Clinical trial NCT03961295
Conditions: Healthy Volunteers
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2018-02-22; Completion date: 2018-08-28
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare PK of single dose of vedolizumab SC 108 milligram (mg) administered as PFS vs investigational device.

Detailed description:
The drug being tested in this study is called vedolizumab SC. The study will assess the PK, and variability of a vedolizumab SC in a PFS vs investigational device.

This study will include 2 different device delivery presentations in 2 treatment groups. Participants in each treatment group will be randomized to one of the three administration sites: Abdomen, thigh, or arm. The study will enroll approximately 24 participants, including 4 participants allocated to each administration site within each treatment group. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

* Group A: Vedolizumab SC PFS
* Group B: Vedolizumab SC Investigational Device

All participants will receive a single dose of study drug on Day 1.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 196 days. Participants will be contacted by telephone on Day 168 after their last dose of study drug for a follow-up assessment which will involve the progressive multifocal leukoencephalopathy (PML) questionnaire survey.

Arms: arm 1: Vedolizumab SC 108 mg, injection, subcutaneously using a PFS, once on Day 1. arm 2: Vedolizumab SC 108 mg, injection, subcutaneously using an investigational device, once on Day 1.
Interventions: intervention 1: Vedolizumab SC
Intervention descriptions: intervention 1: Vedolizumab SC liquid.

Protocol documents:
Prot_000.pdf: 


•
Title: A Phase 1, Open-Label, Randomized, Parallel Group Pilot Study to Compare the 
Pharmacokinetics of Single Subcutaneous Injections of Vedolizumab Administered in Prefilled 
Syringe Versus Prefilled Syringe in Autoinjector in Healthy Subjects
NCT Number: NCT03961295
Protocol Approve Date: 11 December 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.
On February 14, 2018 Takeda submitted a protocol clarification letter for the final protocol, dated 11-
Dec-2017, explaining the discrepancies within the protocol. The clarification letter is appended to the
back of the protocol.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Open-Label, Randomized, Parallel Group Pilot Study to Compare the 
Pharmacokinetics of Single Subcutaneous Injections of Vedolizumab Administered in Prefilled 
Syringe Versus Prefilled Syringe in Autoinjector in Healthy Subjects
Vedolizumab SC PFS+AI Pilot Pharmacokinetic Study
Sponsor:
Takeda Development Center Americas, Inc.
One Takeda Parkway, Deerfield, IL 60015
Study Number:
VedolizumabSC-1021
IND Number:
118980
EudraCT Number:
Not applicable
Compound:
Vedolizumab SC
Date:
11 December 2017
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts
A separate contact information list will be provided to each site.
TDC sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines should 
be provided to the site.
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Medical Monitor
(medical advice on protocol and study drug)
Responsible Medical Officer (carries overall 
responsibility for the conduct of the study)
PPD


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CONFIDENTIAL
1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures are provided on the last page of this document.
PPD


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CONFIDENTIAL
INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ....................................................................................................10
3.0
STUDY REFERENCE INFORMATION ......................................................................13
3.1
Study-Related Responsibilities.................................................................................13
3.2
Principal Investigator...............................................................................................13
3.3
List of Abbreviations ...............................................................................................14
3.4
Corporate Identification...........................................................................................15
4.0
INTRODUCTION.........................................................................................................16
4.1
Background .............................................................................................................16
4.2
Rationale for the Proposed Study.............................................................................17
4.3
Benefit/Risk Profile .................................................................................................17
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................19
5.1
Objectives................................................................................................................19
5.1.1
Primary Objective .......................................................................................19
5.1.2
Additional Objectives..................................................................................19
5.2
Endpoints.................................................................................................................19
5.2.1
Primary Endpoints.......................................................................................19
5.2.2
Additional Endpoints ..................................................................................19
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................20
6.1
Study Design ...........................................................................................................20
6.2
Justification for Study Design, Dose, and Endpoints ................................................21
6.3
Premature Termination or Suspension of Study or Study Site...................................21
6.3.1
Criteria for Premature Termination or Suspension of the Study...................21
6.3.2
Criteria for Premature Termination or Suspension of Study Sites ................21
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s).......................................................................22
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............23
7.1
Inclusion Criteria .....................................................................................................23
7.2
Exclusion Criteria ....................................................................................................23
7.3
Excluded Medications, Supplements, Dietary Products............................................26
7.4
Diet, Fluid, Activity Control ....................................................................................26
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................26


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7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................27
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................29
8.1
Study Drug and Materials ........................................................................................29
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................29
8.1.2
Storage........................................................................................................29
8.1.3
Dose and Regimen ......................................................................................30
8.1.4
Overdose.....................................................................................................30
8.2
Study Drug Assignment and Dispensing Procedures................................................30
8.3
Randomization Code Creation and Storage..............................................................31
8.4
Accountability and Destruction of Sponsor-Supplied Drugs.....................................31
9.0
STUDY PLAN ..............................................................................................................33
9.1
Study Procedures.....................................................................................................33
9.1.1
Informed Consent Procedure.......................................................................33
9.1.2
Demographics, Medical History, and Medication History Procedure...........33
9.1.3
Physical Examination Procedure .................................................................33
9.1.4
Weight, Height, and BMI............................................................................34
9.1.5
Vital Sign Procedure ...................................................................................34
9.1.6
Documentation of Concomitant Medications...............................................34
9.1.7
Documentation of Concurrent Medical Conditions......................................34
9.1.8
Procedures for Clinical Laboratory Samples................................................35
9.1.9
Contraception and Pregnancy Avoidance Procedure....................................36
9.1.10
Pregnancy ...................................................................................................39
9.1.11
ECG Procedure ...........................................................................................39
9.1.12
Immunogenicity Sample Collection.............................................................39
9.1.13
PK Sample Collection.................................................................................40
9.1.14
PK Parameters.............................................................................................40
9.1.15
TB Screening ..............................................................................................41
9.1.16
PML Checklist, Wallet Card, and Follow-up Phone call..............................41
9.1.17
Pain Scale Assessment ................................................................................41
9.1.18
Documentation of Screen Failure ................................................................42
9.1.19
Documentation of Randomization ...............................................................42
9.2
Monitoring Subject Treatment Compliance..............................................................42
9.3
Schedule of Observations and Procedures................................................................42
9.3.1
Screening ....................................................................................................43
9.3.2
Randomization............................................................................................43


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9.3.3
Final Visit or Early Termination..................................................................43
9.3.4
Follow-up Visit ...........................................................................................43
9.4
Blood Volume .........................................................................................................43
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................45
10.1
Definitions...............................................................................................................45
10.1.1
PTEs...........................................................................................................45
10.1.2
AEs.............................................................................................................45
10.1.3
Additional Points to Consider for PTEs and AEs.........................................45
10.1.4
SAEs...........................................................................................................47
10.1.5
AEs of Special Interest................................................................................48
10.1.6
Intensity of PTEs and AEs ..........................................................................48
10.1.7
Relationship of AEs to Study Drug(s) .........................................................49
10.1.8
Relationship to Study Procedures................................................................49
10.1.9
Start Date....................................................................................................49
10.1.10
Stop Date ....................................................................................................49
10.1.11
Frequency ...................................................................................................49
10.1.12
Action Concerning Study Drug ...................................................................49
10.1.13
Outcome .....................................................................................................50
10.2
Procedures...............................................................................................................50
10.2.1
Collection and Reporting of AEs.................................................................50
10.2.2
Collection and Reporting of SAEs...............................................................52
10.2.3
Reporting of Abnormal LFTs......................................................................53
10.3
Follow-up of SAEs ..................................................................................................53
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................53
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................54
11.1
Adjudication Committee..........................................................................................54
11.1.1
Risk Assessment and Minimization for PML...............................................54
12.0
DATA HANDLING AND RECORD KEEPING...........................................................55
12.1
CRFs (Electronic and Paper)....................................................................................55
12.2
Record Retention .....................................................................................................55
13.0
STATISTICAL METHODS..........................................................................................57
13.1
Statistical and Analytical Plans ................................................................................57
13.1.1
Analysis Sets...............................................................................................57
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................57
13.1.3
PK Analysis ................................................................................................57


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13.1.4
Safety Analysis ...........................................................................................58
13.2
Interim Analysis and Criteria for Early Termination ................................................58
13.3
Determination of Sample Size..................................................................................58
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................59
14.1
Study-Site Monitoring Visits ...................................................................................59
14.2
Protocol Deviations..................................................................................................59
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................59
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................61
15.1
IRB and/or IEC Approval ........................................................................................61
15.2
Subject Information, Informed Consent, and Subject Authorization .........................62
15.3
Subject Confidentiality ............................................................................................63
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................63
15.4.1
Publication and Disclosure..........................................................................63
15.4.2
Clinical Trial Registration...........................................................................64
15.4.3
Clinical Trial Results Disclosure .................................................................64
15.5
Insurance and Compensation for Injury....................................................................64
16.0
REFERENCES..............................................................................................................65
LIST OF IN-TEXT TABLES
Table 6.a
Summary of Treatment Groups ..........................................................................20
Table 7.a
Prohibited Medications and Supplements...........................................................26
Table 8.a
Dose and Regimen .............................................................................................30
Table 9.a
Clinical Laboratory Tests...................................................................................35
Table 9.b
Collection of Blood Samples for PK Analysis ....................................................40
Table 9.c
Approximate Blood Volume ..............................................................................43
Table 10.a
Takeda Medically Significant AE List................................................................48
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................20
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................66
Appendix B
Responsibilities of the Investigator.....................................................................68


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Appendix C
Elements of the Subject Informed Consent.........................................................70
Appendix D
Investigator Consent to Use of Personal Information..........................................73
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples..............................74


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc
Compound:
Vedolizumab Injection, for Subcutaneous Use 
(Vedolizumab SC)
Title of Protocol: A Phase 1, Open-Label, Randomized, 
Parallel Group Pilot Study to Compare the 
Pharmacokinetics of Single Subcutaneous Injections of 
Vedolizumab Administered in Prefilled Syringe Versus 
Prefilled Syringe in Autoinjector in Healthy Subjects
IND No.: 118980
EudraCT No.:
Not applicable
Study Number: VedolizumabSC-1021
Phase: 1
Study Design:
This is an open-label, randomized, parallel-group study to compare the pharmacokinetics (PK) of a single dose of 
vedolizumab subcutaneous (SC) 108 mg for injection administered in 2 different device delivery presentations in 
healthy subjects. A minimum of 24 subjects (12 per group) will be randomized to 1 of 2 device presentations (Group A 
or B).
Group
Approximate Number of Subjects
Treatment Description (a)
A
12
Single dose vedolizumab SC 108 mg delivered by prefilled syringe 
(PFS) (reference).
B
12
Single dose vedolizumab SC 108 mg delivered by prefilled syringe 
in autoinjector (PFS+AI) (test).
(a) Subjects randomized to each device will also be randomized for the site of administration (abdomen, thigh, or arm). Thus, within 
each treatment group, there are 3 sites of administration (abdomen, thigh, or arm) randomly assigned, for a total of 6 treatment 
combinations.
Subjects will be screened up to 28 days to determine eligibility before randomization. Enrolled subjects will return to 
the clinic at Check-in (Day -1).
Screening
Treatment
Follow-up 
Days
-28 to -2
Day -1 
(Check-in)
Day 1
Day 2
Days 3-8
Days 10, 15, 29, 
43, 64, 85, 106
Final 
Visit/ 
Early 
Termin
ation
Day 
127 (a)
Day 
168 
Follow
-up 
Phone 
Call 
(b)
Dosing, PK, and safety
PK and safety assessments
----------Confinement --------------
(a) In case abnormal, clinically significant findings are observed upon discharge, subjects may be brought back to the clinic for 
re-evaluation per investigator’s discretion.
(b) Subjects will be followed poststudy by telephone to administer a questionnaire, which will include progressive multifocal 
leukoencephalopathy (PML) questions at Day 168 (±3 days). 
Subjects for all treatments groups will be kept in the study unit for at least 24 hours after dosing for safety and PK 
assessment before discharge. The total confinement period will be 2 days. Subjects will return to the study unit 
periodically according to the schedule for PK sampling and safety assessments. Subjects will be required to participate 
in a long-term follow-up safety survey by telephone at Day 168 (±3 days). Subjects who drop out for nonsafety 
reasons will be replaced at the discretion of the investigator and sponsor.


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Primary Objective:

To compare the PK of single dose of vedolizumab SC 108 mg administered as PFS vs PFS+AI.
Subject Population: Healthy men and women (nonpregnant and nonlactating). 
Number of Subjects:
Per dose group: 12
Estimated Total: 24 randomized
Number of Sites: 
Estimated total: 1 site in the United States
Dose Level(s):
Single dose of vedolizumab SC 108 mg 
Route of Administration:
SC injection
Duration of Treatment:
Subject will receive on Day 1 a single dose of vedolizumab 
SC 108 mg
Period of Evaluation:
196 days including Screening Period 
Main Criteria for Inclusion:
Healthy male and female (nonpregnant, nonlactating) subjects aged 18 to 65 years inclusive, with a body mass index 
from 18 to 28 kg/m² or a body weight >50 kg and <90 kg.
Main Criteria for Exclusion:

The subject has received any investigational or approved biologic or biosimilar within 30 days or 5 half-lives, of 
Screening, whichever is longer. 

The subject has had prior exposure to vedolizumab, or has hypersensitivity to vedolizumab or any of its 
components.

The subject has had previous exposure to approved or investigational anti-integrins (eg, natalizumab, efalizumab, 
etrolizumab, AMG 181) or anti-mucosal addressin cell adhesion molecule-1 (MAdCAM-1) antibodies or 
rituximab. 

Subjects with ≥1 positive responses on the PML subjective symptom checklist at Screening or before dosing on 
Day 1.

Subjects with active or latent tuberculosis, regardless of treatment history.
Main Criteria for Evaluation and Analyses:
PK:
Blood samples (5 mL) will be collected for the determination of serum vedolizumab concentrations at the following 
times: predose (within 30 minutes before the start of SC dosing), 2, 8, 24, 72, 120, and 168 hours after Day 1 dosing, 
and on Days 10, 15, 29, 43, 64, 85, 106, and Final Visit Day 127/Early Termination.
The following serum PK parameters for vedolizumab SC will be analyzed as primary PK endpoints for each 
presentation: maximum observed serum concentration (Cmax), area under the serum concentration-time curve from 
time 0 to time of the last quantifiable concentration (AUClast), area under the serum concentration-time curve from 
time 0 to infinity (AUC∞). Additional PK endpoints include area under the serum concentration-time curve from time 
0 to Week 2 (AUCWeek 2), time of first occurrence of Cmax, and terminal disposition phase half-life. 
Safety:
The following safety variables will be used to characterize the safety and tolerability of vedolizumab SC: physical 
examination findings, treatment-emergent adverse events, clinical laboratory test results (clinical chemistry, 
hematology, urinalysis), vital sign measurements, and 12-lead electrocardiogram. Percentage of subjects who are 
positive for antivedolizumab antibodies (AVA) and/or neutralizing AVA. 
Statistical Considerations:
PK:
For summary statistics and median plots by sampling time, the nominal PK sampling time will be used; for individual 
subject plots by time, the actual PK sampling time will be used.
The PK parameters will be summarized descriptively by treatment within each treatment. For AUCWeek 2, AUClast, 


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CONFIDENTIAL
AUC∞, and Cmax, individual subject parameters will be plotted by treatment. 
Natural log transformed AUCWeek 2, AUC∞(if data permit), AUClast, and Cmax will be analyzed using an analysis of 
covariance model with treatment as a fixed effect and weight as a continuous covariate. Estimates of the adjusted mean 
differences (Test-Reference) and corresponding 90% CIs will be obtained from the model. The adjusted mean 
differences and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of adjusted 
geometric means (Test/Reference) and 90% CIs for the ratios. Single doses of 108 mg of vedolizumab administered as 
PFS (reference treatment) will be compared vs PFS+AI (Test Treatment). 
Sample Size Justification: 
The sample size of 12 subjects per group is considered to be sufficient for exploratory purposes. The study is not 
powered for statistical hypothesis testing.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
or
PPD


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3.3
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC∞
area under the serum concentration-time curve from time 0 to infinity
AUClast
area under the serum concentration-time curve from time 0 to time of the last quantifiable 
concentration.
AUCWeek 2
area under the serum concentration-time curve from time 0 to Week 2.
AVA
antivedolizumab antibodies 
BMI
body mass index
CD
Crohn’s disease
CFR
Code of Federal Regulations
CRF
case report form
Cmax
maximum observed serum concentration
ECG
electrocardiogram
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
-glutamyl transferase
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IAC
Independent Adjudication Committee
ICH
International Conference on Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
IV
intravenous
LFT
liver function test
LTFU
long-term follow-up
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
PFS
prefilled syringe
PFS+AI
prefilled syringe plus autoinjector
PK
pharmacokinetics
PTE
pretreatment event
PML
progressive multifocal leukoencephalopathy
RAMP
Risk Assessment and Minimization for PML


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SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
TB
tuberculosis
TEAE
treatment-emergent adverse event
tmax
time to first occurrence of Cmax
UC
ulcerative colitis
ULN
upper limit of normal
VNS
Visual Numeric Scale
WBC
white blood cell
3.4
Corporate Identification 
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Americas, as applicable
Takeda
TDC Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
Vedolizumab (also known as MLN0002, ENTYVIO, or KYNTELES) is a recombinant
humanized monoclonal antibody (mAb) composed of 2 light chains of the subclass and 
2 immunoglobulin G1 heavy chains that binds specifically to the human lymphocyte integrin 47. 
The 47 integrin is a pivotal mediator of gut immunity and inflammation because of its unique 
role in mediating the migration of lymphocytes into gut-associated lymphoid tissue and lamina 
propria, via binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Thus, 
vedolizumab acts as a gut-selective immunomodulator. 
Vedolizumab intravenous (IV) has been developed as a treatment for ulcerative colitis (UC) and 
Crohn’s disease (CD), which are characterized by inflammation of the gastrointestinal tract. 
Marketing approval has been granted in the United States, European Union, and multiple other 
countries for the treatment of adult patients with moderately to severely active UC or CD who have 
failed conventional therapy (ie, corticosteroids or immunomodulators) or tumor necrosis factor 
alpha antagonists. 
Two presentations of vedolizumab have been developed: a lyophilized powder for IV infusion and 
a liquid for subcutaneous (SC) injection. Vedolizumab SC (also known as Vedolizumab Injection, 
for Subcutaneous Use; Vedolizumab Solution for Injection in Prefilled Syringe; or MLN0002 SC) 
is a liquid presentation that has been developed for SC administration. To develop vedolizumab 
SC, the vedolizumab IV presentation was modified to ensure the long-term stability needed for a 
liquid product. However, the vedolizumab SC drug product presentation is similar to that of the 
vedolizumab IV presentation after reconstitution. No changes were made that would impact the 
primary structure of the protein, and comparable biochemical properties and in vitro functional 
activity have been demonstrated. Therefore, the nonclinical and clinical information from studies 
with vedolizumab IV are considered relevant.
The bioavailability, pharmacokinetics (PK), and safety of vedolizumab following a single SC 
injection of vedolizumab SC at 3 dose levels (54, 108, and 160 mg) relative to a single IV infusion 
of vedolizumab IV 300 mg was examined in a phase 1, open-label study (MLN0002SC_101). 
Forty-eight (24 Japanese and 24 non-Japanese) healthy, adult male and female subjects were 
randomized. A total of 12 subjects received a single dose of vedolizumab IV 300 mg and 
36 subjects received a single dose of vedolizumab SC at 54, 108, or 160 mg (12 subjects per dose 
group). The bioavailability estimate from vedolizumab SC was 75.1%. The SC bioavailability was 
independent of the SC doses evaluated (54, 108, and 160 mg vedolizumab SC). All other PK 
parameters estimates were very similar to the values derived from phase 3 data with vedolizumab 
IV, and there were no PK differences by race (Japanese vs non-Japanese). In study 
MLN0002SC_101, 75.0% of subjects (36 of 48 subjects) had treatment-emergent adverse events 
(TEAEs). The percentage of subjects with a TEAE was the same when comparing subjects who 
received vedolizumab SC and subjects who received vedolizumab IV. All TEAEs were considered 
by the investigator to be mild or moderate in intensity; no TEAEs of severe intensity were 
reported. Four subjects had persistently moderate to high antivedolizumab antibodies (AVA) titers 


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for ≥14 weeks with an impact on PK; these subjects were excluded from population PK analysis 
and were not included in the noncompartmental PK summaries. Overall, vedolizumab SC and 
vedolizumab IV were well tolerated in this study. The observed TEAEs were consistent with the 
overall safety profile of vedolizumab.
Previously conducted clinical studies have characterized the efficacy, safety, tolerability, PK, 
pharmacodynamics, and immunogenicity of vedolizumab IV, a lyophilized formulation. As of 
19 November 2016, vedolizumab exposure has extended for ≥12 months in 1832 subjects, 
≥24 months in 1379 subjects, ≥36 months in 1169 subjects, ≥48 months in 862 subjects, 
≥60 months in 645 subjects, ≥72 months in 308 subjects, ≥84 months in 32 subjects, and 
≥96 months in 22 subjects. Based on the most recent drug shipment data (19 November 2016), the 
cumulative patient exposure to vedolizumab IV since its marketing approval in May 2014 is 
estimated to be approximately 77,382 patient-years.
4.2
Rationale for the Proposed Study
IV infusion may not be convenient as long-term therapy, vedolizumab SC has been developed to 
ultimately enable injection of vedolizumab by patients or their caregivers. The safety and efficacy 
of this formulation is currently being investigated in ongoing phase 3 studies in adults with 
moderately to severely active UC or CD who achieved clinical response following open-label 
vedolizumab IV therapy (MLN0002SC-3027 and MLN0002SC-3031). The current presentation 
of the SC formulation is in a prefilled syringe. 
The purpose of this phase 1 clinical study is to assess the PK, and variability of a vedolizumab SC 
108 mg dose in a prefilled syringe (PFS) vs prefilled syringe in autoinjector (PFS+AI). The 
PFS+AI presentation is planned to be the commercially available device after approval.
The information collected in this study will be used to calculate the sample size in study 
VedolizumabSC-1022. 
4.3
Benefit/Risk Profile 
The proposed study (VedolizumabSC-1021) is designed to evaluate the PK and variability of a 
vedolizumab SC 108 mg dose in a PFS vs PFS+AI. No changes were made to the vedolizumab SC 
drug product composition that would impact the primary structure of the protein, and comparable 
biochemical properties and in vitro functional activity have been demonstrated. Therefore, the 
nonclinical and clinical information from studies with vedolizumab IV are considered relevant.
The safety of the vedolizumab SC presentation is expected to be similar to that of vedolizumab IV 
because of similar exposure, outside of expected local administration site events, such as 
injection-site reactions. The observed adverse events (AEs) with vedolizumab SC are consistent 
with the vedolizumab IV safety profile in ongoing phase 3 clinical studies.
A phase 1 single dose study with the SC formulation in health volunteers was conducted and 
identified no safety concerns. This study is comparing different devices and the safety is expected 
to be similar among these devices. 


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Overall, vedolizumab has been well tolerated in clinical studies, including a phase 1 study of 
vedolizumab SC.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective

To compare the PK of single dose of vedolizumab SC 108 mg administered as PFS vs PFS+AI.
5.1.2
Additional Objectives

To evaluate the safety and tolerability of single dose of vedolizumab SC 108 mg administered 
as PFS and PFS+AI.

To evaluate the development of AVA and neutralizing AVA following single dose of 
vedolizumab SC 108 mg administered as PFS and PFS+AI. 
5.2
Endpoints
5.2.1
Primary Endpoints 
The following serum PK parameters will be analyzed for each presentation following a single dose 
of vedolizumab SC: 

Maximum observed serum concentration (Cmax).

Area under the serum concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast).

Area under the serum concentration-time curve from time 0 to infinity (AUC∞).
5.2.2
Additional Endpoints
5.2.2.1
Safety Endpoints
The following safety variables will be used to characterize the safety and tolerability of 
vedolizumab SC: 

Physical examination findings, TEAEs, clinical laboratory test results, vital sign 
measurements, and 12-lead electrocardiograms (ECG).

Percentage of subjects who are positive for AVA during the study.

Percentage of subjects who have positive neutralizing AVA during the study. 
5.2.2.2
PK Endpoints

Area under the serum concentration-time curve from time 0 to Week 2 (AUCWeek 2).

Terminal disposition phase half-life (t1/2z).

Time to first occurrence of Cmax (tmax).


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is an open-label, randomized, parallel-group study to compare the PK of a single dose of 
vedolizumab SC 108 mg for injection administered in 2 different device delivery presentations in 
healthy subjects. A minimum of 24 subjects (12 per group) will be randomized to 1 of 2 device 
presentations (Group A or B).
A summary of the treatment groups is presented in Table 6.a.
Table 6.a
Summary of Treatment Groups
Group 
Approximate Number 
of Subjects
Treatment (a)
A
12
Single dose of vedolizumab SC 108 mg delivered by PFS (reference).
B
12
Single dose of vedolizumab SC 108 mg delivered by PFS+AI (test).
(a) Subjects randomized to each device will also be randomized for the site of administration (abdomen, thigh, or arm). 
Thus, within each treatment group, there are 3 sites of administration (abdomen, thigh, or arm) randomly assigned, for 
a total of 6 treatment combinations.
Subjects will be screened up to 28 days to determine eligibility before randomization. Eligible 
subjects will return to the clinic at Check-in (Day -1). On Day 1, all doses will be administered by
a health care professional. A schematic of the study design is included as Figure 6.a. A schedule of 
assessments is listed in Appendix A.
Figure 6.a
Schematic of Study Design
Screening
Treatment
Follow-up 
Days
-28 to -2
Day -1 
(Check-in)
Day 1
Day 2
Days 
3-8
Days 10, 15, 29, 
43, 64, 85, 106
Final Visit/ 
Early 
Termination
Day 127 (a)
Day 168 
Follow-up 
Phone Call 
(b)
Dosing, PK, 
and safety
PK and safety assessments
----------Confinement --------------
(a) In case abnormal, clinically significant findings are observed upon discharge, subjects may be brought back to the 
clinic for re-evaluation per investigator’s discretion.
(b) Subjects will be followed poststudy by telephone to administer a questionnaire, which will include progressive 
multifocal leukoencephalopathy (PML) questions at Day 168 (±3 days). 
Subjects for all treatments groups will be kept in the study unit from Day -1 Check-in until at least 
24 hours after dosing (Day 2) for safety and PK assessment before discharge. The minimum 
confinement will be 2 nights (Days -1 to 2, inclusive). Subjects can stay longer at the discretion of 
the investigator. Subjects will return to the study units periodically according to the schedule for 
PK sampling and safety assessments. Subjects will be required to participate in a long-term 
follow-up (LTFU) safety survey by telephone on Day 168. 
At least 40% of each sex group will be enrolled.


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6.2
Justification for Study Design, Dose, and Endpoints
This study is designed in accordance with Food and Drug Administration (FDA) Guidance 
documents [1,2]. The primary PK endpoints Cmax and area under the serum concentration-time 
curve are standard parameters to compare the rate and extent of absorption.
This study will be performed in healthy subjects, rather than the target subject population (ie, 
patients with UC or CD) because of the potential for immunogenicity in subjects after single dose 
administration. Similar PK has been observed in healthy subjects and patients with UC or CD 
following administration of vedolizumab IV.
The study design is open-label, since the primary objective is to assess objective variables, that is, 
vedolizumab PK using multiple device presentations. Because this is an objective measurement, 
there is consequently no risk of potential bias of the study results; hence, neither study blinding nor 
inclusion of a placebo group is required. 
Vedolizumab is a mAb with a long half-life that precludes a crossover design. Therefore, a parallel 
design will be used.
Vedolizumab SC dose of 108 mg was selected for this study as it is the dose being tested in phase 3 
vedolizumab SC studies.
AEs, vital signs, weight, ECG findings, and laboratory test results are commonly used safety 
endpoints.
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.


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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of a 
study site, a study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable study sites during the course of termination 
or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before randomization or first dose or 
other.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization before the initiation 
of any study procedures including requesting that a subject fast for any laboratory evaluations. 
3. The subject is a healthy male or female (nonpregnant and nonlactating) adult aged 18 to 
65 years, inclusive, at the time of informed consent.
4. The subject weighs >50 kg and <90 kg or has a body mass index (BMI) from 18 to 28 kg/m2, 
inclusive, at the time of informed consent.
5. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use adequate contraception* from signing of informed consent and for 
18 weeks after the dose. 
6. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent and 
for 18 weeks after the dose.
* Definitions and highly effective methods of contraception are defined in 
Section 9.1.9 and reporting responsibilities are defined in Section 9.1.10.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has had previous exposure to approved or investigational approved biologic or 
biosimilar agent within 30 days or 5 half-lives of Screening.
2. The subject has had previous exposure to approved or investigational anti-integrins 
(eg, natalizumab, efalizumab, etrolizumab, AMG 181) or anti-MAdCAM-1 antibodies or 
rituximab.
3. The subject has had previous exposure to vedolizumab.
4. The subject has had hypersensitivity or allergies to any of the vedolizumab excipients. 
5. The subject has a history of allergic or anaphylactic reaction to any therapeutic or diagnostic 
mAb or molecules made of components of mAb.


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6. The subject has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, or neurodegenerative disease.
7. The subject has 1 or more positive responses on the PML subjective symptom checklist at 
screening or before dosing on Day 1.
8. The subject has any of the following laboratory abnormalities during the Screening Period:
i.
Hemoglobin level <8 g/dL.
ii. White blood cell (WBC) count <3×109/L.
iii. Lymphocyte count <0.5×109/L.
iv. Platelet count <100×109/L or >1200×109/L.
vi. Alkaline phosphatase >3×upper limit of normal (ULN).
vii. Serum creatinine >2×ULN.
9. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at 
Screening or Check-in (Day -1).
10. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 1 year before the Screening Visit or is unwilling to agree to abstain from alcohol 
for 7 days before Day -1 throughout confinement and for 48 hours before each clinic visit; and 
drugs throughout the study.
11. The subject has taken any excluded medication or supplements during the time periods listed 
in Table 7.a.
12. If female, the subject is lactating or has a positive serum pregnancy test during the Screening 
Period or a positive serum pregnancy test at Check-in (Day -1), before study drug 
administration.
13. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 18 weeks after participating in this study; or intending to donate ova during such time 
period. 
14. If male, the subject intends to donate sperm during the course of this study or for 18 weeks 
thereafter. 
15. The subject has evidence of current cardiovascular, central nervous system, hepatic, 
hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, 
asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the 
participant’s medical history, physical examination, or safety laboratory tests giving 
reasonable suspicion of a disease that would contraindicate taking vedolizumab, or a similar 
drug in the same class, or that might interfere with the conduct of this study. This includes, but 
is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias.


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16. The subject has had a surgical procedure requiring general anesthesia within 30 days before the 
initial Screening Visit or is planning to undergo a surgery that requires general anesthesia 
during the study period through Final Visit Day 127.
17. The subject has a history of cancer, except basal cell carcinoma that has been in remission for 
at least 5 years before Day 1.
18. The subject has evidence of an active infection during the Screening Period.
19. The subject has received any live vaccinations within 30 days before Screening.
20. The subject has 1 of the following at Screening:
a) Chronic hepatitis B virus infection: positive for hepatitis B surface antigen (HBsAg) or 
hepatitis B core antibody, or 
b) Chronic hepatitis C virus (HCV) infection: all subjects who tested positive for HCV 
antibody which is confirmed with a positive HCV RNA viral load test (those treated and 
cured for HCV infection are allowed).
21. The subject has active or latent tuberculosis (TB) as evidenced by the following:
a) A diagnostic TB test performed within 30 days of Screening or during the Screening Period 
that is positive, defined as:
–
Positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests, OR
–
A TB skin test reaction ≥5 mm. 
NOTE: If subjects have received BCG vaccine then a QuantiFERON TB Gold test 
should be performed instead of the TB skin test.
Note: Subjects with documented previously treated TB with a negative QuantiFERON test 
can be included in the study.
22. The subject has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
23. The subject has poor peripheral venous access.
24. The subject is unable to attend all the study visits or comply with study procedures.
25. The subject has donated or lost 450 mL or more of his or her blood volume (including serum 
pheresis), or had a transfusion of any blood product within 45 days before Day 1.
26. The subject has a Screening or Check-in (Day -1) abnormal (clinically significant) ECG. Entry 
of any subject with an abnormal (not clinically significant) ECG must be approved and 
documented by signature by the principal investigator or designee. 
27. The subject has abnormal Screening or Check-in (Day -1) laboratory values that suggest a 
clinically significant underlying disease or subject with the following laboratory 
abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1.5
times the ULN.


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28. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress. 
7.3
Excluded Medications, Supplements, Dietary Products
Use of the agents in Table 7.a is prohibited from the time points specified until the collection of the 
last PK sample.
Table 7.a
Prohibited Medications and Supplements 
28 days before Check-in 
(Day -1)
7 days before Check-in 
(Day -1)
Prescription medications
Vitamin supplements
OTC medications (a)
All live vaccines, except for inactivated influenza vaccine
OTC=over-the-counter. 
(a) Occasional use of acetaminophen/paracetamol (1 g/day) or other medication as approved by Takeda on a 
case-by-case basis is allowed.
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator. Limited use of nonprescription medications that are 
not believed to affect subject safety or the overall results of the study may be permitted on a 
case-by-case basis following approval by the sponsor. 
Subjects will abstain from the use of tobacco or nicotine-containing products before dosing and 
during confinement in the research unit. 
7.4
Diet, Fluid, Activity Control 
The meals served on the day of dosing should be identical for each treatment arm in the study. The 
study menu should be recorded and submitted to the study file with a copy provided to the sponsor 
before the start of the study.
If a blood draw or any study procedure coincides with a meal, the study procedures will take 
precedence followed by the blood draw and then the meal. 
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the case report form (CRF) using the following categories. For screen failure 
subjects, refer to Section 9.1.15.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early 
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.


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
Liver Function Test (LFT) Abnormalities
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any time 
during study drug treatment:
–
ALT or AST >8×ULN, or
–
ALT or AST >5×ULN and persists for more than 2 weeks, or
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
2. Significant protocol deviation. The discovery after the first dose of study drug that the subject 
failed to meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
CRF.
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 because of 
an AE should not be recorded in the “voluntary withdrawal” category.
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the CRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 


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Early Termination Visit. Discontinued or withdrawn subjects will be replaced at the discretion of 
the investigator and the sponsor.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term “study drug” refers to all or any of the drugs defined below.
8.1.1.1
Vedolizumab SC in PFS
The study sites will be supplied with the following medication in an open-label manner: liquid 
vedolizumab SC 108 mg/0.68 mL in single-use bare glass PFS with finger flange (PFS). Each PFS
will be labeled and packaged in a single plastic tray with sealed lidding and individually packed 
into a folding box or carton.
Each sealed tray and folding box or carton will have a single-panel label that will contain, but will 
not be limited to the following: sponsor’s name and address, protocol number, packaging job/lot 
number, name and strength of the product, caution statement, directions for use, and storage 
conditions. 
8.1.1.2
Vedolizumab SC in Autoinjector
The study sites will be supplied with the following medication in an open label manner: liquid 
vedolizumab SC 108 mg/0.68 mL in single-use bare glass PFS housed in an autoinjector
(PFS+AI). Each PFS+AI will be packaged in a single plastic tray with sealed lidding, within a
folding box or carton.
Each sealed tray and folding box or carton will have a single-panel that will contain, but will not be 
limited to the following: sponsor’s name and address, protocol number, packaging job/lot number, 
name and strength of the product, caution statement, directions for use, and storage conditions. 
8.1.2
Storage
All clinical trial material must be kept in an appropriate, limited-access, secure location until it is 
used or returned to the sponsor or designee for destruction. All study medication must be stored 
under the conditions specified on the label, and remain in the original container until dispensed. A 
daily temperature log of the drug storage area must be maintained every working day. 
Vedolizumab SC must be stored in a refrigerator at a temperature between 2°C to 8°C (36ºF to 
46ºF). Do not freeze. Retain in original package to protect from light. The investigator should 
ensure that study medication is used only in accordance with the approved protocol. Study 
medication will be dispensed only for subjects enrolled in the study.


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8.1.3
Dose and Regimen
The investigator or investigator’s designee will instruct the subject on dosing procedures. All 
dosing will occur while subjects are in the clinic under the supervision of the principal investigator
or designee as indicated in Table 8.a.
Table 8.a
Dose and Regimen
Group 
Dose
Treatment Description (a)
A
vedolizumab SC 108 mg
Single dose delivered by PFS (reference).
B
vedolizumab SC 108 mg
Single dose delivered by PFS+AI (test). 
(a) Within each treatment group, there are 3 sites of administration (arm, abdomen, or thigh) randomly assigned, for 
6 treatment combinations total.
Detailed instructions for SC administration of vedolizumab with the PFS and PFS+AI will be 
provided to the study site(s) in a separate Instructions for Use and Medication Guide.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
Subjects will be assigned, in the order in which they are randomized into the study, to receive their 
treatment according to the randomization schedule allocated to the site. The randomization 
sequence number will be entered onto the CRF.
Subjects will be assigned to receive a 4-digit randomization sequence number on Day 1. The 
number will be assigned by the clinic site personnel in sequential order. There will be equal 
assignment of the subjects to 1 of the 6 possible combinations of 2 treatments and 3 administration 
sites. Male subjects will be assigned a randomization sequence number in ascending order; female 
subjects will be assigned a randomization sequence number in descending order. 
This 4-digit number will be used by the clinical site to facilitate the prelabeling of PK samples, and 
will be the only subject identifier used on all PK sample collections. It should also be contained on 
the PK transport vials shipped to the bioanalytical laboratory, and will be used by the laboratory to 
report the subject data results. This 4-digit number should only be used for the purposes described 
in this section. It does not replace the 3-digit subject number which is assigned at the time the 


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informed consent is obtained and which is used for all other procedures to identify the subjects 
throughout the study. 
8.3
Randomization Code Creation and Storage 
The final randomization list will be created, reviewed, and approved by Celerion Randomization 
and Unblinding Administrators who are not members of the study team. After the final 
randomization lists have been approved, the randomization lists will be transferred to the Celerion
Pharmacy and kept in a restricted area to which only the Celerion Pharmacy staff has access.
8.4
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug, the investigator or designee must maintain records of all 
sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each subject, and 
return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment by signing bottom half of the packing list and 
faxing per instructions provided on the form. If there are any discrepancies between the packing 
list versus the actual product received, Takeda must be contacted to resolve the issue. The packing 
list should be filed in the investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Continuously monitoring expiration dates if expiry date is provided to the investigator or 
designee. 

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the lot/medication identification/job number used to 
prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator or designee must record the current inventory of all sponsor-supplied drugs on a 
sponsor-approved drug accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, description 


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of sponsor-supplied drugs, expiry and/or retest date, date and amount dispensed, including initials, 
seal, or signature of the person dispensing the drug, and the date and amount returned to the site by 
the subject, including the initials, seal, or signature of the person receiving the sponsor-supplied 
drug. The log should include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
All used devices must be returned intact (not destroyed) to Takeda or designee.
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. The investigator or designee will retain a 
copy of the documentation regarding sponsor-supplied drug accountability, return, and originals 
will be sent to the sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction.
In the event of expiry date extension of supplies already at the study site, sponsor-supplied drugs 
may be relabeled with the new expiry date at that site. In such cases, Takeda or its designee will 
prepare additional labels, certificates of analyses, and all necessary documentation for completion 
of the procedure at the sites.
The on-site pharmacist (the site designee) will immediately return unused study drugs to the 
sponsor after the study is closed at the study site.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained before the subject entering into the study, and before any 
protocol-directed procedures are performed, including requesting that a subject fast for laboratory 
evaluations.
A unique subject identification number (subject number – site + subject number) will be assigned 
to each subject at the time that informed consent is obtained; this subject number will be used 
throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, Hispanic ethnicity, race as 
described by the subject, alcohol use, and smoking status of the subject at Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 14 days before signing of informed consent.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment before 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) gastrointestinal system; (6) dermatologic system; (7) extremities; 
(8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other.
Any abnormal finding on a pretreatment physical examination assessment must be assessed as not 
clinically significant or clinically significant by the investigator and recorded in the source 
document and CRF. All clinically significant findings/changes will be recorded as a PTE or 
concurrent medical condition in the source document and on the appropriate CRF described in 
Section 10.0 or Section 9.1.7.
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately before the start of the study drug must be assessed as not 
clinically significant or clinically significant by the investigator and recorded in the source 


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document and CRF. Any clinically significant change or new diagnosis as a result of a clinically 
significant change, as determined by the investigator, will be recorded as an AE in source 
documentation and on the PTE/AE CRF described in Section 10.0. 
9.1.4
Weight, Height, and BMI
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed. 
BMI equals a person’s weight in kilograms divided by height in meters squared (BMI=kg/m2). 
BMI will be rounded to the nearest whole number according to the standard convention of 0.1 to 
0.4 rounded down and 0.5 to 0.9 rounded up.
9.1.5
Vital Sign Procedure
Vital signs will include body temperature (oral measurement), respiratory rate, sitting/standing
blood pressure (systolic and diastolic, resting more than 5 minutes), and pulse (beats per minute).
Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained at Screening, 
Check-in (Day -1), Day 1 (predose, postdose), Days 8, 106±3, and Final Visit Day 127±3/Early 
Termination. For Day 1, heart rate and blood pressure will be measured after 5 minutes in the 
supine position and at 1 and 3 minutes after standing. For Days 8, 106±3, and 127±3/Early 
Termination, heart rate and blood pressure will be measured after 5 minutes supine only. 
All measurements will be recorded on the source documents and in the CRF. 
Vital signs should be measured at the same time of the day across visits if possible. Beginning on 
Day 1, when vital signs are scheduled at the same time as blood draws, vital signs will take priority 
and will be obtained approximately 5 minutes before the scheduled blood draw. 
9.1.6
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the sponsor. At each study visit, subjects will be asked whether they have taken any medication 
other than the study drug (used from signing of informed consent through the end of the study), 
and all medication including vitamin supplements, over-the-counter medications, and oral herbal 
preparations, must be recorded in the CRF. Documentation will include generic medication name, 
dose, unit, frequency, route of administration, start and end dates, and reason for use. 
9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at screening examination, according to the judgment of the 
investigator. The condition (ie, diagnosis) should be described.


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9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. With the 
exception of the Screening Visit, laboratory samples will be taken following a minimum 10-hour 
overnight fast before collection on the days stipulated in the Schedule of Study Procedures 
(Appendix A).
Table 9.a lists the tests that will be obtained for each laboratory specimen.
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Special
Red blood cells (RBC)
White blood cells (WBC) 
with differential 
Hemoglobin
Hematocrit
Platelets
PT/INR (a)
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Direct bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Sodium
Glucose
Chloride
Bicarbonate
Calcium
pH
Specific gravity
Protein
Glucose
Blood 
Nitrite
Microscopic Analysis*
(only if positive dipstick 
results):
RBC/high power field
WBC/high power field
Epithelial cells, casts etc
*To be performed if 
abnormal (Verify with PV 
MD and Medical Monitor)
QuantiFERON test (b)
Diagnostic Screening:
Serum
Drug and Alcohol Screen
Female subjects only
hCG (for pregnancy) (c)
At Screening Only:
HIV test
Hepatitis panel, including HBsAg and anti-HCV
FSH if menopause is suspected (d)
Drug screen (urine), including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opiates
Alcohol (breathalyzer/urine)
FSH=follicle-stimulating hormone, GGT=-glutamyl transferase, hCG=human chorionic gonadotropin, 
PT=prothrombin time, RBC=red blood cell. 
(a) Prothrombin time/INR to be performed at Screening and Final Visit Day 127/Early Termination. 
(b) Performed at Screening only. All subjects must have documented evidence of a negative QuantiFERON test at 
Screening. Initial indeterminate results will be repeated; a subject with 2 indeterminate results will be excluded.
(c) Serum hCG pregnancy test will be done on all female subjects of childbearing potential at Screening, Check-in 
(Day -1), Day 8, and at Final Visit Day 127/Early Termination.
(d) FSH level will be obtained for female subjects at Screening if they are postmenopausal by history (ie, 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) and not 
surgically sterile. The FSH result must be >40 IU/L for the subject to be permitted not to use adequate contraception. 


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The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results.
If subjects experience ALT or AST >3×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. (Refer to 
Section 7.5 and Section 10.2.3 for the appropriate guidance on reporting abnormal liver function 
tests.)
If the ALT or AST remains elevated >3×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study drug, discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3
for reporting requirements).
All laboratory safety data will be transferred electronically to Takeda or designee in the format 
requested by Takeda. If the laboratory is unable to electronically transfer data, the investigator or 
designee is responsible for transcribing or attaching laboratory results to the CRF. The investigator 
will maintain a copy of the laboratory accreditation and the reference ranges for the laboratory 
used.
Laboratory reports must be signed and dated by the principal investigator or designee indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified before the first dose will require clear and complete
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with enrollment/randomization.
All clinically significant laboratory abnormalities must be recorded as a PTE/AE in the subject’s 
source documents and on the appropriate CRF. A clinically significant laboratory abnormality that 
has been verified by retesting will be followed until the abnormality returns to an acceptable level 
or a satisfactory explanation has been obtained.
9.1.9
Contraception and Pregnancy Avoidance Procedure
9.1.9.1
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study drug, nonsterilized** male subjects who are sexually active with a female partner of 
childbearing potential *must use barrier contraception (eg, condom with spermicidal cream or 
jelly). In addition, they must be advised not to donate sperm during this period. 
9.1.9.2
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 18 weeks after last 
dose of study drug, female subjects of childbearing potential* who are sexually active with a 


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nonsterilized male partner** must use a highly effective method of contraception (from the list 
below).
In addition they must be advised not to donate ova during this period.
9.1.9.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, that is, fertile, following menarche 
and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high FSH level in the 
postmenopausal range (FSH >40 IU/L) may be used to confirm a postmenopausal state in younger 
women (eg, those <45 years old) or women who are not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
** Sterilized men should be at least 1 year post–bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, the 
acceptable methods of contraception are: 

Nonhormonal Methods: 
–
Intrauterine device. 
–
Bilateral tubal occlusion. 
–
Vasectomized partner (provided that partner is the sole sexual partner of the study
participant and that the vasectomized partner has received medical assessment of the 
surgical success. 
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the 
subject. True abstinence is defined as refraining from heterosexual intercourse during 
the entire period of the study, from 1 month before the first dose until 18 weeks after
last dose.

Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method.
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of study drug OR 


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combined with a barrier method (male condom, female condom or diaphragm) if for 
shorter duration until she has been on contraceptive for 3 months:

Oral. 

Intravaginal (eg, ring).

Transdermal. 
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has been 
on contraceptive for 3 months:

Oral. 

Injectable.

Implantable.
2. Subjects will be provided with information on highly effective methods of contraception as 
part of the subject informed consent process and will be asked to sign a consent form stating 
that they understand the requirements for avoidance of pregnancy, donation of ova, and sperm 
donation during the course of the study.
3. During the course of the study, regular serum hCG pregnancy tests will be performed only for 
women of childbearing potential and all subjects (male and female) will receive continued 
guidance with respect to the avoidance of pregnancy and sperm donation as part of the study 
procedures. Such guidance should include a reminder of the following:
a) Contraceptive requirements of the study.
b) Reasons for use of barrier methods (ie, condom) in males with pregnant partners.
c) Assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
iv. Is there a chance you could be pregnant?
4. In addition to a negative serum hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative serum hCG pregnancy test as close as possible and before first 
dose of study medication, preferably on the same day.


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9.1.10
Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 18 weeks after the last dose should also be 
recorded following authorization from the subject’s partner. 
If the pregnancy occurs during administration of active study drug, for example, after Day 1 or 
within 18 weeks of the last dose of active study drug, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.0.
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 female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All reported pregnancies, including female partners of male subjects, will be followed up to final 
outcome, using the pregnancy form. The outcome, including any premature termination, must be 
reported to the sponsor. An evaluation after the birth of the child will also be conducted.
9.1.11
ECG Procedure
Standard 12-lead ECGs will be recorded at Screening, Check-in (Day -1), Day 1 (predose [within 
0.5 hours before dosing the SC injection]), Day 8, and Final Visit Day 127/Early Termination. 
When an ECG recording is scheduled for the same day as blood draws (eg, PK or AVA sampling), 
the ECG recording will be collected 5 minutes before the nominal time of the blood sample.
Additional unscheduled ECGs may be recorded where clinically necessary for subject safety.
ECGs will be read automatically and also, the investigator or subinvestigator will manually 
interpret the ECG using 1 of the following categories: within normal limits, abnormal but not 
clinically significant, or abnormal and clinically significant. All 12-lead ECGs will be stored for 
manual measurement of intervals, if necessary. Twelve-lead ECGs will be recorded using an ECG 
machine that automatically calculates the heart rate and measures PR interval, RR interval, QRS 
interval, QT interval, QT interval with Fridericia correction method, and QT interval with Bazett 
correction method intervals. Paper ECG traces will be recorded for 10 seconds at a standard paper 
speed of 25 mm/sec and gain of 10 m/mV or digital recordings will be used.
One copy of the 12-lead ECG with the physician’s signature and date of assessment will be filed 
with the source documents and captured in the appropriate CRF. If the original ECG is printed on 
thermal paper, the ECG report must be photocopied and certified. The photocopy will be filed with 
the original ECG in source.
9.1.12
Immunogenicity Sample Collection 
Blood specimens for the assessment of AVA will be collected as shown in the Schedule of Study 
Procedures (Appendix A). A sample will be assessed for neutralizing AVA if AVA is detected. If 


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a subject experiences an SAE, a blood sample for AVA assessment should be obtained at the 
unscheduled visit.
Serum titers of AVA will be determined using a validated assay. Neutralizing AVA will be 
determined using a validated assay. 
Instructions for sample processing and shipment are provided in the Laboratory Manual.
9.1.13
PK Sample Collection
9.1.13.1
Collection of Serum for PK Sampling
Blood samples (one 5 mL sample per scheduled time) for PK analysis of vedolizumab will be 
collected into red-top Vacutainers for serum according to the schedule in Appendix A. Instructions 
for sample processing and shipment are provided in Appendix E.
PK samples should be collected as specified in Table 9.b even if the vedolizumab SC is 
discontinued before the complete dose is administered to the subject.
Table 9.b
Collection of Blood Samples for PK Analysis
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
Vedolizumab
Serum
1
Within 0.5 hours before the SC injection (predose), 2, 8, 24, 72, 
120, and 168 hours after Day 1 dosing, and on Days 10, 15, 29, 43, 
64, 85, 106, and Final Visit Day 127/Early Termination (a)
(a) If a subject experiences an SAE, a blood sample for PK analysis should also be obtained at the unscheduled visit. 
PK samples will be collected at Early Termination at the discretion of the investigator.
The actual date and time of sample collection will be recorded on the source document and CRF. 
Samples collected outside 10% of the nominal time will not be considered protocol deviation as 
long as the exact date and time of PK sampling is recorded in the CRF.
9.1.13.2
Bioanalytical Methods
Serum concentrations of vedolizumab will be measured using a validated assay.
9.1.14
PK Parameters 
The PK parameters of vedolizumab will be determined from the concentration-time profiles for all 
evaluable subjects using a noncompartmental analysis method. Actual sampling times, rather than 
scheduled sampling times, will be used in all computations involving sampling times. The 
following PK parameters will be calculated for serum concentration values of vedolizumab.


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Symbol/Term
Definition
Serum
AUCWeek2
Area under the serum concentration-time curve from time 0 to Week 2.
AUClast
Area under the serum concentration-time curve from time 0 to time of the last quantifiable 
concentration.
AUC∞
Area under the serum concentration-time curve from time 0 to infinity, calculated as 
AUC∞=AUClast+Clast/λz
Cmax
Maximum observed serum concentration.
t1/2z
Terminal disposition phase half-life, calculated as ln(2)/λz.
tmax
Time of first occurrence of Cmax.
Additional PK parameters may be calculated as appropriate. A more detailed description will be 
provided in the clinical pharmacology analysis plan.
9.1.15 TB Screening
All subjects will complete TB screening to determine eligibility. All subjects must complete a 
diagnostic during Screening. Subjects will be excluded from the study if they have active or latent 
TB, regardless of treatment history, as defined in Section 7.2.
9.1.16 PML Checklist, Wallet Card, and Follow-up Phone call
Clinic staff will administer the subject PML checklist during Screening to exclude subjects with 
positive responses from enrolling into the study. The PML subjective checklist will be 
administered at Screening Visit, on Day 1 before dose, Day 127 (±3)/Early Termination Visit, and 
at any unscheduled visits.
A wallet card that denotes key study information, including signs and symptoms of PML, will be 
distributed to all subjects during Screening.
Upon completion or early termination from the study, all subjects will be required to participate by 
telephone in a LTFU safety survey on Day 168. A questionnaire will be administered and will 
include PML and neurological symptom question. Any subjects reporting signs and/or symptoms 
of PML will undergo objective testing and may be referred to a neurologist for a full evaluation, as 
described in the Risk Assessment and Minimization for PML (RAMP) algorithm. The PML 
checklists and the RAMP algorithm and tools are included in a separate manual. All confirmed 
cases of PML will be recorded as SAEs.
9.1.17 Pain Scale Assessment
The Visual Numeric Scale (VNS) [3] for self-reported pain assessment at the injection site will be 
completed by each subject. The VNS will be completed on Day 1 immediately following the SC 
injection and a second assessment will be performed between 15 and 30 minutes following the 
injection. Subjects will be presented with the pain scale and instructed to assess their pain on a 
scale of 0 to 10, with 0=no pain and 10=severe pain.


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9.1.18
Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If a subject is withdrawn at 
the screening visit, the investigator should complete the CRF screen failure form.
The primary reason for screen failure is recorded in the CRF using the following categories:

PTE/AE.

Screen failure (did not meet entrance criteria).

Protocol deviation.

Lost to follow-up.

Withdrawal by subject.

Study terminated by sponsor.

Death.
Subject identification numbers assigned to subjects who fail screening should not be reused. If a 
subject fails screening, but is later successfully rescreened, the data for the subject will be entered 
as if these were 2 separate subjects. Therefore the data should be entered as follows:
1. The screen failure data should be entered as a screen failure subject.
2. Rescreened subjects should be assigned a new subject number and treated as a stand-alone 
subject.
9.1.19
Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable CRF.
9.2
Monitoring Subject Treatment Compliance
Study medication will be administered by a health care professional while subjects are under 
observation in the clinical research unit. The date and time of each dose will be recorded in the 
source documents and on the CRFs. An inventory of the study drug supplies dispensed will be 
performed by the site pharmacist or authorized study designee and recorded onto the Drug 
Accountability Log in the subject’s source document records or equivalent. The exact dose time of 
consecutive subjects may be staggered to facilitate logistics at the site.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).


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9.3.1
Screening 
Subjects will be screened within 28 days before first dose of study drug. Subjects will be screened 
in accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.18 for procedures for documenting screening failures.
9.3.2
Randomization
Randomization will take place on Day 1. 
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized as described according to the randomization 
schedule. Subjects will be administered the first dose of study drug in the unit under the 
supervision of the investigator or designee, as described in Section 8.2. The procedure for 
documenting Screening failures is provided in Section 9.1.18.
9.3.3
Final Visit or Early Termination
A Final Visit will be scheduled 127 (±3) days after the dose of study drug or at the Early 
Termination Visit. For all subjects receiving study drug, the investigator must complete the End of 
Study CRF page.
The reason for discontinuation must be documented in the source document and CRF. For all 
subjects receiving study medication, the investigator must complete the End of Study CRF page.
9.3.4
Follow-up Visit
Follow-up will begin after the last dose of study drug and will continue until for 18 weeks (ie, 
Day 127±3 days) thereafter. 
Additionally, upon completion of or early termination from the study, all subjects will participate 
in a LTFU safety questionnaire. The questionnaire will be administered by telephone at 6 months 
(ie, Day 168±3 days) from the last dose of study drug. 
9.4
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.c
Table 9.c
Approximate Blood Volume
Sample Type
Sample Volume 
(mL)
Number of Samples
Total Volume 
(mL)
Screening and 
Day -1
Days 1 to 127
Clinical laboratory tests (Screening)
20 mL 
1
NA
20
Clinical laboratory tests (Nonscreening)
10 mL
1
4
50
AVA assessment
8.5 mL
0
6
51
PK blood collection
5 mL
0
15
75
Total Approximate Blood Sampling Volume
196
NA=not applicable.


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The maximum volume of blood planned for collection at any single day is approximately 38.5 mL, 
and the approximate total volume of blood for the study is 196 mL. 
Total blood volume collections for the study may increase if additional assessments are needed for 
AE/SAE occurrence, or at the investigators discretion. 


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1
PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but before administration of any study drug; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with the use of a drug whether or not 
it is considered related to the drug.
10.1.3
Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered PTEs or 
AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason. 
PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory or ECG re-test and/or continued monitoring of an abnormal value or finding is not 


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considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, x-rays) should NOT be recorded as PTEs unless related 
to study procedures. However, if the subject experiences a worsening or complication of such a 
concurrent medical condition, the worsening or complication should be recorded appropriately 
as a PTE(worsening or complication occurs before start of study drug) or an AE (worsening or 
complication occurs after start of study drug). Investigators should ensure that the event term 
recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) any 
occurrence of an episode should only be captured as a PTE/AE if the condition becomes more 
frequent, serious or severe in nature. Investigators should ensure that the AE term recorded 
captures the change in the condition from Baseline (eg “worsening of…”).

If a subject has a pre-existing degenerative concurrent medical condition (eg, cataracts, 
rheumatoid arthritis), worsening of the condition should only be recorded as a PTE/AE if 
occurring to a greater extent to that which would be expected. Investigators should ensure that 
the AE term recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the condition (eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening of…”).
Changes in intensity of AEs/serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered PTEs or AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) because of a worsening of the pre-existing condition, the 


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worsening of the condition should be recorded as a PTE or an AE. Complications resulting 
from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the CRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the CRF.
10.1.4
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by 
a medicinal product
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements.
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5
AEs of Special Interest
An AE of Special Interest (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.
10.1.6
Intensity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.


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10.1.7
Relationship of AEs to Study Drug(s)
The relationship (causality) of each AE to study drug(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications and concurrent treatments.
10.1.8
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.
10.1.9
Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator.
10.1.10 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.11 Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.12 Action Concerning Study Drug 

Drug withdrawn – a study drug is stopped because of the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study drug was stopped for a reason other than the particular AE, eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE.

Dose interrupted – the dose was interrupted because of the particular AE. 


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10.1.13 Outcome

Recovered/resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – the AEs/PTEs which are considered as the cause of death.

Unknown – the course of the AE/PTE cannot be followed up because of hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study drug (Day 1) or 
until screen failure. For subjects who discontinue before study drug administration, PTEs are 
collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study drug 
(Day 1). Routine collection of AEs will continue until the Final Visit (Day 127±3 days).
10.2.1.2
PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.


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All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the CRF, whether 
or not the investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event:
1. Event term.
2. Start and stop date and time.
3. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
10.2.1.3
AEs of Special Interest
If these special interest AEs, which occur during the treatment period or the follow-up period, are 
considered to be clinically significant based on the criteria below, they should be recorded in a 
special interest AE CRF or an SAE form. The SAE form should be completed and reported to the 
SAE reporting contact in Section 1.0 within 24 hours.
Hypersensitivity Reactions (Including Injection Site 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. 
Vedolizumab SC will be administered by a healthcare professional, who should be 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 SC administration and for 2 hours following completion of the administration. 
Subjects will be instructed to report the development of rash, hives, pruritus, flushing, urticaria, 
injection site pain, redness and/or swelling, etc, that may represent an administration-related 
reaction to study medication. Subjects will be asked to report administration-related AEs to the sites 
immediately as they are experienced or after having received appropriate medical care. Appropriate 
treatment and follow-up will be determined by the investigator. If signs or symptoms of an 
administration-related reaction are observed during the administration of study medication, it should 


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be immediately discontinued and the subject treated as medically appropriate. Subjects with a severe 
or serious administration-related reaction (eg, shortness of breath, wheezing, stridor, angioedema, 
life-threatening change in vital signs, severe injection site reactions) must be withdrawn from the 
study (see Study Manual). 
Any injection site reaction will be collected and graded as follows:
Grade 1: Tenderness with or without associated symptoms (eg warmth, erythema, itching).
Grade 2: Pain, lipodystrophy, edema, phlebitis.
Grade 3: Ulceration or necrosis, severe tissue damage, operative intervention indicated.
Grade 4: Life threatening consequences; urgent intervention indicated.
Other 
Other special interest AEs include liver injury and PML, which are discussed in Sections 10.2.3
and 11.1.1, respectively.
The special interest AEs have to be recorded as AEs in the CRF. An evaluation form along with all 
other required documentation must be submitted to the sponsor.
10.2.2
Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0. 
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.


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10.2.3
Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases CRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3×ULN and total bilirubin >2×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases CRF must 
be completed and transmitted with the Takeda SAE form (as per Section 10.2.1).
10.3
Follow-up of SAEs
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as expedited report 
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of the 
study drug/sponsor supplied drug or that would be sufficient to consider changes in the study 
drug/sponsor supplied drug administration or in the overall conduct of the study. The study site 
also will forward a copy of all expedited reports to his or her IRB or IEC in accordance with local
regulations.


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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
11.1
Adjudication Committee
A PML Independent Adjudication Committee (IAC) will be implemented for this study. The PML 
IAC will consist of a panel of leading PML experts, including a neurologist, neuroradiologist, and 
a virologist. 
11.1.1 Risk Assessment and Minimization for PML
To address the hypothetical risk of the development of PML in patients treated with vedolizumab, 
the sponsor, with input from renowned PML experts, has developed the RAMP program. The 
complete description of the RAMP program, including materials and instructions for its 
implementation and monitoring, is included in a separate manual. The RAMP is focused on early 
clinical detection and management of PML, including the discontinuation of study drug, if 
applicable. Subjects are assessed for signs and symptoms of PML before the administration of 
study drug using a PML subjective symptom checklist. Subjects with a positive PML subjective 
symptom checklist at any time after enrollment in a vedolizumab clinical study will be evaluated 
according to a prespecified algorithm (the PML Case Evaluation Algorithm). An IAC has been 
established as part of the RAMP program to review new neurological signs and symptoms 
potentially consistent with PML, and will provide input regarding patient evaluation and 
management as defined in the IAC charter.
To ensure the success of the RAMP program, site personnel will be trained to recognize the 
features of PML, and subjects will be trained to report specific neurological signs and symptoms 
without delay. Educational materials for teaching site personnel and patients about PML and the 
RAMP procedures will be distributed to the site. Formal teaching and training will be performed 
for site personnel before the start of the study. Subjects will receive training and educational 
materials before receiving treatment. The informed consent form will contain specific information 
on the hypothetical risk of PML. The PML IAC will be informed of all new neurological signs and 
symptoms potentially consistent with PML per the PML Case Evaluation Algorithm and will 
review the individual subject data. The algorithm and tools are included in the Study Manual. All 
documented cases of PML will be reported as SAEs, regardless of whether hospitalization occurs.


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12.0
DATA HANDLING AND RECORD KEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary.
12.1
CRFs (Electronic and Paper)
Completed CRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply study sites with access to CRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the CRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor and regulatory authorities. 
CRFs must be completed in English. Data are transcribed directly onto CRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included.
The principal investigator must review the CRFs for completeness and accuracy and must e-sign 
the appropriate CRFs as indicated. Furthermore, the investigator must retain full responsibility for 
the accuracy and authenticity of all data entered on the CRFs.
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed 
CRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of CRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 


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approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the study site agreement between the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
A targeted 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.
13.1.1
Analysis Sets
Safety Set:
The safety analysis set will consist of all subjects who are enrolled and received 1 dose of study 
drug. Subjects in this analysis set will be used for demographic, baseline characteristics and safety 
summaries.
PK Set:
The PK set will consist of all subjects who receive study drug and have at least 1 measurable serum 
concentration.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment group. Summary 
statistics (number of subjects, mean, SD, median, minimum and maximum) will be generated for 
continuous variables (eg, age and weight) and the number and percentage of subjects within each 
category will be presented for categorical variables (eg, sex, ethnicity, and race). 
13.1.3
PK Analysis
Concentrations will be listed and summarized descriptively by PK sampling time. Summary will 
be done by treatment. Individual subject and median profiles of the concentration-time data will be 
plotted by treatment. For summary statistics and median plots by sampling time, the nominal PK 
sampling time will be used, for individual subject plots by time, the actual PK sampling time will 
be used.
PK parameters will be summarized descriptively by treatment. For AUCWeek 2, AUC∞, AUClast and 
Cmax, individual subject parameters will be plotted by treatment. 
Natural log transformed AUCWeek 2, AUC∞(if data permit), AUClast and Cmax will be analyzed 
using an analysis of covariance model with treatment as a fixed effect and weight as a continuous 
covariate. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% 
CIs will be obtained from the model. The adjusted mean differences and 90% CIs for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric means 


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(Test/Reference) and 90% CIs for the ratios. Single doses of 108 mg of vedolizumab administered 
as PFS (reference treatment) will be compared vs PFS+AI (test treatment). 
Additional statistical analyses may be performed if deemed appropriate.
A more detailed description of the planned analyses will be presented in the SAP.
13.1.4
Safety Analysis
For all safety summary tables stated under this section, the tables will be summarized by treatment, 
for all subjects. AEs will be summarized using the safety analysis set. 
All AEs will be coded using MedDRA. Data will be summarized using preferred term and primary 
system organ class.
The number and percentage of subjects with TEAEs, defined as any AEs, regardless of 
relationship to study drug, AESIs for vedolizumab (ie, PML, liver injury, injection site reactions), 
and SAEs, which occur on or after dosing in subjects, will be summarized by MedDRA system 
organ class, and preferred term, by severity, and by relationship to study drug. Separate summaries 
will also be generated for AEs by treatment-related and severity. Data listings will be provided for 
all AEs (including PTEs for enrolled subjects), AEs leading to study drug discontinuation, AEs 
leading to study visit discontinuation, SAEs, and AEs resulting in death.
Baseline, postbaseline, and change from Baseline in clinical laboratory tests, vital signs, and ECG 
results will be summarized. Subjects with markedly abnormal values for laboratory tests, vital 
signs and ECG results will be tabulated. The mapping of the subjects who meet the markedly 
abnormal value criteria will be listed as a table. Individual results for clinical laboratory tests, vital 
signs and ECG measures will be listed.
Data from the LTFU survey will be summarized descriptively.
VNS pain scale assessment data will be summarized.
The proportion of subjects with positive AVA and proportion of subjects with positive neutralizing 
AVA during the study will be summarized at each visit. 
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
The sample size of 12 subjects per group is considered to be sufficient for exploratory purposes. 
The study is not powered for statistical hypothesis testing.


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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 CRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information (if separate from the 
informed consent forms), and review of CRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol. 
However, blood samples not collected within the interval specified for the scheduled sample time 
should be reported to Takeda using the Protocol Deviation Form.
Protocol Deviation Forms are to be completed for PK samples collected outside 10% of nominal 
time without date and time of sampling collection.
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 FDA, the United Kingdom Medicines and Healthcare 


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products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and study site guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members because of privacy and conflict of interest concerns should instead provide a Federal 
Wide Assurance Number or comparable number assigned by the Department of Health and 
Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug once the sponsor has confirmed 
the adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the study. Until the site receives notification no 
protocol activities, including screening may occur. 
Study sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the informed 
consent form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals specified 
by the respective IRB or IEC, and submission of the investigator’s final status report to IRB or 
IEC. All IRB and IEC approvals and relevant documentation for these items must be provided to 
the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor before use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and before subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the study site agreement. In the event of any discrepancy between the protocol and 
the study site agreement, the study site agreement will prevail.


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15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.


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16.0
REFERENCES
1. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered 
Drug Products - General Considerations. US Dept of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER). March 2003. 
Publication No. 5356.
2. Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of 
Biosimilarity to a Reference Product. US Department of Health and Human Services, Food 
and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for 
Biologics Evaluation and Research (CBER). May 2014.
3. Stanford Patient Education Research Center. Pain Visual Numeric. Stanford School of 
Medicine. Accessed 09 January 2014. Available at: 
http://patienteducation.stanford.edu/research/vnspain.pdf.


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Appendix A
Schedule of Study Procedures
Procedures or Observations
Screening
Treat-
ment
Follow-up (a)
Days
-28 
to -2
Check-
in Day 
-1
Day
1
Day
2
Day
4
Day
6
Day
8
Day
10±1
Day
15±1
Day
29±2
Day
43±2
Day 
64±3
Day
85±3
Day 
106±3
Final Visit 
Day 127±3 / 
ET
Follow-up 
Phone Call 
Day 168±3
Unscheduled 
Visit
Informed consent (b)
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history 
X
Medication history
X
TB screening (c)
X
PML checklist (d)
X
X
X
X
Dispense PML wallet card (d)
X
LTFU questionnaire 
X
Physical examination (e)
X
X
X
X
X
X
Vital signs (f)
X
X
X
X
Height, weight, and BMI (g)
X
X
X
Concomitant medications (h)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concurrent medical conditions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG (i)
X
X
X
X
Laboratory evaluations (j)
X
X
X
X
X
X
Urine drug screen 
X
X
Alcohol screen 
(breathalyzer/urine)
X
X
PT/INR
X
X
Serum pregnancy test (hCG) (k)
X
X
X
FSH (l)
X
HBsAg, Anti-HCV, and HIV
X
Confinement (m)
X
X
X
Administration of study drug
X
Pain assessment (n)
X
AVA assessment (o)
X
X
X
X
X
X
X
PK blood collection (p)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PTE/AE assessment (q)
X
X
X ---------------------------------------------------------------------------------------------------------X
X
Footnotes are on the next page.


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ET=Early Termination, PT=prothrombin time.
(a) Days 10 and 15 have a ±1-day window. Days 29 and 43 have a ±2-day window. Days 64, 85, 106, 127/ET, and 168 have a ±3 day window.
(b) Informed consent must be signed before any study-specific procedures are performed.
(c) All subjects must have a negative QuantiFERON test at Screening. Initial indeterminate results will be repeated; a subject with 2 indeterminate results will be excluded. 
(d) The PML checklist is administered at Screening, on Day 1 before the administration of study drug, and 127±3/ET, and at any unscheduled visits. A wallet card that denotes key 
study information, including signs and symptoms of PML, will be distributed to all subjects at Screening.
(e) A physical examination will be performed at Screening, on Days -1, 1, 8, 29, and at the Final Visit Day 127/ET. All physical examinations will be performed by the investigator or 
subinvestigator. Clinically significant findings on the physical examination that occur after dosing with study drug will be recorded as AEs.
(f) Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained at Screening, Check-in (Day -1), Day 1 (predose, postdose), and Final Visit Day 127±3/ET. 
For Day 1, heart rate and blood pressure will be measured after 5 minutes in the supine position and at 1 and 3 minutes after standing. For Day 127±3/ET, heart rate and blood pressure 
will be measured after 5 minutes supine only. 
(g) Height and weight will be measured and BMI will be calculated at Screening. Weight will also be measured at Check-in Day -1 and Day 106±3.
(h) All ongoing medications from Screening through Final Visit Day 127/ET will be recorded.
(i) Standard 12-lead ECGs will be recorded at Screening, Check-in (Day -1), Day 1 (predose [within 0.5 hours before dosing the SC injection]), Day 8, and Final Visit Day 127/ET. 
When an ECG recording is scheduled for the same day as blood draws (eg, PK or AVA sampling), the ECG recording will be collected 5 minutes before the nominal time of the blood 
sample. 
(j) With the exception of the Screening Visit, clinical laboratory tests (hematology, serum chemistry, and urinalysis) require a minimum 10-hour overnight fast. 
(k) A serum pregnancy test is required for women of childbearing potential only. Pregnancy avoidance counseling will also be performed. 
(l) An FSH level will be obtained on women who are postmenopausal (ie, 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).
(m) Subjects will be confined to the clinic for 2 nights (Day -1 to Day 2, inclusive). 
(n) The pain scale will be administered immediately following the SC injection, and a second assessment will be performed between 15 and 30 minutes following the injection.
(o) Blood samples for determination of AVA will be collected at predose on Day 1 (within 0.5 hours before dosing), Days 29, 64, 85, 106, and 127/ET postdose. AVA positive 
samples will be further analyzed for neutralizing AVA. If a subject experiences an SAE, a blood sample for AVA assessment should be obtained at the unscheduled visit.
(p) Blood samples for PK analyses of vedolizumab will be collected beginning predose on Day 1 (within 0.5 hours before the SC injection) and then at 2, 8, 24, 72, 120, and 168 hours 
after Day 1 dosing, and on Days 10, 15, 29, 43, 64, 85, 106, and Final Visit Day 127/ET. If a subject experiences an SAE, a blood sample for PK analysis should also be obtained at 
the unscheduled visit. PK samples will be collected at ET at the discretion of the investigator.
(q) PTEs will be captured following the signing of the informed consent at Screening. Routine collection of AEs will occur from the administration of study drug until Final Visit Day 
127/ET and the unscheduled visit. Any new AEs will be recorded in the CRFs and site source document. If any SAE is reported spontaneously to the investigator following the AE 
collection period, the event will be reported to the sponsor if it is considered to be related to study participation.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. 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 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, 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 


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contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 


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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.


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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from Screening and throughout the duration of the study, and for 18 weeks after last 
dose of study drug. Regular pregnancy tests will be performed throughout the study for all 
female subjects of childbearing potential. If a subject is found to be pregnant during study, 
study drug will be discontinued and the investigator will offer the subject the choice to receive 
unblinded treatment information. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 18 weeks after 
last dose. If the partner or wife of the subject is found to be pregnant during the study, the 
investigator will offer the subject the choice to receive unblinded treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov. 


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Appendix D
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


Vedolizumab SC
Study No. VedolizumabSC-1021
Page 74 of 74
Protocol 
11 December 2017
CONFIDENTIAL
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples 
Instructions for Processing of Serum Samples for PK Analysis of Vedolizumab
1. Collect 5 mL of venous blood into a Becton-Dickinson Vacutainer. For all vedolizumab 
samples, blood samples should be collected into red stopper vacutainers. Direct venipuncture 
is the only method of blood collection.
2. Allow the red top Vacutainer to sit at room temperature for approximately 30 to 60 minutes 
(refer to product information for correct time) to ensure proper clot formation.
3. To separate the serum samples, centrifuge the Vacutainers for 10 minutes at approximately 
1100 to 1300 relative centrifugal force at room temperature in a centrifuge. Note: if using a 
collection device other than Becton-Dickinson, refer to manufacturer’s instruction for proper 
centrifugation force and time.
4. To ensure a more homogeneous sample, all serum should first be transferred into 1 aliquot. 
From there, split the serum evenly between the 2 aliquots into polypropylene tubes. A 
minimum of 1.0 mL needs to be obtained for each sample. Labeling may include protocol 
number (VedolizumabSC-1021), matrix (ie, serum), analyte (vedolizumab), randomization 
sequence number, nominal day and time, and either “SET 1” (for original sample) or “SET 2” 
(for duplicate sample).
5. Cap the labeled storage tubes and freeze the serum samples immediately at approximately 
-70°C. No more than 1 hour and 45 minutes must be allowed to elapse between collecting 
blood and freezing the serum sample.
6. Keep samples frozen at approximately -70°C or lower until shipment to Quest Pharmaceutical 
Services (QPS), Newark, DE before shipment to QPS. “SET 1” samples will be shipped first 
on dry ice, followed by shipment of duplicate “SET 2” samples after “SET 1” samples have 
been received.


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PPD



SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Open-Label, Randomized, Parallel Group Pilot Study to Compare the 
Pharmacokinetics of Single Subcutaneous Injections of Vedolizumab Administered in Prefilled 
Syringe Versus Prefilled Syringe in Autoinjector in Healthy Subjects
NCT Number: NCT03961295
SAP Approve Date: 24 May 2018
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: VedolizumabSC-1021
CELERION STUDY NUMBER: CA23618
A Phase 1, Open-Label, Randomized, Parallel Group Pilot Study to Compare the
Pharmacokinetics of Single Subcutaneous Injections of Vedolizumab Administered in 
Prefilled Syringe Versus Prefilled Syringe in Autoinjector in Healthy Subjects
Vedolizumab SC PFS + AI Pilot Pharmacokinetic Study
PHASE 1
Version: Final
Date: 24 May 2018
Prepared by:
Based on:
Protocol Dated: 11 December 2017
Protocol Clarification Letter Dated: 14 February 2018
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


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1.1
Approval Signatures
Study Title:
A Phase 1, Open-Label, Randomized, Parallel Group Pilot Study to 
Compare the Pharmacokinetics of Single Subcutaneous Injections of 
Vedolizumab Administered in Prefilled Syringe Versus Prefilled Syringe in 
Autoinjector in Healthy Subjects - Vedolizumab SC PFS + AI Pilot 
Pharmacokinetic Study
Approvals:
PPD


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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..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Additional Objectives ................................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoints .....................................................................................................9
5.2
Additional Endpoints .................................................................................................9
5.2.1
Safety Endpoints..................................................................................................9
5.2.2
PK Endpoints.......................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................12
7.2
Analysis Sets ...........................................................................................................12
7.3
Disposition of Subjects ............................................................................................13
7.4
Demographic and Other Baseline Characteristics.....................................................13
7.5
Medical History and Concurrent Medical Conditions...............................................13
7.6
Medication History and Concomitant Medications...................................................13
7.7
Study Drug Exposure and Compliance.....................................................................13
7.8
Efficacy Analysis.....................................................................................................14
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................14
7.9.1
Pharmacokinetic Analysis ..................................................................................14
7.9.2
Pharmacodynamic Analysis ...............................................................................15
7.10
Other Outcomes.......................................................................................................15
7.11
Safety Analysis........................................................................................................15
7.11.1 Adverse Events ..................................................................................................15
7.11.2 Clinical Laboratory Evaluations .........................................................................17


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7.11.3 Vital Signs .........................................................................................................18
7.11.4 12-Lead ECGs ...................................................................................................18
7.11.5 Other Observations Related to Safety.................................................................18
7.12
Interim Analysis ......................................................................................................19
7.13
Analysis of Pharmacokinetic Data up to 2 Weeks Postdose......................................20
7.14
Changes in the Statistical Analysis Plan...................................................................20
8.0
REFERENCES..............................................................................................................21
9.0
SUMMARY TABLES AND FIGURES ........................................................................22
9.1
In-text Summary Tables and Figures........................................................................22
9.2
Section 15 Summary Tables and Figures..................................................................23
9.3
Section 16 Data Listings ..........................................................................................26
10.0
TABLE AND FIGURE SHELLS ..................................................................................29
10.1
In-Text Summary Table Shells.................................................................................29
10.2
Figure Shells............................................................................................................35
10.3
Section 15 Summary Table Shells............................................................................41
11.0
LISTING SHELLS........................................................................................................70


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ANCOVA
analysis of covariance
AUC
area under the curve
AUC∞
area under the serum concentration-time curve from time 0 to infinity
AUClast
area under the serum concentration-time curve from time 0 to time of the last 
quantifiable concentration.
AUCWeek2
area under the serum concentration-time curve from time 0 to Week 2.
AVA
antivedolizumab antibodies 
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
Cmax
maximum observed serum concentration
CPAP
Clinical Pharmacology Analysis Plan
CRF
case report form
CS
clinically significant
CSR
clinical study report
CV
coefficient of variation
ECG
electrocardiogram
eCRF
electronic case report form
GCV
geometric coefficient of variation
Geo. Mean
geometric mean
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
ln
natural log
LSM
least-square means
LTFU
long-term follow-up
Mean
arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
PFS
prefilled syringe
PFS+AI
prefilled syringe in autoinjector
PI
Principal Investigator
PK
pharmacokinetics
PML
progressive multifocal leukoencephalopathy
RAMP
Risk Assessment and Minimization for PML
SAE
serious adverse event
SC
subcutaneous
SD
standard deviation
SEM
standard error of the mean


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SOC
system organ class
t½
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TFL
tables, figures and listings
tmax
time to first occurrence of Cmax
VNS
Visual Numeric Scale
WHO
World Health Organisation


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4.0
OBJECTIVES
4.1
Primary Objectives

To compare the pharmacokinetics (PK) of single dose of vedolizumab subcutaneous (SC) 
108 mg administered as prefilled syringe (PFS) vs prefilled syringe in autoinjector (PFS+AI).
4.2
Secondary Objectives
Not applicable.
4.3
Additional Objectives

To evaluate the safety and tolerability of single dose of vedolizumab SC 108 mg 
administered as PFS and PFS+AI.

To evaluate the development of antivedolizumab antibodies (AVA) and neutralizing AVA 
following single dose of vedolizumab SC 108 mg administered as PFS and PFS+AI.
4.4
Study Design
This is an open-label, randomized, parallel-group study to compare the PK of a single dose of 
vedolizumab SC 108 mg for injection administered in 2 different device delivery presentations 
(2 treatments) in healthy subjects. A minimum of 24 subjects (12 per group) will be randomized 
to 1 of 2 device presentations (Group A or B).
A summary of the treatment groups is presented in Table 4-1.
Table 4-1
Summary of Treatment Groups
Group 
Approximate Number 
of Subjects
Treatment (a)
A
12
Single dose of vedolizumab SC 108 mg delivered by PFS (reference)
B
12
Single dose of vedolizumab SC 108 mg delivered by PFS+AI (test)
(a) Subjects randomized to each device (1:1 ratio) were also randomized for the site of administration (abdomen, 
thigh, or arm) (1:1:1 ratio). Thus, within each treatment group, there are 3 sites of administration (abdomen, thigh, 
or arm) randomly assigned, for a total of 6 treatment combinations.
Subjects were randomized to each Group in a 1:1 ratio using 12 blocks of 2. Within each Group 
subjects were randomized to injection site in a 1:1:1 ratio using 4 blocks of 3. No stratification 
factors were used in the randomization. However, at least 40% of each sex will be enrolled. 
Subjects will be screened up to 28 days prior to dosing, to determine eligibility before 
randomization. Eligible subjects will return to the clinic at Check-in (Day -1). On Day 1, all 
doses will be administered by a health care professional. A schematic of the study design is 
included as Figure 4-1.


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Figure 4-1
Schematic of Study Design
Screening
Treatment
Follow-up 
Days
-28 to -2
Day -1 
(Check-in)
Day 1
Day 2
Days 3-8
Days 10, 15, 
29, 43, 64, 85, 
106
Final Visit/ 
Early 
Termination
Day 127 (a)
Day 168 
Follow-up 
Phone Call 
(b)
Dosing, PK, 
and safety
PK and safety assessments
----------Confinement --------------
(a) In the case that abnormal, clinically significant findings are observed upon discharge, subjects may be brought 
back to the clinic for re-evaluation per investigator’s discretion.
(b) Subjects will be followed poststudy by telephone to administer a questionnaire, which will include progressive 
multifocal leukoencephalopathy (PML) questions at Day 168 (±3 days). 
Subjects for all treatment groups will be kept in the study unit from Day -1 Check-in until at least 
24 hours after dosing (Day 2) for safety and PK assessments before discharge. The minimum 
confinement will be 2 nights (Days -1 to 2, inclusively). Subjects can stay longer at the discretion 
of the investigator. Subjects will return to the study unit periodically according to the schedule 
for PK sampling and safety assessments. Subjects will be required to participate in a long-term 
follow-up (LTFU) safety survey by telephone on Day 168.


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The following serum PK parameters will be analyzed for each treatment (PFS and PFS+AI) 
following a single dose of vedolizumab SC:

Maximum observed serum concentration (Cmax).

Area under the serum concentration-time curve (AUC) from time 0 to time of the last 
quantifiable concentration (AUClast).

AUC from time 0 to infinity (AUC∞).
5.2
Additional Endpoints
5.2.1
Safety Endpoints
The following safety variables will be used to characterize the safety and tolerability of 
vedolizumab SC:

Physical examination findings, treatment-emergent adverse events (TEAEs), clinical 
laboratory test results, vital sign measurements, and 12-lead electrocardiograms (ECGs).

Percentage of subjects who are positive for AVA during the study.

Percentage of subjects who have positive neutralizing AVA during the study.
5.2.2
PK Endpoints

AUC from time 0 to Week 2 (AUCWeek2).

Terminal disposition phase half-life (t½).

Time to first occurrence of Cmax (tmax).

Apparent clearance after extravascular administration (CL/F).

Apparent volume of distribution during the apparent terminal phase after extravascular 
administration (Vz/F).


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6.0
DETERMINATION OF SAMPLE SIZE
The sample size of 12 subjects per group is considered to be sufficient for exploratory purposes. 
The study is not powered for statistical hypothesis testing.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All PK analyses will be conducted using 
r higher. All 
statistical analyses will be conducted using
 or higher.
Arithmetic mean (mean), median, and geometric mean (Geo. Mean) values will be presented to 1 
more level of precision than the individual values. Standard deviation (SD) and standard error of 
the mean (SEM) will be presented to 2 more levels of precision than the individual values. 
Minimum and maximum values will be presented to the same precision as the individual values. 
Arithmetic percent coefficient of variation (CV%) and geometric percent coefficient of variation
(GCV%) will be presented to 1 decimal place. 
Geometric least-squares means (LSMs) will be presented with 1 more level of precision than the 
recorded data. Geometric LSMs are least-squares means derived from analysis of covariance 
model with weight as a covariate, and then exponentiated to provide estimates on the original 
scale. Ratios of geometric LSMs (presented as a %) and 90% confidence intervals (CIs) about a 
parameter estimate will be reported as 2-sided and presented using 2 decimal places.
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated by treatment group, 
site of injection, and overall, where applicable. The denominator for the proportion 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 tabulated. 
Concentration values below the limit of quantitation (BLQ) will be presented as ‘BLQ’ in the 
concentration table listings and footnoted accordingly. BLQ values will be treated as zero for the 
calculation of summary statistics, the generation of concentration plots, and the calculation of PK 
parameters, unless they are obvious outliers (eg, BLQ value between 2 measurable values), in 
which case they will be treated as missing.
For the calculation of PK parameters, if actual times are missing, nominal times will be used 
instead.
A subject’s PK parameter data will be included in the listings but excluded from the descriptive 
statistics and statistical evaluation if one or more of the following criteria are met: 
!
A predose (0 hr) concentration is greater than 5% of that subject’s Cmax value in that period 
(eg, single dose BE studies).
!
A subject did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion pharmacokineticist).
!
A subject deviates substantially from the protocol defined study procedures including but not 
limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion pharmacokineticist).
CCI
CCI


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See Clinical Pharmacology Analysis Plan (CPAP) for details on the PK parameter calculations 
and data presentation including specifics on the following:

Insufficient data to determine a reliable t½ value and other terminal elimination rate constant 
dependent parameters.

PK parameters presented by treatment and by site of administration within each treatment, 
including the units, precision, and summary statistics that will be presented in in-text and 
end-of-text tables.

Concentration data presented by treatment, including the units, precision, and summary 
statistics that will be presented in end-of-text tables.

Concentration data file used for PK analysis.

PK parameter WinNonlin® output file used to generate the tables, figures, and listings 
(TFLs).

Analysis of covariance (ANCOVA) results including all subjects and excluding 
AVA-positive subjects (sensitivity analysis) presented in in-text and end-of-text tables.

Arithmetic mean concentration-time figures presented as in-text and end-of-text figures.

Individual concentration-time figures presented in Appendix 16.2.6.

AUC and Cmax scatter plots presented by treatment and by site of administration within each 
treatment as in-text and end-of-text figures.
7.1.1
Study Definitions
7.1.2
Definition of Study Days
Day 1 is defined as the date on which a subject is administered their first dose of the medication. 
Other study days are defined relative to Day 1 with Day -1 being the day prior to Day 1. Study 
day prior to the first dose of treatment will be calculated as: date of assessment/event-date of 
treatment; study day on or after the date of first dose will be calculated as: date of 
assessment/event-date of treatment +1.
7.2
Analysis Sets
Safety Set:
The Safety Set will consist of all subjects who are enrolled and received 1 dose of study drug. 
Subjects in this analysis set will be used for demographic, baseline characteristics and safety 
summaries.
PK Set:
The PK Set will consist of all subjects who receive study drug and have at least 1 measurable 
serum concentration. 


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7.3
Disposition of Subjects
Disposition of subjects (number of subjects dosed, completed the study, discontinued from the 
study, and reason(s) for discontinuation) will be summarized for each treatment and overall. 
Study completion status, including reason for discontinuation, will also be listed by subject. A 
separate listing will be generated for screen failures.
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment group and overall. 
Summary statistics (number of subjects [N], mean, SD, minimum, median, and maximum) will 
be generated for continuous variables (age [calculated from the date of signed Informed Consent 
Form [ICF], weight, height and body mass index [BMI]) and the number and percentage of 
subjects within each category will be presented for categorical variables (sex, race, and 
ethnicity). For height the screening measurement will be reported but for weight and BMI the 
check-in value will be reported. The demographics listing will also include the date each signed 
the ICF. A separate listing will be generated for screen failures.
7.5
Medical History and Concurrent Medical Conditions
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing of 
informed consent. Concurrent medical conditions are those significant ongoing conditions or 
diseases that are present at signing the ICF. Each subject’s medical history and concurrent 
medical conditions will be listed. Any medical condition started after taking the study drug will 
be classified as an adverse event. The medical history listing will include whether the event was 
medical or surgical, the body system or organ class involved, start date (if known) and end date 
or whether the condition was ongoing, and a description of the condition or event. There will be 
no statistical analysis of medical history.
7.6
Medication History and Concomitant Medications
Medication history to be obtained includes any medication relevant to eligibility criteria and 
efficacy/safety evaluation stopped at or within 14 days prior to signing of informed consent. 
Concomitant medications are recorded on the CRF and include any medication other than study 
drug taken at any time between time of signing the informed consent through the end of the 
study (including follow-up visit). All medication history and concomitant medications recorded 
during the study will be coded with the World Health Organization (WHO) Dictionary Version 
01-Sep-2017 and listed. The listing will include the medication name, dosage, route of 
administration, start date and time (if known), end date and time, or whether it continued after 
study completion, and indication for use.
7.7
Study Drug Exposure and Compliance
Not applicable.


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7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Blood samples (one 5 mL sample per scheduled time) for PK analysis of vedolizumab will be 
collected as specified in Table 7-1 even if the vedolizumab SC is discontinued before the 
complete dose is administered to the subject.
Table 7-1
Collection of Blood Samples for Pharmacokinetic Analysis
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
Vedolizumab
Serum
1
Within 0.5 hours before the SC injection (predose), 2, 8, 24, 72, 120, and 
168 hours after Day 1 dosing, and on Days 10 (Hour 216), 15 (Hour 336), 
29 (Hour 672), 43 (Hour 1008), 64 (Hour 1512), 85 (Hour 2016), 106
(Hour 2520), and Final Visit Day 127 (Hour 3024)/Early Termination (a)
(a) If a subject experiences a serious adverse event (SAE), a blood sample for PK analysis should also be obtained at 
the unscheduled visit. PK samples will be collected at Early Termination at the discretion of the investigator.
The actual date and time of sample collection will be recorded on the source document and 
electronic case report form (eCRF).
Samples collected outside 10% of the nominal time will not be considered a protocol deviation 
as long as the exact date and time of PK sampling is recorded in the eCRF.
The PK parameters of vedolizumab listed in the CPAP for this study will be determined from the 
concentration-time profiles for all evaluable subjects using a noncompartmental analysis method. 
Actual sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times. If actual sample times are missing, nominal times may be used.
Concentrations will be listed and summarized descriptively by PK sampling time. Summary will 
be done by treatment using the summary statistics listed in the CPAP. Excluded concentrations 
will be presented and footnoted as such in the concentration table listings, and those values will 
be excluded from the descriptive summary. Individual subject and arithmetic mean profiles of 
the concentration-time data will be plotted by treatment on linear and semi-log scales. For 
summary statistics and arithmetic mean plots by sampling time, the nominal PK sampling time 
will be used, for individual subject plots by time, the actual PK sampling time will be used. 
PK parameters will be summarized descriptively by treatment and by site of administration 
within each treatment using the summary statistics listed in the CPAP. Excluded parameters will 
be presented and footnoted as such in the PK parameter table listings, and those values will be
excluded from the descriptive summary. Scatter plots of the individual AUClast, AUC∞, and Cmax
values, including the median values, will be plotted by treatment and by site of administration 
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Natural log (ln)-transformed AUClast, AUC∞(if data permits), and Cmax will be analyzed using an 
ANCOVA model. The model will include treatment and site of administration as fixed-effects 
and weight as a continuous covariate. The following
will be used for the analysis:
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs will be 
obtained from the model. The adjusted mean differences and 90% CIs for the differences will be 
exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 
90% CIs for the ratios. Single doses of 108 mg of vedolizumab SC administered as PFS+AI (test 
treatment) will be compared vs PFS (reference treatment).
In addition to the analysis described above using all subjects, a sensitivity analysis will be 
performed excluding subjects that are AVA-positive.
The information collected in this study up to Week 2 will be used to calculate the sample size in 
study VedolizumabSC-1022 (Celerion Study Number CA23621).
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Not applicable.
7.11
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, changes from 
baseline in the subjects’ clinical laboratory results, vital signs, and ECG’s using the safety set. 
Reasons for discontinuation will be tabulated. Exposure to study drug will be presented in 
by-subject listings. All clinical safety data will be listed by subject and assessment time points, 
including rechecks, unscheduled assessments, and early termination, chronologically. 
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators.
7.11.1 Adverse Events
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity (mild, moderate or severe), relationship to vedolizumab SC and to 
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study procedures (related or unrelated) and action relative to the study drug and procedures. All 
AEs occurring during this study will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA®), Version 20.1. However, only TEAEs occurring after administration of 
the first dose of study drug and through the end of the study (127 days after the last dose of study 
drug) will be summarized. 
A TEAE is defined as an AE that is starting or worsening at the time of or after study drug 
administration. If an AE increases in severity, that AE will be given a resolution date and time, 
and a new AE will be entered with the new severity. If the severity of an AE remains the same or 
decreases, the AE will be kept open through to resolution.
For each treatment, TEAEs will be coded using MedDRA® Version 20.1 and tabulated by 
System Organ Class (SOC) and Preferred Term. Summary tables will include number of subjects 
reporting the AE and as percent of safety set by treatment. The most commonly reported TEAEs 
(ie, those events reported by >5% of all subjects) will also be summarized.
In addition, they will be summarized as number of AEs and percentage of AEs for each 
treatment. Additional summary tables will be presented by severity and relationship to 
vedolizumab SC and relationship to study procedure. If a subject has multiple AEs with different 
severity levels within the same term, the subject will be counted in the most severe category
only. If a subject has both related and unrelated AEs with the same term, the subject will be 
counted as having related TEAEs.
Adverse events of special interest (AESI) will be summarized by treatment and injection site 
using AESI definitions presented in Table 7-2. 


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Table 7-2
Adverse Events of Special Interest
Adverse Event
MedDRA Terms or definitions
Injection site reaction
Injection Site Reaction (HLT)
Hypersensitivity Reactions
Anaphylactic/anaphylactoid shock conditions SMQ (broad).
Angioedema SMQ (broad).
Hypersensitivity SMQ (broad).
PML
Human polyomavirus infection PT.
JC virus infection PT.
JC virus test positive PT.
Leukoencephalopathy PT.
Polyomavirus test positive PT.
Progressive multifocal leukoencephalopathy PT.
Liver injury
Cholestasis and jaundice of hepatic origin SMQ (Broad) 
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions 
SMQ (Broad)
Hepatitis, non-infectious SMQ (Broad) 
Liver related investigations, signs and symptoms SMQ (Narrow) 
Liver infections SMQ (Broad)
Should any SAEs occur they will be summarized the same way as TEAE. In addition, all SAEs, 
AEs leading to discontinuation, and AEs resulting in death occur during this study these will be 
listed by subject. All AEs will be displayed in the data listings and TEAEs will be discussed in 
the text of the study report.
7.11.2 Clinical Laboratory Evaluations
Hematology, serum chemistry, and urinalysis will be performed at screening, check-in (Day -1) 
and Days 8, 29, 85 and 127 postdose. In addition, laboratory safety tests may be performed at 
various unscheduled time points, if deemed necessary by the Principal Investigator (PI).
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by treatment and assessment time 
points. Change from baseline will be summarized using last assessment including rechecks taken 
prior to dosing.
For each laboratory test, a shift table will be developed comparing the frequency of the results at 
treatment baseline (above normal (H), normal (N), or below normal (L)) with those postdose 
time points for each regimen. For urinalysis tests, the categories are normal (N) and abnormal 
(A). Out-of-range values and corresponding recheck results will be listed. 
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. If a value fails the reference range, it will 
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range, it will be noted as “N” for not clinical significant. If the value fails the CS range, it will be 
flagged with a “Y” which prompts the PI to determine how the out-of-range value should be 
followed using 4 Investigator flags: “N”, not clinically significant, “R”, requesting a recheck, 
“^”, checking at the next scheduled visit, or “Y”, clinically significant. All clinically significant 
lab tests and the corresponding values will be listed by subject. All clinical laboratory data will 
be presented in by-subject data listings.
7.11.3 Vital Signs
Vital signs (oral temperature, respiration, pulse, and blood pressure) will be obtained at 
screening, check-in (Day -1), Day 1 (predose, postdose), Days 8, 106, and Final Visit 
Day 127/Early Termination. For Day 1, heart rate and blood pressure will be measured after 
5 minutes in the supine position and at 1 and 3 minutes after standing. For Days 8, 106, and 
127/Early Termination, heart rate and blood pressure will be measured after 5 minutes supine 
only.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for vital 
sign results and change from baseline by treatment and time point. Baseline is defined as the last 
assessment including rechecks taken prior to dosing. Vital signs will also be displayed in a data 
listing by subject.
7.11.4 12-Lead ECGs
Standard 12-lead ECGs will be recorded at screening, check-in (Day -1), Day 1 (predose; within
0.5 hours before dosing the SC injection), Day 8, and Final Visit Day 127/Early Termination. 
Additional unscheduled ECGs may be recorded where clinically necessary for subject safety. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results and change from baseline by treatment and time point. Baseline is defined as the last 
assessment including rechecks taken prior to dosing. ECG data will also be displayed in a data 
listing by subject.
7.11.5 Other Observations Related to Safety
7.11.5.1 Standardize immunogenicity analysis for AVA data
Definitions of AVA negative, positive and positive neutralizing:

AVA Negative: defined as a sample that was evaluated as negative in the AVA screening 
assay. Samples that were determined to be positive in the AVA screening assay but the result 
was not confirmed in the AVA confirmatory assay were considered negative.

AVA Positive: defined as a sample that was evaluated as positive in both the AVA screening 
and confirmatory assays.

Neutralizing AVA Positive: defined as a sample that was evaluated as positive in the 
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Subject AVA status will be grouped into 3 categories as follows:  

Negative: defined as subjects who did not have confirmed AVA results.

Positive: defined as patient who had at least 1 positive AVA result.
–
Transiently positive: defined as subjects with confirmed positive AVA in 1 sample.
–
Persistently positive: defined as subjects with confirmed positive AVA in 2 or more 
consecutive positive AVA samples.
Subject AVA positive at baseline is defined as a positive AVA sample at Week 0 (predose).
The proportion and percentage of subjects that are AVA negative, AVA positive, and 
neutralizing AVA positive will be presented for each visit by treatment (all injection sites 
combined = overall), by each injection site separately within each treatment, and in total for both 
treatments combined. The proportion and percentage of subjects that are AVA positive will be 
presented for each titer for each visit by treatment (all injection sites combined = overall), by 
each injection site separately within each treatment, and in total for both treatments combined. 
The frequency and percentage of subjects that are AVA negative, AVA positive, transiently 
AVA positive, persistently AVA positive, and neutralizing AVA positive will be presented for 
each visit by treatment (all injection sites combined = overall), by each injection site separately 
within each treatment, and in total for both treatments combined.
The PML subjective checklist will be administered at Screening Visit, on Day 1 before dose, 
Day 127/Early Termination Visit, and at any unscheduled visits. Any subjects reporting signs 
and/or symptoms of PML will undergo objective testing and may be referred to a neurologist for 
a full evaluation, as described in the Risk Assessment and Minimization for PML (RAMP) 
algorithm. PML checklist responses and algorithm results will be displayed in a data listing by 
subject.
The Visual Numeric Scale (VNS) for self-reported pain assessment at the injection site will be 
completed by each subject on Day 1 immediately following the SC injection and a second 
assessment will be performed between 15 and 30 minutes following the injection. Subjects will 
be presented with the pain scale and instructed to assess their pain on a scale of 0 to 10, with 
0=no pain and 10=severe pain. Pain scale assessment responses will be displayed in a data listing 
by subject.
Subjects will self-report any pain, pruritus, erythema, swelling, hematoma, discoloration, 
warmth, or bruising at the injection site to study medication. In addition, the location of the 
reaction (arm, abdomen, thigh), laterality (right or left) and maximum diameter of the reaction 
will be recorded. Injection site reactions will be graded on a 1 to 4 scale. If there are any 
hypersensitivity reactions, a hypersensitivity reaction assessment will be completed. Injection 
site reaction and hypersensitivity reaction (if any) results will be displayed in a data listing.
7.12
Interim Analysis
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7.13
Analysis of Pharmacokinetic Data up to 2 Weeks Postdose
Ln-transformed AUCWeek2 and Cmax will be analyzed using the same ANCOVA model described 
in Section 7.9.1.
Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% CIs will be 
obtained from the model. The adjusted mean differences and 90% CIs for the differences will be 
exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 
90% CIs for the ratios. Single doses of 108 mg of vedolizumab SC administered as PFS+AI (test 
treatment) will be compared vs PFS (reference treatment).
The information collected in this study up to Week 2 will be used to calculate the sample size in 
study VedolizumabSC-1022 (Celerion Study Number CA23621).
7.14
Changes in the Statistical Analysis Plan 
The protocol specified median profiles of the concentration-time data will be plotted by 
treatment; however, arithmetic mean profiles will be generated instead. 
The protocol stated that single doses of 108 mg of vedolizumab SC administered as PFS will be 
compared vs PFS+AI, however single doses of 108 mg of vedolizumab SC administered as 
PFS+AI (test treatment) will be compared vs PFS (reference treatment) instead.
The original protocol included site of administration as a fixed-effect in the statistical model. It 
was later removed when the protocol was amended. However, site of administration is still in the 
protocol for VedolizumabSC-1022. To keep the analysis of the data consistent between the two 
studies, and to ensure that site of administration is included in the sensitivity analysis to be 
performed excluding AVA-positive subjects, site of administration will be included in the 
statistical model for VedolizumabSC-1021.
A sensitivity analysis using the same model as described in Section 7.9.1 will also be performed 
excluding subjects that are AVA-positive.
The protocol states that values of subjects with markedly abnormal values for laboratory tests, 
vital signs and ECG results will be tabulated and mapped. However, after discussions between 
Celerion and Takeda, it was decided that these would not be presented.
In addition to the 3 additional PK endpoints described in the protocol (AUCWeek2, t½ and tmax), 
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8.0
REFERENCES
Not applicable.


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9.0
SUMMARY TABLES AND FIGURES
Summary tables and figures are numbered following the International Conference on 
Harmonisation (ICH) structure but may be renumbered as appropriate during the compilation of 
the tables and figures for the clinical study report (CSR). Please note that PK and safety 
summary tables and figures will be generated using 
or higher.
The following are lists of TFL numbers and titles that will be included within the CSR.
9.1
In-text Summary Tables and Figures
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9.2
Section 15 Summary Tables and Figures
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15.2.2 Pharmacokinetic Data Summary Figures
15.3
Safety Data Summary Tables
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9.3
Section 16 Data Listings
Note: Hepatitis and human immunodeficiency virus (HIV) results that are provided by the 
clinical laboratory will not be presented in subject data listings or included in any database 
transfer.
Data listings are numbered following the ICH structure but may be renumbered as appropriate 
during the compilation of the TFLs for the CSR. The following is a list of appendix numbers and 
titles that will be included as data listings:
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10.0
TABLE AND FIGURE SHELLS 
The following table shells provide a framework for the display of data from this study. The shells 
may change due to unforeseen circumstances. These shells may not be reflective of every aspect 
of this study, but are intended to show the general layout of the tables that will be presented and 
included in the final report. Unless otherwise noted, all tables will be presented in Times New 
Roman font size 8.
 
.
10.1
In-Text Summary Table Shells
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In-text Table 11-2 will be in the following format:
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Appendix 16.2.6.1.X
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11.0
LISTING SHELLS
The following listing shells provide a framework for the display of data from this study. The 
shells may change due to unforeseen circumstances. These shells may not be reflective of every 
aspect of this study, but are intended to show the general layout of the listings that will be 
presented and included in the final report. These listings will be generated off of the 
 
. All 
listings will be presented in Courier New size font 9.
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