Conditions: Crohn Disease
Keywords: Drug Therapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 55
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the effect of triple combination therapy with an anti-integrin (vedolizumab intravenous \[IV\]), a tumor necrosis factor (TNF) antagonist (adalimumab subcutaneously \[SC\]), and an immunomodulator (oral methotrexate) on endoscopic remission in participants with newly-diagnosed CD stratified at higher risk for complications.

Detailed description:
The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat people who have CD. This study will look at the endoscopic remission and mucosal healing of gastrointestinal tract of people who take vedolizumab as triple combination therapy with adalimumab and methotrexate.

The study will enroll approximately 60 participants. Participants will receive triple combination therapy which includes:

* Vedolizumab 300 mg (intravenous)
* Adalimumab 160/80/40 mg (subcutaneous)
* Methotrexate 15 mg (oral)

All participants will receive vedolizumab intravenous infusion on Weeks 0, 2, 6, 14 and 22 along with adalimumab 160 mg, subcutaneous injection at Week 0, 80 mg at Week 2, then 40 mg once at Week 4 and every 2 weeks thereafter until Week 26 along with methotrexate tablets orally, once weekly from Weeks 0 up to Week 34. In monotherapy phase, all participants will receive vedolizumab intravenous infusion once at Weeks 30, 38, 46, 54, 62, 70, 78, 86, 94 and 102.

This multi-center trial will be conducted in the United States and Canada. The overall time to participate in this study is 128 weeks. Participants will make multiple visits to the clinic, plus a final visit 18 weeks after last dose of study drug for a safety follow-up assessment. Participants will also participate in a long-term safety questionnaire, by phone, at 26 weeks (6 months) from the last dose of study drug.

Arms:
arm 1: In Triple Combination Therapy Phase, vedolizumab 300 mg, intravenous (IV) infusion, once at Weeks 0, 2, 6, 14 and 22, with adalimumab 160 mg subcutaneously (SC), once at Week 0, then 80 mg once at Week 2, then 40 mg once at Week 4 and every 2 weeks thereafter until Week 26 along with oral methotrexate 15 mg tablets orally once weekly from Weeks 0 up to Week 34. In Monotherapy Phase, vedolizumab 300 mg IV infusion once at Weeks 30, 38, 46, 54, 62, 70, 78, 86, 94 and 102.

Interventions: intervention 1: Vedolizumab intervention 2: Adalimumab intervention 3: Methotrexate
Intervention descriptions: intervention 1: Vedolizumab intravenous infusion. intervention 2: Adalimumab injection for subcutaneous use. intervention 3: Methotrexate oral tablets.

Protocol document:
SAP_002.pdf: 
NCT Number: NCT02764762
Title: An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Triple Combination 
Therapy With Vedolizumab IV, Adalimumab SC, and Oral Methotrexate in Early Treatment of 
Subjects With Crohn’s Disease Stratified at Higher Risk for Developing Complications
Study Number: Vedolizumab-4006
Document Version and Date: Amendment 2; 21 February 2023
Certain information within this document has been redacted (ie, specific content is masked irreversibly 
from view) to protect either personally identifiable information or company confidential information. 
Statistical Analysis Plan


CONFIDENTIAL
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Vedolizumab-4006
An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Triple Combination
Therapy With Vedolizumab IV, Adalimumab SC, and Oral Methotrexate in Early
Treatment of Subjects With Crohn’s Disease Stratified at Higher Risk for Developing
Complications
PHASE 4
Version: Amendment 2
Date: 21 February 2023
Prepared by:
Based on:
Protocol Version: Amendment 04
Protocol Date: 30 June 2020
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.
Property of Takeda: For Non-C
Versi
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1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objective......................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Additional Objectives ................................................................................................8
4.4
Safety Objective ........................................................................................................9
4.5
Study Design .............................................................................................................9
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Additional Endpoints ...............................................................................................11
5.4
Safety Endpoints......................................................................................................12
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................13
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Study Definitions ...............................................................................................14
7.1.2
Definition of Study Days....................................................................................14
7.1.3
Definition of Baseline Values.............................................................................14
7.1.4
Definition of Screen Failure ...............................................................................15
7.1.5
Definition of Study Visit Windows ....................................................................15
7.1.6
Convention for Calculation of CDAI Scores.......................................................18
7.1.7
Convention for Calculation of PRO-2 Score.......................................................19
7.1.8
Convention for Calculation of IBDQ Sub-domain and Total Score.....................20
7.1.9
Convention for Calculation of WPAI-CD Sub-scores.........................................20
7.1.10 Convention for Calculation of IBD-DI ...............................................................21
7.1.11 Conventions for Missing Adverse Event Dates...................................................21
7.1.12 Conventions for Missing Concomitant Medication Dates...................................22
7.1.13 Conventions for Calculation of Duration of CD..................................................23
7.2
Analysis Sets ...........................................................................................................24
7.3
Disposition of Subjects ............................................................................................24
7.4
Demographic and Other Baseline Characteristics.....................................................25
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7.5
Medical History and Concurrent Medical Conditions...............................................29
7.6
Medication History and Concomitant Medications...................................................29
7.7
Study Drug Exposure and Compliance.....................................................................30
7.8
Efficacy Analysis.....................................................................................................31
7.8.1
Primary Efficacy Endpoint(s).............................................................................31
7.8.2
Secondary Efficacy Endpoint(s).........................................................................31
7.8.3
Additional Efficacy Endpoint(s).........................................................................32
7.8.4
Subgroup Analysis .............................................................................................33
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................34
7.9.1
Pharmacokinetic Analysis ..................................................................................34
7.9.2
Pharmacodynamic Analysis ...............................................................................34
7.10
Other Outcomes.......................................................................................................34
7.11
Safety Analysis........................................................................................................34
7.11.1 Adverse Events ..................................................................................................34
7.11.2 Clinical Laboratory Evaluations .........................................................................36
7.11.3 Vital Signs .........................................................................................................39
7.11.4 12-Lead ECGs ...................................................................................................39
7.11.5 Other Observations Related to Safety.................................................................39
7.12
Interim Analysis ......................................................................................................39
7.13
Changes in the Statistical Analysis Plan...................................................................40
8.0
REFERENCES..............................................................................................................42
9.0
APPENDICES...............................................................................................................43
LIST OF IN-TEXT TABLES
Table 7.a
Visit Windows for Triple Combination Therapy Phase: CDAI, Safety 
Laboratory Parameters, Vital Signs, ADA and Serum/Urine hCG ......................16
Table 7.b
Visit Windows for Triple Combination Therapy Phase: Other Endpoints ...........16
Table 7.c
Visit Windows for Monotherapy Phase: CDAI, Safety Laboratory Parameters, 
Serum/Urine hCG, Vital Signs, and ADA ..........................................................17
Table 7.d
Visit Windows for Monotherapy Phase: Other Endpoints...................................17
Table 7.e
Summary of Demographic and Baseline Characteristics.....................................26
Table 7.f
Summary of CD-Related Baseline Characteristics..............................................27
Table 7.g
Clinical Laboratory Tests...................................................................................38
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LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ................................................................................10
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................44
Appendix B
Crohn's Disease Activity Index (CDAI) .............................................................52
Appendix C
Adverse Events of Special Interest (AESI).........................................................53
Appendix D
Criteria for Identification of Markedly Abnormal Laboratory Values .................54
Appendix E
Criteria for Identification of Markedly Abnormal Values for Vital Signs............56
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3.0
LIST OF ABBREVIATIONS
ADA
antidrug antibodies
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ASCA
anti-Saccharomyces cerevisiae antibody
AST
aspartate aminotransferase
BMI
body mass index
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
eCRF
electronic case report form
CRO
contract research organization
CRP
C-reactive protein
CV
Conventional units
ECG
Electrocardiogram
EHI
endoscopic healing index
FAS
full analysis set
FSH
follicle-stimulating hormone
GGT
-glutamyl transferase
GI
Gastrointestinal
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IBD
Inflammatory bowel disease
IBD-DI
Inflammatory Bowel Disease Disability Index
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonisation
INR
international normalized ratio
IP
Investigational Product
IRT
interactive response technology
IV
Intravenous
LLN
lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
Monitr CD 
Monitr Crohns Disease
nADA
neutralizing antidrug antibodies
PK
Pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PPS
per protocol set
PRO-2
Patient Reported Outcome 2
PROSPECT
Crohn’s Disease Personalized Risk and Outcome Prediction Tool
PTE
pretreatment event
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SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SC
Subcutaneous
SES-CD
Simple Endoscopic Score for Crohn’s Disease
TB
Tuberculosis
TNF
tumor necrosis factor
ULN
upper limit of normal
WBC
white blood cell
WHODrug
World Health Organization Drug Dictionary
WPAI-CD
Work Productivity and Activity Impairment - Crohn’s Disease
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4.0
OBJECTIVES
4.1
Primary Objective
The primary objective is to determine the effect of triple combination therapy with an anti-
integrin (vedolizumab intravenous [IV]), a tumor necrosis factor (TNF) antagonist (adalimumab 
subcutaneous [SC]), and an immunomodulator (oral methotrexate) on endoscopic remission of 
moderate to severe Crohn’s Disease (CD) at Week 26.
4.2
Secondary Objectives
Secondary objectives include:

To evaluate the effect of vedolizumab IV monotherapy on endoscopic remission at Week 102 
following triple combination therapy.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy 
on endoscopic healing at Weeks 26 and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy 
on endoscopic response at Weeks 26 and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy 
on deep remission at Weeks 26 and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy 
on clinical remission by Crohn’s Disease Activity Index (CDAI) at Weeks 10, 26, 52, 78, and 
102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy 
on clinical response by CDAI at Weeks 10, 26, 52, 78, and 102. 
4.3
Additional Objectives
Additional objectives include:

To evaluate the pharmacokinetics (PK) of vedolizumab and adalimumab in CD subjects at 
higher risk for complications at Week 26.

To assess immunogenicity to vedolizumab and adalimumab over the follow-up period.

To evaluate C-reactive protein (CRP) levels at Weeks 10 and 26.

To evaluate fecal calprotectin at Weeks 10, 14, 26, 52, 78, and 102.

To evaluate the impact of triple combination therapy on health-related quality-of-life 
(HRQOL) using the Inflammatory Bowel Disease Questionnaire (IBDQ), Work Productivity 
and Activity Impairment - Crohn’s Disease (WPAI-CD), and the Inflammatory Bowel 
Disease Disability Index (IBD-DI).
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–
To evaluate endoscopic remission, defined as Monitr Crohn’s Disease (Monitr CD) 
Endoscopic Healing Index (EHI) score ≤20, at Weeks 26 and 102. 
–
To evaluate Monitr CD EHI score ≤30 or ≤50 at Weeks 26 and 102.
4.4
Safety Objective
The safety objective is to evaluate the safety of triple combination therapy with an anti-integrin, 
a TNF antagonist, and an immunomodulator over a 26-week period, followed by 76 weeks of 
monotherapy with an anti-integrin.
4.5
Study Design
This is a phase 4, open-label, multicenter study in subjects with newly-diagnosed CD at higher 
risk for complications due to aggressive disease. The study will investigate the efficacy and 
safety of triple combination therapy (300 mg vedolizumab IV, 160/80/40 mg adalimumab SC, 
and 15 mg oral methotrexate) over a 26-week treatment phase for induction of clinical 
endoscopic remission and mucosal healing followed by efficacy and safety of vedolizumab IV 
monotherapy to maintain remission for 76 weeks, for a total treatment phase of 102 weeks.
Approximately 60 subjects with moderate to severe active CD at higher risk for disease 
complications will be studied at approximately 65 sites in the United States and Canada. Subjects 
must be diagnosed with CD within the previous 24 months and be naïve to biologics. Subjects 
will be determined to be at increased risk of CD complications. Subjects at low risk for CD 
complications will be excluded. Subjects will be followed for a total of 128 weeks.
The study consists of up to a 4-week screening period, a 26-week triple combination treatment 
phase, an additional 76-week vedolizumab IV monotherapy treatment phase, and a 26-week 
follow-up period following last dose (with final efficacy evaluations at Week 120). The duration 
of the study from screening to final efficacy visit at Week 120 will be approximately 124 weeks. 
All subjects, including subjects who discontinue early, will participate in a safety follow-up 
telephone call 26 weeks after last dose, for a total follow-up of 128 weeks.
A schematic of the study design is included as Figure 4.a. A schedule of assessments is listed in 
Appendix A.
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Figure 4.a
Schematic of Study Design
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint is the percentage of subjects achieving endoscopic remission (defined as a 
Simple Endoscopic Score for Crohn’s Disease [SES-CD] of 0-2) at Week 26.
5.2
Secondary Endpoints
Secondary endpoints are as follows:

Percentage of subjects achieving endoscopic healing defined as SES-CD ≤4 AND reduction 
from baseline SES-CD of at least 2 points AND no individual SES-CD subscore >1 at 
Week 26.

Percentage of subjects achieving endoscopic response defined as 50% reduction in SES-CD 
from baseline at Week 26.

Change from baseline SES-CD score at Week 26.

Percentage of subjects achieving deep remission (defined as CDAI <150 and SES-CD 0-2) at 
Week 26.

Percentage of subjects achieving clinical remission (defined as CDAI <150) AND 
endoscopic response as a measure of mucosal healing (defined as 50% reduction in SES-CD 
from baseline) at Week 26.

Percentage of subjects achieving clinical remission (CDAI score <150) at Weeks 10 and 26.

Percentage of subjects achieving clinical response (defined as ≥100 point decrease in CDAI 
score) at Weeks 10 and 26.

Change from baseline C-reactive protein (CRP) levels at Weeks 10 and 26.
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
Change in fecal calprotectin concentrations from baseline at Weeks 10, 14, 26, 52, 78, and 
102.

Percentage of subjects achieving clinical remission (defined as CDAI <150) AND CRP <5 
(in subjects with elevated CRP at baseline) at Weeks 26, 52, 78, and 102.

Percentage of subjects using oral corticosteroids at baseline who have discontinued 
corticosteroids and are in clinical remission (CDAI score <150) at Weeks 10, 26, and 102.

Percentage of subjects maintaining clinical remission (defined as CDAI <150) at Weeks 52, 
78, and 102.

Percentage of subjects maintaining clinical response (defined as ≥100 point decrease in 
CDAI score from baseline) at Weeks 52, 78, and 102.

Percentage of subjects maintaining endoscopic remission (defined as SES-CD of 0-2) at 
Week 102.

Percentage of subjects maintaining deep remission (defined as CDAI <150 and SES-CD 0-2) 
at Week 102.

Percentage of subjects maintaining endoscopic healing defined as SES-CD ≤4 AND 
reduction from baseline SES-CD of at least 2 points AND no individual SES-CD 
subscore >1 at Week 102.

Percentage of subjects maintaining endoscopic response defined as 50% reduction in SES-
CD from baseline at Week 102.

Percentage of subjects maintaining clinical remission (defined as CDAI <150) AND 
endoscopic response as a measure of mucosal healing (defined as 50% reduction in SES-CD 
from baseline) at Week 102.

Percentage of subjects with first exacerbation of CD after 26 weeks (defined as a CDAI 
increase of >70 from the prior visit on 2 occasions separated by a 2-week interval, objective 
evidence of disease activity by colonoscopy AND CRP above normal, OR fecal 
calprotectin >250 μg/g alone).
5.3
Additional Endpoints
Additional endpoints include the following:

Change from baseline IBDQ score at Weeks 14, 26, 52, 78, and 102.

Change from baseline WPAI-CD score at Weeks 14, 26, 52, 78, and 102.

Change from baseline in IBD-DI score at Weeks 14, 26, 52, 78, and 102.

Percentage of subjects achieving normalization of CRP defined as <5 mg/L at Week 26 (in 
those elevated at baseline).

Trough concentration of vedolizumab and adalimumab at Week 26.
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
Change from baseline CDAI score at Weeks 26, 52, 78, and 102.

Change from baseline of Patient Reported Outcome 2 (PRO-2) score at Weeks 26, 52, 78, 
and 102.

Change from Week 26 CDAI score at Weeks 52, 78, and 102.

Change from Week 26 PRO-2 score at Weeks 52, 78, and 102.

Change from Week 26 CRP levels at Weeks 52, 78, and 102.

Percentage of subjects with positive antidrug antibodies (ADAs) to vedolizumab and 
adalimumab, and neutralizing ADAs (nADAs) to vedolizumab. (Percentage of subjects with 
nADAs to adalimumab is optional if deemed necessary for the interpretation of the data).

Time to major CD-related events (hospitalizations, bowel surgeries, and CD-related 
procedures).

Percentage of subjects hospitalized from Day 1 to Week 102.

Percentage of subjects hospitalized due to CD from Day 1 to Week 102.

Percentage of subjects requiring surgery other than seton placement for perianal fistula from 
Day 1 to Week 102.

Percentage of subjects achieving a PRO-2 score ≤75 AND an SES-CD ≤4 AND a reduction 
from baseline SES-CD of at least 2 points AND no individual SES-CD subscore >1 at Weeks 
26 and 102.

Percentage of subjects assessed at screening as having moderate-high risk CD with ≥20% 
chance of disease complication by Year 2 as calculated by the Crohn’s Disease Personalized 
Risk and Outcome Prediction Tool (PROSPECT [2, 3]) for subjects for whom that tool was 
used.

Percentage of subjects developing a CD related complication by Week 102 who were 
assessed at screening as having moderate-high risk CD with ≥20% chance of disease 
complication by Year 2 as calculated by the PROSPECT predictive tool for those for whom 
that tool was used.

Percentage of subjects with an EHI score ≤20 at Weeks 26 and 102.

Percentage of subjects with an EHI score ≤30 at Weeks 26 and 102.

Percentage of subjects with an EHI score ≤50 at Weeks 26 and 102.

Change from baseline in EHI score at Weeks 26 and 102.
5.4
Safety Endpoints
Safety will be assessed by adverse events (AEs), adverse events of special interest (AESIs), 
serious adverse events (SAEs), AEs leading to discontinuation, vital signs, physical examination, 
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and results of standard laboratory tests (clinical chemistry, hematology, coagulation, and 
urinalysis).
6.0
DETERMINATION OF SAMPLE SIZE
The sample size was based on an estimate of precision. A sample size of 60 subjects will 
generate 95% confidence intervals for endoscopic remission (defined as SES-CD of 0-2) rate at 
Week 26 with a half width no wider than 12.7% and expected remission of 50%. If the expected 
remission rate is different from 50%, a required sample size would be smaller.
7.0
METHODS OF ANALYSIS AND PRESENTATION
This statistical analysis plan (SAP) is written based on the study protocol Amendment 4, 
30 June 2020 [1].
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.2, or higher. 
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 phase. 
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. 
All confidence intervals, statistical tests, and resulting p-values will be reported as 2-sided and 
will be assessed at α=0.05 significance level unless otherwise stated. P-values will be rounded to 
3 decimal places prior to assessment of statistical significance.
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
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7.1.1
Study Definitions
Study specific definitions are listed below:
Term
Definition
Endoscopic remission
SES-CD of 0-2.
Endoscopic healing
SES-CD ≤4 and reduction from baseline SES-CD of at least 2 points and no 
individual SES-CD subscore >1.
Endoscopic response
50% reduction in SES-CD from baseline.
Deep remission
CDAI <150 and SES-CD 0-2.
Clinical remission
CDAI <150.
Clinical response
≥100 point decrease in CDAI score from baseline.
First exacerbation of CD 
after 26 weeks
CDAI increase of >70 from the prior visit on 2 occasions separated by a 2-week 
interval, or objective evidence of disease activity by colonoscopy and CRP above 
normal, or fecal calprotectin >250 μg/g alone.
Normalization of CRP
CRP <5 mg/L.
Endoscopic remission 
(based on Monitr CD)
EHI ≤20.
Triple combination therapy 
phase
The day of first dose of study medication (Day 1) up to and including the end of the 
Week 26 study window or the day of last dose, whichever occurs earlier.
Monotherapy phase
The day after the Week 26 study window up to and including the day of last dose of 
study medication.
Follow-up phase
The day after the last dose up to and including Week 120 EOS/ET.
7.1.2
Definition of Study Days
Study Day 1 (Day 1) is defined as the day on which a subject is administered their first dose of 
the study medication in the triple combination therapy phase. Other study days are defined 
relative to the Day 1.
The study day prior to the first dose of study drug will be calculated as: 
Date of assessment/event – date of first dose of study drug. 
The study day on or after the first dose of study drug will be calculated as: 
Date of assessment/event – date of first dose of study drug + 1.
7.1.3
Definition of Baseline Values
Baseline values will be defined as the last observed value before the first dose of study 
medication. Any procedures performed on the same day as the first dose of study medication will 
be assumed to have been performed prior to the administration of the study medication.
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7.1.4
Definition of Screen Failure
Screen failure subjects are subjects who signed the informed consent form (ICF) and were not 
enrolled in the triple combination therapy phase of the study. The primary reason for screen 
failure was collected in the eCRF using the following categories:

Pretreatment Event (PTE)/AE.

Did Not Meet Entrance Criteria.

Significant Protocol Deviation.

Lost to Follow-Up.

Voluntary Withdrawal.

Study Termination.

Other.
7.1.5
Definition of Study Visit Windows
Study day will be calculated relative to the date of the first dose of study drug in the triple 
combination therapy phase of the study. The study day prior to the first dose of study drug will 
be calculated as: 
Date of assessment/event – date of first dose of study drug.
The study day on or after the first dose of study drug will be calculated as: 
Date of assessment/event – date of first dose of study drug + 1.
Baseline values are defined in Section 7.1.3. The visit windows for postbaseline visits are 
defined in Table 7.a through Table 7.d. If a subject has more than 1 non-missing measurement in 
the same visit window, the measurement closest to the target day will be used. In case of ties 
between measures located on different sides of the target day, the measurement that occurs later 
will be used. In case of ties located on the same side of the target day (i.e., two or more 
measurements occur on the same day), the average of the values will be used.
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Table 7.a
Visit Windows for Triple Combination Therapy Phase: CDAI, Safety 
Laboratory Parameters, Vital Signs, ADA and Serum/Urine hCG
Visit
Target Study Day
Study Day Range
CDAI, Safety Laboratory 
Parameters Vital Signs, ADA
Serum/Urine hCG
Baseline
1
≤1
≤1
Week 2
15
2-29
2-29
Week 6
43
30-57
30-57
Week 10
71
58-85
58-85
Week 14
99
86-127
86-113
Week 18
127
NA
114-141
Week 22
155
128-169
142-169
Week 26
183
170-197
170-197
Table 7.b
Visit Windows for Triple Combination Therapy Phase: Other Endpoints
Visit
Target 
Study 
Day
Study Day Range
PRO-2
SES-CD, 
Monitr CD 
Test
CRP
Fecal 
calprotectin
IBDQ, 
WPAI, IBD-
DI
Health 
outcomes, CD-
related events
Baseline
1
≤1
≤1
≤1
≤1
≤1
NA
Week 2
15
NA
NA
NA
NA
NA
2-29
Week 6
43
NA
NA
NA
NA
NA
30-57
Week 10
71
NA
NA
2-127
2-85
NA
58-85
Week 14
99
NA
NA
NA
86-141
2-141
86-127
Week 22
155
NA
NA
NA
NA
NA
128-169
Week 26
183
170-197
170-267
128-197
142-197
142-197
170-197
Note: The Week 26 visit window for SES-CD and Monitr CD is extended beyond day 197 due to a data review 
identifying procedures delayed due to the COVID-19 pandemic.
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Table 7.c
Visit Windows for Monotherapy Phase: CDAI, Safety Laboratory 
Parameters, Serum/Urine hCG, Vital Signs, and ADA
Visit
Target 
Study Day
Study Day Range
CDAI, Safety Laboratory 
Parameters, Health 
Outcomes, CD-related 
events
Serum/Urine hCG
Vital Signs
ADA
Week 30
211
*198-239
198-225
198-225
NA
Week 34
239
NA
226-253
226-253
NA
Week 38
267
240-295
254-281
254-281
198-323
Week 42
295
NA
282-309
282-309
NA
Week 46
323
296-351
310-337
310-337
NA
Week 50
351
NA
338-365
338-358
NA
Week 52
365
352-372
NA
359-372
NA
Week 54
379
373-407
366-393
373-393
324-435
Week 58
407
NA
394-421
394-421
NA
Week 62
435
408-463
422-449
422-449
NA
Week 66
463
NA
450-477
450-477
NA
Week 70
491
464-519
478-505
478-505
436-547
Week 74
519
NA
506-533
506-533
NA
Week 78
547
520-575
534-561
534-561
NA
Week 82
575
NA
562-589
562-589
NA
Week 86
603
576-631
590-617
590-617
548-659
Week 90
631
NA
618-645
618-645
NA
Week 94
659
632-687
646-673
646-673
NA
Week 98
687
NA
674-701
674-701
NA
Week 102
715
≥688
≥702
≥702
≥660
*For safety laboratory parameters, only hematology is scheduled.
Table 7.d
Visit Windows for Monotherapy Phase: Other Endpoints
Visit
Target Study Day
Study Day Range
PRO-2
SES-CD, Monitr CD 
Test
CRP, Fecal calprotectin, 
IBDQ, WPAI, IBD-DI
Week 52
365
352-372
NA
198-456
Week 78
547
520-575
NA
457-631
Week 102
715
≥688
≥268
≥632
Data identified on the eCRF as coming from an “unscheduled” visit will be eligible for 
windowing. There will not be a separate “unscheduled” categorization for the reporting of these 
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observations. Data from the End-of Study or Early Termination visit (Week 120) and LTFU 
Phone Call visits (Week 128) will not be included in the visit windows; they will be identified 
from the visit entered in the eCRF and appear in summary tables as “Week 120, EOS/ET” visit. 
The study visit window conventions will not be applied to data listings; the data listings will 
display the visits as collected and entered in the eCRF.
7.1.6
Convention for Calculation of CDAI Scores
The CDAI consists of 8 components: number of liquid or very soft stools, abdominal pain, 
general well-being, extra-intestinal manifestations of CD, use of Lomotil/Imodium/opiates for 
diarrhea, abdominal mass, hematocrit level and body weight. The CDAI total score is derived 
from the 8 components as described below (refer to Appendix B for a tabular summary of the 
derivation).
The CDAI will be derived at each scheduled visit utilizing the most recent available patient 
reported components (number of liquid or very soft stools, abdominal pain, general well-being 
and use of Lomotil/Imodium/opiates for diarrhea are self-reported by subjects via eDiary on a 
daily basis), physician reported outcomes components (extra-intestinal manifestations of CD, 
abdominal mass) and body weight, and hematocrit values as described below:
1. Identify the completion date of the physician reported CDAI components and set it as the 
CDAI calculation/assessment date.
2. Calculate the 3 eDiary sub-scores (liquid/soft stool frequency, abdominal pain and general 
well-being) as follows:
a) Select the diary data from 10 days prior to the CDAI calculation date identified in (1).
b) Exclude the day before, day of and day after colonoscopy. 
c) Take 7 most recent days of diary data.
d) If less than 4 days of diary are non-missing for a component, then the respective 
component sub-score cannot be calculated and is set to missing. 
Otherwise:
i.
If 4 to 6 days of diary are non-missing, calculate the average of non-missing diary
days (sum over non-missing entries/number of non-missing entries), multiply by 7, 
then multiplying by the factor appropriate for the respective component sub-score
(x2 for liquid/soft stools, x5 for abdominal pain, x7 for general well-being) and 
round to the nearest integer.
ii.
If 7 or more days of diary are non-missing, calculate the sum of the most recent 7 
days of non-missing diary and multiply the sum by the factor appropriate for the 
respective component sub-score (see above).
3. Extra-intestinal manifestations of CD sub-score: 
Count the number of check boxes ticked for extra-intestinal manifestations of CD and 
multiply that count by a factor of 20.
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4. Lomotil/Imodium/opiates for diarrhea sub-score: 
If use of Lomotil/Imodium/opiates for diarrhea is reported (“Yes”), then the subscore is 30;
otherwise (“No”), the sub-score is 0. Information on Lomotil/Imodium/opiates use was 
recorded by the subject daily in the eDiary. Therefore the following rule will be applied:
a) Select the diary data from 10 days prior to the CDAI calculation date identified in (1).
b) Exclude the day before, day of and day after colonoscopy. 
c) Take 7 most recent days of diary data.
d) If any use of Lomotil/Imodium/opiates for diarrhea is reported on those days, then the 
subscore is 30; if no use is reported on those days, the sub-score is 0.
If no information on use of Lomotil/Imodium/opiates is available for the last 10 days, 
then the sub-score is set to missing.
5. Abdominal Mass sub-score: 
Responses “Definite”, “Questionable” and “None” will be assigned sub-scores of 50, 20, and 
0, respectively.
6. Hematocrit sub-score: 
a) Identify the corresponding hematocrit result using the visit windows and rules defined in
Section 7.1.5. 
b) Subtract hematocrit value (in %) from 47 for males and from 42 for females, multiply 
result by a factor of 6 and round to the nearest integer. 
If the hematocrit sub-score is <0, set it to 0.
7. Body Weight sub-score: 
a) Identify the corresponding body weight result using the visit windows and rules defined 
in Section 7.1.5.
b) Identify the standard weight based on subject’s gender and baseline height (cm) as 
follows:
i. Standard weight for men in kilogram = (height in cm/100)2×22.1
ii. Standard weight for women in kilogram = (height in cm/100)2×20.8
c) Calculate the maximum of {(1 – (Body weight/Standard Weight)) ×100, -10}; the value 
rounded to the nearest integer is the body weight sub-score.
8. The total CDAI score is the sum of the 8 sub-scores above. If any of the sub-scores are 
missing, the total CDAI score is set to be missing.
7.1.7
Convention for Calculation of PRO-2 Score
The PRO-2 score will be derived at each scheduled visit utilizing liquid/soft stool frequency and 
abdominal pain scores from 7 days prior to the same visit. The sub-scores are calculated in a 
similar way to CDAI subscores (see Section 7.1.6 step 2), however the 7 day average is 
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calculated rather than the 7 day total and the same multiplication factors used (x2 for liquid/soft 
stools, x5 for abdominal pain). The PRO-2 score is the sum of the two sub-scores. If either of the 
sub-scores are missing, the PRO-2 score is set to be missing.
7.1.8
Convention for Calculation of IBDQ Sub-domain and Total Score
The IBDQ is a widely used, health-related quality of life questionnaire used for subjects with 
ulcerative colitis and Crohn’s disease. The questionnaire is regarding the subject’s bowel 
problems and how they affected his or her life during the past 2 weeks. The IBDQ consists of 32 
questions, with each question response ranging from 1 to 7, where 1 indicates worse IBD and 7 
indicates better IBD. Four sub-domains and a total score will be derived.
IBDQ Sub-domain
Calculation
Bowel symptoms score
Sum of (Q1, Q5, Q9, Q13, Q17, Q20, Q22, Q24, Q26, Q29). Ranging from 10 to 
70. 10 questions.
Emotional function score
Sum of (Q3, Q7, Q11, Q15, Q19, Q21, Q23, Q25, Q27, Q30, Q31 and Q32). 
Ranging from 12 to 84. 12 questions. 
Social function score
Sum of (Q4, Q8, Q12, Q16 and Q28). Ranging from 5 to 35. 5 questions.
Systemic symptoms score
Sum of (Q2, Q6, Q10, Q14 and Q18). Ranging from 5 to 35. 5 questions.
Note:
For each component score above, if 50% or less of the component score is missing at a visit, the MEAN of the 
remaining component score will be imputed as the value for the missing component score. If more than 50% of the 
component score is missing for the item, the imputed value will be set to missing.
To calculate the IBDQ total score, the scores for Bowel symptom, Emotion function, Social
function, and Systemic symptoms are summed. The IBDQ total score ranges from 32 to 224, 
with a higher score indicating better quality of life. If any of the component score is missing at a 
visit, the imputed value will be set to missing.
7.1.9
Convention for Calculation of WPAI-CD Sub-scores 
The WPAI-CD consists of 6 questions that evaluate absenteeism (work time missed), 
presenteeism (reduced work productivity), overall work impairment, and activity impairment. 
Each subscore is expressed as impairment percentages, with higher numbers indicating greater 
impairment and less productivity.
WPAI-CD subscore
Calculation
Percentage of work time missed because of CD in the past seven 
days [Absenteeism]
Q2/(Q2+Q4)
Percentage of impairment experienced while at work in the past 
seven days because of CD [Presenteeism]
Q5/10
Overall work productivity loss 
Q2/(Q2+Q4)+ [(1- Q2/(Q2+Q4))×Q5/10]
Percentage of impairment in daily activities due to CD in the past 
seven days [Activity impairment]
Q6/10
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7.1.10
Convention for Calculation of IBD-DI 
The IBD-DI consists of 14 questions that focus on body functions, body structures, activities and 
participation, and environmental factors. Twelve of the 14 items are based on a five-point Likert 
scale (no limitation, slight limitation, moderate limitation, severe limitation, extreme limitation), 
one item (arthritis) is a binary response, and the number of liquid stools is a continuous value. 
The IBD-DI score will be calculated as the sum of the values for the 14 questions:

The response for Arthritis is scored as 0 if the response is “no” and 4 if the response is “yes”. 

The number of liquid stools is categorized as follows: 0 is grouped together and other values 
are categorized into quartiles. 

The responses to all other questions are rescaled to range from 0 to 4. 
A subject at a specific time point should normally not answer both questions 12a and 12b of the 
14-item IBD-DI questionnaire. Should this situation occur, i.e., if a subject has answered both 
12a and 12b (with a value 0 to 4), the primary analysis approach will use the answer to question 
12b if age at visit <19 years and the answer to question 12a if age at visit ≥19 years. As a 
sensitivity analysis, the worst case scenario (with a value 0 to 4) approach will be utilized, i.e. 
choose the answer with the most severe limitation.
If <20% of the questions have missing values for a subject, the IBD-DI score will be rescaled 
from 0 to 100 using the following formula: score×100/(p×4), where p represents the number of 
answered items. If ≥20% of the questions have missing values for a subject, the IBD-DI score 
will be set to missing. 
Scores range between 0 to 100, with 0 to 20 indicating no disability, 20 to 35 mild disability, 35 
to 50 moderate disability, and 50 to 100 severe disability.
7.1.11
Conventions for Missing Adverse Event Dates
Every effort will be made to determine the actual onset date for the event or to obtain a reliable 
estimate for the onset date from the investigator.
For AEs or SAEs, a missing or incomplete onset date will be imputed according to the following 
conventions:
1. If an onset date is missing, the derived onset date will be calculated as the first non-missing 
valid date from the following list (in order of precedence):

First study medication date.

Informed consent date (for SAEs, only when first study medication date is missing).
2. If an onset date is incomplete, the derived onset date will be calculated following:

Missing day, but month and year present: the day will be imputed as the 15th of the 
month. If the month and year are equal to the month and year of the first study 
medication dose and the first study medication dose occurs after the imputed date, the 
derived onset date will be set equal to the first study medication date. If the AE end date 
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occurs prior to the imputed date, the derived onset date will be set equal to the AE end 
date.

Missing day and month, but year present: the day and month will be imputed as the 15th 
June of the year. If the year is equal to the year of the first study medication dose and the 
first study medication dose occurs after the imputed date, the derived onset date will be 
set equal to the first study medication date. If the AE end date occurs prior to the imputed 
date, the derived onset date will be set equal to the AE end date.

If the imputed AE onset date occurs after the database lock date, the imputed AE onset 
date will be imputed as the database lock date.
For AEs or SAEs, a missing or incomplete end date will be imputed according to the following 
conventions:
1. If an end date is missing, the derived end date will be imputed as the last assessment date, if 
the last assessment occurs after the AE start. If the last assessment occurs prior to the AE 
start date, the derived end date will be imputed as the AE start date.
2. If an end date is incomplete, the derived end date will be calculated following: 

Missing day, but month and year present: the day will be imputed as the last date of the 
month.

Missing day and month, but year present: the day and month will be imputed as the 31st 
December of the year.

If the imputed AE end date occurs after the database lock date, the imputed AE end date 
will be imputed as the database lock date.
7.1.12
Conventions for Missing Concomitant Medication Dates
Start and stop dates for all concomitant medications are collected on the eCRF. However, in case 
of missing or partial information in these dates, the following rules will be used:
1. If the start date is partial or unknown:

If the day is missing, the start day will be the first day of the month.

If the month is missing,
–
If the year is the same as the date of first dose of study drug, the start month will be 
the month corresponding to 90 days prior to the date of first dose of study drug with 
exception that the month of first dose is Jan, Feb, or Mar. 
–
If the year is the same as the year of first dose of study drug and the month of first 
dose is Jan, Feb, or Mar, the start month will be Jan.
–
If the year is not the same as the year of first dose of study drug, the start month will 
be Jan.
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
If the year is missing, the start year will be the minimum of the year of the first clinic 
visit or the year of the informed consent date.

If the entire date is unknown:
–
If eCRF indicates that the medication ended prior to the informed consent date, then 
the medication start date will be imputed to the informed consent date minus one day.
–
Otherwise the start date will be the minimum of the date of first dose of study drug 
and the medication end date.
2. If the stop date is partial, unknown or "ongoing":

If the day is missing, the stop day will be the last day of the month reported. If the eCRF 
indicates the medication ended prior to informed consent, and month is the month of 
informed consent, the day should be imputed to informed consent date minus one day. 

If the month is missing:
–
If the year is the same as the date of last assessment, then the stop month will be to 
the month during which the last assessment occurred.
–
If the year is not the same as the year of the last assessment, then the end month will 
be Dec.

If the year is missing or the entire date is unknown or if the medication is "ongoing", the 
stop year will be the year in which the last assessment occurred. If information collected 
on the eCRF indicate that the medication ended prior to the informed consent date, then 
the medication end date will be imputed to the informed consent date minus one day.
7.1.13
Conventions for Calculation of Duration of CD
Duration of CD is calculated as the number of years from CD diagnosis date to first dose date 
(Day 1):
1 + date
  −date
365.25
The duration of CD will be included in the baseline CD characteristics listing. If the date CD was 
diagnosed is partially missing, the following rules will take effect:

Missing day, but month and year are present: the day will be imputed as the 15th day of the 
month.

Missing day and month, but year is present: the day and month will be imputed as 30th June 
of the year.
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7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data:

The safety analysis set (SAF): All subjects who received at least 1 dose of study drug will be 
included in the SAF.

The full analysis set (FAS): All subjects who received at least 1 dose of study medication and 
have a post enrollment efficacy assessment will be included in the FAS.

The per protocol set (PPS): All FAS subjects who do not violate the protocol in a way that 
would impact the primary efficacy will be included in the PPS. All decisions to exclude 
subjects from the PPS will be made prior to the database lock. The hierarchy of reasons for 
exclusion is as follows: inclusion and exclusion criteria violations, study medication dosing 
errors, receiving forbidden concomitant medications such as oral corticosteroids without 
tapering and refusal for Week 26 endoscopy. 

The PK analysis set: All subjects who receive at least 1 dose of study drug and have 
sufficient blood sampling to allow for PK evaluation.
In addition, the population of “all enrolled subjects” may be used for particular data summaries. 
All treated subjects (i.e., the SAF) will be presented in the subject listings.
7.3
Disposition of Subjects
Subject disposition will be summarized and provided in listings. The following summaries will 
be produced:

Study Information including: 
–
date first subject signed ICF
–
date of last subject’s last visit/contact
–
date of last subject’s last procedure for collection of data for primary endpoint
–
Medical Dictionary for Regulatory Activities (MedDRA), World Health Organization 
Drug Dictionary (WHODrug) and SAS® versions used for reporting.

Summary of screen failures including:
–
total number of screen failures
–
descriptive statistics for age
–
counts and percentages for gender, ethnicity, race and the primary reason for screen 
failure. 

Summary of study subjects enrolled by site and country.
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
Summary of subject disposition including:
–
number of subjects completing or prematurely discontinuing study drug along with the 
primary reason for study drug discontinuation (vedolizumab, adalimumab and 
methotrexate will be presented separately)
–
number of subjects completing all study drugs in triple combination therapy phase 
–
number of subjects completing or not completing all planned study visits, specifically 
Weeks 26, 52, 78 and 102 with the reason for discontinuation of the planned study visits

Summary of significant protocol deviations as captured on the eCRF.

Summary of reasons for exclusion from PPS. 

Summary of number of subjects in each analysis set defined in Section 7.2.
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for the SAF. The variables that 
will be tabulated are listed in Table 7.e.
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Table 7.e
Summary of Demographic and Baseline Characteristics
Demography (unit)
Summarized as
Categories
Age (years)
Continuous and 
categorical
<35, >=35
<65, >=65
Gender
Categorical
Male
Female
Ethnicity
Categorical
Hispanic or Latino
Non-Hispanic and Latino
Not Collected
Racea
Categorical
American Indian or Alaska Native
Asian
Black or African American
Native Hawaiian or Other Pacific Islander
White
Multiracial
Height (cm)
Continuous
Weight (kg)
Continuous
Body Mass Index (BMI) (kg/m2)
Continuous
Smoking Classification
Categorical
Never-smoker
Current smoker
Ex-smoker
Female Reproductive Status
Categorical
Postmenopausal
Surgically Sterile
Female of Childbearing Potential
N/A (Subject is a Male)
a  recorded on the eCRF. Subjects who identify themselves as more than one race on the eCRF will be classified as 
Multiracial for tabulation and will be included only in the Multiracial category.
CD-related baseline characteristics will be summarized for the SAF. If there is a large difference 
between the SAF and the FAS (e.g. >5%) then CD related baseline characteristics will be 
summarized for both analysis sets. The characteristics that will be tabulated are listed in
Table 7.f. For categorical responses, a “Missing” category will be added, as needed.
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Table 7.f
Summary of CD-Related Baseline Characteristics
Characteristics (unit)
Summarized as
Categories
Duration of Crohn’s Disease (years)
Continuous and Categorical
<1 year
≥1 to <3 years
≥3 to <7 years
≥7 years
Baseline SES-CD
Continuous and Categorical
4-6 
7-15 (Moderate)
>=16 (Severe)
Baseline CDAI Activity
Continuous and Categorical
≤220
>220 to ≤330
>330
Baseline C-reactive protein (CRP) (mg/L)
Continuous and Categorical
≤2.87 mg/L
>2.87 mg/L to ≤5 mg/L
>5 mg/L to ≤10 mg/L
>10 mg/L
Baseline fecal calprotectin (FC) (µg/g)
Continuous and Categorical
≤250 µg/g
>250 µg/g to ≤500 µg/g
>500 µg/g
Has the patient had any acute exacerbations 
within the past 12 months?
Categorical
Yes
No
Number of acute exacerbations
Continuous
Has the patient had any hospitalizations for 
Crohn’s disease within the past 12 months?
Categorical
Yes
No
Number of hospitalizations
Continuous
Has the patient had a colonoscopy within the 
last 12 months?
Categorical
Yes
No
Location of Crohn’s Disease
Categorical
Ileum
Colon
Rectal Involvement
Other
Each location tabulated separately 
as well as the following 
combination:
Ileal
Colonic
Ileocolonic
Has the patient had surgery for Crohn’s 
disease?
Categorical
Yes
No
How many surgeries?
Continuous
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Table 7.f
Summary of CD-Related Baseline Characteristics
Characteristics (unit)
Summarized as
Categories
Has the patient had any extraintestinal 
manifestations?
Categorical
Yes 
No
Types of Extraintestinal manifestations
Categorical
Arthritis/Arthralgia
Iritis/Uveitis
Erythema nodosum
Pyoderma gangrenosum
Aphthous stomatitis
Anal fissure
Anal fistula
Abscess
Other fistula
Fever over 37.8°C during the past 
week
Estimated number of weeks of corticosteroid 
use over the last 12 months
Continuous
Concomitant use of baseline corticosteroids
Categorical
Yes
No
Method of Complication Risk Assessment
(primary)
Categorical
PI Clinical Assessment
2014 AGA CD Clinical Care 
Pathway
PROSPECT Tool
Method of Complication Risk Assessment (all)
Categorical
PI Clinical Assessment
2014 AGA CD Clinical Care 
Pathway
PROSPECT Tool
Baseline PROSPECT risk score at 2 years
Continuous
Baseline ulcer size (ileum)
Categorical
None
Aphthous 
Large 
Very large 
Baseline ulcer size (colon)
Categorical
None
Aphthous 
Large 
Very large 
Baseline ulcer size (rectum)
Categorical
None
Aphthous 
Large 
Very large 
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7.5
Medical History and Concurrent Medical Conditions
A subject’s medical history will include any significant conditions or diseases relevant to the 
disease under study that stopped at or prior to signing of informed consent. All medical history 
and concurrent medical conditions will be summarized and listed for the SAF. 
Concurrent medical conditions are significant ongoing conditions or diseases that are present at 
signing of informed consent. This includes clinically significant laboratory, electrocardiogram 
(ECG), or physical examination abnormalities noted at the screening or baseline examination. 
The condition (e.g., diagnosis) should be described.
Medical history and concurrent medical conditions will be coded using the latest version of 
MedDRA. The number and percentage of subjects with any significant medical history and any 
concurrent medical conditions will be summarized for each MedDRA system organ class (SOC) 
and preferred term (PT). The tables will include numbers and percentages of subjects and will be 
sorted alphabetically by SOC and descending frequency of PT. A subject will only be counted 
once within a SOC or PT even if he/she has multiple conditions/symptoms for that SOC or PT.
All medical history and concurrent medical condition data will be listed separately by site and 
subject number.
7.6
Medication History and Concomitant Medications
All outputs described in this section will be generated for the SAF. Accordingly, the denominator 
for all percentages is the number of subjects included in the SAF.
Medication history information includes any medication relevant to eligibility criteria which was 
stopped at or within 30 days prior to the signing of informed consent. 
Medication history is captured on the Medication History/Concomitant Medications eCRF page. 
Medication history will be coded using WHODrug and will be summarized by therapeutic 
classification, and preferred medication name. Therapeutic classification will be sorted 
alphabetically and preferred medication names by decreasing frequency using the total number 
of subjects as the denominator. If a subject reports taking 2 medications belonging to the same 
class, he/she will only be counted once within that class.
In addition, a history of any medications taken for the treatment of CD, including the reason for 
discontinuation, that stopped at or prior to signing of informed consent is collected at screening. 
Any prior CD treatment is captured on the Prior CD Treatment eCRF. The prior CD medications 
are not coded; they will be summarized by verbatim term. Verbatim terms will be sorted 
alphabetically. 
Concomitant medications will be summarized by therapeutic classification and preferred 
medication name and will include only those medications taken at any time between informed 
consent and on or prior to the end of study (Week 120) or early termination. Concomitant 
medications will be classified and summarized separately as follows: 

Concomitant medications that started and stopped prior to baseline: any medication stopped 
after time of informed consent and prior to the first dose of the study medication. 
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
Concomitant medications that were ongoing after baseline: any medication that started before 
and was not stopped prior to the first dose of the study medication. 

Concomitant medications that started after baseline: any medication that started at or after the 
first dose of the study medication and on or before the end of study (Week 120) or early 
termination.
Concomitant medications will be coded using WHODrug and summarized by therapeutic 
classification and preferred medication name using the total number of subjects in the SAF for 
the denominator. The concomitant medications that were ongoing after baseline or started during 
the treatment period will be summarized separately for each treatment phase; the denominator 
for each phase will be the number of SAF subjects entering that treatment phase. Therapeutic 
classification will be sorted alphabetically and preferred medication names by decreasing 
frequency based on the total number of subjects. Separate listings for medication history, CD 
prior medications and concomitant medications will be produced by site and subject number. 
7.7
Study Drug Exposure and Compliance
The SAF will be used for all summaries in this section. Study drug exposure and compliance will 
be summarized by study drug and treatment period. 
The exposure to each treatment will be calculated separately as the duration between the first and 
last dose of study drug plus approximately 5 times the half-life of the study drug. Given that the 
mean terminal half-life of vedolizumab, adalimumab and methotrexate is approximately 25.2 
days, 2 weeks and 9 hours respectively, the extent of exposure will be calculated as follows:

Vedolizumab: Date of last dose of vedolizumab – Date of first dose of vedolizumab + 1 + 
126 days (18 weeks).

Adalimumab: Date of last dose of adalimumab – Date of first dose of adalimumab + 1 + 70 
days (10 weeks).

Methotrexate: Date of last dose of methotrexate – Date of first dose of methotrexate + 1 + 2 
days.
The adalimumab SC dosing is recorded in the eCRF for clinic visits and electronic diaries (e-
diaries) for at-home dosing. Duplicate entries will be handled as follows prior to summarizing:

If a clinic visit SC dose is also recorded in the e-diary, data will be taken from the eCRF for 
analysis.

If an e-diary contains multiple dosing records on a single date, the record with the most drug 
injected (complete vs partial) will be used for analysis, regardless of time or location.
The number of completed doses and the number of completed or partial doses will also be 
summarized by study drug and treatment period. Study drug administration data for vedolizumab, 
adalimumab, methotrexate and folic acid (the companion supplement) will be presented in data 
listings.
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7.8
Efficacy Analysis
This section describes the summaries to be provided for the primary, secondary and additional 
efficacy endpoints. Summaries of the efficacy data will be based on the FAS. Summaries of the 
primary endpoint will also be based on the PPS and on observed cases (FAS subset to those with 
a Week 26 colonoscopy).
All subjects with missing data for the determination of binary endpoint status will be considered 
as a value of ‘NO’ in the analysis. In summary tables, the number of subjects not achieving the 
endpoint (a true ‘NO’) will be tabulated as well as the number of total “NO” (true “NO” plus 
imputed “NO”). 
Categorical secondary and additional endpoints will be summarized using the number and 
percentage of subjects and corresponding 95% CI calculated using the Wald asymptotic method, 
unless otherwise noted. 
Continuous secondary and additional efficacy endpoints will be summarized using descriptive 
statistics (n, mean, SD, median, minimum, and maximum). 
7.8.1
Primary Efficacy Endpoint(s)
The primary endpoint is the percentage of subjects achieving endoscopic remission, defined as a 
SES-CD score of 0-2, at Week 26. The number and percentage of subjects achieving/not-
achieving endoscopic remission and corresponding 95% CIs will be summarized by triple 
combination therapy.
7.8.2
Secondary Efficacy Endpoint(s)
Categorical endpoints listed in Section 5.2 will be summarized by the treatment phase in which 
they are measured, that is, endpoints measured up to week 26 will be summarized in the triple 
combination therapy phase and endpoints after week 26 will be summarized in the monotherapy 
phase. The denominator for each treatment phase, is the number of subjects in the FAS that take 
a dose of study medication in that treatment phase. 
For the following secondary endpoints that are the maintenance of a result after Week 26, the 
corresponding analysis will be based on the number of subjects in the FAS that achieved the 
endpoint at Week 26 and continued into the monotherapy phase, e.g. the subject has to meet the 
criterion at both Week 26 and the specified post-Week 26 visit to be considered as a value of 
“YES” in the analysis:

maintaining clinical remission.

maintaining clinical response.

maintaining endoscopic remission.

maintaining deep remission.

maintaining endoscopic healing.
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
maintaining endoscopic response.

clinical remission and endoscopic response.
For the secondary endpoint of the first exacerbation of CD after 26 weeks, the eCRF is only 
completed for subjects starting at Week 30; therefore, the denominator for the summary will be 
the FAS subjects that receive a dose of study medication in the monotherapy phase. 
For each of the continuous endpoints listed in Section 5.2, the change from baseline will be 
calculated and summarized for each post baseline visit the endpoint is scheduled to be measured. 
7.8.3
Additional Efficacy Endpoint(s)
7.8.3.1
Categorical Endpoints
Categorical endpoints listed in Section 5.3 will be summarized by the treatment phase in 
which they are measured, that is, endpoints measured up to week 26 will be summarized in 
the triple combination therapy phase and endpoints after week 26 will be summarized in the 
monotherapy phase. The denominator for each treatment phase, is the number of subjects in 
the FAS that take a dose of study medication in that treatment phase. The exception are the 
following endpoints that will be summarized by planned study visit across both treatment 
phases combined: 

Subjects assessed at screening as having moderate-high risk CD with ≥20% chance of 
disease complication by Year 2 as calculated by the PROSPECT predictive tool for those for 
whom that tool was used.

Subjects developing a CD related complication by Week 102 who were assessed at screening 
as having moderate-high risk CD with ≥20% chance of disease complication by Year 2 as 
calculated by the PROSPECT predictive tool for those for whom that tool was used. 
7.8.3.2
Continuous Endpoints
For the IBDQ (total and sub-scores), WPAI-CD (total and sub-domains), IBD-DI score, CDAI 
score, PRO-2 score, and EHI the change from baseline will be calculated for each post-baseline 
assessment and summarized by visit for the entire study. The visits through Week 26 will be 
summarized in the triple combination therapy phase and visits after Week 26 will be summarized 
in the monotherapy phase. The denominator for each treatment phase, is the number of subjects 
in the FAS that take a dose of study medication in that treatment phase.
For the CDAI score, PRO-2 score, and CRP levels, the change from Week 26 will be calculated 
for each post-Week 26 assessment and summarized by visit for the monotherapy treatment phase. 
If baseline and Week 26 CDAI and PRO-2 scores and their changes from baseline and changes 
from Week 26 are approximately normally distributed, then these changes will be summarized 
using descriptive statistics.
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7.8.3.3
Time to Event Endpoints
The time from the date of first dose to major CD-related events (a single endpoint including
either hospitalizations, bowel surgeries or procedures) will be analyzed descriptively using 
Kaplan-Meier product limit methods. The time to event will be summarized by estimates of 25th, 
50th (median), and 75th percentiles with 95% CI, and the range (Min, Max). Kaplan-Meier plots 
will be presented over the entire study period. The number of subjects at risk, number and 
percentage of subjects with major CD-related events will be presented for Week 26 and Week 
102. The number of subjects at risk will be counted as the subjects that are still in the study (on 
treatment) at the start of the visit window for that visit. The number of events will be assessed at 
the end of the visit window for that visit. 
A subject that does not have any major CD-related events during the study will be censored 
using the date of last visit.
7.8.4
Subgroup Analysis
The following subgroups will be defined:

baseline SES-CD [<=15, >=16]

baseline ulcer size (ileum) [none, aphthous ulcers, large/very large ulcers]

baseline ulcer size (colon) [none, aphthous ulcers, large/very large ulcers - defined using the 
worst category (largest size) out of the right, transverse and left colon locations]

baseline ulcer size (rectum) [none, aphthous ulcers, large/very large ulcers]

baseline CDAI [<=220, >220-<=330, >330]

disease location [ileal, colonic, ileocolonic]

baseline fecal calprotectin [<=500, >500]

baseline CRP [<=5, 5-10, >10]

ADA status [positive AVA only, positive ADA only, positive AVA and ADA, negative AVA 
and ADA] over 26 weeks

ADA status [positive AVA only, positive ADA only, positive AVA and ADA, negative AVA 
and ADA] over 102 weeks.
The primary endpoint endoscopic remission as well as endoscopic healing and endoscopic 
response at Week 26 will be analysed by all subgroups excluding baseline CDAI and ADA status 
over 102 weeks. Clinical remission and clinical response at Week 26 will be analysed by all 
subgroups excluding baseline SES-CD, baseline ulcer size and ADA status over 102 weeks. The 
combined endpoint of clinical remission and endoscopic response at Week 26 will be analysed 
by all subgroups excluding ADA status over 102 weeks.
The maintenance of endoscopic healing and maintenance of endoscopic response at Week 102 
will be analysed by all subgroups excluding baseline CDAI and ADA status over 26 weeks.
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7.9
Pharmacokinetic/Pharmacodynamic Analysis
Pharmacokinetic analysis will be done using the PK analysis set.
7.9.1
Pharmacokinetic Analysis
Blood samples are to be collected for vedolizumab PK analysis on Day 1 and Weeks 6, 10, 14, 
26, 38, 54, 70, 86, and 102. Blood samples are to be collected for adalimumab PK analysis on 
Day 1 and Weeks 6, 10, 14, 22, and 26. Measured serum vedolizumab and adalimumab 
concentrations will be summarized by time and treatment phase using descriptive statistics. 
Individual serum concentration versus time data will be presented in a data listing. 
Ctrough, trough serum concentrations (measured concentration at the end of a dosing interval at 
steady state), will be derived directly before next administration. Ctrough for each medication 
will be summarized using descriptive statistics (number of non-missing values, mean, SD, %CV, 
median, minimum, and maximum).
Additionally, all PK analyses will be analysed by the ADA status subgroups as defined in 
Section 7.8.4.
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
The proportion of subjects with positive antidrug antibodies (ADA) (transient and persistent) and 
the proportion of subjects with positive neutralizing ADA during the study will be summarized 
by treatment phase. A positive ADA subject is defined as a subject who has at least 1 positive 
ADA result in any postbaseline sample, and is further categorized as:

Transiently positive: subjects with at least one confirmed positive ADA sample at a postdose 
visit (excluding last available) and no consecutive positive ADA samples.

Persistently positive: subjects with confirmed positive ADA in 2 or more consecutive ADA 
samples postdose with positive result or last available postdose ADA sample with positive 
result.
The impact of ADA on efficacy, PK and safety will be examined by subgroup analyses described 
in Section 7.8.4, 7.9.1 and 7.11.1.2, respectively.
7.11
Safety Analysis
Safety analyses include AEs, clinical laboratory values, vital signs and ECGs. All safety 
summaries will be presented by treatment phase for the subjects included in the SAF. 
7.11.1
Adverse Events
A pretreatment event is defined as any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study, but prior to administration of 
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any study medication. An AE is defined as any untoward medical occurrence in a clinical 
investigation subject administered a drug. Pretreatment events and AEs will be coded using 
MedDRA. AEs will be summarized using the MedDRA SOC, high level term (HLT) and PT.
Treatment-emergent adverse events (TEAEs) will be defined as any AE that occurs on or after 
the first dose of study drug and up to the last dose of study drug plus 18 weeks follow up or early 
termination. TEAEs with a start day ≤ Day 197 will be assigned to the triple combination therapy, 
TEAEs with a start day >Day 197 and on or before the study day of the last dose of study 
medication will be assigned to the monotherapy treatment period, and TEAEs starting after the 
study day of the last dose of study medication will be assigned to the follow-up period. 
In summaries containing the frequency and percentage of subjects who reported TEAEs, a 
subject will be counted only once for each SOC, HLT or PT when multiple TEAEs are coded to 
the same SOC, HLT or PT. Thus, if a subject has two distinct AEs, each of which corresponds to 
a distinct PT but both of which correspond to the same HLT, then that subject will be counted 
once at that HLT subject-count summary level and once at each of the two preferred-term 
subject-count summary levels within an HLT. This same logic is extended to all PT nested 
within HLT that is in-turn nested within an SOC. 
AEs will be summarized by intensity (mild, moderate and severe). AEs with missing intensity 
will be presented as such in the AE listings, however, will be summarized as severe in summary 
tables. AEs will also be summarized by the relationship to study drug (related or not related). If 
the relationship of an event is missing, the relationship for the event will be considered to have 
been related, but it will be presented as missing in the AE listings. In the cases where a subject 
has multiple AEs with the same SOC or HLT or PT, the AE with the maximum intensity or 
strongest relationship will be summarized. 
In the summary tables, SOCs and HLTs will be sorted in alphabetical order. Within a SOC and a 
HLT, adverse events will be sorted in descending order of total number of subjects with the PT.
All AEs, not just those which are treatment-emergent, will be presented in listings. Special 
listings for TEAEs leading to study discontinuation, SAEs and deaths will also be presented.
7.11.1.1
Treatment-Emergent Adverse Events
An overview of TEAEs will be provided. The summary will include relatedness, severity, 
TEAEs leading to discontinuation, SAEs including relatedness and those leading to 
discontinuation, and deaths. The number of events will be displayed as well and the number and 
percentage of subjects experiencing the event. 
The number and percentage of subjects experiencing TEAEs will be summarized as follows: 

TEAEs by SOC, HLT, and PT.

Intensity of TEAEs and by SOC, HLT, and PT.

Relationship of TEAEs to study drug and by SOC, HLT, and PT.

Intensity of Drug-Related TEAEs and by SOC, HLT and PT.
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
TEAEs leading to study drug discontinuation by SOC, HLT and PT.

Most frequent non-serious TEAEs (i.e., AEs occurring in ≥5% of subjects in any treatment 
phase) by SOC, HLT and PT in descending order of frequency.
The number and percentage of subjects experiencing SAEs will be summarized as follows:

SAEs by SOC, HLT and PT.

SAEs by severity and by SOC, HLT and PT.

SAEs by relationship to the investigational product and by SOC, HLT and PT.
7.11.1.2
TEAEs of Special Interest
Adverse events of special interest are defined as serious infections, opportunistic infection such 
as PML, liver injury, malignancies, infusion-related reactions or systemic reactions and 
hypersensitivity; see Appendix C for details.
The number and percentage of subjects experiencing treatment-emergent AESIs will be 
summarized as follows:

AESI by SOC, HLT, and PT.

AESIs by severity and by SOC, HLT and PT.

AESIs by relationship to the investigational product and by SOC, HLT and PT.
Specifically for hypersensitivity and infusion-related reactions, analyses by SOC, HLT and PT 
will additionally be analysed by the ADA status subgroups as defined in Section 7.8.4.
7.11.1.3
Pretreatment Events
The number and percentage of subjects experiencing pretreatment events will be summarized as 
follows:

Pretreatment Events by SOC, HLT, PT.

Serious Pretreatment Events by SOC, HLT, PT.
7.11.2
Clinical Laboratory Evaluations
The laboratory parameters for serum chemistries, hematology, stool and urinalysis shown in 
Table 7.g were recorded in this study. Refer to Appendix A for scheduled measurements for 
clinical laboratory tests.
Clinical laboratory tests will be evaluated and presented by treatment period using conventional 
units (CV). All laboratory test parameters will be displayed in individual subject data listings in 
CV units. If a lab test with quantitative results has a value that is reported using a non-numeric 
qualifier (e.g., less than a certain value, or greater than a certain value), then the given numeric 
value will be used in the summary statistics, ignoring the non-numeric qualifier.
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Clinical laboratory tests with numeric results will be tabulated using summary statistics for 
observed and change from baseline values at each scheduled time point (baseline and each post 
baseline visit).
Markedly abnormal values (MAV), defined by the criteria in Appendix C and Appendix E, will 
be tabulated. MAV tables will include all laboratory parameters with available MAV criteria. If 
both the baseline and on-treatment values of a parameter are beyond the MAV limit for that 
parameter, then the on-treatment value will be considered a MAV only if it is more extreme than 
the baseline value.
The number and percentage of subjects with Liver Function Test (LFT) abnormalities will be 
presented by period and treatment group. LFT abnormalities are defined as follows:

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.
The laboratory data will be listed in full. Laboratory data outside of the normal reference range 
will be flagged in the listing. In a separate listing, for each subject with a MAV for a parameter, 
all the subject’s values of that parameter will be listed. 
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Table 7.g
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBC
WBC with differential (a)
Hemoglobin
Hematocrit
Platelets
PT/INR
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Bicarbonate
Sodium
Calcium
Chloride
Magnesium
Phosphorus
Uric Acid
Glucose
Amylase
Lipase
eGFR (if calculated)
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Specific Gravity
Other: 
HIV
Hepatitis panel, including HBsAg and anti-HCV
ASCA IgA
ASCA IgG
Anti-CBir1 IgG
ANCA
NOD2 genotype test
Serum
Urine
Stool
CRP
PK samples
ADA/nADA
QuantiFERON for TB
beta hCG (for pregnancy in female subjects of childbearing 
potential only)
FSH, if menopause is suspected (Screening Visit only)
Monitr CD Test (biomarker panel using serum to measure 
hsCRP, SAA 1, CEACAM 1, VCAM 1, ANG 1, ANG 2, IL-7, 
TGFα, EMMPRIN, MMP 1, MMP 2, MMP 3, and MMP 9)
hCG (for pregnancy in female 
subjects of childbearing potential only) 
Fecal calprotectin
C difficile (b)
Abbreviations: ADA,antidrug antibodies; ALT, alanine aminotransferase; ASCA, anti-Saccharomyces cerevisiaeantibody; AST, 
aspartate aminotransferace; anti-CBir1, anti-flagellin; CRP, C-reactive protein; FSH, follicle-stimulating hormone;GGT, γ-
glutamyl transferase; HBsAg, hepatitis B surface antigen; hCG, human chorionic gonadotropin; HCV, hepatitis C virus; HIV, 
human immunodeficiency virus; ANCA, antineutrophil antibody;IgA, immunoglobulinA; IgG, immunoglobulin G; nADA, 
neutralizing antidrug antibodies; NOD2, nucleotide-binding oligomerization domain-containing protein;PK, pharmacokinetic; 
PT, prothrombin time; RBCs, red blood cells; TB, tuberculous; WBC, white blood cell; ULN, upper limit of normal; hsCRP, 
high-sensitivity C-reactive protein; SAA 1, serum amyloid A 1; CEACAM1, carcinoembryonic antigen-related cell adhesion 
molecule 1: VCAM 1, vascular cell adhesion molecule 1; IL-7, interleukin-7; TGFα, transforming growth factor α; EMMPRIN, 
extracellular matrix metalloproteinase inducer; MMP, matrix metalloproteinase (a) WBC differential to include lymphocytes, 
monocytes, basophils, eosinophils, and neutrophils. (b) Not done at screening; only done if subject experiences a flare during the 
study. 
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7.11.3
Vital Signs
Systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse, body temperature, weight 
and respiration rate will be measured (refer to Appendix A for a schedule of vital signs 
measurements). For each vital sign parameter, the observed values at each time point, change 
from baseline, and percent change from baseline at each post baseline visit will be summarized 
by descriptive statistics.
Criteria for MAV vital signs are listed in Appendix E. The number and percentage of subjects 
who meet MAV vital signs criteria will be summarized. 
Vital signs data will be listed with MAVs flagged. 
7.11.4
12-Lead ECGs
Overall ECG interpretation category (normal, not clinically significant abnormal, clinically 
significant abnormal) was collected at Screening. ECG data will be listed by site number and 
subject number. 
7.11.5
Other Observations Related to Safety
Physical examination findings, PML checklist, and LTFU data will be listed.
7.12
Interim Analysis
An interim analysis will be conducted for the purpose of publication when all subjects have 
completed the 26 week combination treatment phase (i.e. Week 26 Visit or early termination (ET) 
Visit). No study decisions will be made based on the interim results and subjects will continue to 
the monotherapy treatment phase. All available data will be included in the interim analysis. 
Data which can be considered final at Week 26 (all data except AEs, concomitant medications, 
and any data post-Week 26) will be cleaned and locked prior to the analysis. The primary 
endpoint is measured at Week 26 so there is no alpha adjustment required in the statistical 
analyses. The interim analysis will follow all methodology outlined in this Statistical Analysis 
Plan (SAP) and all data will be summarized. 
The following data may be included in the interim analysis:
1. Disposition.
2. Demographic and other baseline characteristics.
3. Medical history and concurrent medical conditions.
4. Medication history and concomitant medications.
5. Study drug exposure excluding compliance.
6. Efficacy.
a) Primary endpoint: Endoscopic remission.
b) Secondary endpoints defined through Week 26.
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7. Adverse events.
7.13
Changes in the Statistical Analysis Plan 
The following items were not included in the protocol but will be analysed:

The secondary endpoint maintaining clinical response based on CDAI has been added to 
address the secondary objective. 

Hospitalizations due to CD related issues from Day 1 to Week 102 has been added to the 
summary of additional endpoints.

Change from baseline CDAI score at post-baseline visits has been added to the summary of 
additional endpoints. Whilst it is not specifically described in the protocol as an endpoint, it 
is discussed within the statistical analyses of the protocol.
The following change was made to the planned analyses described in the protocol:

Changes from baseline and changes from Week 26 for CDAI and PRO-2 scores will be 
analysed descriptively rather than using a non-parametric method as data exploration 
suggests that the data are approximately normally distributed.
The following revisions were made after SAP version Final 1.0 was approved:

Study phase definitions updated in Section 7.1.11.

Serum/urine hCG added in Table 7.a and Table 7.c. 

SES-CD added in Table 7.b and Table 7.d.

Time windows for Monitr CD updated in Table 7.b and Table 7.d.

Time windows for ADA updated in Table 7.c.

Category labels for baseline SES-CD updated in Table 7.f.

Concomitant medications during the follow-up phase summarized with concomitant 
medications started after baseline in Section 7.6.

Observed case analysis for the primary endpoint added to Section 7.8.

Compliance excluded from interim analysis in Section 7.12.
The following revisions were made after SAP version Amendment 1 was approved:

CDAI derivation Steps 2 and 4 updated in Section 7.1.6 to remove the diary data from the 
day before, day of and day after colonoscopy.

PRO-2 derivation updated to use 7 day average (per protocol) in Section 7.1.7.

Calculation of IBD-DI adjusted and sensitivity analysis added in Section 7.1.10 due to 
multiple answers to Q12.

Completion of all drugs in triple combination therapy phase added in Section 7.3.
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
Additional details provided for location of Crohn’s disease combination and method of 
complication risk assessment, baseline PROSPECT risk score at 2 years and baseline ulcer 
sizes also added in Table 7.d.

Compliance simplified in Section 7.7 to the number of complete or partial doses. 

Section 7.8.4 added to describe subgroups and the efficacy analyses to which these will be 
applied. Subgroup descriptions also added in Sections 7.9.1, 7.10, 7.11.1.2.

Appendix D updated to be consistent with Vedolizumab-4014.
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CONFIDENTIAL
8.0
REFERENCES
1. An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Triple Combination 
Therapy With Vedolizumab IV, Adalimumab SC, and Oral Methotrexate in Early of Subjects 
With Crohn’s Disease Stratified at Higher Risk for Developing Complications Takeda 
Development Center Americas, Inc., One Takeda Parkway, Deerfield, IL 60015.
2. Siegel CA, Horton H, Siegel LS, Thompson KD, Mackenzie T, Stewart SK, et al. A validated 
web-based tool to display individualised Crohn’s disease predicted outcomes based on 
clinical, serologic and genetic variables. Aliment Pharmacol Ther 2016;43(2):262-71.
3. Siegel C, Siegel L, Hyams J, Kugathasan S, Markowitz J, Rosh J, et al. Real-time tool to 
display the predicted disease course and treatment response for children with Crohn's disease. 
Infllamm Bowel Dis 2011;17(1):30-8.
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Vedolizumab-4006
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Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
9.0
APPENDICES
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Vedolizumab-4006
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Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
Appendix A
Schedule of Study Procedures
Induction Phase (Screening Through Week 26)
Screening
Treatment
Study Week
Wk 0
Wk
2
Wk
4 (r)
Wk
6
Wk
8 (r)
Wk
10
Wk
14
Wk
18 (r)
Wk
22
Wk
26
Study Day ± Visit Window (Days)
Day -28 to
Day -1
1
15 ±3
n/a
43 ±3
n/a
71 ±3
99 ±3
n/a
155 ±7
183 ±7
Visit Number:
1
2
3
n/a
4
n/a
5
6
n/a
7
8
Informed consent
X
Inclusion/exclusion criteria 
X
X
Demographics/medical and 
medication history/ concurrent 
medical conditions
X
CD History
X
Physical examination
X
X
X
X
X
X
X
X
Vital signs (a)
X
X
X
X
X
X
X
X
Access IRT to obtain subject ID
X
Access IRT to register visit
X
X
X
X
X
X
ASCA IgA, ASCA IgG, Anti-CBir1 
IgG, ANCA, NOD2 genotype test 
X
CDAI
X
X
X
X
X
X
X
PRO-2
X
X
X
Ileocolonoscopy (b)
X
X
SES-CD
X
X
CRP
X
X
X
X
Fecal calprotectin (c)
X
X
X
X
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Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Induction Phase (Screening Through Week 26) (continued)
Screening
Treatment
Study Week
Wk 0
Wk
2
Wk
4 (r)
Wk
6
Wk
8 (r)
Wk
10
Wk
14
Wk
18 (r)
Wk
22
Wk
26
Study Day ± Visit Window (Days)
Day -28 to
Day -1
1
15 ±3
n/a
43 ±3
n/a
71 ±3
99 ±3
n/a
155 ±7
183 ±7
Visit Number:
1
2
3
n/a
4
n/a
5
6
n/a
7
8
Tuberculosis QuantiFERON or skin 
test (d)
X
Chemistry, Hematology, Urinalysis
X
X
X
X
X
X
X
X
Hepatitis, HIV
X
Pharmacogenomic DNA and RNA 
samples (f)
X
PK samples for vedolizumab (g)
X
X
X
X
X
PK samples for adalimumab (h)
X
X
X
X
X
X
ADAs samples, vedolizumab
X
X
X
X
ADAs samples, adalimumab
X
X
X
X
X
X
X
Pregnancy test (hCG) (i)
X
Urine pregnancy test (i)
X
X
X
X
X
X
X
Home pregnancy test (j)
X
ECG
X
Vedolizumab (IV) (k)
X
X
X
X
X
Adalimumab (SC) (l)
X (m)
X (m)
X
X (m)
X
X
X (m)
X
X (m)
X
Methotrexate (PO) (n)
X
X
X
X
X
X
X
X
X
X
Folic acid (PO) (o)
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page.
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Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Induction Phase (Screening Through Week 26) (continued)
Screening
Treatment
Study Week
Wk 0
Wk
2
Wk
4 (r)
Wk
6
Wk
8 (r)
Wk
10
Wk
14
Wk
18 (r)
Wk
22
Wk
26
Study Day ± Visit Window (Days)
Day -28 to
Day -1
1
15 ±3
n/a
43 ±3
n/a
71 ±3
99 ±3
n/a
155 ±7
183 ±7
Visit Number:
1
2
3
n/a
4
n/a
5
6
n/a
7
8
AE/SAE assessment
X
X
X
X
X
X
X
Concomitant medications/ 
procedures 
X
X
X
X
X
X
X
X
PML checklist (p)
X
X
X
X
X
X
PML wallet card
X
IBDQ
X
X
X
WPAI
X
X
X
IBD-DI
X
X
X
Health outcomes, CD-related events
X
X
X
X
X
X
Patient diary
X
X
X
X
X
X
X
X
X
X
X
C difficile test (q)
CD Risk by clinical assessment, 
PROSPECT Tool or 2014 AGA CD 
Care Pathway
X
Monitr CD Test
X
X
Footnotes are on last table page.
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Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Maintenance Phase (Week 30 Through Week 128)
Treatment
Study Week
Wk
30
Wk
34 (s)
Wk
38
Wk 42 
(s)
Wk
46
Wk
50 (s)
Wk 52
Wk
54
Wk
58 (s)
Wk
62
Wk
66 (s)
Wk
70
Wk
74 (s)
Wk
78
Wk
82 (s)
Study Day ± Visit Window 
(Days)
211 
±7
239 ±7
267 ±7
295 ±7
323 ±7
351 ±7
365 ±7
379 ±3
407 ±7
435 ±7
463 ±7
491 ±7
519 ±7
547 ±7
575 ±7
Visit Number:
9
9b
10
10b
11
11b
12
13
13b
14
14b
15
15b
16
16b
Physical examination
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
Vital signs (a)
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
Access IRT to register visit
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
CDAI
X
X
X
X
X
X
X
X
PRO-2
X
X
Ileocolonoscopy (b)
SES-CD
CRP
X
X
Fecal calprotectin (c)
X
X
Chemistry, Hematology, 
Urinalysis
X (e)
X
X
X
X
X
X
X
PK samples for 
vedolizumab (g)
X
X
X
ADAs samples, 
vedolizumab
X
X
X
ADAs samples, 
adalimumab
X
X
X
Pregnancy test (hCG) (i)
X
Footnotes are on last table page.
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Page 48 of 56
Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Maintenance Phase (Week 30 Through Week 128)
Treatment
Study Week
Wk
30
Wk
34 (s)
Wk
38
Wk 42 
(s)
Wk
46
Wk
50 (s)
Wk 52
Wk
54
Wk
58 (s)
Wk
62
Wk
66 (s)
Wk
70
Wk
74 (s)
Wk
78
Wk
82 (s)
Study Day ± Visit 
Window (Days)
211 ±7
239 ±7
267 ±7
295 ±7
323 ±7
351 ±7
365 ±7
379 ±3
407 ±7
435 ±7
463 ±7
491 ±7
519 ±7
547 ±7
575 ±7
Visit Number:
9
9b
10
10b
11
11b
12
13
13b
14
14b
15
15b
16
16b
Urine pregnancy test (i)
X
X
X
X
X
X
X
Home pregnancy test (j)
X
X
X
X
Vedolizumab (IV) (k)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
Methotrexate (PO) (n)
X
X
Folic acid (PO) (o)
X
X
AE/SAE assessment
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
Concomitant 
medications/procedures 
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
PML checklist (p)
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
PML wallet card
IBDQ
X
X
WPAI
X
X
IBD-DI
X
X
Health outcomes, 
CD-related events
X
X
X
X
X
X
X
X
Patient diary
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
LTFU questionnaire 
C difficile test (q)
Footnotes are on last table page.
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Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
Appendix A
Schedule of Study Procedures (continued)
Maintenance Phase (Week 30 Through Week 128) (continued)
Treatment
EOS or ET
LTFU Phone Call
Study Week
Wk 86
Wk 90 (s)
Wk 94
Wk 98 (s)
Wk 102
EOT
Wk 120
(18 wks post tx)
Wk 128
(26 wks post tx)
Study Day ± Visit Window (Days)
603 ±7
631 ±7
659 ±7
687 ±7
715 ±7
841 ±7
897 ±7
Visit Number:
17
17b
18
18b
19
20
21
Physical examination
X
X (s)
X
X (s)
X
X
Vital signs (a)
X
X (s)
X
X (s)
X
X
Access IRT to register visit
X
X (s)
X
X (s)
X
X
CDAI
X
X
X
X
PRO-2
X
Ileocolonoscopy (b)
X
X (ET only)
SES-CD
X
CRP
X
Fecal calprotectin (c)
X
Chemistry, Hematology, Urinalysis
X
X
X
X
PK samples for vedolizumab (g)
X
X
ADAs samples, vedolizumab
X
X
ADAs samples, adalimumab
X
X
Pregnancy test (hCG) (i)
(X)
Urine pregnancy test (i)
X
X
X
X
Home pregnancy test (j)
Vedolizumab (IV) (k)
X
X (s)
X
X (s)
X
Footnotes are on last table page.
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Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
Appendix A Schedule of Study Procedures (continued)
Maintenance Phase (Week 30 Through Week 128) (continued)
Treatment
EOS or ET
LTFU Phone Call
Study Week
Wk 86
Wk 90 (s)
Wk 94
Wk 98 (s)
Wk 102
EOT
Wk 120
(18 wks post tx)
Wk 128
(26 wks post tx)
Study Day ± Visit Window (Days)
603 ±7
631 ±7
659 ±7
687 ±7
715 ±7
841 ±7
897 ±7
Visit Number:
17
17b
18
18b
19
20
21
Methotrexate (PO) (n)
Folic acid (PO) (o)
AE/SAE assessment
X
X (s)
X
X (s)
X
X
Concomitant medications/procedures 
X
X (s)
X
X (s)
X
X
PML checklist (p)
X
X (s)
X
X (s)
X
PML wallet card
X
IBDQ
X
WPAI
X
IBD-DI
X
Health outcomes, CD-related events
X
X
X
X
Patient diary
X
X (s)
X
X (s)
X
LTFU questionnaire 
X
C difficile test (q)
Monitr CD Test
X
X (ET only)
Abbreviations; AE, adverse event; ADA, antidrug antibodies; ANCA, perinuclear antineutrophil antibody; ASCA, anti-Saccharomyces cerevisiae antibody; CD, Crohn’s disease; 
CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; DNA, deoxyribonucleic acid; ECG, electrocardiogram; EOS, end of study; EOT, end of treatment; ET, early 
termination; hCG, human chorionic gonadotropin; HIV, human immunodeficiency virus; IBD-DI, Inflammatory Bowel Disease Disability Index; IBDQ, Inflammatory Bowel 
Disease Questionnaire; ID, identification; IgA, immunoglobin; IRT, interactive response technology; IV, intravenous; LTFU, long-term follow-up; n/a=not applicable; NOD2, 
nucleotide-binding oligomerization domain-containing protein 2; PK, pharmacokinetic; PML, progressive multifocal leukoencephalopathy; PO, oral; PRO-2, patient-reported 
outcome 2; RNA, ribonucleic acid; SAE, serious adverse event; SC, subcutaneous; SES-CD, simple endoscopic score for Crohn’s disease; tx, treatment; WPAI,Work Productivity 
and Activity Impairment.
(a) Height collected only at the screening visit. Weight will be measured at every site visit where CDAI is calculated.
(b) Endoscopy to be collected at screening, Weeks 26 and 102, or early termination for central read. Biopsies will also be collected. All biopsies collected per protocol will be 
centrally stored and analyzed at the end of the study. Although it is permissible for the investigator to take additional biopsy samples as deemed necessary for standard of care 
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Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
management of the patient during the protocol required colonoscopy, these will be considered as occurring outside the protocol. Such collection, handling, and analyses of the 
additional samples will be and remain the responsibility of the investigator.
(c) Stool sample to be collected from the first bowel movement in the morning and sent to central laboratory.
(d) QuantiFERON test or tuberculin skin test only. 
(e) Hematology only.
(f) DNA and RNA samples will be collected on Day 1.
(g) PK samples for vedolizumab to be collected predose on dosing days Day 1 and Weeks 6, 10, 14, 26, 38, 54, 70, 86, and 102. at visits where study drug is given. 
(h) PK samples for adalimumab to be collected predose on dosing days (prior to vedolizumab dosing) on Day 1 and Weeks 6, 10, 14, 22, and 26. For Weeks 6, 14, and 22, when 
the subject is self-administering adalimumab at home, the adalimumab PK samples will be collected on the day of vedolizumab PK collection, prior to vedolizumab infusion. 
(i) Women of childbearing potential only. Urine pregnancy testing will be conducted at the site and serum pregnancy testing will be conducted by the central laboratory. Serum 
pregnancy completed at screening and Week 30 or Early Termination if stopped prior to Week 30; urine pregnancy to be completed at other visits. 
(j) Women of childbearing potential only. When site visits shift from every 4 weeks to every 8 weeks, women of childbearing potential will need to take a home pregnancy test 
every other month (in between visits) up until Week 58 and report the results to the site. If the subject experiences an exacerbation and switches to Q4W dosing, then no home 
pregnancy test is required as subject will have urine pregnancy test performed on site before infusion.
(k) Vedolizumab IV 300 mg at Week 0, 2, 6, 14, 22, 30, 38, 46, 54, 62, 70, 78, 86, 94, and 102. Subjects should be observed for 2 hours following the first 2 infusions, at a 
minimum, and 1 hour after each subsequent infusion for monitoring hypersensitivity reactions.
(l) Adalimumab SC 160 mg at Week 0, 80 mg at Week 2, then 40 mg every 2 weeks for a total of 27 weeks. Self injection or caregiver may inject using either the Pen or prefilled 
syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. Adalimumab will be 
self-administered at home at Weeks 2, 4, 8, 10, 12, 16, 18, 20, 24, and 26.
(m) At Weeks 0, 2, 6, 14, and 22, adalimumab will be administered 1 day after the vedolizumab infusion. For Week 0, the subject should return to the site the day after (or within a 
3-day window of) the vedolizumab infusion to self-administer the adalimumab SC injection while instructed and observed by site staff or to have the injection administered by 
qualified site staff. Subsequent doses will be self-administered at home starting at Week 2.
(n) Methotrexate 15 mg (six 2.5-mg tablets) PO once weekly for total of 34 weeks. 
(o) Daily folic acid (1 mg PO capsule or tablet) must be taken during the 34-week period of methotrexate treatment.
(p) PML checklist must be administered at screening and prior to vedolizumab dosing at every vedolizumab dosing visit.
(q) A C difficile test will be done only if a subject experiences a flare up during the study.
(r) Not a clinic visit. Home dosing with adalimumab and methotrexate only.
(s) Optional 4-week vedolizumab dosing visit. If a subject has a first exacerbation of CD after 26 weeks (defined as a CDAI increase of >70 from the prior visit on 2 occasions 
separated by a 2-week interval, objective evidence of disease activity by colonoscopy and CRP above normal, OR fecal calprotectin >250 μg/g alone), then frequency of 
vedolizumab infusions will be changed to vedolizumab 300 mg IV every 4 weeks (instead of every 8 weeks) for the remainder of treatment. Subjects should be monitored for 1 
hour after each infusion for hypersensitivity reactions.
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Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
Appendix B
Crohn's Disease Activity Index (CDAI)
Category
Count
Initial Total
Multiplication 
Factor
Total
Number of liquid or very 
soft stools
7-day total number of liquid or very soft 
stools (reported on the 7 days immediately 
prior to the study visit)
x 2
Abdominal pain
7-day total of daily abdominal pain scores on 
a 3-point scale: 0=none, 1=mild, 2=moderate, 
3=severe (reported on the 7 days immediately 
prior to the study visit)
x 5
General well being
7-day total of daily general well-being scores 
on a 4-point scale: 0=generally well, 
1=slightly under par, 2=poor, 3=very poor, 
4=terrible (reported on the 7 days 
immediately prior to the study visit)
x 7
Extra-intestinal 
manifestations of Crohn’s 
Disease
Total number of checked boxes (check all that 
apply):

Arthritis/arthralgia

Iritis/uveitis

Erythema nodosum/pyoderma 
gangrenosum/aphthous stomatitis

Anal fissure, fistula, or abscess

Other fistula

Fever over 37.8°C during past week
x 20
Lomotil/Imodium/opiates 
for diarrhea
Yes = 1
No = 0
x 30
Abdominal mass
None = 0
Questionable = 2
Definite = 5
x 10
Hematocrit (%) (a)
Males: subtract value from 47
Females: subtract value from 42
x 6
Body Weight (b)
(1 – (Body weight/
Standard Weight)) × 100
x 1
Final Score
Add totals:
Source: Adapted from: Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s disease activity 
index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70 (3):439-44. 
(a) If hematocrit subtotal <0, enter 0. 
(b) If body weight subtotal <-10, enter -10.
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Statistical Analysis Plan Amendment 2
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CONFIDENTIAL
Appendix C
Adverse Events of Special Interest (AESI)
AESI
MedDRA Terms or Definitions
Infections
SOC: INFECTIONS AND INFESTATIONS
Hypersensitivity 
Reactions
Anaphylactic/anaphylactoid shock conditions SMQ (broad).
Angioedema SMQ (broad).
Hypersensitivity SMQ (broad).
Infusion Related Reaction
Analysis for these AEs will occur on two levels:

Investigator defined Infusion Related Reactions (as indicated on the AE 
eCRF).

All AEs that occur on or one calendar day after the infusion date.
Malignancies
SOC: NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS)
PML
Human polyomavirus infection PT.
JC virus infection PT.
JC virus CSF test positive PT.
JC polyomavirus 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)
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Statistical Analysis Plan Amendment 2
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CONFIDENTIAL
Appendix D
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology – Criteria for Markedly Abnormal Values
Parameter
Conventional Units
Takeda Preferred SI Units
Units
Markedly
Abnormal
Value
Units
Markedly
Abnormal
Value
RBC count
×106 cells/µL
<0.8 × LLN, 
>1.2 × ULN
×1012 cells/L
<0.8 × LLN, 
>1.2 × ULN
WBC count
×103 cells/µL
<3.0
×109 cells/L
<3.0
Hemoglobin
g/dL
<8
g/L
<80
Hematocrit
%
<0.8 × LLN, 
>1.2 × ULN
Fraction of 1
<0.8 × LLN, 
>1.2 × ULN
Platelet count
×103/µL
<100, 
>1200
×109 /L
<100, 
>1200
Lymphocytes 
×103 cells/µL
<0.5 
× 109 cells/L
<0.5
PT
Sec
>3 × ULN
Sec
>3 × ULN
INR†
NA
>2.5 x ULN
NA
>2.5 x ULN
LLN = lower limit of normal or lower reference limit; ULN = upper limit of normal or upper reference limit
† Values are for subjects without anticoagulation, based on the normal range provided above for PT.
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Statistical Analysis Plan Amendment 2
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CONFIDENTIAL
Appendix D
Criteria for Identification of Markedly Abnormal Laboratory Values
(continued)
Serum Chemistry – Criteria for Markedly Abnormal Values
Parameter
Conventional Units
Takeda Preferred SI Units
Units
Markedly 
Abnormal
Values
Units
Markedly
Abnormal
Value
ALT
U/L
>3 × ULN
U/L
>3 × ULN
Albumin
g/dL
<3.5
g/L 
<35
Alkaline Phosphatase
U/L
>3 × ULN
U/L
>3 × ULN
AST
U/L
>3 × ULN
U/L
>3 × ULN
Amylase
U/L
>3 x ULN
U/L
>3 x ULN
Bicarbonate
mEq/L
<21,
>33
mmol/L
<21,
>33
Total Bilirubin
mg/dL
>2.2
µmol/L
>37.6
Total Protein
g/dL
<2.0, 
>9.0
g/L
<20, 
>90
Creatinine
mg/dL
>2 x ULN
mmol/L
>2 x ULN
Blood Urea Nitrogen
mg/dL
>2 x ULN
mmol/L
>2 x ULN
Creatine Kinase
U/L
>3 × ULN
U/L
>3 × ULN
GGT*
U/L
>3 × ULN
U/L
>3 × ULN
Lipase
U/L
>3 × ULN
U/L
>3 × ULN
Potassium 
mEq/L
<2.8, 
>6.3
mmol/L
<2.8, 
>6.3
Sodium
mEq/L
<117, 
>160
mmol/L
<117, 
>160
Calcium
mg/dL
<6.1, 
>12.9
mmol/L
<1.52, 
>3.22
Uric Acid
mg/dL
>2 x ULN
µmol/L
>2 x ULN
Glucose
mg/dL
<50, 
>450
mmol/L
<2.5, 
>25
Phosphorus
mg/dL
<2.5
mmol/L
<0.81
LLN = lower limit of normal or lower reference limit; ULN = upper limit of normal or upper reference limit; *
GGT = -Glutamyl Transferase.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Vedolizumab-4006
Page 56 of 56
Statistical Analysis Plan Amendment 2
21 February 2023
CONFIDENTIAL
Appendix E
Criteria for Identification of Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Systolic Blood Pressure
mmHg
<85
>180
Diastolic Blood Pressure
mmHg
<50
>110
Pulse
bpm
<50
>120
Body Temperature
oC
<35.6
>37.7
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


  
ELECTRONIC SIGNATURES
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
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Prot_000.pdf: 



Title: An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Triple Combination 
Therapy With Vedolizumab IV, Adalimumab SC, and Oral Methotrexate in Early Treatment of 
Subjects With Crohn’s Disease Stratified at Higher Risk for Developing Complications
NCT Number: NCT02764762
Protocol Approve Date: 30 June 2020
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL
An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Triple Combination 
Therapy With Vedolizumab IV, Adalimumab SC, and Oral Methotrexate in Early 
Treatment of Subjects With Crohn’s Disease Stratified at Higher Risk for Developing 
Complications
Triple Combination Therapy in High Risk Crohn’s Disease
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421
Study Number:
Vedolizumab-4006
IND Number:
009125
EudraCT Number:
Not applicable
Compounds:
Vedolizumab IV, Adalimumab SC, Methotrexate PO
Date:
30 June 2020
Amendment Number: 
04
Amendment History: 
Date
Amendment 
Number
Amendment Type (for regional 
Europe purposes only)
Region
01 March 2016
Initial Protocol
Not applicable
Global
31 January 2017
01
Substantial
Global
12 March 2018
02
Substantial
Global
08 October 2018
03
Substantial
Global
30 June 2020
04
Substantial
Global
da: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Vedolizumab-4006
Page 2 of 132
Protocol Incorporating Amendment No. 04
30 June 2020
1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts 
A separate contact information list will be provided to each site.
Takeda Development Center Americas, Inc. (TDC Americas) sponsored investigators per 
individual country requirements will be provided with emergency medical contact information 
cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
United States/Canada 
Contact
Serious adverse event and pregnancy reporting
Takeda Development Center Americas, Inc.
Pharmacovigilance Department
Medical Monitor
(medical advice on protocol and compound)
Responsible Medical Officer 
(carries overall responsibility for the conduct of 
the study)
PPD
t to the Applicable Terms of Use
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Property of Takeda: For Non-Commercial U
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Page 3 of 132
Protocol Incorporating Amendment No. 04
30 June 2020
1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES 
The signature of the responsible Takeda medical officer can be found on the signature page.
Electronic Signatures may be found on the last page of this document.
PPD
ubject to the Applicable Terms of Use
rdance
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rdance
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Vedolizumab-4006
Page 4 of 132
Protocol Incorporating Amendment No. 04
30 June 2020
1.3
Protocol Amendment 04 Summary of Changes
This document describes the changes in reference to the protocol incorporating Amendment 
No. 04.
The primary purpose of this amendment is to update the protocol regarding addition of Monitr CD 
testing at Baseline Week 0, Week 26 and 102 or early termination. Monitr CD is a 
laboratory-developed test from Prometheus Labs that evaluates multiple markers of mucosal 
damage and repair processes, regardless of disease location. Other minor changes in procedures or 
definitions are proposed. Minor grammatical, editorial, formatting, and administrative changes are 
included for clarification and administrative purposes only. For specific descriptions of text 
changes and where the changes are located, see Appendix L.
The following is a summary of the changes made in Amendment No. 04: 
1. Takeda address was updated.
2. Section 1.1 Robarts Medical Monitor phone was updated.
3. Section 1.1 Responsible Medical Officer contact was updated. 
4. Sections 2.0 and 6.1 were updated to increase site number from 60-64.
5. Section 4.1.2.2 was updated with the latest exposure data from Investigator Brochure Edition 
23 dated 12 July 2019. 
6. Section 5.1.3 was updated to include the additional objective for Monitr CD testing.
7. Section 5.2.3 was updated to include endpoints for Monitr CD testing.
8. Sections 7.3.1.2, 8.1.3, 9.3.6, and Appendix A footnote (s) were updated to clarify 
exacerbation of CD language.
9. Section 7.4 Adverse Event withdrawal criteria was clarified to include criteria for Leukopenia 
or Lymphopenia.
10. Section 9.1.4 genitourinary system was removed from physical exam procedures.
11. Section 9.1.10 and Appendix A Schedule of Procedures table updated to include Monitr CD 
testing.
12. Section 9.1.11 and Appendix A Schedule of Procedures table and footnote (b) clarified 
colonoscopy may be performed at Early Termination visit.
13. Section 9.1.20 approximate total blood volume was updated. 
14. Table 9.a was updated to include Monitr CD biomarkers.
15. Section 9.1.24 clarification of predose ADA sample collection timing.
16. Section 9.1.27.3 correction of reason for use of barrier methods (b).
17. Appendix A Schedule of Procedures table and footnote (j) were updated to clarify pregnancy 
testing for Q4 dosing.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Page 5 of 132
Protocol Incorporating Amendment No. 04
30 June 2020
18. Appendix A Schedule of Procedures footnote (a) was updated to clarify weight measurement 
visits.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Vedolizumab IV
Vedolizumab-4006
Page 6 of 132
Protocol Incorporating Amendment No. 04
30 June 2020
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, the 
vedolizumab IV (Entyvio) package insert, the adalimumab package insert, the methotrexate 
package insert, and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and also to protect the rights, safety,
privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement. 

Appendix B, Responsibilities of the investigator,
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
Commercial Use Only and Subject to the Applicable Terms of Use
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Page 7 of 132
Protocol Incorporating Amendment No. 04
30 June 2020
TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 04 Summary of Changes..........................................................4
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................18
3.1
Study-Related Responsibilities.................................................................................18
3.2
Principal Investigator/Coordinating Investigator ......................................................18
3.3
List of Abbreviations ...............................................................................................19
3.4
Corporate Identification...........................................................................................21
4.0
INTRODUCTION.........................................................................................................22
4.1
Background .............................................................................................................22
4.1.1
Disease and Current Treatments.......................................................................22
4.1.2
Vedolizumab ...................................................................................................23
4.1.2.1
Nonclinical..............................................................................................23
4.1.2.2
Human Experience ..................................................................................23
4.1.3
Adalimumab....................................................................................................24
4.1.4
Methotrexate....................................................................................................26
4.2
Rationale for the Proposed Study.............................................................................27
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................29
5.1
Objectives................................................................................................................29
5.1.1
Primary Objective............................................................................................29
5.1.2
Secondary Objectives ......................................................................................29
5.1.3
Additional Objectives ......................................................................................29
5.1.4
Safety Objective ..............................................................................................30
5.2
Endpoints.................................................................................................................30
5.2.1
Primary Endpoints ...........................................................................................30
5.2.2
Secondary Endpoints .......................................................................................30
5.2.3
Additional Endpoints.......................................................................................31
5.2.4
Safety Endpoints..............................................................................................32
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................32
6.1
Study Design ...........................................................................................................32
6.2
Justification for Study Design, Dose, and Endpoints ................................................33
6.3
Premature Termination or Suspension of Study or Investigational Site.....................35
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Protocol Incorporating Amendment No. 04
30 June 2020
6.3.1
Criteria for Premature Termination or Suspension of the Study........................35
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites .......35
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) .............................................................36
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............36
7.1
Inclusion Criteria .....................................................................................................36
7.2
Exclusion Criteria ....................................................................................................37
7.2.1
Gastrointestinal Exclusion Criteria...................................................................37
7.2.2
Infectious Disease Exclusion Criteria...............................................................38
7.2.3
General Exclusion Criteria...............................................................................38
7.3
Excluded Medications..............................................................................................41
7.3.1
Permitted Medications and Treatments ............................................................42
7.3.1.1
Oral Corticosteroid Dosing and Tapering.................................................42
7.3.1.2
Medications for CD Exacerbation After 26 Weeks...................................42
7.4
Criteria for Discontinuation or Withdrawal of a Subject...........................................43
7.5
Procedures for Discontinuation or Withdrawal of a Subject......................................44
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................44
8.1
Study Medication and Materials...............................................................................45
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ..................................45
8.1.1.1
Vedolizumab IV ......................................................................................45
8.1.1.2
Adalimumab SC ......................................................................................45
8.1.1.3
Oral Methotrexate....................................................................................45
8.1.2
Storage ............................................................................................................46
8.1.3
Dose and Regimen...........................................................................................46
8.1.4
Overdose .........................................................................................................47
8.2
Investigational Drug Assignment and Dispensing Procedures ..................................47
8.3
Accountability and Destruction of Sponsor-Supplied Drugs.....................................48
8.4
Companion Medication............................................................................................49
9.0
STUDY PLAN ..............................................................................................................49
9.1
Study Procedures.....................................................................................................49
9.1.1
Informed Consent Procedure............................................................................50
9.1.2
Demographics, Medical History, and Medication History Procedure................50
9.1.3
Crohn’s Disease History ..................................................................................50
9.1.4
Physical Examination Procedure......................................................................50
9.1.5
Weight, Height ................................................................................................51
9.1.6
Vital Sign Procedure........................................................................................51
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Protocol Incorporating Amendment No. 04
30 June 2020
9.1.7
PML Checklist.................................................................................................51
9.1.8
Documentation of Concurrent Medical Conditions...........................................51
9.1.9
ECG Procedure................................................................................................51
9.1.10
Predicting CD Disease Course .........................................................................51
9.1.10.1
Investigator clinical assessment ...............................................................51
9.1.10.2
AGA CD Clinical Care Pathway..............................................................52
9.1.10.3
PROSPECT CD Tool ..............................................................................52
9.1.10.4
Monitr Crohn's Disease Test....................................................................52
9.1.11
Colonoscopy and Biopsy Procedure.................................................................53
9.1.12
Primary Efficacy Measurement........................................................................54
9.1.13
The SES-CD....................................................................................................54
9.1.14
CDAI...............................................................................................................54
9.1.15
CDAI Diary Completion..................................................................................54
9.1.16
PRO-2 .............................................................................................................54
9.1.17
Additional Patient-Reported Outcome Measures..............................................54
9.1.17.1
Inflammatory Bowel Disease Questionnaire ............................................54
9.1.17.2
Work Productivity and Activity Impairment - Crohn’s Disease................55
9.1.17.3
Inflammatory Bowel Disease - Disability Index.......................................55
9.1.18
Documentation of Concomitant Procedures .....................................................55
9.1.19
Documentation of Concomitant Medications ...................................................55
9.1.20
Procedures for Clinical Laboratory Samples ....................................................56
9.1.21
Fecal Calprotectin Sample Collection ..............................................................58
9.1.22
Stool Sample Collection ..................................................................................58
9.1.23
Pharmacokinetic Sample Collection.................................................................58
9.1.24
Anti-Drug Antibodies Sampling.......................................................................58
9.1.25
Pharmacogenomic Sampling............................................................................59
9.1.26
Tuberculosis Screening....................................................................................60
9.1.27
Contraception and Pregnancy Avoidance Procedure ........................................60
9.1.27.1
Male Subjects and Their Female Partners ................................................60
9.1.27.2
Female Subjects and Their Male Partners ................................................60
9.1.27.3
Definitions and Procedures for Contraception and Pregnancy Avoidance
................................................................................................................60
9.1.27.4
General Guidance With Respect to the Avoidance of Pregnancy..............62
9.1.28
Pregnancy........................................................................................................63
9.1.29
Documentation of Screen Failure.....................................................................63
9.1.30
Documentation of Study Entrance....................................................................63
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Protocol Incorporating Amendment No. 04
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9.2
Monitoring Subject Treatment Compliance..............................................................64
9.3
Schedule of Observations and Procedures................................................................64
9.3.1
Screening (Visit 1)...........................................................................................64
9.3.2
Enrollment (Day 1) (Visit 2)............................................................................64
9.3.3
Week 102 or Final Treatment Visit (Visit 19) ..................................................64
9.3.4
Week 120 or End-of-Study Visit (18 Weeks Post-Treatment) ..........................64
9.3.5
Poststudy Long-term Follow-up (26 Weeks Post-Treatment) ...........................65
9.3.6
Unscheduled Visits Due to Exacerbation of CD...............................................65
9.3.7
Poststudy Care.................................................................................................65
9.4
Biological Sample Retention and Destruction ..........................................................66
10.0
PRETREATMENT EVENTS, ADVERSE EVENTS, AND PRODUCT 
COMPLAINTS .............................................................................................................67
10.1
Definitions...............................................................................................................67
10.1.1
PTEs................................................................................................................67
10.1.2
AEs .................................................................................................................67
10.1.3
PCs..................................................................................................................67
10.1.4
Additional Points to Consider for PTEs and AEs .............................................67
10.1.5
SAEs ...............................................................................................................69
10.1.6
Special Interest AEs.........................................................................................70
10.1.7
Severity of PTEs and AEs................................................................................72
10.1.8
Causality of AEs..............................................................................................72
10.1.9
Relationship to Study Procedures.....................................................................72
10.1.10 Start Date.........................................................................................................72
10.1.11 Stop Date.........................................................................................................72
10.1.12 Frequency........................................................................................................72
10.1.13 Action Concerning Study Medication ..............................................................72
10.1.14 Outcome..........................................................................................................73
10.2
Procedures...............................................................................................................73
10.2.1
Collection and Reporting of AEs .....................................................................73
10.2.1.1
PTE and AE Collection Period.................................................................73
10.2.1.2
PTE and AE Reporting ............................................................................74
10.2.1.3
Special Interest AE Reporting..................................................................74
10.2.2
Collection and Reporting of SAEs ...................................................................75
10.2.3
Reporting of Abnormal Liver Function Tests...................................................75
10.3
Follow-up of SAEs ..................................................................................................75
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...76
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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11.0
STUDY-SPECIFIC COMMITTEES .............................................................................76
11.1
Adjudication Committee..........................................................................................76
11.1.1
Risk Assessment and Minimization for PML (RAMP) Program.......................76
12.0
DATA HANDLING AND RECORDKEEPING............................................................77
12.1
eCRFs......................................................................................................................77
12.2
Record Retention .....................................................................................................78
13.0
STATISTICAL METHODS..........................................................................................78
13.1
Statistical and Analytical Plans ................................................................................78
13.1.1
Analysis Sets ...................................................................................................79
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................79
13.1.3
Efficacy Analysis.............................................................................................79
13.1.4
PK Analysis.....................................................................................................80
13.1.5
Anti-Drug Antibodies Analysis........................................................................80
13.1.6
Safety Analysis................................................................................................80
13.1.7
Other Analyses ................................................................................................80
13.2
Interim Analysis and Criteria for Early Termination ................................................80
13.3
Determination of Sample Size..................................................................................81
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................81
14.1
Study-Site Monitoring Visits ...................................................................................81
14.2
Protocol Deviations..................................................................................................81
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................81
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................82
15.1
IRB and/or IEC Approval ........................................................................................82
15.2
Subject Information, Informed Consent, and Subject Authorization .........................83
15.3
Subject Confidentiality ............................................................................................84
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................84
15.4.1
Publication and Disclosure...............................................................................84
15.4.2
Clinical Trial Registration................................................................................85
15.4.3
Clinical Trial Results Disclosure......................................................................85
15.5
Insurance and Compensation for Injury....................................................................85
16.0
REFERENCES..............................................................................................................85
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Page 12 of 132
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LIST OF IN-TEXT TABLES
Table 8.a
Dose and Regimen .............................................................................................47
Table 9.a
Clinical Laboratory Tests...................................................................................56
Table 10.a
Takeda Medically Significant AE List................................................................70
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................33
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................91
Appendix B
Responsibilities of the Investigator.....................................................................99
Appendix C
Elements of the Subject Informed Consent.......................................................101
Appendix D
Investigator Consent to Use of Personal Information........................................104
Appendix E
AGA CD Clinical Care Pathway ......................................................................105
Appendix F
SES-CD...........................................................................................................107
Appendix G
CDAI...............................................................................................................108
Appendix H
Table for Determining Standard Body Weight (CDAI Variable) ......................109
Appendix I
PRO-2..............................................................................................................110
Appendix J
IBDQ...............................................................................................................111
Appendix K
Collection, Storage, and Shipment of Bioanalytical Samples............................122
Appendix L
Detailed Description of Amendments to Text...................................................124
cial Use Only and Subject to the Applicable Terms of Use
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Descript
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Vedolizumab-4006
Page 13 of 132
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compounds:
Vedolizumab intravenous (IV), Adalimumab 
subcutaneous (SC), Methotrexate oral (PO)
Title of Protocol: An Open-Label, Phase 4 Study to 
Evaluate the Efficacy and Safety of Triple Combination 
Therapy With Vedolizumab IV, Adalimumab SC, and Oral 
Methotrexate in Early Treatment of Subjects With Crohn’s 
Disease Stratified at Higher Risk for Developing 
Complications
IND No.: 
009125
EudraCT No.:
Not applicable
Study Number: Vedolizumab-4006
Phase: 4
Study Design:
A phase 4, open-label, multicenter study in subjects with newly-diagnosed Crohn’s disease (CD) at higher risk for 
complications due to aggressive disease. The study will investigate the efficacy and safety of triple combination 
therapy (300 mg vedolizumab IV, 160/80/40 mg adalimumab SC, and 15 mg oral methotrexate) over a 26-week 
treatment period for induction of endoscopic remission and mucosal healing followed by efficacy and safety of 
vedolizumab IV monotherapy to maintain remission for 76 weeks, for a total treatment period of 102 weeks.
The study will be conducted in the United States and Canada and will include 60 subjects with moderate to severe CD 
and judged by the investigator to be at moderate-high risk for complications. CD must have been diagnosed within the 
previous 24 months and subjects must be naïve to biologics.
Subjects who meet the inclusion criteria and none of the exclusion criteria will receive vedolizumab 300 mg IV 
infusion on Day 1 and Weeks 2, 6, 14, 22, 30, 38, 46, 54, 62, 70, 78, 86, 94, and 102; adalimumab 160 mg SC injection 
on Day 2, 80 mg at Week 2, then 40 mg every 2 weeks thereafter until Week 26; and oral methotrexate 15 mg weekly 
from Day 1 through Week 34.
Primary Objectives:

To determine the effect of triple combination therapy with an anti-integrin (vedolizumab IV), a tumor necrosis 
factor (TNF) antagonist (adalimumab SC), and an immunomodulator (oral methotrexate) on endoscopic 
remission at Week 26.
Secondary Objectives:

To evaluate the effect of vedolizumab IV monotherapy on maintaining endoscopic remission at Week 102 
following triple combination therapy.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on endoscopic 
healing at Weeks 26 and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on endoscopic 
response at Weeks 26 and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on deep remission at 
Weeks 26 and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on clinical remission 
by Crohn’s Disease Activity Index (CDAI) at Weeks 10, 26, 52, 78, and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on clinical response 
by CDAI at Weeks 10, 26, 52, 78, and 102.
Additional Objectives:

To evaluate the pharmacokinetics of vedolizumab and adalimumab in CD subjects at higher risk for CD 
complications at Week 26.

To assess immunogenicity to vedolizumab and adalimumab over the follow-up period.
Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Vedolizumab-4006
Page 14 of 132
Protocol Incorporating Amendment No. 04
30 June 2020

To evaluate C-reactive protein (CRP) levels at Weeks 10 and 26.

To evaluate fecal calprotectin at Weeks 10, 14, 26, 52, 78, and 102.

To evaluate the impact of triple combination therapy on health-related quality-of-life (HRQOL) using the 
Inflammatory Bowel Disease Questionnaire (IBDQ), Work Productivity and Activity Impairment - Crohn’s 
Disease (WPAI-CD), and the Inflammatory Bowel Disease Disability Index (IBD-DI).

To evaluate endoscopic remission, defined as Monitr CD Endoscopic Healing Index (EHI) score ≤20, at Weeks 
26 and 102.

To evaluate Monitr CD EHI score ≤30 or ≤50 at Weeks 26 and 102.
Safety Objective:

To evaluate the safety of triple combination therapy with an anti-integrin, a TNF antagonist, and an 
immunomodulator over a 26-week period, followed by 76 weeks of monotherapy with an anti-integrin.
Subject Population: Adult subjects at higher risk for progressive CD, with CD diagnosed within the previous 
24 months. Subjects will be naïve to biologics.
Number of Subjects:
Approximately 60 subjects
Number of Sites: 
Approximately 64 sites in the United States and 
Canada 
Dose Level(s):
Vedolizumab 300 mg IV at Weeks 0, 2, 6, and then every 8 
weeks for total of 102 weeks.
Adalimumab SC 160 mg at Week 0, 80 mg at Week 2, and 
then 40 mg every 2 weeks for a total of 26 weeks.
Methotrexate 15 mg PO weekly for 34 weeks.
Route of Administration:
Vedolizumab IV
Adalimumab SC
Methotrexate PO
Duration of Treatment:
102-week treatment period.
Subjects will receive triple combination treatment for 26 
weeks, followed by a 76-week treatment period of 
vedolizumab IV maintenance treatment for those who 
achieve clinical response (≥100-point decrease in CDAI).
Period of Evaluation:
The study includes a 4-week screening period, a 
26-week triple combination treatment period, an 
additional 76-week vedolizumab monotherapy 
treatment period (with last dose at Week 102), and a 
26-week follow-up period following last dose. The 
duration of the study from screening to final study 
assessments at Week 120 will be approximately 124
weeks. All subjects will participate in a safety 
follow-up telephone call 26 weeks after last dose, for a 
total follow-up of 128 weeks.
Main Criteria for Inclusion:

Adult subjects, aged 18 to 65 years at time of screening.

CD diagnosed in the previous 24 months prior to screening.

Simple Endoscopic Score for Crohn’s Disease (SES-CD) score ≥7 (or ≥4 if isolated ileal disease).

Subjects judged by the investigator as having CD at moderate-high risk for complications based on clinical 
assessment, the Crohn's Disease Personalized Risk and Outcome Prediction Tool (PROSPECT), or criteria 
defined by the 2014 American Gastroenterology Association (AGA) CD care pathway.

If a subject is on corticosteroids, they must be willing to follow a mandatory taper of prednisone or budesonide 
within 60 days after enrollment.

If a subject is on 5-aminosalicylate (5-ASA), antibiotics, or probiotic, they must be willing to stop that treatment 
at enrollment. 
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Vedolizumab IV
Vedolizumab-4006
Page 15 of 132
Protocol Incorporating Amendment No. 04
30 June 2020
Main Criteria for Exclusion:

Subjects who have any evidence of active infection during Screening.

Subjects who have a history of any bacterial, viral, and other infection due to opportunistic pathogens.

History of tuberculosis (TB), a chest radiograph suggestive of TB infection, or positive tuberculin skin test with 
purified protein derivative OR positive QuantiFERON GOLD test.

Subjects who have had prior exposure to any TNF antagonist biologic therapy, or to vedolizumab, natalizumab, 
efalizumab, or rituximab.

Any prior CD-related surgery or CD complication requiring surgery.

History of any lymphoma or lymphoproliferative disease.

History of congestive heart failure (New York Heart Association class III/IV) or unstable angina.

Subjects with a medical history that contraindicates the use of methotrexate or adalimumab or indicates an 
intolerance to methotrexate or adalimumab.
Main Criteria for Evaluation and Analyses:
Primary endpoint: Percentage of subjects achieving endoscopic remission (defined as SES-CD 0-2) at Week 26. 
Secondary endpoints: 

Percentage of subjects achieving endoscopic healing defined as SES-CD ≤4 AND reduction from baseline 
SES-CD of at least 2 points AND no individual SES-CD subscore >1 at Week 26.

Percentage of subjects achieving endoscopic response defined as 50% reduction in SES-CD from baseline at 
Week 26.

Change from baseline SES-CD score at Week 26.

Percentage of subjects achieving deep remission (defined as CDAI<150 and SES-CD 0-2) at Week 26.

Percentage of subjects achieving clinical remission (defined as CDAI <150) AND endoscopic response as a 
measure of mucosal healing (defined as 50% reduction in SES-CD from baseline) at Week 26.

Percentage of subjects achieving clinical remission (CDAI score <150) at Weeks 10 and 26.

Percentage of subjects achieving clinical response (defined as ≥100-point decrease in CDAI score) at Weeks 10 
and 26.

Change from baseline CRP levels at Weeks 10 and 26.

Change in fecal calprotectin concentrations from baseline at Weeks 10, 14, 26, 52, 78, and 102.

Percentage of subjects achieving clinical remission (defined as CDAI <150) AND CRP <5 (in subjects with 
elevated CRP at baseline) at Weeks 26, 52, 78, and 102.

Percentage of subjects using oral corticosteroids at baseline who have discontinued corticosteroids and are in 
clinical remission (CDAI score <150) at Weeks 10, 26, and 102. 

Percentage of subjects maintaining clinical remission (defined as CDAI <150) at Weeks 52, 78, and 102.

Percentage of subjects maintaining endoscopic remission defined as SES-CD 0-2 at Week 102.

Percentage of subjects maintaining deep remission (defined as CDAI <150 and SES-CD 0-2) at Week 102.

Percentage of subjects maintaining endoscopic healing defined as SES-CD ≤4 AND reduction from baseline 
SES-CD of at least 2 points AND no individual SES-CD subscore >1 at Week 102.

Percentage of subjects maintaining endoscopic response defined as 50% reduction in SES-CD from baseline at 
Week 102.

Percentage of subjects maintaining clinical remission (defined as CDAI <150) AND endoscopic response as a 
measure of mucosal healing (defined as 50% reduction in SES-CD from baseline) at Week 102.

Percentage of subjects with first exacerbation of CD after 26 weeks (defined as a CDAI increase of >70 from the 
prior visit on 2 occasions separated by a 2-week interval, objective evidence of disease activity by colonoscopy, 
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Vedolizumab IV
Vedolizumab-4006
Page 16 of 132
Protocol Incorporating Amendment No. 04
30 June 2020
AND CRP above normal, OR fecal calprotectin >250 μg/g alone).
Additional endpoints:

Change from baseline IBDQ score at Weeks 14, 26, 52, 78, and 102.

Change from baseline WPAI-CD score at Weeks 14, 26, 52, 78, and 102.

Change from baseline in IBD-DI score at Weeks 14, 26, 52, 78, and 102.

Percentage of subjects achieving normalization of CRP defined as <5 mg/L at Week 26 (in those elevated at 
baseline).

Trough concentration of vedolizumab and adalimumab at Week 26.

Change from baseline of Patient Reported Outcome 2 (PRO-2) score at Weeks 26, 52, 78, and 102.

Change from Week 26 CDAI score at Weeks 52, 78, and 102.

Change from Week 26 PRO-2 score at Weeks 52, 78, and 102.

Change from Week 26 CRP levels at Weeks 52, 78, and 102.

Percentage of subjects with positive antidrug antibodies (ADAs) to vedolizumab and adalimumab, and 
neutralizing ADAs (nADAs) to vedolizumab. (Percentage of subjects with nADAs to adalimumab is optional if 
deemed necessary for the interpretation of the data). 

Time to major CD-related events (hospitalizations, bowel surgeries, procedures).

Percentage of subjects hospitalized from Day 1 to Week 102.

Percentage of subjects requiring surgery other than seton placement for perianal fistula from Day 1 to Week 102.

Percentage of subjects achieving a PRO-2 score ≤75 and an SES-CD ≤4 AND a reduction from baseline SES-CD 
of at least 2 points AND no individual SES-CD subscore >1 at Weeks 26 and 102.

Percentage of subjects assessed at screening as having moderate-high risk CD with ≥20% chance of disease 
complication by Year 2 as calculated by the PROSPECT predictive tool for those for whom that tool was used.

Percentage of subjects developing a CD-related complication by Week 102 who were assessed at screening as 
having moderate-high risk CD with ≥20% chance of disease complication by Year 2 as calculated by the 
PROSPECT predictive tool for those for whom that tool was used.

Percentage of subjects with an EHI score ≤20 at Weeks 26 and 102.

Percentage of subjects with an EHI score ≤30 at Weeks 26 and 102.

Percentage of subjects with an EHI score ≤50 at Weeks 26 and 102.

Change from baseline in EHI at Weeks 26 and 102.
Safety Endpoints:
Safety will be assessed by adverse events (AEs), adverse events of special interest (AESIs), serious adverse events 
(SAEs), adverse events leading to discontinuation, vital signs, physical examination, and results of standard laboratory 
tests (clinical chemistry, hematology, coagulation, and urinalysis).
Statistical Considerations: 
For all dichotomous endpoints, corresponding rates and a 95% CIs will be reported. 
Time-to-event endpoints will be analyzed by survival analysis procedures estimated by Kaplan-Meier product limit 
methods and presented with appropriate 95% CIs.
Change from baseline in CDAI and PRO-2 scores will be analyzed using Wilcoxon signed-rank test for paired data; 
the median change and its nonparametric 95% CI will also be presented.
Other endpoints will be summarized descriptively.
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Vedolizumab IV
Vedolizumab-4006
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Protocol Incorporating Amendment No. 04
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Sample Size Justification:
The sample size was based on an estimate of precision. A sample size of 60 subjects will generate a 95% CI for 
endoscopic remission (defined as SES-CD 0-2) at Week 26 with a half width no wider than 12.7% and expected 
remission of 50%. If the expected remission rate is different from 50%, a required sample size would be smaller.
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Vedolizumab IV
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Page 18 of 132
Protocol Incorporating Amendment No. 04
30 June 2020
3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities document. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Vedolizumab-4006
Page 19 of 132
Protocol Incorporating Amendment No. 04
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3.3
List of Abbreviations
5-ASA
5-aminosalicylate
Act-1
murine predecessor to vedolizumab antibody
ADA
antidrug antibodies
AE
adverse event
AESI
adverse event of special interest
AGA
American Gastroenterology Association
ALT
alanine aminotransferase
ASCA
anti-Saccharomyces cerevisiae antibody
AST
aspartate aminotransferase
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CDEIS
Crohn’s Disease Endoscopic Index of Severity
CIMS
Central Image Management Solution
CRO
contract research organization
CRP
C-reactive protein
ECG
electrocardiogram
eCRF
electronic case report form 
eGFR
estimated glomerular filtration rate
ELISA
enzyme linked immunosorbent assay
EHI
endoscopic healing index
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
GI
gastrointestinal
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
hCG
human chorionic gonadotropin
HRQOL
health-related quality of life
IAC
Independent Adjudication Committee
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBD-DI
Inflammatory Bowel Disease Disability Index
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IgG1
immunoglobulin G1
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INR
international normalized ratio
IP
Investigational Product
IRB
institutional review board
IUD
intrauterine device
IV
intravenous
IRT
interactive response technology
JCV
John Cunningham virus
LFT
liver function tests
LTFU
long-term follow-up
LTS
long-term safety
mAb
monoclonal antibody
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
Med ID
medication identification number
Monitr CD
Monitr Crohn’s Disease 
nADA
neutralizing antidrug antibodies
NOD2
nucleotide-binding oligomerization domain-containing protein 2
NSAID
nonsteroidal anti-inflammatory drug
pANCA
perinuclear antineutrophil antibody
PC
product complaint
PD
pharmacodynamic(s)
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PO
orally
PP
per protocol
PRO-2
Patient Reported Outcome 2
PROSPECT
Crohn’s Disease Personalized Risk and Outcome Prediction Tool
PTE
pretreatment event
Q4W
every 4 weeks
Q8W
every 8 weeks
RAMP
Risk Assessment and Minimization for PML
RCF
relative centrifugal force
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SC
subcutaneous
SES-CD
Simple Endoscopic Score for Crohn’s Disease
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TNF
tumor necrosis factor
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TNF-α
tumor necrosis factor-alpha
TNF-β
tumor necrosis factor-beta
TYSABRI
natalizumab
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
VCAM-1
vascular cell adhesion molecule-1
WBC
white blood cell
WHODRUG
World Health Organization Drug Dictionary
WOCBP
woman of childbearing potential
WPAI-CD
Work Productivity and Activity Impairment - Crohn’s Disease
3.4
Corporate Identification 
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Americas
Takeda
TDC Americas
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4.0
INTRODUCTION
4.1
Background
4.1.1
Disease and Current Treatments
Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder of the 
gastrointestinal (GI) tract that includes 2 entities, namely ulcerative colitis (UC) and Crohn’s 
disease (CD). In contrast to the diffuse, superficial, continuous inflammation limited to the colon 
in UC, the inflammation of CD is focal, may be transmural, and can involve any segment of the GI 
tract from mouth to anus. The prevalence of CD is approximately 150/100,000 of the United States 
(US) population [1]. The characteristic pathology involves a chronic inflammatory infiltrate 
consisting of neutrophils and macrophages. Hallmarks of CD include granulomatous 
inflammation and aphthous ulceration. CD is neither medically or surgically curable at the current 
time. 
Untreated CD patients commonly develop structural complications that include stricture and 
fistula formation, which commonly result in hospitalizations and surgery over time. When 
examining 306 CD patients from the United States, Thia et al. showed that the cumulative risk of 
developing CD complications of either stricturing or penetrating disease was 33.7% at 5 years and 
50.8% at 20 years after establishment of CD diagnosis [2]. The natural course of the disease can 
range from an indolent course with prolonged periods of remission to aggressive, incapacitating 
disease associated with structural bowel wall damage. Certain patients have aggressive CD, which 
could be defined as having a high relapse rate, development of penetrating disease, need for repeat 
surgery, or multiple admissions for flares [3]. The pathophysiology of IBD is complex as multiple 
environmental factors interact with the genotype of an individual to cause expression of disease. 
Published risk factors for aggressive disease include involvement of the upper GI tract and ileum, 
penetrating disease, early age at diagnosis, smoking, extensive ulceration of the mucosa, high titers 
of certain serum antibodies, and mutations of the nucleotide-binding oligomerization 
domain-containing protein 2 (NOD2) gene [4]. The ability to more readily predict which patients 
will be at higher risk for complications and target more intensive, early treatment to that group 
would be invaluable. The 2014 American Gastroenterology Association (AGA) Clinical Care 
Pathway outlined criteria for patients considered at moderate-high risk for disease complications 
that included: <30 years of age at initial diagnosis, extensive anatomic involvement, perianal or 
severe rectal disease, deep ulcers, prior surgical resection or structuring, and/or penetrating 
behavior [5]. Additionally, the Crohn's Disease Personalized Risk and Outcome Prediction Tool 
(PROSPECT), which incorporates clinical, serological, and genetic variables, has been developed 
by Siegel et al. This tool is used to predict the probability of developing complications related to 
CD, specifically strictures or internal penetrating disease. The output of the predictive model 
allows risk stratification of patients from low to medium to high risk of complications within a 
3-year period [4,6].
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4.1.2
Vedolizumab
Vedolizumab (also called MLN0002) is a humanized immunoglobulin G1 (IgG1) monoclonal 
antibody (mAb) directed against the human lymphocyte integrin α4β7. The α4β7 integrin mediates 
lymphocyte trafficking to GI mucosa and gut-associated lymphoid tissue through adhesive 
interaction with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed 
on the endothelium of mesenteric lymph nodes and GI mucosa [7-10]. Vedolizumab binds the 
α4β7 integrin, antagonizing its adherence to MAdCAM-1 and as such, impairs the migration of gut 
homing lymphocytes into GI mucosa. As a result, vedolizumab acts as a gut-selective 
immunomodulator [11]. 
Vedolizumab IV (also known as ENTYVIO; Vedolizumab for Injection, for Intravenous Use; 
Vedolizumab Powder for Concentrate for Solution for Infusion; or MLN0002 IV) has been 
granted marketing approval in multiple countries globally. Vedolizumab intravenous (IV) is 
approved for the treatment of adult patients with moderately to severely acute UC or CD who have 
had an inadequate response with, lost response to, or were intolerant to a tumor necrosis factor 
(TNF) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or 
demonstrated dependence on corticosteroids. The approved dosing and administration regimen is 
300 mg vedolizumab IV infused intravenously at Weeks 0, 2, and 6, then once every 8 weeks 
(Q8W) thereafter. 
Previously conducted clinical studies have characterized the efficacy, safety, tolerability, 
pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of vedolizumab in healthy 
subjects and subjects with UC or CD.
4.1.2.1
Nonclinical
Nonclinical in vitro and in vivo studies have been conducted with vedolizumab and its murine 
homologue, murine predecessor to vedolizumab antibody (Act-1). Act-1 has demonstrated clinical 
and histomorphologic evidence of efficacy in an animal model of IBD (cotton-top tamarins). 
Extensive nonclinical evaluations of the cardiovascular, acute, local, subchronic, chronic, 
immunologic, and reproductive toxicity of vedolizumab in pharmacologically responsive species 
(New Zealand white rabbits and cynomolgus monkeys) have been conducted and support its 
clinical development. Nonclinical studies also show that vedolizumab does not antagonize α4β1 
integrin [11].
4.1.2.2
Human Experience
As of 19 May 2019, approximately 6376 subjects (679 healthy subjects, 2671 subjects with UC, 
and 2920 subjects with CD) have received at least 1 dose of vedolizumab across all studies in the 
clinical development program (see current version of Investigator’s Brochure). Vedolizumab 
exposure has extended for ≥12 months in 2553 subjects, ≥24 months in 1636 subjects, ≥36 months 
in 1126 subjects, ≥48 months in 908 subjects, ≥60 months in 675 subjects, and ≥72 months in 
378 subjects as of 19 May 2019. Based on drug shipment data, the patient exposure to 
vedolizumab since its approval in May 2014 is estimated to be approximately 
336,400 patient-years.
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In subjects with moderately to severely active CD (Study C13007), including subjects who had 
failed treatment with 1 or more therapies including tumor necrosis factor-alpha (TNF-α) 
antagonists, vedolizumab 300 mg infusion at Weeks 0 and 2 (induction) followed by either once 
every 4 weeks (Q4W) or Q8W from Weeks 6 through 52 (maintenance) demonstrated differences 
in efficacy compared to placebo for both the Induction Phase and Maintenance Phase. The study 
met its primary endpoint for the Induction Phase, clinical remission at Week 6, but did not meet the 
second primary endpoint of enhanced clinical response (Crohn’s Disease Activity Index 
[CDAI]-100) at Week 6 in the overall population, although the treatment difference favored 
vedolizumab. The study did meet its primary endpoint for the Maintenance Phase, clinical 
remission at Week 52, as well as important secondary endpoints, including enhanced clinical 
response at Week 52 and corticosteroid-free clinical remission at Week 52 [12].
Rates of mucosal healing were recently reported in 27 CD subjects who received IV vedolizumab 
monotherapy. Mucosal healing was reported in 30% of subjects who had a baseline colonoscopy 
before vedolizumab, 73% of whom were not TNF-antagonist naïve. The subjects’ second 
colonoscopy occurred 12 to 52 weeks after vedolizumab induction (median of 22 weeks). Mucosal 
healing was defined as an absence of ulceration. Endoscopic improvement was 52% [13].
Vedolizumab has shown an acceptable and consistent safety profile in clinical trials (see current 
version of IB). In the pivotal phase 3 studies (C13006 in UC and C13007 in CD), the most 
common (≥5% and at a higher incidence than placebo) adverse reactions in subjects administered 
vedolizumab were nausea, nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, 
fatigue, headache, and cough. Most serious adverse events (SAEs) have been related to 
exacerbations or complications of the underlying UC or CD. For those infections that were 
reported more frequently in vedolizumab-treated subjects, the sites of these infections correlated 
with the known tissue distribution of MAdCAM-1 binding sites. Anal abscess, abdominal abscess, 
and gastroenteritis were the most frequently reported serious infections. Extraintestinal infections 
(bronchitis, pneumonia, urinary tract infection, sepsis) occurred at low frequency (<1%). A total of 
4% of vedolizumab-treated subjects and 3% of placebo-treated subjects experienced an 
infusion-related reaction. In C13006 and C13007, 10% of subjects were positive for 
anti-vedolizumab antibodies 16 weeks following the last dose of vedolizumab. Results from the 
clinical program to date do not suggest an increased risk for malignancy with vedolizumab 
treatment. Overall, the safety profile following long-term treatment with vedolizumab in C13008, 
a long-term safety study, is consistent with safety in the completed studies.
Concomitant use of corticosteroids and/or conventional immunomodulators did not appear to be 
associated with any increased rate of infections based on the comparative rates of infections in the 
phase 3 trials among subjects who had and had not received these medications. Overall, 
vedolizumab was well tolerated in clinical studies. For additional safety related information from 
the clinical trials experience, see full prescribing information [14].
4.1.3
Adalimumab
Adalimumab is a recombinant human IgG1 mAb specific for human TNF-α. Adalimumab binds 
specifically to TNF-α and blocks its interaction with the p55 and p75 cell surface TNF-α receptors. 
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Adalimumab also lyses surface TNF-α expressing cells in vitro in the presence of complement. 
Adalimumab does not bind or inactivate lymphotoxin (TNF-β). TNF-α is a naturally occurring 
cytokine that is involved in normal inflammatory and immune responses. TNF-α plays an 
important role in both the pathologic inflammation and the joint destruction that are hallmarks of 
inflammatory diseases. Adalimumab also modulates biological responses that are induced or 
regulated by TNF-α, including changes in the levels of adhesion molecules responsible for 
leukocyte migration.
Adalimumab is approved globally for the treatment of moderately to severely active CD in patients 
who have had an inadequate response to conventional therapy. Additionally, adalimumab is 
approved for reducing signs and symptoms and inducing clinical remission in these patients if they 
have also lost response to or are intolerant to infliximab.
Adalimumab 40 mg weekly or every other week has been shown to be effective for maintaining 
clinical remission in patients with CD who have responded to adalimumab induction therapy. 
Adalimumab has also been shown to have corticosteroid-sparing effects in patients with CD [15]. 
In CLASSIC I, a dose ranging, randomized, controlled induction trial of adalimumab, 299 subjects 
with moderate to severe CD who were naïve to TNF-α antagonists were evaluated. The study 
demonstrated that an adalimumab loading dose regimen of 160 mg subcutaneous (SC) at Week 0 
and 80 mg SC at Week 2 was significantly more effective than placebo (36% vs 12%, p=0.001). 
CLASSIC II, a maintenance follow-up trial to CLASSIC I, demonstrated that adalimumab SC 
every other week or weekly was superior to placebo in maintaining remission over a 56-week 
period in 55 subjects with moderate to severe CD naïve to TNF-antagonist therapy who 
experienced remission with adalimumab induction therapy. In this rerandomized cohort of 
55 subjects, 79% who received adalimumab 40 mg every other week and 83% who received 
40 mg weekly maintained remission through Week 56 (primary endpoint) compared with 44% for 
placebo (p< 0.05 for both adalimumab groups vs placebo). The subjects from CLASSIC I who had 
not been in remission entered an open-label arm and received adalimumab 40 mg every other week 
(dosages could be increased to 40 mg weekly if there was a nonresponse or flare) [16].
The CHARM study included 854 subjects with moderate to severe CD who were TNF antagonist 
therapy naïve, had been exposed to infliximab in the past, and had either lost response or become 
intolerant to infliximab. The primary endpoint was clinical remission at Weeks 26 and 56 among 
subjects who responded to adalimumab. The subjects received open-label adalimumab SC at doses 
of 80 mg at Week 0 and 40 mg at Week 2 with response defined by a decrease in CDAI score of 
70 points at Week 4. Overall, 499 (approximately 60%) subjects responded at Week 4 and were 
randomized to 1 of 3 treatment arms: adalimumab 40 mg every other week, adalimumab 40 mg 
weekly, or placebo. At Week 26, 40% of the adalimumab 40-mg every other week group, 47% of 
the adalimumab 40 mg weekly group, and 17% of the placebo group were in remission (p=0.001 
for both groups compared to placebo, no difference between active groups). This benefit was 
maintained out to Week 56 with 36% of the adalimumab 40 mg every-other-week group, 41% of 
the adalimumab 40 mg weekly group, and 12% of the placebo group remaining in remission 
(p=0.001) [17].
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The GAIN study, a placebo-controlled, randomized, controlled trial evaluated 325 subjects with 
moderate to severe CD who had failed infliximab therapy (defined as intolerant of infliximab or 
having previously responded then lost response to infliximab). Subjects were treated with 
adalimumab (160 mg at Week 0 then 80 mg at Week 2) or placebo. A total of 301 subjects 
completed the trial, and at Week 4 induction of remission was greater for adalimumab than for 
placebo (21% vs 7% p<0.001) [18].
Adalimumab was well tolerated in the efficacy-based studies discussed above. SAEs have been 
reported in 25% of patients, including injection-site reactions (20%), malignant neoplasm (1.7%), 
opportunistic infection (2.1%), and tuberculosis ([TB] 0.2%). Other adverse events (AEs) 
associated with adalimumab include increased risk of infections, antibody formation, 
autoimmunity, skin eruption, abnormal liver function tests (LFTs), demyelization, and congestive 
heart failure.
4.1.4
Methotrexate 
Methotrexate is an antimetabolite that is approved for the treatment of certain neoplastic diseases, 
severe psoriasis, and adult rheumatoid arthritis. Methotrexate was originally developed as an 
antineoplastic, and is an inhibitor of the enzyme dihydrofolate reductase, which catalyzes a 
reaction in the production of tetrahydrofolic acid. This pathway is essential to the synthesis of the 
purine and pyrimidine components of DNA, and thus the drug slows cellular division. Although 
the mechanism of action of low-dose methotrexate in the treatment of autoimmune disease is not 
well understood, there is evidence supporting both immunosuppressive and anti-inflammatory
effects.
In rheumatoid arthritis, methotrexate is a mainstay of treatment because of its excellent 
anti-inflammatory effect, rapid onset of action, and acceptable safety profile. Recently, 
methotrexate has become the agent of choice for combination therapy with the newer biologics in 
rheumatoid arthritis [19], [20], [21], [22].
TNF antagonist therapy and methotrexate appear to have additive effects with respect to efficacy 
in rheumatoid arthritis. In CD, the additive effect may be relevant from a mechanistic perspective 
since both drugs induce apoptosis. Cell death mechanisms and apoptosis are important to the 
pathogenesis of CD.
Following oral administration of low-dose methotrexate (<5 mg), absorption approaches 100%. 
The peak blood concentration is observed within 1 to 2 hours. Methotrexate is 50% protein bound, 
displacement occurs in competition with other highly protein-bound compounds, and distribution 
is widespread. In 1987, Kozarek was the first to report the results of intramuscular methotrexate 
therapy in patients with refractory IBD (14 CD; 7 UC) and two-thirds of patients with steroid 
refractory disease showed an improvement in symptoms and a concomitant reduction in 
prednisone requirements [23]. Some patients demonstrated endoscopic remission. In subsequent 
studies when methotrexate was used as a monotherapy in patients requiring corticosteroids, 
response rates were suboptimal [24]. The use of methotrexate for induction and maintenance 
therapy in CD was definitively established based on the results of the placebo-controlled trials of 
the North American Crohn’s Study Group Investigators published in 1995 and 2000 [25], [26]. In 
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these studies, steroid-dependent CD patients treated with 25 mg methotrexate intramuscularly 
each week achieved steroid-free remission rates in 39% compared with 19% on placebo, and 
maintained remission with 15 mg methotrexate per week in 65% compared with 39% on placebo. 
In spite of these excellent clinical data for methotrexate in CD, it has never been widely utilized as 
a monotherapy in adults but is increasingly used clinically in combination with biologic therapy to 
reduce immunogenicity [24]. The combination of maintenance methotrexate and infliximab in the 
COMMIT trial is the most recent study to demonstrate immunogenicity efficacy of methotrexate 
on infliximab trough and anti-infliximab antibody levels [27]. The study did not, however, reveal a 
difference in clinical outcomes between combination methotrexate/infliximab and infliximab 
monotherapy, despite the positive effects of methotrexate on antibody formation to infliximab and 
infliximab trough levels. These results are in contrast to the results of the study of biologic and 
immunomodulatory-naive patients in the SONIC CD study, which demonstrated an increased 
effectiveness of azathioprine/infliximab combination therapy compared with infliximab 
monotherapy in inducing and maintaining remission, and was corroborated by higher infliximab 
trough levels and lower anti-infliximab antibodies [28].
The most frequently observed adverse event of methotrexate therapy is nausea (in up to 25% of 
treated patients), which often can be well-controlled and/or avoided with concomitant ondansetron 
tablets given 1 to 2 hours before and 12 to 24 hours after methotrexate administration [24]. 
Methotrexate also may cause bone marrow suppression. In 1 series, mild leukopenia (white blood 
cell [WBC] count 2.8-4.0×109/L) was encountered at least once in 21% of patients with 
rheumatoid arthritis treated with 15 mg weekly [29]. In all cases, leukopenia was transient, 
responded to minimal dose reduction, and did not lead to cessation of therapy. Although severe 
leukopenia and associated infection has been reported with methotrexate, it is rare with low-dose
therapy. Leukopenia is usually correctable by dose reduction and is almost always asymptomatic. 
Thrombocytopenia is rarely seen. Additionally, acute pulmonary toxicity is an uncommon adverse 
reaction to methotrexate. This hypersensitivity reaction presents with acute dyspnea associated 
with bilateral alveolar or interstitial pulmonary changes. A high clinical index of suspicion and 
prompt treatment with steroids usually leads to resolution without chronic sequelae. No increased 
incidence of cancer or lymphoma has been reported for methotrexate although overall rates of use 
are lower than that of other immunomodulator therapies [24]. Methotrexate may promote rise of 
liver enzymes, which is observed in 3% to 33% of IBD patients treated with methotrexate, and 
necessitates discontinuing therapy in around 6% to 8% [24]. Recommendations for stopping 
therapy are based on the degree of absolute change in liver enzymes and the duration of 
abnormalities on serial measurements. Underlying liver diseases such as nonalcoholic fatty liver 
disease, diabetes, or excess alcohol consumption are important cofactors for methotrexate-induced 
liver toxicity. However, methotrexate-associated advanced liver fibrosis is rarely seen in patients 
with IBD or rheumatoid arthritis. Other GI complaints including stomatitis and diarrhea are less 
common. The teratogenic effects of methotrexate are well established.
4.2
Rationale for the Proposed Study
CD is a chronic inflammatory disorder of the GI tract. Treatment with TNF-antagonist therapy 
substantially improved the care of patients with CD refractory to corticosteroids, 
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immunomodulators, and mesalamine. In 2010, the SONIC trial demonstrated that combination 
therapy with the TNF antagonist infliximab and immunomodulator azathioprine further 
significantly improved treatment efficacy [30]. About 40% of patients, however, will not achieve 
remission after initiation of a combined TNF antagonist and immunomodulator [30]. This raises 
the question as to whether we can improve remission rates and modify disease progression by 
adding a third agent, vedolizumab, with a different mechanism of action to TNF antagonists, to the 
combination regimen, particularly for patients who are at higher risk for CD complications. 
Vedolizumab is an α4β7 anti-integrin, approved in the United States in 2014 to treat both moderate 
to severe CD and UC and in Canada in 2015 to treat UC, after demonstrating efficacy and safety in 
the GEMINI studies [12,31,32]. Subjects who have failed TNF-antagonist therapy have been 
shown to have higher levels of tissue MAdCAM and lower levels of circulating α4β7-positive cells. 
Subjects who responded to therapy with infliximab or adalimumab have been shown to have a 
decrease in MAdCAM and an increase in α4β7-positive cells [33]. This suggests that the 
vedolizumab pathway is active and that vedolizumab may work well as part of a combination 
therapy regimen. Combining biologic therapies with alternate mechanisms of action, such as the 
anti-integrin vedolizumab and the TNF antagonist adalimumab, may provide clinically relevant 
synergy.
There is growing evidence that mucosal healing is an important outcome in CD treatment. 
Rutgeerts et al. demonstrated this in the postoperative setting showing that CD patients with 
endoscopic evidence of active disease were more likely to have a clinical recurrence in the 
following 4 to 8 years [34]. In clinical trials with biologics, patients who have mucosal healing 
have been shown to have increased rates of steroid-free remission and a decreased risk of surgery 
and hospitalization [35]. In view of these findings, clinical practice is moving toward a “treat to 
target” approach, where the goals of treatment go beyond controlling symptoms and instead aim 
for improving objective measures such as mucosal healing and deep remission [36].
Further subgroup analyses in CD biologic clinical trials have demonstrated higher response rates 
in patients who are treated earlier in the course of their disease (less than 1 or 2 years from 
diagnosis). In a recent study, using a combination of a TNF antagonist, infliximab, and 
azathioprine, clinical remission and full mucosal healing was observed in more than 65% of 
patients with early disease of less than 18 months in duration [37,38]. The REACT trial 
demonstrated that early introduction of combination therapy with adalimumab and an 
immunomodulator decreased the chance of hospitalizations, complications, and surgeries at 
2 years compared to conventional therapy [39]. 
Importantly, our understanding of which patients with CD are at higher risk for an aggressive 
disease course has improved, as various risk factors are identified and predictive tools have been 
developed [6,40]. Involvement of the upper GI tract and ileum, penetrating disease, early age at 
diagnosis, smoking, extensive ulceration of the mucosa, high titers of serum antibodies, and 
mutations of the NOD2 gene all have been determined to be markers of aggressive CD [3].This can 
allow for targeting of earlier combination therapy for those at highest risk. 
The hypothesis of this study is that triple combination therapy with 2 biologics with different 
mechanisms of action (the anti-integrin vedolizumab IV and the TNF antagonist adalimumab SC) 
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and an immunomodulator (oral methotrexate) will be effective and have an acceptable safety 
profile at inducing endoscopic remission over a 26-week period. Endoscopic remission will be 
defined as a Simple Endoscopic Score for Crohn’s Disease (SES-CD) 0 to 2. Only subjects with 
suspected aggressive CD at increased risk for disease complications will be enrolled in the study. 
By investigator judgement, subjects will be assessed as having CD at moderate-high risk for 
complications based on clinical assessment, the PROSPECT tool, or criteria defined by the 2014 
AGA CD Clinical Care Pathway [4-6]. Importantly, the triple combination approach is 
hypothesized to modify disease progression in newly diagnosed CD subjects at higher risk for 
complications related to more aggressive disease.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to determine the effect of triple combination therapy with an anti-integrin 
(vedolizumab IV), a TNF antagonist (adalimumab SC), and an immunomodulator (oral 
methotrexate) on endoscopic remission at Week 26.
5.1.2
Secondary Objectives

To evaluate the effect of vedolizumab IV monotherapy on endoscopic remission at Week 102 
following triple combination therapy.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on 
endoscopic healing at Weeks 26 and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on 
endoscopic response at Weeks 26 and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on 
deep remission at Weeks 26 and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on 
clinical remission by CDAI at Weeks 10, 26, 52, 78, and 102.

To evaluate the effect of triple combination therapy followed by vedolizumab monotherapy on 
clinical response by CDAI at Weeks 10, 26, 52, 78, and 102.
5.1.3
Additional Objectives 
Additional objectives include:

To evaluate the PK of vedolizumab and adalimumab in CD subjects at higher risk for 
complications at Week 26.

To assess immunogenicity to vedolizumab and adalimumab over the follow-up period.
mmercial Use Only and Subject to the Applicable Terms of Use
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
To evaluate C-reactive protein (CRP) levels at Weeks 10 and 26.

To evaluate fecal calprotectin at Weeks 10, 14, 26, 52, 78, and 102.

To evaluate the impact of triple combination therapy on health-related quality-of-life (HRQOL) 
using the Inflammatory Bowel Disease Questionnaire (IBDQ), Work Productivity and 
Activity Impairment - Crohn’s Disease (WPAI-CD), and the Inflammatory Bowel Disease 
Disability Index (IBD-DI).

To evaluate endoscopic remission, defined as Monitr CD Endoscopic Healing Index (EHI) 
score ≤20, at Weeks 26 and 102.

To evaluate Monitr CD EHI score ≤30 or ≤50 at Weeks 26 and 102.
5.1.4
Safety Objective
The safety objective is to evaluate the safety of triple combination therapy with an anti-integrin, a 
TNF antagonist, and an immunomodulator over a 26-week period, followed by 76 weeks of 
monotherapy with an anti-integrin.
5.2
Endpoints
5.2.1
Primary Endpoints 
The primary endpoint is the percentage of subjects achieving endoscopic remission (defined as an 
SES-CD 0-2) at Week 26.
5.2.2
Secondary Endpoints 
Secondary endpoints are as follows:

Percentage of subjects achieving endoscopic healing defined as SES-CD ≤4 AND reduction 
from baseline SES-CD of at least 2 points AND no individual SES-CD subscore >1 at Week 
26.

Percentage of subjects achieving endoscopic response defined as 50% reduction in SES-CD 
from baseline at Week 26.

Change from baseline SES-CD score at Week 26.

Percentage of subjects achieving deep remission (defined as CDAI<150 and SES-CD 0-2) at 
Week 26.

Percentage of subjects achieving clinical remission (defined as CDAI <150) AND endoscopic 
response as a measure of mucosal healing (defined as 50% reduction in SES-CD from baseline) 
at Week 26.

Percentage of subjects achieving clinical remission (CDAI score <150) at Weeks 10 and 26.

Percentage of subjects achieving clinical response (defined as ≥100-point decrease in CDAI 
score) at Weeks 10 and 26.
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
Change from baseline CRP levels at Weeks 10 and 26.

Change in fecal calprotectin concentrations from baseline at Weeks 10, 14, 26, 52, 78, and 102.

Percentage of subjects achieving clinical remission (defined as CDAI <150) AND CRP <5 (in 
subjects with elevated CRP at baseline) at Weeks 26, 52, 78, and 102.

Percentage of subjects using oral corticosteroids at baseline who have discontinued 
corticosteroids and are in clinical remission (CDAI score <150) at Weeks 10, 26, and 102. 

Percentage of subjects maintaining clinical remission (defined as CDAI <150) at Weeks 52, 78, 
and 102.

Percentage of subjects maintaining endoscopic remission defined as SES-CD 0-2 at Week 102.

Percentage of subjects maintaining deep remission (defined as CDAI <150 and SES-CD 0-2) 
at Week 102.

Percentage of subjects maintaining endoscopic healing defined as SES-CD ≤4 AND reduction 
from baseline SES-CD of at least 2 points AND no individual SES-CD subscore >1 at Week 
102.

Percentage of subjects maintaining endoscopic response defined as 50% reduction in SES-CD 
from baseline at Week 102.

Percentage of subjects maintaining clinical remission (defined as CDAI <150) AND 
endoscopic response as a measure of mucosal healing (defined as 50% reduction in SES-CD 
from baseline) at Week 102.

Percentage of subjects with first exacerbation of CD after 26 weeks (defined as a CDAI 
increase of >70 from the prior visit on 2 occasions separated by a 2-week interval, objective 
evidence of disease activity by colonoscopy AND CRP above normal, OR fecal 
calprotectin >250 μg/g alone).
5.2.3
Additional Endpoints 
Additional endpoints include the following:

Change from baseline IBDQ score at Weeks 14, 26, 52, 78, and 102.

Change from baseline WPAI-CD score at Weeks 14, 26, 52, 78, and 102.

Change from baseline in IBD-DI score at Weeks 14, 26, 52, 78, and 102.

Percentage of subjects achieving normalization of CRP defined as <5 mg/L at Week 26 (in 
those elevated at baseline).

Trough concentration of vedolizumab and adalimumab at Week 26.

Change from baseline of Patient Reported Outcome 2 (PRO-2) score at Weeks 26, 52, 78, and 
102.
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
Change from Week 26 CDAI score at Weeks 52, 78, and 102.

Change from Week 26 PRO-2 score at Weeks 52, 78, and 102.

Change from Week 26 CRP levels at Weeks 52, 78, and 102.

Percentage of subjects with positive antidrug antibodies (ADAs) to vedolizumab and 
adalimumab, and neutralizing ADAs (nADAs) to vedolizumab. (Percentage of subjects with 
nADAs to adalimumab is optional if deemed necessary for the interpretation of the data).

Time to major CD-related events (hospitalizations, bowel surgeries, and CD-related 
procedures).

Percentage of subjects hospitalized from Day 1 to Week 102.

Percentage of subjects requiring surgery other than seton placement for perianal fistula from 
Day 1 to Week 102.

Percentage of subjects achieving a PRO-2 score ≤75 AND an SES-CD ≤4 AND a reduction 
from baseline SES-CD of at least 2 points AND no individual SES-CD subscore >1 at 
Weeks 26 and 102.

Percentage of subjects assessed at screening as having moderate-high risk CD with ≥20% 
chance of disease complication by Year 2 as calculated by the PROSPECT predictive tool for 
those for whom that tool was used.

Percentage of subjects developing a CD related complication by Week 102 who were assessed 
at screening as having moderate-high risk CD with ≥20% chance of disease complication by 
Year 2 as calculated by the PROSPECT predictive tool for those for whom that tool was used.

Percentage of subjects with an EHI score ≤20 at Weeks 26 and 102.

Percentage of subjects with an EHI score ≤30 at Weeks 26 and 102.

Percentage of subjects with an EHI score ≤50 at Weeks 26 and 102.

Change from baseline in EHI score at Weeks 26 and 102.
5.2.4
Safety Endpoints
Safety will be assessed by AEs, adverse events of special interest (AESIs), SAEs, AEs leading to 
discontinuation, vital signs, physical examination, and results of standard laboratory tests (clinical 
chemistry, hematology, coagulation, and urinalysis).
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 4, open-label, multicenter study in subjects with newly-diagnosed CD at higher risk 
for complications due to aggressive disease. The study will investigate the efficacy and safety of 
triple combination therapy (300 mg vedolizumab IV, 160/80/40 mg adalimumab SC, and 15 mg 
mercial Use Only and Subject to the Applicable Terms of Use
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6.0


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oral methotrexate) over a 26-week treatment period for induction of clinical endoscopic remission 
and mucosal healing followed by efficacy and safety of vedolizumab IV monotherapy to maintain 
remission for 76 weeks, for a total treatment period of 102 weeks.
Approximately 60 subjects with moderate to severe active CD at higher risk for disease 
complications will be studied at approximately 64 sites in the United States and Canada. Subjects 
must be diagnosed with CD within the previous 24 months and be naïve to biologics. Subjects will 
be determined to be at increased risk of CD complications. Subjects at low risk for CD 
complications will be excluded. Subjects will be followed for a total of 128 weeks. 
The study consists of up to a 4-week screening period, a 26-week combination treatment period, an 
additional 76-week vedolizumab IV monotherapy treatment period, and a 26-week follow-up 
period following last dose (with final efficacy evaluations at Week 120). The duration of the study 
from screening to final efficacy visit at Week 120 will be approximately 124 weeks. All subjects, 
including subjects who discontinue early, will participate in a safety follow-up telephone call 26 
weeks after last dose, for a total follow-up of 128 weeks. 
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
6.2
Justification for Study Design, Dose, and Endpoints
The aim of the current study is to evaluate the efficacy and safety of triple combination therapy of 
vedolizumab, adalimumab, and methotrexate in the induction of clinical remission and endoscopic 
healing and remission as a measure of mucosal healing of subjects with newly diagnosed CD at 
higher risk for complications due to aggressive disease followed by efficacy and safety of 
vedolizumab monotherapy to maintain remission. Therapeutic goals for CD have evolved from 
control of symptoms to mucosal healing. Achieving clinical remission, biomarker remission, and 
mucosal healing has become one of the treatment goals for subjects with CD and is associated with 
ubject to the Applicable Terms of Use
Subject
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better outcomes of steroid-free remission and decreased risk of surgery and hospitalization. 
Complete mucosal healing, however, is only achieved by a minority of subjects in clinical practice 
and trials. The Crohn’s Disease Endoscopic Index of Severity (CDEIS) and the SES-CD are robust, 
validated, endoscopic indices that show high reproducibility among central readers [41]. The 
absence of validated score thresholds associated with specific prognostic values or with 
endoscopic healing, however, represents a weakness of both the CDEIS and the SES-CD. While 
most thresholds for remission in trials have been chosen arbitrarily by investigators, specialists in 
the field of IBD recently agreed on a SES-CD of 0–2 for the definition of endoscopic remission. 
Endoscopic response as a >50% decrease in SES-CD was also proposed [41].
There are different treatment agents and combinations used currently in clinical practice to achieve 
the goal of endoscopic and clinical remission. Combination therapy for CD appears to lead to 
significantly improved efficacy; however, many subjects treated with combined TNF-antagonist 
and immunomodulator therapy do not achieve mucosal healing [30]. Vedolizumab has a unique, 
gut-selective, immunomodulatory mechanism of action that provides the basis for its development 
as a treatment for CD. In a pivotal phase 3 clinical trial, vedolizumab IV was effective for 
induction and maintenance therapy in subjects with CD [12]. The goal of adding vedolizumab, 
which has a different mechanism of action, to a TNF antagonist and immunomodulator, is to safely 
and effectively improve remission rates in CD patients. Coadministration of the 2 biologics 
infliximab and natalizumab was previously studied for 10 weeks in 52 CD subjects and was well 
tolerated without increased adverse events compared to infliximab monotherapy [42].
The primary endpoint evaluated in this study will be endoscopic remission at Week 26. Based on 
a post hoc analysis of the SONIC trial, 26 weeks is the minimum time for the majority of patients 
to achieve deep remission with combination therapy [43]. CD patients treated early in their course 
of disease with combination therapy have reduced chances of hospitalization, complications, and 
surgeries [39]. 
Our understanding of which patients with CD are at higher risk for aggressive disease course has 
improved. A number of clinical factors have been identified that predict CD progression including 
disease location, young age at diagnosis, disease behavior, perianal disease, use of steroids at 
diagnosis, and smoking. Some serological tests, such as antibodies against Saccaromyces 
cerevisae and genetic markers, have also been used in an effort to improve risk stratification. In 
2014, the AGA published CD Clinical Care Pathway, which includes patient stratification 
according to their disease burden (Appendix E) [5]. Using this care pathway, patients are 
considered being at moderate-high risk for CD complications due to disease progression if they are 
<30 years of age at initial diagnosis, have extensive anatomic involvement, have perianal and/or 
severe rectal disease, have deep ulcers, or have had prior surgical resection and structuring and/or 
penetrating behavior. Siegel et al. created a web-based tool, the PROSPECT CD Risk Calculator, 
which has been used to predict outcomes and response to treatment for individuals [4,6]. This tool 
has been validated in pediatric and adult patients with CD. About 20% of patients with CD have an 
indolent course of disease from the time of diagnosis and are considered low risk for disease 
complications. Only subjects with suspected aggressive CD at increased risk for disease 
complications will be enrolled in the study.
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As CD is a progressive disease with long-term structural complications, the proposed duration of 
this study is 102 weeks, in order to provide long-term efficacy data of vedolizumab maintenance 
therapy following triple combination induction therapy. Secondary endpoints will include 
achieving and maintaining clinical remission and maintaining endoscopic remission, and 
additional endpoints will include PROs and AEs. All subjects will receive vedolizumab IV 300 mg 
on Day 1, Weeks 2 and 6, and Q8W thereafter until Week 102; adalimumab 160 mg SC on Day 2, 
80 mg SC at Week 2, and 40 mg SC every 2 weeks thereafter until Week 26; and oral methotrexate 
15 mg weekly until Week 34. The initial dosing recommendations in the dosing regimen for both 
vedolizumab IV and adalimumab SC follow the approved labels [14,44].
If a subject has an exacerbation of CD after 26 weeks, defined as a CDAI increase of >70 from the 
prior visit on 2 occasions separated by a 2-week interval, with objective evidence of disease 
activity by colonoscopy AND elevated CRP, OR fecal calprotectin >250 μg/g alone, then 
frequency of vedolizumab infusions will be changed to vedolizumab 300 mg IV Q4W, instead of 
vedolizumab 300 mg IV Q8W for the remainder treatment. Clinical remission and response rates 
increased in patients who lost response to Entyvio Q8W in GEMINI I and II when Entyvio dosing 
frequency was increased to Q4W in GEMINI long-term safety (LTS) study [45]. In CD, increased 
dosing frequency from every 8 weeks (GEMINI II) to every 4 weeks (GEMINI LTS) improved 
outcomes in patients who had withdrawn early from GEMINI II, with 47% experiencing clinical 
response and 32% in remission at Week 52 of GEMINI LTS, up from 39% and 4% before the dose 
increase. Analysis of real world data has similarly demonstrated that administration Q4W may 
help capture response in subjects who have lost response with dosing Q8W [46]. 
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the triple combination 
of vedolizumab, adalimumab, and methotrexate 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 Investigational Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to enrollment. In the case of 
subject screen failure, the subject may be considered for rescreening on a case-by-case basis but 
only with the consultation of the Medical Monitor.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative has signed and 
dated a written, informed consent form and any required privacy authorization prior to the 
initiation of any study procedures. 
3. The subject is male or non-pregnant, non-breast-feeding female and aged 18 to 65 years, 
inclusive at time of Screening.
4. The subject has an initial diagnosis of CD established within 24 months prior to Screening with 
involvement of the ileum and/or colon that can be assessed by ileocolonoscopy. 
5. The subject has moderate to severely active CD during Screening defined by a centrally 
assessed SES-CD score ≥7 (or ≥4 if isolated ileal disease).
6. By investigator judgement, the subject is assessed as having CD at moderate-high risk for 
complications. Investigator judgement may include clinical assessment, the PROSPECT tool, 
or criteria defined by the 2014 AGA CD Clinical Care Pathway.
7. The subject may be receiving a stable therapeutic dose of conventional therapies for CD listed 
in the permitted medications and treatments below.
8. If the subject is on corticosteroids, they must be on a stable dose of oral corticosteroids up to 
30 mg of prednisone daily or 9 mg of budesonide daily for at least 7 days prior to enrollment.
9. If the subject is on corticosteroids, they must be willing to follow a mandatory taper of 
prednisone or budesonide within 60 days after enrollment.
10. The subject must be willing to stop treatment with 5-aminosalicylate (5-ASA), antibiotics, and 
probiotics for luminal CD at enrollment.
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11. [Previous criterion 11 deleted in amendment number 1].
12. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use adequate contraception* from signing of informed consent throughout 
the duration of the study and for 18 weeks after last dose.
13. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 18 weeks after last dose. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.27 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.28 Pregnancy.
14. Subjects with a family history of colorectal cancer, personal history of increased colorectal 
cancer risk, age >50 years, or other known risk factors must be up-to-date on colorectal cancer 
surveillance (may be performed during Screening as standard of care).
7.2
Exclusion Criteria
The exclusion criteria are divided into 3 categories: GI exclusion criteria, infectious disease 
exclusion criteria, and general exclusion criteria. Subjects meeting any of the following criteria 
will not qualify for entry into the study: 
7.2.1
Gastrointestinal Exclusion Criteria
1. The subject has a diagnosis of UC or indeterminate colitis.
2. [Previous criterion 2 deleted in amendment number 1].
3. The subject has clinical evidence of a current abdominal abscess or a history of prior 
abdominal abscess.
4. The subject has a known perianal fistula with abscess. (The subject may have a perianal fistula 
without abscess.)
5. The subject has a known fistula (other than perianal fistula).
6. The subject had non-CD related abdominal surgery within 6 months prior to enrollment.
7. The subject has any prior CD-related surgery OR CD complication requiring surgery at any 
time (other than seton placement for perianal fistula without abscess).
8. The subject has a history of 2 or more non-CD related small bowel resections or diagnosis of 
short bowel syndrome.
9. The subject has extensive non-CD related colonic resection, ie, subtotal or total colectomy 
with <15 cm colon remaining.
10. The subject has an ileostomy or colostomy.
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11. The subject has a history or evidence of adenomatous colonic polyps that have not been 
removed.
12. The subject has a history or evidence of colonic mucosal dysplasia.
13. The subject has intolerance or contraindication to undergo ileocolonoscopy.
14. The subject has known fixed stricture or stenosis of the intestine.
7.2.2
Infectious Disease Exclusion Criteria
15. The subject has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection).
16. Subject has undergone organ transplantation.
17. The subject has evidence of an active infection during Screening.
18. Infections requiring treatment with oral (PO) or IV antibiotics, antivirals, or antifungals within 
28 days of enrollment.
19. The subject has active or latent TB, regardless of treatment history, as evidenced by any of the 
following:
a) History of TB.
b) A diagnostic TB test performed during Screening that is positive, as defined by:
i. A positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests OR
ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in subjects receiving the equivalent 
of >15 mg/day prednisone)
20. The subject has a history of listeria, histoplasmosis, coccidioidomycosis, blastomycosis, 
candidiasis, aspergillosis, legionella, or pneumocystosis.
21. The subject has a history of any bacterial, viral, and other infection due to opportunistic 
pathogens.
22. The subject has chronic hepatitis B virus* (HBV) or hepatitis C virus (HCV) infection. *HBV 
immune subjects (ie, being hepatitis B surface antigen negative and hepatitis B surface 
antibody positive), may however, be included.
23. The subject has evidence of active Clostridium difficile infection or is having treatment for C 
difficile infection or other intestinal pathogens during Screening.
24. The subject has received any live vaccinations within 28 days prior to enrollment.
7.2.3
General Exclusion Criteria
25. The subject has other inflammatory or rheumatic diseases (eg, psoriasis, rheumatoid arthritis, 
ankylosing spondylitis).
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26. The subject had a surgical procedure requiring general anesthesia within 60 days prior to 
enrollment or is planning to undergo major surgery during the study period.
27. The subject is required to take any excluded medications (as listed in Section 7.3).
28. The subject has received either approved or investigational biologic or nonbiologic agents for 
the treatment of IBD in an investigational protocol.
29. The subject has had prior exposure to any TNF antagonist including infliximab, certolizumab 
pegol, golimumab, adalimumab, or biosimilar TNF antagonist agents.
30. The subject has had prior exposure to approved or investigational anti-integrin antibodies (eg,
vedolizumab, natalizumab, efalizumab, etrolizumab, AMG 181, anti-MAdCAM-1 antibodies,
or rituximab).
31. The subject has received either approved or investigational biologic agents for the treatment of 
non-IBD conditions, other than localized injections (eg, intraocular injections for wet macular 
degeneration).
32. The subject has a history of hypersensitivity or allergies to methotrexate, vedolizumab, 
adalimumab, or their components.
33. The subject has a medical history that contraindicates the use of vedolizumab, adalimumab, or 
methotrexate as per each drug’s package insert.
34. The subject has conditions which, in the opinion of the investigator, may interfere with the 
subject’s ability to comply with the study procedures.
35. The subject has a history of any lymphoma or lymphoproliferative disease.
36. The subject has a history of congestive heart failure (New York Heart Association class III/IV) 
or unstable angina.
37. The subject has renal insufficiency, ascites, pleural effusion, or underlying liver disease.
38. The subject has any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, 
genitourinary, hematological, coagulation, immunological, endocrine/metabolic, neurologic, 
or other medical disorder that, in the opinion of the investigator, would confound the study 
results or compromise subject safety.
39. The subject has had gastric bypass surgery. 
40. The subject has symptoms of shortness of breath and cough and/or a diagnosis of clinically 
significant lung disease. 
41. The subject has a history of malignancy, except for the following: adequately-treated 
nonmetastatic basal cell skin cancer; squamous cell skin cancer that has been adequately 
treated and that has not recurred for at least 1 year prior to Screening; and history of cervical 
carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years 
prior to Screening. Subjects with a remote history of malignancy (eg, >10 years since 
completion of curative therapy without recurrence) will be considered based on the nature of 
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the malignancy and the therapy received; this must be discussed with the sponsor on a 
case-by-case basis prior to enrollment.
42. The subject has a history of any major neurological disorders, including stroke, central nervous 
system demyelinating disease, brain tumor, or neurodegenerative disease.
43. The subject has a positive progressive multifocal leukoencephalopathy (PML) subjective 
symptom checklist during Screening or prior to the administration of study drug on Day 1.
44. The subject has a history of pre-existing blood dyscrasias, such as bone marrow hypoplasia, 
leukopenia (WBC count <3 × 109/L), thrombocytopenia (platelet count <100 × 109/L), or 
significant anemia (hemoglobin level <8 g/dL).
45. The subject has rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or 
glucose-galactose malabsorption.
46. The subject has any of the following laboratory abnormalities during the Screening period:
a) Hemoglobin level <8 g/dL.
b) WBC count <3 x 109/L.
c) Lymphocyte count <0.5 x 109/L.
d) Platelet count <100 x 109/L or >1200 x 109/L.
e) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5 the upper limit 
of normal (ULN).
f)
Alkaline phosphatase >1.5 x ULN.
g) Renal dysfunction (serum creatinine concentration greater than 1.5 mg per deciliter [133 
μmol per liter]) or estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 at 
Screening
Note: Retesting laboratory values during the screening interval may be considered with 
consultation from the Medical Monitor.
47. The subject has a history of high alcohol consumption (more than 7 drinks per week), a history 
of prior alcohol abuse within 5 years prior to enrollment, has alcoholic liver disease, has 
withdrawal symptoms, or a history of illicit drug use. 
48. The subject has an active psychiatric problem that, in the investigator’s opinion, may interfere 
with compliance with study procedures.
49. The subject is unable to attend all the study visits or comply with study procedures.
50. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress.
51. The subject’s body mass index is >37.
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52. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 6 months after participating in this study; or intending to donate ova during such time 
period.
53. If male, the subject intends to father a child or donate sperm during the course of this study or 
for 6 months thereafter.
7.3
Excluded Medications 
The following medications are excluded from use during the study, from the time of informed 
consent to Week 102, unless specified otherwise:

Any treatment for CD other than those listed below in Section 7.3.1 (either approved or 
investigational).

Azathioprine and 6-mercaptopurine must be discontinued within 28 days prior to enrollment 
(Day 1).

Investigational or noninvestigational nonbiologic therapies.

Trimethoprim/sulfamethoxazole.

Leflunomide.

Theophylline. 

Tizanidine.

Phenytoin, phenylbutazone, or probenecid.

All live vaccines within 28 days prior to enrollment, throughout the study treatment period, 
and for at least 6 months after the last dose of study drug.

Either approved or investigational biologic agents for the treatment of non-IBD conditions, 
other than localized injections (eg, intraocular injections for wet macular degeneration).

Oral corticosteroids for CD except as described in Section 7.3.1.1; 5-ASA or corticosteroid 
enemas/suppositories are to be discontinued prior to enrollment.

Chronic nonsteroidal anti-inflammatory drug (NSAID) or salicylates use. (Note: Occasional 
use of NSAIDs and acetaminophen for headache, arthritis, myalgias, menstrual cramps, etc, 
and daily use of baby or low-dose [81-162.5 mg] aspirin for cardiovascular prophylaxis are 
permitted.)

Oral 5-ASA compounds, probiotics (eg, Culturelle, Saccharomyces boulardii), and antibiotics 
for luminal CD must be discontinued prior to enrollment.
Other medications may reduce the clearance of methotrexate. Subjects receiving the following 
additional medications during the study should be carefully monitored for increased side effects: 
penicillins, oral antibiotics (ciprofloxacin, tetracycline, chloramphenicol), nonabsorbable broad 
spectrum antibiotics, aminoglycosides, amphotericin B, and kanamycin.
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator.
7.3.1
Permitted Medications and Treatments
The following medications for CD are permitted during the study:

Oral corticosteroid therapy for CD with mandatory tapering completed by 60 days after study 
enrollment as described in Section 7.3.1.1.

Antidiarrheals for control of chronic diarrhea.

Systemic antibiotics for treatment of non-CD indications or perianal CD prior to or after seton 
placement are permitted for a maximum of 14 consecutive days.
Subjects will take folic acid as a companion medication through Week 34 (while taking 
methotrexate).
Subjects are permitted to have seton placement surgery for perianal fistula.
7.3.1.1
Oral Corticosteroid Dosing and Tapering
The maximum dose of oral corticosteroids for the treatment of CD that may be co-administered 
with vedolizumab IV is 30 mg/day prednisone or 9 mg/day budesonide (or equivalent) as long as 
the dose has been stable for at least 7 days prior to enrollment.
It is required that subjects receiving oral corticosteroids begin a tapering regimen by 14 days after 
enrollment and that the taper is completed within 60 days after enrollment. The recommended 
tapering schedule is as follows:

For prednisone at doses >10 mg/day (or equivalent), the dose should be reduced at a rate of 
5 mg/week until 5 mg/day is reached, and then the dose should be reduced at a rate of 
2.5 mg/week until discontinuation. 

For prednisone at doses ≤10 mg/day (or equivalent) achieved by tapering, the dose should be 
reduced at a rate of 2.5 mg/week until discontinuation.

Budesonide should be reduced at a rate of 3 mg every 2 weeks until discontinuation.
7.3.1.2
Medications for CD Exacerbation After 26 Weeks
If a subject has a first exacerbation of CD after 26 weeks as defined in the following paragraph, 
then the frequency of vedolizumab infusions will be changed to vedolizumab 300 mg IV Q4W, 
instead of vedolizumab 300 mg IV Q8W, for the remainder treatment to Week 102.
A first exacerbation of CD after 26 weeks is defined as either:

A CDAI increase of >70 from the prior visit on 2 occasions separated by a 2-week interval, OR

Objective evidence of disease activity by colonoscopy and CRP above normal, OR

Fecal calprotectin >250 μg/g alone.
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A


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7.4
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the electronic case report form (eCRF) using the following 
categories. For screen failure subjects, refer to Section 9.1.29.
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.

LFT Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.20), if the following circumstances occur at any 
time during study medication treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

Leukopenia or Lymphopenia. WBC and lymphocyte counts will be monitored for all 
subjects. Methotrexate, if applicable, should be discontinued and the dose of study drug 
held for an absolute lymphocyte count <0.5 × 109/L at any point in the study. The absolute 
lymphocyte count must be repeated at appropriate intervals as determined by the 
investigator. The next dose of study drug can be administered only if the absolute 
lymphocyte count is ≥0.5 × 109/L. If the absolute lymphocyte count remains <0.5 × 109/L, 
study drug should be discontinued and the subject withdrawn from the study.
2. Subjects who require surgical intervention for the treatment of CD except for seton placement 
for perianal fistula without abscess.
3. Significant protocol deviation. The discovery postenrollment that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and/or continued 
participation poses an unacceptable risk to the subject’s health.
4. 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.
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (eg, withdrawal due to an 
AE or lack of efficacy).
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
7. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.28.
8. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment (including the CD worsening criteria listed below) and continued 
participation would pose an unacceptable risk to the subject. 
–
Subjects with CD worsening during the first 26 weeks defined as ≥100-point increase in 
CDAI score since Screening that occurs after Week 10 on 2 consecutive visits and a CDAI 
score ≥220 points OR
–
Subjects with a second exacerbation of CD after Week 26 defined as a >70-point increase 
in CDAI score from the prior visit on 2 consecutive visits separated by a 2-week interval 
and CRP above normal, or defined as fecal calprotectin >250 μg/g alone.
9. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.5
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.3.1.2. 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 early termination visit as well as the long-term follow-up (LTFU) phone call at 
26 weeks post treatment. Discontinued or withdrawn subjects will not be replaced.
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
mmercial Use Only and Subject to the Applicable Terms of Use
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8.1
Study Medication and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Vedolizumab IV 
The study sites will be supplied by the sponsor with the following medication in an open-label 
manner: vedolizumab IV 300 mg/vial, for single use, in 20 mL vials. The study medication will be 
provided in a glass vial as a lyophilized solid for reconstitution using 4.8 mL of sterile water for 
injection and dilution in 250 mL of sterile 0.9% sodium chloride. Each vial will be packaged in an 
appropriately labeled single vial carton. 
All infusions will be administered IV over approximately 30 minutes. Longer infusion times of up 
to 60 minutes may be used based on subject observations. Subjects should be observed for 2 hours 
following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion in a room 
where appropriate treatment for infusion-related reactions is available. The subject should be 
considered clinically stable by the investigator or designee prior to discharge.
Additional reference information and administration instructions can be found in the pharmacy 
manual.
8.1.1.2
Adalimumab SC
The study sites will be supplied by the sponsor with the following medication in an open-label 
manner: adalimumab 40 mg in prefilled syringes. Adalimumab will be supplied in a clinical carton 
containing 1 prefilled syringe. The clinical carton and each prefilled syringe will be labeled with a 
single-panel or multilingual booklet label that will contain, but will not be limited to, the following: 
sponsor’s name and address, protocol number, packaging job/lot number, name and strength of the 
product, caution statement, directions for use, and storage conditions.
Additional reference information and administration instructions can be found in the pharmacy 
manual and Instructions for Use for study participants. 
8.1.1.3
Oral Methotrexate
The study sites will be supplied by the sponsor with the following medication in an open-label 
manner: methotrexate 2.5 mg tablets in a 100-count bottle. The subject will take six 2.5 mg tablets 
(for a total dose of 15 mg) at 1 time.
Methotrexate will be supplied in the manufacturer’s original bottle. Each bottle will be 
appropriately labeled with a single-panel or multilingual booklet label that will contain, but will 
not be limited to the following: sponsor’s name and address, protocol number, packaging job/lot 
number, name and strength of the product, caution statement, directions for use, and storage 
conditions.
Additional reference information and administration instructions can be found in the pharmacy 
manual and Instructions for Use for study participants.
f Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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8.1.2
Storage
Investigational drugs must be kept in an appropriate, limited-access, secure place until they are 
used or returned to the sponsor or designee for destruction. Investigational drugs must be stored 
under the conditions specified on the labels, and remain in the original containers until dispensed. 
A daily temperature log of the drug storage area must be maintained.
Vedolizumab IV must be stored in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Do not 
use if frozen even if the drug has been thawed.
Adalimumab must be stored in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). It should be kept in its 
original container and protected from light until administered. Do not freeze. Do not use if frozen 
even if it has been thawed.
Oral methotrexate tablets must be stored at room temperature between 20C and 25C (68F and 
77F) with excursions permitted to 15C to 30C (59F-86F). The tablets should be stored in the 
packaging provided, which prevents access of moisture and provides protection from light.
8.1.3
Dose and Regimen
The dose and regimen for all subjects is provided in Table 8.a.
Vedolizumab infusion will take place at the study center and be administered intravenously over 
30 minutes. Instructions for reconstitution and administration will be provided in the pharmacy 
manual. Subjects should be observed for 2 hours following the first 2 infusions, at a minimum, and 
1 hour after each subsequent infusion.
Adalimumab SC will be administered at the clinical site on Day 1 (160 mg/mL). The subject 
should return to the site the day after (or within a 3-day window of) the vedolizumab infusion to 
self-administer the adalimumab SC injection while instructed and observed by site staff or to have 
the injection administered by qualified site staff. Subsequent doses (80 mg/mL and then 40 mg/mL) 
will be self-administered at home starting at Week 2. Weeks 2, 6, 14, and 22 adalimumab will be 
administered 1 day after the vedolizumab infusion. Additional reference information and 
administration instructions can be found in the pharmacy manual and Instructions for Use for 
study participants.
Methotrexate will be taken weekly on the same day each week in the form of six 2.5 mg tablets (for 
a total dose of 15 mg). Subjects must take a daily folic acid supplement (1 mg PO) during the 
34 weeks of methotrexate treatment.
When adalimumab and vedolizumab are due to be given to a subject on the same day, the 
vedolizumab infusion should be given as scheduled at the study center and then the subject should 
self-administer the adalimumab SC injection at home the next day.
If a subject has a first exacerbation of CD after 26 weeks, defined as a CDAI increase of >70 from 
the prior visit on 2 occasions separated by a 2-week interval, OR objective evidence of disease 
activity by colonoscopy and CRP above normal, OR fecal calprotectin >250 μg/g alone, then 
frequency of vedolizumab infusions will be changed to vedolizumab 300 mg IV Q4W, instead of 
vedolizumab 300 mg IV Q8W for the remainder treatment.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Table 8.a
Dose and Regimen
Treatment Phase
Dose
Treatment Description
Triple 
Combination 
Therapy
Vedolizumab 300 mg IV
Adalimumab (a)
160 mg (4 x 40 mg), 
80 (2 x 40 mg), 
40 mg SC
IV infusion with vedolizumab at Weeks 0, 2, 6, 14, and 22.
Induction: 160 mg at Week 0, 80 mg at Week 2, 40 mg at Week 4 
and every 2 weeks after until Week 26.
Methotrexate 15 mg PO
15 mg PO weekly from Weeks 0 to Week 34 (with folic acid 
supplement taken during this period).
Monotherapy
Vedolizumab 300 mg IV
IV infusion with vedolizumab at Weeks 30, 38, 46, 54, 62, 70, 78, 
86, 94, and 102.
(Subjects with a first exacerbation of CD after 26 weeks will 
receive vedolizumab 300 mg IV every 4 weeks following the 
exacerbation. Please refer to the Schedule of Study Procedures in 
Appendix A for dosing schedule.)
Abbreviations: CD, Crohn’s disease; IV, intervenous; PO, oral.
(a) At Weeks 0, 2, 6, 14, and 22, adalimumab will be administered 1 day after the vedolizumab infusion. For Week 0, 
the subject should return to the site the day after (or within a 3-day window of) the vedolizumab infusion to 
self-administer the adalimumab SC injection while instructed and observed by site staff or to have the injection 
administered by qualified site staff. Subsequent doses will be self-administered at home starting at Week 2.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE eCRF(s) according to Section 10.0, Pretreatment 
Events, Adverse Events and Product Complaints. 
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Investigational Drug Assignment and Dispensing Procedures
Subjects will receive treatment according to study schedule.
The investigator or investigator’s designee will access the interactive response technology (IRT) at 
screening to obtain the subject study number. During this contact, the investigator or designee will 
provide the necessary subject-identifying information, including the subject number assigned at 
screening.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Week 4
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t to 
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to the Sch
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The medication identification number (Med ID) of the investigational drug to be dispensed will 
then be provided by the IRT by email notification to the site pharmacist/nurse. If sponsor-supplied 
drug (vials or prefilled syringes) is lost or damaged, the site staff can request a replacement from 
the IRT. 
Refer to the IRT manual provided separately. At subsequent drug-dispensing visits, the 
investigator or designee will again contact the IRT to request additional investigational drug for a 
subject.
8.3
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator and investigator’s designated site pharmacy must ensure that the sponsor- or 
contract research organization (CRO)-supplied drug is used in accordance with the protocol and is 
dispensed only to subjects enrolled in the study. To document appropriate use of the 
sponsor-supplied drugs (vedolizumab IV, adalimumab prefilled syringes, and methotrexate 
tablets), the investigator pharmacy/site must maintain records of drug delivery to the site, site 
inventory, dispensation and use by each subject, and return to the sponsor or designee. The use of 
the CRO-supplied supplement (folic acid) must be documented in the subject's medical record. 
Upon receipt of sponsor-supplied drug, the designated site pharmacy must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, designated site 
pharmacy should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and by recording in IRT. If there are any discrepancies between the packing list versus the 
actual product received, Takeda must be contacted to resolve the issue. The packing list should be 
filed in the investigator’s essential document file.
The investigator’s designated site pharmacy must maintain 100% accountability for all 
sponsor-supplied drugs received and dispensed during his or her entire participation in the study. 
Proper drug accountability includes, but is not limited to:

Monitoring expiration dates (monitored via IRT).

Frequently verifying that actual inventory matches documented inventory.

Verifying that the drug accountability log is completed for the Med ID used to prepare each 
dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
The investigator’s designated site pharmacy must record the current inventory of all the 
sponsor-supplied drugs (vedolizumab IV, adalimumab prefilled syringes, and methotrexate tablets) 
on a sponsor-approved drug accountability log. The following information will be recorded at a 
akeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
m
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minimum: protocol number and title, name of investigator, site identifier and number, description 
of sponsor-supplied drugs, expiry date and amount dispensed, and amount returned to the 
pharmacy (if applicable) including initials, seal, or signature of the person dispensing the drug. 
The log should include all required information as a separate entry for each subject (by subject 
identifier) to whom the drug is dispensed. 
The investigator’s designated site staff administering the study drug infusion must complete an 
individual subject accountability log to document if infusion was complete or if incomplete and 
study drug was returned to the pharmacy, including the date and amount returned to the pharmacy, 
including the initials, seal, or signature of the person administering the infusion.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
Investigator sites that have the ability to destroy Investigational Product /Materials locally (not 
returned to Sponsor or it’s designee for destruction), must have an SOP governing IP destruction 
and provide a copy of the SOP to the Sponsor/Sponsor Representative for review and 
approval. The site must provide a certificate of destruction for all IP/materials destroyed on-site. If 
the site does not have a certificate of destruction form they can use the form that is available in the 
IRT system. A file-note should be written stating that IP/materials was destroyed in compliance 
with the site SOP, and the file-note should be attached to the site IP accountability logs for 
verification and reconciliation.
If an Investigator site is not able to store their Investigational Product/Materials until the site CRA 
has performed verification and reconciliation, then the site must provide a copy of the governing 
SOP to the Sponsor/Sponsor representative for approval. If an Investigator site is utilizing an 
electronic system to manage IP/materials, they must provide evidence that the system is 21 CFR 
PART 11 compliant. Investigator designated site Pharmacists must be delegated duties on the site 
Delegation of Authority log. 
8.4
Companion Medication
Treatment with folic acid is required from enrollment/Day 1 though Week 34 (while taking 
methotrexate). Subjects will take a single 1-mg capsule or tablet PO daily per the investigator’s 
instruction. Folic acid will be provided by the CRO/Site.
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.
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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9.1.1
Informed Consent Procedure
The requirements of the informed consent process are described in Section 15.2 and Appendix C.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained through the IRT system; this subject number will be used 
throughout the study.
Pharmacogenomic (PGx) informed consent is a component of the overall study informed consent. 
The requirements are described in Section 15.2. Subjects will have the capability to opt out of the 
PGx component of the informed consent, if requested.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth or age, sex, Hispanic ethnicity 
(as applicable), race as described by the subject, and smoking status of the subject at screening.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that stopped at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.8.)
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 30 days prior to signing of informed consent. Medication history 
should be captured on the Medication History/Concomitant Medications eCRF page.
In addition, a history of all prior biologic use and any medications taken for the treatment of CD, 
including the reason for discontinuation, that stopped at or prior to signing of informed consent, is 
to be collected at screening for subjects where possible. Any prior CD treatment should be 
captured on the Prior CD Treatment eCRF only, and CD treatment started after signing informed 
consent, should be captured on the Concomitant Medications eCRF page only.
9.1.3
Crohn’s Disease History
CD history collected at screening will include details of CD diagnosis, disease severity, surgery, 
hospitalizations, and extraintestinal manifestations. After signing of informed consent all subjects 
should have CD included on the Concurrent Medical Condition eCRF page.
9.1.4
Physical Examination Procedure
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and 
(11) other. All subsequent physical examinations should assess clinically significant changes from 
the assessment prior to first dose examination. Additionally, abdominal mass assessment will be 
performed at all visits where CDAI is calculated.
akeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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9.1.5
Weight, Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters without decimal places and for 
weight it is kilograms (kg) with 1 decimal place.
9.1.6
Vital Sign Procedure
Vital signs will include body temperature (oral or tympanic measurement), respiratory rate, blood 
pressure (resting more than 5 minutes), and pulse (resting more than 5 minutes).
9.1.7
PML Checklist
Site staff will administer the subjective PML checklist during screening to exclude subjects with 
positive responses from enrolling into the study. The subjective PML checklist will be 
administered prior to dosing at each visit, as shown in Appendix A, to evaluate symptoms 
suggestive of PML. Any subjects reporting signs or symptoms of PML will undergo objective 
testing and may be referred to a neurologist for a full evaluation, as described in the Risk 
Assessment and Minimization for PML (RAMP) algorithm referenced in Section 11.1.1. The 
symptoms from a positive PML checklist obtained after enrollment will be recorded as an AE. 
Additional information and tools for the RAMP can be found in the Reference Binder.
9.1.8
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, electrocardiogram 
(ECG), or physical examination abnormalities noted at the screening or baseline examination. The 
condition (ie, diagnosis) should be described.
9.1.9
ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the 
investigational site) will interpret the ECG using one of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. A copy of the 
ECG trace should be kept with the subject’s notes.
9.1.10
Predicting CD Disease Course
The investigator will assess whether the subject has CD at moderate-high risk for complications. 
Investigator judgement may include clinical assessment, the PROSPECT tool, or criteria defined 
by the 2014 AGA CD Clinical Care Pathway [4-6]. 
9.1.10.1
Investigator clinical assessment
Clinical criteria that predict CD progression and complications include:

Involvement of the upper GI tract and/or ileum, 

Young age at diagnosis, 
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
Penetrating CD behavior (Subjects with a known non-perianal fistula are however excluded 
from this study), 

Perianal disease, 

Use of steroids at diagnosis, 

Smoking. 
9.1.10.2
AGA CD Clinical Care Pathway
Using the AGA 2014 Clinical Care Pathway [5], patients may be assessed as moderate-high risk 
for CD complications due to disease progression using the following criteria:

<30 years of age at initial diagnosis, 

Extensive anatomic involvement, 

Perianal or severe rectal disease, 

Deep ulcers, 

Prior surgical resection or stricturing and/or penetrating behavior.
9.1.10.3
PROSPECT CD Tool 
The PROSPECT CD Risk Calculator is a web-based tool used to predict outcomes and response to 
treatment [4,6]. For subjects whom the investigator chooses to implement the PROSPECT tool, 
their blood will be drawn at the time of informed consent and shipped to Prometheus Labs, San 
Diego, CA (or other lab) for serologic and genetic markers. If an investigator chooses not to utilize 
the PROSPECT tool to assess a subject’s risk of developing CD complications, blood may still be 
collected for serologic and genetic markers for the endpoint analysis of PROSPECT tool 
performance at any time during the subject’s screening period. Further instruction on the 
collection and handling of these samples can be found in the study Laboratory Manual. The results 
of these tests will be used as inputs to the PROSPECT predictive tool. This mathematical 
prediction tool incorporates basic disease characteristics including disease location and time since 
diagnosis, in addition to serologic markers such as anti-Saccharomyces cerevisiae antibody 
(ASCA), CBir, perinuclear antineutrophil antibody (pANCA), and a single genetic polymorphism 
of NOD2. The results of the serologic and genetic markers will be sent to the PROSPECT 
coordinator who will input the results to create an output graphical representation of that 
individual’s risk with ≥20% chance of disease complication by Year 2. These results will be then 
sent to the site investigator to be considered as part of the investigator’s assessment of a subject’s 
risk of CD complications.
9.1.10.4
Monitr Crohn's Disease Test
The Monitr Crohn's Disease Test is a laboratory-developed test from Prometheus Labs that 
evaluates multiple markers of mucosal damage and repair processes, regardless of disease 
location. It applies a proprietary algorithm to 13 biomarkers to produce a quantitative Endoscopic 
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Healing Index Score, ranging from 0 to 100, to aid in distinguishing endoscopic remission from 
active disease in adult CD patients [47].
A blood sample for Monitr CD will be collected at Week 26 and Week 102 or early termination.
In addition, Baseline Week 0, Week 26 and Week 102 samples may be analyzed for subjects who 
have already completed those visits prior to Amendment #4. After PK and Immunogenicity testing 
are completed, any residual frozen serum aliquots from PK and/or Immunogenicity testing may be 
repurposed for this testing. These samples will only be used after receiving subject 
consent/reconsent.
Further instruction on the collection and handling of these samples can be found in the study
Laboratory Manual.
9.1.11
Colonoscopy and Biopsy Procedure
Colonoscopy will be performed during screening and at Weeks 26 and 102 or early termination. 
All study colonoscopies will be video-recorded using the Robarts Central Image Management 
Solution (CIMS). All study endoscopy videos will be subject to central review to ensure consistent 
grading. A central reviewer will confirm the SES-CD inclusion criterion prior to subject 
enrollment. Central reviewer’s grading will stand as final assessment for eligibility. CIMS will 
communicate incidental findings observed during central review to the investigator/study team for 
additional follow up.
At each colonoscopy, up to 4 biopsies for histopathology will be collected from 5 segments (for a 
total of up to 20 biopsies): the rectum, left colon, transverse colon, right colon, and ileum. Biopsies 
will be taken in the vicinity of the most prominent ulcerative lesions, if present. If there is more 
than 1 area of inflammation within a segment, 2 biopsies should be taken from the most severely 
affected area of inflammation and 2 biopsies should be taken from the normal mucosa adjacent to 
this area of inflammation. For each colonic segment, biopsies from inflamed and normal mucosa
should be placed in separate specimen containers. In those instances in which the mucosa of an 
entire segment appears normal, 2 biopsies should be taken from normal mucosa. Additionally, if 
the mucosa of an entire segment is inflamed, 2 biopsies should be obtained from the most severely 
affected area of inflammation.
The site of the biopsy collection will be recorded. Work Instructions will detail the requirements 
for study colonoscopy and biopsy. Subject preparation for colonoscopy should follow the site’s 
usual clinical practice (such as polyethylene glycol). 
All biopsies collected per protocol will be centrally stored and analyzed at the end of the study. 
Although it is permissible for the investigator to take additional biopsy samples as deemed 
necessary for standard of care management of the patient during the protocol-required 
colonoscopy, these will be considered as occurring outside the protocol. Such collection, handling, 
and analyses of the additional samples will be and remain the responsibility of the investigator.
akeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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9.1.12
Primary Efficacy Measurement
The primary efficacy measure is the percentage of subjects who achieve endoscopic remission, 
defined as SES-CD 0-2 at Week 26.
9.1.13
The SES-CD
The SES-CD [48] evaluates 4 endoscopic variables (ulcer size, proportion of the surface area that 
is ulcerated, proportion of the surface area affected, and stenosis) by scoring each variable on a 
scale from 0 to 3 where higher scores indicate more severe disease, in 5 bowel segments (ileum, 
right colon, transverse colon, left colon, and rectum). 
The score for each endoscopic variable is the sum of the values obtained for each segment. The 
SES-CD Total is the sum of the 4 endoscopic variable scores from 0 to 56. See Appendix F.
9.1.14
CDAI
A CDAI [49] score will be calculated at baseline Week 0, using subject diary entries during 
screening within 14 days prior to enrollment, and is based on the most recent 7 days with complete 
and valid data within a maximum consecutive 10 day period. Note that diary entries on the day 
prior, day of, and the day after the colonoscopy cannot be used for CDAI sub-score calculation. 
For the baseline CDAI the hematocrit results collected during screening should be used. A CDAI 
score will also be derived at the time points specified in the Schedule of Events and at any 
unscheduled visit(s) due to disease exacerbation. See Appendix G. A Standard Weight Table is 
provided in Appendix H.
9.1.15
CDAI Diary Completion
Diary entries will be made daily by subjects and will be used for CDAI score calculation. During 
screening, subjects will be instructed on how to appropriately complete the daily diary. The 
symptoms of CD must be recorded throughout the study, including the screening period. Entries 
should be reviewed and monitored by the study staff.
9.1.16
PRO-2
A 2-item patient-reported outcome, PRO-2, will be derived from 2 elements of the CDAI diary 
(stool frequency and abdominal pain) from the 7 days prior to score calculation [50]. See 
Appendix I. 
9.1.17
Additional Patient-Reported Outcome Measures
Subjects will complete the IBDQ, WPAI-CD, and the IBD-DI at the time points specified in the 
schedule of events (Appendix A). 
9.1.17.1
Inflammatory Bowel Disease Questionnaire
The IBDQ is a valid and reliable [51-53] instrument used to assess HRQOL in adult subjects with 
IBD. It includes 32 questions on 4 domains of HRQOL: Bowel Systems (10 items), Emotional 
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Function (12 items), Social Function (5 items), and Systemic Function (5 items). Subjects are 
asked to recall symptoms and quality of life from the last 2 weeks and rate each item on a 7-point 
Likert scale (higher scores equate to higher quality of life). A total IBDQ score is calculated by 
summing the scores from each domain; the total IBDQ score ranges from 32 to 224. See 
Appendix J.
9.1.17.2
Work Productivity and Activity Impairment - Crohn’s Disease
The WPAI-CD consists of 6 questions that evaluate absenteeism (work time missed), presenteeism 
(reduced work productivity), overall work impairment, and activity impairment [54,55]. The 
WPAI-CD questionnaire will be self-administered by the study subjects. 
9.1.17.3
Inflammatory Bowel Disease - Disability Index
The IBD-DI is the first specific instrument for evaluating disability in IBD. It is based on core 
sections of the World Health Organization’s International Classification of Functioning, Disability, 
and Health and was designed to evaluate the long-term effects of IBD on subject functional status 
and to provide a new endpoint in disease-modification studies [56]. The IBD-DI consists of 14 
questions that focus on body functions, body structures, activities and participation, and 
environmental factors. Scores range between 0 to 100, with 0 to 20 indicating no disability, 
20 to 35 mild disability, 35 to 50 moderate disability, and 50 to 100 severe disability. The IBD-DI 
recently has been validated for use in clinical trials, including results from 150 subjects with CD, 
having shown high internal consistency, interobserver reliability, and construct validity, as well as 
moderate intraobserver reliability [57].
9.1.18
Documentation of Concomitant Procedures
At each visit, subjects will be asked whether they have had any CD-related events since their last 
visit including hospitalizations, bowel surgeries, or CD-related procedures that are not part of the 
protocol. The timing of the event will be collected relative to the start of treatment on Day 1 of the 
study through the last clinic visit (Week 120). All events with timing will be recorded in the eCRFs. 
The underlying symptom or diagnosis should correspondingly be recorded as an AE as applicable.
9.1.19
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the required study medication 
(methotrexate, vedolizumab, adalimumab, or the companion folate). These may be prescribed by a 
physician or obtained by the subject over the counter. Concomitant medication is not provided by 
Takeda. At each study visit, subjects will be asked whether they have taken any medication other 
than the study-specified medication (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 eCRF. Concomitant medication information will be 
collected through Week 120 (18 weeks post last dose).
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9.1.20
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 45 mL, and the approximate total volume of 
blood for the study is 476 mL. Details of these procedures, specimen handling and required safety 
monitoring will be given in the laboratory manual. 
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
RBC
WBC with differential (a)
Hemoglobin
Hematocrit
Platelets
PT/INR
ALT
Albumin
Alkaline phosphatase
AST 
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
GGT
Potassium
Bicarbonate
Sodium
Calcium
Chloride
Magnesium
Phosphorus
Uric Acid
Glucose
Amylase
Lipase
eGFR (if calculated)
Bilirubin
Blood
Glucose
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Leukocyte esterase
Nitrite
pH
Protein
Specific Gravity
Other:
HIV
Hepatitis panel, including HBsAg and anti-HCV
ASCA IgA
ASCA IgG
Anti-CBir1 IgG
ANCA
NOD2 genotype test
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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Serum
Urine
Stool
CRP
PK samples
ADA/nADA 
QuantiFERON for TB
hCG (for pregnancy in female 
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only) 
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C difficile (b)
beta hCG (for pregnancy in female subjects of 
childbearing potential only)
FSH, if menopause is suspected (screening visit only)
Monitr CD Test (biomarker panel using serum to 
measure hsCRP, SAA 1, CEACAM 1, VCAM 1, ANG 1, 
ANG 2, IL-7, TGFα, EMMPRIN, MMP 1, MMP 2, 
MMP 3, and MMP 9)
Abbreviations: ADA,antidrug antibodies; ALT, alanine aminotransferase; ASCA, anti-Saccharomyces cerevisiae antibody; AST, 
aspartate aminotransferace; anti-CBir1, anti-flagellin; CRP, C-reactive protein; FSH, follicle-stimulating hormone;GGT, 
γ-glutamyl transferase; HBsAg, hepatitis B surface antigen; hCG, human chorionic gonadotropin; HCV, hepatitis C virus; HIV, 
human immunodeficiency virus; ANCA, antineutrophil antibody; IgA, immunoglobulin A; IgG, immunoglobulin G; nADA, 
neutralizing antidrug antibodies; NOD2, nucleotide-binding oligomerization domain-containing protein; PK, pharmacokinetic; PT, 
prothrombin time; RBCs, red blood cells; TB, tuberculous; WBC, white blood cell; ULN, upper limit of normal; hsCRP, 
high-sensitivity C-reactive protein; SAA 1, serum amyloid A 1; CEACAM1, carcinoembryonic antigen-related cell adhesion 
molecule 1: VCAM 1, vascular cell adhesion molecule 1; IL-7, interleukin-7; TGFα, transforming growth factor α; EMMPRIN, 
extracellular matrix metalloproteinase inducer; MMP, matrix metalloproteinase 
(a) WBC differential to include lymphocytes, monocytes, basophils, eosinophils, and neutrophils.
(b) Not done at screening; only done if subject experiences a flare during the study.
The central laboratory will perform laboratory tests for hematology, serum chemistries, stool, and 
urinalysis. The results of safety 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, γ-glutamyl transferase (GGT), and INR) should 
be performed within a maximum of 7 days and preferably within 48 to 72 hours after the 
abnormality was noted.
(Please refer to Section 7.3.1.2 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in 
conjunction with total bilirubin >2 ×ULN.)
If the ALT or AST remains elevated >3 ×ULN on 2 consecutive occasions the investigator must 
contact the Medical Monitor for consideration of additional testing, close monitoring, possible 
discontinuation of study medication, discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3
Reporting of Abnormal Liver Function Tests for reporting requirements).
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9.1.21
Fecal Calprotectin Sample Collection
A stool sample will be collected from the first bowel movement in the morning at the time points 
indicated in the Schedule of Study Procedures (Appendix A) for the analysis of fecal calprotectin, 
a biomarker of intestinal inflammatory activity. Sites are encouraged to provide subjects with a 
stool sample kit at the time of clinic visits. Stool samples may be stored in the refrigerator at 4C 
and should be returned to the clinic within 48 hours of collection. 
9.1.22
Stool Sample Collection
A stool sample will be obtained to perform a C difficile assay at any point in the study when a 
subject becomes symptomatic, including worsening or return of disease activity.
9.1.23
Pharmacokinetic Sample Collection 
Vedolizumab - Blood samples (5 mL) will be drawn for vedolizumab serum PK analysis in all 
subjects on Day 1 and at the time points indicated in the Schedule of Study Procedures 
(Appendix A). Blood samples should be drawn prior to start of infusion at visits where study drug 
is given. 
Adalimumab - Blood samples (5 mL) will be drawn for adalimumab serum PK analysis in all 
subjects on the same day as the visit and prior to vedolizumab dosing on Day 1 and at the time 
points indicated in the Schedule of Study Procedures (Appendix A).
At time points where both vedolizumab and adalimumab require blood samples, separate samples 
will be drawn for each drug.
Serum concentrations of vedolizumab will be measured by a sandwich enzyme-linked 
immunosorbent assay (ELISA) assay with a validated range of 0.20 to 8.0 µg/mL. 
Serum concentrations adalimumab will be measured by a sandwich ELISA assay with a validated 
range of 0.25 to 10.0 µg/mL. 
Samples collected outside that window will not be considered protocol deviations as long as they 
are collected prior to vedolizumab dosing, and the dosing and sampling dates and times are 
accurately collected in the eCRF.
It is important that the EXACT date and time of dosing (start and end of infusion for vedolizumab) 
and PK sampling for both drugs be recorded in the eCRF.
Detailed instructions for the handling and shipping of samples are provided in Appendix K.
9.1.24
Anti-Drug Antibodies Sampling
Blood samples for ADA assessments for vedolizumab will be obtained on Day 1 prior to dosing at 
the time points indicated in the Schedule of Study Procedures (Appendix A).
Blood samples for ADA assessments for adalimumab will be obtained on Day 1 prior to 
vedolizumab dosing at the time points indicated in the Schedule of Study Procedures 
(Appendix A).
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Serum titers of ADA to vedolizumab and adalimumab will be determined using a validated assay. 
A separate assay will be required for each drug. nADAs to vedolizumab will be determined on 
ADA-positive samples using a validated assay. nADAs to adalimumab will only be determined if 
deemed necessary for the interpretation of the data.
Please refer to the Reference Binder for information on sample collection and preparation.
9.1.25
Pharmacogenomic Sampling
When sampling of whole blood for PGx analysis occurs, every subject must sign informed 
consent/be consented in order to participate in the study. 
Two whole blood samples (3 mL per sample) for DNA isolation will be collected before dosing on 
Day 1 from each subject in the study, into plastic K2EDTA spray-coated tubes, and stored under 
frozen conditions. If necessary and feasible, a second aliquot of blood may be taken if isolation of 
DNA from the first sample was not successful or possible.
Two whole blood RNA samples (2.5 mL per sample) for RNA PGx analysis will be collected on 
Day 1 from each subject in the study, into a PaxGeneTM tube. If DNA or RNA samples are not 
obtained on Day 1, they may be collected at any point in the study. Please refer to the Reference 
Binder for information on sample collection and preparation.
DNA forms the basis for the genes that make the body produce proteins such as enzymes, drug 
transporters, or drug targets. RNA has multiple vital roles in the codes, decoding, regulation, 
expression of genes and sensing and communicating responses to cellular signals. Both DNA and 
RNA from tissues such as blood may be evaluated for the genetic contribution of how the drug is 
broken down, or how the drug affects the body. This is called a “Pharmacogenomics research 
study.” Specific purposes of this study include:

Identifying genetic reasons why certain people respond differently to vedolizumab.

Finding out more information about how vedolizumab works. 

Generating information needed for research, development, and regulatory approval of tests to 
predict response to vedolizumab.

Identifying variations in genes related to the biological target of vedolizumab.
This information may be used, for example, to develop a better understanding of the safety and 
efficacy of vedolizumab and other study medications, and for improving the efficiency, design and 
study methods of future research studies.
The samples will be stored for no longer than 15 years after completion of the study. No samples 
will be stored for longer than permitted by the applicable law and samples will be destroyed upon 
notification from Takeda. “Stored samples” are defined as samples that are key-coded (the 
samples are stripped of all personal identifying information but a key links the samples to the 
clinical data collected from the sample donor) and are used in the analysis of investigational drug 
or related drugs.
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Detailed instructions for the handling and shipping of samples will be provided by the central 
laboratory in the laboratory manual.
9.1.26
Tuberculosis Screening
All subjects will complete TB screening to determine eligibility. All subjects must complete either 
a QuantiFERON test or a tuberculin skin test within 30 days of Screening or during Screening. 
Chest X-ray should be completed if high risk for TB or indeterminate skin test or QuantiFERON. 
Subjects will be excluded from the study if they have active or latent TB, regardless of treatment 
history.
9.1.27
Contraception and Pregnancy Avoidance Procedure
9.1.27.1
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 medication, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with or without 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period. Females of childbearing potential who are partners of male subjects are also advised to use 
additional contraception as shown in the list containing highly effective/effective contraception 
below.
9.1.27.2
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 medication, female subjects of childbearing potential* who are sexually active 
with a nonsterilized male partner** must use a highly effective/effective method of contraception 
(from list below). In addition, they must be advised not to donate ova during this period.
9.1.27.3
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 (WOCBP), ie, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as 
no menses for 12 months without an alternative medical cause. A high follicle-stimulating 
hormone (FSH) level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a 
postmenopausal state in younger women (eg, those <45 years old) or women who are not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.
**Sterilized males should be at least 1 year postbilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
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The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, the 
only acceptable methods of contraception are: 

Nonhormonal Methods: 
–
Intrauterine device (IUD).
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
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 prior to 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 prior to the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months;

Oral.

Intravaginal (eg, ring).

Transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months prior to the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has been
on contraceptive for 3 months;

Oral.

Injectable.

Implantable.
2. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.
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
Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
3. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
4. During the course of the study, regular urine human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women of childbearing potential and all subjects (male and 
female) will receive continued guidance with respect to the avoidance of pregnancy and sperm 
donation as part of the study procedures. Such guidance should include a reminder of the 
following:
a) Contraceptive requirements of the study.
b) Reasons for use of barrier methods (ie, condom) in males with female partners of 
childbearing potential.
c) Assessment of subject compliance through questions such as:
i.
Have you used the contraception consistently and correctly since the last visit?
ii.
Have you forgotten to use contraception since the last visit?
iii.
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)?
iv.
Is there a chance you could be pregnant?
5. In addition to a negative serum hCG pregnancy test at screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative urine hCG pregnancy test as close as possible and prior to 
receiving any dose of Lead-in medication (ie, standard of care) and study medication and at the 
Week 102/End of Treatment Visit and Week 120/ Safety Follow-up Visit. 
Methotrexate is in Pregnancy Category X. Methotrexate is contraindicated in pregnant women as 
it can cause fetal death or teratogenic effects. Women of childbearing potential should not be 
started on methotrexate until pregnancy is excluded and pregnancy should be avoided if either 
partner is receiving methotrexate.
9.1.27.4
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the recommendations previously described in 
Section 9.1.27.3, Item 4.
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9.1.28
Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn and vedolizumab, 
adalimumab, and methotrexate should be immediately discontinued. The subject will be 
withdrawn as per the procedures in Section 5. 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 medication, eg, after Visit 1 or within 
18 weeks of the last dose of active study medication, 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 subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of the open label treatment the subject received.
All pregnancies in subjects on active study drug 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.
9.1.29
Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is found to be not eligible at the screening visit, the investigator should complete the 
eCRF. The IRT should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria (specify reason).

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal (specify reason).

Study termination.

Other, specify.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.30
Documentation of Study Entrance
Enrollment will be performed through the IRT system. Only subjects who meet all of the inclusion 
criteria and none of the exclusion criteria are eligible for entrance (enrollment) into the treatment 
phase.
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If the subject is found to be not eligible for treatment phase, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
A vedolizumab dispensing log, including records of drug received from the sponsor and volume of 
vedolizumab dispensed to each subject intravenously, will be maintained by the site. 
An adalimumab and methotrexate dispensing log, including records of drug received from the 
sponsor and drug dispensed for home administration to each subject and returned by each subject, 
will be maintained by site. 
If a subject is persistently noncompliant with the study medication, it may be appropriate to 
withdraw the subject from the study. 
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A.
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening (Visit 1)
Subjects will be screened within 28 days prior to enrollment. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. Subjects 
may be enrolled at any time during the screening period provided that all screening procedures 
have been completed and eligibility has been confirmed. See Section 9.1.29 for procedures for 
documenting screening failures.
Procedures to be completed at screening (Visit 1) can be found in the Schedule of Study 
Procedures (Appendix A).
9.3.2
Enrollment (Day 1) (Visit 2)
Enrollment of eligible subjects will take place on Day 1. The Day 1 procedures are documented in
Appendix A. 
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria, the subject 
should be enrolled using the IRT as described in Section 8.2. Subjects will be given instructions for 
the first doses of triple combination therapy as described in Section 8.1.3. The procedure for 
documenting screening failures is provided in Section 9.1.29.
9.3.3
Week 102 or Final Treatment Visit (Visit 19)
The final treatment visit will be performed at Week 102 (Visit 19) (see Appendix A). 
9.3.4
Week 120 or End-of-Study Visit (18 Weeks Post-Treatment)
Follow-up will begin the first day after the last dose of vedolizumab and will continue for 
18 weeks. This follow-up visit (Visit 20) will be scheduled for final efficacy and safety 
e Only and Subject to the Applicable Terms of Use
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assessments (Appendix A). For all subjects enrolled, the investigator must complete the End of 
Study Drug and End of Study Visits eCRF pages.
9.3.5
Poststudy Long-term Follow-up (26 Weeks Post-Treatment)
Upon completion of the study or at early termination from the study, all subjects will participate in 
a 26-week (6-month) LTFU safety questionnaire. This questionnaire will be administered at 26 
weeks (6 months) from the last dose of study drug. The questionnaire will be administered via 
direct subject contact through either the study site or the designated study call center.
9.3.6
Unscheduled Visits Due to Exacerbation of CD
Subjects who are seen by the investigator or site staff at a time point not required by the protocol 
(ie, unscheduled visit) due to disease exacerbation will undergo the following:

Symptom-directed physical examination.

Vital signs assessment.

Recording of concomitant mediations.

Collection of AEs and SAEs.

Clinical chemistry, CRP, and hematology, as indicated.

Stool sample collection, including stool for C difficile and fecal calprotectin, if indicated.

Fistula assessment, if indicated.

CDAI.

ADA sample.

Colonoscopy, if indicated.
If a subject has a first exacerbation of CD after 26 weeks as defined in the following paragraph, 
then the frequency of vedolizumab infusions will be changed to vedolizumab 300 mg IV Q4W, 
instead of vedolizumab 300 mg IV Q8W, for the remainder of treatment to Week 102.
A first exacerbation of CD after 26 weeks is defined as either:

A CDAI increase of >70 from the prior visit on 2 occasions separated by a 2-week interval, OR

Objective evidence of disease activity by colonoscopy and CRP above normal, OR

Fecal calprotectin >250 μg/g alone.
9.3.7
Poststudy Care
Vedolizumab IV, adalimumab SC, and methotrexate will not be supplied upon completion of the 
subject’s participation in the study. The subject should be returned to the care of a physician and 
standard therapies as required. The subject may be continued on a commercial supply of 
vedolizumab, if approved in their country, at the discretion of their physician.
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
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9.4
Biological Sample Retention and Destruction
In this study, specimens for genome/gene analysis will be collected as described in Section 9.1.25.
The genetic material will be preserved and retained for up to but not longer than 15 years or as 
required by applicable law. The sponsor has put into place a system to protect the subjects’ 
personal information to ensure optimal confidentiality and defined standard processes for sample 
and data collection, storage, analysis, and destruction.
The samples will be sent to a central laboratory that processes the blood sample and serves as a 
secure storage facility. The sponsor and researchers working with the sponsor will have access to 
the samples collected and any test results. All samples collected during the study will be stored 
securely with limited access and the sponsor will require anyone who works with the samples to 
agree to hold the research information and any results in confidence.
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided PGx samples can withdraw their consent and request 
disposal of a stored sample at any time. Notify sponsor of consent withdrawal. 
In this study, ileocolonoscopy tissue samples will be preserved and retained for up to but not 
longer than 15 years or as required by applicable law. The sponsor has put into place a system to 
protect the subjects’ personal information to ensure optimal confidentiality and defined standard 
processes for sample and data collection, storage, analysis, and destruction. 
The tissue samples will be sent to a central laboratory that serves as a secure storage facility. The 
sponsor and researchers working with the sponsor will have access to the samples collected. All 
samples collected during the study will be stored securely with limited access and the sponsor will 
require anyone who works with the samples to agree to hold the research information in 
confidence. 
The sample will be labeled with a unique sample identifier similar to labeling in the main study but 
using a code that is different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers. This link means that the subject may be identified but only indirectly. The code 
numbers will be kept secure by or on behalf of the sponsor. 
Subjects who consented and provided ileocolonoscopy tissue samples can withdraw their consent 
and request disposal of a stored sample at any time. Notify sponsor of consent withdrawal.
da: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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10.0
PRETREATMENT EVENTS, ADVERSE EVENTS, AND PRODUCT 
COMPLAINTS
10.1
Definitions
10.1.1
PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
10.1.3
PCs
A product complaint (PC) is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product and/or device 
(eg, prefilled syringe).
An investigator who is made aware of or identifies a potential PC should immediately report the 
event to Takeda in accordance with the contact list provided to the site. Whenever possible, the 
associated product should be maintained in accordance with the instructions pending further 
guidance from a Takeda representative.
10.1.4
Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication 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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory retest and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).
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
If the subject experiences a worsening or complication of an AE after any change in study
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the eCRF.
10.1.5
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
Commercial Use Only and Subject to the Applicable Terms of Use
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5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.6
Special Interest AEs
An AESI (serious or nonserious) is an AE of scientific and medical concern specific to the 
compound or program, for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. Such events may require further investigation in order 
to characterize and understand them and would be described in protocols and instructions provided 
for investigators as to how and when they should be reported to Takeda.
AESIs for vedolizumab are serious infections including opportunistic infection such as PML, liver 
injury, malignancies, infusion-related or systemic reactions, and hypersensitivity, as described in 
further detail below.
Injection and/or Infusion Site Reactions and Hypersensitivity
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to subjects receiving vedolizumab; hence, such 
premedications are unlikely to be necessary or beneficial. At the discretion of the investigator, 
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
AE Lis
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however, subjects may be administered premedication prior to any study drug administration. 
Corticosteroids, if given as a premedication, should be limited to the day of administration. 
Study drugs should be administered by a health care practitioner prepared to manage 
hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and 
medical support measure should be available for immediate use. Subjects should be observed for 
2 hours following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion of 
vedolizumab.
Subjects and caregivers 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 (ie, infusion-related reaction) to study medication. Subjects will be 
asked to report administration-related AEs to the sites immediately as they are experienced. 
Appropriate treatment and follow-up will be determined by the investigator. If signs or symptoms 
of an administration-related reaction are observed during the administration of study medication, it 
should be immediately discontinued and the subject treated as medically appropriate. In the case of
a mild reaction, study drug administration may be reinitiated (with appropriate premedication and 
investigator supervision) at the discretion of the investigator. Subjects with a severe or serious 
administration-related reaction (eg, shortness of breath, wheezing, stridor, angioedema, 
life-threatening change in vital signs, severe injection site reactions) must be withdrawn from the 
study. 
In all cases of administration-related reaction, the medical monitor must be informed as soon as 
practical. The disposition of subjects with less severe administration-related reactions should be 
discussed with the medical monitor.
Serious Infections 
Subjects will be monitored for signs and symptoms of infection and for changes in WBC, 
hemoglobin, and platelets during the study. Subjects with signs and symptoms suggestive of 
infections, including GI infections, will be treated as clinically indicated. Interventions may 
include antibiotic treatment, if appropriate and/or discontinuation of concomitant 
immunomodulators. Blood, sputum, urine, and/or stool cultures should be obtained as appropriate 
for the detection and diagnosis of infection. Withholding or terminating study drug administration 
may be considered as described in Section 7.3.1.2.
Malignancies
All cases of malignancies that are detected during the study will be reported as AEs. Local medical 
practices for the management of malignances will apply. Subjects with history of malignancy 
(except for specific cancers) or at high risk for malignancy will be excluded from the study per the 
exclusion criteria. 
Other 
Other special interest AEs include liver injury and PML, which are discussed in Sections 10.2.3
and 11.1.1, respectively.
or Non-Commercial Use Only and Subject to the Applicable Terms of Use
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10.1.7
Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.8
Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.9
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related. 
10.1.10
Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician, and the time, if available.
10.1.11
Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died, and the time, if available.
10.1.12
Frequency 
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.13
Action Concerning Study Medication 

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.
mmercial Use Only and Subject to the Applicable Terms of Use
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
Not Applicable – a study medication was stopped for a reason other than the particular AE (eg, 
the study has been terminated, the subject died, dosing with study medication was already
stopped before the onset of the AE).

Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.14
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved.”

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – the AEs/PTEs which are considered as the cause of death. 

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
PTE and AE Collection Period
Start of PTE collection:
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication (Day 1; 
Visit 2) or until screen failure. For subjects who discontinue prior to study medication 
administration, PTEs are collected until the subject discontinues study participation.
Start of AE collection: 
AEs must be collected from the time that the subject is first administered study medication (Day 1; 
Visit 2). Any drugs provided by the sponsor are considered study medications.
ercial Use Only and Subject to the Applicable Terms of Use
to the A
able
to the A
diagnos
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e improv
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osis, sig
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AE/PTE
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End of AE collection: 
Routine collection of AEs will continue until the end-of-study follow-up (Week 120; Visit 20).
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.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event:
1. Event term.
2. Start and stop date, and time (if available).
3. Severity.
4. Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (related or not related) (not completed for PTEs).
5. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
6. Action concerning study medication (not applicable for PTEs).
7. Outcome of event.
8. Seriousness.
CDAI and quality of life instruments will not be used as a primary means to collect AEs. However, 
should the investigator become aware of a potential AE through the information collected with 
these instruments, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied.
10.2.1.3
Special Interest AE Reporting
If an AESI, which occurs during the treatment period or the follow-up period, is considered to be 
clinically significant based on the criteria in Section 10.1.6, it should be recorded in a special 
interest AE eCRF or SAE Form. The applicable form should be completed and reported to the 
SAE reporting contact in Section 1.1 within 24 hours.
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The special interest AEs have to be recorded as AEs in the eCRF. An evaluation form along with 
all other required documentation must be submitted to the sponsor.
10.2.2
Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE eCRF or form must be completed in English and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE eCRF should be completed within 24 hours of first onset or notification of the event. 
However, as a back-up, if required, the SAE form should be completed and reported to Takeda 
Pharmacovigilance or designee within 24 hours to the attention of the contact listed in Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3
Reporting of Abnormal Liver Function Tests
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.20 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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(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 an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal products administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
11.0
STUDY-SPECIFIC COMMITTEES
No data safety monitoring committee will be used in this study.
11.1
Adjudication Committee
A PML Independent Adjudication Committee (IAC) will be instituted for this study. The PML 
IAC will consist of a panel of leading PML experts, including a neurologist, neuroradiologist, and 
a virologist.
11.1.1
Risk Assessment and Minimization for PML (RAMP) Program
Natalizumab (TYSABRI), another integrin receptor antagonist, has been associated with PML, a 
rare and often fatal opportunistic infection of the central nervous system. PML is caused by the 
John Cunningham virus (JCV) and typically only occurs in subjects who are immunocompromised 
[58,59]. Natalizumab is a pan- α4 integrin antagonist that binds to both the α4β1 and α4β7 
integrins and inhibits cellular adhesion to vascular cell adhesion molecule-1 (VCAM-1) and 
MAdCAM-1 [60,61]. In contrast, vedolizumab binds to the α4β7 integrin only [11] and inhibits 
adhesion to MAdCAM-1, but not VCAM-1. A risk of PML cannot be ruled out with vedolizumab.
To address the theoretical risk of the development of PML in subjects treated with vedolizumab, 
the sponsor, with input from renowned PML experts, has developed a RAMP program. The 
complete description of the RAMP program, including materials and instructions for its 
implementation and monitoring, is included in the Reference Binder.
The RAMP is focused on early clinical detection and management of that specific safety risk, 
including the discontinuation of study drug, if applicable. Subjects are assessed for signs and 
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symptoms of PML prior to the administration of each dose of study drug using a PML subjective 
symptom checklist. Subjects with a positive PML subjective symptom checklist at any time after 
enrollment in a vedolizumab clinical study will be evaluated according to a prespecified algorithm 
(the PML Case Evaluation Algorithm). The next dose of study drug will be held until the 
evaluation is complete and results are available. Subsequent doses of study drug will be 
administered only if the possibility of PML is definitively excluded, as described in the RAMP 
algorithm. An IAC has been established as part of the RAMP program to review new neurological 
signs and symptoms potentially consistent with PML, and will provide input regarding subject 
evaluation and management as defined in the IAC charter. 
To ensure success of the RAMP program, site personnel will be trained to recognize the features of 
PML, and subjects will be trained to report specific neurological signs and symptoms without 
delay. Educational materials for teaching site personnel and subjects about PML and the RAMP 
procedures will be distributed to all sites and are included in the Reference Binder. Formal 
teaching and training will be performed for site personnel prior to the start of the study. Subjects 
will receive training and educational materials prior to receiving treatment. The informed consent 
form will contain specific information on the hypothetical risk of PML. Any documented case of 
PML will be reported as an SAE, regardless of whether hospitalization occurs.
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
Drug Dictionary (WHODRUG).
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor or 
delegated CRO will make arrangements to train appropriate site staff in the use of the eCRF. These 
forms are used to transmit the information collected in the performance of this study to the sponsor 
and regulatory authorities. eCRFs must be completed in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to data analyses. The SAP 
will provide further details regarding the definition of analysis variables and analysis methodology 
to address all study objectives.
A data review will be conducted prior to commencing analysis. This review will assess the 
accuracy and completeness of the study database, subject evaluability, and appropriateness of the 
planned statistical methods.
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13.1.1
Analysis Sets
All subjects who received at least 1 dose of study medication and have a postenrollment efficacy 
assessment will be included in the full analysis set (FAS). The FAS population will be used for the 
efficacy analysis and constitutes the primary analysis population for efficacy. 
All FAS subjects who do not have any major protocol violations will be included in the per 
protocol (PP) population. Major protocol violations will be specified in the SAP. All decisions to 
exclude subjects from the PP population dataset will be made prior to the commencement of 
analysis of the study. Analyses using the PP population may be provided as a sensitivity analysis.
Safety analyses will be based on the safety analysis set (SAF). All subjects who received at least 1 
dose of study drug will be included in the SAF analysis set.
The PK evaluable population is defined as all subjects who receive at least 1 dose of study drug 
and have sufficient blood sampling to allow for PK evaluation.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Baseline and demographic information will be listed and summarized. For continuous variables, 
the summary will consist of descriptive statistics (number of subjects, mean, SD, minimum, 
median, and maximum). For categorical variables, the summary will consist of number and 
percentage of subjects in each category.
Medical history and concurrent medical conditions will be summarized by system organ class and 
preferred term. Medication history and concomitant medications will be summarized by preferred 
term.
13.1.3
Efficacy Analysis
No inferential statistical testing will be performed in this study. Instead, an estimation approach 
will be taken.
The primary efficacy endpoint for this study is the percentage of subjects who achieve endoscopic 
remission, defined as SES-CD 0-2 at Week 26. 
Secondary endpoints include the percentage of subjects who maintain endoscopic remission at 
Weeks 52 and 102 in subjects who achieved endoscopic remission at Week 26.
For all dichotomous endpoints (having achieved endoscopic remission at Week 26 and those 
maintaining deep remission at Weeks 52, 78, and 102), corresponding percentages and their 
appropriate 95% CIs will be reported. Time-to-event endpoints will be analyzed by survival 
analysis procedures and percentages will be estimated by Kaplan-Meier product limit methods and 
presented with appropriate 95% CIs.
Change from baseline in CDAI and PRO-2 scores will be analyzed using Wilcoxon signed-rank 
test for paired data; the median change and its nonparametric 95% CI will also be presented.
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13.1.4
PK Analysis 
Serum concentrations of vedolizumab and adalimumab will be summarized by time using 
descriptive statistics. Individual serum concentration data versus time will be presented in a data 
listing. Additional PK analyses may be performed if deemed necessary for the interpretation of the 
data.
More details will be provided in the SAP. 
13.1.5
Anti-Drug Antibodies Analysis
Immunogenicity will be summarized by time and by treatment.
The percentage of subjects with positive ADA and the percentage of ADA positive subjects with 
positive nADA during the study will be summarized (anti-vedolizumab only). The impact of ADA 
on efficacy and safety will be explored. 
13.1.6
Safety Analysis
Safety analyses will be based on the SAF analysis set.
No formal statistical tests or inference will be performed for safety analyses. 
The number and percentage of subjects with AEs (regardless of relationship to study drug), AEs of 
special interest (ie, serious infections including opportunistic infection such as PML, liver injury, 
malignancies, infusion-related or systemic reactions, and hypersensitivity), AEs leading to 
discontinuation, and SAEs that occur on or after the first dose date and up to 18 weeks after the last 
dose date of the study drug will be summarized by MedDRA system organ class, high-level term, 
and preferred term overall, by severity, and by relationship to study drug. If a subject experienced 
more than 1 AE for a given preferred term, severity is defined as the severity of the most severe 
event and relationship to study drug is the relationship of the most related event. 
Change from baseline in clinical laboratory tests, vital signs and weight will be summarized. 
Subjects with markedly abnormal values for laboratory tests and vital signs will be tabulated.
Physical examination findings and PML checklist data will be presented in data listings.
Data from the LTFU survey will be summarized descriptively.
13.1.7
Other Analyses
Additional details regarding any further analyses will be specified in detail in the SAP.
13.2
Interim Analysis and Criteria for Early Termination
An interim analysis will be conducted once all subjects have completed their Week 26 study visit, 
in order to assess the primary endpoint. 
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13.3
Determination of Sample Size
The sample size was based on an estimate of precision. A sample size of 60 subjects will generate 
95% CIs for endoscopic remission (defined as SES-CD 0-2) rate at Week 26 with a half width no 
wider than 12.7% and expected remission of 50%. If the expected remission rate is different from 
50%, a required sample size would be smaller.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, study medication, subject medical records, 
informed consent documentation, documentation of subject authorization to use personal health 
information (if separate from the informed consent forms), and review of eCRFs and associated 
source documents. It is important that the investigator and other study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the Food and Drug Administration [FDA], the United Kingdom 
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Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator and institution guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. The 
Principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, the vedolizumab IV (Entyvio) 
package insert, the adalimumab package insert, the methotrexate package insert, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements and 
other documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title,
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will 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 trial. Until the site receives notification, no 
protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the 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 
Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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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.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
mmercial Use Only and Subject to the Applicable Terms of Use
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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.
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 study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
y of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for American investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
16.0
REFERENCES
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3. Yarur AJ, Strobel SG, Deshpande AR, Abreu MT. Predictors of aggressive inflammatory 
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
r and to
erm
r and to
gister 
Te
gister 
v or othe
ble 
v or othe
andard
cab
andard
gators), 
plic
gators), 
sest to th
the A
sest to th
callers r
to th
callers r
o
t
on, they
ct to
n, they
encour
bject
encour
rocess. I
Subje
rocess. I
uld be re
d Su
uld be re
is inform
and
is inform
at
l
ation no
ly a
ion no
e
rial
l U
rials
Us
s on 
Us
on 
cy/Stand
cial U
cy/Stand
ensatio
mer
ensatio
ust be in
Com
ust be in
icipat
-Co
icipating
o
ing
linical s
Non-
linical s
al Study
r No
al Study
nd treatm
For 
nd treatm
ontact th
a: F
ontact th
REFER
ked
REFER
Loftus E
f Ta
Loftus E
and e
y of 
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2
erty
2.
r
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y
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4. Siegel CA, Horton H, Siegel LS, Thompson KD, Mackenzie T, Stewart SK, et al. A validated 
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
bl
-ti
le
time to
e T
me to
Crohn's 
able
Crohn's 
te traffi
App
te traffi
 adhesio
to th
 adhesio
m
b
m S, Wi
bjec
S, Wi
m
b
m
pressed 
Subj
pressed 
A, Laza
y an
A, Laza
in alpha
Only 
in alpha
nt T, Eg
Use
nt T, Eg
ab
al
ab, an a
al U
, an a
bowel
cia
bowel d
a
d
l
a
l
Rutgeer
me
Rutgeer
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omm
n and m
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Non
N, Gilb
nd safet
r No
nd safet
402
Fo
402-9.
or 
-9.
 (vedo
da: 
 (vedolili
field, IL
keda
field, IL
Behm
Tak
Behm B
ak
B
m
ak
m
di
of T
disea
of T
sea
16.
erty
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y
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18. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, et al. 
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rheumatoid arthritis. Arthritis Rheum 2007;56(7):2129-34.
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early
ms
early
atoid 
Term
atoid 
with 
e T
with 
o
b
omized
ble 
mized
Wolde S,
Appli
Wolde S,
in pat
e Ap
n patie
p
ie
velka K
t to t
velka K
achieve
ect t
achieve
xate alon
bjec
xate alon
hen SB, 
nd 
hen SB, 
zed, dou
y an
zed, dou
versus m
Only 
versus m
d arthrit
e On
d arthrit
):26
Use
):26-37.
se 
-37.
nd MD, 
al U
nd MD, 
remissio
rcia
remissio
89;110(5
mer
89;110(5
n MD, L
omm
n MD, L
Disease
Co
Disease
hon J, F
Non
hon J, F
of Crohn
or N
of Crohn
1995;3
For
1995;3
BG, Fe
da: 
BG, Fe
ethotrex
ked
ethotrex
American
Tak
American
7.7. Feag
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29. Grove ML, Hassell AB, Hay EM, Shadforth MF. Adverse reactions to disease-modifying 
anti-rheumatic drugs in clinical practice. QJM 2001;94(6):309-19.
30. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. 
Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 
2010;362(15):1383-95.
31. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. 
Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 
2013;369(8):699-710.
32. Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, et al. Effects of 
Vedolizumab Induction Therapy for Patients With Crohn's Disease in Whom Tumor Necrosis 
Factor Antagonist Treatment Had Failed. Gastroenterology 2014.
33. Biancheri P, Di Sabatino A, Rovedatti L, Giuffrida P, Calarota SA, Vetrano S, et al. Effect of 
tumor necrosis factor-alpha blockade on mucosal addressin cell-adhesion molecule-1 in 
Crohn's disease. Inflamm Bowel Dis 2013;19(2):259-64.
34. Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Predictability of the 
postoperative course of Crohn's disease. Gastroenterology 1990;99(4):956-63.
35. Osterman MT, Sandborn WJ, Colombel JF, Robinson AM, Lau W, Huang B, et al. Increased 
risk of malignancy with adalimumab combination therapy, compared with monotherapy, for 
Crohn's disease. Gastroenterology 2014;146(4):941-9.
36. Bouguen G, Levesque BG, Feagan BG, Kavanaugh A, Peyrin-Biroulet L, Colombel JF, et al. 
Treat to target: a proposed new paradigm for the management of Crohn's disease. Clin 
Gastroenterol Hepatol 2015;13(6):1042-50.e2.
37. Peyrin-Biroulet L, Loftus EV, Jr., Colombel JF, Sandborn WJ. Early Crohn disease: a 
proposed definition for use in disease-modification trials. Gut 2010;59(2):141-7.
38. D'Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, et al. Early 
combined immunosuppression or conventional management in patients with newly diagnosed 
Crohn's disease: an open randomised trial. Lancet 2008;371(9613):660-7.
39. Khanna R, Bressler B, Levesque BG, Zou G, Stitt LW, Greenberg GR, et al. Early combined 
immunosuppression for the management of Crohn's disease (REACT): a cluster randomised 
controlled trial. Lancet 2015.
40. Blonski W, Buchner AM, Lichtenstein GR. Clinical predictors of aggressive/disabling disease: 
ulcerative colitis and crohn disease. Gastroenterol Clin North Am 2012;41(2):443-62.
41. Vuitton L, Marteau P, Sandborn WJ, Levesque BG, Feagan B, Vermeire S, et al. IOIBD 
technical review on endoscopic indices for Crohn's disease clinical trials. Gut 2015.
42. Sands BE, Kozarek R, Spainhour J, Barish CF, Becker S, Goldberg L, et al. Safety and 
tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in 
remission while receiving infliximab. Inflamm Bowel Dis 2007;13(1):2-11.
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al. 
al. 
l. 
l
l. 
ngl J M
able
ngl J M
et al
App
et al. E
pp
. E
n Who
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SA, V
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4.
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and
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Robinso
Only 
Robinso
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4;146(4
Use O
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n BG, K
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paradig
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F, van 
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For 
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o
41
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41


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43. Colombel JF, Reinisch W, Mantzaris GJ, Kornbluth A, Rutgeerts P, Tang KL, et al. 
Randomised clinical trial: deep remission in biologic and immunomodulator naive patients 
with Crohn's disease - a SONIC post hoc analysis. Aliment Pharmacol Ther 
2015;41(8):734-46.
44. Humira (adalimumab) injection, for subcutaneous use. Summary of Product Characteristics. 
North Chicago, IL: AbbVie Inc., Revised December 2014.
45. Vermeire S, Loftus EV, Jr, Colombel JF, Feagan BG, Sandborn WJ, Sands BE, et al. 
Long-term efficacy of vedolizumab for Crohn's Disease. J Crohns Colitis 2017;11(4):412-24.
46. Mendoza Ladd AH, Scott FI, Grace R, Bownik H, Lichtenstein GR. Dose escalation of 
vedolizumab from every 8 weeks to every 4 or 6 weeks enables patients with inflammatory 
bowel disease to recapture response [abstract]. Gastroenterology 2016;150(4):S235-S6.
47. D'Haens G, Kelly O, Battat R, Silverberg MS, Laharie D, Louis E, et al. Development and 
validation of a test to monitor endoscopic activity in patients with Crohn’s disease based on 
serum levels of proteins. Gastroenterology 2020;158(3):515-26.
48. Daperno M, D'Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development 
and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. 
Gastrointest Endosc 2004;60(4):505-12.
49. Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn's disease activity 
index. National Cooperative Crohn's Disease Study. Gastroenterology 1976;70(3):439-44.
50. Khanna R, Zou G, D'Haens G, Feagan BG, Sandborn WJ, Vandervoort MK, et al. A 
retrospective analysis: the development of patient reported outcome measures for the 
assessment of Crohn's disease activity. Aliment Pharmacol Ther 2015;41(1):77-86.
51. Irvine EJ. Development and subsequent refinement of the inflammatory bowel disease 
questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel disease. 
J Pediatr Gastroenterol Nutr 1999;28(4):S23-7.
52. Guyatt G, Mitchell A, Irvine EJ, Singer J, Williams N, Goodacre R, et al. A new measure of 
health status for clinical trials in inflammatory bowel disease. Gastroenterology 
1989;96(3):804-10.
53. Guyatt GH, Deyo RA, Charlson M, Levine MN, Mitchell A. Responsiveness and validity in 
health status measurement: a clarification. J Clin Epidemiol 1989;42(5):403-8.
54. Reilly MC, Gerlier L, Brabant Y, Brown M. Validity, reliability, and responsiveness of the 
work productivity and activity impairment questionnaire in Crohn's disease. Clin Ther 
2008;30(2):393-404.
55. Feagan BG, Reilly MC, Gerlier L, Brabant Y, Brown M, Schreiber S. Clinical trial: the effects 
of certolizumab pegol therapy on work productivity in patients with moderate-to-severe 
Crohn's disease in the PRECiSE 2 study. Aliment Pharmacol Ther 2010;31(12):1276-85.
-Commercial Use Only and Subject to the Applicable Terms of Use
erist
Ter
eristic
erm
ics.
m
s.
E, et al.
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E, et al.
017;11(
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017;11(
ose esca
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2016;15
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2016;15
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:515
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Disease S
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wo


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56. Peyrin-Biroulet L, Cieza A, Sandborn WJ, Coenen M, Chowers Y, Hibi T, et al. Development 
of the first disability index for inflammatory bowel disease based on the international 
classification of functioning, disability and health. Gut 2012;61(2):241-7.
57. Gower-Rousseau C, Sarter H, Savoye G, Tavernier N, Fumery M, Sandborn WJ, et al. 
Validation of the Inflammatory Bowel Disease Disability Index in a population-based cohort. 
Gut 2015.
58. Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory 
therapies. Annu Rev Med 2010;61:35-47.
59. Steiner I, Berger JR. Update on progressive multifocal leukoencephalopathy. Curr Neurol 
Neurosci Rep 2012;12(6):680-6.
60. Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. 
Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med 
2005;353(18):1912-25.
61. TYSABRI (natalizumab) injection. Full Prescribing Information. Cambridge, MA: Biogen 
Idec Inc., Revised May 2015.
to the Applicable Terms of Use
d cohort
erm
d cohort
mo
abl
modul
ble
dul
pathy
App
pathy. C
pp
. C
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to th
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nformati


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CONFIDENTIAL
Appendix A
Schedule of Study Procedures 
Induction Phase (Screening Through Week 26)
Screening
Treatment
Study Week
Wk 0
Wk
2
Wk
4 (r)
Wk
6
Wk
8 (r)
Wk
10
Wk
14
Wk
18 (r)
Wk
22
Wk
26
Study Day ± Visit Window (Days)
Day -28 to
Day -1
1
15 ±3
n/a
43 ±3
n/a
71 ±3
99 ±3
n/a
155 ±7
183 ±7
Visit Number:
1
2
3
n/a
4
n/a
5
6
n/a
7
8
Informed consent
X
Inclusion/exclusion criteria 
X
X
Demographics/medical and 
medication history/ concurrent 
medical conditions
X
CD History
X
Physical examination
X
X
X
X
X
X
X
X
Vital signs (a)
X
X
X
X
X
X
X
X
Access IRT to obtain subject ID
X
Access IRT to register visit
X
X
X
X
X
X
ASCA IgA, ASCA IgG, Anti-CBir1 
IgG, ANCA, NOD2 genotype test 
X
CDAI
X
X
X
X
X
X
X
PRO-2
X
X
X
Ileocolonoscopy (b)
X
X
SES-CD
X
X
CRP
X
X
X
X
Fecal calprotectin (c)
X
X
X
X
Tuberculosis QuantiFERON or skin 
test (d)
X
Chemistry, Hematology, Urinalysis
X
X
X
X
X
X
X
X
Hepatitis, HIV
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Te
ca
p
Wk
e A
Wk
10
he
10
Ap
ct to
ct t
a
t
a
th
to
bject
n/a
ject
n/a
ct
Su
Subje
bje
Su
Su
Su
S
nl
d
nl
Onl
Onlnlnly
nl
O
se O
Use
se
al U
l U
l U
al
X
r
X
aia
er
m
om
X
-C
X
Co
n
No
r N
X
F
X
or r
X
a: F
X
F
n 
n 
da
ked
nalysis
Ta
nalysis
Tak
f T
y o


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CONFIDENTIAL
Induction Phase (Screening Through Week 26)
Screening
Treatment
Study Week
Wk 0
Wk
2
Wk
4 (r)
Wk
6
Wk
8 (r)
Wk
10
Wk
14
Wk
18 (r)
Wk
22
Wk
26
Study Day ± Visit Window (Days)
Day -28 to
Day -1
1
15 ±3
n/a
43 ±3
n/a
71 ±3
99 ±3
n/a
155 ±7
183 ±7
Visit Number:
1
2
3
n/a
4
n/a
5
6
n/a
7
8
Pharmacogenomic DNA and RNA 
samples (f)
X
PK samples for vedolizumab (g)
X
X
X
X
X
PK samples for adalimumab (h)
X
X
X
X
X
X
ADAs samples, vedolizumab
X
X
X
X
ADAs samples, adalimumab
X
X
X
X
X
X
X
Pregnancy test (hCG) (i)
X
Urine pregnancy test (i)
X
X
X
X
X
X
X
Home pregnancy test (j)
X
ECG
X
Vedolizumab (IV) (k)
X
X
X
X
X
Adalimumab (SC) (l)
X (m)
X (m)
X
X (m)
X
X
X (m)
X
X (m)
X
Methotrexate (PO) (n)
X
X
X
X
X
X
X
X
X
X
Folic acid (PO) (o)
X
X
X
X
X
X
X
X
X
X
AE/SAE assessment
X
X
X
X
X
X
X
Concomitant medications/ 
procedures 
X
X
X
X
X
X
X
X
PML checklist (p)
X
X
X
X
X
X
PML wallet card
X
IBDQ
X
X
X
WPAI
X
X
X
IBD-DI
X
X
X
Health outcomes, CD-related events
X
X
X
X
X
X
Patient diary
X
X
X
X
X
X
X
X
X
X
X
nly and Subject to the Applicable Terms of Use
Te
e
ab
W
c
W
lic
pp
71 ±3
the
71 ±3
Ap
to
t
th
to
bject to
ject to
to
to
to
Su
Subje
bje
Su
Su
Su
S
X
nd
X
d
l
X
an
X
an
l
Onl
Only
nl
On
e On
On
n-Commercial
n
Use 
e
al U
l Us
Us
alal 
alalalal
X (m)
erc
X (m)
rc
X
me
X
me
m
om
X
C
X
Co
f Takeda: For Non-
X
Non
X
n-
r N
r N
r N
r N
r N
Fo
a:
ed
ed
ed
ed
ked
ak
rty of Tak
ed
of
ed event
of T
event
f T
o
Property
rty


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Protocol Incorporating Amendment No. 04
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CONFIDENTIAL
Induction Phase (Screening Through Week 26)
Screening
Treatment
Study Week
Wk 0
Wk
2
Wk
4 (r)
Wk
6
Wk
8 (r)
Wk
10
Wk
14
Wk
18 (r)
Wk
22
Wk
26
Study Day ± Visit Window (Days)
Day -28 to
Day -1
1
15 ±3
n/a
43 ±3
n/a
71 ±3
99 ±3
n/a
155 ±7
183 ±7
Visit Number:
1
2
3
n/a
4
n/a
5
6
n/a
7
8
C difficile test (q)
CD Risk by clinical assessment, 
PROSPECT Tool or 2014 AGA 
CD Care Pathway
X
Monitr CD Test 
X
X
Footnotes are on last table page.
to the Applicable Terms of Use
Te
e
ab
W
c
W
lic
pp
71 ±3
the
71 ±3
Ap
to
t
th
to
to
ect to
to
to
and S
to
Subjec
Subjec
S
Property of Takeda: For Non-Commercial Use Only and
an


Vedolizumab IV
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Protocol Incorporating Amendment No. 04
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CONFIDENTIAL
Maintenance Phase (Week 30 Through Week 128)
Treatment
Study Week
Wk
30
Wk
34 (s)
Wk
38
Wk 42 
(s)
Wk
46
Wk
50 (s)
Wk 52
Wk
54
Wk
58 (s)
Wk
62
Wk
66 (s)
Wk
70
Wk
74 (s)
Wk
78
Wk
82 (s)
Study Day ± Visit 
Window (Days)
211 ±7
239 ±7
267 ±7
295 ±7
323 ±7
351 ±7
365 ±7
379 ±3
407 ±7
435 ±7
463 ±7
491 ±7
519 ±7
547 ±7
575 ±7
Visit Number:
9
9b
10
10b
11
11b
12
13
13b
14
14b
15
15b
16
16b
Physical examination
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
Vital signs (a)
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
Access IRT to register 
visit
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
CDAI
X
X
X
X
X
X
X
X
PRO-2
X
X
Ileocolonoscopy (b)
SES-CD
CRP
X
X
Fecal calprotectin (c)
X
X
Chemistry,
Hematology, Urinalysis
X (e)
X
X
X
X
X
X
X
PK samples for 
vedolizumab (g)
X
X
X
ADAs samples, 
vedolizumab
X
X
X
ADAs samples, 
adalimumab
X
X
X
Pregnancy test (hCG) 
(i)
X
Urine pregnancy test (i)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Home pregnancy test (j)
X
X
X
X
Vedolizumab (IV) (k)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
X
X (s)
Methotrexate (PO) (n)
X
X
Folic acid (PO) (o)
X
X
r Non-Commercial Use Only and Subject to the Applicable Terms of Use
Te
e
ab
2
A
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pplplic
Wk
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Wk
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66
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66
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Use
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alalalal
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X
N
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on
Takeda: For 
n
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F
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eda:
X
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X
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ake
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X
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X
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Property of T k
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X
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of T
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o
rtytytyty


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CONFIDENTIAL
Maintenance Phase (Week 30 Through Week 128)
Treatment
Study Week
Wk
30
Wk
34 (s)
Wk
38
Wk 42 
(s)
Wk
46
Wk
50 (s)
Wk 52
Wk
54
Wk
58 (s)
Wk
62
Wk
66 (s)
Wk
70
Wk
74 (s)
Wk
78
Wk
82 (s)
Study Day ± Visit 
Window (Days)
211 ±7
239 ±7
267 ±7
295 ±7
323 ±7
351 ±7
365 ±7
379 ±3
407 ±7
435 ±7
463 ±7
491 ±7
519 ±7
547 ±7
575 ±7
Visit Number:
9
9b
10
10b
11
11b
12
13
13b
14
14b
15
15b
16
16b
AE/SAE assessment
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
Concomitant 
medications/procedures 
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
PML checklist (p)
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
PML wallet card
IBDQ
X
X
WPAI
X
X
IBD-DI
X
X
Health outcomes, 
CD-related events
X
X
X
X
X
X
X
X
Patient diary
X
X (s)
X
X (s)
X
X (s)
X
X
X (s)
X
X (s)
X
X (s)
X
X (s)
LTFU questionnaire 
C difficile test (q)
Footnotes are on last table page.
ly and Subject to the Applicable Terms of Use
Te
e
ab
2
A
2
pplplic
Wk
plic
Wk
pp
66
p
66
lic
pp
t
435 ±7
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435 ±7
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Use
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Property of Takeda: For Non-Comme
m
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mm
mm
mm


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Vedolizumab-4006
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Protocol Incorporating Amendment No. 04
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CONFIDENTIAL
Maintenance Phase (Week 30 Through Week 128) (continued)
Treatment
EOS or ET
LTFU Phone Call
Study Week
Wk 86
Wk 90 (s)
Wk 94
Wk 98 (s)
Wk 102
EOT
Wk 120
(18 wks post tx)
Wk 128
(26 wks post tx)
Study Day ± Visit Window (Days)
603 ±7
631 ±7
659 ±7
687 ±7
715 ±7
841 ±7
897 ±7
Visit Number:
17
17b
18
18b
19
20
21
Physical examination
X
X (s)
X
X (s)
X
X
Vital signs (a)
X
X (s)
X
X (s)
X
X
Access IRT to register visit
X
X (s)
X
X (s)
X
X
CDAI
X
X
X
X
PRO-2
X
Ileocolonoscopy (b)
X
X (ET only)
SES-CD
X
CRP
X
Fecal calprotectin (c)
X
Chemistry, Hematology, Urinalysis
X
X
X
X
PK samples for vedolizumab (g)
X
X
ADAs samples, vedolizumab
X
X
ADAs samples, adalimumab
X
X
Pregnancy test (hCG) (i)
(X)
Urine pregnancy test (i)
X
X
X
X
X
X
Home pregnancy test (j)
Vedolizumab (IV) (k)
X
X (s)
X
X (s)
X
Methotrexate (PO) (n)
Folic acid (PO) (o)
AE/SAE assessment
X
X (s)
X
X (s)
X
X
Concomitant medications/procedures 
X
X (s)
X
X (s)
X
X
PML checklist (p)
X
X (s)
X
X (s)
X
PML wallet card
X
f Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Te
e
EOS o
cab
EOS o
ab
W
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W
(18
pp
(18
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y


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Protocol Incorporating Amendment No. 04
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CONFIDENTIAL
Maintenance Phase (Week 30 Through Week 128) (continued)
Treatment
EOS or ET
LTFU Phone Call
Study Week
Wk 86
Wk 90 (s)
Wk 94
Wk 98 (s)
Wk 102
EOT
Wk 120
(18 wks post tx)
Wk 128
(26 wks post tx)
Study Day ± Visit Window (Days)
603 ±7
631 ±7
659 ±7
687 ±7
715 ±7
841 ±7
897 ±7
Visit Number:
17
17b
18
18b
19
20
21
IBDQ
X
WPAI
X
IBD-DI
X
Health outcomes, CD-related events
X
X
X
X
Patient diary
X
X (s)
X
X (s)
X
X
LTFU questionnaire 
X
C difficile test (q)
Monitr CD Test 
X
X (ET only)
Abbreviations; AE, adverse event; ADA, antidrug antibodies; ANCA, perinuclear antineutrophil antibody; ASCA, anti-Saccharomyces cerevisiae antibody; CD, Crohn’s disease; 
CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; DNA, deoxyribonucleic acid; ECG, electrocardiogram; EOS, end of study; EOT, end of treatment; ET, early 
termination; hCG, human chorionic gonadotropin; HIV, human immunodeficiency virus; IBD-DI, Inflammatory Bowel Disease Disability Index; IBDQ, Inflammatory Bowel 
Disease Questionnaire; ID, identification; IgA, immunoglobin; IRT, interactive response technology; IV, intravenous; LTFU, long-term follow-up; n/a=not applicable; NOD2, 
nucleotide-binding oligomerization domain-containing protein 2; PK, pharmacokinetic; PML, progressive multifocal leukoencephalopathy; PO, oral; PRO-2, patient-reported 
outcome 2; RNA, ribonucleic acid; SAE, serious adverse event; SC, subcutaneous; SES-CD, simple endoscopic score for Crohn’s disease; tx, treatment; WPAI,Work Productivity 
and Activity Impairment; hsCRP, high-sensitivity C-reactive protein; SAA 1, serum amyloid A 1; CEACAM1, carcinoembryonic antigen-related cell adhesion molecule 1: VCAM 1, 
vascular cell adhesion molecule 1; IL 7, interleukin-7; TGFα, transforming growth factor α; EMMPRIN, extracellular matrix metalloproteinase inducer; MMP, matrix 
metalloproteinase.
(a) Height collected only at the screening visit. Weight will be measured at every site visit where CDAI is calculated.
(b) Endoscopy to be collected at screening, Weeks 26 and 102, or early termination for central read. Biopsies will also be collected. All biopsies collected per protocol will be centrally 
stored and analyzed at the end of the study. Although it is permissible for the investigator to take additional biopsy samples as deemed necessary for standard of care management of 
the patient during the protocol required colonoscopy, these will be considered as occurring outside the protocol. Such collection, handling, and analyses of the additional samples will 
be and remain the responsibility of the investigator.
(c) Stool sample to be collected from the first bowel movement in the morning and sent to central laboratory.
(d) QuantiFERON test or tuberculin skin test only. 
(e) Hematology only.
(f) DNA and RNA samples will be collected on Day 1.
(g) PK samples for vedolizumab to be collected predose on dosing days Day 1 and Weeks 6, 10, 14, 26, 38, 54, 70, 86, and 102. at visits where study drug is given. 
mercial Use Only and Subject to the Applicable Terms of Use
Te
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EOS o
cab
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ab
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9
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Sub
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On
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Use 
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No
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ough it is 
or N
ough it is 
oscopy, th
For
oscopy, th
estigator.
a: F
estigator.
Property of Taked
he first bo
eda
he first bo
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aked
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of T
will be co
olizumab t
ty o
olizumab t


Vedolizumab IV
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Protocol Incorporating Amendment No. 04
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CONFIDENTIAL
(h) PK samples for adalimumab to be collected predose on dosing days (prior to vedolizumab dosing) on Day 1 and Weeks 6, 10, 14, 22, and 26. For Weeks 6, 14, and 22, when the 
subject is self-administering adalimumab at home, the adalimumab PK samples will be collected on the day of vedolizumab PK collection, prior to vedolizumab infusion. 
(i) Women of childbearing potential only. Urine pregnancy testing will be conducted at the site and serum pregnancy testing will be conducted by the central laboratory. Serum 
pregnancy completed at screening and Week 30 or Early Termination if stopped prior to Week 30; urine pregnancy to be completed at other visits. 
(j) Women of childbearing potential only. When site visits shift from every 4 weeks to every 8 weeks, women of childbearing potential will need to take a home pregnancy test every 
other month (in between visits) up until Week 58 and report the results to the site. If the subject experiences an exacerbation and switches to Q4W dosing, then no home pregnancy test 
is required as subject will have urine pregnancy test performed on site before infusion.
(k) Vedolizumab IV 300 mg at Week 0, 2, 6, 14, 22, 30, 38, 46, 54, 62, 70, 78, 86, 94, and 102. Subjects should be observed for 2 hours following the first 2 infusions, at a minimum, 
and 1 hour after each subsequent infusion for monitoring hypersensitivity reactions.
(l) Adalimumab SC 160 mg at Week 0, 80 mg at Week 2, then 40 mg every 2 weeks for a total of 27 weeks. Self injection or caregiver may inject using either the Pen or prefilled 
syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. Adalimumab will be 
self-administered at home at Weeks 2, 4, 8, 10, 12, 16, 18, 20, 24, and 26.
(m) At Weeks 0, 2, 6, 14, and 22, adalimumab will be administered 1 day after the vedolizumab infusion. For Week 0, the subject should return to the site the day after (or within a 
3-day window of) the vedolizumab infusion to self-administer the adalimumab SC injection while instructed and observed by site staff or to have the injection administered by 
qualified site staff. Subsequent doses will be self-administered at home starting at Week 2.
(n) Methotrexate 15 mg (six 2.5-mg tablets) PO once weekly for total of 34 weeks. 
(o) Daily folic acid (1 mg PO capsule or tablet) must be taken during the 34-week period of methotrexate treatment.
(p) PML checklist must be administered at screening and prior to vedolizumab dosing at every vedolizumab dosing visit.
(q) A C difficile test will be done only if a subject experiences a flare up during the study.
(r) Not a clinic visit. Home dosing with adalimumab and methotrexate only.
(s) Optional 4-week vedolizumab dosing visit. If a subject has a first exacerbation of CD after 26 weeks (defined as a CDAI increase of >70 from the prior visit on 2 occasions 
separated by a 2-week interval, OR objective evidence of disease activity by colonoscopy and CRP above normal, OR fecal calprotectin >250 μg/g alone), then frequency of 
vedolizumab infusions will be changed to vedolizumab 300 mg IV every 4 weeks (instead of every 8 weeks) for the remainder of treatment. Subjects should be monitored for 1 hour 
after each infusion for hypersensitivity reactions.
rcial Use Only and Subject to the Applicable Terms of Use
Te
, and 26. F
ble 
, and 26. F
ction, prio
abl
ction, prio
be
pl
be conduc
plica
conduc
leted at o
ppl
leted at o
ng potentia
Ap
ng potentia
n and swi
he A
n and swi
observed
to 
observed
s. Self inj
bjec
s. Self inj
roper train
ubj
roper train
nfusion. F
nd S
nfusion. F
hile instru
and
hile instru
eriod of m
e O
eriod of m
osing at e
Use
osing at e
ng the stu
l U
ng the stu
Property of Takeda: For Non-Comme
ly.
ci
ly.
exacerbati
erc
exacerbati
ctivity by
me
ctivity by
IV every 
mm
IV every 


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Protocol Incorporating Amendment No. 04
30 June 2020
Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on Investigators from the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572) which must be completed and 
signed before the Investigator may participate in this study.
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
Commercial Use Only and Subject to the Applicable Terms of Use
d and 
rms
d and 
outi
he A
outine/n
e A
ne/n
ini
e A
ini
prior to
o the
prior to
conduct 
bjec
conduct 
by an a
nd S
by an a
for init
Only
for initi
RB/IEC a
e On
RB/IEC a
east y
Use 
east yea
ea
ithin 3 m
l Us
ithin 3 m
formed 
rcia
formed 
onsent f
Comm
onsent f
a: For Non-C
the sub
Co
the sub
by the IR
on-C
by the IR
ct
N
ctio
No
ion th
No
n th
(
F
(includi
For N
includi
n inform
: Fo
n inform
Property of Taked
gator m
da:
gator m
ect’s leg
ked
ect’s leg
Prepare
f Ta
Prepare
eCR
y of 
eCR
2
y
2


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
13. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
Terms of Use
or 
or 
T
m 
T
m 
ble Te
is indiv
le T
is indiv
ble
uld imp
able
uld imp
cab
Property of Takeda: For Non-Commercial Use Only and Subject to the Applic
lic
erforme
lica
erforme


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Appendix C
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if so, 
what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
Non-Commercial Use Only and Subject to the Applicable Terms of Use
es.
ic
es.
lit
ub
lity 
ubj
y fo
bje
for r
je
r r
reatmen
and
reatmen
ri
n
risks or
nly 
sks or
g infant.
On
g infant.
ubject or
Use
ubject or
nded cli
al U
nded cli
alternat
mer
alternati
r
i
ect and 
omm
ect and 
ng the e
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ng the e
d, and a 
Non
d, and a 
f Takeda: For N
r may in
r No
r may in
he subjec
For 
he subjec
arch inv
da: F
arch inv
an explan
keda
an explan
hat they
Take
hat they
Property of T
. The a
of T
The a
17.
rty
17. T
y
T
1
e
1


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participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(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.
eda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
 inform
Ter
 inform
ubject’s
ble T
ubject’s
d to an 
plic
d to an 
s partici
the A
s partici
nformed
ect t
nformed
templat
bjec
templat
uding pe
Subj
uding pe
orizat
d S
orizatio
S
io
the subj
and
he subj
sonal he
Only 
sonal he
untries 
On
untries 
t
U
tio
s
ion,
se
n, to 
e O
to 
partners
l Us
partners
cies and
cial 
cies and
al info
merc
al inform
r
rm
rred to c
mm
rred to c
evel o
Com
evel of
m
f
a will m
n-C
a will m
e will n
Non
e will n
onal info
For N
onal info
a’s rese
: Fo
a’s rese
t
d
ty 
da
y 
Property of Take
and e
da: 
and e
developi
ked
developi
clinic
Tak
clinic
d)
of T
d) th
T
th


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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from screening throughout the duration of the study. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study medication will be discontinued and the investigator 
will offer the subject the choice to receive unblinded treatment information.
26. Male subjects must use adequate contraception (as defined in the informed consent) from 
screening throughout the duration of the study. If the partner or wife of the subject is found to 
be pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information.
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ect is
ms o
ect is
tigator 
erms
igator 
sent) fro
ble 
sent) fro
ubject i
icab
ubject i
oice to r
plic
ice to r
licly dis
the 
licly dis


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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 medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
on-Commercial Use Only and Subject to the Applicable Terms of Use
eg, the
rms
eg, the
d transf
to t
d transf
g:
e
g:
dy
u
dy and/o
ubje
and/o
y
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y
he study
d S
he study
esults.
an
esults.
lat
O
lating to
Only
ing to
ory
Use
ory f
se
f
y
se
y ilin
e 
ilin
fif
e
fif
tudy
l Us
tudy.
U
.
regulato
rcia
regulato
to other 
merc
to other 
ound pre
mm
ound pre
tigat
Co
igatio
Co
io
of Takeda: For No
n
nd inter
Non
nd inter
nd audit 
For N
nd audit 
invest
da: F
investig
F
ig
al trial r
keda
al trial r
t
T
tigator’
Tak
igator’
Property of
otecti
of T
otection
T
on
country
ty o
country
Inv
er
Inv


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Appendix E
AGA CD Clinical Care Pathway
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
the Ap
Use Only and Subject to the
: For Non-Commercial Us
erty of Takeda: 


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Source: Sandborn WJ. Crohn’s Disease Evaluation and Treatment: Clinical Decision Tool. Gastroenterology. 
2014:147:702-705.
e Applicable Terms of Use
Only and Subject to the A
r Non-Commercial Use On
Propert
erty of Takeda: For N


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Appendix F
SES-CD
Variable
SES-CD values
0
1
2
3
Ulcers
None
Aphthous ulcers
(Diameter 0.1-0.5 cm)
Large ulcers
(Diameter 0.5-2 cm)
Very large ulcers 
(Diameter >2 cm)
Ulcerated 
surface
None
<10%
10% - 30%
>30%
Affected 
surface
Unaffected segment
<50%
50% - 75%
>75%
Stenosis
None
Single, can be passed
Multiple, can be 
passed
Cannot be passed
Source: Adapted from: Daperno M, D'Haens G, Van Assche G, et al. Development and validation of a new, simplified 
endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest Endosc 2004; 60:505-12.
Abbreviation: SES-CD, Simple Endocopic Score for Crohn’s Disease.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
o
ulcers
erm
ulcers
er >2 cm
Ter
er >2 cm
ms
>30%
le T
>30%
T
>
ca
App
t and val
to th
t and val
c 2004; 
t to
c 2004; 
th


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Appendix G
CDAI
Category
Count
Initial 
Total
Multiplication 
Factor
Total
Number of liquid or very 
soft stools
7-day total number of liquid or very soft 
stools (reported on the 7 days immediately 
prior to the study visit)
x 2
Abdominal pain
7-day total of daily abdominal pain scores on
a 3-point scale: 0=none, 1=mild, 
2=moderate, 3=severe (reported on the 7 
days immediately prior to the study visit)
x 5
General well being
7-day total of daily general well-being scores 
on a 4-point scale: 0=generally well, 
1=slightly under par, 2=poor, 3=very poor, 
4=terrible (reported on the 7 days 
immediately prior to the study visit)
x 7
Extra-intestinal 
manifestations of Crohn’s
Disease
Total number of checked boxes (check all
that apply):
□
Arthritis/arthralgia
□
Iritis/uveitis
□
Erythema nodosum/pyoderma 
gangrenosum/aphthous stomatitis
□
Anal fissure, fistula, or abscess 
□
Other fistula
□
Fever over 37.8°C during past week
x 20
Lomotil/Imodium/opiates 
for diarrhea
Yes = 1
No = 0
x 30
Abdominal mass
None = 0 
Questionable = 2
Definite = 5
x 10
Hematocrit (%) (a)
Males: subtract value from 47
Females: subtract value from 42
x 6
Body Weight (b)
(1 – (Body weight/ 
Standard Weight)) × 100
x 1
Final Score
Add totals:
Source: Adapted from: Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn’s disease activity 
index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70 (3):439-44.
Abbreviation: CDAI, Crohn’s Disease Acivity Index,
(a) If hematocrit subtotal <0, enter 0. (b) If body weight subtotal <-10, enter -10.
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
otal
s
otal
ms
5
le
Ap
yoderma 
Only
yoderma 
hous stom
e O
hous stom
stula, or 
Use
stula, or 
la
ia
la
over 37.
erc
over 37.
bjbjbje
1
m
1
= 0
Com
= 0
me
None =
n-C
None =
Que
on
Que
C
a)a)
Fo
ght (b)
ked
ght (b)
d
nal Score
of T
nal Score
f T
Property o
Source:
ty o
Source:
index
erty
index
A
e
A
o


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Appendix H
Table for Determining Standard Body Weight (CDAI Variable)
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ty of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of


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Appendix I
PRO-2
Variable
Count
7-day 
Average
Multiplication 
Factor
Total
Number of liquid or 
very soft stools
7-day average number of liquid or very 
soft stools (reported on the 7 days 
immediately prior to the study visit)
x 2
Abdominal pain
7-day average daily abdominal pain 
scores on a 3-point scale: 0=none, 
1=mild, 2=moderate, 3=severe (reported 
on the 7 days immediately prior to the 
study visit)
x 5
PRO-2 SCORE
Add totals:
Source: Adapted from: Khanna R, et al. A retrospective analysis: the development of patient reported outcome 
measures for the assessment of Crohn's disease activity. Aliment Pharmacol Ther. 2015 Jan;41(1):77-86.
Abbreviation: PRO-2, patient-reported outcome 2.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
l
s
e T
Add tota
he 
Add tota
e A
nt of
to t
nt of pati
o th
pati
her.
ct t
her. 2015
to
2015
th


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Appendix J
IBDQ
The 32-item McMaster University IBDQ will be employed to assess for changes in quality of life 
in each subject at select study visits relative to Baseline, based on bowel function, systemic 
symptoms, social function and emotional state. This questionnaire will be completed by each 
subject prior to any clinical assessment and will be based on a 2-week recall period.
Instructions for the self-administered IBDQ:
This questionnaire is designed to measure the effects of your inflammatory bowel disease on your 
daily function and quality of life. You will be asked about symptoms you have been having as a 
result of your bowel disease, the way you have been feeling in general, and how your mood has 
been. On this questionnaire there are 32 questions. Each question has a graded response numbered 
from 1 through 7. Please read each question carefully and answer the number which best describes 
how you have been feeling in the past 2 weeks.
EXAMPLE:
How often have you felt unwell as a result of your bowel problem in the past 2 weeks?
Please choose only 1 number:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
If you are having trouble understanding a question, STOP for a moment! Think about what the 
question means to you. How has it been affected by your bowel problem? Then answer the 
question as best as you can. You will have a chance to ask the nurse questions after completing the 
questionnaire. This takes only a few minutes to complete.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
fe 
o
fe 
ch
rm
ch
wel 
lic
wel disea
ica
disea
ave been
Appli
ave been
nd how 
e Ap
nd how 
graded
the 
graded
e numbe
to th
e numbe
l
d
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proble
ouble u
No
ouble u
to y
For
to you. H
or 
ou. H
est as yo
a: Fo
est as yo
aire. Thi
da:
aire. Thi


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QUALITY OF LIFE IN INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE
(IBDQ)
1. How frequent have your bowel movements been during the last 2 weeks? Please indicate how 
frequent your bowel movements have been during the last 2 weeks by picking 1 of the options 
from:
1. Bowel movements as or more frequent than they have ever been.
2. Extremely frequent.
3. Very frequent.
4. Moderate increase in frequency of bowel movements.
5. Some increase in frequency of bowel movements.
6. Slight increase in frequency of bowel movements.
7. Normal, no increase in frequency of bowel movements.
2. How often has the feeling of fatigue or of being tired and worn out been a problem for you 
during the past 2 weeks? Please indicate how often the feeling of fatigue or tiredness has been a 
problem for you during the last 2 weeks by picking 1 of the options from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
3. How often during the last 2 weeks have you felt frustrated, impatient, or restless? Please choose 
an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
da: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ow 
s
ow 
ons
rm
ons
and wor
d Su
and wor
he feelin
and 
he feelin
g 1 of th
y an
g 1 of th
g the la
r No
g the la
time.
a: F
time.
y of Taked
f the tim
keda
f the tim
good bit
Tak
good bit
Som
of T
Some o
T
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Property 
5. A li
rty o
5. A li
6. 
er
6. 


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4. How often during the last 2 weeks have you been unable to attend school or do your work 
because of your bowel problem? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time
7. None of the time
5. How much of the time over the last 2 weeks have your bowel movements been loose? Please 
choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
6. How much energy have you had during the last 2 weeks? Please choose an option from:
1. No energy at all.
2. Very little energy.
3. A little energy.
4. Some energy.
5. A moderate amount of energy.
6. A lot of energy.
7. Full of energy.
7. How often during the last 2 weeks did you feel worried about the possibility of needing to have 
surgery because of your bowel problem? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
vement
to th
vement
ad durin
merc
ad durin
amount 
For
amount 
nergy.
da: F
nergy.
f 
k
f energ
ked
energ
. How o
of T
. How o
surge
rty 
surge
1. 
er
1. 


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6. Hardly any of the time.
7. None of the time.
8. How often during the last 2 weeks have you had to delay or cancel a social engagement because 
of your bowel problem? Please choose an option from:
1. All of the time.
2. Most of the time
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
9. How often during the last 2 weeks have you been troubled by cramps in your abdomen? Please 
choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
10. How often during the last 2 weeks have you felt generally unwell? Please choose an option 
from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
11. How often during the last 2 weeks have you been troubled because of fear of not finding the 
washroom (bathroom, toilet)? Please choose an option from:
1. All of the time.
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ecause 
ms 
ecause 
bled by 
d Su
bled by 
the last 
on-C
the last 
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F
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6. Har
7. 
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7. 


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2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
12. How much difficulty have you had, as a result of your bowel problems, doing leisure or sports 
activities you would have liked to have done during the last 2 weeks? Please choose an option 
from:
1. A great deal of difficulty; activities made impossible.
2. A lot of difficulty.
3. A fair bit of difficulty.
4. Some difficulty.
5. A little difficulty
6. Hardly any difficulty.
7. No difficulty; the bowel problems did not limit sports or leisure activities.
13. How often during the last 2 weeks have you been troubled by pain in the abdomen? Please 
choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
14. How often during the last 2 weeks have you had problems getting a good night’s sleep, or been 
troubled by waking up during the night? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
oing leis
pplic
oing leis
se choo
App
se choo
mit spor
Only
mit spor
ave y
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1. All o
2. M
erty
2. M


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7. None of the time.
15. How often during the last 2 weeks have you felt depressed or discouraged? Please choose an 
option from:
1. All of the time.
2. Most of the time
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
16. How often during the last 2 weeks have you had to avoid attending events where there was no 
washroom (bathroom, toilet) close at hand? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
17. Overall, in the last 2 weeks, how much of a problem have you had with passing large amounts 
of gas? Please choose and option from:
1. A major problem.
2. A big problem.
3. A significant problem.
4. Some trouble.
5. A little trouble.
6. Hardly any of the time.
7. No trouble.
18. Overall, in the last 2 weeks, how much of a problem have you had maintaining, or getting to, 
the weight you would like to be at? Please choose an option from:
1. A major problem.
2. A big problem.
y of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
an 
an 
d attendi
ubje
d attendi
e an opt
Sub
e an opt
weeks, h
Com
weeks, h
and opti
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and opti
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7. No 


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3. A significant problem.
4. Some trouble.
5. A little trouble.
6. Hardly any of the time.
7. No trouble.
19. Many patients with bowel problems often have worries and anxieties related to their illness. 
These include worries about getting cancer, worries about never feeling any better, and worries 
about having a relapse. In general, how often during the last 2 weeks have you felt worried or 
anxious? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
20. How much of the time during the last 2 weeks have you been troubled by a feeling of 
abdominal bloating? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
21. How often during the last 2 weeks have you felt relaxed and free of tension? Please choose an 
option from:
1. None of the time.
2. A little of the time.
3. Some of the time.
4. A good bit of the time.
5. Most of the time.
6. Almost all of the time.
Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
to their 
cab
to their 
etter, an
plic
etter, an
y
A
you f
App
ou fel
pp
el
fef
pp
fef t
p
tltl
p
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t 2 week
Use
t 2 week
n option
ial U
n option
e.
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e.
th
o
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or N
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: Fo
e time.
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Take
ow often
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on f
f Ta
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T
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frf
T
frf
Property 
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1. None
2. A
erty
2. A
3


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7. All the time.
22. How much of the time during the last 2 weeks have you had a problem with rectal bleeding 
with your bowel movements? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
23. How much of the time during the last 2 weeks have you felt embarrassed as a result of your 
bowel problem? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
24. How much of the time during the last 2 weeks have you been troubled by a feeling of having to 
go to the bathroom even though your bowels were empty? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
25. How much of the time during the last 2 weeks have you felt tearful or upset? Please choose an 
option from:
1. All of the time.
2. Most of the time.
keda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
g
f
b
fel
bj
el
fef
b
fef t emb
ubje
t emb
ltl
bj
ltl
during 
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during 
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7. Non


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3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
26. How much of the time during the last 2 weeks have you been troubled by accidental soiling of 
your underpants? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
27. How much of the time during the last 2 weeks have you felt angry as a result of your bowel
problem? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
28. To what extent has your bowel problem limited sexual activity during the last 2 weeks? Please 
choose an option from:
1. No sex as a result of bowel disease.
2. Major limitation as a result of bowel disease.
3. Moderate limitation as a result of bowel disease.
4. Some limitation as a result of bowel disease.
5. A little limitation as a result of bowel disease.
6. Hardly any limitation as a result of bowel disease.
7. No limitation as a result of bowel disease.
ty of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
idental 
cab
idental 
eeks hav
Only
eeks hav
me.
on
me.
e.
r
e.
t extent
da: 
t extent
an option
ked
an option
 sex as 
Tak
 sex as 
. Maj
of T
. Maj
Property
or 
f T
or 
3. Mo
rty 
3. Mo
4.
e
4.


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29. How much of the time during the last 2 weeks have you been troubled by nausea or feeling sick 
to your stomach? Please choose an option from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
30. How much of the time during the last 2 weeks have you felt irritable? Please choose an option 
from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
31. How often during the last 2 weeks have you felt a lack of understanding from others? Please 
choose 1 of the options from:
1. All of the time.
2. Most of the time.
3. A good bit of the time.
4. Some of the time.
5. A little of the time.
6. Hardly any of the time.
7. None of the time.
32. How satisfied, happy, or pleased have you been with your personal life during the past 2 weeks? 
Please choose 1 of the following options from:
1. Very dissatisfied, unhappy most of the time
2. General dissatisfied, unhappy.
3. Somewhat dissatisfied, unhappy.
f Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
irritable
ect t
irritable
2 week
mm
2 week
m:
Co
m:
the tim
For 
the tim
he time.
a: F
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of the 
keda
of the 
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ak
any
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ak
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32
er
32


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4. Generally satisfied, pleased.
5. Satisfied most of the time, happy.
6. Very satisfied most of the time, happy.
7. Extremely satisfied, could not have been more happy or pleased.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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Appendix K
Collection, Storage, and Shipment of Bioanalytical Samples
Vedolizumab
Instructions for Processing of Serum Samples for PK Vedolizumab Analysis
1. Collect 5 mL of venous blood into a Becton-Dickinson Vacutainer. For all vedolizumab 
samples, blood samples should be collected into glass red stopper vacutainers. Direct 
venipuncture is the only method of blood collection.
2. Allow the glass red top Vacutainer to sit at room temperature for approximately 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 (RCF) 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, mix well and split the serum evenly between the 2 aliquots into polypropylene 
tubes. A minimum of 0.8 mL needs to be obtained for each sample. 
5. Cap the labeled storage tubes and freeze the serum samples immediately at 
approximately -20°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 -20°C or lower until shipment to PPD Central Lab,
Highland Heights, KY. “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.
Shipping of Serum Samples for PK Analysis for Vedolizumab
The investigative site will ship samples to PPD Central Laboratory on a monthly basis using the 
laboratory carton (kit) provided, following packaging and shipping instructions provided in the 
central laboratory manual.
Adalimumab
Instructions for Processing of Serum Samples for PK Adalimumab Analysis 
1. Collect 5 mL of venous blood into a Becton-Dickinson Vacutainer. For all adalimumab 
samples, blood samples should be collected into glass red stopper vacutainers. Direct 
venipuncture is the only method of blood collection.
2. Allow the glass red top Vacutainer to sit at room temperature for approximately 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 RCF 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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
mab 
Ter
mab 
irect
le T
irect
mately
plica
mately 6
ca
6
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mation.
App
mation.
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ure in a c
o th
ure in a c
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ct to
o manu
to
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Subj
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ween th
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ween th
ed for ea
and
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serum s
Only 
serum s
ur and 4
On
ur and 4
m sampl
Use O
m sampl
tely 
al U
tely -
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merc
s after “
s for PK
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s for PK
ill ship s
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manual
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ons for
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ons for
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ollect 5
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ven
2.
er
2.


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4. To ensure a more homogeneous sample, all serum should first be transferred into 1 aliquot. 
From there, mix well and split the serum evenly between the 2 aliquots into polypropylene 
tubes. A minimum of 0.8 mL needs to be obtained for each 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 PPD Central Lab, 
Highland Heights, KY. “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.
Shipping of Serum Samples for PK Analysis for Adalimumab
The investigative site will ship samples to PPD Central Laboratory on a monthly basis using the 
laboratory carton (kit) provided, following packaging and shipping instructions provided in the 
central laboratory manual.
to the Applicable Terms of Use
ly
m
ly
cting
Term
cting
Central 
able
Central 
o
li
owed b
lica
wed b
A
on a m
o th
on a mo
h
o
Property of Takeda: For Non-Commercial Use Only and Subject 
ng instru
ct to
ng instru


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Appendix L
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 04. 
Minor editorial changes that had no impact on content have not been detailed here. 
Change 1: Takeda address was updated.
Initial 
wording:
Takeda Development Center Americas, Inc.
One Takeda Parkway
Deerfield, IL 60015
Amended 
or new 
wording:
Takeda Development Center Americas, Inc.
One Takeda Parkway 95 Hayden Avenue
Deerfield, IL 60015 Lexington, MA 02421
Rationale for Change: Corporate address change.
Change 2: Section 1.1 Robarts Medical Monitor phone was updated.
The primary change occurs in Section 1.1 Contacts.
Initial 
wording:
Amended 
or new 
wording:
Rationale for Change: Change in personnel.
Change 3: Section 1.1 Responsible Medical Officer contact was updated.
The primary change occurs in Section 1.1 Contacts.
Initial 
wording:
Amended 
or new 
wording:
Rationale for Change: Change in personnel.
PPD
PPD
PPD
PPD
y and Subject to the Applicable Terms of Use
Te
p
to
s update
ubje
s update
jec
Su
nd
se
se
Non-Commer
ge 
m
ge in pe
mme
in pe
me
esponsib
Co
esponsib
om
occurs i
Non
occurs i
n-
N
Property of Take
Amende
y of 
Amende
or ne
erty
or ne
wo
e
wo
f T
se Only a
ercial Use
keda: For N


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Change 4: Sections 2.0 and 6.1 were updated to increase site number from 60-64.
The primary change occurs in Section 2.0 STUDY SUMMARY.
Initial 
wording:
Approximately 60 sites in the United States and Canada
Amended 
or new 
wording:
Approximately 60 64 sites in the United States and Canada
Rationale for Change: To add additional sites to contribute to enrollment.
Section 6.1 Study Design also contains this change. 
Change 5: Section 4.1.2.2 was updated with the latest exposure data from Investigator Brochure 
Edition 23 dated 12 July 2019.
The primary change occurs in Section 4.1.2.2 Human Experience.
Initial 
wording:
As of 19 May 2015, approximately 3600 subjects (309 healthy subjects, 1393 subjects 
with UC, and 1896 subjects with CD) have received at least 1 dose of vedolizumab 
across all studies in the clinical development program (see current version of 
Investigator’s Brochure). Vedolizumab exposure has extended for ≥12 months in 
1667 subjects, ≥24 months in 1306 subjects, ≥36 months in 935 subjects, ≥48 months 
in 676 subjects, ≥60 months in 267 subjects, and ≥72 months in 26 subjects as of 19 
May 2015. Based on drug shipment data, the patient exposure to vedolizumab since its 
approval in May 2014 is estimated to be approximately 11,943 patient-years.
Amended 
or new 
wording:
As of 19 May 2015 2019, approximately 3600 6376 subjects (309 679 healthy 
subjects, 1393 2671 subjects with UC, and 1896 2920 subjects with CD) have received 
at least 1 dose of vedolizumab across all studies in the clinical development program 
(see current version of Investigator’s Brochure). Vedolizumab exposure has extended 
for ≥12 months in 1667 2553 subjects, ≥24 months in 1306 1636 subjects, ≥36 months 
in 935 1126 subjects, ≥48 months in 676 908 subjects, ≥60 months in 267 675
subjects, and ≥72 months in 26 378 subjects as of 19 May 2015 2019. Based on drug 
shipment data, the patient exposure to vedolizumab since its approval in May 2014 is 
estimated to be approximately 11,943 336,400 patient-years.
Rationale for Change: Updated with the latest exposure data from Investigator Brochure Edition 
23 dated 12 July 2019.
mercial Use Only and Subject to the Applicable Terms of Use
o
Te
p
e A
data from
t to 
data from
o t
erience
Subj
erience
bj
subjects
and 
subjects
have rec
y an
have rec
elopmen
Only 
elopmen
zumab e
e On
zumab e
1306
Use
1306 su
su
s in 267
l Us
s in 267
ug shipm
cial 
ug shipm
4 is est
erc
4 is esti
d S
: For Non-Comm
15
m
15 2019
mm
2019
m
2671
Com
2671 s
m
s
ose of v
n-C
ose of v
rent ver
Non
rent ver
12
o
12 mo
or N
mon
N
n
935
Fo
935 112
o
112
Fo
Property of Takeda
subject
da: 
subject
ship
eda
ship
e
e
e
m
Rational
of T
Rational
23 dat
rty o
23 dat
f T
er


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Change 6: Section 5.1.3 was updated to include the additional objective for Monitr CD testing.
The primary change occurs in Section 5.1.3 Additional Objectives.
New 
wording:

To evaluate endoscopic remission, defined as Monitr CD Endoscopic Healing 
Index (EHI) score ≤20, at Weeks 26 and 102.

To evaluate Monitr CD EHI score ≤30 or ≤50 at Weeks 26 and 102.
Rationale for Change: The primary endpoint of the study is Week 26 endoscopic remission 
which requires patients to go through a Week 26 endoscopy. Another endoscopy is required at 
Week 102 to evaluate the secondary endpoint of maintenance of remission. As a result of 
COVID-19 situation and to ensure safety of patients and hospital staff, endoscopies are not being 
performed at many sites. In order to ensure the safety of the subjects and to be able to still capture 
some relevant data on mucosal healing at Week 26 and Week 102 we are introducing the 
Monitr CD tool.
Change 7: Section 5.2.3 was updated to include endpoints for Monitr CD testing.
The primary change occurs in Section 5.2.3 Additional Endpoints.
New 
wording:

Percentage of subjects with an EHI score ≤20 at Weeks 26 and 102.

Percentage of subjects with an EHI score ≤30 at Weeks 26 and 102.

Percentage of subjects with an EHI score ≤50 at Weeks 26 and 102.

Change from baseline in EHI score at Weeks 26 and 102.
Rationale for Change: The primary endpoint of the study is Week 26 endoscopic remission 
which requires patients to go through a Week 26 endoscopy. Another endoscopy is required at 
Week 102 to evaluate the secondary endpoint of maintenance of remission. As a result of 
COVID-19 situation and to ensure safety of patients and hospital staff, endoscopies are not being 
performed at many sites. In order to ensure the safety of the subjects and to be able to still capture 
some relevant data on mucosal healing at Week 26 and Week 102 we are introducing the 
Monitr CD tool.
Change 8: Sections 7.3.1.2, 8.1.3, 9.3.6, and Appendix A footnote (s) were updated to clarify 
exacerbation of CD language.
The primary change occurs in Section 7.3.1.2 Medications for CD Exacerbation After 26 Weeks.
Initial 
wording:

A CDAI increase of >70 from the prior visit on 2 occasions separated by a 2-week 
interval and objective evidence of disease activity by colonoscopy and CRP above 
normal, OR

Fecal calprotectin >250 μg/g alone.
Amended 
or new 

A CDAI increase of >70 from the prior visit on 2 occasions separated by a 2-week 
rcial Use Only and Subject to the Applicable Terms of Use
ng
m
ng
o
pic remis
icab
pic remis
opy
pli
opy i
plic
i
y
pli
y s
ic
s re
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re
 As a re
App
 As a re
endosco
he A
endosco
and to b
o the
and to b
we are 
t to 
we are 
bl
 for Mo
Subj
 for Mo
bje
al Endpo
nd S
al Endpo
S
HI score
nly a
HI score
an EHI s
e On
an EHI s
ith an 
Use
ith an E
e
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ne in EH
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ne in EH
an
a: For Non-Commerc
mary en
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through
mm
through
seconda
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d to ens
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Non
tes. In 
iti
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a on m
or N
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eda
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of Tak
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bation o
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of T
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Ta
Property o
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o


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wording:
interval, OR

Objective evidence of disease activity by colonoscopy and CRP above normal, OR

Fecal calprotectin >250 μg/g alone.
Rationale for Change: Clarification of existing text.
Section 8.1.3 Dose and Regimen, and Section 9.3.6 Unscheduled Visits Due to Exacerbation of 
CD and Appendix A Schedule of Study Procedures also contain this change.
Change 9: Section 7.4 Adverse Event withdrawal criteria was clarified to include criteria for 
Leukopenia or Lymphopenia.
The primary change occurs in Section 7.4 Criteria for Discontinuation or Withdrawal of a Subject.
Initial 
wording:
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.

LFT Abnormalities
Study medication should be discontinued immediately with appropriate 
clinical follow-up (including repeat laboratory tests, until a subject’s 
laboratory profile has returned to normal/baseline status, see Section 9.1.20), if 
the following circumstances occur at any time during study medication 
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%).
Amended 
or new 
wording:
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.

LFT Abnormalities
Study medication should be discontinued immediately with appropriate 
clinical follow-up (including repeat laboratory tests, until a subject’s 
laboratory profile has returned to normal/baseline status, see Section 9.1.20), if 
the following circumstances occur at any time during study medication 
to the Applicable Terms of Use
rm
cerbat
ble 
cerbatioio
T
clude cr
ppli
clude cr
lic
n or Wit
the
n or Wit
he
ercial Use Only and Subject to
s experi
ct to
s experi
particip
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particip
the sub
Subj
the sub
discon
Only
discon
ding rep
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ding rep
returned
Use
returned
mstanc
al U
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da: For Non-Comm
AST >8
mer
AST >8
T or AS
Com
T or AS
ALT or
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ALT or
ULN
Non
ULN
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or
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A
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d 
k
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Property of 
w
T
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rding:
of Ta
rding:
P
a
P
da


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treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × 
ULN or international normalized ratio (INR) >1.5, or
–
ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).

Leukopenia or Lymphopenia. WBC and lymphocyte counts will be monitored 
for all subjects. Methotrexate, if applicable, should be discontinued and the 
dose of study drug held for an absolute lymphocyte count <0.5 × 109/L at any 
point in the study. The absolute lymphocyte count must be repeated at 
appropriate intervals as determined by the investigator. The next dose of study 
drug can be administered only if the absolute lymphocyte count is ≥0.5 × 
109/L. If the absolute lymphocyte count remains <0.5 × 109/L, study drug 
should be discontinued and the subject withdrawn from the study.
Rationale for Change: Patients with severe leukopenia/lymphopenia are at increased risk of 
developing infections; opportunistic and infections for which gut is a defensive barrier are 
potential risks for vedolizumab.
Change 10: Section 9.1.4 genitourinary system was removed from physical exam procedures.
The primary change occurs in Section 9.1.4 Physical Examination Procedure.
Initial 
wording:
A physical examination will consist of the following body systems: (1) eyes; (2) ears, 
nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal 
system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) 
nervous system; (10) lymph nodes; (11) genitourinary system; and (12) other. All 
subsequent physical examinations should assess clinically significant changes from 
the assessment prior to first dose examination. Additionally, abdominal mass 
assessment will be performed at all visits where CDAI is calculated.
Amended 
or new 
wording:
A physical examination will consist of the following body systems: (1) eyes; (2) ears, 
nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal 
system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) 
nervous system; (10) lymph nodes; (11) genitourinary system; and (12 11) other. All 
subsequent physical examinations should assess clinically significant changes from 
the assessment prior to first dose examination. Additionally, abdominal mass 
assessment will be performed at all visits where CDAI is calculated.
Rationale for Change: Clarification of existing text.
ercial Use Only and Subject to the Applicable Terms of Use
n >2 × 
erm
n >2 × 
 vo
ab
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able
mitin
e
in
osinoph
lica
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ounts wi
App
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Only
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n
da


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Change 11: Section 9.1.10 and Appendix A Schedule of Procedures table updated to include 
Monitr CD testing.
The primary change occurs in Section 9.1.10.4 Monitr Crohn's Disease Test.
New 
wording:
The Monitr Crohn's Disease Test is a laboratory-developed test from Prometheus Labs 
that evaluates multiple markers of mucosal damage and repair processes, regardless of 
disease location. It applies a proprietary algorithm to 13 biomarkers to produce a 
quantitative Endoscopic Healing Index Score, ranging from 0 to 100, to aid in 
distinguishing endoscopic remission from active disease in adult CD patients.
A blood sample for Monitr CD will be collected at Week 26 and Week 102 or early 
termination.
In addition, Baseline Week 0, Week 26 and Week 102 samples may be analyzed for 
subjects who have already completed those visits prior to Amendment #4. After PK 
and Immunogenicity testing are completed, any residual frozen serum aliquots from 
PK and/or Immunogenicity testing may be repurposed for this testing. These samples 
will only be used after receiving subject consent/reconsent.
Further instruction on the collection and handling of these samples can be found in the 
study Laboratory Manual.
Rationale for Change: The primary endpoint of the study is Week 26 endoscopic remission 
which requires patients to go through a Week 26 endoscopy. Another endoscopy is required at 
Week 102 to evaluate the secondary endpoint of maintenance of remission. As a result of 
COVID-19 situation and to ensure safety of patients and hospital staff, endoscopies are not being 
performed at many sites. In order to ensure the safety of the subjects and to be able to still capture 
some relevant data on mucosal healing at Week 26 and Week 102 we are introducing the 
Monitr CD tool.
Appendix A Schedule of Study Procedures also contains this change.
Change 12: Section 9.1.11 and Appendix A Schedule of Procedures table and footnote (b) 
clarified colonoscopy may be performed at Early Termination visit.
The primary change occurs in Section 9.1.11 Colonoscopy and Biopsy Procedure.
Initial 
wording:
Colonoscopy will be performed during screening and at Weeks 26 and 102. All study 
colonoscopies will be video-recorded using the Robarts Central Image Management 
Solution (CIMS). All study endoscopy videos will be subject to central review to 
ensure consistent grading. A central reviewer will confirm the SES-CD inclusion 
criterion prior to subject enrollment. Central reviewer’s grading will stand as final 
assessment for eligibility. CIMS will communicate incidental findings observed 
during central review to the investigator/study team for additional follow up.
Amended 
or new 
Colonoscopy will be performed during screening and at Weeks 26 and 102 or early 
termination. All study colonoscopies will be video-recorded using the Robarts Central 
Commercial Use Only and Subject to the Applicable Terms of Use
f
eus Lab
erm
eus Lab
egardles
Te
egardles
produce
ble 
produce
, to aid 
cab
, to aid 
CD pati
plic
CD pati
and Wee
App
and Wee
samp
to t
sample
t
le
rior to A
ect t
rior to A
esidual
bjec
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purposed
Subj
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nsent/re
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d handli
ms
int of th
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int of th
Week 26
Use
Week 26
ndpoint
ial U
ndpoint
safet
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ia
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er to ens
mer
er to ens
al
m
al h
mm
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mm
ealin
On
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a: For N
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or N
on 9.1.
oscopy
Fo
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y
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y
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ording:
of T
ording:
C
ke


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wording:
Image Management Solution (CIMS). All study endoscopy videos will be subject to 
central review to ensure consistent grading. A central reviewer will confirm the 
SES-CD inclusion criterion prior to subject enrollment. Central reviewer’s grading 
will stand as final assessment for eligibility. CIMS will communicate incidental 
findings observed during central review to the investigator/study team for additional 
follow up.
Rationale for Change: To allow for colonoscopy collection at early termination.
Appendix A Schedule of Study Procedures also contain this change.
Change 13: Section 9.1.20 approximate total blood volume was updated.
The primary change occurs in Section 9.1.20 Procedures for Clinical Laboratory Samples.
Initial 
wording:
All samples will be collected in accordance with acceptable laboratory procedures. 
The maximum volume of blood at any single visit is approximately 45.2 mL, and the 
approximate total volume of blood for the study is 464.2 mL. Details of these 
procedures, specimen handling and required safety monitoring will be given in the 
laboratory manual. 
Amended 
or new 
wording:
All samples will be collected in accordance with acceptable laboratory procedures. 
The maximum volume of blood at any single visit is approximately 45.2 45 mL, and 
the approximate total volume of blood for the study is 464.2 476 mL. Details of these 
procedures, specimen handling and required safety monitoring will be given in the 
laboratory manual. 
Rationale for Change: Blood volume updated to include Monitr CD testing.
Change 14: Table 9.a was updated to include Monitr CD biomarkers.
The primary change occurs in Table 9.a Clinical Laboratory Tests. 
New 
wording:
Monitr CD Test (biomarker panel using serum to measure hsCRP, SAA 1, CEACAM 
1, VCAM 1, ANG 1, ANG 2, IL-7, TGFα, EMMPRIN, MMP 1, MMP 2, MMP 3, and 
MMP 9)
hsCRP, high-sensitivity C-reactive protein; SAA 1, serum amyloid A 1; CEACAM1, carcinoembryonic 
antigen-related cell adhesion molecule 1: VCAM 1, vascular cell adhesion molecule 1; IL-7, interleukin-7; TGFα, 
transforming growth factor α; EMMPRIN, extracellular matrix metalloproteinase inducer; MMP, matrix 
metalloproteinase 
Rationale for Change: The primary endpoint of the study is Week 26 endoscopic remission 
which requires patients to go through a Week 26 endoscopy. Another endoscopy is required at 
Week 102 to evaluate the secondary endpoint of maintenance of remission. As a result of 
COVID-19 situation and to ensure safety of patients and hospital staff, endoscopies are not being 
performed at many sites. In order to ensure the safety of the subjects and to be able to still capture 
some relevant data on mucosal healing at Week 26 and Week 102 we are introducing the 
Monitr CD tool.
and Subject to the Applicable Terms of Use
erms
iti
r
ti
ititi onal
rm
onal
e
ca
App
Labora
o the
Labora
he
ceptable
ct to
ceptable
t is appr
bjec
t is appr
dy
S
dy i
Sub
i
y
S
y s 464
Subj
s 464
d safet
d Su
d safety
u
y
to
Use Only a
ordance
Only 
ordance
at any
On
at any si
n
si
y
n
y
of blood
Use O
of blood
of Takeda: For Non-Commercial U
ling and
l Us
ling and
y a
ol
m
olume u
mer
ume u
lul
m
lul
rc
updated
Com
updated
mm
curs in
on-C
curs in
Co
r CD Te
r No
r CD Te
VCAM 1
For 
VCAM 1
MMP 9)
a: F
MMP 9)
hsCR
eda
hsCR
ant
e
ant
No
Property o
Ratio
rty o
Ratio
wh
ert
wh
o


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Appendix A Schedule of Study Procedures also contains this change.
Change 15: Section 9.1.24 clarification of predose ADA sample collection timing.
The primary change occurs in Section 9.1.24 Anti-Drug Antibodies Sampling.
Initial 
wording:
Blood samples for ADA assessments for vedolizumab will be obtained on Day 1 and 
within 30 minutes prior to dosing at the time points indicated in the Schedule of Study 
Procedures (Appendix A).
Blood samples for ADA assessments for adalimumab will be obtained on Day 1 and 
within 30 minutes prior to vedolizumab dosing at the time points indicated in the 
Schedule of Study Procedures (Appendix A).
Amended 
or new 
wording:
Blood samples for ADA assessments for vedolizumab will be obtained on Day 1 and 
within 30 minutes prior to dosing at the time points indicated in the Schedule of Study 
Procedures (Appendix A).
Blood samples for ADA assessments for adalimumab will be obtained on Day 1 and 
within 30 minutes prior to vedolizumab dosing at the time points indicated in the 
Schedule of Study Procedures (Appendix A).
Rationale for Change: Clarification of existing text.
Change 16: Section 9.1.27.3 correction of reason for use of barrier methods (b).
The primary change occurs in Section 9.1.27.3 Definitions and Procedures for Contraception and 
Pregnancy Avoidance.
Initial 
wording:
b) Reasons for use of barrier methods (ie, condom) in males with pregnant partners.
Amended 
or new 
wording:
b) Reasons for use of barrier methods (ie, condom) in males with pregnant female 
partners of childbearing potential.
Rationale for Change: Clarification of existing text.
Change 17: Appendix A Schedule of Procedures table and footnote (j) were updated to clarify 
pregnancy testing for Q4 dosing.
The primary change occurs in Appendix A Schedule of Study Procedures.
Initial 
wording:
(j) Women of childbearing potential only. When site visits shift from every 4 weeks to every 8 weeks, women of 
childbearing potential will need to take a home pregnancy test every other month (in between visits) up until Week 
58 and report the results to the site. 
Amended 
or new 
wording:
(j) Women of childbearing potential only. When site visits shift from every 4 weeks to every 8 weeks, women of 
childbearing potential will need to take a home pregnancy test every other month (in between visits) up until Week 
58 and report the results to the site. If the subject experiences an exacerbation and switches to Q4W dosing, then no 
home pregnancy test is required as subject will have urine pregnancy test performed on site before infusion.
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Vedolizumab IV
Vedolizumab-4006
Page 132 of 132
Protocol Incorporating Amendment No. 04
30 June 2020
Rationale for Change: Clarification of existing text.
Change 18: Appendix A Schedule of Procedures footnote (a) was updated to clarify weight 
measurement visits.
The primary change occurs in Appendix A Schedule of Study Procedures.
Initial 
wording:
(a) Height collected only at the screening visit.
Amended 
or new 
wording:
(a) Height collected only at the screening visit. Weight will be measured at every site visit where CDAI is 
calculated.
Rationale for Change: Clarification of existing text.
the Applicable Terms of Use
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sit where
plic
sit where
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Property of Takeda: For Non-Commercial Use Only and Subject to th
th
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680de44f5
Amendment 04 to An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Triple Combination
Therapy With Vedolizumab IV, Adalimumab SC, and Oral Methotrexate in Early Treatment of Subjects with
Crohn’s Disease Stratified at Higher Risk for Developing Complications
Medical Affairs Approval
01-Jul-2020 21:42 UTC
Biostatistics Approval
02-Jul-2020 15:38 UTC
PPD
ble Terms of Use
e Te
ate 
T
ate 
ble T
HH:mm ‘U
ble 
HH:mm ‘U
Ter
plicable
ble
2 UTC
able
2 UTC
Property of Takeda: For Non-Commercial Use Only and Subject to the App
20 15:38 
pli
20 15:38