Conditions: Hematopoietic Stem Cells
Keywords: Drug Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 343
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen on intestinal aGvHD-free survival by Day +180 in participants who receive allo-HSCT as treatment for a hematologic malignancy or myeloproliferative disorder.

Detailed description:
The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat people who are undergoing allo-HSCT transplantation. This study will look at the efficacy and safety of vedolizumab in the prophylaxis of intestinal aGvHD in participants undergoing allo-HSCT transplantation.

The study will enroll approximately 558 participants. Participants will be randomly assigned (by chance, like flipping a coin) in 1:1 ratio to one of the two treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need) along with background GvHD prophylaxis regimen:

* Vedolizumab 300 mg
* Placebo (dummy inactive intravenous infusion)

This multi-center trial will be conducted Worldwide. The overall time to participate in this study is 12 months.

Arms:
arm 1: Vedolizumab placebo-matching, intravenous (IV) infusion, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT up to the end of study treatment (up to 182 days). arm 2: Vedolizumab 300 mg, IV infusion, once on Day -1 along with background GvHD prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT up to the end of study treatment (up to 182 days).

Interventions: intervention 1: Vedolizumab Placebo intervention 2: Vedolizumab
Intervention descriptions: intervention 1: Vedolizumab placebo-matching IV infusion. intervention 2: Vedolizumab IV infusion.

Protocol document:
Prot_000.pdf: 
Title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the 
Efficacy and Safety of Vedolizumab in the Prophylaxis of Intestinal Acute 
Graft-Versus-Host Disease in Subjects Undergoing Allogeneic Hematopoietic Stem Cell 
Transplantation 
NCT Number: NCT03657160 
Protocol Approve Date: 18 September 2019 
Ce1tain info1mation within this protocol has been redacted (ie, specific content is masked ineversibly from 
view with a black/blue bar) to protect either personally identifiable info1mation (PPD) or company 
confidential info1mation (CCI). 
This may include, but is not limited to, redaction of the following: 
• Named persons or organizations associated with the sn1dy. 
• Propiietaiy info1mation, such as scales or coding systems, which ai·e considered confidential 
info1mation under prior agreements with license holder. 
• Other info1mation as needed to protect confidentiality of Takeda or paitners, personal info1mation, or 
to othe1wise protect the integrity of the clinical sn1dy. 


PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the 
Efficacy and Safety of Vedolizumab in the Prophylaxis of Intestinal Acute 
Graft-Versus-Host Disease in Subjects Undergoing Allogeneic Hematopoietic Stem Cell 
Transplantation
Vedolizumab in the prophylaxis of intestinal acute graft vs host disease in subjects undergoing 
allogeneic hematopoietic stem cell transplantation.
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA USA 02139
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as 
“Millennium,” “sponsor,” or “Takeda”.
Study Number:
Vedolizumab-3035
EudraCT Number:
2018-002141-11
Compound:
Vedolizumab IV
Date:
18 September 2019
Amendment Number:
07
Amendment History: 
Date
Amendment Number
Amendment Type
Region
13 June 2018
Initial Protocol
Not applicable
Global
13 November 2018
Amendment 01
Nonsubstantial
Local/France
07 November 2018
Amendment 02
Nonsubstantial
Local/Sweden
07 November 2018
Amendment 03
Nonsubstantial
Local/United Kingdom
12 November 2018
Amendment 04
Nonsubstantial
Local/Norway
06 December 2018
Amendment 05
Nonsubstantial
Local/Germany
10 June 2019
Amendment 06
Substantial
Global
18 September 2019
Amendment 07
Substantial
Global
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 2 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are in 
the study manual.
cable Terms of Use
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Vedolizumab IV
Study No. Vedolizumab-3035
Page 4 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
prescribing information, and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International 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 10.0 of this 
protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix C).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 5 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
1.3
Protocol Amendment No. 07 Summary of Changes
This document describes the changes to the Protocol Incorporating Amendment No. 07. This 
amendment is considered a substantial amendment as the primary purpose of this amendment is to 
open enrollment to adolescent subjects aged 12 years and greater and weighing ≥30 kg, as a 
required condition of the European Medicines Agency’s Paediatric Committee–endorsed 
paediatric investigational plan for vedolizumab as prophylaxis of acute graft versus host disease 
(aGvHD) after allogeneic hematopoietic stem cell transplantation. Other changes incorporated 
into this amendment are outlined below and are detailed in Appendix G.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
For specific description of text changes and where the changes are located, see Appendix G.
Changes in Amendment 07:
1. Clarification of the description of the disease to be treated in adolescent subjects.
2. Addition of results from nonclinical studies related to inclusion of adolescent subjects.
3. Updated human experience as reported in the 9th development safety update report.
4. Update to the study rationale to support the inclusion of adolescent subjects.
5. Update to the benefit:risk profile to support the inclusion of adolescent subjects.
6. Addition of data supporting the dose regimen in adolescent subjects.
7. Update of the inclusion criteria impacted by inclusion of adolescent subjects.
8. Update to permitted medications to include use of topical anesthetic in adolescent subjects.
9. Clarification to the procedures to be conducted after discontinuation or withdrawal of a 
subject.
10. Added assessment of height to be collected at the end of study visit.
11. Updated the pregnancy testing and contraception requirements to include female adolescent 
subjects aged 12 years and greater.
12. Addition of necessary age-appropriate documentation that must be completed for adolescent 
subjects.
13. Addition of blood collection volumes for adolescent and adult subjects.
14. Update to the version of Common Terminology Criteria for Adverse Events to be used for the
grading of adverse events.
15. Update to stratification to include age group and data assessments in adolescent subjects.
16. Updates to Appendix A, Schedule of Events footnotes, to align with updates in text.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Study No. Vedolizumab-3035
Page 6 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
17. Update to Appendix B regarding methotrexate treatment to support the inclusion of adolescent 
subjects.
18. Update to Appendix F to include age-appropriate assessments of aGvHD clinical stage and 
Mount Sinai Acute GVHD International Consortium severity index for aGvHD.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
and 
ms
and 


Vedolizumab IV
Study No. Vedolizumab-3035
Page 7 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment No. 07 Summary of Changes ...................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Principal Investigator/Coordinating Investigator ......................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.1.1
Disease to be Treated.....................................................................................20
4.1.2
Vedolizumab IV............................................................................................21
4.2
Rationale for the Proposed Study.............................................................................23
4.3
Benefit:Risk Profile .................................................................................................24
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................27
5.1
Objectives................................................................................................................27
5.1.1
Primary Objective .........................................................................................27
5.1.2
Safety Objective............................................................................................27
5.1.3
Secondary Objectives ....................................................................................27
5.2
Endpoints.................................................................................................................28
5.2.1
Primary Endpoint ..........................................................................................28
5.2.2
Safety Endpoint.............................................................................................28
5.2.3
Secondary Endpoints.....................................................................................29
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................31
6.1
Overview of Study Design.......................................................................................31
6.1.1
Schedule of Observations and Procedures......................................................31
6.2
Justification for Study Design and Dose...................................................................34
6.2.1
Study Design.................................................................................................34
6.2.2
Dose Selection...............................................................................................34
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6.3
Premature Termination or Suspension of Study or Investigational Site.....................35
6.3.1
Criteria for Premature Termination or Suspension of the Study .....................35
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites.....35
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) ...........................................................35
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............37
7.1
Inclusion Criteria .....................................................................................................37
7.2
Exclusion Criteria ....................................................................................................38
7.3
Medications and Treatments ....................................................................................40
7.3.1
Excluded Concomitant Medications and Treatments While On-study............40
7.3.2
Permitted Medications and Treatments..........................................................40
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................41
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................42
8.0
STUDY DRUG/CLINICAL TRIAL MATERIAL MANAGEMENT ............................43
8.1
Study Medication.....................................................................................................43
8.1.1
Vedolizumab IV or Matching Placebo...........................................................43
8.1.2
Storage..........................................................................................................43
8.1.3
Dose and Regimen.........................................................................................43
8.1.4
Overdose.......................................................................................................44
8.2
Treatment Assignment and Dispensing Procedures ..................................................46
8.3
Investigation Blind Maintenance..............................................................................46
8.4
Unblinding Procedure..............................................................................................46
8.5
Accountability and Destruction of Sponsor-Supplied Drugs.....................................47
8.6
Precautions and Restrictions ....................................................................................48
8.6.1
Study Drug Dosing........................................................................................48
8.6.2
Reproductive Effects .....................................................................................48
8.7
Management of Clinical Events ...............................................................................49
8.7.1
Hypersensitivity Reactions ............................................................................49
8.7.2
Leukopenia or Lymphopenia .........................................................................49
8.7.3
CMV Colitis..................................................................................................49
8.7.4
Malignancy ...................................................................................................50
8.7.5
Liver Injury...................................................................................................50
8.7.6
Hepatitis B Reactivation................................................................................50
8.7.7
Other Clinical Events ....................................................................................51
9.0
STUDY CONDUCT......................................................................................................52
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9.1
Study Personnel and Organizations..........................................................................52
9.2
Randomization.........................................................................................................52
9.3
Study Procedures.....................................................................................................52
9.3.1
Informed Consent..........................................................................................52
9.3.2
Inclusion/Exclusion.......................................................................................52
9.3.3
Demographics ...............................................................................................52
9.3.4
Medical History.............................................................................................53
9.3.5
Physical Examination ....................................................................................53
9.3.6
Weight and Height.........................................................................................53
9.3.7
Vital Signs.....................................................................................................53
9.3.8
Electrocardiogram.........................................................................................53
9.3.9
Performance Status........................................................................................53
9.3.10
Assessment of GvHD ....................................................................................54
9.3.11
PML Checklist ..............................................................................................54
9.3.12
Health-related Quality of Life Questionnaires................................................54
9.3.13
Concomitant Medications and Procedures .....................................................55
9.3.14
AEs ...............................................................................................................55
9.3.15
Clinical Laboratory Evaluations ....................................................................55
9.3.16
9.3.17
9.3.18
Healthcare Resource Utilization Data Collection ...........................................58
9.3.19
Contraception and Pregnancy Avoidance Procedure ......................................58
9.3.20
Pregnancy......................................................................................................59
9.4
Documentation of Screen Failure.............................................................................60
9.5
Completion of Study Treatment (for Individual Subjects) ........................................60
9.6
Study Compliance....................................................................................................61
9.7
Post Study Care .......................................................................................................61
10.0
ADVERSE EVENTS ....................................................................................................62
10.1
Definitions...............................................................................................................62
10.1.1
PTEs .............................................................................................................62
10.1.2
AEs ...............................................................................................................62
10.1.3
Additional Points to Consider for AEs...........................................................62
10.1.4
SAEs.............................................................................................................64
10.1.5
AEs of Special Interest ..................................................................................65
10.1.6
Severity of AEs .............................................................................................66
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Study No. Vedolizumab-3035
Page 11 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................81
15.1
IRB and/or IEC Approval ........................................................................................81
15.2
Subject Information, Informed Consent, and Subject Authorization .........................82
15.3
Subject Confidentiality ............................................................................................83
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................83
15.4.1
Publication ....................................................................................................83
15.4.2
Clinical Trial Registration .............................................................................84
15.4.3
Clinical Trial Results Disclosure ...................................................................84
15.5
Insurance and Compensation for Injury....................................................................84
16.0
REFERENCES..............................................................................................................86
LIST OF IN-TEXT TABLES
Table 9.a
Clinical Hematology, Coagulation, Chemistry, and LFTs...................................57
Table 10.a
Takeda Medically Significant AE List................................................................65
LIST OF IN-TEXT FIGURES
Figure 6.a
Study Design for Study Vedolizumab-3035........................................................33
Figure 8.a
Dosing of Study Drug,
................................45
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................91
Appendix B
Recommended Prophylaxis Treatment: A Combination of CNI (TAC or CYS) 
+ MTX and ATG ...............................................................................................94
Appendix C
Responsibilities of the Investigator.....................................................................96
Appendix D
Investigator Consent to Use of Personal Information..........................................98
Appendix E
Performance Status Assessments........................................................................99
Appendix F
Clinical Stages and Grades of GvHD ...............................................................101
Appendix G
Amendment 07 Detailed Summary of Changes ................................................103
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Study No. Vedolizumab-3035
Page 12 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
2.0
STUDY SUMMARY
Name of Sponsor(s): 
Millennium Pharmaceuticals, Inc.
Compound: 
Vedolizumab IV
Title of Protocol: A Randomized, Double-Blind, 
Placebo-Controlled, Multicenter Study to Evaluate the 
Efficacy and Safety of Vedolizumab in the Prophylaxis of 
Intestinal Acute Graft-Versus-Host Disease in Subjects 
Undergoing Allogeneic Hematopoietic Stem Cell 
Transplantation
EudraCT No.: 2018-002141-11
Study Number: Vedolizumab-3035
Phase: 3
Study Design:
This is a phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of 
vedolizumab compared to placebo as prophylaxis for intestinal acute graft-versus-host disease (aGvHD) in subjects
undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of hematological 
malignancies or myeloproliferative disorder. 
Subjects will be randomized into 2 arms at 1:1 ratio, vedolizumab versus placebo. Randomization will be stratified by
age (≥18 years or adolescents aged 12 to <18 years), human leukocyte antigen (HLA) match (8/8 or 7/8), conditioning 
regimen (myeloablative or reduced intensity conditioning), and with or without antithymocyte globulin (ATG) 
(antithymocyte globulin-Fresenius [ATG-F] or thymoglobulin). Subjects will subsequently be followed and evaluated 
for development of intestinal aGvHD for the first 180 days after allo-HSCT. The study day numbering convention will 
be based on the first day of cell infusion, which will be Day 0. Pretransplant procedure days are designated with 
negative numbers (eg, Day -1), whereas posttransplant procedure days are designated with positive numbers (eg, Day 
+13).
The study consists of a 30-day screening period, 155-day treatment period, and a follow-up period for safety 
assessments and survival for up to 12 months after allo-HSCT. Subjects randomized to the vedolizumab treatment arm
will receive vedolizumab intravenously (IV) at a 300-mg dose at the start of the treatment period on Day -1 before 
allo-HSCT and then on Day +13, Day +41, Day +69, Day +97, Day +125, and Day +153. Subjects randomized in the 
placebo treatment arm will receive placebo IV on Day -1, Day +13, Day +41, Day +69, Day +97, Day +125, and 
Day +153.
The vedolizumab 300 mg dose has been evaluated in the previous graft-versus-host disease (GvHD) 
Vedolizumab-1015 phase 1b study, and the dose and schedule of vedolizumab in this study is similar to the approved 
dose and schedule of vedolizumab administered to subjects with ulcerative colitis or Crohn’s disease.
All subjects will receive a background GvHD prophylaxis regimen consisting of a combination of a calcineurin 
inhibitor (CNI, cyclosporine [CYS] or tacrolimus [TAC]) with methotrexate (MTX) (Appendix B). ATG (ATG-F or 
thymoglobulin) may be included in prophylaxis therapy per institutional practice and mycophenolate mofetil (MMF) 
may be used in place of MTX at the discretion of the investigator. TAC and CYS will be administered IV or orally 
during conditioning and subsequent dosing should be adjusted according to whole blood concentration and toxicity, 
per institutional practice. The recommended targeted whole blood concentration for CNIs and tapering schedule is 
provided (Appendix B).
Assessment of Intestinal aGvHD
Subjects will be followed and evaluated for development of intestinal aGvHD according to the Bone Marrow 
Transplant Clinical Trials Network modified International Bone Marrow Transplant Registry index summarized in 
Appendix F.
akeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 13 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Primary Objective:
To evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis regimen compared to 
placebo and background aGvHD prophylaxis regimen on intestinal aGvHD-free survival by Day +180 in subjects who 
receive allo-HSCT as treatment for hematologic malignancy or myeloproliferative disorder.
Secondary Objectives:

To evaluate the effect of vedolizumab versus placebo on intestinal aGvHD-free, relapse-free (free of 
underlying malignancy) survival by Day +180.

To evaluate the effect of vedolizumab compared to placebo on Grade C-D aGvHD-free (any organ 
involvement) survival by Day +180.

To evaluate the effect of vedolizumab compared to placebo on nonrelapse mortality (NRM) in subjects by 
Day +180.

To evaluate the effect of vedolizumab compared to placebo on overall survival by Day +180.

To evaluate the effect of vedolizumab compared to placebo on Grade B-D aGvHD-free (any organ 
involvement) survival by Day +180.
Safety Objective:
To evaluate the safety of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo 
and background aGvHD prophylaxis regimen.
Subject Population: Subjects aged 18 years or adolescents aged 12 years and greater and weighing ≥30 kg at time of 
randomization, who are undergoing their first allo-HSCT from an unrelated donor for the treatment of hematologic 
malignancy or myeloproliferative disorder.
Number of Subjects:
Per treatment group (placebo/vedolizumab): 279
Estimated total: 558 subjects undergoing allo-HSCT for the 
treatment of hematologic malignancy or myeloproliferative 
disorder.
Number of Sites: 
Approximately 150 sites in approximately 30 countries 
worldwide.
Dose Level(s):
Vedolizumab IV, 300 mg
Route of Administration:
IV
Duration of Treatment: 
Vedolizumab or placebo at Day -1, Day +13, Day +41, Day 
+69, Day +97, Day +125, and Day +153.
Period of Evaluation: This study includes a 30-day 
screening period, 155-day treatment period, and a 
posttreatment follow-up period to be completed by
12 months after allo-HSCT. 
Subjects will be followed for development of intestinal 
aGvHD for 12 months after allo-HSCT or until 
subject’s death, withdrawal of consent, or termination 
of the study by the sponsor. Additionally, all subjects
will be required to participate in a long-term follow-up
safety survey completed 6 months after the last dose of 
study drug.
Main Criteria for Inclusion:
Male and female subjects aged ≥18 years and, in selected countries (where local requirements permit and based on 
feasibility), adolescents aged 12 years and greater and weighing ≥30 kg at time of randomization, with a diagnosis of 
hematologic malignancy or myeloproliferative disorder who are candidates for HLA-matched or mismatched (8/8 or
7/8) unrelated donor allo-HSCT (per institutional criteria) using either peripheral blood or bone marrow as the stem 
cell source. 
Planned medical care for allo-HSCT-eligible subjects must include a background GvHD prophylaxis regimen with a 
y and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 14 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
combination CNI (CYS or TAC) and MTX (MMF may be used in place of MTX at the discretion of the investigator). 
When considered part of standard prophylactic treatment for GvHD, ATG (ATG-F or thymoglobulin) may be used at 
the discretion of the treating physician; however, the proportion of subjects receiving ATG shall comprise no more 
than approximately 25% of the total number of subjects enrolled into the study. 
At the time of allo-HSCT, eligible status of underlying disease stage (hematologic malignancy or myeloproliferative 
disorder), as defined on the basis of the specific malignancy, is as follows: 
a.
for subjects with acute leukemia or chronic myelogenous leukemia, no circulating blasts and <5% blasts in the 
bone marrow; 
b.
for subjects with myelodysplasia, no circulating blasts and 10% blasts in the bone marrow; 
c.
for subjects with chronic lymphocytic leukemia and small lymphocytic lymphoma, chemosensitive disease 
(partial response or complete response to last salvage therapy) at time of transplantation; 
d.
for subjects with other non-Hodgkin lymphoma or Hodgkin lymphoma, a response to last salvage therapy or 
chemo-sensitive disease per institutional guidelines; and 
e.
for subjects with myelofibrosis and other myeloproliferative disorders, <5% blasts in the blood and bone marrow. 
Performance status must be assessed as 2 using Eastern Cooperative Oncology Group performance status for
subjects aged ≥18 years at randomization or as ≥60% using the Karnofsky performance status for adolescent subjects
aged ≥16 years at randomization and Lansky performance status for adolescent subjects aged 12 to <16 years at 
randomization.
Main Criteria for Exclusion:
Subjects who have received prior allogeneic transplants or who are planned to undergo umbilical cord blood 
transplant.
Subjects who are planned to receive ex vivo T cell-depleted hematopoietic stem cells, in vivo T cell-depleting 
antibodies (with the exception of ATG-F or thymoglobulin), or posttransplant cyclophosphamide.
Subjects with any active cerebral/meningeal disease (including central nervous system involvement of the primary 
disease) or signs and symptoms of progressive multifocal leukoencephalopathy (PML) or any history of PML. 
Subjects who are planned to undergo allo-HSCT for a nonmalignant hematological disorder (eg, aplastic anemia, 
sickle cell anemia, thalassemias, Fanconi anemia or immunodeficiency).
Subjects with clinically active systemic infection during screening. 
Excluded Concomitant Medications:
Any therapy for GvHD prophylaxis, including approved, investigational or T cell-depleting agents other than ATG
(ATG-F or thymoglobulin), and other than that specified in the inclusion criteria.
Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is intestinal aGvHD-free survival by Day 180 in subjects after allo-HSCT for 
treatment of primary malignancy or myeloproliferative disorders. The study will also determine the number and 
percentage of subjects who experience treatment-emergent adverse events or serious adverse events from the 
administration of the first dose of study drug through 18 weeks after administration of the last dose of study drug. 
Secondary endpoints for this study are to determine: intestinal aGvHD-free, relapse-free (of underlying malignancy) 
survival by Day +180; Grade C-D aGvHD-free (any organ involvement) survival by Day +180; NRM by Day +180; 
overall survival by Day +180; and Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
a: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 15 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Statistical Considerations:
All statistical testing will be performed at a 2-sided 0.05 level of significance. To control the overall Type I error rate 
for the comparison between vedolizumab and placebo groups for the primary and secondary efficacy endpoints, a 
gatekeeping procedure will be used. Specifically, the statistical testing of the first secondary efficacy endpoint will 
only be performed if the treatment difference for primary efficacy endpoint is statistically significant, the next 
secondary efficacy endpoint will only be tested if the treatment difference for the first secondary efficacy endpoint is 
significant and so on for each subsequent secondary efficacy endpoint.
All time-to-event endpoints will be analyzed using log-rank tests. Cox proportional hazards models, stratified by 
randomization strata will be fit with hazard ratios reported. All dichotomous efficacy endpoints will be analyzed using 
Cochran-Mantel-Haenszel tests for risk differences, stratified by randomization strata. Details of the data analyses will 
be specified in the statistical analysis plan. 
Sample Size Justification: Assuming the rate for the primary endpoint is 34.1% for the placebo group and 21.8% for 
the vedolizumab group, a sample size of 279 subjects per group is expected to generate 148 primary endpoint events 
and provide 90% power at 2-sided 0.05 level of significance. Assuming the event rate for the first secondary endpoint 
is 39.5% for the placebo group and 27.1% for the vedolizumab group, this sample size is expected to generate 177 
events for the first secondary endpoint and provide approximately 86% power at 2-sided 0.05 level of significance. 
t to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 16 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research, and 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.
ct to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 17 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
3.3
List of Abbreviations
Acronym
Definition
AE
adverse event
AESI
adverse event of special interest
aGvHD
acute graft-versus-host disease
allo-HSCT
allogeneic hematopoietic stem cell transplantation
ALT
alanine aminotransferase
ANSM
Agence nationale de sécurite du médicament et des produits de santé
APC
antigen-presenting cell
AST
aspartate aminotransferase
ATG
antithymocyte globulin
ATG-F
antithymocyte globulin-Fresenius
CD
Crohn’s disease
CMV
cytomegalovirus
CNI
calcineurin inhibitor
CRO
contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
CYS
cyclosporine
DLI
donor leukocyte infusion
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DSUR
development safety update report
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
end of study
EOT
end of treatment
EQ-5D
EuroQOL-5 Dimension
ET
early termination
EU
European Union
FACT-BMT
Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GALT
gut-associated lymphoid tissue
GCP
Good Clinical Practice
GI
gastrointestinal
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Adverse 
On
Adverse 
mmittee
erc
mmittee
ty update
mme
ty update
gram
Com
gram
ooperativ
-Co
ooperativ
nic case 
Non
nic case 
ctronic d
r No
ctronic d
end of 
For
end of s
end o
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end o
E
a
E
FACT
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FACT-
o
-B
f
B
FAS
erty
FAS
FD
e
FD


Vedolizumab IV
Study No. Vedolizumab-3035
Page 18 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
GvHD
graft-versus-host disease
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HRQOL
health-related quality of life
HSC
hematopoietic stem cell
HSCT
hematopoietic stem cell transplantation
IAC
Independent Adjudication Committee
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBMTR
International Bone Marrow Transplant Registry Database
ICF
informed consent form
ICH
International Council for Harmonisation
ID
identification
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IRR
infusion-related reaction
IRT
interactive response technology system
IV
intravenous
LFT
liver function test
LTFU
long-term follow-up
MA
myeloablative
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MAGIC
Mount Sinai Acute GVHD International Consortium
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MLN0002
vedolizumab, also known as ENTYVIO, KYNTELES
MMF
mycophenolate mofetil
MPA
Medical Products Agency of Sweden
MTX
methotrexate
MUD
matched unrelated donor
NOMA
Norwegian Medicines Agency
NRM
nonrelapse mortality
OS
overall survival
PCR
polymerase chain reaction
PK
pharmacokinetic(s)
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
e
e
e
ogy syst
l U
ogy syst
up
mm
up
e
C
e
nal antibo
n-C
nal antibo
al addre
Non
al addre
ount Sina
r N
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Medica
Fo
Medica
Med
a: 
Med
A
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A
MTX
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MTX
MUD
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MUD
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 19 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PML
progressive multifocal leukoencephalopathy
PTE
pretreatment event
Q4W
every 4 weeks
Q8W
every 8 weeks
RAMP
Risk Minimization Action Plan for PML
RIC
reduced intensity conditioning
SAE
serious adverse event
SAP
statistical analysis plan
SOE
schedule of events
TAC
tacrolimus
TB
tuberculosis
TEAE
treatment-emergent adverse event
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable
mmercial Use Only and Subject to the Applicable Terms of Use
cals, Inc,
e O
cals, Inc,
any Limi
Use 
any Limi
ent Cente
l Us
ent Cente
pment C
cial
pment C
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Com
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 20 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
4.0
INTRODUCTION
4.1
Background
4.1.1
Disease to be Treated
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important and potentially
curative therapy for many hematologic malignancies, but its use is limited by the major 
complication of graft-versus-host disease (GvHD) [1,2]. GvHD is a common complication of 
allo-HSCT and a major cause of morbidity and mortality. Acute GvHD results from the activation 
of alloreactive donor lymphocytes by histocompatibility antigens on host antigen-presenting cells 
(APCs) [3,4]. The risk of GvHD and its severity depends on several factors including recipient 
age, cell source, donor characteristics, degree of histocompatibility between the donor and 
recipient, the conditioning regimen used, and the GvHD prophylaxis strategy used [1,5-7]. Despite 
GvHD prophylaxis, approximately 40% to 70% of all allo-HSCT recipients (inclusive of pediatric 
and adult subjects) develop Grade 2 to 4 acute GvHD (aGvHD) [5,6,8-11]. Approximately 45% to 
56% of pediatric allo-HSCT (ranging from <1 to 20 years of age) from unrelated donors will 
develop Grade 2 to 4 aGvHD, and nonrelapse mortality (NRM) appears to be greater in those 
pediatric patients with intestinal involvement [12-14]. Classical aGvHD occurs around the time of 
engraftment (~10-21 days following HSCT infusion) up to Day 100 [15] and late aGvHD occurs 
greater than 100 days from allo-HSCT [16,17].
aGvHD most commonly involves the skin, liver, and gut and results from an activation of 
alloreactive donor lymphocytes by histocompatibility antigens on host APCs [3,4]. 
Immunocompetent donor T cells migrate to lymphoid tissues soon after infusion, recognize host 
alloantigens, and become activated upon interaction with host APCs [18]. Homing of these 
alloreactive donor T cells to the gastrointestinal (GI) tract, which is dependent on the expression of 
the integrin α4β7 molecule on the donor T cells, is fundamental to the pathogenesis of intestinal 
aGvHD [19-21]. Data from the Center for International Blood & Marrow Transplant Research 
showed that 76% of Grade II to IV aGvHD cases in 2006 to 2012 had intestinal involvement [22]. 
Intestinal aGvHD is the most serious form and may be less responsive than liver and skin GvHD to 
first-line corticosteroids, and corticosteroid resistance develops in 73% of subjects with severe 
intestinal GvHD (stage 3-4) [23,24]. 
Given the high level of immunosuppression, the risk of opportunistic infections is increased in 
subjects who develop intestinal aGvHD [25,26] and overall survival (OS) for stage 3 to 4 intestinal 
aGvHD has been reported as 25in a study from the Fred Hutchinson Cancer Center [24]. 
GvHD prophylaxis is employed for all subjects undergoing allo-HSCT and routine prophylaxis 
commonly consists of calcineurin inhibitors (CNIs) in combination with a short course 
methotrexate (MTX) or mycophenolate mofetil (MMF) [6,8,9,11,27]. CNI (cyclosporine [CYS] or 
tacrolimus [TAC]) and MTX are typically administered during conditioning, with subsequent CNI 
doses adjusted according to whole blood concentration and toxicity. T cell-depleting agents, 
including antithymocyte globulins (ATG) (antithymocyte globulin-Fresenius [ATG-F] or 
thymoglobulin) or alemtuzumab, may be added to prophylaxis therapy; however, use of these 
Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 21 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
agents have raised concerns for delayed immune recovery and increased risk of infection and 
relapse [27]. 
Reducing the risk of developing aGvHD without systemic immunosuppression has the potential to 
improve overall outcomes in allo-HSCT and possibly extend and/or save lives from this rare 
disease.
4.1.2
Vedolizumab IV
Vedolizumab (also called MLN0002) is a humanized immunoglobulin (Ig) G1 monoclonal 
antibody (mAb) directed against the human lymphocyte integrin 4β7. The 4β7 integrin 
mediates lymphocyte trafficking to GI mucosa and gut-associated lymphoid tissue (GALT) 
through adhesive interaction with antimucosal addressin cell adhesion molecule-1 (MAdCAM-1), 
which is expressed on the endothelium of mesenteric lymph nodes and GI mucosa [28-31]. 
Vedolizumab specifically binds the 4β7 integrin, selectively 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 [32]. Vedolizumab has been 
developed as a treatment for ulcerative colitis (UC) and Crohn’s disease (CD), which are 
characterized by inflammation of the GI tract.
Vedolizumab IV (also known as ENTYVIO; KYNTELES; Vedolizumab for Injection, for 
Intravenous Use; Vedolizumab Powder for Concentrate for Solution for Infusion; or MLN0002 
IV) is a lyophilized solid which after appropriate reconstitution and dilution is intended for 
intravenous (IV) infusion that has been granted marketing approval in several regions, including 
the US and EU. Vedolizumab IV is approved for the treatment of adults with moderately to 
severely active UC or CD who have had an inadequate response with, lost response to, or were 
intolerant to a tumor necrosis factor-alpha blocker or immunomodulator; or had an inadequate 
response with, were intolerant to, or demonstrated dependence on corticosteroids. The approved 
dosing and administration regimen for adults consists of 300 mg vedolizumab infused IV over 
approximately 30 minutes at Weeks 0, 2, and 6, then once every 8 weeks (Q8W) thereafter. 
Vedolizumab dosing every 4 weeks (Q4W) is also approved in most parts of the world. Previously 
conducted clinical studies in healthy subjects and subjects with UC and CD have characterized the 
efficacy, safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and immunogenicity of
vedolizumab.
The ongoing clinical development program of vedolizumab IV includes clinical studies in 
pediatric subjects (aged 2-17 years) with UC or CD that are summarized in the current edition of 
the investigator’s brochure (IB).
4.1.2.1
Nonclinical
Several published key nonclinical studies support the use of vedolizumab for the prevention of 
GvHD. Nonclinical pharmacology studies in murine models of aGvHD suggest that the prevention 
of T cell trafficking to GALT, via interruption of the α4β7/MAdCAM-1 interaction, may prevent 
GvHD [33-35]. In a mouse model of GvHD, when using donor cells sorted and purified based on 
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Vedolizumab IV
Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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18 September 2019
the presence or absence of α4β7, the absence of α4β7+ cells greatly delayed and reduced the 
presence of GvHD [19]. Like these results, α4β7 expression on donor T cells has been shown to be 
important in the induction of GvHD [20]. By blocking the infiltration of cells into the intestines,
vedolizumab may act to reduce the severity and intensity of intestinal GvHD. Extensive 
nonclinical evaluations of the cardiovascular, acute, local, subchronic, chronic, immunologic, and 
reproductive toxicity of vedolizumab in pharmacologically responsive species (New Zealand 
white rabbits and cynomolgus monkeys) have been conducted. Vedolizumab bound with similar 
affinity to rabbit, monkey, and human α4β7 integrin. 
Results from a 13-week toxicity study in juvenile cynomolgus monkeys identified 100 mg/kg 
(human equivalent dose 1920 mg in a 60-kg human) as the no-observed-adverse-effect level.
(NOAEL). Inclusion of sexually immature monkeys in the 3- and 6-month toxicity studies support 
administration of vedolizumab in clinical studies with adolescent subjects (aged 12 years and 
greater). 
Nonclinical studies also show that vedolizumab does not antagonize 4β1 integrin [3]. 
4.1.2.2
Human Experience
As of 19 May 2019, approximately 6376 subjects (healthy or patients with UC or CD, pouchitis, 
melanoma, or undergoing allo-HSCT) have received at least 1 dose of vedolizumab across all 
studies in the clinical development program. As reported in the 9th development safety update 
report (DSUR, for the period 20 May 2018 to 19 May 2019), global cumulative postmarketing 
patient exposure to vedolizumab IV is estimated to be approximately 336,400 patient-years. 
Vedolizumab has shown an acceptable and consistent safety profile in clinical studies and in 
postmarketing experience. Adverse reactions that have been reported following vedolizumab 
administration include: nasopharyngitis, bronchitis, upper respiratory tract infection, influenza, 
sinusitis, headache, oropharyngeal pain, cough, nausea, rash, pruritus, arthralgia, back pain, pain 
in extremities, pyrexia, fatigue, and injection site reactions. Risks associated with vedolizumab 
treatment have been identified and categorized. Important identified risks are hypersensitivity 
reactions, including infusion-related reactions (IRRs) and upper respiratory infections, including 
nasopharyngitis, sinusitis, bronchitis, and influenza. Most IRRs are mild/moderate in intensity and 
resolve with minimal or no intervention. Important potential risks are infections, including 
gastrointestinal infections and systemic infections against which the gut constitutes a defensive 
barrier; serious infections, including opportunistic infections such as progressive multifocal 
leukoencephalopathy (PML); malignancy; and liver injury. Reported serious infections include 
tuberculosis, sepsis, Salmonella sepsis, Listeria meningitis, and cytomegaloviral colitis.
Most serious adverse events (SAEs) were related to exacerbations or complications of the 
underlying UC or CD. Similar safety profiles for vedolizumab have been observed in subjects who 
received vedolizumab IV Q4W or Q8W and in subjects following long-term Q4W treatment for up 
to 8 years, and in subjects administered vedolizumab subcutaneously (SC). With the exception of 
injection site reactions, the safety profile for vedolizumab SC is consistent with that for 
vedolizumab IV. 
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 23 of 122
Protocol Incorporating Amendment No. 07
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18 September 2019
In the phase 1b Study Vedolizumab-1015, conducted in 24 subjects who underwent allo-HSCT, 
vedolizumab (at 75 or 300 mg on Days -1, +13, and +42) was added to standard GvHD 
prophylaxis (TAC and MTX) therapy. All subjects engrafted and no new safety signals were 
reported. In clinical studies, no safety concerns were identified in subjects with aGvHD or 
undergoing allo-HSCT, and the events reported were consistent with known risks in these patient 
populations.
In addition, no new safety information that alters the benefit:risk balance of vedolizumab was 
identified in the IBD clinical development program, including ongoing studies in pediatric 
subjects with UC or CD (DSUR, for the period 20 May 2018 to 19 May 2019).
Overall, vedolizumab has been well tolerated in clinical studies. Further detail on the safety profile 
of vedolizumab can be found in the current edition of the IB. 
4.2
Rationale for the Proposed Study
The objective of this proposed study is to evaluate the safety and efficacy of vedolizumab 
compared to placebo when added to a background aGvHD prophylaxis regimen in prophylaxis of 
intestinal aGvHD within the first 180 days after allo-HSCT from unrelated donors. Vedolizumab 
binds the 4β7 integrin, antagonizing its adherence to MAdCAM-1 and as such, impairs the 
migration of gut homing leukocytes into GI mucosa, effectively acting as a gut-selective 
immunomodulator [32]. Vedolizumab (ENTYVIO) is approved for treatment of CD and UC and 
demonstrates efficacy in clinical remission in CD and UC. Inflammation and damage to the GI 
tract is a major mechanism for amplification of systemic aGvHD [36] and several key similarities 
exist with intestinal aGvHD and other immune-mediated diseases like inflammatory bowel disease 
(IBD). In IBD, the migration of T cells to the GI tract appears to play important role in induction 
and perpetuation of GI inflammation. Once in the GI tract, the interaction between effector T cells 
and APCs result in downstream uncontrolled production of inflammatory mediators as well as 
recruitment and activation of additional leukocytes resulting in chronic gut inflammation [37]. 
The migration of naive donor T cells to the GALT where they are activated and migration of 
activated donor T cells to the target tissues, especially the intestinal mucosa, are essential steps in 
aGvHD in both children and adults [4,38]. Intestinal aGvHD in children and adults is often 
involved in Grade 3 to 4 aGvHD and is a major cause of morbidity and mortality after allo-HSCT. 
Systemic immunosuppression for aGvHD prophylaxis increases the risk for infections and can 
affect the graft-versus-tumor effect. Therefore, using standard nonspecific systemic 
immunosuppressive therapies involves a fine balance of prevention of life-threatening aGvHD 
against life-threatening infection and recurrence of underlying malignant disease. Therapy that 
targets the trafficking of cells to the GI tract and reduces GI inflammation without adding to 
systemic immunosuppression could have profound effects on the morbidity and mortality of
intestinal GvHD. 
Results from Vedolizumab-1015, a phase 1b study that enrolled 24 subjects aged ≥18 years, 
demonstrated the safety and tolerability of adding vedolizumab on Day -1 (before allo-HSCT) and 
then on Days +13 and +42 after allo-HSCT to a background aGvHD prophylaxis regimen 
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Vedolizumab IV
Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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(TACMTX) in subjects undergoing allo-HSCT. Vedolizumab dose finding was cohort-based and 
followed a rule-based dose-finding study design with PK guidance. After a tolerated dose with 
acceptable PK was identified, the cohort at that dose level was expanded to further assess the 
tolerability and effectiveness of vedolizumab. Dose escalation started with a low dose cohort of
vedolizumab 75 mg IV. With no dose-limiting toxicities (DLTs) and no engraftment failures in the 
75 mg dose cohort, the next cohort received vedolizumab 300 mg IV. A total of 3 subjects were 
enrolled in the 75 mg dose cohort and 21 subjects were enrolled in the 300 mg dose cohort. The 
300-mg dose cohort consisted of adult subjects for whom a myeloablative conditioning or RIC 
regimen was planned and who were candidates for HLA-matched or 1-locus (antigen or allele) 
mismatched unrelated or related donor allo-HSCT (using either peripheral blood stem cells or 
bone marrow as the cell source) for treatment of hematologic malignancy or myeloproliferative 
neoplasm. No subject in either cohort experienced a DLT and all subjects engrafted (median time 
to neutrophil engraftment was 22 days in the vedolizumab 75 mg dose cohort and 14 days in the 
vedolizumab 300 mg dose cohort). The PK of 300 mg vedolizumab in this subject population was 
similar to that of subjects with IBD and provides serum concentrations above 10 µg/mL up to Day 
100. The study results demonstrate less than expected intestinal aGvHD events and less than 
expected Grade 3-4 aGvHD events in the 300 mg dose cohort. By Day +100, 3 of 21 subjects who 
received vedolizumab 300 mg IV developed maximum stage 1 lower intestinal aGvHD and no 
subjects developed stage 2 or greater lower intestinal aGvHD. By 12 months, lower intestinal 
aGvHD developed in 3 of 21 subjects (2 subjects developed maximum stage 1 intestinal aGvHD 
and 1 subject developed maximum stage 2 intestinal aGvHD). In subjects who received 
vedolizumab 300 mg IV, Grade 2-4 aGvHD developed in 4 of 21 subjects by Day +100 and in 5 of 
21 subjects by 12 months after allo-HSCT. Grade 3 aGvHD developed in 1 of 21 subjects by Day 
+100 and in 2 of 21 subjects by 12 months and no subject developed Grade 4 aGvHD by Day +100 
and by 12 months. Overall survival and non-relapse mortality in the vedolizumab 300 mg cohort 
was 84.7% and 5.6% by 12-month follow-up, respectively. The results of this study support further 
evaluation of the vedolizumab 300 mg IV dose in subjects undergoing allo-HSCT. 
The proposed vedolizumab dose and regimen in this phase 3 study is 300 mg on Days -1, +13, +41, 
+69, +97, +125, and +153. This is based on the results of Vedolizumab-1015 and, similarly, on the 
known safety profile of Q4W vedolizumab schedule evaluated in phase 3 studies and long-term
follow-up (LTFU) of IBD subjects. The proposed duration of vedolizumab prophylaxis is intended 
to provide coverage during the posttransplant period, when subjects are at risk of developing 
classic and late aGvHD.
4.3
Benefit:Risk Profile
The proposed phase 3 study is designed to evaluate the efficacy and safety of vedolizumab 
compared to placebo when added to background aGvHD prophylaxis regimen as prophylaxis for 
intestinal aGvHD for subjects undergoing allo-HSCT. The mechanism of action of vedolizumab, 
results from nonclinical studies demonstrating the role of T cell trafficking in GvHD, and results of 
the phase 1b Study Vedolizumab-1015, all support further investigation of vedolizumab in this 
indication. Vedolizumab specifically targets the α4β7 integrin expressed on the surface of T 
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Vedolizumab IV
Study No. Vedolizumab-3035
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lymphocytes, thus preventing T cells from binding to MAdCAM-1 expressed on the endothelium, 
subsequently preventing T cells from homing to the intestinal tract. Nonclinical pharmacology
studies in murine model demonstrate that inhibition of the α4β7/MAdCAM-1 pathway via 
neutralizing anti-MAdCAM-1 antibodies attenuated the development of the graft versus host
reaction [33] and the absence of α4β7+ cells on donor cells greatly delayed and reduced the 
presence of GvHD [19]. Furthermore, in Study Vedolizumab-1015, a low incidence of intestinal 
aGvHD was observed in adults undergoing allo-HSCT for a hematologic malignancy or 
myeloproliferative disorder who received vedolizumab 300 mg IV in combination with standard 
GvHD prophylaxis. There remains an unmet medical need in patients undergoing allo-HSCT who,
despite routine prophylaxis, remain at risk of developing intestinal aGvHD and its associated 
complications. 
The available PK data, nonclinical toxicology data, and clinical data are supportive of the 
inclusion of adolescent subjects aged ≥12 years and weighing ≥30 kg in this phase 3 study. In 
phase 3 studies in adults with UC or CD, body weights ranged from 28.7 to 170 kg. Safety data 
from these studies showed that there was no difference in the incidence of treatment-emergent 
adverse events (TEAEs) based on weight or age (18-70 years). Furthermore, a similar safety 
profile has been observed in adults with UC or CD who received vedolizumab IV Q8W or Q4W. 
No additive risk of infection was identified among subjects who received a concomitant 
immunosuppressant. Results of population PK analyses in subjects with IBD indicate that a 
weight-based dosing regimen is not required and that a tiered flat-dose is appropriate for different 
weight groups. Age was not a clinically meaningful covariate. PK data from Study
Vedolizumab-1015 indicates that the PK of vedolizumab in subjects undergoing an allo-HSCT 
who received 300 mg is similar to that of subjects with UC or CD. In addition, no new safety 
information that alters the benefit:risk balance of vedolizumab have been identified in the UC/CD 
clinical development program, including ongoing studies in pediatric subjects (aged 2-17 years).
Therefore, the benefit:risk profile is expected to be similar in adults and adolescent subjects aged 
≥12 years and weighing ≥30 kg. 
All subjects will receive a standardized GvHD prophylaxis regimen consisting of a CNI (CYS or 
TAC) and MTX or MMF with or without the addition of ATG (ATG-F or thymoglobulin). The 
dosing of vedolizumab in combination with a CNI (TAC) and MTX was well tolerated in the phase 
1b clinical study in this subject population. Similarly, vedolizumab in conjunction with systemic 
immunosuppressive therapy (such as MTX, 6-mercaptopurine, and prednisone) has been well 
tolerated in clinical studies in subjects with IBD.
The subject population was chosen because it represents a high-risk, vulnerable population for 
development of intestinal aGvHD, a driver for poor outcomes, mortality, and for whom a 
significant unmet medical need exists. The risks of this subject population include those that are 
associated with hematological transplantation. Specifically, allo-HSCT patients are at risk of 
infections (opportunistic, GI, and CNS infections); liver injury; infusion-related reactions (IRR) 
and hypersensitivity reactions, and relapse or new primary malignancy. The important identified 
risks specific for vedolizumab include IRRs and upper respiratory tract infections, including 
bronchitis, influenza, nasopharyngitis, and sinusitis. The important potential risks for vedolizumab 
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Vedolizumab IV
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are: malignancies, liver injury; infections (GI infections and systemic infections [serious and 
nonserious]); and other serious infections, including opportunistic infections such as PML. Several 
risk mitigation strategies are incorporated in this phase 3 study including exclusion of subjects 
with ongoing or active infections (Section 7.2), criteria for discontinuation and withdrawal of
subjects (Section 7.4), and instructions for managing these risks (Section 8.7). The mitigation 
strategies are adequate to monitor safety of the subjects participating in the study. In combination 
with the results from the phase 1b Study Vedolizumab-1015 and supported by the available 
nonclinical, clinical, and PK data, the benefit:risk profile is expected to be similar in adults and 
adolescent subjects aged 12 years and greater and weighing ≥30 kg, supporting further 
investigation of vedolizumab in the subject population with significant unmet medical need.
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Vedolizumab IV
Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is: 

To evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis 
regimen compared to placebo and background aGvHD prophylaxis regimen on intestinal 
aGvHD-free survival by Day +180 in subjects who receive allo-HSCT as treatment for a 
hematologic malignancy or myeloproliferative disorder. 
5.1.2
Safety Objective
The safety objective is to evaluate the safety of vedolizumab when added to background aGvHD 
prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen.
5.1.3
Secondary Objectives
The secondary objectives are:

To evaluate the effect of vedolizumab compared to placebo on intestinal aGvHD-free, 
relapse-free (free of underlying malignancy) survival by Day +180.

To evaluate the effect of vedolizumab compared to placebo on Grade C-D aGvHD-free (any 
organ involvement) survival by Day +180.

To evaluate the effect of vedolizumab compared to placebo on NRM in subjects by Day +180.

To evaluate the effect of vedolizumab compared to placebo on OS by Day +180. 

To evaluate the effect of vedolizumab compared to placebo on Grade B-D aGvHD-free (any 
organ involvement) survival by Day +180.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 28 of 122
Protocol Incorporating Amendment No. 07
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18 September 2019
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is intestinal aGvHD-free survival by Day +180 after allo-HSCT. Intestinal 
aGvHD is defined as Stage 1-4 intestinal involvement per Acute Graft-versus-Host Disease 
Clinical Stage criteria (Appendix F).
5.2.2
Safety Endpoint
Safety as assessed by adverse events (AEs), adverse events of special interest (AESIs), SAEs, vital 
signs, results of standard laboratory test and procedures (eg, clinical chemistry, hematology, 
coagulation).
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 29 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
5.2.3
Secondary Endpoints
The secondary endpoints are:

Intestinal aGvHD-free and relapse-free (of the underlying malignancy) survival by Day +180.

Grade C-D aGvHD-free (any organ involvement) survival by Day +180.

NRM by Day +180.

OS by Day +180.

Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
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Vedolizumab IV
Study No. Vedolizumab-3035
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Overview of Study Design
This is a phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of vedolizumab when added to a background aGvHD prophylaxis regimen as 
prophylaxis for intestinal aGvHD in subjects undergoing allo-HSCT. The subject population will 
consist of subjects with hematologic malignancies or myeloproliferative disorders for whom
allo-HSCT from an unrelated donor is planned, using either peripheral blood or bone marrow as 
the stem cell source.
Eligibility will be determined during the screening period, which may last for up to 30 days before 
Day -1 (designation of the day of the first IV infusion of study drug). Subjects who meet all 
eligibility criteria and provide written informed consent will be randomized into this study within 
2 days of the first dose of study drug on Day -1. Approximately 558 subjects will be randomized in 
a 1:1 fashion to 2 treatment arms (vedolizumab IV or placebo IV). Randomization will be stratified 
by age (≥18 years or adolescents aged 12 to <18 years), HLA match or mismatch (8/8 or 7/8), 
conditioning regimen (myeloablative or reduced intensity conditioning), and treatment with or 
without ATG (ATG-F or thymoglobulin). Subjects randomized to the vedolizumab IV arm will 
receive 7 doses of vedolizumab IV, beginning on Day -1 before allo-HSCT and then on Days +13, 
+41, +69, +97, +125, and +153 after allo-HSCT. Subjects randomized to the placebo IV arm will 
receive 7 doses of placebo IV, beginning on Day -1 before allo-HSCT and then on Days +13, +41, 
+69, +97, +125, and +153 after allo-HSCT. 
6.1.1
Schedule of Observations and Procedures
The study consists of a 30-day screening period, 155-day treatment period, a visit on Day +180 
after allo-HSCT, and a posttreatment follow-up period for safety assessments and survival to be 
completed by 12 months after allo-HSCT. The study overview is depicted in Figure 6.a.
6.1.1.1
Screening
Subjects will be screened within 30 days before Day -1. Subjects will be screened in accordance 
with predefined inclusion and exclusion criteria as described in Sections 7.1 and 7.2. See 
Section 9.4 for procedures for documenting screening failures. Rescreening is permitted in 
consultation with the medical monitor. 
Procedures to be completed at screening can be found in the Schedule of Events (SOE) 
(Appendix A).
6.1.1.2
Randomization
Randomization will take place within 2 days of the first dose of study drug on Day -1. If the subject 
has satisfied all of the inclusion criteria and none of the exclusion criteria, the subject should be 
randomized using the interactive response technology system (IRT), as described in Section 8.2.
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Vedolizumab IV
Study No. Vedolizumab-3035
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Subjects will be administered the first dose of study drug as described in Section 8.1.1. The 
procedure for documenting screening failures is provided in Section 9.4.
6.1.1.3
Final Visit or Early Termination
The final visit (end of study [EOS]) will be performed 12 months after allo-HSCT. Subjects who
discontinue study drug treatment (refer to Section 7.4) will complete an early termination (ET) 
visit upon discontinuation and a final visit 12 months after allo-HSCT. The global study will end 
after the last subject has completed the final visit 12 months after allo-HSCT, or the subject has 
died, withdrawn consent, or been lost to follow-up.
6.1.1.4
Posttreatment Follow-up
The end-of-treatment visit will be conducted on Day +180 after allo-HSCT. All subjects will 
participate in posttreatment follow-up as outlined in the SOE (Appendix A) that will begin after 
the Day +180 visit or after ET, will include a Day +280 final safety visit (or 18 weeks after the last 
dose of study drug), and will conclude 12 months after allo-HSCT. In addition, upon completion or 
ET, all subjects or their parents/legally acceptable representative will be administered by
telephone the LTFU safety questionnaire 6 months after their last dose of study drug. For all 
subjects receiving study drug, the investigator must complete the EOS electronic case report form 
(eCRF) 12 months after allo-HSCT. 
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Vedolizumab IV
Study No. Vedolizumab-3035
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Vital signs, physical examinations, AE assessments, and laboratory values (chemistry, 
hematology, liver function tests [LFTs] as specified in Section 9.3.15) will be obtained as 
described in the SOE (Appendix A) to evaluate the safety and tolerability of the study drug. To 
exclude subjects with PML, the PML checklist will be administered at screening and before each 
administration of study drug beginning on Day -1 and thereafter as shown in the SOE 
(Appendix A).
Sparse blood samples for determination of the serum concentration of vedolizumab 
 will 
be collected pre- and postdose on study drug dosing days as shown in the SOE (Appendix A). 
6.2
Justification for Study Design and Dose
6.2.1
Study Design
The subject population was chosen because it represents a high-risk, vulnerable population for 
development of intestinal aGvHD, a driver for poor outcomes, mortality, and for whom a 
significant unmet medical need exists with no currently approved medical therapy. The incidence 
of Grade B-D aGvHD has been reported to be 39for HLA-matched sibling donors and 59for 
HLA-matched unrelated donors (MUD) in 1 study [9] and 33for matched related donor 
recipients, 51in 8 of 8 HLA-MUD recipients, and 53in 7/8 HLA-MUD recipients, with OS
(45) lowest in the 7 of 8 HLA-MUD recipients [39]. Among pediatric subjects with allo-HSCT 
from unrelated donors, up to 56% will develop Grade 2 to 4 aGvHD and 29% will develop Grade 3 
to 4 aGvHD [13,14]. The intestinal tract is often involved in Grade 3 to 4 aGvHD, and when the 
intestinal tract is involved in pediatric patients, NRM increases [40]. All subjects will receive a 
background GvHD prophylaxis regimen consisting of a CNI (CYS or TAC) and MTX or MMF. 
When considered a part of standard prophylactic treatment for GvHD, ATG (ATG-F or 
thymoglobulin) may be used at the discretion of the treating physician; however, the proportion of 
subjects receiving ATG shall comprise no more than approximately 25% of the total number of 
subjects enrolled into the study. Subjects who have received or are receiving prophylactic agents 
other than those listed in the inclusion criteria, including approved or other investigational
therapies, are excluded. 
6.2.2
Dose Selection
All subjects will receive a combination of CNI (CYS or TAC) and MTX or MMF [41-43], which is
commonly prescribed as prophylaxis of GvHD for subjects undergoing allo-HSCT. ATG (ATG-F 
or thymoglobulin) may be included as noted in Section 6.2.1.
The vedolizumab dose and schedule for this phase 3 study are 300 mg on Days -1, +13, +41, +69, 
+97, +125, and +153. This dose selection is based on safety, efficacy and PK data from Study
Vedolizumab-1015 and the IBD program. The dosing regimen selected is estimated to provide 
serum concentrations above 10 μg/mL for 180 days. PK data from Study Vedolizumab-1015 
indicates that the PK of vedolizumab in subjects with GvHD who received 300 mg is similar to 
that of subjects with IBD. 
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Vedolizumab IV
Study No. Vedolizumab-3035
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The 300 mg dose of vedolizumab was well tolerated in subjects in Study Vedolizumab-1015 
without delay of engraftment (median 14 days for the vedolizumab 300 mg cohort) or new safety 
concerns. Repeated vedolizumab dosing during the 6 months after the allo-HSCT is proposed, 
during which time subjects are at the highest risk of developing intestinal aGvHD. 
The same vedolizumab dose regimen to be administered to adults (aged ≥18 years) planned to 
undergo allo-HSCT for prophylaxis of intestinal aGvHD is considered appropriate for 
administration to adolescents aged 12 years and greater and weighing ≥30 kg. In phase 3 studies in 
adults with IBD, body weights ranged from 28.7 to 170 kg. Safety data from these studies showed 
no difference in the incidence of TEAEs and a similar safety profile in adults receiving
vedolizumab IV Q8W or Q4W (Section 4.3). A population PK model was developed using pooled 
phase 1, 2, and 3 study data from the vedolizumab IV clinical program in adults with UC or CD to 
characterize the PK of vedolizumab and to assess the impact of patient demographic 
characteristics (eg, age and body weight) on PK. This model indicated that weight-based dosing is 
not required and that age was not a clinically meaningful covariate (Section 4.3). In addition, 
results from Study Vedolizumab-1015 indicated that the PK of vedolizumab (300 mg) in adults
with aGvHD was similar to that in adults with UC or CD.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or ET of the study. 

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known benefit/risk profile for the product, such that the 
benefit/risk is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objective or compromises subject safety.

The sponsor elects to terminate or suspend the study due to plans to modify, suspend, or 
discontinue development of the study drug. 
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of an 
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Study No. Vedolizumab-3035
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investigational site, a study-specific procedure for ET or suspension will be provided by the 
sponsor; the procedure will be followed by applicable investigational sites during the course of 
termination or study suspension. The competent regulatory authority will be notified in case of
study termination or suspension following local regulations. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Each subject must meet all the following inclusion criteria to be enrolled in the study:
1. The subject or, when applicable, the subject’s legally acceptable representative voluntarily 
signs and dates a written, informed consent form (ICF) and any required privacy authorization 
before performance of any study-related procedures not part of standard medical care, with the 
understanding that consent may be withdrawn by the subject at any time without prejudice to 
future medical care. As applicable, a parent/both parents or legally acceptable representative 
must provide signature of informed consent, and there must be documentation of 
age-appropriate assent by the subject.
2. Male or female subjects 18 years of age and, in selected countries (where local requirements 
permit and based on feasibility), adolescents aged 12 years and greater and weighing ≥30 kg at 
time of randomization. 
3. Subjects must undergo DNA-based HLA matching and be 8 of 8 or 7 of 8 HLA-matched 
(single allele or antigen mismatch at HLA-A, -B, and -C, and HLA-DRB1 is allowable) 
unrelated hematopoietic stem cell transplantation (HSCT) from either peripheral blood or bone 
marrow stem cells for a hematologic malignancy or myeloproliferative disorder. Subjects 
should follow local practice for additional HLA-match, for example France, 9/10 or 10/10 
HLA match.
4. Subjects for whom a myeloablative conditioning or RIC is planned. 
5. Allo-HSCT eligible (meeting institutional criteria)-subjects planned medical care should
include aGvHD prophylaxis with a combination of CNI (CYS or TAC) and MTX or CNI and 
MMF. With the exception of ATG (ATG-F or thymoglobulin), all other therapies, approved or 
investigational, for GvHD prophylaxis are excluded. 
6. Status of the primary disease as follows:
a) Subjects with acute leukemia or chronic myelogenous leukemia: no circulating blasts and 
<5% blasts in the bone marrow.
b) Subjects with myelodysplasia: no circulating blasts and 10% blasts in the bone marrow.
c) Subjects with chronic lymphocytic leukemia or small lymphocytic lymphoma with
chemosensitive disease at the time of transplantation (partial or complete response to last 
salvage therapy).
d) Subjects with other nonHodgkin or Hodgkin lymphoma with a response to last salvage 
therapy or chemo-sensitive disease per institutional standards at the time of 
transplantation.
e) For subjects with myelofibrosis and other myeloproliferative disorders: <5% blasts in the 
blood and bone marrow.
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Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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7. Eastern Cooperative Oncology Group (ECOG) performance status of 2 for subjects aged ≥18 
years at randomization or ≥60% using the Karnofsky performance status for adolescent 
subjects aged ≥16 years at randomization or the Lansky performance status for adolescent 
subjects aged 12 to <16 years at randomization (Appendix E). 
8. Sufficient cognitive ability to reliably complete the PML checklist at baseline. 
9. Female subjects who are:

Postmenopausal for at least 1 year before signing of the informed consent (specified in 
Section 9.3.19), OR

Surgically sterile, OR

If they are aged 12 years and greater and not postmenopausal (Section 9.3.19) or surgically 
sterilized must use a highly effective method of contraception (specified in Section 9.3.19)
during the study and through 18 weeks after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male subjects, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice an acceptable effective barrier method of contraception (specified in 
Section 9.3.19) during the entire study treatment period and through 18 weeks after the last 
dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
10. Suitable venous access for the study-required blood sampling, including PK sampling.
7.2
Exclusion Criteria
Subjects meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Prior allo-HSCT.
2. Planned umbilical cord blood transplant or planned to receive posttransplant 
cyclophosphamide, in vivo or ex vivo T cell-depleted hematopoietic stem cells (HSCs) with
the exception of ATG (ATG-F or thymoglobulin).
3. Planned allo-HSCT for nonmalignant hematological disorders (eg, aplastic anemia, sickle cell 
anemia, thalassemias, Fanconi anemia or immunodeficiency).
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Study No. Vedolizumab-3035
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4. Known active cerebral/meningeal disease (including central nervous system involvement of 
the primary disease), or signs or symptoms of PML, any history of PML, or a positive PML 
subjective checklist before the administration of study drug on Day -1.
5. Evidence of encephalopathy at screening.
6. History of any major neurological disorder, including stroke, multiple sclerosis, brain tumor, 
or neurodegenerative disease.
7. Prior or current therapy with 4 and/or 7 integrin inhibitors (including, but not limited to
natalizumab, etrolizumab, AMG-181), MAdCAM-1-antibodies, anti-CD11a mAb (eg, 
efalizumab) within 60 days or 5 half-lives, whichever is longer from randomization.
8. Prior known exposure of the transplant recipient to vedolizumab.
9. Any serious medical or psychiatric condition that could, in the investigator or medical 
monitor’s opinion, potentially interfere with the completion of treatment according to this 
protocol.
10. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, 
coagulation, immunological, endocrine/metabolic, neurologic or other medical disorder not 
related to the subject’s primary disease that, in the opinion of the investigator, would confound 
the study results or compromise subject safety.
11. Clinically active systemic infection during screening.
12. Clinically active cytomegalovirus (CMV) colitis during screening.
13. Clinically active Clostridium difficile infection or other intestinal pathogen during screening.
14. Active or latent tuberculosis (TB), regardless of treatment history, as evidenced by any of the 
following: history of TB, OR positive QuantiFERON test or T-spot or 2 successive 
indeterminate QuantiFERON or T-spot tests, OR a tuberculin skin test reaction 10 mm
(5 mm in subjects receiving the equivalent of >15 mg/day prednisone).
15. Chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive [HBsAg]) or hepatitis C 
infection (evident by active viral replication by polymerase chain reaction [PCR] if hepatitis C 
virus antibody positive). Hepatitis B core antibody (HBcAb) positive (HBcAb+) and negative 
for hepatitis B surface antigen (HBsAg) may be enrolled if viral DNA is undetectable.
16. History of human immunodeficiency virus (HIV) positive test.
17. Treatment with anti-T cells antibody such as alemtuzumab (anti-CD52), excluding ATG 
(ATG-F or thymoglobulin), within 4 months before the first dose of study drug on Day -1.
18. Treatment with any live vaccinations within 30 days before randomization.
19. If female, the subject is pregnant, lactating or breastfeeding, 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. 
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Study No. Vedolizumab-3035
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20. Diagnosed or treated for another malignancy within 2 years before the first dose of study drug 
or previously diagnosed with another malignancy and have any evidence of residual disease. 
Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if 
they have undergone complete resection. 
7.3
Medications and Treatments
7.3.1
Excluded Concomitant Medications and Treatments While On-study

Any investigational agent (other than vedolizumab), including agents other than 
corticosteroids for treatment of GvHD.

Checkpoint inhibitors. 

Any therapy for aGvHD prophylaxis other than that specified in the inclusion criteria 
(Appendix B). Should 1 of the GvHD prophylaxis agents specified in the inclusion criteria be 
discontinued due to toxicity and an alternative agent started, the subject may be permitted to 
remain on study drug after consultation with the medical monitor.

All live vaccines from 30 days before randomization to at least 6 months after the last dose of 
study drug.

Either approved or investigational monoclonal antibody or equivalent biologics for the 
treatment of other conditions (eg, rheumatoid arthritis), other than localized injections (eg, 
intra-ocular injections for wet macular degeneration).
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator.
7.3.2
Permitted Medications and Treatments
Other medications considered necessary for the safety and well-being of the subject may be 
administered at the discretion of the investigator. Corticosteroids may be initiated for treatment of 
GvHD; however, if lower intestinal tract aGvHD occurs, study drug must be discontinued (Section 
7.4). Any concomitant medications added or discontinued during the study should be recorded on 
the eCRF.
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence, such premedication 
is unlikely to be necessary or beneficial. At the discretion of the investigator, however, subjects 
may be administered premedication before any study drug administration. Use of topical
anesthetic (eg, lidocaine, tetracaine, prilocaine) is recommended for blood draws or IV insertions 
for the comfort of subjects aged 12 to <18 years. This use will not be recorded as a concomitant 
medication. Corticosteroids, if given as a premedication, should be limited to the day of
administration.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 41 of 122
Protocol Incorporating Amendment No. 07
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18 September 2019
7.4
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study
medication should be recorded in the eCRF using the following categories.

The subject has experienced an AE that requires ET because continued participation imposes 
an unacceptable risk to the subject’s health or the subject is unwilling to continue because of 
that AE, such as:

PML or tuberculosis

LFT Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.3.15.3), if the following circumstances occur at any
time during study medication treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 
8 times the upper limit of normal (ULN), or
–
ALT or AST more than 5 times the ULN and persists for more than 2 weeks, or
–
ALT or AST more than 3 times the ULN in conjunction with elevated total bilirubin 
more than 2 times the ULN or international normalized ratio (INR) more than 1.5 with 
no alternate etiology, or
–
ALT or AST more than 3 times the ULN with appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, with fever and rash.

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.

Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented. 

Voluntary withdrawal. The subject wishes to withdraw from the study, or the subject’s 
parent/legally acceptable representative wishes to have the subject withdrawn from the study. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE or lack of efficacy). 

Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.

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 9.3.20.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 42 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019

Lack of efficacy. Subjects who develop lower intestinal aGvHD (stage 1-4 per Table 1: 
aGvHD Clinical Stage, as defined in Appendix F) should discontinue study drug.

Other. Note: The specific reasons should be recorded in the "specify" field of the eCRF.
7.5
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.4. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by
the investigator. In addition, efforts should be made to perform all procedures scheduled for the ET 
visit, the final safety visit, and the 6-month LTFU safety survey. Discontinued or withdrawn 
subjects will not be replaced.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn subject and added to the existing data or any database.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 43 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
8.0
STUDY DRUG/CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding study medication and materials provided directly by 
the sponsor, and/or sourced by other means, that are required by the study protocol.
8.1
Study Medication 
All protocol-specific criteria for administration of study drug must be met and documented before
study drug administration. Study drug will be administered only to eligible subjects under the 
supervision of the investigator or identified subinvestigator(s). The drugs contained in the 
background GvHD prophylaxis regimen (Appendix B) will be obtained by the study sites.
8.1.1
Vedolizumab IV or Matching Placebo
The study sites will be supplied by the sponsor with the following medication in an open-label 
manner: vedolizumab IV 300 mg/vial, for single use, in 20 mL vials. The study medication will be 
provided in a glass vial as a lyophilized solid formulation for reconstitution using sterile water for 
injection. Each vial will be packaged in an appropriately labeled single vial carton. Sites  provide 
all other materials for infusion. 
The placebo infusion will be 250 mL of 0.9% sodium chloride and should be provided by the sites.
For all infusions, the unblinded investigational pharmacist or designee will mask the IV bags after 
preparation to maintain the study blind.
Additional reference information and administration instructions can be found in the pharmacy 
manual. 
8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug must be transported and 
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), protected from light. A daily 
temperature log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
The dosing regimen for all subjects is shown in Figure 8.a. All subjects will receive double-blind 
treatment of study drug by IV infusion per the designated schedule. The Vedolizumab IV dose is 
300 mg on each dosing day. 
All infusions will be administered IV over approximately 30 minutes. Longer infusion times of up 
to 60 minutes may be used based on study observations. Subjects should be observed for 2 hours 
after the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion in a room where 
appropriate treatment for IRRs is available (see Section 8.7.1). The subject should be considered 
clinically stable by the investigator or designee before discharge.
Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 44 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF to capture this important safety information consistently in the database. Cases of 
overdose without manifested signs or symptoms are not considered AEs. AEs associated with an 
overdose will be documented on AE eCRF(s) according to Section 10.0, pretreatment events 
(PTEs) and AEs.
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Vedolizumab IV
Study No. Vedolizumab-3035
Page 46 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
8.2
Treatment Assignment and Dispensing Procedures
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization. Subjects will receive the treatment for the assigned treatment arm and 
according to the study schedule.
The investigator or investigator’s designee will access the IRT at screening to obtain the subject 
study number. The investigator or the investigator’s designee will utilize the IRT to randomize the 
subject into the study. The medication identification (ID) number of the investigational drug to be 
dispensed will then be provided by the IRT by email notification to the unblinded site 
pharmacist/nurse. To maintain the blind the IRT will ensure the investigator or designee is 
unaware of a medication ID assigned to the subject. If sponsor-supplied drug is lost or damaged, 
the unblinded site staff can request a replacement from IRT. 
At subsequent drug-dispensing visits, the investigator or designee will again contact the IRT to 
request additional investigational drug for a subject. The medication ID number of the 
investigational drug to be dispensed will be provided by the IRT to the unblinded site staff only.
The IRT will include all required information as a separate entry for each subject to whom
sponsor-supplied drug is dispensed.
Additional information is provided in the study manual. 
8.3
Investigation Blind Maintenance
The investigational drug blind will be maintained using the IRT. All subjects and study personnel 
except for those directly involved with study drug preparation will be blinded to study drug 
assignment for the entire study.
8.4
Unblinding Procedure
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational drug is necessary for the medical treatment of the subject. In the 
event of a medical emergency, the investigational drug blind can be broken without permission 
from the sponsor, although the medical monitor should be contacted immediately. In non-urgent 
cases (ie, a non-medical emergency), the medical monitor must be contacted before the subject is 
unblinded. 
For unblinding a subject, the investigational drug blind can be obtained by the investigator, by
accessing the IRT. Additional information for unblinding a subject is provided in the study 
manual. 
Subjects discontinuing study participation for any other reason will be kept blind.
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the eCRF. 
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 47 of 122
Protocol Incorporating Amendment No. 07
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18 September 2019
8.5
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee or destroyed at the site. The site will maintain source documents in addition to entering 
data into the IRT.
The blinded investigator or blinded designee and the unblinded investigational pharmacist or 
designee must ensure that the sponsor-supplied drug is used in accordance with the protocol and is 
dispensed only to subjects enrolled in the study. To document appropriate use of sponsor-supplied 
drug, the unblinded investigational pharmacist or designee must maintain records of all 
sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each subject, and 
return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the unblinded investigational pharmacist 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, the unblinded investigational pharmacist or designee should acknowledge the receipt 
of the shipment in the IRT. If there are any discrepancies between the packing list versus the actual 
product received, Takeda must be contacted to resolve the issue. The packing list should be filed in 
the investigator’s essential document file.
The investigator must ensure that 100% accountability is maintained for all sponsor-supplied 
drugs received and dispensed during his or her entire participation in the study. The unblinded 
investigational pharmacist will maintain 100% accountability, including but not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the medication ID used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.

Continuously monitoring expiration dates, if expiry date is provided.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The unblinded investigational pharmacist or designee will acknowledge all sponsor-supplied 
drugs in the IRT and maintain the drug accountability logs as described in the unblinded pharmacy 
manual. The following information will be recorded at a minimum: protocol number and title, 
name of investigator, site identifier and number, description of sponsor-supplied drugs, date and 
amount dispensed, and the initials, seal, or signature of the person dispensing the drug.
Before site closure or at appropriate intervals, a representative from the sponsor or its designee will 
perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied drugs 
are returned to the sponsor or its designee for destruction or destroyed at the site. Accountability 
Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 48 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
for clinical study material being destroyed at the site must be documented using a study
accountability tracking document or equivalent document. In addition, a certificate of destruction 
document must be provided by the sites that can identify or allow traceability to the batches, and/or 
medication ID numbers involved, and actual quantities destroyed. The investigator or designee 
will retain a copy of the documentation regarding sponsor-supplied drug accountability, return, 
and/or destruction, and originals will be sent to the sponsor or designee.
8.6
Precautions and Restrictions
8.6.1
Study Drug Dosing
After a subject has received the first dose of study drug on Day -1 before allo-HSCT, if the clinical 
events described in Section 8.7 are observed, subjects may not receive subsequent study drug 
doses after allo-HSCT as indicated in the SOE (Appendix A). 
8.6.2
Reproductive Effects
It is not known what effects vedolizumab has on human pregnancy or development of the embryo
or fetus. Therefore, female subjects participating in this study should avoid becoming pregnant, 
and male subjects should avoid impregnating a female partner. Nonsterilized female subjects of
reproductive age group and male subjects should use effective methods of contraception (specified 
in Section 9.3.19) through defined periods during and after study treatment as specified in the 
following.
Female subjects must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit (specified in Section 9.3.19), or

Surgically sterile, or

If they are aged 12 years and greater and are not postmenopausal (Section 9.3.19) or surgically 
sterilized, must use a highly effective method of contraception (specified in Section 9.3.19)
during the study and through 18 weeks after the last dose of study drug, or 

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods] and withdrawal are not acceptable methods of contraception.)
Male subjects, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice an acceptable effective barrier method of contraception (specified in Section 9.3.19)
during the entire study treatment period and through 18 weeks after the last dose of study drug, 
or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner] and withdrawal are not acceptable methods of contraception.)
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 49 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
In addition, using the approved product information for the medicinal products used as part of a 
subject’s routine care, including the conditioning regimen, investigators should advise subjects on 
the appropriate duration for use of contraception after the last dose of such medicinal products. 
8.7
Management of Clinical Events
8.7.1
Hypersensitivity Reactions
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence such 
premedications are unlikely to be necessary or beneficial. At the discretion of the investigator, 
however, subjects may be administered premedication before any study drug administration. 
Corticosteroids, if given as a premedication, should be limited to the day of administration. Study 
drug should be administered by a health care professional prepared to manage hypersensitivity 
reactions including anaphylaxis, if they occur. Appropriate monitoring and medical support 
measure should be available for immediate use. Subjects should be observed during the infusion 
and until the infusion is complete. 
Subjects, parents, or legally acceptable representatives should be instructed to report the 
development of rash, hives, pruritus, flushing, urticaria, etc. that may represent an IRR to study 
medication. If signs or symptoms of IRR are observed during the administration of study drug, it 
should be immediately discontinued and the subject treated as medically appropriate. In the case of 
a mild reaction, study drug administration may be reinitiated (with appropriate premedication) at 
the discretion of the investigator. Subjects with severe or serious IRRs (eg, stridor, angioedema, 
life-threatening change in vital signs) must be withdrawn from the study.
In all cases of administration-related reaction, the medical monitor must be informed as soon as 
practical. The disposition of subjects with less severe IRRs should be discussed with the project 
clinician. 
8.7.2
Leukopenia or Lymphopenia
Leukocyte and lymphocyte counts will be monitored for all subjects with a hematological panel
(see Section 9.3.15.3) and the use of prophylactic myeloid growth factors (ie, granulocyte-colony 
stimulating factor) may be started with the product, dose, and route of administration at the 
discretion of the treating institution. If engraftment has not occurred by Day +21 (defined as 
absolute neutrophil count >500/mm3 for 3 consecutive days or >2000/mm3 for 1 day), it is 
recommended that prophylactic myeloid growth factors be started. Failure to engraft by Day +28 
will be considered as primary graft failure and should be reported as an SAE, and study drug 
should be discontinued.
8.7.3
CMV Colitis
Regular assessments will include symptom-directed assessment for GI toxicity and monitoring for 
CMV reactivation per institutional standards. Preemptive CMV therapy will be initiated per 
institutional standards. Subjects with active CMV colitis during screening will be excluded from
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Vedolizumab IV
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the study. For subjects with suspected CMV colitis, it is recommended that an endoscopy be 
performed. Subjects with confirmed CMV colitis during the study will require dosing hold, and the 
medical monitor should be contacted before resuming study drug. In subjects suspected of having 
aGvHD for whom the cause of posttransplantation diarrhea and/or enterocolitis is unclear, the 
subject will require endoscopy and histologic analyses of intestinal biopsy specimens as clinically 
appropriate.
8.7.4
Malignancy
All cases of malignancies that are detected during the study, including relapse of primary disease 
will be reported as SAEs. Study drug should be discontinued, and subjects will continue to be 
followed as specified per the SOE (Appendix A). 
8.7.5
Liver Injury 
For subjects with normal baseline ALT/AST, a subject noted to have ALT or AST elevated more 
than 3 times the ULN for 2 consecutive weeks, the abnormality should be recorded as an AE. In 
addition, an LFT Increases eCRF must be completed providing additional information on relevant 
recent history, risk factors, clinical signs and symptoms and results of any additional diagnostic 
tests performed.
For subjects who had elevated ALT or AST at baseline, if elevations of ALT or AST are more than 
2 times the baseline value or ALT or AST is more than 5 times the ULN, the abnormality should be 
recorded as an AE and reported via the LFT Increases eCRF. 
For both of these scenarios, study drug will be held until further discussion with the medical 
monitor. The investigator must contact the medical monitor for discussion of the relevant subject 
details and possible alternative etiologies, such as acute viral hepatitis A, B, or E, reactivation of 
hepatitis B, or acute liver GvHD or other acute liver disease or medical history/concurrent medical 
conditions before subsequent dosing. Follow-up laboratory tests as described in Section 9.3.15.3
must also be performed. 
If a subject is noted to have ALT or AST more than 3 times the ULN and total bilirubin more than 
2 times the 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; treatment with study drug should be 
immediately held. The investigator must contact the medical monitor to discuss alternate 
etiologies. In addition, an LFT Increases eCRF must be completed. 
In addition, an event meeting any of the criteria listed for LFT Abnormalities (Section 7.4) should 
be reported as an SAE.
8.7.6
Hepatitis B Reactivation
Subjects who are HBcAb+ and HBsAgwith a detectable hepatitis B virus (HBV) DNA by PCR at 
screening should be excluded from the study. Only subjects with a negative PCR evident by
undetectable HBV DNA may be enrolled in the study. Assessments for reactivation in such 
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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subjects should be monitored periodically (at the minimum every 3 months) by determination of
HBV serology and HBV DNA. All subjects who meet any of the following criteria will be 
immediately discontinued from study drug. All reactivation events should be reported as an SAE.

Detectable HBV DNA.

Reverse seroconversion from HBsAgto HBsAg.

Jaundice.
8.7.7
Other Clinical Events
8.7.7.1
Serious Infections
Subjects who, in the opinion of the investigator, have serious infections will be monitored during 
the study. Subjects with serious infections, including viral, fungal, and bacterial infections, will be 
treated as clinically indicated. Interventions may include antibiotic treatment, if appropriate and/or 
discontinuation of concomitant immunomodulators. Blood, sputum, urine, cerebrospinal fluid, 
and/or stool cultures should be obtained as appropriate for the detection and diagnosis of infection.
Study drug should be withheld, and the medical monitor should be contacted before resuming 
study drug. Terminating study drug administration may be considered as described in Section 7.5.
8.7.7.2
PML
All subjects will be screened for new neurological signs and symptoms potentially consistent with 
PML using the PML subjective checklist (see Section 9.3.11) before dosing with study drug. Any 
subjects in whom signs or symptoms of PML are reported will undergo objective testing. If a 
subject demonstrates a neurologic deficit related to PML upon administration of the PML 
checklist, no further doses of study drug should be administered to that subject. The subject should 
be referred to the study neurologist for further testing and the sponsor must be notified of this 
action.
Subsequent doses of study drug will be administered only if the possibility of PML is definitively 
excluded, as described in the Risk Minimization Action Plan for PML (RAMP) algorithm.
8.7.7.3
Donor Leukocyte Infusion
Planned donor leukocyte infusion (DLI) is not permitted.; however, for subjects who experience 
mixed chimerism, DLI may be permitted after consultation with the medical monitor. For subjects 
who require DLI for other reasons, such as disease relapse, study drug should be discontinued, and 
subjects will continue to be followed as specified in the SOE (Appendix A). 
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Vedolizumab IV
Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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18 September 2019
9.0
STUDY CONDUCT
This study will be conducted in compliance with the protocol, GCP, applicable regulatory
requirements, and International Council for Harmonisation (ICH) guidelines.
9.1
Study Personnel and Organizations
The contact information for the Takeda project clinician for this study, the central laboratory and 
any additional clinical laboratories, the coordinating investigator for each member state/country
(where applicable), and the contract research organization (CRO) team may be found in the study 
manual. A full list of investigators is available in the sponsor’s investigator database.
9.2
Randomization
Randomization will take place within 2 days of the first dose of study drug on Day -1 provided the 
subject has satisfied all of the inclusion criteria and none of the exclusion criteria. The subject 
should be randomized using the IRT as described in Section 8.2. The procedure for documenting 
screening failures is provided in Section 9.4. Rescreening is permitted in consultation with the 
medical monitor. 
9.3
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. Refer to 
the SOE (Appendix A) for timing of assessments. Additional details are provided as necessary in 
the sections that follow.
9.3.1
Informed Consent
The requirements of the informed consent/age-appropriate assent are described in Section 15.2.
Informed consent/age-appropriate assent must be obtained before the subject enters into the study, 
and before any protocol-directed procedures are performed.
Subjects reaching an age that is not covered by their signed assent must provide consent for their 
appropriate age group to remain in the study. Subjects who reach the age of consent must provide 
consent with a signed ICF to remain in the study.
9.3.2
Inclusion/Exclusion
The inclusion/exclusion criteria will be assessed during screening (within 30 days before the first 
dose of study drug on Day -1).
9.3.3
Demographics
Demographic information to be obtained may include (depending on local regulations) the date of 
birth or age, race, ethnicity, and sex of the subject and are to be recorded during screening.
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Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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9.3.4
Medical History
During the screening period, a complete medical history will be compiled for each subject. The 
history will emphasize the background and progress of the subject’s malignancy and include a 
description of prior therapies for it. In addition, concomitant medications will be recorded as 
specified in Section 9.3.13.
9.3.5
Physical Examination
A baseline physical examination (defined as the assessment before the first dose of study drug) 
will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) GI system; (6) dermatologic system; (7) extremities; 
(8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other. All subsequent 
physical examinations should assess clinically significant changes from the assessment before the
first dose of study drug. 
Any physical examination finding that is assessed by the investigator as a clinically significant 
change (worsening) compared to baseline value will be considered an AE and will be recorded and 
monitored as described in Section 10.2.
9.3.6
Weight and Height
A subject should have weight and height measured while wearing indoor clothing and without 
shoes, socks, or hats. The Takeda standard for collecting weight is kilograms (kg) with 1 decimal 
place. 
Height should be recorded to the nearest tenth of a centimeter (if possible). Height may be 
measured using a wall-mounted stadiometer using replicated measurements (average of 
3 measurements). Height will be measured during screening (within 30 days before the first dose 
of study drug on Day -1) and at EOS.
9.3.7
Vital Signs
Vital sign measurements include blood pressure, heart rate, respiration rate, and body temperature 
to be determined at the times specified in the SOE (Appendix A). On dosing days, vital signs are 
taken predose. 
9.3.8
Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed at the time points specified in the 
SOE (Appendix A). 
9.3.9
Performance Status
The type of performance status scale to be used is based on subject age at randomization. The 
ECOG performance status is used for subjects aged ≥18 years, the Karnofsky performance status
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Vedolizumab IV
Study No. Vedolizumab-3035
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for adolescent subjects aged ≥16 years, and the Lansky performance status for adolescent subjects 
aged 12 to <16 years will be assessed at the time points specified in the SOE (Appendix A). 
9.3.10 Assessment of GvHD
aGvHD will be staged according to the extent and severity of each organ involvement (Stages 0-4) 
on the basis of objective clinical criteria (Appendix F). These stages are then combined to generate 
an overall clinical grade, which are Grades 0 through IV in the modified Glucksberg system 
(Appendix F), MAGIC system, and Grades A through D in the International Bone Marrow 
Transplant Registry Database (IBMTR) system (Appendix F). Glucksberg and IBMTR performed 
similarly in explaining variability in OS by grade in aGvHD. aGvHD events will be recorded and 
staged according to aGvHD Clinical Stage criteria (Appendix F) and graded per the IBMTR 
system in this study unless otherwise noted.
In subjects suspected of having intestinal aGvHD, endoscopy with rectal biopsy is recommended, 
and infectious etiologies (eg, C. difficile, CMV colitis) should be evaluated.
9.3.11 PML Checklist
Clinic staff will administer the age-appropriate subjective PML checklist during screening to 
exclude subjects with positive responses from enrolling into the study. The subjective PML 
checklist will be administered (before dosing, if applicable) at the time points specified in the SOE 
(Appendix A) to probe for symptoms suggestive of PML. The checklist must be administered by 
appropriate clinic staff as it is not designed to be completed by a subject, parent, or legally 
acceptable representative. If a new and persistent change(s) is reported per the subjective checklist, 
the corresponding objective test(s) must be completed, and the subject may be referred to a 
neurologist for a full evaluation as described in the RAMP algorithm. The PML checklist and the 
RAMP algorithm and tools are included in the Study Manual. See Section 10.7 for additional 
details regarding the RAMP program.
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Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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9.3.13 Concomitant Medications and Procedures
Medications used by the subject and therapeutic procedures completed by the subject will be
recorded in the eCRF from the first dose of study drug on Day -1 through 12 months after 
allo-HSCT. See Section 7.3.1 and Section 7.3.2 for a list of medications and therapies that are 
prohibited and/or allowed during the study.
9.3.14 AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the SOE (Appendix A). Refer to Section 10.0 for details regarding definitions, documentation, and 
reporting of PTEs, AEs, and SAEs.
9.3.15 Clinical Laboratory Evaluations
Clinical laboratory evaluations as specified in the SOE (Appendix A) will be performed by a 
central laboratory. Local laboratories may be used to conduct assessments needed more rapidly 
and for urgent medical management throughout the study per investigator’s discretion. In 
adolescent subjects aged 12 years and greater and weighing ≥30 kg, the maximum volume of 
blood collected at any single visit 
) is approximately 14
mL, and the approximate total volume of blood for the study is 144 mL. The maximum volume of 
blood collected from adult subjects is 29 mL and 300 mL, respectively. Clinical laboratory
evaluations to be conducted during this study are summarized in Table 9.a.
9.3.15.1 TB Screening
All subjects will complete TB screening to determine eligibility. All subjects must complete a 
diagnostic test during screening, either a QuantiFERON test, T-Spot, or a tuberculin skin test. 
Subjects will be excluded from the study if they have active or latent TB, regardless of treatment 
history, as defined in Section 7.2.
9.3.15.2 Pregnancy Test
For female subjects aged 12 years and greater who are not postmenopausal (Section 9.3.19) or 
surgically sterilized, a serum pregnancy (choriogonadotropin beta) test will be completed at 
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Vedolizumab IV
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screening before the first dose of study drug, and a urine pregnancy test will be completed predose 
on each study drug dosing day (and in the UK, on Day 180; and in Norway, on Day +180, 
Day +280 [or 18 weeks after the last dose of study drug], and at ET; and in Argentina, monthly 
from Day +153 up to 18 weeks after the last dose of study drug). The results from these tests must 
be available and negative before the study drug is administered. Additional pregnancy testing may 
be performed during the study at the discretion of the investigator, upon request of an IEC/IRB, or 
if required by local regulations. 
9.3.15.3 Clinical Hematology, Coagulation, Chemistry, and LFT
The clinical laboratory tests (clinical hematology, coagulation testing, blood chemistry, and LFTs) 
to be conducted during the study are summarized in Table 9.a. The central laboratory will perform
these tests and return the results to the investigator, who is responsible for reviewing and filing 
them. Blood samples for these analyses will be obtained at the time points specified in the SOE 
(Appendix A).
If subjects experience ALT or AST more than 3 times the ULN, follow-up laboratory tests (at a 
minimum, serum alkaline phosphatase, ALT, AST, total bilirubin, γ-glutamyl transferase, and 
INR) should be performed within a maximum of 7 days and preferably within 48 to 72 hours after 
the abnormality was noted.
(Please refer to Section 7.4 for discontinuation criteria, and Section 8.7.5 for the appropriate 
guidance on reporting of abnormal LFTs in relation to ALT or AST more than 3 times the ULN in 
conjunction with total bilirubin more than 2 times the ULN.)
If the ALT or AST remains elevated more than 3 times the ULN on these 2 consecutive weeks, the 
investigator must contact the Medical Monitor for consideration of additional testing, close 
monitoring, possible discontinuation of study medication, discussion of the relevant subject 
details, and possible alternative etiologies. The abnormality should be recorded as an AE (refer to 
Section 8.7.5 reporting of abnormal LFTs for reporting requirements).
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Vedolizumab IV
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Protocol Incorporating Amendment No. 07
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18 September 2019
Table 9.a
Clinical Hematology, Coagulation, Chemistry, and LFTs
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Red blood cells (RBC)
Leukocytes with differential including 
neutrophils, monocytes, and lymphocytes
Platelets
Albumin
Bicarbonate (HCO3)
Blood urea nitrogen (BUN)
Calcium
Creatinine
Chloride
Glucose
Phosphate
Potassium
Sodium
Urate
Coagulation a
Liver Functions
Prothrombin (PT)/INR
Activated partial thromboplastin time (aPTT)
Alkaline phosphatase (ALP)
ALT
AST
Bilirubin (total and direct)
Lactate dehydrogenase (LDH)
Other:
HIV
Hepatitis panel, including HBsAg, anti-HCV, and 
HCV PCR (as applicable)
QuantiFERON for TB
beta hCG and urine pregnancy hCG (predose on dosing days)
for female subjects of childbearing potential
FSH, if menopause is suspected
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
; FSH, follicle-stimulating hormone; HBsAg, hepatitis B surface antigen; hCG, 
human chorionic gonadotropin; HCV, hepatitis C virus; HIV, human immunodeficiency virus; INR, international 
normalized ratio; PCR, polymerase chain reaction; TB, tuberculosis.
a Performed in subjects as specified in the SOE (Appendix A).
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Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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18 September 2019
9.3.19 Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study medication, female subjects aged 12 years and greater who are not postmenopausal 
or surgically sterilized and who are sexually active with a nonsterilized male partner** must use a 
highly effective method of contraception (Section 8.6.2). In addition, they must be advised not to 
donate ova during this period.
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 considered effective in men (eg, 
condom with spermicidal cream or jelly) (Section 8.6.2). In addition, they must be advised not to 
donate sperm during this period.
*Females NOT of childbearing potential are defined as those who have been surgically 
sterilized (hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal
(eg, defined as at least 1 year since last regular menses with an FSH >40 IU/L or at least 5 years 
since last regular menses, confirmed before any study medication is implemented) (Section 
8.6.2). 
**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 (Section 8.6.2).
A highly effective 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 
highly effective methods of contraception are:
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Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation, including oral, intravaginal, and transdermal 
formulations.

Progestogen-only hormonal contraception associated with inhibition of ovulation, 
including oral, injectable, and implantable formulations.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion.

Vasectomised partner. 

Sexual abstinence.
Barrier methods (eg, 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) can be used each time the subject has intercourse in addition to methods listed in 
the table above to ensure acceptable protection level.
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, urine hCG pregnancy tests will be performed (Section 8.6.2) for 
female subjects aged 12 years and greater who are not postmenopausal or surgically sterilized, and 
these subjects will receive continued guidance with respect to the avoidance of pregnancy and ova 
donation as part of the study procedures (Appendix A). In addition to a negative serum hCG 
pregnancy test at screening, female subjects aged 12 years and greater who are not postmenopausal 
or surgically sterilized must have a negative urine hCG pregnancy test before receiving any dose of 
study drug, preferably on the same day. 
Male subjects must be advised not to donate sperm from signing of informed consent through 
18 weeks after the last dose of study medication.
Using the approved product information for the medicinal products used as a part of a subject’s 
routine care, including the conditioning regimen, investigators should advise subjects on the 
appropriate duration for use of contraception after the last dose of such medicinal products. 
9.3.20 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn, and any
sponsor-supplied study drug should be immediately discontinued. In addition, any pregnancies in 
the partner of a male subject during the study or through 18 weeks after the last dose, should also 
be recorded following authorization from the subject’s partner. 
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Study No. Vedolizumab-3035
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If the pregnancy occurs during administration of study drug, eg, after the first dose on Day -1 or 
through 18 weeks after the last dose of study drug, the pregnancy should be reported immediately, 
using a pregnancy notification form, to the contact listed in the study manual.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received (blinded or unblinded, as applicable).
All pregnancies in subjects on vedolizumab or placebo will be followed up to final outcome, using 
the pregnancy form. Pregnancies will remain blinded to the study team. The outcome, including 
any premature termination, must be reported to the sponsor. An evaluation after the birth of the 
child will also be conducted.
9.4
Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent/age-appropriate assent.
If the subject is found to be not eligible at this visit, the investigator should complete the eCRF. 
The IRT should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

An existing substantial AE.

Did not meet inclusion criteria or did meet exclusion criteria. 

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal.

Study termination.

Other.
Subject numbers assigned to subjects who fail screening should not be reused. 
9.5
Completion of Study Treatment (for Individual Subjects)
Subjects will be considered to have completed study treatment if they receive 7 doses of study drug
and completed the Day +180 study visit.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 61 of 122
Protocol Incorporating Amendment No. 07
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18 September 2019
9.6
Study Compliance
Study drug will be administered or dispensed only to eligible subjects under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing.
If a subject is persistently noncompliant with the study medication, it may be appropriate to 
withdraw the subject from the study. All subjects should be reinstructed about the dosing 
requirements during study contacts. The authorized study personnel conducting the re-education 
must document the process in the subject source records. 
9.7
Post Study Care 
Study drug is administered for defined duration in addition to background aGvHD prophylaxis as 
part of the prophylaxis regimen. Therefore, the study drug will not be supplied by the sponsor after 
the subject has completed the study. The subject should return to the care of a physician and 
standard therapies as required.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 62 of 122
Protocol Incorporating Amendment No. 07
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18 September 2019
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is any untoward medical occurrence in a patient or subject who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is 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 therefore can be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is considered related to the medicinal product. In 
addition, drug-device AEs related to quality or malfunction will be collected.
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 preexisting conditions underlying disease should not be considered or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

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 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 
expected in this subject population). A laboratory retest and/or continued monitoring of an 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
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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.
Preexisting conditions:

Preexisting 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 PTEs unless related to study
procedures. However, if the subject experiences a worsening or complication of such a 
concurrent condition, the worsening or complication should be recorded appropriately as 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 preexisting 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 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 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs:

If the subject experiences changes in severity of an AE, the event should be captured once with 
the maximum severity recorded.
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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before 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 preexisting 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 preexisting 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
SAE means any untoward medical occurrence that at any dose:
1. Results in death.
2. Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).
3. Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).
4. Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).
5. Is a congenital anomaly/birth defect.
6. Is a medically important event that satisfies any of the following: 

may require intervention to prevent one of the outcomes listed above (1-5).
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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18 September 2019

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
Terms
Acute respiratory failure/acute respiratory distress 
syndrome
Anaphylactic shock
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizure
Pulmonary fibrosis
Agranulocytosis 
Confirmed or suspected endotoxic shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Neuroleptic malignant syndrome/malignant 
hyperthermia
Hepatic necrosis
Spontaneous abortion/stillbirth and fetal death
Acute liver failure
10.1.5 AEs of Special Interest
An AESI (serious or nonserious) is one of scientific and medical concern specific to the compound 
or program, for which ongoing monitoring and rapid communication by the investigator to Takeda 
may be appropriate. Such events may require further investigation 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. 
The following will be reported AESIs:

serious infections, 

PML, 

Malignancy, including relapse of the primary disease,

Liver injury, 

Hypersensitivity reactions including IRRs and injection site reactions, 

Leukopenia or lymphopenia, 
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Vedolizumab IV
Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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
CMV colitis, and 

CMV reactivation. 
10.1.6 Severity of AEs
All AEs, including clinically significant treatment-emergent laboratory abnormalities, will be 
graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
version 5.0. Grade descriptions are:
1. Mild: asymptomatic or mild symptoms, clinical or diagnostic observations only; intervention 
not indicated.
2. Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living.
3. Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living.
4. Life-threatening consequences; urgent intervention indicated.
5. Fatal AE: an event that results in the death of the subject.
10.1.7 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.
10.1.9 Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
physician.
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10.1.10 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. 
10.1.11 Frequency
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous. 
10.1.12 Action Concerning Study Medication

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE (eg, 
the study has been terminated, the subject died, dosing with study medication was already
stopped before the onset of the AE).

Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.13 Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE 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 – AEs that are considered 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. 
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Vedolizumab IV
Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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10.2
Procedures 
10.2.1 Collecting and Reporting AEs 
10.2.1.1 AE Collection Period
Nonserious AEs must be collected from the time of the first dose of study drug until 18 weeks after
the last dose of study medication.
10.2.1.2 AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects, parents, or legally acceptable representatives may report AEs occurring at any other time 
during the study. 
All subjects experiencing AEs after study drug administration, 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 the drug treatment. 
The following information will be documented for each event:
1. Event term.
2. Start and stop date.
3. Severity.
4. Investigator's opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related).
5. Investigator's opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
6. Action concerning study medication.
7. Outcome of event.
8. Seriousness.
10.2.1.3 AESI Reporting
If AESIs occur during the study period or the posttreatment follow-up period and are considered 
clinically significant based on the criteria below, the AEs should be recorded in the AESI eCRF 
and an SAE Form, as applicable. The SAE form should be completed and reported within 24 hours 
to the SAE reporting contact number recorded in the study manual.
Injection Site Reactions and/or IRRs and Hypersensitivity
Refer to Section 8.7.1.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 69 of 122
Protocol Incorporating Amendment No. 07
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Serious Infections
Refer to Section 8.7.7.1. Withholding or terminating study drug administration may be considered 
as described in Section 7.4.
Malignancies
Refer to Section 8.7.4. All cases of malignancies that are detected during the study will be reported 
as SAEs. 
Liver Injury
Refer to Section 8.7.5.
Other
Other AESIs include leukopenia or lymphopenia and PML and are discussed in Sections 8.7.2
and 10.7, respectively. 
10.2.2 Collection and Reporting of SAEs
SAEs must be collected from the time the subject signs the informed consent/age-appropriate
assent to participate in the study until the EOS or the subject discontinues study participation.
SAEs should be reported according to the following procedure: 
A Takeda SAE eCRF or Form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of the first onset or notification of the event. The information 
should be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject 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 the study
manual.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation. 
Reporting SAEs that occur before the first dose of study drug will follow the procedure described 
for SAEs.
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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18 September 2019
10.3
Follow-Up of SAEs
Regardless of causality, SAEs must be reported (see Section 10.4 for the period of observation) by 
the investigator to the Takeda Global Pharmacovigilance department or designee within 24 hours 
of becoming aware of the event. This will be done by transmitting an electronic data capture 
(EDC) SAE report. If transmission of an EDC SAE report is not feasible, then a facsimile or email 
of the completed Takeda paper-based SAE form will be sent. A sample of the paper-based SAE 
form and processing directions are in the study manual. Information in the SAE report or form 
must be consistent with the data provided on the eCRF.
If information not available at the time of the first report becomes available at a later date, then the 
investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an EDC 
SAE report is not feasible) or provide other documentation immediately within 24 hours of receipt. 
Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.4
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be collected from the first dose of study drug through 18 weeks after administration 
of the last dose of study drug and recorded in the eCRFs. 

Only serious PTEs will be collected and reported to the Takeda Global Pharmacovigilance 
department or designee from the time of signing of the ICF up to the first dose of study drug 
and recorded in the eCRF.

Related and unrelated SAEs will be collected and reported to the Takeda Global 
Pharmacovigilance department or designee from the signing of the informed consent through 
EOS and recorded in the eCRF. 
10.5
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a female subject becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study drug. The 
sponsor must also be contacted immediately by sending a completed pregnancy form to the 
Takeda Global Pharmacovigilance department or designee. The pregnancy must be followed for 
the final pregnancy outcome.
If a female partner of a male subject becomes pregnant during the male subject’s participation in 
this study, the sponsor must also be contacted immediately by sending a completed pregnancy 
form to the Takeda Global Pharmacovigilance department or designee. Every effort should be 
made to follow the pregnancy for the final pregnancy outcome.
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 71 of 122
Protocol Incorporating Amendment No. 07
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18 September 2019
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, including the European Medicines 
Agency, investigators, and IRBs and IECs, as applicable, in accordance with national regulations 
in the countries where the study is conducted. Relative to the first awareness of the event by/or 
further provision to the sponsor or sponsor’s designee, suspected unexpected serious adverse 
reactions will be submitted to the regulatory authorities as expedited reports within 7 days for fatal 
and life-threatening events and within 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 
product’s administration or in the overall conduct of the study. The investigational site also will
forward a copy of all expedited reports to his or her IRB or IEC in accordance with national 
regulations. 
10.7
RAMP Program
Subjects who have undergone HSCT are immunocompromised because of underlying disease, 
prior therapies, HSCT conditioning, and GvHD prophylaxis and treatment. The baseline risk of 
PML in the population of subjects who have undergone allo-HSCT for the treatment of
malignancy can be estimated at 35.4 per 100,000 person-years (95% CI: 0.90, 197.29) compared 
with 0.2 per 100,000 subjects with autoimmune diseases who did not have HIV or malignancy
(including subjects with IBD) [46,47]. To minimize the risk of the development of PML in 
subjects treated with vedolizumab, the sponsor, with input from PML experts, has developed the 
RAMP. The complete description of the RAMP program, including materials and instructions for 
its implementation and monitoring, is included in the study manual.
The RAMP is focused on early clinical detection and management of that specific safety risk, 
including the discontinuation of study drug, if applicable. Subjects are assessed for signs and 
symptoms of PML before the administration of each dose of study drug using an age-appropriate
PML subjective symptom checklist. Subjects with a positive PML subjective symptom checklist at 
any time after enrollment in a vedolizumab clinical study will be evaluated according to a 
prespecified algorithm (the PML Case Evaluation Algorithm). The next dose of vedolizumab will 
be held until the evaluation is complete and results are available. Subsequent doses of vedolizumab
will be administered only if the possibility of PML is definitively excluded, as described in the 
RAMP algorithm. An independent adjudication committee (IAC) has been identified as part of the 
RAMP program to review new neurological signs and symptoms potentially consistent with PML, 
and will provide input regarding subject evaluation and management as defined in the IAC charter.
To ensure success of the RAMP program, site personnel will be trained to recognize the features of 
PML, and subjects/parents/legally acceptable representatives will be trained to report specific 
neurological signs and symptoms without delay. Educational materials for teaching site personnel 
and subjects/parents/legally acceptable representatives about PML and the RAMP procedures will 
be distributed to all sites and are included in the study manual. Formal teaching and training will be 
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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performed for site personnel before the start of the study. Subjects will receive age-appropriate 
training and educational materials before receiving treatment. The ICF will contain specific 
information on the hypothetical risk of PML. Any documented case of PML will be reported as an 
SAE, regardless of whether hospitalization occurs.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 73 of 122
Protocol Incorporating Amendment No. 07
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11.0
STUDY-SPECIFIC COMMITTEES
11.1
DMC
A DMC will be utilized in the study for safeguarding the interest of study participants, assessing 
the safety and efficacy of the interventions during the study while maintaining the integrity of the 
study. The DMC will conduct periodic scheduled reviews of safety and conduct an interim 
analysis. Further details of the interim analysis can be found in Section 13.2.
The composition of, working procedures for, and frequency of DMC meetings are defined in the 
DMC Charter and will be provided to the DMC members before their first meeting. The DMC 
Charter is not included in this protocol.
11.2
Adjudication Committee 
An IAC has been identified as part of the RAMP program to review new neurological signs and 
symptoms potentially consistent with PML, and will provide input regarding subject evaluation 
and management as defined in the IAC charter. Details of the adjudication procedure are captured 
in the RAMP program that is contained in the study manual.
Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, 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.
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an ICF/assent.
The sponsor or its designee will supply investigative sites with access to eCRFs and 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, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs 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 designee) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, contact information of the person making the 
correction, the date the correction was made, and the reason for the change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor (or 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 ID log of all participating 
subjects, medical records, temporary media such as thermal-sensitive paper, source worksheets, all 
original signed and dated ICFs/assents, subject authorization forms regarding the use of personal 
health information (if separate from the ICFs), electronic copies of eCRFs including the audit trail, 
and detailed records of drug disposition to enable evaluations or audits from regulatory authorities 
and the sponsor (or designees). Any source documentation printed on degradable thermal-sensitive 
paper should be photocopied by the site and filed with the original in the subject’s chart to ensure 
long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain essential 
r Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Study No. Vedolizumab-3035
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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 for record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
The primary analysis for efficacy and safety data will be performed at the end of treatment (EOT), 
when all subjects have completed Day +180, withdrawn from the study, or ET, or when the 
planned number of primary endpoint events as determined by the sample size adaptation rule in the 
interim analysis are accrued. 
To protect the integrity of the study and ensure the unbiased study conduct from EOT to EOS, a 
selected group of Takeda personnel will be identified to conduct the unblinded primary analysis. 
Study investigators, participating subjects, and sponsor personnel responsible for conduct of the 
remainder of the study will remain blinded. Details of unblinding for primary analysis will be 
provided in the SAP and/or data access management plan (DAMP). The EOS analysis will be 
performed after the final database lock at EOS.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods. Data may also be summarized descriptively by age group (aged 
≥18 years and ≥12 years to <18 years). 
13.1.1 Analysis Sets
The populations used for analysis will include the following:

Full analysis set (FAS): Following the intent-to-treat principle, the FAS will include all 
subjects who are randomized, receive at least 1 dose of the treatment, and undergo allo-HSCT. 
The analysis will be based on the treatment to which the subjects are randomized.

Per-protocol population is defined to include all randomized subjects who received any
amount of blinded study drug and have no significant protocol deviations. All decisions to 
exclude subjects from the per-protocol population dataset will be made before to the study is 
un-blinded. Analyses using the per-protocol population may be provided as a sensitivity 
analysis.

Safety analysis set will include all subjects who receive at least 1 dose of study drug. Subjects 
in this set will be analyzed according to the treatment actually received.
CCI
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Vedolizumab IV
Study No. Vedolizumab-3035
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13.1.2 Analysis of Demographics and Other Baseline Characteristics
Baseline and demographic information will be listed and summarized by treatment group and for 
the overall FAS. For continuous variables, the summary will consist of descriptive statistics 
(number of subjects, mean, SD, minimum, median, and maximum). For categorical variables, the 
summary will consist of number and percentage of subjects in each category.
Medical history and concurrent medical conditions will be summarized by system organ class and 
preferred term. Medication history and concomitant medications will be summarized by preferred 
term.
13.1.3 Efficacy Analysis
All statistical testing will be performed at a 2-sided 0.05 level of significance. To control the 
overall Type I error rate for the comparison between vedolizumab and placebo groups for the 
primary and secondary efficacy endpoints, a gatekeeping procedure will be used. Specifically, the 
statistical testing of the first secondary efficacy endpoint will only be performed if the treatment 
difference for primary efficacy endpoint is statistically significant. The next secondary efficacy 
endpoint will only be tested if the treatment difference for the first secondary efficacy endpoint is 
significant, and so on for each subsequent secondary efficacy endpoint.
The order of the statistical testing for the key secondary endpoints is:
1. Intestinal aGvHD-free and relapse-free survival by Day +180.
2. Grade C-D aGvHD-free (any organ involvement) survival by Day +180.
3. NRM by Day +180.
4. OS by Day +180.
5. Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
All time-to-event endpoints will be analyzed using log-rank tests. Cox proportional hazard 
models, stratified by randomization strata, will also be fit with hazard ratios reported. All 
dichotomous efficacy endpoints will be analyzed using Cochran-Mantel-Haenszel tests for risk 
differences, stratified by randomization strata; for dichotomous endpoints, subjects with a missing 
outcome will be included in the analysis based on nonresponder imputation, ie, treated as having 
the undesirable outcome. 
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Vedolizumab IV
Study No. Vedolizumab-3035
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13.1.6 Safety Analysis
Safety analysis will be performed using the safety analysis set. No statistical inference will be 
made for safety analyses. 
The number and percentage of subjects with treatment-emergent AEs (defined as any AEs newly 
occurring or worsening from the first dose and 18 weeks after last dose of study treatment, 
regardless of relationship to study drug), AESIs (ie, serious infections, PML, malignancies, liver 
injury, infusion reactions, injection site reactions), and SAEs that occur on or after the first dose 
date and through EOS will be summarized by MedDRA System Organ Class, High Level Term, 
and Preferred Term overall, by severity, and by relationship to study drug for each treatment 
group. Separate summaries will also be generated for treatment-related AEs overall and by 
severity. Change from baseline in clinical laboratory tests and vital signs will be summarized by
treatment group.
13.2
Interim Analysis and Criteria for ET
One interim analysis for futility and sample size re-estimation is planned for this study, which will 
occur after approximately 30of the targeted primary endpoint events (ie, approximately 44 
events) have been accrued. The analysis will be performed by an independent statistical center in a 
manner that maintains the blinding to the study team, the investigators, and the subjects. The 
interim analysis results will be presented to the DMC but will not be shared with the sponsor. 
Specific criteria for DMC recommendations will be provided in the DMC charter. The futility 
stopping is considered nonbinding.
If 148 primary endpoint events are accrued before all subjects have completed Day +180 or 
dropped out, the primary analysis for efficacy may be performed at that time.
Details of Type I error control following sample size re-estimation will be provided in the SAP.
13.3
Determination of Sample Size
Assuming the event rate for the primary endpoint is 34.1% for the placebo group and 21.8% for the 
vedolizumab group and the rate of loss-to-follow-up is 10% for both groups, a sample size of 279
subjects per group (558 subjects total) is expected to generate 148 primary endpoint events and 
hence provide 90% power at 2-sided 0.05 level of significance. Assuming the event rate for the 
first secondary endpoint is 39.5% for the placebo group and 27.1% for the vedolizumab group, this 
sample size is expected to generate 177 events for the first secondary endpoint and hence provide 
approximately 86% power at 2-sided 0.05 level of significance.
CCI
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h


Vedolizumab IV
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized) including, but not limited to, the investigator’s binder, 
study medication, subject medical records, informed consent/age-appropriate assent
documentation, documentation of subject authorization to use personal health information (if 
separate from the ICFs/age-appropriate assents), and review of eCRFs and associated source 
documents. It is important that the investigator and other study personnel are available during the 
monitoring visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of the primary study 
assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it will be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
The investigator should document all protocol deviations. 
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the US Food and Drug Administration [FDA], the UK 
Medicines and Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and 
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
t all
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n of da
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and re
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 80 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Medical Devices Agency of Japan [PMDA]). 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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Vedolizumab IV
Study No. Vedolizumab-3035
Page 81 of 122
Protocol Incorporating Amendment No. 07
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the responsibilities of the investigator that are listed in Appendix C.
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, federal, and/or local
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member of 
the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and where 
applicable, age-appropriate assent(s), and if applicable, subject recruitment materials,
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/age-appropriate assent must be obtained and submitted to 
the sponsor or designee before commencement of the study, ie, before shipment of the 
sponsor-supplied drug or study-specific screening activity. The IRB or IEC approval must refer to 
the study by its exact protocol title, number, and version date; identify versions of other documents 
(eg, ICF) reviewed; and state the approval date. If required by country or regional regulations or 
procedures, approval from the competent regulatory authority will be obtained before 
commencement of the study or implementation of a substantial amendment. The sponsor will ship 
drug/notify site once the sponsor has confirmed the adequacy of site regulatory documentation 
and, when applicable, the sponsor has received permission from the competent authority to begin
the study. Until the site receives drug/notification, no protocol activities, including screening, may 
occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the 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 
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 
designee).
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent/age-appropriate assent documents will embody the elements of informed consent 
as described in the Declaration of Helsinki and the ICH Guidelines for GCP and will be in 
accordance with all applicable laws and regulations. The ICF/age-appropriate assent, subject 
authorization form (if applicable), and subject information sheet (if applicable) describe the 
planned and permitted uses, transfers, and disclosures of the subject’s personal and personal health 
information for purposes of conducting the study. The ICF/age-appropriate assent and the subject 
information sheet (if applicable) further explain the nature of the study, its objectives, and 
potential risks and benefits, and the date informed consent is given. The ICF/age-appropriate 
assent will detail the requirements of the participant and the fact that he or she is free to withdraw 
at any time without giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
ICF/age-appropriate assent and, if applicable, the subject authorization form. The 
ICF/age-appropriate assent, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be approved by both the IRB or IEC and the sponsor before use.
The ICF/age-appropriate assent, subject authorization form (if applicable), and subject 
information sheet (if applicable) must be written in a language fully comprehensible to the 
prospective subject. It is the responsibility of the investigator to explain the detailed elements of 
the ICF/age-appropriate assent, subject authorization form (if applicable), and subject information 
sheet (if applicable) to the subject. Information should be given in both oral and written form 
whenever possible and in the manner deemed appropriate by the IRB or IEC. If the subject is not 
capable of rendering adequate written informed consent/age-appropriate assent, then the subject’s 
legally acceptable representative may provide such consent for the subject in accordance with 
applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to 
(1) inquire about details of the study and (2) decide whether to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines that he or she will participate 
in the study, then the ICF/age-appropriate assent 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 before the subject enters into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using a ballpoint pen with either blue or black ink. The investigator must also sign and date the 
ICF/age-appropriate assent and subject authorization (if applicable) at the time of consent and 
before the subject enters 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/age-appropriate assent, subject authorization form (if applicable), 
and subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent/age-appropriate assent
in the subject’s medical record. Copies of the signed ICF/age-appropriate assent, the signed 
Commercial Use Only and Subject to the Applicable Terms of Use
ent 
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subject authorization form (if applicable), and subject information sheet (if applicable) shall be 
given to the subject.
All revised ICFs/age-appropriate assents 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/age-appropriate assent was obtained should be recorded in 
the subject’s medical record, and the subject should receive a copy of the revised 
ICF/age-appropriate assent.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will be linked to the 
sponsor’s clinical study database or documentation only 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 monitor or designee’s monitor, representatives from any
regulatory authority (eg, US FDA, UK MHRA, Japan PMDA), the sponsor’s designated auditors, 
and the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents) including, but not limited to, laboratory test result reports, ECG reports, admission and 
discharge summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific authorization 
of the subject as part of the informed consent/assent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, 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 
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 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 
a: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
or the
ms o
or the
formed 
Term
formed 
ecorded
Te
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ct’s righ
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Property of Taked
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ty
an


Vedolizumab IV
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Protocol Incorporating Amendment No. 07
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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
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 on or before start of study, as defined by Takeda policy/standards. Takeda contact 
information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods preferred by callers requesting trial information. Once subjects 
receive investigator contact information, they may call the site requesting enrollment into the trial. 
The investigative sites are encouraged to handle the trial inquiries according to their established 
subject screening process. If the caller asks additional questions beyond the topic of trial 
enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov, clinicaltrialsregister.eu for 
studies conducted in the EU, and other publicly accessible websites (including the Takeda 
corporate site) and registries, as required by Takeda policy/standards, applicable laws, and/or 
regulations.
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving subject care. Qualified independent researchers will be permitted 
to use data collected from subjects during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the subject’s disease. The data provided to external 
researchers will not include information that identifies subjects personally.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the clinical study site agreement regarding the sponsor’s policy on subject compensation 
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
to com
Te
to comp
mp
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nt
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ble 
erven
blicly a
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15
er
15


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and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Vedolizumab IV
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16.0
REFERENCES
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Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and 
therapy. Nat Rev Immunol 2012;12(6):443-58.
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Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324(10):667-74.
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Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell 
transplantation. Annu Rev Immunol 2007;25:139-70.
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Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced 
mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 
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McDonald GB, Tabellini L, Storer BE, Lawler RL, Martin PJ, Hansen JA. Plasma 
biomarkers of acute GVHD and nonrelapse mortality: predictive value of measurements 
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Murray S. Engraftment. In: Maziarz RT, Slater SS, editors. Blood and Marrow Transplant 
Handbook. 2nd ed: Springer; 2015; Chapter 14, p. 161-66.
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Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. 
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Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for 
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Martin CR, Blanco PG, Keach JC, Petz JL, Zaman MM, Bhaskar KR, et al. The safety and 
efficacy of oral docosahexaenoic acid supplementation for the treatment of primary
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Pasquini MC. Impact of graft-versus-host disease on survival. Best Pract Res Clin Haematol 
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Eapen M, Horowitz MM, Klein JP, Champlin RE, Loberiza FR, Jr., Ringden O, et al. Higher 
mortality after allogeneic peripheral-blood transplantation compared with bone marrow in 
children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working 
Committee of the International Bone Marrow Transplant Registry. J Clin Oncol
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Davies SM, Wang D, Wang T, Arora M, Ringden O, Anasetti C, et al. Recent decrease in 
acute graft-versus-host disease in children with leukemia receiving unrelated donor bone 
marrow transplants. Biol Blood Marrow Transplant 2009;15(3):360-6.
l Use Only and Subject to the Applicable Terms of Use
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Study No. Vedolizumab-3035
Page 87 of 122
Protocol Incorporating Amendment No. 07
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18 September 2019
14.
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16.
Arora M, Cutler CS, Jagasia MH, Pidala J, Chai X, Martin PJ, et al. Late Acute and Chronic 
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17.
Holtan SG, DeFor TE, Lazaryan A, Bejanyan N, Arora M, Brunstein CG, et al. Composite 
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Dutt S, Ermann J, Tseng D, Liu YP, George TI, Fathman CG, et al. L-selectin and beta7 
integrin on donor CD4 T cells are required for the early migration to host mesenteric lymph 
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Khoury HJ, Wang T, Hemmer MT, Couriel D, Alousi A, Cutler C, et al. Improved survival 
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Castilla-Llorente C, Martin PJ, McDonald GB, Storer BE, Appelbaum FR, Deeg HJ, et al. 
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Labbe AC, Su SH, Laverdiere M, Pepin J, Patino C, Cohen S, et al. High incidence of 
invasive aspergillosis associated with intestinal graft-versus-host disease following 
nonmyeloablative transplantation. Biol Blood Marrow Transplant 2007;13(10):1192-200.
Commercial Use Only and Subject to the Applicable Terms of Use
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Study No. Vedolizumab-3035
Page 88 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
27.
Servais S, Beguin Y, Delens L, Ehx G, Fransolet G, Hannon M, et al. Novel approaches for 
preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell 
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regional immunity. Adv Immunol 1999;72:209-53.
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Immunol Rev 2005;206:100-13.
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Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, et al. Human 
mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and 
associated lymphoid tissue. Am J Pathol 1997;151(1):97-110.
31.
Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. Expression
and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. 
Immuno 1994;153(2):517-28.
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Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and 
selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in 
development for inflammatory bowel diseases. J Pharmacol Exp Ther 2009;330(3):864-75.
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Murai M, Yoneyama H, Ezaki T, Suematsu M, Terashima Y, Harada A, et al. Peyer's patch is 
the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat 
Immunol 2003;4(2):154-60.
34.
Ueha S, Murai M, Yoneyama H, Kitabatake M, Imai T, Shimaoka T, et al. Intervention of 
MAdCAM-1 or fractalkine alleviates graft-versus-host reaction associated intestinal injury
while preserving graft-versus-tumor effects. J Leukoc Biol 2007;81(1):176-85.
35.
Waldman E, Lu SX, Hubbard VM, Kochman AA, Eng JM, Terwey TH, et al. Absence of 
beta7 integrin results in less graft-versus-host disease because of decreased homing of 
alloreactive T cells to intestine. Blood 2006;107(4):1703-11.
36.
Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute 
graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow 
transplantation. Blood 2000;95(9):2754-9.
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Koboziev I, Karlsson F, Grisham MB. Gut-associated lymphoid tissue, T cell trafficking, 
and chronic intestinal inflammation. Ann N Y Acad Sci 2010;1207 Suppl 1:E86-93.
38.
Ferrara JL. Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. 
J Hematother Stem Cell Res 2000;9(3):299-306.
39.
Saber W, Opie S, Rizzo JD, Zhang MJ, Horowitz MM, Schriber J. Outcomes after matched 
unrelated donor versus identical sibling hematopoietic cell transplantation in adults with
acute myelogenous leukemia. Blood 2012;119(17):3908-16.
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Goussetis E, Paisiou A, Kitra V, Peristeri I, Vessalas G, Stefanaki K, et al. Acute 
gastrointestinal graft-versus-host disease in pediatric patients: serum albumin on day 5 from 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
g and 
Term
g and 
nd comm
able
nd comm
J, et al.
App
J, et al.
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acute an
Use O
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H, Ki
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ersus
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Study No. Vedolizumab-3035
Page 89 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
initiation of therapy correlates with nonrelapse mortality and overall survival. Biol Blood 
Marrow Transplant 2011;17(7):1058-66.
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Ruutu T, van Biezen A, Hertenstein B, Henseler A, Garderet L, Passweg J, et al. Prophylaxis 
and treatment of GVHD after allogeneic haematopoietic SCT: a survey of centre strategies 
by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 
2012;47(11):1459-64.
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Choi SW, Braun T, Chang L, Ferrara JL, Pawarode A, Magenau JM, et al. Vorinostat plus 
tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor 
reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 
1/2 trial. Lancet Oncol 2014;15(1):87-95.
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Reshef R. Prevention of graft-versus-host disease. Clin Adv Hematol Oncol 
2012;10(10):663-5.
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measurement in bone marrow transplantation: development of the Functional Assessment of 
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1997;19(4):357-68.
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of the EuroQol questionnaire in patients with inflammatory bowel disease. Eur J 
Gastroenterol Hepatol 2002;14(11):1205-15.
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factors for progressive multifocal leukoencephalopathy among patients with selected 
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response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical 
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49.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 
Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 
1995;15(6):825-8.
50.
Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ, et al. 
IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison 
with Glucksberg grade. Br J Haematol 1997;97(4):855-64.
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Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, et al. International, 
Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A 
Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow 
Transplant 2016;22(1):4-10.
ercial Use Only and Subject to the Applicable Terms of Use
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Study No. Vedolizumab-3035
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Protocol Incorporating Amendment No. 07
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18 September 2019
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Vedolizumab IV
Study No. Vedolizumab-3035
Page 91 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Appendix A
Schedule of Events
Study Period: Screening
Treatment
Posttreatment
Days
(3 d)
(7 d)
(7 d)
Screening a Day
1
Day
0
6
13
20
27
34
41
69
97
125
153
Day
180 b
ET/
UnsV c
Day
280/
FSV b, d
12 mo/
final
FU e
Informed consent/assent f
X
X
Inclusion/exclusion criteria
X
X
Demographics/medical history
X
Complete PE g
X
Height
X
X
Targeted PE g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG (triplicate) i
X
Performance status j
X
X
X
X
X
X
X
X
X
X
X
X
X
GvHD assessment k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PML checklist l
X
X
X
X
X
X
X
X
PML wallet card
X
HRQOL m
X
X
X
X
X
Healthcare resource utilization
Recorded from first dose of study drug through 12 months after allo-HSCT
LTFU safety survey
All subjects, including those who withdraw from the study, will be required to complete a LTFU safety survey by phone 6 months after 
the last dose of study drug.
Monitoring of concomitant 
medications and procedures
Recorded from first dose of study drug through 12 months after allo-HSCT
AE reporting
AEs will be recorded from the first dose of study drug through 18 weeks after the last dose of study drug
SAEs will be recorded and reported from the signing of the ICF through the end of study
Only and Subject to the Applicable Terms of Use
9

ct

ct t
Property of Takeda: For Non-Commercial Use O
97
t t
97
X
e
X
X
e O
X
X
X
Use
X
X
X
r
X
X
mer
X
X
m
X
All subje
For 
All subje


Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Vedolizumab IV
Study No. Vedolizumab-3035
Page 94 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Appendix B
Recommended Prophylaxis Treatment: A Combination of CNI (TAC or CYS) 
+ MTX and ATG
The background aGvHD prophylaxis regimen described herein is recommended. Dose and 
regimen modification are allowed based on toxicity per investigator discretion, per institutional 
practice, and/or per local prescribing information. 
CNI:
1. TAC
a.
TAC treatment should start during conditioning, before infusion of the graft.
b. The goal TAC treatment should be to achieve a trough concentration of 5 to 20 ng/mL.
c.
Recommended to keep at therapeutic levels through Day +100 or per institutional 
standard.
d. Taper off after Day +100 if no signs of GvHD are observed.
e.
The goal should be to discontinue TAC treatment by Day +180 after allo-HSCT.
f.
Doses may be modified or held based on toxicity and institutional practice.
2. CYS
a.
CYS should start during conditioning, before infusion of the graft.
b. The goal CYS treatment should be to achieve 150 to 450 ng/mL 
c.
Recommended to keep at therapeutic levels through Day +100 or per institutional 
standard. 
d. Taper off after Day +100 if no signs of GvHD are observed
e.
The goal should be to discontinue CYS treatment by Day +180 after allo-HSCT.
f.
Doses may be modified or held based on toxicity and institutional practice. 
MTX a
a.
Administer after allo-HSCT at 10 to 15 mg/m2 IV on Day +1, and 10 mg/m2 IV on Days +3
and +6 to all subjects, with a recommended fourth dose for subjects aged ≥18 years on Day 
+11.
b. Doses may be modified or held based on toxicity and institutional practice.
c.
Leucovorin rescue may be administered per institutional practice.
ATG
1. ATG-F
a.
Administer up to 10 mg/kg/day (up to a cumulative dose of 30 mg/kg in divided doses) 
and per institutional practice. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
S)
o
S)
onal
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onal
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on of th
e Ap
n of th
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Day
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Day +10
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+10
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b.


Vedolizumab IV
Study No. Vedolizumab-3035
Page 95 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
b. NOT to be administered on the same day as study drug (eg, Day -1).
2. Thymoglobulin
a.
Administer up to 2.5 mg/kg/day (up to a cumulative dose of 7.5 mg/kg in divided 
doses) and per institutional practice.
b. NOT to be administered on the same day as study drug (eg, Day -1).
a MMF may be substituted for MTX at investigator’s discretion. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ed 
rm
ed 


Vedolizumab IV
Study No. Vedolizumab-3035
Page 96 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Appendix C
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 investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated.
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments, are NOT performed on potential subjects before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
9. Obtain valid informed consent/age-appropriate assent 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.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
al Use Only and Subject to the Applicable Terms of Use
ble
s
ble
rty to pe
Appl
rty to pe
ensure 
e Ap
ensure 
es and f
the
es and f
d duti
to t
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ecific (n
ubje
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ia
S
ial subj
Sub
l subj
s.
nd
s.
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ting in 
ly a
ing in 
any chan
se O
any chan
a: For Non-Commerci
ts.
U
ts.
respons
cial
respons
ort to th
merc
ort to th
s. Make
mme
s. Make
nal repo
Com
nal repo
ments fo
n-C
ments fo
inform
For 
inform
and do
a: Fo
and do
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da:
t is the 
ect auth
aked
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Tak
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Property of T
study
of T
study
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y o
a s


Vedolizumab IV
Study No. Vedolizumab-3035
Page 97 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ent
ms
entia
ms
ial
s o
l
l
-
e
-suppli
le T
suppli
notify t
plica
notify t


Vedolizumab IV
Study No. Vedolizumab-3035
Page 98 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
UK, 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.
The 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 the 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.
The 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 the investigator’s 
own country.
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.
al Use Only and Subject to the Applicable Terms of Use
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Term
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 99 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Appendix E
Performance Status Assessments
ECOG Scale for Performance Status for Adult Subjects (aged ≥18 years)
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
Source: Oken MM, 1982 [48].
to the Applicable Terms of Use
riction.
e T
riction.
ory and a
able
ory and a
e to carry
ppli
e to carry
o bed or c
he A
o bed or c
Property of Takeda: For Non-Commercial Use Only and Subject to
lf
t
lf-
t
-f-f-f care. T
t to 
care. T


Vedolizumab IV
Study No. Vedolizumab-3035
Page 100 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Karnovsky/Lansky Performance Status for Adolescent Subjects (aged 12 to <18 years)
Karnovsky Scale (recipient age ≥16 years)
Lansky Scale (recipient age 12 to <16 years)
Score Description
Score Description
Able to carry on normal activity; no special care 
is needed
Able to carry on normal activity; no special care 
is needed
100
Normal, no complaints, no evidence of disease
100
Fully active
90
Able to carry on normal activity
90
Minor restriction in physically strenuous play
80
Normal activity with effort
80
Restricted in strenuous play, tires more easily, 
otherwise active
Unable to work, able to live at home, cares for 
most personal needs, a varying amount of 
assistance is needed
Mild to moderate restriction
70
Cares for self, unable to carry on normal activity 
or to do active work
70
Both greater restrictions of, and less time spent in 
active play
60
Requires occasional assistance but is able to care 
for most needs
60
Ambulatory up to 50% of time, limited active play 
with assistance/supervision
50
Requires considerable assistance and frequent 
medical care
50
Considerable assistance required for any active 
play, fully able to engage in quiet play
Unable to care for self, requires equivalent of 
institutional or hospital care, disease may be 
progressing rapidly
Moderate to severe restriction
40
Disabled, requires special care and assistance
40
Able to initiate quiet activities
30
Severely disabled, hospitalization indicated, 
although death not imminent
30
Needs considerable assistance for quiet activity
20
Very sick, hospitalization necessary
20
Limited to very passive activity initiated by others 
(eg, TV)
10
Moribund, fatal process progressing rapidly
10
Completely disabled, not even passive play
0
Dead
Source: CIBMTR.org (www.cibmtr.org/manuals/fim/1/en/topic/appendix-L-karnofsky-lansky-performance-status); 
accessed 12July2019.
Abbreviation: CIBMTR, Center for International Blood & Marrow Transplant Research.
mmercial Use Only and Subject to the Applicable Terms of Use
special ca
Ter
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CIBMT


Vedolizumab IV
Study No. Vedolizumab-3035
Page 101 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Appendix F
Clinical Stages and Grades of GvHD
Table F-1: aGvHD Clinical Stage
Stage
Skin
Liver
Intestinal Tract a
Bilirubin: SI units
(standard units)
Diarrhea/day
Subjects ≥18 yrs or
<18 yrs and ≥50 kg
Subjects 
<18 yrs and <50 kg
1
Maculopapular rash <25% 
of body surface b
34-50 µmol/L
(2-3 mg/dL)
>500 mL diarrhea/day
10-19.9 mL/kg/d
2
Maculopapular rash 
25%-50% of body surface
51-102 µmol/L
(3.1-6 mg/dL)
>1000 mL diarrhea/day
20-30 mL/kg/d
3
Rash >50% of body surface
103-255 µmol/L
(6.1-15 mg/dL)
>1500 mL diarrhea/day
>30 mL/kg/d
4
Generalized erythroderma 
with bullous formation
>255 µmol/L
(>15 mg/dL)
Severe abdominal pain, 
with or without ileus
Severe abdominal pain, 
with or without ileus
Source: Przepiorka et al., 1995 [49].
Abbreviations: aGvHD, acute graft-versus-host disease; GvHD, graft-versus-host disease; SI, International System of 
Units.
a Staging of intestinal tract should be assessed based on subject’s age and weight at the time of assessment.
b Use the “Rule of Nines” or burn chart to determine the extent of the rash.
Table F-2: Criteria for IBMTR Severity Index for aGvHD
Skin
Liver
Intestinal Tract
Index
Stage (max)
Stage (max)
Stage (max)
A
1
0
0
B
2
or
1-2
or
1-2
C
3
or
3
or
3
D
4
or
4
or
4
Source: Adapted from Rowlings et al., 1997 [50].
Abbreviations: aGvHD, acute graft-versus-host disease; IBMTR, International Bone Marrow Transplant Registry 
Database.
Table F-3: aGvHD Grade (modified Glucksberg)
Grade
Skin
Liver
Intestinal Tract
I
Stage 1-2
None
None
II
Stage 3 or 
Stage 1 or 
Stage 1
III
-
Stage 2-3 or 
Stage 2-4
IV
Stage 4 or 
Stage 4
-
Source: Przepiorka et al., 1995 [49].
Abbreviations: aGvHD, acute graft-versus-host disease.
e Only and Subject to the Applicable Terms of Use
Subjec
able
Subjec
18
lic
18 y
ica
yrs
ca
rs a
10
pp
10
a/day
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a/day
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Sub
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ly a
vHD, graf
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ne the ex
Use 
ne the ex
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rcia
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3
4
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3: 
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Grade
y o
Grade
I
y
I


Vedolizumab IV
Study No. Vedolizumab-3035
Page 102 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Table F-4: Criteria for MAGIC Severity Index for aGvHD
Skin
Liver
Upper GI
Intestinal Tract a
Stage
(active erythema only)
(bilirubin)
(stool output/day)
Subjects ≥18 yrs or
<18 yrs and ≥50 kg
Subjects 
<18 yrs and <50 kg
0
No active (erythematous) 
GVHD rash
2 mg/dL
No or intermittent 
nausea, vomiting or 
anorexia
500 mL/day or 
3 episodes/day
<10 mL/kg/d or
<4 episodes/day
1
Maculopapular rash 
<25% of body surface (a)
2-3 mg/dL
Persistent nausea, 
vomiting or 
anorexia
500-999 mL/day or
3-4 episodes/day
10-19.9 mL/kg/d or
4-6 episodes/day
2
Maculopapular rash 
25%-50% of body 
surface
3.1-6 mg/dL
-
1000-1500 mL/day or 
5-7 episodes/day
20-30 mL/kg/d or
7-10 episodes/day
3
Maculopapular rash 
>50% of body surface
6.1-15 mg/dL
-
1500 mL/day or 
7 episodes/day
>30 mL/kg/d or
>10 episodes/day
4
Generalized 
erythroderma (>50% 
BSA) plus bullous 
formation and 
desquamation
>5% body surface
15 mg/dL
-
Severe abdominal 
pain with or without 
ileus, or
grossly bloody stool 
(regardless of stool 
volume)
Severe abdominal 
pain with or without 
ileus, or
grossly bloody stool 
(regardless of stool 
volume)
Source: Harris et al, 2016 [51].
Abbreviations: aGvHD, acute graft-versus-host disease; BSA, body surface area; GI, gastrointestinal; 
GVHD, graft-versus-host disease; MAGIC, Mount Sinai Acute GVHD International Consortium.
Overall clinical grade (based upon most severe target organ involvement):

Grade 0: No stage 1-4 of any organ

Grade I: Stage 1-2 skin without liver, upper GI or lower GI involvement

Grade II: Stage 3 rash and/or Stage 1 liver and/or Stage 1 upper GI and/or Stage 1 lower GI

Grade III: Stage 2-3 liver and/or Stage 2-3 lower GI, with Stage 0-3 skin and/or Stage 0-1 upper GI

Grade IV: Stage 4 skin, liver or lower GI involvement, with Stage 0-1 upper GI.
a Staging of intestinal tract should be assessed based on subject’s age and weight at the time of assessment.
ial Use Only and Subject to the Applicable Terms of Use
ects 
Ter
ects 
and
Te
and <50
Te
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ble
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Property of Takeda: For N
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No
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For N
al tract sh


Vedolizumab IV
Study No. Vedolizumab-3035
Page 103 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Appendix G
Amendment 07 Detailed Summary of Changes
The primary sections of the protocol affected by the changes in Amendment 07 are indicated. The 
corresponding text has been revised throughout the protocol.
Change 1: Clarification of the description of the disease to be treated in adolescent subjects.
The primary change occurs in Section 4.1.1 Disease to be Treated:
Added text: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important and 
potentially curative therapy for many hematologic malignancies, but its use is limited 
by the major complication of graft-versus-host disease (GvHD) [1,2]. GvHD is a 
common complication of allo-HSCT and a major cause of morbidity and mortality. 
Acute GvHD results from the activation of alloreactive donor lymphocytes by 
histocompatibility antigens on host antigen-presenting cells (APCs) [3,4]. The 
risk of GvHD and its severity depends on several factors including recipient age, cell 
source, donor characteristics, degree of histocompatibility between the donor and 
recipient, the conditioning regimen used, and the GvHD prophylaxis strategy used 
[1,5-7]. Despite GvHD prophylaxis, approximately 40% to 70% of all allo-HSCT 
recipients (inclusive of pediatric and adult subjects) develop Grade 2 to 4 acute 
GvHD (aGvHD) [5,6,8-11]. Approximately 45% to 56% of pediatric allo-HSCT 
(ranging from <1 to 20 years of age) from unrelated donors will develop Grade 2 
to 4 aGvHD, and nonrelapse mortality (NRM) appears to be greater in those 
pediatric patients with intestinal involvement [12-14]. Classical aGvHD occurs 
around the time of engraftment (~10-21 days following HSCT infusion) up to Day
100 [15] and late aGvHD occurs greater than 100 days from allo-HSCT [16,17].
Rationale for Change: Clarified the presentation of aGvHD that occurs commonly in both adult 
and adolescent subjects. 
Section 6.2.1 Study Design also contains this change. 
ubject to the Applicable Terms of Use
The 
s o
The
bjects.
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is an im
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Property of Takeda: For N
Design
No
Design


Vedolizumab IV
Study No. Vedolizumab-3035
Page 104 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 2: Addition of results from nonclinical studies related to inclusion of adolescent subjects.
The primary change occurs in Section 4.1.2.1 Nonclinical:
Initial
wording:
Several published key nonclinical studies support the use of vedolizumab for the 
prevention of GvHD. Nonclinical pharmacology studies in murine models of aGvHD 
suggest that the prevention of T cell trafficking to GALT, via interruption of the 
α4β7/MAdCAM-1 interaction, may prevent GvHD [30-32]. In a mouse model of 
GvHD, when using donor cells sorted and purified based on the presence or absence of 
α4β7, the absence of α4β7+ cells greatly delayed and reduced the presence of GvHD 
[16]. Like these results, α4β7 expression on donor T cells has been shown to be 
important in the induction of GvHD [17]. By blocking the infiltration of cells into the 
intestines, vedolizumab may act to reduce the severity and intensity of intestinal 
GvHD. Extensive nonclinical evaluations of the cardiovascular, acute, local, 
subchronic, chronic, immunologic, and reproductive toxicity of vedolizumab in 
pharmacologically responsive species (New Zealand white rabbits and cynomolgus 
monkeys) have been conducted and support its clinical development. Nonclinical 
studies also show that vedolizumab does not antagonize 4β1 integrin [13]. 
Amended 
or new 
wording:
Several published key nonclinical studies support the use of vedolizumab for the 
prevention of GvHD. Nonclinical pharmacology studies in murine models of aGvHD 
suggest that the prevention of T cell trafficking to GALT, via interruption of the 
α4β7/MAdCAM-1 interaction, may prevent GvHD [30 32][33-35]. In a mouse model 
of GvHD, when using donor cells sorted and purified based on the presence or absence 
of α4β7, the absence of α4β7+ cells greatly delayed and reduced the presence of 
GvHD [16][19]. Like these results, α4β7 expression on donor T cells has been shown 
to be important in the induction of GvHD [17][20]. By blocking the infiltration of cells 
into the intestines, vedolizumab may act to reduce the severity and intensity of 
intestinal GvHD. Extensive nonclinical evaluations of the cardiovascular, acute, local, 
subchronic, chronic, immunologic, and reproductive toxicity of vedolizumab in 
pharmacologically responsive species (New Zealand white rabbits and cynomolgus 
monkeys) have been conducted and support its clinical development. Vedolizumab 
bound with similar affinity to rabbit, monkey, and human α4β7 integrin. 
Results from a 13-week toxicity study in juvenile cynomolgus monkeys identified 
100 mg/kg (human equivalent dose 1920 mg in a 60-kg human) as the 
no-observed-adverse-effect level (NOAEL). Inclusion of sexually immature 
monkeys in the 3- and 6 month toxicity studies support administration of 
vedolizumab in clinical studies with adolescent subjects (aged 12 years and 
greater).
Nonclinical studies also show that vedolizumab does not antagonize 4β1 integrin
[13][3].
mmercial Use Only and Subject to the Applicable Terms of Use
the 
erm
the 
of aGvH
Te
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on of th
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Property of Takeda
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 105 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Rationale for Change: Addition of results from nonclinical studies related to inclusion of 
adolescent subjects.
Change 3: Updated human experience as reported in the 9th development safety update report.
The primary change occurs in Section 4.1.2.2 Human Experience:
Initial
wording:
As of 19 Nov 2017, approximately 5224 subjects (healthy or patients with UC or CD, 
aGvHD, pouchitis, or melanoma) have received at least 1 dose of vedolizumab across 
all studies in the clinical development program. As reported in the development safety 
update report (dated 19 May 2017), cumulative patient exposure to vedolizumab, in 
more than 5100 patients and including approximately 3 years of marketing
experience, was estimated at 114,071 patient-years. 
Vedolizumab has shown an acceptable and consistent safety profile in clinical studies 
and in postmarketing experience. Adverse reactions that have been reported following 
vedolizumab administration include: nasopharyngitis, bronchitis, upper respiratory
tract infection, influenza, sinusitis, headache, oropharyngeal pain, cough, nausea, 
rash, pruritus, arthralgia, back pain, pain in extremities, and pyrexia. Risks associated 
with vedolizumab treatment have been identified and categorized. Important 
identified risks are infusion-related reactions (IRRs) and hypersensitivity reactions, 
and upper respiratory infections, including bronchitis, influenza, nasopharyngitis, and 
sinusitis. Important potential risks are GI infections and systemic infections against 
which the gut constitutes a defensive barrier; serious infections, including 
opportunistic infections such as progressive multifocal leukoencephalopathy (PML); 
malignancy; and liver injury. 
Most serious adverse events (SAEs) were related to exacerbations or complications of 
the underlying UC or CD. Similar safety profiles for vedolizumab have been observed 
in subjects who received vedolizumab IV Q4W or Q8W and in subjects following 
long-term Q4W treatment for up to 8 years. 
In the phase 1b Study Vedolizumab-1015, conducted in 24 subjects who underwent 
allo-HSCT, vedolizumab (at 75 or 300 mg on Days -1, +13, and +42) was added to 
standard GvHD prophylaxis (TAC and MTX) therapy. All subjects engrafted and no 
new safety signals were reported.
Overall, vedolizumab has been well tolerated. Further detail on the safety profile of 
vedolizumab can be found in the current edition of the investigator’s brochure (IB).
mmercial Use Only and Subject to the Applicable Terms of Use
e report
Ter
e report
ents with
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ents with
of vedo
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in the d
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the
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3
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In the 
da: 
In the 
allo
ed
allo


Vedolizumab IV
Study No. Vedolizumab-3035
Page 106 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Amended 
or new 
wording:
As of 19 Nov May 20179, approximately 5224 6376 subjects (healthy or patients with 
UC or CD, aGvHD, pouchitis, or melanoma, or undergoing allo-HSCT) have 
received at least 1 dose of vedolizumab across all studies in the clinical development 
program. As reported in the 9th development safety update report (datedDSUR, for 
the period 20 May 2018 to 19 May 20172019), global cumulative postmarketing 
patient exposure to vedolizumab, in more than 5100 patients and including IV is 
estimated to be approximately 3 years of marketing experience, was estimated at 
114,071336,400 patient-years. 
Vedolizumab has shown an acceptable and consistent safety profile in clinical studies 
and in postmarketing experience. Adverse reactions that have been reported following 
vedolizumab administration include: nasopharyngitis, bronchitis, upper respiratory
tract infection, influenza, sinusitis, headache, oropharyngeal pain, cough, nausea, 
rash, pruritus, arthralgia, back pain, pain in extremities, and pyrexia, fatigue, and 
injection site reactions. Risks associated with vedolizumab treatment have been 
identified and categorized. Important identified risks are hypersensitivity reactions,
including infusion-related reactions (IRRs) and hypersensitivity reactions, and upper 
respiratory infections, including bronchitis, influenza, nasopharyngitis, and sinusitis, 
bronchitis, and influenza. Most IRRs are mild/moderate in intensity and resolve 
with minimal or no intervention. Important potential risks are GIinfections, 
including gastrointestinal infections and systemic infections against which the gut 
constitutes a defensive barrier; serious infections, including opportunistic infections 
such as progressive multifocal leukoencephalopathy (PML); malignancy; and liver 
injury. Reported serious infections include tuberculosis, sepsis, Salmonella sepsis, 
Listeria meningitis, and cytomegaloviral colitis. 
Most serious adverse events (SAEs) were related to exacerbations or complications of 
the underlying UC or CD. Similar safety profiles for vedolizumab have been observed 
in subjects who received vedolizumab IV Q4W or Q8W and in subjects following 
long-term Q4W treatment for up to 8 years, and in subjects administered 
vedolizumab subcutaneously (SC). With the exception of injection site reactions, 
the safety profile for vedolizumab SC is consistent with that for vedolizumab IV. 
In the phase 1b Study Vedolizumab-1015, conducted in 24 subjects who underwent 
allo-HSCT, vedolizumab (at 75 or 300 mg on Days -1, +13, and +42) was added to 
standard GvHD prophylaxis (TAC and MTX) therapy. All subjects engrafted and no 
new safety signals were reported. In clinical studies, no safety concerns were 
identified in subjects with aGvHD or undergoing allo-HSCT, and the events 
reported were consistent with known risks in these patient populations.
In addition, no new safety information that alters the benefit:risk balance of 
vedolizumab was identified in the IBD clinical development program, including 
ongoing studies in pediatric subjects with UC or CD (DSUR, for the period 
20 May 2018 to 19 May 2019).
Use Only and Subject to the Applicable Terms of Use
ment
ms o
ment
R, for
erms
R, for
arketing
Ter
arketing
ng
ble
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App
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ve been 
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Sub
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s) and 
nd S
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 107 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Overall, vedolizumab has been well tolerated in clinical studies. Further detail on the 
safety profile of vedolizumab can be found in the current edition of the investigator’s 
brochure (IB). 
Rationale for Change: Updated human experience as reported in the 9th DSUR.
Section 4.1.2 Vedolizumab IV also contains this change. 
Change 4: Update to the study rationale to support the inclusion of adolescent subjects.
The primary change occurs in Section 4.2 Rationale for the Proposed Study:
Added text:The migration of naive donor T cells to the GALT where they are activated and 
migration of activated donor T cells to the target tissues, especially the intestinal 
mucosa, are essential steps in aGvHD in both children and adults [52]. Intestinal 
aGvHD in children and adults is often involved in Grade 3 to 4 aGvHD and is a 
major cause of morbidity and mortality after allo-HSCT. Systemic 
immunosuppression for aGvHD prophylaxis increases the risk for infections and can 
affect the graft-versus-tumor effect. Therefore, using standard nonspecific systemic 
immunosuppressive therapies involves a fine balance of prevention of life-threatening 
aGvHD against life-threatening infection and recurrence of underlying malignant 
disease. Therapy that targets the trafficking of cells to the GI tract and reduces GI 
inflammation without adding to systemic immunosuppression could have profound 
effects on the morbidity and mortality of intestinal GvHD.
Results from Vedolizumab-1015, is a phase 1b study (that enrolled 24 subjects 
enrolled) that aged ≥18 years, demonstrated the safety and tolerability of adding 
vedolizumab on Day -1 (before allo-HSCT) and then on Days +13 and +42 after 
allo-HSCT to a background aGvHD prophylaxis regimen (TACMTX) in subjects 
undergoing allo-HSCT.
   
Rationale for Change: Update to the study rationale to support inclusion of adolescent subjects. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 108 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 5: Update to the benefit:risk profile to support the inclusion of adolescent subjects.
The primary change occurs in Section 4.3 Benefit:Risk Profile:
Added text: The proposed phase 3 study is designed to evaluate the efficacy and safety of
vedolizumab compared to placebo when added to background aGvHD prophylaxis 
regimen as prophylaxis for intestinal aGvHD for subjects undergoing allo-HSCT. 
The mechanism of action of vedolizumab, results from nonclinical studies 
demonstrating the role of T cell trafficking in GvHD, and results of the phase 1b 
Study Vedolizumab-1015, all support further investigation of vedolizumab in this 
indication. Vedolizumab specifically targets the α4β7 integrin expressed on the 
surface of T lymphocytes, thus preventing T cells from binding to MAdCAM-1 
expressed on the endothelium, subsequently preventing T cells from homing to the 
intestinal tract. Nonclinical pharmacology studies in murine model demonstrate that 
inhibition of the α4β7/MAdCAM-1 pathway via neutralizing anti-MAdCAM-1 
antibodies attenuated the development of the graft versus host reaction [30][33] and 
the absence of α4β7+ cells on donor cells greatly delayed and reduced the presence of 
GvHD [16][19]. Furthermore, in Study Vedolizumab-1015, a low incidence of 
intestinal aGvHD was observed in adults undergoing allo-HSCT for a hematologic 
malignancy or myeloproliferative disorder who received vedolizumab 300 mg IV in 
combination with standard GvHD prophylaxis. There remains an unmet medical 
need in patients undergoing allo-HSCT who, despite routine prophylaxis,
remain at risk of developing intestinal aGvHD and its associated complications.
The available PK data, nonclinical toxicology data, and clinical data, are
supportive of the inclusion of adolescent subjects aged ≥12 years and weighing 
≥30 kg in this phase 3 study. In phase 3 studies in adults with UC or CD, body 
weights ranged from 28.7 to 170 kg. Safety data from these studies showed that 
there was no difference in the incidence of treatment-emergent adverse events 
(TEAEs) based on weight or age (18-70 years). Furthermore, a similar safety 
profile has been observed in adults with UC or CD who received vedolizumab 
IV Q8W or Q4W. No additive risk of infection was identified among subjects 
who received a concomitant immunosuppressant. Results of population PK 
analyses in subjects with IBD indicate that a weight-based dosing regimen is not 
required and that a tiered flat-dose is appropriate for different weight groups. 
Age was not a clinically meaningful covariate. PK data from Study 
Vedolizumab-1015 indicates that the PK of vedolizumab in subjects undergoing 
an allo-HSCT who received 300 mg is similar to that of subjects with UC or CD. 
In addition, no new safety information that alters the benefit:risk balance of 
vedolizumab have been identified in the UC/CD clinical development program, 
including ongoing studies in pediatric subjects (aged 2-17 years). Therefore, the 
benefit:risk profile is expected to be similar in adults and adolescent subjects 
aged ≥12 years and weighing ≥30 kg.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 109 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
....
The subject population was chosen because it represents a high-risk, vulnerable 
population for development of intestinal aGvHD, a driver for poor outcomes, 
mortality, and for whom a significant unmet medical need exists. The risks of this 
subject population include those that are associated with hematological 
transplantation. Specifically, allo-HSCT patients are at risk of infections 
(opportunistic, GI, and CNS infections); liver injury; infusion-related reactions (IRR) 
and hypersensitivity reactions, and relapse or new primary malignancy. The 
important identified risks specific for vedolizumab include IRRs and upper 
respiratory tract infections, including bronchitis, influenza, nasopharyngitis, and 
sinusitis. The important potential risks for vedolizumab are: malignancies, liver 
injury; infections (GI infections and systemic infections [serious and nonserious]); 
and other serious infections, including opportunistic infections such as PML. Several 
risk mitigation strategies are incorporated in this phase 3 study including exclusion of 
subjects with ongoing or active infections (Section 7.2), criteria for discontinuation 
and withdrawal of subjects (Section 7.4), and instructions for managing these risks 
(Section 8.7). The mitigation strategies are adequate to monitor safety of the subjects 
participating in the study. In combination with the results from the phase 1b Study
Vedolizumab-1015, and supported by the available nonclinical, clinical, and PK 
data, the benefit:risk profile supports is expected to be similar in adults and 
adolescent subjects aged 12 years and greater and weighing ≥30 kg, supporting
further investigation of vedolizumab in the subject population with significant unmet
medical need. 
Rationale for Change: Update to the benefit:risk profile to support the inclusion of adolescent 
subjects.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 110 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 6: Addition of data supporting the dose regimen in adolescent subjects.
The primary change occurs in Section 6.2.2 Dose Selection:
Added text: The 300 mg dose of vedolizumab was well tolerated in subjects in Study
Vedolizumab-1015 without delay of engraftment (median 14 days for the 
vedolizumab 300 mg cohort) or new safety concerns. Repeated vedolizumab dosing 
during the 6 months after the allo-HSCT is proposed, during which time subjects are 
at the highest risk of developing intestinal aGvHD. 
The same vedolizumab dose regimen to be administered to adults (aged 
≥18 years) planned to undergo allo-HSCT for prophylaxis of intestinal aGvHD 
is considered appropriate for administration to adolescents aged 12 years and 
greater and weighing ≥30 kg. In phase 3 studies in adults with IBD, body 
weights ranged from 28.7 to 170 kg. Safety data from these studies showed no 
difference in the incidence of TEAEs and a similar safety profile in adults 
receiving vedolizumab IV Q8W or Q4W (Section 4.3). A population PK model 
was developed using pooled phase 1, 2, and 3 study data from the vedolizumab 
IV clinical program in adults with UC or CD to characterize the PK of 
vedolizumab and to assess the impact of patient demographic characteristics 
(eg, age and body weight) on PK. This model indicated that weight-based dosing 
is not required and that age was not a clinically meaningful covariate (Section 
4.3). In addition, results from Study Vedolizumab-1015 indicated that the PK of 
vedolizumab (300 mg) in adults with aGvHD was similar to that in adults with 
UC or CD.
Rationale for Change: Addition of data to support the dose regimen in adolescent subjects. 
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 111 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 7: Update of the inclusion criteria impacted by inclusion of adolescent subjects. These 
changes are detailed as Change 7a – Change 7c.
Change 7a: Clarification to informed consent/age-appropriate assent and who provides this.
The primary change occurs in Section 7.1 Inclusion Criteria, criterion #1: 
Added text: 1. The subject or, when applicable, the subject’s legally acceptable representative 
voluntarily signs and dates a written, informed consent form (ICF) and any 
required privacy authorization before performance of any study-related 
procedures not part of standard medical care, with the understanding that consent 
may be withdrawn by the subject at any time without prejudice to future medical 
care. As applicable, a parent/both parents or legally acceptable 
representative must provide signature of informed consent and there must be 
documentation of age-appropriate assent by the subject.
Rationale for Change: Clarification to informed consent/age-appropriate assent and who 
provides this.
The following sections also contain this change:

Section 6.1.1.4 Posttreatment Follow-up.

Section 7.4 Criteria for Discontinuation or Withdrawal of a Subject.

Section 8.7.1 Hypersensitivity Reactions.

Section 9.3.1 Informed Consent.

Section 9.3.11 PML Checklist.

Section 9.4 Documentation of Screen Failure.

Section 10.2.1.2 AE Reporting.

Section 10.2.2 Collection and Reporting of SAEs.

Section 10.7 RAMP Program.

Section 12.1 eCRFs.

Section 14.1 Study-Site Monitoring Visits.

Section 15.1 IRB and/or IEC Approval

Section 15.2 Subject Information, Informed Consent, and Subject Authorization.

Appendix A Schedule of Events, footnote f.

Appendix C Responsibilities of the Investigator, item 9.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 112 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 7b: Clarification regarding eligibility of adolescent subjects.
The primary change occurs in Section 7.1 Inclusion Criteria, criterion #2: 
Added text: 2. Male or female subjects ≥18 years of age. and, in selected countries (where local 
requirements permit and based on feasibility), adolescents aged 12 years and 
greater and weighing ≥30 kg at time of randomization.
Rationale for Change: Clarification to specify the eligibility of adolescent subjects.
Section 2.0 STUDY SUMMARY also contains this change:
Change 7c: Clarification regarding use of age-appropriate performance status scales.
The primary change occurs in Section 7.1 Inclusion Criteria, criterion #7: 
Added text: 7. Eastern Cooperative Oncology Group (ECOG) performance status of 2 for 
subjects aged ≥18 years at randomization or ≥60% using the Karnofsky 
performance status for adolescent subjects aged ≥16 years at randomization 
or the Lansky performance status for adolescent subjects aged 12 to 
<16 years at randomization (Appendix E).
Rationale for Change: Clarification regarding use of age-appropriate performance status scales.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 9.3.9 Performance Status.

Section Appendix A Schedule of Events, footnote j.

Appendix E Performance Status Assessments (new table added).
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 113 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 8: Update to permitted medications to include use of topical anesthetic in adolescent 
subjects.
The primary change occurs in Section 7.3.2 Permitted Medications and Treatments:
Added text: Currently, there is no evidence to support the routine prophylactic administration of 
premedication (eg, antihistamines, corticosteroids) to subjects receiving 
vedolizumab; hence, such premedication is unlikely to be necessary or beneficial. At 
the discretion of the investigator, however, subjects may be administered 
premedication before any study drug administration. Use of topical anesthetic (eg, 
lidocaine, tetracaine, prilocaine) is recommended for blood draws or IV 
insertions for the comfort of subjects aged 12 to <18 years. This use will not be 
recorded as a concomitant medication. Corticosteroids, if given as a 
premedication, should be limited to the day of administration.
Rationale for Change: Clarification to include use of local anesthetic in adolescent subjects.
Change 9: Clarification to the procedures to be conducted after discontinuation or withdrawal of a
subject.
The primary change occurs in Section 7.5 Procedures for Discontinuation or Withdrawal of a 
Subject:
Added text: The investigator may discontinue a subject’s study participation at any time during 
the study when the subject meets the study termination criteria described in Section 
7.4. In addition, a subject may discontinue his or her participation without giving a 
reason at any time during the study. Should a subject’s participation be discontinued, 
the primary criterion for termination must be recorded by the investigator. In 
addition, efforts should be made to perform all procedures scheduled for the ET 
Vvisit, the final safety visit, and the 6-month LTFU safety survey. Discontinued 
or withdrawn subjects will not be replaced.
Rationale for Change: Clarification to the procedures to be conducted after discontinuation or 
withdrawal of a subject.
n-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 114 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 10: Added assessment of height to be collected at the end of study visit.
The primary change occurs in Section 9.3.6 Weight and Height:
Added text: Height should be recorded to the nearest tenth of a centimeter (if possible). Height 
may be measured using a wall-mounted stadiometer using replicated measurements 
(average of 3 measurements). Height will be measured only during screening (within 
30 days before the first dose of study drug on Day -1) and at EOS. 
Rationale for Change: Added assessment of height to be collected at the end of study visit. 
Appendix A Schedule of Events, footnote g also contains this change. 
Change 11: Updated the pregnancy testing and contraception requirements to include female 
adolescent subjects aged 12 years and greater. These changes are detailed as Change 11a and 
Change 11b.
Change 11a: Clarification to pregnancy testing to include female adolescent subjects aged 
12 years and greater.
The primary change occurs in Section 9.3.15.2 Pregnancy Test:
Added text: For female subjects aged 12 years and greater who are not postmenopausal 
(Section 9.3.19) or surgically sterilized, a serum pregnancy (choriogonadotropin 
beta) test will be completed at screening before the first dose of study drug, and a 
urine pregnancy test will be completed predose on each study drug dosing day (and 
in the UK, on Day 180; and in Norway, on Day +180, Day +280 [or 18 weeks after 
the last dose of study drug], and at ET; and in Argentina, monthly from Day +153 up 
to 18 weeks after the last dose of study drug). The results from these tests must be 
available and negative before the study drug is administered. Additional pregnancy
testing may be performed during the study at the discretion of the investigator, upon 
request of an IEC/IRB, or if required by local regulations.
Rationale for Change: Clarification to pregnancy testing to include female adolescent subjects 
aged 12 years and greater.
Appendix A Schedule of Events, footnote o also contains this change. 
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 115 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 11b: Clarification to the requirements for contraception and pregnancy avoidance to 
include female adolescent subjects aged 12 years and greater.
The primary change occurs in Section 9.3.19 Contraception and Pregnancy Avoidance Procedure:
Initial
wording:
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 a highly 
effective method of contraception (Section 8.6.2). In addition, they must be advised 
not to donate ova during this period.
…   
During the course of the study, urine hCG pregnancy tests will be performed (Section 
8.6.2) only for women of childbearing potential and female subjects will receive 
continued guidance with respect to the avoidance of pregnancy and ova donation as 
part of the study procedures (Appendix A). In addition to a negative serum hCG 
pregnancy test at screening, women of childbearing potential must have a negative 
urine hCG pregnancy test before receiving any dose of study drug, preferably on the 
same day.
Amended 
or new 
wording:
From signing of informed consent, throughout the duration of the study, and for 18 
weeks after last dose of study medication, female subjects aged 12 years and 
greater who are not postmenopausal (Section 9.3.19) or surgically sterilized and
of childbearing potential* who are sexually active with a nonsterilized male 
partner** must use a highly effective method of contraception (Section 8.6.2). In 
addition, they must be advised not to donate ova during this period.
...
During the course of the study, urine hCG pregnancy tests will be performed (Section 
8.6.2) only for female subjects aged 12 years and greater who are not 
postmenopausal or surgically sterilized women of childbearing potential and 
female these subjects will receive continued guidance with respect to the avoidance 
of pregnancy and ova donation as part of the study procedures (Appendix A). In 
addition to a negative serum hCG pregnancy test at screening, female subjects aged 
12 years and greater who are not postmenopausal or surgically sterilized women 
of childbearing potential must have a negative urine hCG pregnancy test before 
receiving any dose of study drug, preferably on the same day.
Rationale for Change: Clarification to the requirements for contraception and pregnancy 
avoidance to include female adolescent subjects aged 12 years and greater
Section 8.6.2 Reproductive Effects also contains this change. 
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 116 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 12: Addition of necessary age-appropriate documentation that must be completed for 
adolescent subjects.These changes are detailed as Change 12a – Change 12d.
Change 12a: Clarification regarding the informed consent/age-appropriate assent procedure for 
adolescent subjects.
The primary change occurs in Section 9.3.1 Informed Consent:
Added text: The requirements of the informed consent/age-appropriate assent are described in 
Section 15.2. 
Informed consent/age-appropriate assent must be obtained before the subject enters 
into the study, and before any protocol-directed procedures are performed.
Subjects reaching an age that is not covered by their signed assent must provide 
consent for their appropriate age group to remain in the study. Subjects who 
reach the age of consent must provide consent with a signed ICF to remain in 
the study.
Rationale for Change: Clarification regarding the informed consent/age-appropriate assent 
procedure for adolescent subjects.
Appendix A Schedule of Events footnote f also contains this change. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 117 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 12b: Clarification regarding completion of PML checklists.
The primary change occurs in Section 9.3.11 PML Checklist:
Initial
wording:
Clinic staff will administer the subjective PML checklist during screening to exclude 
subjects with positive responses from enrolling into the study. The subjective PML 
checklist will be administered (before dosing, if applicable) at the time points 
specified in the SOE (Appendix A) to probe for symptoms suggestive of PML. The 
checklist must be administered by appropriate clinic staff as it is not designed as a 
subject questionnaire. A subject who reports a new and persistent change(s) per the 
subjective checklist must have the corresponding objective test(s) and may be referred 
to a neurologist for a full evaluation, as described in the RAMP algorithm. The PML 
checklist and the RAMP algorithm and tools are included in the Study Manual. See 
Section 10.7 for additional details regarding the RAMP program.
Amended 
or new 
wording:
Clinic staff will administer the age-appropriate subjective PML checklist during 
screening to exclude subjects with positive responses from enrolling into the study. 
The subjective PML checklist will be administered (before dosing, if applicable) at the 
time points specified in the SOE (Appendix A) to probe for symptoms suggestive of 
PML. The checklist must be administered by appropriate clinic staff as it is not 
designed as a subject questionnaire. A subject who reports to be completed by a 
subject, parent, or legally acceptable representative. If a new and persistent 
change(s) is reported per the subjective checklist, must have the corresponding 
objective test(s) and must be completed, and the subject may be referred to a 
neurologist for a full evaluation, as described in the RAMP algorithm. The PML 
checklist and the RAMP algorithm and tools are included in the Study Manual. See 
Section 10.7 for additional details regarding the RAMP program.
Rationale for Change: Clarification regarding completion of PML checklists.
The following sections also contain this change:

Section 8.7.7.2 PML.

Appendix A Schedule of Events, footnote l.
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 118 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 12c: Clarification of age-appropriate use of the FACT-BMT.
The primary change occurs in Section 9.3.12.1 FACT-BMT:
Initial
wording:
The FACT-BMT instrument is a valid and reliable measure of QOL in bone marrow 
transplant subjects and combines the functional assessment of cancer therapy general 
tool with the bone marrow transplant subscale [40]. FACT-BMT is a 47-item tool that 
assesses responses on a Likert scale. This measure assesses across 5 domains: physical 
well-being, social/family well being, emotional well-being, functional well-being, and 
additional concerns.
Amended 
or new 
wording:
The FACT-BMT instrument will be used for subjects aged 18 years at the time of 
randomization and is a valid and reliable measure of HRQOL in bone marrow 
transplant subjects and that combines the functional assessment of a cancer therapy
general tool with the bone marrow transplant subscale [40][44]. FACT-BMT is a 
47-item tool that assesses responses on a Likert scale. This measure assesses across 5 
domains: physical well-being, social/family well-being, emotional well-being, 
functional well-being, and additional concerns.
Rationale for Change: Added the age-appropriate range for use of the FACT-BMT.
Appendix A Schedule of Events, footnote m also contains this change. 
Change 12d: Clarification regarding completion of the EQ-5D in adolescent subjects. 
The primary change occurs in Section 9.3.12.2 EQ-5D:
Added text:
Rationale for Change
Appendix A Schedule of Events, footnote m also contains this change.
CCI
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 119 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 13: Addition of blood collection volumes for adolescent and adult subjects.
The primary change occurs in Section 9.3.15 Clinical Laboratory Evaluations:
Added text: Clinical laboratory evaluations as specified in the SOE (Appendix A) will be 
performed by a central laboratory. Local laboratories may be used to conduct 
assessments needed more rapidly and for urgent medical management throughout the 
study per investigator’s discretion. In adolescent subjects aged 12 years and 
greater and weighing ≥30 kg, the maximum volume of blood collected at any 
single visit 
 is approximately 14 mL,
and the approximate total volume of blood for the study is 144 mL. The 
maximum volume of blood collected from adult subjects is 29 mL and 300 mL, 
respectively. Clinical laboratory evaluations to be conducted during this study are 
summarized in Table 9.a.
Rationale for Change: Added specifications regarding maximum blood collections from all
subjects as required by European regulations regarding adolescent subjects. 
Change 14: Update to the version of Common Terminology Criteria for Adverse Events to be 
used for the grading of adverse events.
The primary change occurs in Section 10.1.6 Severity of AEs:
Initial
wording:
All AEs, including clinically significant treatment-emergent laboratory abnormalities, 
will be graded according to National Cancer Institute Common Terminology Criteria 
for Adverse Events, version 4.03. Grade descriptions are: 
Amended 
or new 
wording:
All AEs, including clinically significant treatment-emergent laboratory abnormalities, 
will be graded according to National Cancer Institute Common Terminology Criteria 
for Adverse Events, version 4.035.0. Grade descriptions are:
Rationale for Change: Update to the version of CTCAE to be used for the grading of adverse 
events. 
CCI
bject to the Applicable Terms of Use
duct
Te
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h
b
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ble T
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hr
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hr
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Vedolizumab IV
Study No. Vedolizumab-3035
Page 120 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 15: Update to stratification to include age group and data assessments in adolescent 
subjects. These changes are detailed as Change 15a and Change 15b.
Change 15a: Update to include stratification by age group.
The primary change occurs in Section 6.1 Overview of Study Design:
Added text: Eligibility will be determined during the screening period, which may last for up to 
30 days before Day -1 (designation of the day of the first IV infusion of study drug). 
Subjects who meet all eligibility criteria and provide written informed consent will be 
randomized into this study within 2 days of the first dose of study drug on Day -1. 
Approximately 558 subjects will be randomized in a 1:1 fashion to 2 treatment arms 
(vedolizumab IV or placebo IV). Randomization will be stratified by age (≥18 years 
or adolescents aged 12 to <18 years), HLA match or mismatch (8/8 or 7/8), 
conditioning regimen (myeloablative or reduced intensity conditioning), and 
treatment with or without ATG (ATG-F or thymoglobulin).
Rationale for Change: Update to include stratification by age group.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Figure 6.a Study Design for Study Vedolizumab-3035.
Change 15b: Update that data assessments may be summarized descriptively by age group.
The primary change occurs in Section 13.1 Statistical and Analytical Plans:
Added text: A targeted data review will be conducted before database lock. This review will 
assess the accuracy and completeness of the study database, subject evaluability, and 
appropriateness of the planned statistical methods. Data may also be summarized 
descriptively by age group (aged ≥18 years and ≥12 years to <18 years).
Rationale for Change: Update that data assessments may be summarized descriptively by age 
group.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Vedolizumab IV
Study No. Vedolizumab-3035
Page 122 of 122
Protocol Incorporating Amendment No. 07
EudraCT Number: 2018-002141-11
18 September 2019
Change 17: Update to Appendix B regarding methotrexate treatment to support the inclusion of 
adolescent subjects.
The primary change occurs in Appendix B Recommended Prophylaxis Treatment: A Combination 
of CNI (TAC or CYS) + MTX and ATG:
Initial
wording:
MTX a
a.
Administer at 10 to 15 mg/m2 IV on Day +1, and 10 mg/m2 IV on Days +3 and 
+6, and recommended fourth dose on Day +11 after allo-HSCT. 
Amended 
or new 
wording:
MTX a
a.
Administer after allo-HSCT at 10 to 15 mg/m2 IV on Day +1, and 10 mg/m2
IV on Days +3 and +6, and to all subjects, with a recommended fourth dose 
for subjects aged ≥18 years on Day +11 after allo HSCT. 
Rationale for Change: Updates to Appendix B regarding MTX treatment to support inclusion of
adolescent subjects.
Change 18: Update to Appendix F to include age-appropriate assessments of aGvHD clinical 
stage and Mount Sinai Acute GVHD International Consortium severity index for aGvHD.
The primary change occurs in Appendix F Clinical Stages and Grades of GvHD:
Added text: Addition of age-appropriate columns for assessments in adolescent subjects to: 
Table F-1 (aGvHD Clinical Stage) and Table F-4 (Criteria for MAGIC Severity 
Index for aGvHD).
Addition of footnotes that the intestinal tract should be assessed based on the 
subject’s age and weight at the time of assessment. 
Rationale for Change: To include the age-appropriate assessments of aGvHD clinical stage and 
MAGIC severity index for aGvHD in adolescent subjects.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
natio
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the 
Efficacy and Safety of Vedolizumab in the Prophylaxis of Intestinal Acute 
Graft-Versus-Host Disease in Subjects Undergoing Allogeneic Hematopoietic Stem Cell 
Transplantation
NCT Number: NCT03657160
SAP Approve Date: 22 October 2021
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Vedolizumab-3035
Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and 
Safety of Vedolizumab in the Prophylaxis of Intestinal Acute Graft-Versus-Host Disease in 
Subjects Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Vedolizumab in the prophylaxis of intestinal acute graft vs host disease in subjects undergoing 
allogeneic hematopoietic stem cell transplantation.
PHASE 3
Version: 3.0
Date: 22 October 2021
Prepared by:
Based on:
Protocol Version: Amendment 07
Protocol Date: 18 Sep 2019
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Vedolizumab-3035
Page 2 of 46
Statistical Analysis Plan 
22 October 2021
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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Vedolizumab-3035
Page 3 of 46
Statistical Analysis Plan 
22 October 2021
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objectives ....................................................................................................8
4.2
Safety Objective ........................................................................................................8
4.3
Secondary Objectives.................................................................................................8
4.4
Additional Objectives ................................................................................................8
4.5
Study Design .............................................................................................................9
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Safety Endpoints......................................................................................................10
5.4
.............................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................12
7.1.1
Study Definitions.............................................................................................12
7.1.2
Definition of Study Days .................................................................................14
7.1.3
Definition of Study Visit Windows..................................................................14
7.1.4
Conventions for Missing Adverse Event Dates ................................................15
7.1.5
Conventions for Missing Concomitant Medication Dates.................................16
7.1.6
Methods for Handling of Missing Efficacy Data ..............................................17
7.2
Analysis Sets ...........................................................................................................17
7.3
Disposition of Subjects ............................................................................................17
7.3.1
Study Information............................................................................................17
7.3.2
Disposition of Subjects ....................................................................................18
7.4
Demographic and Other Baseline Characteristics.....................................................19
7.5
Medical History and Concurrent Medical Conditions...............................................20
7.6
Medication History and Concomitant Medications...................................................20
7.7
Study Drug Exposure and Compliance.....................................................................20
7.8
Efficacy Analysis.....................................................................................................21
7.8.1
Primary Efficacy Endpoint(s)...........................................................................22
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Vedolizumab-3035
Page 4 of 46
Statistical Analysis Plan 
22 October 2021
7.8.2
Secondary Efficacy Endpoint(s).......................................................................23
7.8.3
Additional Efficacy Endpoint(s).......................................................................23
7.8.4
Sensitivity Analysis .........................................................................................25
7.8.5
Subgroup Analysis...........................................................................................26
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................27
7.9.1
Pharmacokinetic Analysis................................................................................27
7.9.2
Pharmacodynamic Analysis.............................................................................28
7.10
Other Outcomes.......................................................................................................28
7.10.1
7.10.2
Health-Related Quality of Life.........................................................................28
7.10.3
Healthcare Resource Utilization.......................................................................29
7.11
Safety Analysis........................................................................................................29
7.11.1
Adverse Events................................................................................................29
7.11.2
Clinical Laboratory Evaluations.......................................................................31
7.11.3
Vital Signs.......................................................................................................32
7.11.4
12-Lead ECGs .................................................................................................32
7.11.5
Other Observations Related to Safety...............................................................33
7.12
Interim Analysis ......................................................................................................33
7.12.1
Analysis Endpoints..........................................................................................33
7.12.2
Assessment of Conditional Power....................................................................33
7.12.3
Interim Decision Rules ....................................................................................34
7.12.4
Multiplicity Adjustment...................................................................................35
7.12.5
Data to be Presented ........................................................................................35
7.13
Planned End of Treatment (EOT) Analysis and End of Study (EOS) Analysis .........35
7.13.1
Planned EOT Analysis.....................................................................................35
7.13.2
Planned EOS Analysis.....................................................................................36
7.14
Changes in the Statistical Analysis Plan...................................................................36
7.14.1
Revision History..............................................................................................36
8.0
REFERENCES..............................................................................................................37
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.14.1
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Vedolizumab-3035
Page 5 of 46
Statistical Analysis Plan 
22 October 2021
LIST OF IN-TEXT TABLES
Table 7.a
Date of Event/Censor for primary endpoint by Day +180 after allo-HSCT .........14
Table 7.b
Visit Windows to be used for the summary of the endpoints...............................15
Table 7.c
List of subgroups of interest...............................................................................27
Table 7.d
Clinical Hematology, Coagulation, Chemistry, and LFTs...................................32
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Vedolizumab-3035
Page 6 of 46
Statistical Analysis Plan 
22 October 2021
3.0
LIST OF ABBREVIATIONS
Acronym
Definition
AE
adverse event
AESI
adverse event of special interest
aGvHD
acute graft-versus-host disease
allo-HSCT
allogeneic hematopoietic stem cell transplantation
ALT
alanine aminotransferase
APC
antigen-presenting cell
AST
aspartate aminotransferase
ATG
antithymocyte globulin
ATG-F
antithymocyte globulin-Fresenius
CD
Crohn’s disease
CMV
cytomegalovirus
CNI
calcineurin inhibitor
CRO
contract research organization
CYS
cyclosporine
DLI
donor leukocyte infusion
DMC
Data Monitoring Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EQ-5D
EuroQol-5 Dimension
ET
early termination
FACT-BMT
Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GALT
gut-associated lymphoid tissue
GCP
Good Clinical Practice
GI
gastrointestinal
GvHD
graft-versus-host disease
HIV
human immunodeficiency virus
HRQOL
health-related quality of life
HSC
hematopoietic stem cell
HSCT
hematopoietic stem cell transplantation
IAC
Independent Adjudication Committee
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
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follicle
gut
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HIV
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Statistical Analysis Plan 
22 October 2021
Acronym
Definition
IBMTR
International Bone Marrow Transplant Registry Database
ICF
informed consent form
ICH
International Council for Harmonisation
ID
identification
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IRR
infusion-related reaction
IV
intravenous
IRT
interactive response technology system
LFT
liver function test
LTFU
long-term follow-up
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MAGIC
Mount Sinai Acute GVHD International Consortium
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MMF
mycophenolate mofetil
MTX
methotrexate
MUD
matched unrelated donor
NRM
nonrelapse mortality
OS
overall survival
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PML
progressive multifocal leukoencephalopathy
PTE
pretreatment event
Q4W
every 4 weeks
Q8W
every 8 weeks
QOL
quality of life
RAMP
Risk Minimization Action Plan for PML
SAE
serious adverse event
SAP
statistical analysis plan
SOE
schedule of events
TAC
tacrolimus
TB
tuberculosis
UC
ulcerative colitis
ULN
upper limit of normal
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Statistical Analysis Plan 
22 October 2021
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective is: 
!
To evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis 
regimen compared to placebo and background aGvHD prophylaxis regimen on intestinal 
aGvHD-free survival by Day +180 in subjects who receive allo-HSCT as treatment for a 
hematologic malignancy or myeloproliferative disorder.
4.2
Safety Objective
The safety objective is to evaluate the safety of vedolizumab when added to background aGvHD 
prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen.
4.3
Secondary Objectives
The secondary objectives are:
!
To evaluate the effect of vedolizumab compared to placebo on intestinal aGvHD-free, 
relapse-free (free of underlying malignancy) survival by Day +180.
!
To evaluate the effect of vedolizumab compared to placebo on Grade C-D aGvHD-free (any 
organ involvement) survival by Day +180.
!
To evaluate the effect of vedolizumab compared to placebo on nonrelapse mortality (NRM) 
in subjects by Day +180.
!
To evaluate the effect of vedolizumab compared to placebo on OS by Day +180. 
!
To evaluate the effect of vedolizumab compared to placebo on Grade B-D aGvHD-free (any 
organ involvement) survival by Day +180.
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Page 9 of 46
Statistical Analysis Plan 
22 October 2021
4.5
Study Design
This is a phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy and safety of vedolizumab when added to a background aGvHD prophylaxis 
regimen as prophylaxis for intestinal aGvHD in subjects undergoing allo-HSCT. The subject 
population will consist of subjects with hematologic malignancies or myeloproliferative 
disorders for whom allo-HSCT from an unrelated donor is planned using either peripheral blood 
or bone marrow as the stem cell source.
Eligibility will be determined during the screening period, which may last for up to 30 days 
before Day -1 (designation of the day of the first IV infusion of study drug). Subjects who meet 
all eligibility criteria and provide written informed consent will be randomized into this study
within 2 days of the first dose of study drug on Day -1. Approximately 558 subjects will be 
randomized in a 1:1 fashion to 2 treatment arms (vedolizumab IV or placebo IV). Randomization 
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Statistical Analysis Plan 
22 October 2021
will be stratified by age (≥18 years or adolescents aged 12 to <18 years), HLA match or 
mismatch (8/8 or 7/8), conditioning regimen (myeloablative or reduced intensity conditioning), 
and treatment with or without ATG (ATG-F or thymoglobulin). Subjects randomized to the 
vedolizumab IV arm will receive 7 doses of vedolizumab IV, beginning on Day -1 before 
allo-HSCT and then on Days +13, +41, +69, +97, +125, and +153 after allo-HSCT. Subjects 
randomized to the placebo IV arm will receive 7 doses of placebo IV, beginning on Day -1 
before allo-HSCT and then on Days +13, +41, +69, +97, +125, and +153 after allo-HSCT.
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint is intestinal aGvHD-free survival by Day +180 after allo-HSCT. Intestinal 
aGvHD is defined as Stage 1-4 intestinal involvement per Acute Graft-versus-Host Disease 
Clinical Stage criteria.
5.2
Secondary Endpoints
The secondary endpoints are:
!
Intestinal aGvHD-free and relapse-free (of the underlying malignancy) survival by Day +180.
!
Grade C-D aGvHD-free (any organ involvement) survival by Day +180.
!
Non-relapse Mortality (NRM) by Day +180.
!
Overall Survival (OS) by Day +180.
!
Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
5.3
Safety Endpoints
!
Safety as assessed by adverse events (AEs), adverse events of special interest (AESIs), SAEs, 
vital signs, results of standard laboratory test and procedures (eg, clinical chemistry, 
hematology, coagulation). 
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Vedolizumab-3035
Page 11 of 46
Statistical Analysis Plan 
22 October 2021
6.0
DETERMINATION OF SAMPLE SIZE
Assuming the event rate for the intestinal aGvHD-free survival by Day +180 after allo-HSCT is 
34.1% for the placebo group and 21.8% for the vedolizumab group and the rate of 
loss-to-follow-up is 10% for both groups, a sample size of 279 subjects per group (558 subjects 
total) is expected to generate 148 events for the intestinal aGvHD-free survival and hence 
provide 90% power at the at alpha of 0.05 for a 2-sided hypothesis based on log-rank test. 
Assuming the event rate for the intestinal aGvHD-free and relapse-free survival is 39.5% for the 
placebo group and 27.1% for the vedolizumab group, this sample size is expected to generate 
177 events for the intestinal aGvHD-free and relapse-free survival and hence provide 
approximately 86% power at alpha of 0.05 for a 2-sided hypothesis.
7.0
METHODS OF ANALYSIS AND PRESENTATION
The End of Treatment Analysis (ie, primary analysis) for efficacy and safety data will be 
performed at the end of treatment (EOT), when all subjects have completed Day +180 or 
withdrawn from the study, or when the planned number of primary endpoint events as 
determined by the sample size adaptation rule in the interim analysis are accrued. The End of 
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Statistical Analysis Plan 
22 October 2021
Study Analysis (ie, final analysis) will be performed after the final database lock at the end of the 
study (EOS). Please refer to Section 7.1.3 for details.
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.4, or higher. 
All statistical testing will be 2-sided performed at an alpha level of 0.05. All confidence intervals 
(CI) reported will be 2-sided 95%, unless stated otherwise. P-values will be rounded to 4 decimal 
places prior to assessment of statistical significance.
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
A visit window convention will be used to determine the analysis value for a given study visit for 
observed data analyses, unless otherwise stated. 
Where appropriate, variables will be summarized descriptively by analysis visit. For the 
categorical variables, counts and percentages of each possible value will be tabulated. The 
denominator for the percentage will be based on the number of subjects who provided 
non-missing responses to the categorical variable. For continuous variables, the number of 
subjects with non-missing values, mean, median, SD, minimum, and maximum values will be 
presented.
7.1.1
Study Definitions
Endpoint
Definition
Intestinal aGvHD-free survival
by Day +180 after allo-HSCT*
Time from the date of first study drug administration (Day-1, see 7.1.2) to 
intestinal aGvHD event/death, where an event is defined as death due to any 
cause or Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease 
Clinical Stage criteria. It will be censored for subjects who have not had the
intestinal aGvHD event or died or have had the event after pre-specified timing, 
eg, last contact or Day+180 after allo-HSCT whichever occurs first. If a subject 
had intestinal aGvHD event and died due to any cause including intestinal 
aGvHD, time to event will be derived as time to first qualifying event, ie,
intestinal aGvHD event.(see Table 7.a)
Intestinal aGvHD-free survival
by 12 months after allo-HSCT*
Time from the date of first study drug administration (Day-1, see 7.1.2) to 
intestinal aGvHD event/death, where an event is defined as death due to any 
cause or Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease 
Clinical Stage criteria. It will be censored for subjects who have not had the
intestinal aGvHD event or died or have had the event after pre-specified timing, 
eg, last contact or Day+365 after allo-HSCT whichever occurs first. If a subject 
had intestinal aGvHD event and died due to any cause including intestinal 
aGvHD, time to event will be derived as time to first qualifying event, ie,
intestinal aGvHD event.(see Table 7.a)
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Vedolizumab-3035
Page 13 of 46
Statistical Analysis Plan 
22 October 2021
Endpoint
Definition
Intestinal aGvHD-free and 
relapse-free survival by Day 
+180 after allo-HSCT*
Time from the date of first study drug administration (Day-1, see 7.1.2) to 
intestinal aGvHD event/death/relapse, where an event is defined as death or 
Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical 
Stage criteria, or relapse. It will be censored for subjects who have not had the
event or have had the event after pre-specified timing, eg, last contact or 
Day+180 after allo-HSCT whichever occurs first.
Intestinal aGvHD-free and 
relapse-free survival by 12 
months after allo-HSCT*
Time from the date of first study drug administration (Day-1, see 7.1.2) to 
intestinal aGvHD event/death/relapse, where an event is defined as death or 
Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical 
Stage criteria, or relapse. It will be censored for subjects who have not had the
event or have had the event after pre-specified timing, eg, last contact or 
Day+365 after allo-HSCT whichever occurs first.
Grade C-D aGvHD-free (any 
organ involvement) survival by 
Day +180 after allo-HSCT
An event is defined as Grade C-D aGvHD any organ involvement per IBMTR 
Severity Index for aGvHD or death. It will be censored for subjects who have 
not had the event or have had the event after pre-specified timing, eg, last 
contact or Day+180 after allo-HSCT whichever occurs first.
Grade C-D aGvHD-free (any 
organ involvement) survival by 
12 months after allo-HSCT
An event is defined as Grade C-D aGvHD any organ involvement per IBMTR 
Severity Index for aGvHD or death. It will be censored for subjects who have 
not had the event or have had the event after pre-specified timing, eg, last 
contact or last contact or Day+365 after allo-HSCT whichever occurs first.
NRM by Day +180 after 
allo-HSCT
An event is defined as death without occurrence of a relapse. It will be censored 
for subjects who have not had the event or have had the event after pre-
specified timing, eg, last contact or Day+180 after allo-HSCT whichever occurs 
first.
NRM by 12 months after 
allo-HSCT
An event is defined as death without occurrence of a relapse. It will be censored 
for subjects who have not had the event or have had the event after pre-
specified timing, eg, last contact or Day+365 after allo-HSCT whichever occurs 
first.
OS by Day +180 after allo-HSCT
An event is defined as death from any cause. It will be censored for subjects 
who have not had the event or have had the event after pre-specified timing, eg,
last contact or Day+180 after allo-HSCT whichever occurs first.
OS by 12 months after 
allo-HSCT
An event is defined as death from any cause. It will be censored for subjects 
who have not had the event or have had the event after pre-specified timing, eg,
last contact or Day+365 after allo-HSCT whichever occurs first.
Grade B-D aGvHD-free (any 
organ involvement) survival by 
Day +180 after allo-HSCT
An event is defined as death or grade B-D any organ involvement per IBMTR 
Severity Index for aGvHD. It will be censored for subjects who have not had 
the event or have had the event after pre-specified timing, eg, last contact or 
Day+180 after allo-HSCT whichever occurs first.
Grade B-D aGvHD-free (any 
organ involvement) survival by 
12 months after allo-HSCT
An event is defined as death or grade B-D any organ involvement per IBMTR 
Severity Index for aGvHD. It will be censored for subjects who have not had 
the event or have had the event after pre-specified timing, eg, last contact or 
Day+365 after allo-HSCT whichever occurs first.
*For the determination of Intestinal aGvHD in these endpoints, if an investigator diagnoses a subject as having an 
Intestinal aGvHD event even though the corresponding Diarrhea Volume data is missing or not defined as Stage 1-4 
on the eCRF, it will be considered as a valid primary efficacy event in the efficacy analysis.
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Page 14 of 46
Statistical Analysis Plan 
22 October 2021
Table 7.a
Date of Event/Censor for primary endpoint by Day +180 after allo-HSCT
Reported
Intestinal
aGvHD Event?
Death?
Consider as Primary 
Efficacy Event?
Date of Primary 
Efficacy Event
Date of censoring
Yes
No
Yes
Date of reported 
intestinal aGvHD
Yes
Yes
Yes
Date of first reorted 
event, ie, intestinal 
aGvHD
No
Yes
Yes
Date of death
No
No
No. Censor
Date of last observation, or 
last contact, EOS visit, 
Day+180, or interim datacut 
date whichever occurs first
Note: Event or Death that occurs after Day +180 will be censored at Day +180.
Note: In the case that liver or skin aGvHD has occurred but neither intestinal aGvHD nor death has occurred, such 
subjects will be censored subject.
7.1.2
Definition of Study Days
Per study protocol, Study Day 0 is defined as the date on which HSC infusion occurs (no sooner 
than 12 hours after completion of IV infusion of study drug on Day –1. Other study days are 
defined relative to the Study Day 0 with Day +1 being the day after, and Day -1 being the day
prior to Study Day 0.
However, Day -1 per study protocol corresponds to Analysis Day 1 in ADaM datasets following 
the CDISC ADaM implementation guide. Similarly, other analysis study days in ADaM datasets 
are defined relative to the Analysis Day 1 (ie, Study Day -1 per protocol) with Analysis Day 2 
being the day after (ie, Study Day 0 per protocol).
For time to event, the day until event/censor after allo-HSCT is following formula:
!
The date of event/censor – the date of the first dose of study drug + 1.
7.1.3
Definition of Study Visit Windows
Baseline is defined as the last non-missing measurement prior to or on the date of the first dose 
of study drug (Study Day -1). 
Subjects do not always adhere strictly to the visit timing in the protocol. Therefore, the 
designation of visits throughout the study will be based on the actual day of evaluation relative to 
the start date of the study rather than the nominal visit recorded in the CRF. The visit windows 
for the post-baseline visits are defined by the middle point of the consecutive scheduled days,
allowing equally distanced windows (See Table 7.b) between the scheduled days when 
applicable. The visit windows should be used to summarize the endpoints that are defined to 
target the scheduled visit days with the exception of time to event endpoints. If a subject has 
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Vedolizumab-3035
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Statistical Analysis Plan 
22 October 2021
more than 1 measurement in the same visit window, the measurement closest to the scheduled 
visit will be used. If 2 measurements in the same window are of equal distance to the scheduled 
visit, the measurement that occurs after the scheduled visit will be used. If 2 or more 
measurements occur on the same day, the mean value will be used. 
Table 7.b
Visit Windows to be used for the summary of the endpoints
Visit
Scheduled 
Visit Day
Assessment of 
GvHD (as 
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Vital signs
Laboratory 
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-1*
≤-1
≤-1
≤-1
≤-1
≤-1
Day 6
+6
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+0 — +10
+0 — +10
Day 13
+13
+11 — +16
+11 — +16(a)
+11 — +16
Day 20
+20
+17 — +23
+17 — +23
+17 — +23
Day 27
+27
+24 — +30
+24 — +30
+24 — +30
Day 34
+34
+31 — +37
+31 — +37
+31 — +37
Day 41
+41
+38 — +55
+38 — +55(a)
+38 — +55
+0 — +69
Day 69
+69
+56 — +83
+56 — +83(a)
+56 — +83
Day 97
+97
+84 — +111
+84 — +111(a)
+84 — +111
+0 — +139
+70 — +138
Day 125
+125
+112 — +139
+112 — +139(a)
+112 — +139
Day 153
+153
+140 — +167
+140 — +167(a)
+140 — +167
Day 180
+180
+168 — +187
+168 — +230
+168 — +230
+140 — +270
+139 — +230
Day 280
+280
+188 — +320
≥+231
≥+231
≥+231
Month 12
+365
≥+321
≥+271
(a) Vital signs will be obtained before and within 60 minutes of completion of IV infusion of vedolizumab.
* Scheduled visit Day -1 per protocol corresponds to Analysis Day 1 in ADaM.
7.1.4
Conventions for Missing Adverse Event Dates
Every effort will be made to determine the actual onset date for the event or to obtain a reliable 
estimate for the onset date from the investigator.
For AEs or SAEs, a missing or incomplete onset date will be imputed according to the following 
conventions:
1. If an onset date is missing, the derived onset date will be calculated as the first non-missing 
valid date from the following list (in order of precedence):
–
First study medication date.
–
Consent date (for SAEs only).
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Vedolizumab-3035
Page 16 of 46
Statistical Analysis Plan 
22 October 2021
2. If an onset date is incomplete, the derived onset date will be calculated following:
–
Missing day, but month and year present: the day will be imputed as the 15th of the month. 
If the first study medication dose occurs after the imputed date in the same month, the 
derived onset date will be set equal to the first study medication date.
–
Missing day and month, but year present: the day and month will be imputed as the 30th
June of the year. If the first study medication dose occurs after the imputed date, the 
derived onset date will be set equal to the first study medication date.
For AEs or SAEs, a missing or incomplete end date will be imputed according to the following 
conventions:
1. If an end date is missing, the derived end date will be imputed the last assessment date. 
2. If an end date is incomplete, the derived end date will be calculated following:
–
Missing day, but month and year present: the day will be imputed as the last date (for 
example February 2009 will be imputed as 28 February 2009) of the month.
–
Missing day and month, but year present: the day and month will be imputed as the 31st
December of the year.
7.1.5
Conventions for Missing Concomitant Medication Dates
Start and stop dates for all concomitant medications are collected on the CRF. However, in case 
of missing or partial information in these dates, the following rules will be used:
If the start date is unknown or partial:
!
If the day is missing, the start day will be the first day of the month.
!
If the month is missing, 
–
If the year is the same as the date of first dose of study drug, the start month will be the 
month of the dose first study drug.
–
If the year is not the same as the date of first dose of study drug, the start month will be 
January.
!
If the year is missing, the start year will be the minimum of the year of the first clinic visit or 
the year of the informed consent date.
!
If the entire start date is unknown, the start date will be the date of first study drug 
administration.
If the stop date is missing, partial or “ongoing:”
!
If the day is missing, the stop day will be the last day of the month reported.
!
If the month is missing, 
–
If the year is the same as the date of last assessment, the stop month will be the month 
during which the last assessment occurred.
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Vedolizumab-3035
Page 17 of 46
Statistical Analysis Plan 
22 October 2021
–
If the year is not the same as the year of the last assessment, then the end month will be 
December.
!
If the year is missing”, the stop year will be the year in which the last in which the last 
assessment occurred.
!
If the entire stop date is unknown or if the medication is “ongoing”, the stop date will be the 
date of last assessment.
7.1.6
Methods for Handling of Missing Efficacy Data
Through the end of the double-blind period, the missing dichotomous efficacy data (eg, intestinal 
aGvHD event as dichotomous endpoint) will be handled using the non-responder imputation 
method, ie, any subject with missing information for determination of endpoint status will be 
considered as having an undesirable outcome in the analysis. 
Missing data for continuous endpoints will be imputed using last available post-baseline 
observation carried forward (LOCF) method. For subjects without any non-missing post-baseline 
measurement, the missing data will be imputed using baseline observation carried forward 
method. Other missing data imputation method (eg, multiple imputations or repeated measure 
mixed effects model) may be explored.
Missing data for time to event endpoints will not be imputed. 
Other missing data handling method may be explored.
7.2
Analysis Sets
The analysis sets used for analysis will include the following:
Randomized Set will be included all subjects who are randomized.
Full Analysis Set (FAS): Following the intent-to-treat principle, the FAS will include all 
subjects who are randomized, receive at least 1 dose of the treatment, and undergo allo HSCT. 
The analysis will be based on the treatment to which the subjects are randomized. This 
population will be used for efficacy analysis.
Safety Analysis Set (SAF) will include all subjects who receive at least 1 dose of study drug. 
Subjects in this set will be analyzed according to the treatment actually received. This population 
will be used for safety analysis.
7.3
Disposition of Subjects
7.3.1
Study Information
General study information will be provided, including the date the first subject signed informed 
consent, the date of the last subject’s last visit/contact, the date of the last subject’s last visit for 
ill be th
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Statistical Analysis Plan 
22 October 2021
collection of data for primary endpoint, MedDRA version, WHODrug version and SAS version
used for creating the datasets. 
7.3.2
Disposition of Subjects
Summary of the subject disposition will be summarized for each treatment group and overall, 
and will include the following:
!
Summary of screen failures using all subjects who were not randomized.
!
Summary of eligibility for randomization using all subjects who signed the informed consent 
form.
!
Summary of study subjects randomized by site, geographic region (See Appendix D) using 
randomized set.
!
Summary of patients for each pre-defined population using randomized set: full analysis set, 
per-protocol population, safety analysis set,
population.
!
Summary of subjects completing study drug using randomized set.
!
Summary of subjects completing study using randomized set.
!
Disposition of subjects based on the reasons for discontinuation of treatment and for failing 
to complete the study using randomized set.
!
Significant protocol deviations will be summarized descriptively using randomized set.
To assess the impact of COVID-19 on the safety of participating subjects, the following analyses 
of COVID-19 impact will be conducted if data permits. Additional tables and listings may be 
generated.
!
Disposition of subjects based on the COVID-19 related discontinuation, including 
discontinuation due to adverse events in light of COVID-19 infection and discontinuation 
due to COVID-related reasons other than COVID-infection (eg, travel limitation, reduced 
site staff, etc) using randomized set.
!
Significant protocol deviations due to COVID-19 pandemic will be summarized descriptively
using randomized set.
!
Summary of COVID-19 Impact including the summary statistics of Number of Missed Visits, 
Visits with Missed Assessments and Visits with Alternative method of Contact and the 
number and percentage of subjects with at least one missed visit and missed visits by study
visit.
When calculating percentages for the reasons for not being treated, the total number of subjects 
not treated by the study drug will be used as the denominator. When calculating percentages for 
the reasons for discontinuation, the total number of subjects who prematurely discontinued will 
be used as the denominator.
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Statistical Analysis Plan 
22 October 2021
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics variables will be summarized using the FAS.
For continuous variables (age, weight, height, body mass index [BMI], Total CD34+, Stem Cell 
Dose: Total nucleated cell dose, and Stem Cell Dose: CD3+, underlying disease duration since 
diagnosis), summary statistics will be generated. BMI (in kg/m2) will be calculated using the 
subject’s height at screening and baseline weight measurements and summarized.
For categorical variables (age [<18, and ≥-18] [<40, 40 to 60, and >60], gender, ethnicity, race), 
the number and percentage of subjects in each category will be presented.
The following GvHD-related baseline characteristics will be summarized by treatment group for 
subjects: 
Baseline Disease Characteristics
Categories
Geographic region
North America, South America, Western/ Northern 
Europe, Central Europe, Eastern Europe, Asia / 
Australia
Baseline ECOG Status
0, 1, 2, 3, 4
HLA Match
7/8, 8/8
Conditioning Regimen
Myeloablative, 
Reduced Intensity Conditioning
ATG
With, Without
CNI
Tacro vs Cyclosporine
GvHD Prophylaxis
Tacro + MTX, Tacro + MMF, Tacro + MTX + ATG, 
Tacro +MMF + ATG, Cyclo + MTX, Cyclo + MMF, 
Cyclo +MTX +ATG, Cyclo + MMF + ATG
Primary Disease
Acute Myeloid Leukaemia, Acute Lymphoid 
Leukaemia, Chronic Myeloid Leukaemia, Other 
Myeloproliferative Disorder, Myelodisplastic Syndrome, 
Chronic Lymphocytic Leukemia, Non-Hodgkin 
Lymphoma
Donor/Recipient CMV Match
D-/R+, D+/R+, D+/R-, D-/R-
Cytogenetic results (for AML/MDS)
AML
!
Favourable (for AML only)
!
Intermediate (for AML only)
!
Unfavourable (for AML only)
!
Unknown
MDS
!
Low (for MDS only)
!
Intermediate1 (for MDS only)
!
Intermediate2 (for MDS only)
!
High (for MDS only)
!
Unknown
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Statistical Analysis Plan 
22 October 2021
Baseline Disease Characteristics
Categories
Prior Exposure-Disease Status at time of HSCT (ALL 
and AML and CML)
ALL and AML
!
Complete Remission 1 (ALL and AML only)
!
Complete Remission >1 (ALL and AML only)
!
Other (ALL and AML only), CML
!
1st Chronic phase (CML only)
!
Failing TKI (CML only)
!
Accelerated phase or >1st Chronic phase (CML 
only)
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Blast crisis (CML only)
!
Progression (CML only)
Source of Stem Cells
Bone Marrow, Peripheral Blood Mononuclear Cell
Donor-recipient Gender Match
Female Subject-Female Donor, Female Subject-Male 
Donor, Male Subject-Female Donor, Male Subject-Male 
Donor
Locus of Mismatch
HLA-A Gene, HLA-B Gene, HLA-C Gene, HLA-DRB1 
Gene, Other Gene
7.5
Medical History and Concurrent Medical Conditions
During the screening period, a complete medical history will be compiled for each subject. The 
history will emphasize the background and progress of the subject’s malignancy and include a 
description of prior therapies for it. Medical and Surgical History will be summarized by system 
organ class and preferred term based on Safety analysis set.
7.6
Medication History and Concomitant Medications
Medications used by the subject and therapeutic procedures completed by the subject will be 
recorded in the eCRF from the first dose of study drug on Day -1 through 12 months after 
allo-HSCT.
Concomitant medications will be coded using WHO Drug. The number and percentage of 
patients taking concomitant medications will be tabulated by standardized medication name 
WHO drug generic term in the Safety analysis set, and categorized as follows:
!
Concomitant medications that started and stopped prior to baseline.
!
Concomitant medications that started prior to and were ongoing at baseline and those that 
started after baseline.
!
Data listings of Concomitant medications of COVID-19 Vaccine will be presented separately
from other Concomitant mediations.
7.7
Study Drug Exposure and Compliance
Vedolizumab will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
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Vedolizumab-3035
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Statistical Analysis Plan 
22 October 2021
records of vedolizumab receipt and dispensing. The number of doses will be summarized as both 
continuous and ordinal categorical variable using the safety analysis set. 
The duration of exposure will be calculated as (date of last dose of study drug - date of first dose 
of study drug) + 127 days. If last dose date is missing, then 127 days will be imputed as 
treatment period. 
Overall study drug compliance (%) will be determined as (total count of complete infusions 
taken / total number of infusions expected during study treatment, ie, 7 infusions expected for all
subjects) ∀100%. A subject must receive at least 75% of the infusion in order for it to be 
considered complete for each dose.
The number and percentage of subjects with overall study drug compliance will also be 
summarized in the following categories[<80%, 80 to 90%, ≥90%].
If data permits, additional data listing and/or summary table may be presented to evaluate the 
subject’s adherence to study treatment as affected by COVID-19 pandemic, and subject’s 
treatment accessibility as affected by COVID-19 pandemic. 
7.8
Efficacy Analysis
Efficacy data will be analyzed based on the FAS. Missing data will be handled according to 
Section 7.1.6.
Efficacy endpoints and the associated supporting data will be descriptively summarized by age 
groups and overall respectively, and presented in supporting data listings. Unless stated 
otherwise, all statistical comparisons will be conducted in the overall population. 
All statistical testing will be 2-sided performed at an alpha level of 0.05. To control the overall 
Type I error rate for the comparison between vedolizumab and placebo groups for the primary 
and key secondary efficacy endpoints in the overall population, a fixed-sequence testing 
approach will be used. Specifically, the statistical testing of the intestinal aGvHD-free and 
relapse-free survival will only be performed if the treatment difference for primary efficacy 
endpoint is statistically significant (ie, p < 0.05). The next secondary efficacy endpoint will only 
be tested if the treatment difference for the first secondary efficacy endpoint is significant 
(ie, p <0.05), and so on for each subsequent secondary efficacy endpoint.
The order of the statistical testing for the primary and key secondary endpoints is as follows:
1. Intestinal aGvHD-free survival by Day +180 after allo-HSCT.
2. Intestinal aGvHD-free and relapse-free survival by Day +180.
3. Grade C-D aGvHD-free (any organ involvement) survival by Day +180.
4. NRM by Day +180.
5. OS by Day +180.
6. Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
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Statistical Analysis Plan 
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The testing of the additional efficacy endpoints will not be multiplicity-adjusted. Nominal 
p-values will be presented.
7.8.1
Primary Efficacy Endpoint(s)
The primary endpoint is intestinal aGvHD-free survival by Day +180 after allo-HSCT. Intestinal 
aGvHD is defined as Stage 1-4 intestinal involvement per Acute Graft-versus-Host Disease 
Clinical Stage criteria. The primary efficacy endpoint event is defined as death due to any cause 
or Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria.
7.8.1.1
Primary Efficacy Analyses
The null and alternative hypotheses for the primary efficacy endpoint, intestinal aGvHD-free 
survival by Day +180 after allo-HSCT, are: 
H0: Intestinal aGvHD-free Survival by Day +180 Vedolizumab = Intestinal aGvHD-free Survival by 
Day +180 Placebo 
versus
HA: Intestinal aGvHD-free Survival by Day +180 Vedolizumab ≠ Intestinal aGvHD-free Survival by 
Day +180 Placebo
The primary endpoint will be analyzed using the log-rank test, with Kaplan-Meier estimates 
presented. Subjects without documented intestinal aGvHD events or death before reaching 
Day +180 after allo-HSCT will be censored at the date of last assessment/visit/contact or 
Day +180, whichever occurs first. The randomized subjects who did not receive any of their 
assigned study drug will be censored at Day -1. The statistical significance of treatment effect 
will be tested against 2-sided alpha level of 0.05. 
The primary efficacy endpoint will also be analyzed using a Cox proportional hazards model 
with treatment group, stratified by randomization strata. Point estimate of hazard ratio and the 
corresponding 95% CI will be presented. The randomization strata are as follows:
!
Age (≥18, ≥12 and <18).
!
HLA Match (7/8, 8/8).
!
Conditioning Regimen (Myeloablative, Reduced Intensity Conditioning).
!
ATG (With, Without).
In addition, summary statistics and Kaplan-Meier estimates by treatment group will be provided, 
including:
!
Number and percentage of events,
!
Number and percentage of censored observations,
!
Median time to event and 95% CI,
!
25th percentile of the time to event and 95% CI,
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Vedolizumab-3035
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Statistical Analysis Plan 
22 October 2021
!
75th percentile of the time to event and 95% CI,
!
Range (minimum and maximum time to event),
!
Kaplan-Meier estimates of the event rates (percentage and n) at 6 months,
!
Kaplan-Meier estimates of the event rates (percentage and n) at 12 months,
!
Plots of the Kaplan-Meier estimated survival curves.
The Kaplan-Meier mentioned above will be based on LIFETEST procedure in SAS®.
7.8.2
Secondary Efficacy Endpoint(s)
The secondary endpoints are:
!
Intestinal aGvHD-free and relapse-free (of the underlying malignancy) survival by Day +180.
!
Grade C-D aGvHD-free (any organ involvement) survival by Day +180.
!
NRM by Day +180.
!
OS by Day +180.
!
Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
All time-to-event endpoints will be analyzed in a similar way as primary efficacy endpoint, using 
log-rank test in the FAS. Cox proportional hazards model will be fitted with treatment group, 
stratified by the randomization strata. Point estimate of hazard ration and the corresponding 95% 
CI will be presented.
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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7.8.4
Sensitivity Analysis 
To assess the robustness of the analysis for primary efficacy endpoint and key secondary
endpoints, the following sensitivity analysis will be performed. 
!
To accommodate the events of interest that occur within the protocol-defined +/-7 day
window, the primary and secondary efficacy endpoints will be analyzed by Day +187 after 
allo-HSCT. Subjects who have not had an event by Day +187 after allo HSCT will be 
censored at last contact or Day+187 after allo HSCT whichever occurs first.
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Statistical Analysis Plan 
22 October 2021
!
If any clinical site has detected or reported significant noncompliance with regulatory
requirements during the course of study, sensitivity analysis may be conducted for the in the 
FAS excluding all subjects from that particular site. 
!
Primary and secondary efficacy endpoint will be analyzed using stratified log-rank test using 
the FAS, stratified by randomization stratification factors.
!
Primary, secondary, 
 efficacy endpoint may be explored using the competing 
risk analysis to accommodate the competing nature of multiple causes to the same event.
Additional sensitivity analysis may be performed as appropriate (eg, related to COVID-19 
impact). If there is inconsistency in stratification information collected in IRT versus EDC, 
sensitivity analysis for inconsistency among them may also be performed.
7.8.5
Subgroup Analysis
This section applies to primary efficacy endpoint as well as the following selected efficacy
endpoints:
1. Intestinal aGvHD-free survival by Day +180 after allo-HSCT
2. Intestinal aGvHD-free and relapse-free survival by Day +180.
3. Grade C-D aGvHD-free (any organ involvement) survival by Day +180.
4. NRM by Day +180.
5. OS by Day +180.
6. Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
The subpopulations of interest are defined by the following baseline characteristics outlined 
Table 7.c.
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Statistical Analysis Plan 
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Table 7.c
List of subgroups of interest
Subgroup of Interest
Subgroup Categories
Gender 
Male, Female
Race 
White, Non-White
Geographic Region
North America, South America, Western/ Northern Europe, Central 
Europe, Eastern Europe, Asia / Australia
HLA Antigen Match
7/8, 8/8
Conditioning Regimen
Myeloablative, 
Reduced Intensity Conditioning
ATG
With, Without
Primary Disease
Acute Leukemia, Chronic Myelogenous Leukemia, Myelodysplasia, 
Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma with 
chemosensitive disease, Other nonHodgkin or Hodgkin Lymphoma, 
Myelofibrosis and other Myeloproliferative disorders
GvHD Prophylaxis Therapies
CNI +MTX+ATG, CNI +MTX-ATG, CNI + MMF+ATG, and CNI + 
MMF-ATG
CNI
Tacrolimus vs Cyclosporine
Stem Cell Source
Bone Marrow, Peripheral Blood Mononuclear Cel
If the value of the baseline grouping variable cannot be determined, the subject will be excluded 
from the corresponding subgroup analysis. If the number of subjects in any subgroup is less than 
10, that subgroup will not be presented. 
The results will be tabulated and the corresponding forest plots for the subgroup analyses will be 
presented as well.
To evaluate the impact of COVID-19 on the efficacy of the participating subjects, additional 
subgroup analysis may be performed (eg, COVID-19 infected subjects vs COVID-19 not-
infected subjects).
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Statistical Analysis Plan 
22 October 2021
7.9.2
Pharmacodynamic Analysis
Not applicable
7.10
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Statistical Analysis Plan 
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7.11
Safety Analysis
Safety analysis will be performed using the Safety Analysis Set with the actual treatment 
received. The analysis of safety endpoints will include AEs, clinical laboratory values, and vital
signs. No statistical inference will be made for safety analyses.
7.11.1
Adverse Events
Adverse events (AEs) will be coded by MedDRA, and summarized by System Organ Class, 
High Level Term, and Preferred Term. AEs will also be summarized by severity, and by
relationship to study investigational product respectively. All AEs and SAEs collected in the 
database (including those starting prior to first dose of study drug) will be listed. Any other 
information collected (eg, relatedness to study drug, action taken etc.) will be listed as 
appropriate.
A Treatment Emergent AE (TEAE) is defined as any AEs newly occurring or worsening from 
the first dose and 18 weeks after last dose of study treatment. A Serious Treatment Emergent AE 
(TEAE) is defined as SAE newly occurring or worsening from the first dose up to 18 weeks after 
last dose of study treatment, regardless of relationship to study drug. SAEs will also be collected
from 18 weeks after last dose of study treatment to EOS. The number of percentage of subjects 
with TEAEs, serious TEAEs, and SAEs will be summarized. Key guidelines for determining the 
incidence of AEs are as follows: 
!
AEs with missing or unknown severity will be considered as severe. 
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Statistical Analysis Plan 
22 October 2021
!
AEs with missing or unknown relationship to study drug will be counted as related. 
!
A subject with 2 or more AEs within the same level of the MedDRA term will be counted 
only once in that level.
The incidence rates of treatment-emergent AEs, as well as the frequency of occurrence of overall 
toxicity categorized by maximum toxicity grades (severity), will be described. Toxicity grade
will be evaluated according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE version 5.0). In addition, treatment-emergent AEs will be 
summarized by causal relationship to study treatment (in the opinion of the investigator) and 
TEAE leading to drug discontinuation. Serious treatment-emergent AEs (Serious TEAEs) and 
SAEs, TEAE leading to death, both overall and by causal relationship to study treatment, will
also be summarized. Exposure adjusted TEAE rates (eg, per 100 subject-years) will be 
summarized as well to accommodate variable subject follow-up time, where the 
exposure-adjusted incidence rate is defined as the number of subjects experiencing the AE 
divided by the total exposure-time among subjects, where each subject’s exposure is calculated 
as ([(date of last dose of study drug + 126) – date of first dose of study drug] +1) / 365.25. 
!
TEAEs by system organ class (SOC), high level term (HLT), and preferred term (PT).
!
Exposure-adjusted TEAEs by SOC, HLT, and PT.
!
Drug related TEAEs by SOC, HLT and PT.
!
Serious Pre-treatment Events by SOC, HLT, and PT.
!
Serious TEAEs by SOC, HLT and PT.
!
Serious AEs occurring beyond 18 weeks after last dose until the EOS by SOC, HLT and PT.
!
Serious drug related TEAEs by SOC, HLT and PT.
!
Serious drug related AEs occurring beyond 18 weeks after last dose until the EOS by SOC, 
HLT and PT.
!
TEAEs leading to treatment discontinuation by SOC, HLT, and PT.
!
TEAEs by PT by descending order of frequency.
!
Grade 3 or higher TEAEs by SOC, HLT, and PT.
!
Grade 3 or higher Drug-Related TEAEs by SOC, HLT, and PT.
!
Most frequent AEs by PT (sorted by frequency, occurring in #5% of subjects in any 
treatment arm).
!
COVID-19 related TEAEs (eg, PT containing “COVID-19”, “SARS-CoV-2”, “Coronavirus” 
Terms).
!
Serious AEs in COVID-19 infected subjects.
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Vedolizumab-3035
Page 31 of 46
Statistical Analysis Plan 
22 October 2021
!
AEs of special interest by SOC, HLT, and PT.
–
Serious Infections.
–
PML.
–
Malignancy of AEs.
–
Liver injury.
–
Hypersensitivity Reactions including IRRs and Injection Site Reactions of AEs.
–
Leukopenia or Lymphopenia.
–
CMV colitis.
–
CMV Reactivation.
–
All AESI.
On-study deaths will be summarized based on Serious Adverse Event and End of Study CRF. 
All adverse events will be listed by treatment, study center, subject number and onset date of the 
adverse event. The listing will contain: subject identifier, age, sex, body weight, race, adverse
event (preferred term and reported term), SOC, onset date, end date or whether the event was 
ongoing, duration, frequency, intensity, action taken concerning study drug, causality to study
drug, the outcome, whether the adverse event was an SAE and whether the event was an adverse 
event of special interest (AESI).
The incidence rates of CMV Reactivation will be described by donor CMV IgG status and 
recipient CMV IgG status.
All CMV Reactivation infections of AEs will also be listed by treatment, study center, subject 
number and onset date of the adverse event. The listing will contain the reported verbatim term
in addition to the contents mentioned above.
All deaths and PML checklist data will be listed. 
7.11.2
Clinical Laboratory Evaluations
Blood samples for analysis of the Hematology, Serum Chemistry, Coagulation, and Liver 
Functions parameters shown in following table.
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Vedolizumab-3035
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Statistical Analysis Plan 
22 October 2021
Table 7.d
Clinical Hematology, Coagulation, Chemistry, and LFTs
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Red blood cells (RBC)
Leukocytes with differential including 
neutrophils, monocytes, and lymphocytes
Platelets
Albumin
Bicarbonate (HCO3)
Blood urea nitrogen (BUN)
Calcium
Creatinine
Chloride
Glucose
Phosphate
Potassium
Sodium
Urate
Coagulation a
Liver Functions
Prothrombin (PT)/INR
Activated partial thromboplastin time (aPTT)
Alkaline phosphatase (ALP)
ALT
AST
Bilirubin (total and indirect)
Lactate dehydrogenase (LDH)
The analysis of the laboratory data will include parameters tabulation for each assessment visit 
by treatment group, using the following:
!
Number of subjects with non-missing values (n),
!
Arithmetic mean,
!
Median,
!
Standard deviation (SD),
!
Minimum and maximum observed values (Min, Max).
For the post-baseline assessments, the summary will also include the change from baseline 
values. 
Mean laboratory values over time will be plotted for key laboratory parameters (eg, hematology, 
chemistry, and LFTs). Shift tables for laboratory parameters will be generated based on changes 
in the classification with low, normal and high values relative to the normal range from baseline 
to post-baseline values. Subjects with markedly abnormal values for laboratory tests will be 
tabulated (see Appendix E for details).
7.11.3
Vital Signs
Vital signs, including heart rate, respiratory rate, systolic and diastolic blood pressure, and 
temperature will be summarized descriptively following the windowing convention for visits
specified events. Subjects with markedly abnormal values for vital signs values will be tabulated 
(see Appendix F for details).
7.11.4
12-Lead ECGs
Not applicable
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Vedolizumab-3035
Page 33 of 46
Statistical Analysis Plan 
22 October 2021
7.11.5
Other Observations Related to Safety
Not applicable
7.12
Interim Analysis
One interim analysis for futility and sample size re-estimation is planned for this study, which 
will occur after approximately 30∃of the targeted primary endpoint events (ie, approximately 
44 intestinal aGvHD/death events by Day +180 after allo-HSCT) have been accrued. The 
analysis will be performed by an independent statistical center (ie, an external vendor) in a 
manner that maintains the blinding to the sponsor study team, the investigators, and the subjects. 
The interim analysis results will be presented to the DMC but will not be shared with the sponsor. 
Based on the result, the DMC will make a recommendation to the Sponsor Liaison (who has 
been specified in DMC charter) and Sponsor Executive Committee (SEC) (who generally does 
not involve in daily trial management or attend the DMC meeting). The SEC and Sponsor 
Liaison may communicate information in the Open Report to the Sponsor’s senior management 
and may inform them of the DMC-recommendation in which the SEC and Sponsor Liaison has 
reached a final decision agreeing with the recommendation. Specific criteria for DMC 
recommendations will be provided in the DMC charter. The futility stopping is considered 
nonbinding. Details on the DMC recommendation and communication between DMC and SEC 
will be documented in the DMC Charter.
If 148 primary endpoint events are accrued before all subjects have completed Day +180 or 
dropped out, the primary analysis for efficacy (ie, EOT analysis) may be performed at that time.
7.12.1
Analysis Endpoints
7.12.1.1
Primary Efficacy Endpoint 
The efficacy endpoint of interest is intestinal aGvHD-free survival by Day +180 after allo-HSCT.
Events are considered death due to any cause or Stage 1-4 intestinal involvement per Acute Graft 
versus-Host Disease Clinical Stage criteria. Subjects who have completed Day +180 or 
withdrawn from the study prior to Day +180 but without an observed primary efficacy event and 
subjects who are still ongoing and have not reached Day +180 by the time of IA will be censored 
at the date of last assessment/visit/contact, or Day +180, or interim data cut date, whichever 
occurs first.
The cumulative incidences of Intestinal aGvHD-free survival by Day +180 after allo-HSCT and 
the two-sided 95% confidence intervals will be provided by treatment group using the Kaplan-
Meier method. Log-rank test statistic will be used to derive conditional power for interim 
decisions.
7.12.2
Assessment of Conditional Power
Conditional power for the primary efficacy endpoint will be assessed based on the log-rank test 
statistic using the observed intestinal aGvHD-free survival data at IA. 
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Vedolizumab-3035
Page 34 of 46
Statistical Analysis Plan 
22 October 2021
The calculation of the conditional power is based on B-value (Lan et. al. 1988). When data are 
monitored at t, B(t) is observed, and the conditional power assuming the trend indicated by the 
interim data is calculated as
CP
 = 1 −Φ 
z(
) −B(t)/t
√1 −t

–
t is information fraction at the time of IA relative to the originally planned sample size.
 =

 , where 1 is the observed number of primary efficacy events at IA; and N is the 
originally planned number of primary efficacy events (ie, N=148).
–
B(t) is B-value at IA. B(t) = Z
√t,  Z
 denotes a negative value of the observed log-rank 
test statistic  at the interim analysis, ie, Z
 = −. Note that the observed hazard 
ratio  at the interim analysis is approximately  = exp #
$%&
'(&
)
*.
–
Φ is the standard normal cumulative distribution function. 
–
α = 0.05.
7.12.3
Interim Decision Rules
The study design employs promising zone design, an adaptive sample size re-assessment 
approach (Mehta and Pocock, 2011) that strongly controls the overall type I error rate. The 
conditional power (see Section 7.12.2 for details) will be calculated based on primary efficacy
endpoint, intestinal aGvHD-free survival. If the conditional power falls in the promising zone, 
the sample size will be increased according to a prespecified sample size adaptation rule; if the 
conditional power falls in the futility zone, the study may stop for futility; otherwise the study
will continue with the sample size unadjusted. The DMC may also recommend that the study be 
stopped because of concerns about the safety for the study participants. 
The DMC will consider the following guidelines based on conditional power for making 
recommendations at the Interim Analysis. Of note the actual unblinded conditional power 
thresholds of promising zone design and sample size adaptation rule will be prepared by an 
independent design statistician in a separate document and will only be available to DMC and 
independent design statistician.
1. Futility Assessment: If the conditional power is below a prespecified cutoff, 10%
(ie, CP <10%), the recommendation will be to stop the trial for futility. The sponsor may or 
may not follow the recommendation of futility stopping.
2. If the conditional power falls into an “unfavorable” zone, ie, above 10% but below a 
prespecified k2 (where k2 ≥50%) (eg, 10% ≤CP < 50%), the recommendation will be to 
continue the trial with no sample size modification.
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Statistical Analysis Plan 
22 October 2021
3. If the conditional power falls into an “promising” zone, ie, above k2 but below a prespecified 
k3 (eg, 50% ≤CP < 90%), the recommendation will be to continue the trial with an increase 
in the sample size. The increase in the event size will be a step function up to maximum 35% 
increase from the original planned number of primary events (ie, approximately 52 additional 
events). The sponsor may or may not follow the recommendation of sample size increase.
4. If the conditional power falls into a “favorable” zone, ie, above k3 (eg, CP ≥90%), the 
recommendation will be to continue the trial with no sample size modification.
Note the actual k2 and k3 in the pre-specified sample size adaptation rule document prepared by
independent design statistician may be different from the numeric examples above. 
In addition to the above formal criteria, relevant safety data from the current study will be used 
to guide the potential modification of design of the study. The DMC may also recommend that the 
study be stopped because of concerns about the safety for the study participants. Potential 
modifications that the DMC can recommend include:
!
Continue trial without modifications (favorable or unfavorable zone).
!
Continue trial with sample size adjustment (promising zone).
!
Terminate trial due to lack of efficacy (futility zone).
!
Terminate trial due to safety (at the discretion of the DMC).
Any recommendation other than “continue trial without modifications” must be accompanied by 
justifications for the recommendations and other follow up requirements as deemed necessary.
7.12.4
Multiplicity Adjustment
The 50% conditional power (CP) principle will be implemented, which allows sample size 
increase only when the unblinded interim results are promising or the conditional power is 
greater than 50% (Chen, DeMets, and Lan, 2004; Mehta and Popock, 2011; Broberg, 2013). 
Thus, the conventional unweighted test statistics and critical values can be used without inflation 
of type I error rate. The interim analysis results will be presented to the DMC but will not be 
shared with the sponsor. 
7.12.5
Data to be Presented
A list of TLFs to be generated for this planned IA with interim SSR are specified in Appendix B.
Additional data-summaries or listings requested by the DMC may be generated.
7.13
Planned End of Treatment (EOT) Analysis and End of Study (EOS) Analysis 
7.13.1
Planned EOT Analysis
The EOT analysis (ie, primary analysis) for efficacy and safety data was planned at the end of 
treatment (EOT), when all subjects have completed Day +180 or withdrawn from the study, or 
when the planned number of primary endpoint events as determined by the sample size 
adaptation rule in the interim analysis has been accrued per Protocol Amendment 7 (dated 
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Vedolizumab-3035
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Statistical Analysis Plan 
22 October 2021
18Sept2019). However, the sponsor has decided to terminate the enrollment of Vedolizumab-
3035 due to the unexpected of COVID-19 pandemic and a shift in standard of care in transplant 
practice. Subsequently, the EOT analysis will not be performed as planned. The final analysis (ie, 
EOS analysis) will be performed after the final database lock at the end of study.
7.13.2
Planned EOS Analysis
The EOS analysis (ie, final analysis) will be performed after the final database lock at the end of 
the study. All available efficacy and safety data will be included in the EOS analysis. 
7.14
Changes in the Statistical Analysis Plan 
7.14.1
Revision History
Version 
Date 
Description of Revision
1.0
16Oct2019
N/A
2.0
27Aug2020
!
Added COVID-19 related analyses in Section 7.3.2, 7.7, 7.8.4, 7.8.5 and 7.11.1
to assess the impact of COVID-19
!
!
Modified the classification of shift table in Section 7.11.2 to present low, 
normal and high values relative to normal range instead of NCI CTCAE grade 
based on the discussion within the study team
!
Modified prespecified cutoff value for futility assessment for Interim Analysis 
in Section 7.12.3 based on the discussion within the study team.
!
Updated the definition of aGvHD to include the criteria for adolescent subjects 
in Appendix G
3.0
22Oct2021
!
Clarified the determination of Intestinal aGvHD event in Section 7.1.1;
!
Clarified the relationship between study day per protocol versus analysis day in 
ADaM in Section 7.1.2;
!
Removed PPS from Section 7.2;
!
Removed sensitivity analysis based on PPS from Section 7.8;
!
Removed subgroup analysis by age from Section 7.8.5;
!
Added references of EQ-5D and FACT-BMT scoring
!
Removed the EOT analysis from Section 7.13.
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Statistical Analysis Plan 
22 October 2021
8.0
REFERENCES
Chen, YHJ, DeMets, DL, Gordon Lan KK. Increasing the sample size when the unblinded 
interim result is promising. Stat Med 2004; 23(7):1023–1038.
Broberg, P. Sample size re-assessment leading to a raised sample size does not inflate type I 
error rate under mild conditions. BMC Medical Research Methodology 2013; 13:94.
Gernot, W, Werner, B. Group Sequential and Confirmatory Adaptive Designs in Clinical Trials.
2016. Switzerland: Springer International Publishing.
Mehta, CR, Pocock, SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stat Med 2011;30(28):3267-84.
Lan, KG, Wittes, J. The B-value: a tool for monitoring data. Biometrics 1988; 1:579-85.
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Statistical Analysis Plan 
22 October 2021
Appendix A
AEs of Special Interest
Based on the mechanism of action of vedolizumab, certain adverse events of special interest 
(AESIs) have been predefined. The categories of adverse events of special interest, and other 
planned analyses, are described below. 
Events
MedDRA Terms or definitions
Infections
!
SOC: Infections and Infestations expect PT of cytomegalovirus colitis.
!
Gastrointestinal infections HLGT in the Gastrointestinal SOC.
PML
!
PT: Human polyomavirus infection in the Infections and Infestations SOC.
!
PT: JC virus infection in the Infections and Infestations SOC.
!
PT: JC virus test positive in the Infections and Infestations SOC.
!
PT: Leukoencephalopathy in the Infections and Infestations SOC.
!
PT: Polyomavirus test positive in the Infections and Infestations SOC.
!
PT: Progressive multifocal leukoencephalopathy in the Infections and 
Infestations SOC.
Malignancies including 
relapse of the primary disease
!
SOC: Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Liver injury
!
Cholestasis and jaundice of hepatic origin SMQ (Broad) 
!
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions 
SMQ (Broad)
!
Hepatitis, non-infectious SMQ (Broad) 
!
Liver related investigations, signs and symptoms SMQ (Narrow)
!
Liver infections SMQ (Broad)
Hypersensitivity Reactions
!
Anaphylactic/anaphylactoid shock conditions SMQ (broad).
!
Angioedema SMQ (broad).
!
Hypersensitivity SMQ (broad).
Leukopenia or Lymphopenia !
PT: Lymphopenia
!
PT: Leukopenia neonatal
!
PT: Leukopenia
!
PT: Radiation leukopenia
!
CMV colitis
!
PT: Cytomegalovirus colitis in the Infections and Infestations SOC
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Statistical Analysis Plan 
22 October 2021
Appendix B
Table, Figures, and Listings for IA
A separate documented labeled as “DMC TLF shells” will summarize the IA report presentation 
details.
Number
Table Title 
Blinded
Unblinded
1
Demographic and Other Baseline Characteristics
Y
Y
2
Summary of Primary Efficacy Endpoint and Conditional Power 
Assessment
Y
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Statistical Analysis Plan 
22 October 2021
Appendix C Recommended Prophylaxis Treatment: A Combination of CNI (TAC or CYS) 
+ MTX and ATG
The background aGvHD prophylaxis regimen described herein is recommended. Dose and 
regimen modification are allowed based on toxicity per investigator discretion, per institutional
practice, and/or per local prescribing information. 
CNI:
1. TAC
a) TAC treatment should start during conditioning, before infusion of the graft.
b) The goal TAC treatment should be to achieve a trough concentration of 5 to 20 ng/dL.
c) Recommended to keep at therapeutic levels through Day +100 or per institutional 
standard.
d) Taper off after Day +100 if no signs of GvHD are observed.
e) The goal should be to discontinue TAC treatment by Day +180 after allo-HSCT.
f)
Doses may be modified or held based on toxicity and institutional practice.
2. CYS
a) CYS should start during conditioning, before infusion of the graft.
b) The goal CYS treatment should be to achieve 150 to 450 ng/L 
c) Recommended to keep at therapeutic levels through Day +100 or per institutional 
standard. 
d) Taper off after Day +100 if no signs of GvHD are observed
e) The goal should be to discontinue CYS treatment by Day +180 after allo-HSCT.
f)
Doses may be modified or held based on toxicity and institutional practice. 
MTX a
a) Administer at 10 to 15 mg/m2 IV on Day +1, and 10 mg/m2 IV on Days +3 and +6, and 
recommended fourth dose on Day +11 after allo-HSCT.
b) Doses may be modified or held based on toxicity and institutional practice.
c) Leucovorin rescue may be administered per institutional practice.
ATG
1. ATG-F
a) Administer up to 10 mg/kg/day (up to a cumulative dose of 30 mg/kg in divided doses) 
and per institutional practice. 
b) NOT to be administered on the same day as study drug (eg, Day -1).
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Vedolizumab-3035
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Statistical Analysis Plan 
22 October 2021
2. Thymoglobulin
a) Administer up to 2.5 mg/kg/day (up to a cumulative dose of 7.5 mg/kg in divided doses) 
and per institutional practice.
b) NOT to be administered on the same day as study drug (eg, Day -1).
a MMF may be substituted for MTX at investigator’s discretion.
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Statistical Analysis Plan 
22 October 2021
Appendix D
Geographic Regions
Region
Countries
North America
Canada
United States
South America
Mexico
Brazil
Argentina
Western/ Northern Europe
Belgium
Italy
Spain
Latvia 
Sweden
France 
Switzerland
Portugal
Germany
Netherlands
United Kingdom
Norway
Central Europe
Czech Republic
Austria
Greece
Hungary
Serbia
Poland
Slovak Republic
Eastern Europe
Estonia
Turkey
Israel
Romania
Russia
Asia / Australia
Australia
Hong Kong
Japan
Taiwan
Republic of Korea
Singapore
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Statistical Analysis Plan 
22 October 2021
Appendix E
Criteria for Identification of Markedly Abnormal Laboratory Values and 
Vital Sign Values.
Hematology—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
Hemoglobin
<0.8 × LLN,
>1.2 × ULN
Hematocrit
<0.8 × LLN,
>1.2 × ULN
RBC count 
<0.8 × LLN, 
>1.2 × ULN
WBC count 
<2.0 ×103/%L
>1.5 × ULN
Platelet count
<70 ×103/%L
>600 × 103/%L
RBC=red blood cell, WBC=white blood cell. LLN=lower limit of normal, ULN=upper limit of normal.
Chemistry—Criteria for Markedly Abnormal Values
Parameter
Low Abnormal
High Abnormal
ALT
--
>3x ULN
AST
--
>3x ULN
GGT
--
>3x ULN
Alkaline phosphatase
--
>3x ULN
Total bilirubin
--
>2.0 mg/dL
Albumin
<2.5 g/dL
--
Total protein
<0.8x LLN
>1.2x ULN
Creatinine
--
>2.0 mg/dL
Sodium
<130 mEq/L
>150 mEq/L
Potassium
<3.0 mEq/L
>6.0 mEq/L
Bicarbonate
<8.0 mmol/L
--
Chloride
<75 mmol/L
>126 mmol/L
Calcium
<1.50 mmol/L
>3.25 mmol/L
Glucose
≤2.8 mmol/L
≥20 mmol/L
Phosphorous
<0.52 mmol/L
>2.10 mmol/L
CPK
--
>5x ULN
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=&-glutamyl transferase, CPK=creatine 
phosphokinase, LLN=lower limit of normal, ULN=upper limit of normal.
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Vedolizumab-3035
Page 44 of 46
Statistical Analysis Plan 
22 October 2021
Appendix F
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85 
>180 
Diastolic blood pressure
mm Hg
<50 
>110
Body temperature
oC
<35.6
>37.7
oF
<96.1
>99.9
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Vedolizumab-3035
Page 45 of 46
Statistical Analysis Plan 
22 October 2021
Appendix G
Clinical Stages and Grades of GvHD
aGvHD Clinical Stage
Stage
Skin
Liver
Intestinal Tracta
Bilirubin: SI units
(standard units)
Diarrhea/day
Subjects ≥18 yrs
or
<18 yrs and ≥50 kg
Subjects <18 yrs 
and <50 kg
1
Maculopapular rash <25% of body 
surface b
34-50 μmol/L
(2-3 mg/dL)
>500 mL 
diarrhea/day
10-19.9 mL/kg/d
2
Maculopapular rash 25%-50% of body 
surface
51-102 μmol/L
(3.1-6 mg/dL)
>1000 mL 
diarrhea/day
20-30 mL/kg/d
3
Rash >50% of body surface
103-255 μmol/L
(6.1-15 mg/dL)
>1500 mL 
diarrhea/day
>30 mL/kg/d
4
Generalized erythroderma with bullous 
formation
>255 μmol/L
(>15 mg/dL)
Severe abdominal 
pain, with or 
without ileus
Severe abdominal 
pain, with or 
without ileus
Source: Przepiorka et al., 1995 [45].
Abbreviations: aGvHD, acute graft-versus-host disease; GvHD, graft-versus-host disease; SI, International System 
of Units.
a Staging of intestinal tract should be assessed based on subject’s age and weight at the time of assessment.
b Use the “Rule of Nines” or burn chart to determine the extent of the rash.
Criteria for IBMTR Severity Index for aGvHD
Skin
Liver
Intestinal Tract
Index
Stage (max)
Stage (max)
Stage (max)
A
1
0
0
B
2
or
1-2
or
1-2
C
3
or
3
or
3
D
4
or
4
or
4
Source: Adapted from Rowlings et al., 1997 [46].
Abbreviations: aGvHD, acute graft-versus-host disease; IBMTR, International Bone Marrow Transplant Registry 
Database.
aGvHD Grade (modified Glucksberg)
Grade
Skin
Liver
Intestinal tract
I
Stage 1-2
None
None
II
Stage 3 or 
Stage 1 or 
Stage 1
III
-
Stage 2-3 or 
Stage 2-4
IV
Stage 4 or 
Stage 4
-
Source: Przepiorka et al., 1995 [45].
Abbreviations: aGvHD, acute graft-versus-host disease; ECOG PS, Eastern Cooperative Oncology Group 
performance status.
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Vedolizumab-3035
Page 46 of 46
Statistical Analysis Plan 
22 October 2021
Criteria for MAGIC Severity Index for aGvHD
Skin
Liver
Upper GI
Intestinal Tracta
Stage
(active erythema only)
(bilirubin)
(stool output/day)
Subjects ≥18 yrs 
or
<18 yrs and ≥50 kg
Subjects <18 yrs 
and <50 kg
0
No active (erythematous) 
GVHD rash
∋2 mg/dL
No or intermittent 
nausea, vomiting 
or anorexia
∋500 mL/day or 
∋3 episodes/day
<10 mL/kg/d or
<4 episodes/day
1
Maculopapular rash <25% 
of body surface (a)
2-3 mg/dL
Persistent nausea, 
vomiting or 
anorexia
500-999 mL/day or 
3-4 episodes/day
10-19.9 mL/kg/d
or
4-6 episodes/day
2
Maculopapular rash 
25%-50% of body surface
3.1-6 mg/dL
-
1000-1500 mL/day
or 5-7 episodes/day
20-30 mL/kg/d 
or
7-10 
episodes/day
3
Maculopapular rash >50% 
of body surface
6.1-15 mg/dL
-
(1500 mL/day or 
(7 episodes/day
>30 mL/kg/d or
>10 
episodes/day
4
Generalized erythroderma 
(>50% BSA) plus bullous 
formation and 
desquamation
>5% body surface
(15 mg/dL
-
Severe abdominal 
pain with or without 
ileus, or
grossly bloody stool 
(regardless of stool 
volume)
Severe 
abdominal pain 
with or without 
ileus, or
grossly bloody 
stool (regardless 
of stool volume)
Source: Harris et al, 2016 [47].
Abbreviations: aGvHD, acute graft-versus-host disease; BSA, body surface area; GI, gastrointestinal; 
GVHD, graft-versus-host disease; MAGIC, Mount Sinai Acute GVHD International Consortium.
Overall clinical grade (based upon most severe target organ involvement):
!
Grade 0: No stage 1-4 of any organ.
!
Grade I: Stage 1-2 skin without liver, upper GI or lower GI involvement.
!
Grade II: Stage 3 rash and/or Stage 1 liver and/or Stage 1 upper GI and/or Stage 1 lower GI.
!
Grade III: Stage 2-3 liver and/or Stage 2-3 lower GI, with Stage 0-3 skin and/or Stage 0-1 upper GI.
!
Grade IV: Stage 4 skin, liver or lower GI involvement, with Stage 0-1 upper GI.
a Staging of intestinal tract should be assessed based on subject’s age and weight at the time of assessment.
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