subjects will receive continued guidance with respect to the 
avoidance of pregnancy and sperm/ova donation as part of the study procedures. 
(h) This will include collection of AEs, SAEs, and AESIs and will include collection of additional safety information on 
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important clinical events (eg, PML-related AEs, IBD-related hospitalizations, malignancies, hypersensitivity, hepatic events, and 
serious infections). AE assessment includes review of the subject’s alert card. AEs from the qualifying study which are ongoing 
at the time of signing informed consent to participate in this study will not be as AEs collected in this study but will be captured 
as concurrent medical conditions. 
(i) At screening, if the procedure has been conducted within the last 24 hours, the results of that test can be used and the 
procedure does not need to be redone. 
 
Revised Text 
Appendix A 
Schedule of Study Procedures for Main XAP Study 
 
XAP Procedures a 
 
Enrollment Visit 
(Final Visit of Qualifying Study) 
Infusion Visit b 
Safety Follow-up Visit c 
(Final Study Infusion 
+18 Weeks) 
Visit Number: 
1 
2 onwards 
– 
Informed consent 
X 
– 
– 
Alert card 
X 
– 
X 
Assess inclusion/exclusion criteria 
X 
– 
– 
Assessment for continued eligibility 
– 
X d 
– 
Demographics/medical and prior 
therapies/concurrent medical conditions 
X 
– 
– 
UC/CD history 
X 
– 
– 
Physical examination e 
X f 
– 
– 
Vital signs g 
X f 
X 
X 
Weight and BMI g 
X f 
X 
X 
Height 
X f 
– 
– 
Concomitant medications h 
X 
X 
X 
Pregnancy testing i 
X f 
X 
X 
Pregnancy avoidance 
X 
X 
– 
Call IVRS/IWRS for Subject ID/Medication 
ID/subject status 
X 
X 
X 
Administer vedolizumab 
– 
X 
– 
AE/SAE assessment j 
X 
X 
X 
AE: adverse event; AESI: adverse event of special interest; BMI: body mass index; CD: Crohn’s disease; 
COVID-19: coronavirus disease 2019; hCG: human chorionic gonadotropin; IBD: inflammatory bowel disease; 
ID: identification; IV: intravenous; IVRS: interactive voice response system; IWRS: interactive web response 
system; PML: progressive multifocal leukoencephalopathy; SAE: serious adverse event; UC: ulcerative colitis; 
XAP: extended access program.  
a At the time of this protocol amendment, the COVID-19 pandemic continues to affect the way clinical studies are being 
conducted such that alternative measures are being implemented to maintain subject safety and to ensure data quality 
and integrity. A detailed description of COVID-19-related protocol considerations/mitigations is provided in Section 9.3.7. 
b The first infusion visit should be no more than 8 weeks (± 7 days) after the last dose in the subject’s qualifying study. Infusion 
visits should occur every 8 weeks (± 7 days). A detailed description is provided in Section 6.1. 
c Subjects will return 18 weeks after their final study infusion visit for a safety follow-up visit. Subjects should return for the 
follow-up visit regardless of whether they remain on vedolizumab after the study (ie, they left the study due to commercial 
availability of vedolizumab, or they withdrew from the study for other reasons). 
d At each visit, the investigator should assess the subject for continued eligibility (see Section 7.6) and determine if vedolizumab 
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is available to the subject through commercial channels, including reimbursement, for the subject’s clinical scenario.  
e A symptom-directed physical examination will be performed at baseline. Any clinically significant findings on the physical 
examination will be recorded as AEs. 
f At screening, if the procedure has been conducted within the last 24 hours, the results of that test can be used and the 
procedure does not need to be redone. 
g Should occur prior to dosing at infusion visits. 
h Concomitant medication is any drug given in addition to the study medication. The information will be collected for all subjects 
at the enrollment visit and subsequent visits as detailed in Section 9.1.10. 
i Urine pregnancy test will be performed via dipstick test for all female subjects of childbearing potential prior to dose of 
vedolizumab at infusion visits. In addition to a negative urine hCG pregnancy test at screening, female subjects must also have a 
negative urine hCG pregnancy test prior to receiving each IV dose. Subjects will receive continued guidance with respect to the 
avoidance of pregnancy and sperm/ova donation as part of the study procedures. 
j This will include collection of AEs, SAEs, and AESIs and will include collection of additional safety information on important 
clinical events (eg, PML-related AEs, IBD-related hospitalizations, malignancies, hypersensitivity, hepatic events, and serious 
infections). AE assessment includes review of the subject’s alert card. AEs from the qualifying study which are ongoing at the 
time of signing informed consent to participate in this study will not be as AEs collected in this study but will be captured as 
concurrent medical conditions. 
 
Rationale for Amendment 
Added list of abbreviations and footnote text to cross-refer details of COVID-19-related protocol 
considerations/mitigations. 
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1.3
Protocol Amendment 6 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment 6.
The primary purpose of this amendment is to provide additional clarifications and include all 
changes made to the original version of the protocol (dated 17 March 2016). Full details regarding 
changes made to the text are given in Appendix I. Minor grammatical and editorial changes are 
included for clarification purposes only. The below table summarizes the main changes in the 
protocol.
Change in Protocol
Rationale/Justification
Version of amendment (s) in 
which change was made 
effective
Cover Page
Included Takeda sponsor companies in 
the European and Asian regions.
This is a global study.
Inadvertently omitted in Initial Protocol 
version.
Amendment 1 (Local- South 
Africa only); Amendment 2 
(Global – sites participating in 
XAP-PK substudy); and 
Amendment 3 (Global)
Investigator Agreement
Included language per DoH 
requirement. 
To be fully compliant with this DoH 
requirement.
Amendment 1 (Local- South 
Africa only); Amendment 2 
(Global – sites participating in 
XAP-PK substudy) 
Section 2.0 Summary
Included Takeda sponsor companies in 
the European and Asian regions.
This is a global study. 
Inadvertently omitted in Initial Protocol 
version.
Amendment 1 (Local- South 
Africa only); Amendment 2 
(Global – sites participating in 
XAP-PK substudy); and 
Amendment 3 (Global)
Section 2.0 Summary
Included additional qualifying study
An additional qualifying study 
MLN0002-3028 was added along with the 
existing study C13008. Included to clarify 
the completion of qualifying study for 
enrolled subjects.
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK 
substudy)
Section 2.0 Summary
Details related to subject’s population 
and dose level have been modified for 
clarity.
Clarification added related to the window 
period of ±7 days with every dose 
administered to subject and dosing regimen
permitted in the study.
Text updated as per the modifications in 
respective sections within protocol main 
body text.
Amendment 6 (Global)
3.4 Corporate Identification
Included Takeda sponsor companies in 
the European and Asian regions.
This is a global study.
Inadvertently omitted in Initial Protocol 
version.
Amendment 1 (Local- South 
Africa only); Amendment 2 
(Global – sites participating in 
XAP-PK substudy); and 
Amendment 3 (Global)
4.1.2 Vedolizumab IV
4.3 Risk: Benefit Assessment
Updated number of subject received 
Text updated as per details in the current 
version of the IB.
Amendment 6 (Global)
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Change in Protocol
Rationale/Justification
Version of amendment (s) in 
which change was made 
effective
and exposure duration details to 
vedolizumab till 19 Nov 2016.
6.1 Study Design
Included additional qualifying study 
and clarified study design text.
An additional qualifying study, 
MLN0002-3028 has been added along with 
the existing study C13008 for the main XAP 
study only.
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK 
substudy)
6.1 Study Design
Included countries name and clarified 
study design text.
Text has been added to clarify the XAP 
study design related to dosing regimen 
permitted in the study and timepoint of first 
dose in the XAP study.
Countries for XAP and XAP-PK studies 
have been clarified to avoid ambiguity for 
the sites involved in XAP-PK substudy. No 
subjects will be enrolled in the XAP-PK 
substudy from countries that are not 
specifically listed in the protocol. Similarly, 
no subjects will be rolled-over from the 
C13008 or MLN0002-3028 studies unless 
country name is specifically listed in
protocol.
Amendment 6 (Global)
6.2 Number of Subjects
Included additional text related to 
subject enrollment in XAP study.
Added clarification for the subject 
participation from the qualifying study to 
XAP study.
Amendment 6 (Global)
6.3 Duration of Study
Included additional text related to study 
design text and study completion.
Text has been added to clarify the duration 
of the XAP study.
Amendment 6 (Global)
6.4 Justification for Study Design, Dose 
and Endpoints 
Text updated as per details in the current 
version of the IB.
Amendment 6 (Global)
8.1.3. Dose and Regimen
8.2 Drug Dosing and Dispensing 
Procedures
Included additional text related to dose 
regimen.
Text has been added to clarify the dose 
schedule and regimen along with window 
period of ±7 days with every dose.
Amendment 6 (Global)
8.4 Accountability and Destruction of 
Sponsor-Supplied Drugs
Included additional text related to 
remote drug reconciliation and 
destruction
Text has been added to clarify that the drug 
reconciliation will be completed remotely 
and destruction can be carried out locally or 
by a contracted third party as per local 
regulations.
Amendment 6 (Global)
9.1.5 Documentation of Concurrent 
Medical Conditions
Included text regarding the recording of 
ongoing AEs from qualifying study.
Added clarification that “ongoing AEs” 
from qualifying study, at the time of signing 
informed consent to participate in this XAP 
study, will be captured as a concurrent 
medical condition.
Amendment 6 (Global)
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Change in Protocol
Rationale/Justification
Version of amendment (s) in 
which change was made 
effective
9.1.7 Physical Examination
Included text regarding procedures that 
have been conducted within last 
24 hours.
Added clarification that if physical 
examination has been conducted within the 
last 24 hours at the enrollment visit, the 
results of that test can be used and the 
procedure does not need to be redone.
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK 
substudy)
9.1.8 Vital Sign Procedure
Included text regarding procedures that 
have been conducted within last 
24 hours.
Added clarification that if vital sign 
measurements have been conducted within 
the last 24 hours at the enrollment visit, the 
results of that test can be used and the 
procedure does not need to be redone.
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK 
substudy)
9.1.9 Weight, Height, and BMI
Included text regarding procedures that 
have been conducted within last 
24 hours.
In addition, BMI calculation details 
have been added.
Added clarification that if weight and height 
have been conducted within the last 24 hours 
at the enrollment visit, the results of that test 
can be used and the procedure does not need 
to be redone.
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK 
substudy)
9.1.11 Contraception & Pregnancy 
Avoidance Procedure
Clarification that spermicides are not 
commercially available in South 
Africa. South African subjects will be 
counseled to use other double-barrier 
methods.
Clarification to support applicable 
double-barrier contraception and pregnancy 
avoidance procedures in South African trial 
sites.
Amendment 1 (Local- South 
Africa only); Amendment 2 
(Global – sites participating in 
XAP-PK substudy)
9.1.11 Contraception & Pregnancy 
Avoidance Procedure
Included text regarding procedures that 
have been conducted within last 
24 hours.
Added clarification that if pregnancy test 
result has been recorded within the last 
24 hours at screening, the results of that test 
can be used and the procedure does not need 
to be redone.
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK 
substudy)
9.1.15 Collection of AEs and SAEs
Included text related to the time of 
collection of AEs and SAEs during the 
study.
Added clarification that AEs and SAEs will 
be collected from the time when the subject 
signs the informed consent to participate in 
the study through to follow-up visit.
Amendment 6 (Global)
9.3.2 Treatment Period
Included text to clarify study treatment 
and completion period.
Text has been added to clarify the dose 
schedule and regimen.
Amendment 6 (Global)
9.3.6 Follow-up Period
Included text to clarify study procedure 
to be followed at follow-up period.
Added clarification over the follow-up 
period and procedure to be followed.
Amendment 6 (Global)
10.1.3 Additional Points to Consider 
for AEs
10.1.5 Severity of AEs
10.2.1.2 AE Reporting
Added to reduce the ambiguity between the 
terminologies.
Amendment 6 (Global)
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Change in Protocol
Rationale/Justification
Version of amendment (s) in 
which change was made 
effective
13.1.4 Safety Analysis
The term ‘severity” of AEs changed to 
‘intensity’ of AEs recorded during the 
study.
Included text related to the time of 
collection of AEs and SAEs during the 
study.
10.1.11 Action Concerning Study 
Medication
Every 8-week changed to Q8W
Editorial change added for consistency and 
defining dosing schedule technically.
Amendment 6 (Global)
10.2.1.1 AE collection period
Included text regarding the collection 
of ongoing AEs from qualifying study, 
and AEs during the study and safety 
follow-up. 
13.1.4 Safety Analysis
Added clarification that ongoing AEs from 
qualifying study at the time of signing 
informed consent to participate in this study 
will be captured as a concurrent medical 
condition and AEs/SAEs will be collected 
from the time when the subject signs the 
informed consent to participate in the study, 
through study till safety follow-up visit.
Amendment 6 (Global)
15.0 Ethical Aspects of the Study
Re-emphasized the objective of the 
global Extended Access Program 
(XAP).
Clarification to satisfy Declaration of 
Helsinki requirements.
Amendment 1 (Local- South 
Africa only); Amendment 2 
(Global – sites participating in 
XAP-PK substudy) 
15.1 IRB and/or IEC Approval 
Added clarifications for funding, 
sponsors, institutional affiliations and 
potential conflicts of interest.
Clarification to satisfy Declaration of 
Helsinki requirements.
Amendment 1 (Local- South 
Africa only); Amendment 2 
(Global – sites participating in 
XAP-PK substudy) 
15.2 Subject Information, Informed 
Consent, Subject Authorization
Added references to the “assent form” 
for use if applicable, eg, mentally 
incapacitated persons or subjects 
deemed otherwise incapable of 
providing informed consent.
Clarification to satisfy Declaration of 
Helsinki requirements.
Amendment 1 (Local- South 
Africa only); Amendment 2 
(Global – sites participating in 
XAP-PK substudy) 
Appendix A Schedule of Study 
Procedures for Main XAP Study
Included footnote to the procedures that 
are not required to be repeated if 
performed within 24 hours of the 
screening/enrollment visit and clarified 
the timing of the initial study visit for 
additional qualifying study.
To include the timing of the initial study 
visit for MLN0002-3028 and to clarify that 
the results of procedures that have been 
conducted in last 24 hours at enrollment visit 
can be used and the procedure does not need 
to be redone.
Amendment 3 (Global) and 
Amendment 4 (Global – sites 
participating in XAP-PK 
substudy)
Appendix A Schedule of Study 
Procedures for Main XAP Study
Footnotes have been reduced to remove 
redundancy.
Amendment 6 (Global)
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Study No. Vedolizumab-4013 
Page 9 of 124
Protocol Incorporating Amendment 6
17 July 2018
CONFIDENTIAL
Change in Protocol
Rationale/Justification
Version of amendment (s) in 
which change was made 
effective
Footnotes were shortened to remove 
repetitive details.
Details of XAP-PK substudy procedures 
moved to a separate Appendix F
2.0 Summary
Included details about XAP-PK 
substudy.
4.2.1 Rationale for XAP-PK Substudy
5.1.2 Exploratory Objectives for 
XAP-PK Substudy 
5.2.2 Exploratory Endpoints for 
XAP-PK Substudy
6.1.1 Study Design of the XAP-PK 
Substudy
6.2 Number of Subjects 
6.3 Duration of Study 
6.4 Justification for Study Design, 
Dose, and Endpoints
6.5.1 Criteria for Premature 
Termination or Suspension of the Study
7.1 Inclusion Criteria
7.6 Criteria for Discontinuation or 
Withdrawal of a Subject
7.7 Procedures for Discontinuation or 
Withdrawal of a Subject
9.1.1.1 XAP-PK Substudy Informed 
Consent Procedure
9.1.9 Weight, Height, and BMI
9.1.16 Partial Mayo Score
9.1.17 Harvey-Bradshaw Index Score 
9.1.18 Sample Collection and Analysis
9.3.1 Enrollment Visit 1
9.3.2 Treatment Period
9.3.6 Follow-up Period
13.1.1 Analysis Sets
13.3 Determination of Sample Size
13.4 XAP-PK Substudy Analysis
Appendix E Details Specific to 
XAP-PK Substudy
Appendix F Schedule of Study 
Procedures for XAP-PK Substudy
Details related to rationale, objectives, 
endpoints, study design, subjects, inclusion 
and withdrawal criteria, study procedures, 
and statistical considerations were added to 
explain XAP-PK substudy.
All these changes are now described 
separately as XAP-PK substudy in 
Appendix E and schedule of study 
procedures for XAP-PK substudy are 
summarized in Appendix F.
For XAP-PK substudy additional 
clarifications have been included to specify 
that end of substudy and Week 56 are same 
i.e. end of substudy visit/Week 56. 
Clarification that End of Sub-study/Week 56 
visit should be scheduled in conjunction 
with a regular infusion visit of the Main 
study has been added.
Mention of predictive models for XAP-PK 
substudy have been removed as they were 
added inadvertently
Amendment 2 (Global) and 
Amendment 6 (moved to 
separate Appendix) 
Amendment 5 (Global): 
Removed MLN0002-3028 from 
eligibility to participate in the 
XAP-PK substudy. It was added 
in error in Amendment 4. 
Subjects in MLN0002-3028 are 
not switching from Q4W to 
Q8W dosing and are therefore an 
inappropriate population for the 
substudy.
Amendment 6 (Global)
Appendix C Elements of the Subject 
To include a statement to cover the 
Amendment 2 (Global)
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 10 of 124
Protocol Incorporating Amendment 6
17 July 2018
CONFIDENTIAL
Change in Protocol
Rationale/Justification
Version of amendment (s) in 
which change was made 
effective
Informed Consent
requirements for the XAP-PK substudy
Appendix G Partial Mayo Score
Scale copy has been added for reference
Amendment 6 (Global)
Appendix H Harvey Bradshaw Index
Scale copy has been added for reference
Amendment 6 (Global)
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 5 of 93
Protocol Incorporating Amendment 5
07 February 2017
CONFIDENTIAL
1.3
Protocol Amendment 5 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment 5.
The primary purpose of this amendment is to remove MLN0002-3028 as a study eligible for the 
XAP-PK substudy. Full details regarding changes made to the text are given in Appendix E. Minor 
grammatical and editorial changes are included for clarification purposes only.
Change in Protocol
Rationale/Justification
Section 2.0 Summary
Removed MLN0002-3028 as a qualifying study for 
the XAP-PK substudy.
MLN0002-3028 was included in the previous version in error. 
Subjects in MLN0002-3028 are not switching from once every 
4 weeks (Q4W) to once every 8 weeks (Q8W dosing and are 
therefore an inappropriate population for the extended access 
program-pharmacokinetic (XAP-PK) substudy.
Section 4.2.1 Rationale for the XAP-PK Substudy
Section 5.2.2 Exploratory Endpoints for XAP-PK 
Substudy
Section 6.1.1Study Design of the XAP Substudy
Section 6.2 Number of Subjects
Section 7.1 Inclusion Criteria
Section 9.1.18 Sample Collection and Analysis
Removed reference to the inclusion of 
MLN0002-3028 in the XAP-PK substudy.
MLN0002-3028 was included in the previous version in error. 
Subjects in MLN0002-3028 are not switching from Q4W to 
Q8W dosing and are therefore an inappropriate population for 
the XAP-PK substudy.
Appendix A Schedule of Study Procedures 
Removed reference to the inclusion of 
MLN0002-3028 in the XAP-PK substudy in a 
footnote to the procedures table. 
MLN0002-3028 was included in the previous version in error. 
Subjects in MLN0002-3028 are not switching from Q4W to 
Q8W dosing and are therefore an inappropriate population for 
the XAP-PK substudy.
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 5 of 103
Protocol Incorporating Amendment 4
21 November 2016
CONFIDENTIAL
1.3
Protocol Amendment 4 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment 4.
The primary purpose of this amendment is to add an additional qualifying study, MLN0002-3028, 
and to clarify the timing of the initial study visit for this additional study. Full details regarding 
changes made to the text are given in Appendix E. Minor grammatical and editorial changes are 
included for clarification purposes only.
Change in Protocol
Rationale/Justification
Section 2.0 Summary
Included additional qualifying study
An additional qualifying study MLN0002-3028 was 
added along with the existing study C13008
Section 4.2.1 Rationale for the XAP-PK 
Substudy
Section 5.2.2 Exploratory Endpoints for 
XAP-PK Substudy
Section 6.2 Number of Subjects
Section 7.1 Inclusion Criteria
Section 9.1.18 Sample Collection and 
Analysis
Included additional qualifying study
An additional qualifying study MLN0002-3028 was 
added along with the existing study C13008
Section 6.1 Study Design
Section 6.1.1 Study Design of the XAP-PK 
Substudy
Included additional qualifying study and 
clarified study design text
Text has been clarified for study design related to the 
XAP study and an additional qualifying study, 
MLN0002-3028, has been added along with the 
existing study C13008
Section 9.1.7 Physical Examination
Included text regarding procedures that have 
been conducted within last 24 hours
Added clarification that if physical examination has 
been conducted within the last 24 hours at the 
enrollment visit, the results of that test can be used 
and the procedure does not need to be redone
Section 9.1.8 Vital Sign Procedure
Included text regarding procedures that have 
been conducted within last 24 hours
Added clarification that if vital sign measurements 
have been conducted within the last 24 hours at the 
enrollment visit, the results of that test can be used 
and the procedure does not need to be redone
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 6 of 103
Protocol Incorporating Amendment 4
21 November 2016
CONFIDENTIAL
Change in Protocol
Rationale/Justification
Section 9.1.9 Weight, Height, and BMI
Included text regarding procedures that have 
been conducted within last 24 hours
Added clarification that if weight and height have 
been conducted within the last 24 hours at the 
enrollment visit, the results of that test can be used 
and the procedure does not need to be redone
Section 9.1.11 Contraception and Pregnancy 
Avoidance Procedure
Included text regarding procedures that have 
been conducted within last 24 hours
Added clarification that if pregnancy test result has 
been recorded within the last 24 hours at screening, 
the results of that test can be used and the procedure 
does not need to be redone
Section 10.2 to Section 12.2
Subsections rearranged as per original protocol for 
better readability
Appendix A Schedule of Study Procedures 
Included footnote to the procedures that are 
not required to be repeated if performed 
within 24 hours of the screening/enrollment 
visit and clarified the timing of the initial 
study visit for additional qualifying study. 
To include the timing of the initial study visit for 
MLN0002-3028 and to clarify that the results of 
procedures that have been conducted in the last 
24 hours at enrollment visit can be used and the 
procedure does not need to be redone. 
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 5 of 77
Protocol Incorporating Amendment 3
10 October 2016
CONFIDENTIAL
1.3
Protocol Amendment 3 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment 3.
The primary purpose of this amendment is to add an additional qualifying study, MLN0002-3028 
and to clarify the timing of the initial study visit for this additional study. Full details regarding 
changes made to the text are given in Appendix E. Minor grammatical and editorial changes are 
included for clarification purposes only. 
Change in Protocol
Rationale/Justification
Cover Page 
Included Takeda sponsor companies in the 
European and Asian regions.
This is a global study. 
Inadvertently omitted in initial protocol version.
2.0 Summary
Included Takeda sponsor companies in the 
European and Asian regions.
This is a global study. 
Inadvertently omitted in initial protocol version.
2.0 Summary
Included additional qualifying study
An additional qualifying study MLN0002-3028 was 
added along with the existing study C13008
3.4 Corporate Identification
Included Takeda sponsor companies in the 
European and Asian regions.
This is a global study.
Inadvertently omitted in initial protocol version.
6.1 Study Design
Included additional qualifying study and 
clarified study design text
Text has been clarified for study design related to the 
XAP study and an additional qualifying study, 
MLN0002-3028 has been added along with the 
existing study C13008.
9.1.7 Physical Examination
Included text regarding procedures that have 
been conducted within last 24 hours
Added clarification that if physical examination has 
been conducted within the last 24 hours at the 
enrollment visit, the results of that test can be used 
and the procedure does not need to be redone
9.1.8 Vital Sign Procedure
Included text regarding procedures that have 
been conducted within last 24 hours
Added clarification that if vital sign measurements 
have been conducted within the last 24 hours at the 
enrollment visit, the results of that test can be used 
and the procedure does not need to be redone
9.1.9 Weight and Height
Included text regarding procedures that have 
been conducted within last 24 hours
Added clarification that if weight and height have
been conducted within the last 24 hours at the 
enrollment visit, the results of that test can be used 
and the procedure does not need to be redone
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 6 of 77
Protocol Incorporating Amendment 3
10 October 2016
CONFIDENTIAL
Change in Protocol
Rationale/Justification
9.1.11 Contraception and Pregnancy 
Avoidance Procedure
Included text regarding procedures that have 
been conducted within last 24 hours
Added clarification that if pregnancy test result has
been recorded within the last 24 hours at screening, 
the results of that test can be used and the procedure 
does not need to be redone
Appendix A Schedule of Study Procedures 
Included footnote to the procedures that are 
not required to be repeated if performed 
within 24 hours of the screening/enrollment 
visit and clarified the timing of the initial 
study visit for additional qualifying study
To include the timing of the initial study visit for 
MLN0002-3028 and to clarify that the results of 
procedures that have been conducted in last 24 hours 
at enrollment visit can be used and the procedure 
does not need to be redone.
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 5 of 116
Protocol Incorporating Amendment 2
12 August 2016
CONFIDENTIAL
1.3
Protocol Amendment 2 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment 2.
The primary purpose of this amendment is to add a pharmacokinetic (PK) substudy to the extended 
access program (XAP-PK). The protocol has also been updated to provide clarifications that
satisfy all elements of the Declaration of Helsinki for use in the Vedolizumab-4013 study. 
Clarification is also outlined for the provision of study drug after the trial. Full details regarding
changes made to the text are given in Appendix E. Minor grammatical and editorial changes are 
included for clarification purposes only. 
Change in Protocol
Rationale/Justification
Cover Page 
Included Takeda sponsor companies in the 
European and Asian regions.
This is a global study. 
Inadvertently omitted in initial protocol version.
Investigator Agreement
Included language per Declaration of 
Helsinki requirement.
To be fully compliant with the Declaration of 
Helsinki requirement. 
2.0 Summary
Included Takeda sponsor companies in the 
European and Asian regions.
This is a global study. 
Inadvertently omitted in initial protocol version.
2.0 Summary
Included details about XAP-PK substudy.
Details related to study design, objectives, subjects, 
endpoints, and statistical considerations added to 
explain the procedures for substudy.
3.4 Corporate Identification
Included Takeda sponsor companies in the 
European and Asian regions.
This is a global study.
Inadvertently omitted in initial protocol version.
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 6 of 116
Protocol Incorporating Amendment 2
12 August 2016
CONFIDENTIAL
Change in Protocol
Rationale/Justification
4.2.1 Rationale for XAP-PK Substudy
5.1.2 Exploratory Objectives for XAP-PK 
Substudy 
5.2.2 Exploratory Endpoints for XAP-PK 
Substudy
6.1.1 Study Design of the XAP-PK Substudy
6.2 Number of Subjects
6.3 Duration of Study
6.4 Justification for Study Design, Dose, and 
Endpoints
6.5.1 Criteria for Premature Termination or 
Suspension of the Study
7.1 Inclusion Criteria
7.6 Criteria for Discontinuation or 
Withdrawal of a Subject
7.7 Procedures for Discontinuation or 
Withdrawal of a Subject
9.1.1.1 XAP-PK Substudy Informed 
Consent Procedure
9.1.9 Weight, Height, and BMI
9.1.16 Partial Mayo Score
9.1.17 Harvey-Bradshaw Index Score
9.1.18 Sample Collection and Analysis
9.3.1 Enrollment Visit 1
9.3.2 Treatment Period
9.3.6 Follow-up Period
13.1.1 Analysis Sets
13.3 Determination of Sample Size
13.4 XAP-PK Substudy Analysis
13.5 Predictive Models
Details related to rationale, objectives, endpoints, 
study design, subjects, inclusion and withdrawal 
criteria, study procedures, and statistical 
considerations were added to explain XAP-PK 
substudy.
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 7 of 116
Protocol Incorporating Amendment 2
12 August 2016
CONFIDENTIAL
Change in Protocol
Rationale/Justification
9.1.11 Contraception and Pregnancy 
Avoidance Procedure
Clarification that spermicides are not 
commercially available in South Africa. 
South African subjects will be counseled to 
use other double-barrier methods.
Clarification to support applicable double-barrier 
contraception and pregnancy avoidance procedures
in South African trial sites.
15.0 Ethical Aspects of the Study
Re-emphasized the objective of the global 
extended access program (XAP).
Clarification to satisfy Declaration of Helsinki 
requirements.
15.1 IRB and/or IEC Approval 
Added clarifications for funding, sponsors,
potential conflicts of interest, and
institutional affiliations.
Clarification to satisfy Declaration of Helsinki 
requirements.
15.2 Subject Information, Informed 
Consent, Subject Authorization
Added references to the “assent form” for 
use if applicable, eg, mentally incapacitated 
persons or subjects deemed otherwise 
incapable of providing informed consent.
Clarification to satisfy Declaration of Helsinki 
requirements.
Appendix A Schedule of Study Procedures 
(Main XAP Study and XAP-PK Substudy)
Included assessments for XAP-PK substudy.
To include the XAP-PK substudy procedures.
Appendix C Elements of the Subject 
Informed Consent
To include a statement to cover the requirements for 
the XAP-PK substudy.
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 5 of 76
Protocol Incorporating Amendment No. 1
19 April 2016
CONFIDENTIAL
1.3
Protocol Amendment 1 Summary of Changes 
This document describes the changes in reference to the Protocol Incorporating Amendment No. 1.
The primary purpose of this amendment is to update the protocol to provide clarifications which 
satisfy all elements of the Declaration of Helsinki for use in the Vedolizumab-4013 study in the 
Republic of South Africa. Clarification is also outlined for the provision of study drug post-trial. 
Full details on changes of text are given in Appendix E.
Change in Protocol
Rationale/Justification
Cover Page 
Included Takeda sponsor companies in the 
European and Asian regions.
This is a global study. 
Inadvertently omitted in Initial Protocol version.
Investigator Agreement
Included language per DoH requirement. 
To be fully compliant with this DoH requirement. 
2.0 Summary
Included Takeda sponsor companies in the 
European and Asian regions.
This is a global study. 
Inadvertently omitted in Initial Protocol version.
3.4 Corporate Identification
Included Takeda sponsor companies in the 
European and Asian regions.
This is a global study.
Inadvertently omitted in Initial Protocol version.
9.1.11 Contraception & Pregnancy 
Avoidance Procedure
Clarification that spermicides are not 
commercially available in South Africa. 
South African subjects will be counseled to 
use other double-barrier methods.
Clarification to support applicable double-barrier 
contraception and pregnancy avoidance procedures 
in South African trial sites.
15.0 Ethical Aspects of the Study
Re-emphasized the objective of the global 
Extended Access Programme (XAP)
Clarification to satisfy Declaration of Helsinki 
requirements.
15.1 IRB and/or IEC Approval 
Added clarifications for funding, sponsors, 
institutional affiliations and potential 
conflicts of interest.
Clarification to satisfy Declaration of Helsinki 
requirements.
For non-commercial use only

Vedolizumab IV
Study No. Vedolizumab-4013 
Page 6 of 76
Protocol Incorporating Amendment No. 1
19 April 2016
CONFIDENTIAL
Change in Protocol
Rationale/Justification
15.2 Subject Information, Informed 
Consent, Subject Authorisation
Added references to the “assent form” for 
use if applicable, eg, mentally incapacitated 
persons or subjects deemed otherwise 
incapable of providing informed consent.
Clarification to satisfy Declaration of Helsinki 
requirements.
For non-commercial use only