Conditions: Crohn Disease
Keywords: Drug Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
The main aim is to see if TAK-018 reduces the recurrence of intestinal inflammation after abdominal resection surgery in adults with Crohn's disease.

Participants will take either TAK-018 or placebo tablets by mouth, 2 times each day for up to 26 weeks after surgery. The placebo looks like TAK-018 but will not have any medicine in it.

Participants will have 6 study visits while receiving treatment. Visits 1 and 6 will be conducted at the study clinic. The others can be in the clinic or at the participant's home. Follow-up will occur 4 weeks after final treatment.

Detailed description:
The drug being tested in this study is called TAK-018 (Sibofimloc). TAK-018 is used for the prevention of postoperative CD recurrence. This study will evaluate the efficacy of TAK-018 in reducing endoscopic recurrence of intestinal inflammation in postoperative participants with CD after planned laparoscopic ileocecal resection with primary anastomosis.

The study will enroll approximately 96 participants. Participants will be randomly assigned (by chance, like flipping a coin) in 1:1:1 ratio to one of the three treatment groups-which will remain undisclosed to the participants and study doctor during the study (unless there is an urgent medical need):

* TAK-018 0.30 g Low dose
* TAK-018 1.5 g High dose
* Placebo

All participants will be asked to take the tablets twice daily immediately after a meal (that is, breakfast and dinner) with water, approximately 8 to 12 hours apart.

Participants will have flexibility to either to opt for home health care (HHC) solutions at Screening, Week 3, Week 6, Week 12, Week 18 and Week 30 or travel to the clinic for all scheduled visits per protocol as permitted by local regulations. This flexible approach is designed in response to health care delivery challenges presented by the coronavirus disease (COVID-19) pandemic and to provide additional flexibility during the course of the trial. Assessments after surgery and endoscopy at Week 26 will be conducted at the clinic. All other study visits may be conducted by telehealth and home health care (HHC).

This multi-center trial will be conducted in the United States, United Kingdom, France, Austria and Germany. The overall time to participate in this study is approximately 34 weeks. Participants will make final visit to the clinic or can opt for HHC visit at Week 30 (30 days after the Week 26 endoscopy) for safety follow-up.

Arms:
arm 1: TAK-018 placebo-matching tablets, orally, twice daily (BID) for up to 27.7 weeks. arm 2: TAK-018 0.30 gram (g), tablets, orally, BID for up to 31.7 weeks. arm 3: TAK-018 1.5 g, tablets, orally, BID for up to 26.1 weeks.

Interventions: intervention 1: TAK-018 intervention 2: TAK-018 Placebo
Intervention descriptions: intervention 1: TAK-018 immediate-release tablets. intervention 2: TAK-018 placebo-matching tablets.

Protocol document:
Prot_000.pdf: 
For non-commercial use only


 
 
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 2a Study to Evaluate 
the Safety, Tolerability, and Early Proof of Concept of TAK-018 for the Prevention of 
Postoperative Crohn’s Disease Recurrence
TAK-018 for Prevention of the Recurrence of Postoperative Crohn’s Disease
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA USA 02421
Study Number:
TAK-018-2001
IND Number:
137694
EudraCT Number:
2019-000886-19
Compound:
TAK-018 (Sibofimloc)
Date:
08 October 2021
Amendment Number:
05
Amendment History:
Date
Amendment Number
Amendment Type
Region
01 March 2019
Initial Protocol
Not applicable
Global
02 July 2019
Amendment 01
Substantial
Global
05 December 2019
Amendment 02
Nonsubstantial
France
14 January 2020
Amendment 03
Substantial
Global
30 July 2020
Amendment 04
Substantial
Global
08 October 2021
Amendment 05
Substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are in 
the study manual. 
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
prescribing information, and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator. (Appendix G)
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix I of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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1.3
Protocol Amendment No. 05 Summary and Rationale
This section describes the changes to the protocol incorporating Amendment 05. The primary 
reason for this amendment is to update the legal entity to Takeda Development Center Americas, 
Inc. and to update its address. In addition, study signatories have been updated to align with 
changes in study personnel, and the International Nonproprietary Name (INN) “sibofimloc” has 
been added.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
Protocol Amendment 05
Summary of Changes Compared With TAK-018-2001 Amendment 04
Description of Each Change and Rationale
Section(s) Affected by Change
Description
Rationale 
1
Identification of the legal entity.
To clarify that the legal entity has 
changed.
Title page, Sponsor
2
Updates to the study signatories. To identify changes in study 
personnel. 
Section 1.2 Approval
3
Addition of the INN: sibofimloc. To include the INN nomenclature. Title page, Compound
Section 2.0 STUDY SUMMARY
4
Changes in Appendix J
To be compliant with process, 
updated this appendix to 
accurately capture and reflect 
protocol history. 
Appendix J, Protocol History
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment No. 05 Summary and Rationale................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Principal Investigator...............................................................................................15
3.3
List of Abbreviations ...............................................................................................16
3.4
Corporate Identification...........................................................................................17
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.1.1
Disease Under Study........................................................................................18
4.1.2
Investigational Medicinal Product (Study Drug) ..............................................19
4.2
Rationale for the Proposed Study.............................................................................19
4.3
Benefit/Risk Profile .................................................................................................20
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................22
5.1
Objectives................................................................................................................22
5.1.1
Primary Objective............................................................................................22
5.1.2
Safety Objective ..............................................................................................22
5.1.3
Secondary Objectives ......................................................................................22
5.1.4
Exploratory Objectives ....................................................................................22
5.2
Endpoints.................................................................................................................22
5.2.1
Primary Endpoint.............................................................................................22
5.2.2
Safety Endpoint ...............................................................................................22
5.2.3
Secondary Endpoints .......................................................................................23
5.2.4
Exploratory Endpoints .....................................................................................23
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................23
6.1
Overview of Study Design.......................................................................................23
6.2
Justification for Study Design Components..............................................................26
6.2.1
Subject Population...........................................................................................26
6.2.2
Sample Size.....................................................................................................26
6.2.3
Study Drug Dose .............................................................................................26
6.2.4
Duration of Study ............................................................................................26
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6.2.5
Endpoints ........................................................................................................27
6.3
Premature Termination or Suspension of Study or Study Site...................................27
6.3.1
Criteria for Premature Termination or Suspension of the Study........................27
6.3.2
Criteria for Premature Termination or Suspension of Study Sites.....................27
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of the Study Sites ........................................................................28
7.0
STUDY POPULATION................................................................................................28
7.1
Inclusion Criteria .....................................................................................................28
7.2
Exclusion Criteria ....................................................................................................29
8.0
STUDY DRUG/CLINICAL STUDY MATERIAL MANAGEMENT...........................31
8.1
Study Drug Administration......................................................................................31
8.1.1
TAK-018 or Matching Placebo ........................................................................31
8.1.1.1
TAK-018 Investigational Drug Product ...................................................31
8.1.1.2
Matching Placebo ....................................................................................31
8.1.1.3
Storage of Study Drug .............................................................................32
8.1.2
Dose and Regimen...........................................................................................32
8.2
Treatment Assignment and Dispensing Procedures ..................................................32
8.3
Excluded Concomitant Medications and Procedures While On-study.......................32
8.4
Permitted Concomitant Medications and Procedures................................................33
8.5
Precautions and Restrictions ....................................................................................33
8.5.1
Reproductive Effects........................................................................................33
8.6
Management of Clinical Events ...............................................................................34
8.6.1
Liver Test Abnormalities .................................................................................34
8.6.2
Vomiting .........................................................................................................34
8.6.3
Recurrence of CD ............................................................................................34
8.7
Unblinding Procedure..............................................................................................34
8.8
Accountability and Destruction of Sponsor-Supplied Drugs.....................................35
9.0
STUDY CONDUCT......................................................................................................36
9.1
Study Personnel and Organizations..........................................................................36
9.2
Informed Consent and Screening .............................................................................36
9.2.1
Informed Consent Procedure............................................................................36
9.2.2
Screening.........................................................................................................36
9.3
Study Procedures.....................................................................................................37
9.3.1
Inclusion/Exclusion Criteria.............................................................................37
9.3.2
Randomization and Enrollment........................................................................37
9.3.3
Demographics and Medical History.................................................................37
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10.1.1
SAEs ...............................................................................................................48
10.1.2
Overdose .........................................................................................................49
10.2
AE Procedures.........................................................................................................50
10.2.1
Assigning Severity of AEs...............................................................................50
10.2.2
Assigning Causality of AEs .............................................................................50
10.2.3
Collection and Reporting of AEs, SAEs, Overdose, and Abnormal Liver Test 
Results.............................................................................................................50
10.2.3.1
Collection Period.....................................................................................50
10.2.3.2
Reporting SAEs.......................................................................................51
10.2.3.3
Reporting Overdose.................................................................................52
10.2.3.4
Reporting of Abnormal Liver Test Results and Other Laboratory Test 
Abnormalities..........................................................................................52
10.2.3.5
Reporting Pregnancy ...............................................................................52
10.3
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........52
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................53
12.0
DATA HANDLING AND RECORDKEEPING............................................................53
12.1
eCRFs......................................................................................................................53
12.2
Record Retention .....................................................................................................54
13.0
STATISTICAL METHODS..........................................................................................54
13.1
Statistical and Analytical Plans ................................................................................54
13.1.1
Analysis Sets ...................................................................................................54
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................55
13.1.3
Efficacy Analysis.............................................................................................55
13.1.4
PK Analysis.....................................................................................................55
13.1.5
.............................................................................56
13.1.6
...............................................................56
13.1.7
Safety Analysis................................................................................................56
13.2
Interim Analysis ......................................................................................................56
13.3
Determination of Sample Size..................................................................................57
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................57
14.1
Study-Site Monitoring Visits ...................................................................................57
14.2
Protocol Deviations..................................................................................................57
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................58
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................58
15.1
IRB and/or IEC Approval ........................................................................................58
15.2
Subject Information, Informed Consent, and Subject Authorization .........................59
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15.3
Subject Confidentiality ............................................................................................60
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................60
15.4.1
Publication and Disclosure...............................................................................60
15.4.2
Clinical Trial Registration................................................................................61
15.4.3
Clinical Trial Results Disclosure......................................................................61
15.5
Insurance and Compensation for Injury....................................................................62
16.0
REFERENCES..............................................................................................................62
LIST OF IN-TEXT TABLES
Table 8.a
TAK-018 Dose and Regimen .............................................................................32
Table 9.a
Clinical Hematology, Chemistry, and Liver Tests ..............................................40
Table 9.b
Clinical Urinalysis Tests ....................................................................................41
Table 10.a
Takeda Medically Significant AE List by System Organ Class...........................49
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of TAK-018-2001 Study Design........................................................25
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................66
Appendix B
Schedule of PK Samples ....................................................................................70
Appendix C
Rutgeerts Grading Scale for Endoscopic Recurrence at the Ileocolonic 
Anastomosis and Preanastomotic Ileum .............................................................71
Appendix D
Guidance on Liver Test Abnormality Monitoring, Evaluation, and Follow-up....72
Appendix E
................................................................................................................76
Appendix F
............................................................................77
Appendix G
Responsibilities of the Investigator.....................................................................78
Appendix H
Elements of the Subject Informed Consent.........................................................80
Appendix I
Investigator Consent to Use of Personal Information..........................................83
Appendix J
Protocol History.................................................................................................84
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center Americas, Inc.
Compound:
TAK-018 (Sibofimloc)
Title of Protocol: A Randomized, Double-Blind, 
Placebo-Controlled, Multicenter, Phase 2a Study to 
Evaluate the Safety, Tolerability, and Early Proof of 
Concept of TAK-018 for the Prevention of Postoperative 
Crohn’s Disease Recurrence
IND No.: 137694
EudraCT No.: 
2019-000886-19
Study Number: TAK-018-2001
Phase: 2a
Study Design:
This is a randomized, placebo-controlled, double-blind study of TAK-018 (INN: sibofimloc; previously known as 
EB8018) in approximately 96 postoperative subjects with Crohn’s disease (CD) who are undergoing a planned 
laparoscopic ileocecal resection with primary anastomosis. Of note, the laparoscopic ileocecal resection is not 
considered a study procedure and should be completed per institutional standard of care. All eligible subjects will be 
randomized 1:1:1 to either TAK-018 low dose (0.30 g taken twice daily [BID]), TAK-018 high dose (1.5 g taken 
BID), or placebo (BID) for a 26-week treatment period. Randomization will be stratified by smoking status (active 
smoker vs nonsmoker/previous smoker). Subjects will receive the first dose of study drug on Day 1 (D1, within 
72 hours after surgery) administered twice daily immediately after a meal (ie, breakfast and dinner) with water, 
approximately 8 to 12 hours apart. Subjects will have study visits at Week 3 (W3), Week 6 (W6), Week 12 (W12), 
Week 18 (W18), and Week 26 (W26), with a final study visit at Week 30 (W30), 30 days after the W26 endoscopy. 
Study visits at D1 and W26 are clinic visits; study visits at screening, W3, W6, W12, W18, and W30 may be
conducted as clinic or home health care (HHC) visits to provide flexibility to subjects. 
Blood samples will be collected presurgery and at all scheduled study visits after dosing starts to characterize disease 
progression, response to study drug, safety parameters, and the pharmacokinetics (PK) of TAK-018. Subjects will also 
provide stool samples before surgery during the screening period and at W3, W6, W12, W18, W26, and W30. Fecal 
calprotectin will be measured before surgery during the screening period and in every stool collection. Endoscopic 
assessments will be performed at the end of the 26-week treatment period (ie, W26 clinic visit). Intestinal resection 
tissue will be collected at surgery and biopsies of the neoterminal ileum will be performed at W26. Subjects who 
relapse clinically or endoscopically (Rutgeerts score ≥i2) during the study will discontinue study drug, receive 
institutional standard of care, attend an early termination visit 30 days after their last dose of study drug, and be 
discontinued from the study. The end of study visit will occur at W30 or, for subjects who discontinue early, will occur 
30 days after their last dose of study drug.
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Number of Subjects:
Estimated total approximately () 96 subjects:
Placebo: 32 subjects
TAK-018 low dose: 32 subjects
TAK-018 high dose: 32 subjects
Number of Sites: 
Approximately 40 sites globally.
Dose Level(s):
TAK-018 at 2 doses:
Low: 0.30 g per dose taken BID
High: 1.5 g per dose taken BID
Placebo BID
Route of Administration:
TAK-018: oral
Placebo: oral
Duration of Treatment:
26 weeks of BID dosing
Period of Evaluation:
30 day screening period, 26 weeks of treatment with 
study visits on W3, W6, W12; W18, W26, and W30.
Total Duration of Study:
An individual subject’s participation is up to 34 weeks (4-week screening period, 26-week treatment period, 4-week 
safety follow-up) with the global study duration of approximately 2 to 3 years.
Main Criteria for Inclusion:
1.
Male or female subject aged ≥18 years or local legal age at signing of informed consent
2.
Subject has a documented diagnosis of CD confirmed by endoscopic biopsy before resection or by tissue obtained 
at resection.
3.
Subject is planned to undergo laparoscopic ileocecal resection with primary anastomosis within 72 hours before 
randomization (D1). Confirmation that no active disease has been left behind after resection will be based on the 
surgeon’s documentation in the operative report.
4.
Subject with postoperative discontinuation of all concomitant medications related specifically to the treatment of 
CD. This includes anti-tumor necrosis factor and anti-integrin therapy, anti-IL 12/23, thiopurines and other 
immunomodulators, steroids, 5-aminosalicylates, and prophylactic use of antibiotics for the prevention of 
postoperative recurrence such as metronidazole.
5.
Subject has resumed oral intake and is capable of swallowing tablets within 72 hours after surgery.
6.
If female of child-bearing potential, subject must agree to comply with the contraception requirements.
7.
A male subject who is nonsterilized and sexually active with a female partner of child-bearing potential must 
agree to comply with protocol-defined contraception requirements.
Main Criteria for Exclusion:
1.
Subject has active perianal CD.
2.
Subject has had >3 previous surgical procedures for CD.
3.
Subject has macroscopically active CD that was not resected at the time of surgery as documented in the 
surgeon’s operative report.
4.
Subject with small bowel resection that exceeds 100 cm or a subject who is considered at risk for short bowel 
syndrome.
5.
Subject has any significant intraoperative or postoperative complications such as anastomotic leak, surgical site 
infection, or inability to tolerate oral intake. 
6.
Subject is unable or unwilling to undergo or has contraindications to ileocolonoscopic procedures as assessed by 
the investigator. 
7.
Subject has inadequate renal or hepatic function postsurgery and before the first dose of study drug on the basis of 
one of the following laboratory parameters: total bilirubin >1.5× the institutional upper limit of normal (ULN) 
unless subject has known Gilbert’s syndrome that can explain the elevation of bilirubin, serum alanine 
aminotransferase >3× the institutional ULN, creatinine >1.5× the institutional ULN or estimated creatinine 
clearance <50 mL/minute/1.73 m2 for subjects with serum creatinine concentrations above institutional limits.
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Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is the percentage of subjects with endoscopic recurrence of CD at W26. 
Endoscopic recurrence is defined as Rutgeerts score ≥i2 (i2, i3, i4). 
Safety endpoints are measured from the administration of the first dose of study drug through 30 days after the last 
dose of study drug. Safety endpoints will include the percentage of subjects who experience treatment-emergent 
adverse events (TEAEs), serious adverse events (SAEs), and/or clinically significant changes in vital signs, standard 
laboratory tests and procedures (eg, clinical chemistry, hematology, urinalysis). 
Secondary endpoints for this study are: fecal calprotectin (FCP) >135 µg/g at W3, W6, W12, W18, W26, and W30; 
and observed plasma trough concentrations of TAK-018 at W3. 
Statistical Considerations:
The study endpoints will be analyzed using the full analysis set (FAS) that contains all randomized subjects who 
receive at least 1 dose of study treatment. 
Primary Efficacy Analysis: The proportion of subjects with endoscopic recurrence of CD at W26 in each of the 
2 TAK-018 dose arms will be compared to placebo using the Cochran-Mantel-Haenszel (CMH) test stratified by 
smoking status at randomization. The point estimates for the treatment difference (TAK-018 – placebo) for each of the 
2 dose levels, along with the 80% and 95% confidence intervals (CI) will be presented.
Secondary 
 Analyses: Continuous longitudinal endpoints will be analyzed using a mixed-effect model 
repeated measures (MMRM) model to compare each dose of the TAK-018 arms to the placebo arm. Continuous 
endpoints measured at a single time point will be analyzed using an ANCOVA model. Binary endpoints will be 
analyzed using the methodology used for the primary efficacy endpoint. 
Safety Analysis: The percentage of subjects with TEAEs and/or SAEs will be summarized descriptively by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class and preferred terms, by severity, and by 
relationship to study drug for each treatment arm.
Change from baseline in clinical laboratory tests and vital signs will be summarized descriptively by treatment arm 
and by visit. Subjects with markedly abnormal values for laboratory tests and vital signs will be summarized and 
listed.
Sample Size Justification: 
This study is planned to randomize approximately 96 subjects in a 1:1:1 ratio to each of the 3 treatment arms (2 active, 
1 placebo, approximately 32 subjects per arm).
Assuming the true recurrence rate in the placebo arm to be 50%, a total of 81 subjects will provide at least 75% power 
to detect a 25% or larger difference in recurrence rates between treatment and placebo arms for a 2-sided chi-squared 
test at a 0.2 level of significance. To account for an assumed dropout rate of 15%, approximately 96 subjects will be 
randomized in this study. 
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical study supplier list or equivalent. The vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal 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 and the study drug, their expertise in the therapeutic area and the conduct of clinical 
research, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
Acronym
Definition
AE
adverse event
AIEC
adherent-invasive Escherichia coli
ALT
alanine aminotransferase
anti-TNF-
anti-tumor necrosis factor-alpha
AST
aspartate aminotransferase
AUCt
plasma area under the concentration-time curve from administration to last observed 
concentration at time t
BID
twice daily
CD
Crohn’s disease
CEACAM6
carcinoembryonic antigen-related cell-adhesion molecule 6
CFR
Code of Federal Regulations
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
COVID-19
coronavirus disease 2019
CRO
contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
D1
Day 1
EB8018
former name of the investigational agent also known as TAK-018
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
ET
early termination
FCP
fecal calprotectin
FDA
Food and Drug Administration
FAS
full analysis set
FimH
adhesin portion of type 1 fimbriae (mediates attachment to mucosal epithelial surfaces)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GP2
glycoprotein
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HED
human equivalent dose
HHC
home health care
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
IL
interleukin
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Acronym
Definition
IMP
investigational medicinal product
INN
International Nonproprietary Name
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology system
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MMRM
mixed-effect model repeated measures
MOA
mechanism of action
NOEL
no-observed effect level
NOAEL
no-observed adverse effect level
PI
principal investigator
PK
pharmacokinetics
PO
orally
QD
once daily
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SOE
schedule of events
TEAE
treatment-emergent adverse event
TNF-
tumor necrosis factor-alpha
ULN
upper limit of normal
UK
United Kingdom
US
United States
VAS
visual analog score
W3
Week 3
W6
Week 6
W12
Week 12
W18
Week 18
W26
Week 26
W30
Week 30
3.4
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
4.1.1
Disease Under Study
Crohn’s disease (CD) is a chronic, relapsing inflammatory disease of the gastrointestinal tract with 
no known cure. Its incidence globally is on the rise, reaching 20 per 100,000 person-years in 
Western countries [1]. A third of patients with CD will require a major abdominal resection within 
5 years after diagnosis, and up to 60% of patients within a decade [2,3]. Up to 70% of patients who 
undergo resection develop postoperative endoscopic recurrence within 1 year, and one third need 
repeat surgery within 10 years [4-6]. 
The pathophysiology of CD relies on a complex interaction of host genetics, the microbiome and 
inflammatory responses [7,8]. Significant human gut commensal community functional 
breakdown or dysbiosis is observed in CD [9,10]. Genome-wide association study (GWAS) 
results in CD underscore the theme of aberrant host-microbiome interactions, specifically 
ineffective pathogen clearance from the mucosa because of genetic defects in bacterial pattern 
recognition (Nod2) and in autophagy [11]. Chronic immune stimulation by bacterial antigens is 
well established as patients with CD have detectable antibodies to bacterial cell constituents such 
as OmpC and Flagellin, with higher titers of antibodies being associated with a more severe 
“complicated” disease phenotype [12]. The question that arises is whether immune recognition of 
proteobacteria is causative for inflammation in CD or is it a secondary phenomenon due to 
mucosal barrier disruption? Recent evidence shows that antibacterial antibodies can be detected in 
serum of patients with CD several years before clinical symptoms and diagnosis, supporting the 
hypothesis of an initial bacterial insult that triggers inflammation [13]. In addition, metagenomic 
approaches coupled with classic culture microbiology from mucosal biopsies from the terminal 
ileum of patients with Crohn’s ileitis support the case for proteobacteria as pathobionts in CD [10].
The specific association of Escherichia coli with invasive properties, termed adherent-invasive 
Escherichia coli (AIEC), with CD was first reported by Darfeuille-Michaud et al [14,15]. Since 
then, AIEC have been isolated from multiple independent studies involving adult and pediatric 
patients with CD. Using the multi-component definition of Darfeuille-Michaud et al [16], the 
reported prevalence of AIEC in the literature varies from approximately 36% to over 90% in 
patients with CD when evaluating mucosa-associated and intracellular E coli [17]. 
AIEC are distinct from other strains of E coli because they show non-classic virulence factors of 
adherence and invasion. In particular, AIEC are able to survive and replicate in intestinal epithelial 
cells and macrophages, thereby stimulating the production of inflammatory cytokines such as 
tumor necrosis factor-alpha (TNF-α) [18]. The interaction between AIEC and the intestinal 
epithelial cells is primarily mediated by the FimH adhesin located at the tip of type 1 pili present on 
the bacterial surface [19].
Although type 1 pili genes are present in the genomes of all E coli, AIEC strains specifically 
express FimH adhesin and variants that allow them to more efficiently bind to mannose [20]. 
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These mechanisms set the stage for a selective over-colonization of the epithelium by AIEC and 
subsequent biofilm formation [21]. The type 1 pili interact with glycoproteins such as 
carcinoembryonic antigen-related cell-adhesion molecule 6 (CEACAM6) on intestinal epithelial 
cells [22,23], TLR4 on immune cells [24], and glycoprotein (GP2) on intestinal M cells [25,26] in 
a mannose-dependent manner. CEACAM6 and TLR4 receptors are upregulated by inflammatory 
cytokines in patients with CD with ileal disease [27]. The binding of FimH to TLR4 induces the 
production of TNF-α, interleukin (IL)-6 and IL-8 in the gut, independently of lipopolysaccharide 
(LPS). Additionally, FimH binding to GP2 on the surface of M cells in the Peyer’s patches allow 
AIEC to enter into the lamina propria. The subsequent phagocytosis of the AIEC by the 
macrophages further contributes to the chronic production of TNF-α. A vicious cycle of 
proinflammatory cytokine release is produced by the TNFα-driven overexpression of CEACAM6 
and increase in M-cell development [28]. Thus, FimH appears as a critical factor both in the 
production of pro-inflammatory cytokines from the gut epithelium and in the invasion of the 
lamina propria [25,29,30].
4.1.2
Investigational Medicinal Product (Study Drug)
TAK-018 
(1-(2,7-bis(((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxylmethyl)tetrahydro-2H-pyran-2-yl) 
ethynyl)spiro[fluorene-9,4ʹ-piperidin]-1ʹ-yl)ethan-1-one), previously known as EB8018, is a 
first-in-class FimH blocker being developed for the treatment of CD that blocks FimH-mediated 
binding to mannose and can aggregate FimH-expressing bacteria and facilitate their clearance. 
TAK-018 is comprised of 2 mannoside residues held together by a chemically inert linker. These 
mannosides efficiently compete for binding with mannose residues such as those found on 
glycosylated proteins like CEACAM6 and GP2. Furthermore, because of its “bi-valent” nature, 
TAK-018 can bind a FimH receptor on 1 bacterial cell, and another FimH on a different bacterial 
cell at the same time resulting in the enchaining of several bacterial cells together [31]. This leads 
to the “clumping” of the bacteria within the lumen, enabling their clearance from the gut lumen 
[32]. In addition to facilitating clearance, the clumping process may significantly slow or prevent 
the penetration of FimH-expressing bacteria into the mucus layer and the intestinal epithelium. As 
a result, binding and activation of receptors such as TLR4, CEACAM6 and GP2, that contribute to 
the inflammation in the gut of patients with CD, are attenuated. Enterome’s translational 
MOBIDIC study (clinicaltrials.gov/ct/show/NCT02882841; accessed 07January 2019) showed 
that a majority (61%, 74 of 111) of patients with CD with ileitis had invasive/adherent 
proteobacteria that could be cultured from mucosal biopsies and aggregated in the presence of 
TAK-018 [33]. 
4.2
Rationale for the Proposed Study
As most patients with CD eventually require an intestinal resection, postoperative recurrence 
poses a significant burden to the CD population. Disease recurrence on the histological level is 
observed within days after ileocolonic anastomosis [34]. Most CD therapies, such as probiotics, 
aminosalicylates, thiopurines, steroids, antibiotics, and biologics, have yielded either negative or 
equivocal results in terms of preventing relapse. Because of its unique mechanism of action 
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(MOA), TAK-018 should block the pathobiont entry underlying chronic inflammation and bowel 
wall damage observed in patients with CD. This MOA is distinct from the conventional approach 
of neutralizing inflammatory mediators such as TNF-and IL-23, thereby allowing patients with 
CD to maintain remission without lifelong immune suppression.
The purpose of this phase 2a, randomized, multicenter, double-blind study is to evaluate the safety, 
tolerability, and early proof of concept of TAK-018 for the prevention of postoperative CD 
recurrence.
4.3
Benefit/Risk Profile 
TAK-018 is a first-in-class investigational medical product (IMP) and has no known class effects. 
Nonclinical studies with TAK-018 have been conducted in rats, rabbits, and dogs. In the 14-day 
toxicity study in rats, TAK-018 was administered subcutaneously (SC) for 14 days at 40, 100, 400 
mg/kg/day. Transient clinical signs (skin swelling of head/ears/limbs likely related to histamine 
release; reddish discoloration of extremities), observed during the first 3 days of treatment and 
intermittently up to Day 8 in males at 100 and 400 mg/kg/day and in females at 400 mg/kg/day, 
resolved despite continued dosing. Increased histamine levels were also reported in the 400 
mg/kg/day treatment group that indicated a possible pseudo-allergic reaction. These clinical signs 
were not observed in rabbits or dogs. 
TAK-018 showed no evidence effects on embryo-fetal development studies in rats or rabbits dosed 
SC from Gestation Days 6 to 17 at doses up to 1000 mg/kg, with the exception of maternal toxicity 
in rabbits where the no-observed-adverse-effect level (NOAEL) was 300 mg/kg. There was no 
evidence or potential for teratogenicity.
In addition, TAK-018 showed no stimulatory effect on human mucosal mast cells in an in vitro 
study. Therefore, the swelling and discoloration observed in the 14-day rat study are likely related 
to rodent-specific histamine release resulting from high local concentration after SC 
administration.
TAK-018 was administered SC (50, 150, 300 mg/kg/day) and orally ([PO]; 200, 600, and 
2000 mg/kg/day) and SC (400 mg/kg/day) in the 12-week and 13-week rat toxicity studies, 
respectively. Similar transient clinical signs (ie, pseudo-allergic reactions) were observed after SC 
administration in the 12-week study and in the 13-week study (400 mg/kg/day SC group only) as 
were noted in the 14-day rat toxicity study. The NOAEL was established at 300 mg/kg/day for SC 
and 2000 mg/kg/day for PO. 
In the 400 mg/kg/day SC group, minimal to moderate tubular degeneration in the kidneys of male 
rats was observed that was considered to be adverse. This finding showed no correlation to clinical 
laboratory values and was not observed in any other species or in any other rat study at any other 
dose and is therefore considered to be likely of low toxicologic significance. The male-only 
occurrence suggests that this could be part of spontaneous rat nephropathy that is more frequently 
seen in male rats. These findings are likely to be of low clinical significance. Urinalysis will be 
done at baseline and each study visit and abnormalities will be treated per routine standard of care. 
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In the 14-day toxicity study in dogs, TAK-018 administered PO twice daily ([BID]; 100, 300, 
1000 mg/kg) was well tolerated and did not result in any signs of overt toxicity. The no-observed 
effect level (NOEL) for TAK-018 was 2000 mg/kg/day.
The NOEL, derived from 14-day rat SC (most sensitive species), was 40 mg/kg for males and 100 
mg/kg for females. The estimated human equivalent dose (HED) was 387 mg (40 mg/kg [NOEL in 
14-day rat SC] /6.2 [rat conversion factor] = 6.45 mg/kg × 60 kg human = 387 mg). A 10-fold 
safety factor was applied to the HED to obtain the maximum starting dose of 38.7 mg. Considering 
the expected lower bioavailability in humans compared to rats used in the HED calculation, 50 mg 
was used as the starting dose in the single ascending dose (SAD) part of the first study in healthy 
volunteers. 
The phase 1a study EBFIM116 in healthy volunteers included 2 parts: SAD of 50, 250, 750, 1500, 
and 3000 mg or placebo, and multiple ascending doses of 750 and 1500 mg, or placebo 
administered PO BID for 14 days. The safety data suggested that oral TAK-018 up to 1500 mg 
BID for 14-days was well-tolerated: no subjects discontinued treatment, adverse events (AEs) 
were of mild intensity, and no serious adverse events (SAEs) were reported. Consistent with 
nonclinical data, there was low plasma exposure in phase 1a, suggesting low bioavailability of 
TAK-018 in healthy volunteers when administered capsules PO. The geometric mean terminal 
half-life ranged from 12.63 to 45.63 hours over the SAD range of 50 to 3000 mg. 
In the 12-week toxicity study in dogs (TAK-018 dosed PO [300 and 1000 mg/kg/day] and SC [10, 
20, and 40 mg/kg/day]), the NOAEL was identified as 40 mg/kg once daily (QD) SC with a 
corresponding average plasma area under the concentration-time curve from time 0 to 24 hours 
(AUC0-24hr) at the end of treatment of 102,739 ng*h/mL. Using this value from the dog toxicity 
study (the higher species), the estimated safety margin exceeded 100-fold the plasma exposure in 
healthy volunteers. 
In the chronic 39-week toxicity study in dogs (TAK-018 dosed PO [600 and 2000 mg/kg/day] and 
SC [10, 20, and 40 mg/kg/day]), the NOAEL was identified as 40 mg/kg QD SC with a 
corresponding average plasma area under the concentration-time curve from administration to last 
observed concentration at time t (AUCt) at the end of treatment (Week 39) of 115,044 ng*h/mL. In 
addition, in the chronic 26-week toxicity study in rats (TAK-018 dosed PO [600 and 2000 
mg/kg/day] and SC [50, 150, and 300 mg/kg/day]), the NOAEL was identified as 300 mg/kg QD 
SC with a corresponding average plasma AUCt at the end of treatment (Week 26) of 112,313 
ng*h/mL. These exposure values in the chronic studies (dog and rat) support the previously 
estimated safety margins in healthy volunteers.
In the phase 1b study EBFIM117 in subjects with active CD, TAK-018 tablets are administered 
PO (1.5 g BID) for 13 days. Preliminary observations from the first 6 subjects confirmed that the 
study drug is well tolerated with no SAEs reported nor study drug discontinuations. The 
preliminary exposure data from the first 4 subjects in this study suggested that the average 
systemic exposure of TAK-018 in subjects with active CD was approximately 2 to 5-fold higher 
with more variability than that observed in healthy subjects. Safety margins, re-evaluated based on 
the exposure data in subjects with active CD, still exceed 10-fold, supporting the highest dose of 
3.0 g daily to be administered in the current study.
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As a first-in-class IMP and because TAK-018 has been administered to only a small number of 
human subjects, the types of AEs that may be observed in this phase 2a study are not known. The 
phase 2a study will include routine monitoring for AEs and SAEs. Currently there are no identified 
or potential risks associated with TAK-018 treatment based on the evidence from two phase 1 
clinical studies and toxicology studies.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective 

To evaluate the efficacy of TAK-018 in reducing endoscopic recurrence of intestinal 
inflammation in postoperative subjects with CD after planned laparoscopic ileocecal resection 
with primary anastomosis.
5.1.2
Safety Objective

To assess the safety and tolerability of TAK-018 in postoperative subjects with CD after 
planned laparoscopic ileocecal resection with primary anastomosis.
5.1.3
Secondary Objectives

To evaluate the effect of TAK-018 on intestinal inflammation based on serial fecal calprotectin 
measures.

To characterize the pharmacokinetics (PK) of TAK-018 in postoperative subjects with CD 
after planned laparoscopic ileocecal resection with primary anastomosis. 
5.1.4
Exploratory Objectives
 
.
5.2
Endpoints
5.2.1
Primary Endpoint 
The percentage of subjects with endoscopic recurrence of CD at Week 26 (W26). Endoscopic 
recurrence is defined as Rutgeerts score ≥i2 (i2, i3, i4; Appendix C).
5.2.2
Safety Endpoint
The percentage of subjects who experience treatment-emergent adverse events (TEAEs), defined 
as AEs that begin or worsen after the first dose of study treatment regardless of relationship to 
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treatment, subjects will have study visits at W3, W6, W12, W18, and W26, with a final study visit 
at W30, 30 days after the W26 endoscopy. Study visits at D1 and W26 are clinic visits; study visits 
at screening, W3, W6, W12, W18, and W30 may be conducted as clinic or HHC visits to provide 
flexibility for subjects. 
Blood samples will be collected presurgery and at all study visits after dosing starts to characterize 
disease progression, response to study drug, safety parameters, and the PK of TAK-018 (see 
Appendix B). Blood samples will be collected at all study visits not to exceed 425 mLs per subject 
over the study period. Subjects will also provide stool samples before surgery during the screening 
period and at W3, W6, W12, W18, W26, and W30. Fecal calprotectin will be measured before 
surgery during the screening period and in every stool collection. Endoscopic assessment will be 
performed at the end of the 26-week treatment period (W26) and will be assessed by central 
readers.
The study consists of a screening period (up to 30 days before randomization), a 26-week 
treatment period that begins within 72 hours after surgery (starting when the subject arrives at the 
postsurgery recovery ward or unit), and a final study visit at W30, 30 days after the W26 
endoscopy. The end of study visit will be the final study visit at W30 or, for subjects who 
discontinue early, will occur 30 days after their last dose of study drug. The study overview is 
depicted in Figure 6.a. 
Subjects who discontinue study drug treatment (refer to Section 9.6) will complete an early 
termination (ET) visit upon discontinuation and a final visit 30 days after their last dose of study 
drug. 
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6.2
Justification for Study Design Components
6.2.1
Subject Population
Up to 60% of patients with CD will require a major abdominal resection within 10 years of their 
diagnosis, and a majority of them will develop postoperative recurrence within 1 year after surgery 
[2-6]. The high prevalence of AIEC reported in patients with CD is likely associated with the high 
recurrence rate after bowel resection [16,33,35,36] (MOBIDIC study; 
clinicaltrials.gov/ct/show/NCT02882841; accessed 07 January 2019). Since TAK-018 is designed 
to prevent AIEC adhesion and subsequent invasion of the gut epithelium, we expect it to inhibit or 
reduce AIEC gut recolonization in the postoperative CD population after surgery. Given the 
unique MOA of TAK-018, subjects should be administered study drug as soon as possible after 
surgery. The majority of ileocecal resections for CD are laparoscopic, which has resulted in 
reduced postoperative complications, earlier oral tolerance for diet, and earlier hospital discharge 
[37]. Therefore, subjects eligible for this study will have undergone a planned laparoscopic 
ileocecal resection and are able to take study drug within 72 hours after surgery. The proof of 
concept data derived from the postoperative CD subject population will inform the further 
development of TAK-018. 
6.2.2
Sample Size
This study is planned to randomize approximately 96 subjects stratified by smoking status (active 
smoker vs nonsmoker/previous smoker) in a 1:1:1 ratio to each of 3 treatment arms (Figure 6.a). 
Sample size justification is described in Section 13.3. 
6.2.3
Study Drug Dose
TAK-018 will be investigated at a low dose and high dose to characterize the benefit-risk profile 
and exposure-response relationship. The available safety data from healthy volunteers and subjects 
with active CD have demonstrated that TAK-018 is tolerated up to 1.5 g BID for 2 weeks. Safety 
margin calculations (Section 4.3) based on plasma exposure data from both healthy volunteers and 
subjects with active CD support further investigation. The higher dose (1.5 g) is selected to further 
evaluate the safety profile when dosed for a longer duration and also to better explore the 
therapeutic benefit for subjects with postoperative CD. Based on 99% inhibitory concentration 
(IC99) values estimated from in vitro potency tests, a lower dose (0.3 g), projected to provide 
benefit, is selected to explore the efficacious dose/exposure range of TAK-018 and to inform dose 
selection in future studies. 
6.2.4
Duration of Study
The pivotal 39- and 26-week toxicity studies in dogs and rats, respectively, administered oral and 
SC TAK-018 support the 26-week treatment period with TAK-018 in the current study. An 
individual subject’s participation in this study is up to 34 weeks (4-week screening period, 
26-week treatment period, 4-week safety follow-up) with the global study duration of 
approximately 2 to 3 years. 
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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of the Study Sites
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of a study 
site, a study-specific procedure for ET or suspension will be provided by the sponsor. The 
procedure will be followed by applicable study sites during termination or study suspension.
7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each subject must meet all of the following inclusion criteria to be randomized into the study. A 
subject is considered enrolled in the study after randomization and upon receiving the first dose of 
study drug on D1. 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. Subject signs and dates a written informed consent form (ICF), and any required privacy 
authorization before performance of any study-related procedures not part of standard medical 
care, with the understanding that consent may be withdrawn by the subject at any time without 
prejudice to future medical care. 
3. Male or female subject aged ≥18 years or local legal age at signing of ICF.
4. Subject must have a documented diagnosis of CD confirmed by endoscopic biopsy before 
resection or by tissue obtained at resection.
5. Subject is planned to undergo a laparoscopic ileocecal resection with primary anastomosis 
within 72 hours before randomization (D1). Confirmation that no active disease has been left 
behind after resection will be based on surgeon’s documentation in the operative report. 
6. Subject with postoperative discontinuation of all concomitant medications specifically related 
to the treatment of CD. This includes anti-TNF-and anti-integrin therapy, anti-IL 12/23, 
thiopurines and other immunomodulators, steroids, 5-aminosalicylates, and prophylactic use 
of antibiotics for the prevention of postoperative recurrence such as metronidazole. 
7. Subject has resumed oral intake and is capable of swallowing tablets within 72 hours after 
surgery. 
8. Female subject who is: 

Postmenopausal for at least 1 year before signing of the informed consent, OR

Surgically sterile, OR

If she is of childbearing potential, agrees to practice 1 highly effective method of 
contraception (specified in Section 9.3.17) and 1 additional effective (barrier) method at 
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the same time, from the time of signing the informed consent through 40 days after the last 
dose of study drug, OR

Agrees to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male subject, even if surgically sterilized (ie, status postvasectomy), who: 

Agrees to practice effective barrier contraception (specified in Section 9.3.17) during the 
entire study treatment period and through 100 days after the last dose of study drug, OR

Agrees to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
9. Subject with suitable venous access for the study-required blood sampling, including PK 
sampling. 
7.2
Exclusion Criteria
Subjects meeting any of the following exclusion criteria are not to be randomized into the study. 
1. Subject has active perianal CD.
2. Subject has had >3 previous surgical procedures for CD.
3. Subject has macroscopically active CD that was not resected at the time of surgery as 
documented in the surgeon’s operative report.
4. Subject with small bowel resection that exceeds 100 cm or a subject who is considered at risk 
of short bowel syndrome by the surgeon or investigator.
5. Subject has any significant intraoperative or postoperative complications such as anastomotic 
leak, surgical site infection, or inability to tolerate oral intake.
6. Subject is unable or unwilling to undergo or has contraindications to ileocolonoscopic 
procedures as assessed by the investigator.
7. Subject has inadequate renal or hepatic function postsurgery and before randomization based 
on the following laboratory parameters:

Total bilirubin >1.5× the institutional upper limit of normal (ULN) unless subject has 
known Gilbert’s syndrome that can explain the elevation of bilirubin, or

Serum alanine aminotransferase (ALT) >3× the institutional ULN, or

Creatinine >1.5× the institutional or central laboratory ULN or estimated creatinine 
clearance <50 mL/minute/1.73 m2 for subjects with serum creatinine concentrations above 
the institutional or central laboratory limits. 
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8. Subject has any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, 
genitourinary, coagulation, immunological, endocrine/metabolic, neurologic, active substance 
abuse, psychiatric or other medical disorder not related to the subject’s primary disease that, in 
the opinion of the investigator, would confound the study results, compromise subject safety, 
or interfere with completion of the study.
9. Subject has active or latent tuberculosis, regardless of treatment history, as evidenced by any 
of the following: history of tuberculosis, OR positive QuantiFERON test or 2 successive 
indeterminate QuantiFERON tests, OR a tuberculin skin test reaction 10 mm (5 mm in 
subjects receiving the equivalent of >15 mg/day prednisone).
10. Subject has chronic hepatitis B (hepatitis B surface antigen positive, or positive for both 
hepatitis B surface antibody and hepatitis B core antibody but negative for hepatitis B surface 
antigen) or hepatitis C infection (evident by viral replication by polymerase chain reaction) 
within 30 days of randomization.
11. Subject has a history of HIV or tests positive for HIV at screening.
12. If female, the subject is pregnant, lactating or breastfeeding, or intending to become pregnant 
before, during, or within 40 days after last dose of the study drug; or intending to donate ova
during such time period. 
13. If male, the subject intends to donate sperm during this study or for 100 days thereafter. 
14. Subject has a current diagnosis of biliary obstruction. 
15. Subject demonstrates significant undernutrition at the time of screening (body mass index 
<18.5 kg/m2, and weight loss >15% within 6 months, and serum albumin <3 g/dL) [39]. 
16. A subject who, in the opinion of the investigator, is unwilling or unlikely to comply with the 
requirements of the study.
17. Subject has participated in another clinical study within the past 30 days before completing 
informed consent or has received any investigational compound within 30 days before 
screening.
18. Subject has received TAK-018 (previously known as EB8018) in a previous clinical study.
19. 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.
20. Subject has a history of hypersensitivity or allergies to TAK-018, including any excipients 
contained in the study drug formulation.
21. Subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse 
within the past 12 months.
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22. Subject takes or is required to take excluded medications listed in Section 8.3.
Exclusion Criteria 9 through 11 are included as a precaution because rescue therapy with 
immunomodulating or immunosuppressing agents is allowed for subjects with recurrent CD 
after which these subjects will discontinue from the study. There are no concerns specific to 
study drug regarding these criteria.
8.0
STUDY DRUG/CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol.
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
administration. Subjects in the PK subgroup (Appendix B) will take their first dose of study drug 
at the clinic on D1 (if previously discharged) after predose blood collection. For the study visit at 
W3, study drug should be taken after the predose blood collection completes.
8.1.1
TAK-018 or Matching Placebo
The sponsor will supply study sites with study drug (ie, TAK-018 and placebo tablets with 
identical appearance) to be taken PO immediately after a meal (ie, breakfast and dinner) with water 
BID approximately 8 to 12 hours apart. If a subject forgets to take the study drug at the scheduled 
time, regularly scheduled dosing should be resumed without re-adjusting the schedule of 
administration. Subjects should take their study drug tablets with approximately 8 ounces (1 cup, 
240 mL) of water at each administration. If emesis occurs after taking study drug, symptoms 
should be managed with standard antiemetic therapy; a repeat (replacement) dose of study drug 
should not be taken. Subjects should adhere to the dosing schedule and resume dosing at the next 
scheduled time with the prescribed dosage. 
Subjects should swallow the study medication whole and not chew it, grind it, or manipulate it in 
any way before swallowing.
8.1.1.1
TAK-018 Investigational Drug Product
The sponsor will supply study sites with TAK-018 tablets containing TAK-018 active substance 
and other commonly used compendial excipients including mannitol, microcrystalline cellulose, 
crospovidone Type A, povidone, colloidal anhydrous silica, and magnesium stearate with Opadry 
QX pink as the film coating. The tablets are supplied as 100 mg and 500 mg immediate-release, 
film-coated tablets, identical in appearance. Tablets are packed in bottles. 
8.1.1.2
Matching Placebo
The sponsor will supply study sites with placebo tablets containing commonly used compendial 
excipients including mannitol, microcrystalline cellulose, povidone, colloidal anhydrous silica, 
and magnesium stearate with Opadry QX pink as the film coating, formulated to be identical in 
appearance to the active TAK-018 tablets.
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8.1.1.3
Storage of Study Drug
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study drug tablets are to be stored in the original 
container at controlled room temperature as defined in the Pharmacy Manual. Study drug must be 
transported and stored under the conditions specified on the label, and remain in the original 
container until dispensed. 
8.1.2
Dose and Regimen
Table 8.a describes the dose and tablet count that will be provided to each arm.
Table 8.a
TAK-018 Dose and Regimen
Treatment Arm
Dose
Treatment Description Dose
Number of Tablets per Dose
A
Placebo BID
Three placebo tablets
B
TAK-018 BID
Low dose (0.30 g)
Three 0.10 g tablets
C
TAK-018 BID
High dose (1.5 g)
Three 0.50 g tablets
BID: twice daily.
8.2
Treatment Assignment and Dispensing Procedures
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria at screening 
are eligible for randomization on D1. 
The investigator or investigator’s designee will access the interactive response technology system 
(IRT) at screening to obtain the subject screen number. The investigator or the investigator’s 
designee will use the IRT to randomize the subject into the study. The medication identification 
(ID) number of the study drug to be dispensed will then be provided by the IRT. The 
investigational drug blind will be maintained using the IRT. If sponsor-supplied drug is lost or 
damaged, site staff can request a replacement from IRT. 
At subsequent drug-dispensing visits, the investigator or designee will again contact the IRT to 
request additional IMP for a subject. The medication ID number of the study drug to be dispensed 
will be provided by the IRT.
The IRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed. 
Additional information is provided in the pharmacy/IRT manuals.
8.3
Excluded Concomitant Medications and Procedures While On-study

Any medications intended specifically for the treatment of CD after surgery, including 
anti-TNF or anti-integrin therapy, anti-IL 12/23, thiopurines and other immunomodulators, 
steroids, 5-aminosalicylates, and prophylactic use of antibiotics for the prevention of 
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postoperative recurrence such as metronidazole. Systemic steroids for indications other than 
CD are not permitted. 

Any investigational agent other than the study drug administered as part of this study.

Either approved or investigational biological agents for the treatment of other conditions (eg, 
rheumatoid arthritis), other than topicals or localized injections (eg, intraocular injections for 
wet macular degeneration).
8.4
Permitted Concomitant Medications and Procedures
Other medications considered necessary for the safety and well-being of the subject may be 
administered at the discretion of the investigator. These include prescription antibiotics for 
infections such as urinary tract infection and bronchitis. Use of anti-inflammatory agents is 
generally discouraged but short term use defined as ≤72 hours at any given time during the study 
period is permitted. Aspirin use for cardiovascular disease prophylaxis is permitted. Stress dose 
systemic steroids for surgery are permitted, and patients need to be tapered off all systemic steroids 
within 15 days after surgery. Topical steroids, inhaled steroids and intra-articular injections of 
steroids are permitted.
Any concomitant medications or supplements added or discontinued during the study and any dose 
or dose regimen changes should be recorded on the electronic case report form (eCRF). 
8.5
Precautions and Restrictions
8.5.1
Reproductive Effects
It is not known what effects the study drug has on human pregnancy or development of the embryo 
or fetus. Therefore, female subjects participating in this study should avoid becoming pregnant, 
and male subjects should avoid impregnating a female partner. Nonsterilized female subjects of 
reproductive age group and male subjects should use effective methods of contraception (specified 
in Section 9.3.17) through defined periods during and after study treatment as specified in the 
following.
Female subjects must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 2 effective methods of contraception 
(specified in Section 9.3.17) from the time of signing of the ICF through a minimum of 40 days 
after the last dose of study drug, or 

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods] and withdrawal are not acceptable methods of contraception.)
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Male subjects, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice effective barrier contraception (specified in Section 9.3.17) during the entire study 
treatment period and through a minimum of 100 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner] and withdrawal are not acceptable methods of contraception.)
8.6
Management of Clinical Events
8.6.1
Liver Test Abnormalities
For subjects with treatment-emergent ALT elevations ≥3× ULN, see Appendix D for additional 
monitoring, evaluation, and follow-up recommendations. 
For any subject with ALT ≥3× ULN AND total bilirubin >2× ULN OR international normalized 
ratio (INR) >1.5× ULN for which an alternative etiology has not been found, report the event as an 
SAE, contact the sponsor’s medical monitor within 24 hours, and follow the additional monitoring, 
evaluation, and follow-up recommendations in Appendix D. Potential events will be reported as 
SAEs (Section 10.2.3.4).
All subjects with liver abnormalities will be closely followed and follow-up laboratory tests as 
described in Appendix D must also be performed. Subjects will be followed until abnormalities 
return to normal or baseline or until all attempts to determine resolution of the event are exhausted.
8.6.2
Vomiting
For subjects who vomit after taking study drug, symptoms should be managed with standard 
antiemetic therapy. Subjects should not take a replacement dose but should adhere to the dosing 
schedule and resume dosing at the next scheduled time. In cases of recurrent vomiting, subjects 
should contact the site investigator. 
8.6.3
Recurrence of CD
Based on clinical assessment, if the investigator feels that appropriate treatment is warranted for 
recurrence, the subject will discontinue study drug, begin institutional standard of care, will attend 
an early termination visit 30 days after last dose of study drug, and will be withdrawn from the 
study. The methodology used by the investigator to define recurrence (eg, endoscopic result, 
clinical instrument score, or other) should be documented in the eCRF. 
8.7
Unblinding Procedure 
The study drug blind shall not be broken by the investigator unless information concerning the 
study drug is necessary for the medical treatment of the subject. All study assessments and 
causality assessments should be performed before unblinding, if possible. In the event of a medical 
emergency, the study drug blind can be broken without permission from the sponsor, although the 
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medical monitor should be contacted immediately. In non-urgent cases (ie, a nonmedical 
emergency), the medical monitor must be contacted before the subject is unblinded. 
For unblinding a subject, the study drug blind can be obtained by the investigator, by accessing the 
IRT.
Subjects discontinuing study participation for any other reason will be kept blind.
The sponsor must be notified as soon as possible if the study drug blind is broken. The date, time, 
and reason the blind is broken must be recorded in the source documents and the same information 
(except the time) must be recorded on the eCRF.
8.8
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee. The site will maintain source documents in addition to entering data into the IRT.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug, the investigator or designee must maintain records of all 
sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each subject, and 
return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, the investigator or 
designee should acknowledge the receipt of the shipment in the IRT. If there are any discrepancies 
between the packing list versus the actual product received, Takeda must be contacted to resolve 
the issue. The packing list should be filed in the investigator’s essential document file.
The investigator or designee must ensure that 100% accountability is maintained for all 
sponsor-supplied drugs received and dispensed during his or her entire participation in the study. 
Proper drug accountability includes but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.

Continuously monitoring expiration dates, if expiry date is provided.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.
All study drug not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log.
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Before site closure or at appropriate intervals, a representative from the sponsor or its designee will 
perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied drugs 
are returned to the sponsor or its designee for destruction. Accountability for clinical study 
material being destroyed at the site must be documented using a study accountability tracking 
document or equivalent document. In addition, a certificate of destruction document must be 
provided by the sites that can identify or allow traceability to the batches, and/or medication ID 
numbers involved, and actual quantities destroyed. The investigator or designee will retain a copy 
of the documentation regarding sponsor-supplied drug accountability, return, and/or destruction, 
and originals will be sent to the sponsor or designee.
9.0
STUDY CONDUCT
9.1
Study Personnel and Organizations
The contact information for the Takeda project clinician for this study, the central laboratory and 
any additional clinical laboratories, the coordinating investigator for each member state/country 
(where applicable), and the contract research organization (CRO) team may be found in the study 
manual. A full list of investigators is available in the sponsor’s investigator database.
9.2
Informed Consent and Screening
9.2.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained to begin screening and before any protocol-directed 
procedures are performed. 
9.2.2
Screening
Investigators must account for all subjects who sign informed consent. If a subject is found to be 
not eligible, the investigator should complete the appropriate eCRF, noting the primary reason for 
screen failure. The IRT should be contacted as a notification of screen failure. Subject numbers 
assigned to subjects who fail screening should not be reused. 
Rescreening of subjects is permitted in this study based on investigator discretion and approval by 
the sponsor or the sponsor’s designee for the following reasons: 

If laboratory test results are outside protocol-defined limits (Section 7.2), the test can be 
repeated once during screening at the principal investigator’s (PI's) discretion. If the repeat 
value is again outside protocol limits, then the subject is a screen failure.

A subject’s scheduled surgical procedure is delayed, resulting in randomization on Day 1 to 
fall outside the 30-day period after their initial screening.
Before a subject may be rescreened, a new ICF must be completed. Rescreened subjects must be 
assigned a new screen number using IRT and all Part 1 screening procedures must be repeated for 
each subject who is rescreened. 
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9.3
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. Refer to 
the schedule of events (SOE), in Appendix A, for timing of assessments. Additional details are 
provided as necessary in the sections that follow. Of note, the ileocecal resection is an entry 
criterion and not considered a study-related procedure and should be completed as per institution’s 
standard of care. D1 of the clinical study begins within 72 hours after surgery when the patient has 
been randomized to 1 of the 3 study arms. 
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood collected over the course of the study from an individual subject is not to exceed 
425 mL. 
9.3.1
Inclusion/Exclusion Criteria
The inclusion and exclusion criteria will be assessed during screening and before randomization.
9.3.2
Randomization and Enrollment
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization. All eligible subjects will be randomized on D1 (using the IRT as described in 
Section 8.2) 1:1:1 to either TAK-018 low dose (0.30 g BID), TAK-018 high dose (1.5 g BID), or 
placebo (BID) for a 26-week treatment period. Randomization will be stratified by smoking status 
collected as active smokers versus nonsmokers and previous smokers (defined as subjects who 
stopped smoking at least 3 months before ileocecal resection) [40]. Subjects will receive the 
treatment for the assigned study arm and according to the study schedule. Study procedures for D1 
are shown in Appendix A and Appendix B.D1 procedures will occur either in the hospital before 
discharge or during an office visit if the subject has already been discharged.
A subject is considered enrolled in the study upon completion of the ICF. 
9.3.3
Demographics and Medical History
Demographic information to be obtained during screening will include but is not limited to the date 
of birth or age depending on local regulations, race, ethnicity, and sex of the subject. 
During the screening period, a complete medical and surgical history will be compiled for each 
subject, including whether the subject has or had any significant conditions or diseases relevant to 
the disease under study. All CD-related medications taken previously and CD-related procedures 
should be recorded in the medical history. In addition, concomitant medications will be recorded 
as specified in Section 9.3.9. 
9.3.4
Physical Examination
A physical examination (complete or targeted) will be completed at the times specified in the SOE 
(Appendix A). Any clinically relevant findings at baseline will be documented. The physical 
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W30. The results from these tests must be available and negative before subsequent doses of study 
drug are taken. Additional pregnancy testing may be performed during the study at the discretion 
of the investigator, upon request of an IEC/IRB, or if required by local regulations.
9.3.11.2
Clinical Hematology, Chemistry, and Liver Tests
The clinical laboratory tests (clinical hematology, blood chemistry, and liver tests) to be conducted 
during the study are summarized in Table 9.a. The central laboratory will perform these tests and 
return the results to the investigator, who is responsible for reviewing and filing them. Blood 
samples for these analyses will be obtained at the time points specified in the SOE (Appendix A).
For subjects with treatment-emergent ALT elevations ≥3× ULN, see Appendix D for additional 
monitoring, evaluation, and follow-up recommendations. Graded laboratory abnormalities will be 
defined using CTCAE Version 5. 
Table 9.a
Clinical Hematology, Chemistry, and Liver Tests
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Red blood cells (RBC)
Leukocytes with differential including 
neutrophils, monocytes, and lymphocytes
Platelets
Albumin
Bicarbonate (HCO3)
Blood urea nitrogen (BUN)
Calcium
Creatinine
Chloride
Glucose
Phosphate
Potassium
Sodium
Urate
Liver Tests
Alkaline phosphatase
ALT
AST
Bilirubin (total, direct, and indirect)
GGT
Lactate dehydrogenase
Other:
HIV
Hepatitis panel, including HBsAg, anti-HCV, and 
HCV PCR
C-reactive protein
INR
Urine pregnancy hCG (predose on dosing days) and beta hCG to 
confirm positive urine result
for female subjects of childbearing potential
FSH, if menopause is suspected
ALT: alanine aminotransferase; AST: aspartate aminotransferase; FSH: follicle-stimulating hormone; GGT: gamma 
glutamyl transferase; HBsAg: hepatitis B surface antigen; hCG: human chorionic gonadotropin; HCV, hepatitis C 
virus; INR: international normalized ratio; PCR: polymerase chain reaction.
9.3.11.3
Urinalysis
Urine samples will be analyzed centrally. Urinalysis will include the parameters shown in 
Table 9.b and urine samples will be obtained at the time points specified in the SOE (Appendix A).
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9.3.16
Changes to Study Procedures Due to a Pandemic
The following information provides guidance regarding changes to the study procedures that could 
be implemented for study participants or study sites that are impacted by a pandemic 
(eg, coronavirus disease [COVID-19] or other future similar unexpected public health concerns) 
that require physical distancing that may result in subjects missing their visits. This guidance takes 
references from the Food and Drug Administration (FDA) Guidance on Conduct of Clinical Trials 
of Medical Products during COVID-19 Public Health Emergency Guidance for Industry, 
Investigators, and Institutional Review Boards, March 2020 and updated on 02 July 2020, the 
European Medicines Agency (EMA) Guidance on the Management of Clinical Trials During the 
COVID-19 (Coronavirus) Pandemic, Version 3 (28 April 2020), and the EMA Points to consider 
on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing 
clinical trials, dated 26 June 2020.
Because a pandemic (eg, COVID-19) may peak in different regions at different times and 
restrictions implemented by local laws and recommendations may vary, any decision on 
procedural changes should be made on a case-by-case basis by the PI, in consultation with the 
study team (and the medical team as needed), while maintaining patient safety and confidentiality 
as the priority.
Procedural changes due to COVID-19 (or other similar pandemic) may include the following:

ICF Procedure: If necessary, informed consent from a potential or current study participant 
may be obtained via electronic informed consent capabilities, or an electronic face-to-face 
consent interview when these individuals are unable to travel to the site, based on local 
regulations or requirements.

Subject visits at screening, W3, W6, W12, W18, and W30 may be conducted as clinic or HHC 
visits to extend flexibility to patients during a pandemic (eg, COVID-19 or other similar 
pandemic). HHC visits will be documented in the study records. The data collected from HHC 
visits may be handled differently in the final data analysis, with this documented in the 
statistical analysis plan (SAP).

Study visit windows are extended to ±7 days to provide more flexible scheduling for HHC or 
telehealth visits (Appendix A).

For HHC visits, collection of clinical laboratory samples (blood draws or other diagnostic tests) 
will be performed by the investigator or the study coordinator or by a qualified health care 
professional who are allowed to enter the study participant’s home.

ECG procedures: For HHC visits, ECGs may be performed by a qualified health care 
professional who is authorized/certified to perform such tests routinely.

Allow ‘remote visits’ via virtual communications (eg, TeleHealth application) in conjunction 
with HHC visits and/or as an unscheduled safety assessment on subject well-being.

Allow the use of a web-based back-up system on electronic devices.
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
Allow transfer of study participants to investigational sites away from risk zones or closer to 
their home.

Deviations from protocol-specified procedures (eg, not collecting a study sample such as 
postdose bloodwork) will be recorded as related to a pandemic (eg, COVID-19 or other similar 
pandemic).

Secure direct-to-patient delivery of the study drug from the investigational site to subjects 
electing to engage in HHC visits. 
9.3.17
Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for a minimum of 
40 days after the last dose of study drug, female subjects of childbearing potential* who are 
sexually active with a nonsterilized male partner** must use adequate contraception 
(Section 8.5.1). In addition, they must be advised not to donate ova during this period.
From signing of informed consent, throughout the duration of the study, and for a minimum of 
100 days after the last dose of study drug, nonsterilized** male subjects who are sexually active 
with a female partner of childbearing potential* must use barrier contraception (eg, condom with 
spermicidal cream or jelly) (Section 8.5.1). In addition, they must be advised not to donate sperm 
during this period.
*Females NOT of childbearing potential are defined as those who have been surgically 
sterilized (hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal 
(eg, defined as at least 1 year since last regular menses with a follicle-stimulating hormone 
[FSH] >40 IU/L or at least 5 years since last regular menses, confirmed before any study
medication is implemented) (Section 8.5.1).
**Sterilized males should be at least 1 year post-vasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate (Section 8.5.1).
A highly effective method of contraception is defined as one that has no higher than a 1% failure 
rate. In this study, the only highly effective methods of contraception are:

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation, including oral, intravaginal, and transdermal formulations.

Progestogen-only hormonal contraception associated with inhibition of ovulation, including 
oral, injectable, and implantable formulations.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion.

Vasectomized partner.
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
Sexual abstinence.
Barrier methods (eg, male condom PLUS spermicide, cap [plus spermicidal cream or jelly] PLUS 
male condom and spermicide, diaphragm [plus spermicidal cream or jelly] PLUS male condom 
and spermicide) can be used each time the subject has intercourse in addition to methods listed in 
the table above to ensure acceptable protection level.
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the study.
During the course of the study, urine human chorionic gonadotropin (hCG) pregnancy tests will be 
performed (Section 8.5.1) only for women of childbearing potential and female subjects will 
receive continued guidance with respect to the avoidance of pregnancy and ova donation as part of 
the study procedures (Appendix A). In addition to a negative serum hCG pregnancy test at 
screening, women of childbearing potential must have urine hCG pregnancy test administered at 
clinic visits on D1 and W26, and on study visits at W3, W6, W12, W18, and W30. Negative results 
are required before receiving or taking subsequent doses of study drug. 
Male subjects must be advised not to donate sperm from signing of informed consent to a 
minimum of 100 days after the last dose of study drug.
9.4
Completion of Study Treatment
Subjects will be considered to have completed study drug treatment if they discontinue study drug 
for any of the reasons outlined in Section 9.6. For subjects who discontinue due to AEs, all AEs 
must be collected and reported as indicated in sections 10.2 and 10.3. For all other subjects, 
treatment will be considered completed after the final dose of study drug at W26. 
9.5
Completion of Study
Study completion will occur once all randomized subjects have completed all study procedures 
(including the final study visit 30 days after the W26 endoscopy) as specified in the SOE 
(Appendix A). The primary reason for completion of study will be recorded in the eCRF.
9.6
Discontinuation of Treatment with Study Drug
Study drug must be permanently discontinued for subjects meeting any of the criteria presented 
below. The primary reason for discontinuation from treatment with study drug or withdrawal of 
the subject from the study should be recorded in the eCRF using the following categories. For 
screen failure subjects, refer to Section 9.2.2.
1. Recurrence of CD that requires immunosuppressive or immunomodulating therapy per 
assessment by investigator.
2. The subject has experienced a pretreatment event or AE that requires ET because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the pretreatment event or AE. In addition, dosing for any individual 
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subject will be discontinued if the subject experiences an AE Grade ≥3 (based on CTCAE 
criteria Version 5.0) that is considered related to study drug treatment by the investigator or 
sponsor. Dosing for any individual subject will also be discontinued if the subject experiences 
an AE that warrants discontinuation from further dosing, as determined by the investigator, for 
that subject’s well being. Subjects who prematurely discontinue study drug will complete all 
study procedures for ET as specified in the SOE (Appendix A).
3. Subjects with treatment-emergent ALT elevations should be evaluated to determine whether 
study drug should be continued, interrupted, or discontinued. See Appendix D.
4. Significant protocol deviation. The discovery post-randomization that the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
5. Pregnancy. The subject is found to be pregnant and must be withdrawn immediately. The 
procedure is described in Section 10.2.3.5. 
6. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
7. Voluntary withdrawal by subject. The subject wishes to withdraw from the study. The reason 
for withdrawal, if provided, should be recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category). 
8. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.
Once study drug has been prematurely discontinued, all study procedures outlined for the ET visit 
will be completed as specified in the SOE (Appendix A). 
Those subjects who discontinue study drug before completing the full treatment course are 
allowed to remain in the study for posttreatment assessments and procedures as outlined in the 
SOE (Appendix A) if no alternate therapy is started. If alternate therapy is started for recurrence of 
CD, subjects will complete an ET visit 30 days after the last dose of study drug and no further 
study procedures will be completed.
9.7
Withdrawal of Subjects from Study
The investigator may discontinue a subject’s study participation at any time during the study. A 
subject may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Study (or study arm) terminated by sponsor.

Voluntary withdrawal by subject.
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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.
When subjects request disposal of a stored sample during the retention period, the site will notify 
the storage facility to destroy the sample according to the procedure specified in the laboratory 
manual. The facility will destroy the sample in accordance with the procedure and notify the site 
and sponsor.
Subjects who consented and provided such samples can withdraw their consent and request 
disposal of stored samples at any time. The sponsor should be notified of consent withdrawal.
10.0
ADVERSE EVENTS
10.1
Definitions
An AE (nonserious and serious) is any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study. The event does not necessarily 
have to have a causal relationship with the drug. An AE can be any unfavorable and unintended 
sign or symptom, or disease temporally associated with the use of the drug, whether or not it is 
considered related to the investigational product.
AE (Nonserious and Serious) Guidelines
AEs include
AEs do not include

Worsening of a pre-existing illness or condition.

An increase in frequency or intensity of a 
pre-existing episodic event or condition.

Continuous persistent disease or symptoms present 
at baseline that worsen following the administration 
of study drug.

Complications from elective surgery or procedures.

Signs or symptoms associated with an overdose.

Pre-existing disease or conditions present before 
treatment that do not worsen.

The disease being treated or associated symptoms or 
signs unless more severe than the subject's baseline 
condition.

Preplanned or elective surgery or procedures.

Medical or surgical procedures - the condition that 
leads to the procedure is the AE. 
AE: adverse event.
10.1.1
SAEs
An SAE is any untoward medical occurrence that at any dose:
1. Results in death.
2. Is life threatening. The term “life threatening” refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe.
3. Requires inpatient hospitalization or prolongation of existing hospitalization.
4. Results in persistent or significant disability/incapacity.
5. Is a congenital anomaly/birth defect.
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6. Is an important medical event. 
Medical and scientific judgement should be exercised in deciding whether an event is an important 
medical event. An important medical event may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the other outcomes listed in the definition above. These events should be considered serious.
The events in Takeda Medically Significant AE List (Table 10.a) are considered important 
medical events that should be handled as serious.
Table 10.a
Takeda Medically Significant AE List by System Organ Class
Blood and lymphatic system disorders
Pregnancy, puerperium, and perinatal conditions
Agranulocytosis
Spontaneous abortion 
Aplastic anaemia
Stillbirth and fetal death
Cardiac disorders
Renal and urinary disorders
Torsade de pointes
Acute renal failure
Ventricular fibrillation
Respiratory, thoracic, and mediastinal disorders
Ventricular tachycardia
Acute respiratory distress syndrome
Hepatobiliary disorders
Acute respiratory failure
Acute liver failure
Pulmonary fibrosis 
Hepatic necrosis
Pulmonary hypertension
Immune system disorders
Skin and subcutaneous tissue disorders
Anaphylactic shock
Stevens-Johnson syndrome
Infections and infestations 
Toxic epidermal necrolysis
Confirmed or suspected endotoxin shock
Vascular disorders
Confirmed or suspected transmission of infectious 
agent by a medicinal product
Malignant hypertension
COVID-19 pneumonia
COVID-19–related disease
Nervous system disorders
Convulsive seizure
Malignant hyperthermia
Neuroleptic malignant syndrome
AE: adverse event; COVID-19: coronavirus disease 2019.
Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements. 
10.1.2
Overdose
An overdose is a known deliberate or accidental administration of study drug, either to or by a 
study subject, at a dose above that assigned to that individual subject. 
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10.2
AE Procedures
10.2.1
Assigning Severity of AEs
All AEs, including clinically significant treatment-emergent laboratory abnormalities, will be 
graded according to National Cancer Institute CTCAE, Version 5.0. Grade descriptions are:
Grade 1
Mild: asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated.
Grade 2
Moderate: minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Fatal AE: an event that results in the death of the subject.
Refer to the full version of the CTCAE V 5.0 grading when evaluating the severity of AEs. 
10.2.2
Assigning 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 a causal 
relationship is at least a reasonable possibility (ie, the relationship between 
drug administration 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 medications 
and concurrent treatments.
10.2.3
Collection and Reporting of AEs, SAEs, Overdose, and Abnormal Liver Test 
Results
10.2.3.1
Collection Period
Collection of AEs (ie, AEs and SAEs) will commence at the time the subject signs the informed 
consent and will continue until 30 weeks after the first dose of study drug or until screen failure. A 
final study visit will be conducted at W30, 30 days after the W26 endoscopy, for final study 
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assessments. For subjects who discontinue before administration of study medication, AEs will be 
followed until the subject discontinues study participation. For subjects who discontinue study 
drug treatment or ET, collection of AEs/SAEs will continue for 30 days after their last dose of 
study drug or last study visit, including defined follow-up visits. 
10.2.3.2
Reporting SAEs
Regardless of causality, SAEs must be reported by the investigator to the Takeda medical monitor 
and the Global Patient Safety Evaluation department or designee within 24 hours of becoming 
aware of the event. Reporting to the Global Patient Safety Evaluation department or designee will 
be done by transmitting an EDC SAE report. If transmission of an EDC SAE report is not feasible 
within 24 hours of receiving the event, then a facsimile (fax) of the completed Takeda paper-based 
SAE form should be submitted to the fax number provided below. A sample of the paper-based 
SAE form and processing directions are in the study manual.
SAE Reporting Contact Information
Fax numbers:
United States and Canada
+1-224-554-1052
Rest of World
+1-224-554-1052
Email address:
PVSafetyAmericas@tpna.com
eupv@tgrd.com
In case of fax, site personnel need to confirm successful transmission of all pages and include an 
email address on the cover sheet so that an acknowledgment of receipt can be returned via email 
within 1 business day.
Email submission of SAE forms with a PDF attachment should only be used in the case where fax 
is not possible and EDC is not feasible within 24 hours of receiving the event. In case of email, site 
personnel need to confirm successful transmission by awaiting an acknowledgment of the receipt 
via email within 1 business day. 
If SAEs are reported via fax or by email, EDC must be updated as soon as possible with the 
appropriate information. Information in the SAE report or form must be consistent with the data 
provided on the eCRF.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
SAE Follow-up
If information not available at the time of the first report becomes available at a later date, then the 
investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an EDC 
SAE report is not feasible) or provide other documentation immediately within 24 hours of receipt. 
Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested.
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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. 
10.2.3.3
Reporting Overdose
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on eCRF(s). SAEs associated with overdose should be 
reported according to the procedure outlined in Section 10.2.3.2.
10.2.3.4
Reporting of Abnormal Liver Test Results and Other Laboratory Test Abnormalities
For any subject with ALT ≥3× ULN AND total bilirubin >2× ULN OR INR >1.5× ULN for which 
an alternative etiology has not been found, report the event as an SAE, contact the sponsor’s 
medical monitor within 24 hours, and follow the additional monitoring, evaluation, and follow-up 
recommendations in Appendix D. 
Other Grade 3 or 4 laboratory abnormalities (per CTCAE Version 5) should be assessed for 
clinical significance by the investigator or qualified subinvestigator. Clinically significant 
laboratory abnormalities should be confirmed by repeat testing and the medical monitor should be 
contacted. 
10.2.3.5
Reporting Pregnancy
If any subject is found to be pregnant within 40 days of the last dose of study drug, she should be 
withdrawn from the study. In addition, any pregnancies in the partner of a male subject during the 
study or within 100 days after the last dose (whichever comes later) should also be recorded 
following authorization from the subject’s partner. 
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
Subjects randomized to placebo need not be followed. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug will 
be followed up to final outcome, using the pregnancy form. Pregnancies will remain blinded to the 
study team. The outcome, including any premature termination, must be reported to the sponsor. 
An evaluation after the birth of the child will also be conducted.
10.3
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, including the EMA, investigators and 
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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, suspected unexpected serious adverse reactions will be submitted 
to the regulatory authorities as expedited reports within 7 days for fatal and life-threatening events 
and 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 a study drug/sponsor supplied drug or that would be 
sufficient to consider changes in the study drug/sponsor supplied drug administration or in the 
overall conduct of the study. The study site also will forward a copy of all expedited reports to his 
or her IRB or IEC in accordance with local regulations.
11.0
STUDY-SPECIFIC COMMITTEES
An external data and safety monitoring committee is not being considered for this study as the 
MOA of the investigational TAK-018 is locally acting on gut microbiota and does not suppress or 
interact with a subject’s immune response. Safety data will be monitored continuously throughout 
the study. Study level stopping criteria are outlined in Section 6.3.1. 
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, medical history, and concurrent medical conditions will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the 
World Health Organization Drug Dictionary. 
12.1
eCRFs
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or its designee will supply study investigative sites with access to eCRFs and will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor, CRO partners, 
and regulatory authorities. Investigative sites must complete eCRFs in English. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Any change, modification, or addition to the data on the eCRFs should be made by the investigator 
or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that captures the 
old information, the new information, contact information of the person making the correction, the 
date the correction was made, and the reason for change.
The PI must review the eCRFs for completeness and accuracy and must sign and date the 
appropriate eCRFs as indicated. Furthermore, the PI must retain full responsibility for the accuracy 
and authenticity of all data entered on the eCRFs.
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eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by sponsor monitors. The sponsor (or designee) will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor. 
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the ID log of all participating 
subjects, medical records, temporary media such as thermal sensitive paper, source worksheets, all 
original signed and dated ICFs, subject authorization forms regarding the use of personal health 
information (if separate from the ICFs), electronic copies of eCRFs, including the audit trail, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities and 
the sponsor (or designees). Any source documentation printed on degradable thermal sensitive 
paper should be photocopied by the site and filed with the original in the subject’s chart to ensure 
long term legibility. Furthermore, 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 study site agreement between the 
investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A SAP will be prepared and finalized before database lock. This document will provide further 
details regarding the definition of analysis variables and analysis methodology to address all study 
objectives.
13.1.1
Analysis Sets
The following analysis sets will be used:

Full analysis set (FAS) will include all subjects who are randomized and received at least 
1 dose of study drug. Subjects in this set will be analyzed by the treatment arm to which the 
subjects were randomized.
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
Safety analysis set will include all randomized subjects who receive at least 1 dose of study 
drug. Subjects in this set will be analyzed according to the treatment received.

Response-evaluable set will include all randomized subjects who received at least 1 dose of 
study drug and who underwent endoscopy at W26. 

PK analysis set: Subjects from the safety analysis set with at least 1 reported PK concentration. 
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Baseline and demographic information will be listed and summarized by treatment arm and overall 
using the full analysis set. 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 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 and therapeutic class.
13.1.3
Efficacy Analysis
All efficacy endpoints will be analyzed using the FAS. 
Primary efficacy analysis: The primary endpoint of proportion of subjects with endoscopic 
recurrence of CD at W26 in each of the two TAK-018 dose arms will be compared to the 
corresponding proportion in the placebo arm using the Cochran-Mantel-Haenszel (CMH) test 
using the randomization stratification factor (smoking status). In the case of small cell sizes (<5), 
the Fisher’s exact test will be used instead of the CMH test. The point estimates for the treatment 
difference (TAK-018 – placebo) for each dose, along with the associated 80% and 95% CIs will be 
presented. When data necessary in the determination of the primary endpoint is missing, it will be 
handled using nonresponder imputation, eg, a subject will be classified as a nonresponder at W26 
if no endoscopy was performed. In addition, sensitivity analysis will be performed for the primary 
efficacy analysis using the response-evaluable set.
The secondary efficacy endpoint of percentage of subjects with FCP >135µg/g will be 
summarized descriptively by treatment arm for each time point.
Continuous longitudinal efficacy endpoints will be analyzed using a mixed-effect model repeated 
measures (MMRM) model to compare each dose of the TAK-018 arms to the placebo arm. 
Continuous endpoints measured at a single time-point will be analyzed using an ANCOVA model. 
Binary endpoints will be analyzed using the methodology used for the primary efficacy endpoint. 
Further details will be provided in the SAP.
13.1.4
PK Analysis 
Measured plasma concentrations of TAK-018 by time will be summarized descriptively using the 
PK set. Individual plasma concentration data versus time will be presented in a data listing. Further 
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13.3
Determination of Sample Size
This study is planned to randomize approximately 96 subjects stratified by smoking status (active 
smoker vs nonsmoker/previous smoker) in a 1:1:1 ratio to each of 3 treatment arms 
(approximately 32 subjects per arm). 
Assuming the true recurrence rate in the placebo arm to be 50% [40,46], a total of 81 subjects will 
provide at least 75% power to detect a 25% or larger difference in recurrence rates between 
treatment and placebo arms for a 2-sided chi-squared test at a 0.2 level of significance. To account 
for an assumed dropout rate of 15%, approximately 96 subjects will be randomized in this study. 
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 sponsor’s 
designee (as long as blinding is not jeopardized), including but not limited to the investigator’s 
binder, study drug, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the ICFs), and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. 
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it will be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
The investigator should document all protocol deviations.
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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 United States [US] FDA and the United Kingdom [UK] 
Medicines and Healthcare products Regulatory Agency [MHRA]). 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 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 G. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state, federal, and/ 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 investigator’s brochure (IB), a copy 
of the ICF, and, if applicable, subject recruitment materials and 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 
activity. The IRB or IEC approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (eg, ICF) reviewed; and state the approval date. 
If required by country or regional regulations or procedures, approval from the competent 
regulatory authority will be obtained before commencement of the study or implementation of a 
substantial amendment. The sponsor will ship drug/notify site once the sponsor has confirmed the 
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adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the study. Until the site receives drug/notification, 
no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor (or 
designee).
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, and the date informed consent is given. 
The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, 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. 
The subject must be given ample opportunity to: (1) inquire about details of the study and 
(2) decide whether to participate in the study. If the subject determines he or she will participate in 
the study, then the ICF and subject authorization form (if applicable) must be signed and dated by 
the subject at the time of consent and before the subject enters into the study. The subject should be 
instructed to sign using their legal names, not nicknames, using a ballpoint pen with either blue or 
black ink. The investigator must also sign and date the ICF and subject authorization (if applicable) 
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at the time of consent and before the subject enters into the study; however, the sponsor may allow 
a designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised ICF.
Subjects who consented and provided a pharmacogenomic sample for DNA and RNA analysis can 
withdraw their consent and request disposal of a stored sample at any time prior to analysis. 
Investigators will notify sponsor of consent withdrawal.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will be linked to the 
sponsor’s clinical study database or documentation only via an unique ID number. As permitted by 
all applicable laws and regulations, limited subject attributes, such as sex, age, or date of birth, and 
subject initials may be used to verify the subject and accuracy of the subject’s unique ID number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, UK MHRA), 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 
identifying personal information removed, eg, subject name, address, and other identifier fields 
not collected on the subject’s eCRF.
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication 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 
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disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail.
15.4.2
Clinical Trial Registration
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/standards. Takeda contact information, 
along with investigator’s city, state (for Americas investigators), country, and recruiting status will 
be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods preferred by callers requesting trial information. Once subjects 
receive investigator contact information, they may call the site requesting enrollment into the trial. 
The investigative sites are encouraged to handle the trial inquiries according to their established 
subject screening process. If the caller asks additional questions beyond the topic of trial 
enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov, clinicaltrialsregister.eu for 
studies conducted in the European Union, and other publicly accessible websites (including the 
Takeda corporate site) and registries, as required by Takeda policy/standards, applicable laws, 
and/or regulations.
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving subject care. Qualified independent researchers will be permitted 
to use data collected from subjects during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the subject’s disease. The data provided to external 
researchers will not include information that identifies subjects personally. 
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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
1.
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing 
incidence and prevalence of the inflammatory bowel diseases with time, based on systematic 
review. Gastroenterology 2012;142(1):46-54 e42; quiz e30.
2.
Lakatos PL, Golovics PA, David G, Pandur T, Erdelyi Z, Horvath A, et al. Has there been a 
change in the natural history of Crohn's disease? Surgical rates and medical management in a 
population-based inception cohort from Western Hungary between 1977-2009. Am J 
Gastroenterol 2012;107(4):579-88.
3.
Zhulina Y, Udumyan R, Tysk C, Montgomery S, Halfvarson J. The changing face of Crohn's 
disease: a population-based study of the natural history of Crohn's disease in Orebro, Sweden 
1963-2005. Scand J Gastroenterol 2016;51(3):304-13.
4.
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.
5.
Pascua M, Su C, Lewis JD, Brensinger C, Lichtenstein GR. Meta-analysis: factors predicting 
post-operative recurrence with placebo therapy in patients with Crohn's disease. Aliment 
Pharmacol Ther 2008;28(5):545-56.
6.
Buisson A, Chevaux JB, Allen PB, Bommelaer G, Peyrin-Biroulet L. Review article: the 
natural history of postoperative Crohn's disease recurrence. Aliment Pharmacol Ther 
2012;35(6):625-33.
7.
Sartor RB, Wu GD. Roles for intestinal bacteria, viruses, and fungi in pathogenesis of 
inflammatory bowel diseases and therapeutic approaches. Gastroenterology 
2017;152(2):327-39 e4.
8.
Barnich N, Darfeuille-Michaud A. Role of bacteria in the etiopathogenesis of inflammatory 
bowel disease. World J Gastroenterol 2007b;13(42):5571-6.
9.
Gevers D, Kugathasan S, Denson LA, Vazquez-Baeza Y, Van Treuren W, Ren B, et al. The 
treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 
2014;15(3):382-92.
10.
Haberman Y, Tickle TL, Dexheimer PJ, Kim MO, Tang D, Karns R, et al. Pediatric Crohn 
disease patients exhibit specific ileal transcriptome and microbiome signature. J Clin Invest 
2014;124(8):3617-33.
For non-commercial use only


TAK-018 (Sibofimloc)
Study No. TAK-018-2001
Page 63 of 89
Protocol Incorporating Amendment No. 05
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CONFIDENTIAL
11.
Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe 
interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 
2012;491(7422):119-24.
12.
Lichtenstein GR, Targan SR, Dubinsky MC, Rotter JI, Barken DM, Princen F, et al. 
Combination of genetic and quantitative serological immune markers are associated with 
complicated Crohn's disease behavior. Inflamm Bowel Dis 2011;17(12):2488-96.
13.
Choung RS, Princen F, Stockfisch TP, Torres J, Maue AC, Porter CK, et al. Serologic 
microbial associated markers can predict Crohn's disease behaviour years before disease 
diagnosis. Aliment Pharmacol Ther 2016;43(12):1300-10.
14.
Darfeuille-Michaud A, Neut C, Barnich N, Lederman E, Di Martino P, Desreumaux P, et al. 
Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn's disease. 
Gastroenterology 1998;115(6):1405-13.
15.
Darfeuille-Michaud A. Adherent-invasive Escherichia coli: a putative new E. coli pathotype 
associated with Crohn's disease. Int J Med Microbiol 2002;292(3-4):185-93.
16.
Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N, et al. High 
prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's 
disease. Gastroenterology 2004;127(2):412-21.
17.
Elliott TR, Hudspith BN, Wu G, Cooley M, Parkes G, Quinones B, et al. Quantification and 
characterization of mucosa-associated and intracellular Escherichia coli in inflammatory 
bowel disease. Inflamm Bowel Dis 2013;19(11):2326-38.
18.
Buisson A, Bringer MA, Barnich N, Vazeille E. Macrophages versus Escherichia coli: A 
decisive fight in Crohn's disease. Inflamm Bowel Dis 2016;22(12):2943-55.
19. Busch A, Phan G, Waksman G. Molecular mechanism of bacterial type 1 and P pili assembly. 
Philos Trans A Math Phys Eng Sci 2015;373(2036).
20.
Dreux N, Denizot J, Martinez-Medina M, Mellmann A, Billig M, Kisiela D, et al. Point 
mutations in FimH adhesin of Crohn's disease-associated adherent-invasive Escherichia coli 
enhance intestinal inflammatory response. PLoS Pathog 2013;9(1):e1003141.
21.
Martinez-Medina M, Garcia-Gil LJ. Escherichia coli in chronic inflammatory bowel 
diseases: An update on adherent invasive Escherichia coli pathogenicity. World J 
Gastrointest Pathophysiol 2014;5(3):213-27.
22.
Barnich N, Carvalho FA, Glasser AL, Darcha C, Jantscheff P, Allez M, et al. CEACAM6 
acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in 
Crohn disease. J Clin Invest 2007;117(6):1566-74.
23.
Barnich N, Darfeuille-Michaud A. Abnormal CEACAM6 expression in Crohn disease 
patients favors gut colonization and inflammation by adherent-invasive E. coli. Virulence 
2010;1(4):281-2.
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24.
Mossman KL, Mian MF, Lauzon NM, Gyles CL, Lichty B, Mackenzie R, et al. Cutting edge: 
FimH adhesin of type 1 fimbriae is a novel TLR4 ligand. J Immunol 2008;181(10):6702-6.
25.
Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M, et al. Uptake through 
glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature 
2009;462(7270):226-30.
26.
Chassaing B, Rolhion N, de Vallee A, Salim SY, Prorok-Hamon M, Neut C, et al. Crohn 
disease--associated adherent-invasive E. coli bacteria target mouse and human Peyer's 
patches via long polar fimbriae. J Clin Invest 2011;121(3):966-75.
27.
Abraham C, Cho JH. Bugging of the intestinal mucosa. N Engl J Med 2007;357(7):708-10.
28.
Bennett KM, Parnell EA, Sanscartier C, Parks S, Chen G, Nair MG, et al. Induction of 
colonic M cells during Intestinal Inflammation. Am J Pathol 2016;186(5):1166-79.
29. Martinez-Medina M, Aldeguer X, Lopez-Siles M, Gonzalez-Huix F, Lopez-Oliu C, Dahbi G, 
et al. Molecular diversity of Escherichia coli in the human gut: new ecological evidence 
supporting the role of adherent-invasive E. coli (AIEC) in Crohn's disease. Inflamm Bowel 
Dis 2009b;15(6):872-82.
30.
Ragnarsdottir B, Lutay N, Gronberg-Hernandez J, Koves B, Svanborg C. Genetics of innate 
immunity and UTI susceptibility. Nat Rev Urol 2011;8(8):449-68.
31.
Moore JM, Correa R, Rosenberg SM, Hastings PJ. Persistent damaged bases in DNA allow 
mutagenic break repair in Escherichia coli. PLoS Genet 2017;13(7):e1006733.
32.
Spaulding CN, Klein RD, Ruer S, Kau AL, Schreiber HL, Cusumano ZT, et al. Selective 
depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature 
2017;546(7659):528-32.
33.
Paillarse JM, Bonny C, Habibian M, Plassais J, Taquin P, Ostos M, et al. Association 
Between QPCR assays targeting FIMS/FIMH and aggregation to EB8018 : results of the 
MOBIDIC STUDY (molecular biomarkers and adherent and invasive Escherichia coli 
(AIEC) detection study in Crohn's disease patients). Gastroenterol 2019;156(6):S-1148-9. 
Tu1854.
34.
D'Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of 
recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. 
Gastroenterology 1998;114(2):262-7.
35.
Barnich N, Buisson A, Auzolle C, Rodrigues M, Stefanescu C, Nancey S, et al. The presence 
of adherent-invasive Escherichia coli strains on the surgical specimen is a predictor of severe 
endoscopic postoperative recurrence in Crohn's disease. J Crohns Colitis 2017;11(suppl 
1):S475-S6. 12th Congress of ECCO, Abstract No. P772.
36.
Neut C, Bulois P, Desreumaux P, Membre JM, Lederman E, Gambiez L, et al. Changes in 
the bacterial flora of the neoterminal ileum after ileocolonic resection for Crohn's disease. 
Am J Gastroenterol 2002;97(4):939-46.
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Appendix A
Schedule of Events
Study Period
Screening a
Study Visits b
ET h
Part 1 c
Part 2
W0 d,e
W3 e,f
W6 e
W12 e
W18 e
W26 e,g
W30 e,g
D1
D21 
±7d
D42 
±7d
D84 
±7d
D126 
±7d
D182 
±7d
D212 
±7d
Informed consent 
X
Inclusion/Exclusion criteria
X
X
Randomization d
X
Demographics/Medical
/Surgical history
X
Complete PE f
X
X
Targeted PE i
X
X
X
X
X
X
X
Vital signs j
X
X
X
X
X
X
X
X
X
ECG k
X
X
X
X
X
X
Concomitant medications and 
procedures
Recorded from the signing of the ICF through a maximum of 30 weeks after the first dose of study drug.
AE reporting
AEs are recorded from signing of the ICF for a maximum of 30 weeks after the first dose of study drug. g, h
Laboratory Assessments
HIV, Hepatitis B/C l
X
FSH / Pregnancy test m
X
X
X
X
X
X
X
X
X
Hematology/Chemistry n
X
X
X
X
X
X
X
X
X
Liver tests n
X
X
X
X
X
X
X
X
X
INR
X
X
X
X
X
X
X
X
X
Urinalysis o
X
X
X
X
X
X
X
X
X
Resected tissue c
X
Other Samples/Assessments
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Study Period
Screening a
Study Visits b
ET h
Part 1 c
Part 2
W0 d,e
W3 e,f
W6 e
W12 e
W18 e
W26 e,g
W30 e,g
D1
D21 
±7d
D42 
±7d
D84 
±7d
D126 
±7d
D182 
±7d
D212 
±7d
Plasma PK collection: 
continuous PK p
X
X
Plasma PK: sparse PK p
X
X
X
X
X
X
Blood sample for RNA q
X
X
X
X
Stool sample for fecal 
calprotectin q
X
X
X
X
X
X
X
X
Ileocolonoscopy 
 
X
Study drug distribution and 
compliance check u
X
X
X
X
X
X
X
AE: adverse event; COVID-2019: coronavirus disease 2019; D: day; ECG: electrocardiogram; eCRF: electronic case report form; ET: early termination; FSH: 
follicle stimulating hormone; HHC: home health care; ICF: informed consent form; IEC: independent ethics committee; INR: international normalized ratio; IRB: 
institutional review board; PE: physical examination; PK: pharmacokinetics; 
; W: week.
a Part 1 of screening visit must occur before the subject’s planned laparoscopic ileocecal resection (Part 2). The ICF must be signed before protocol-specified 
procedures are conducted. Unless otherwise noted, the screening visit must occur within 30 days before randomization (W0/D1). The ICF may be signed >30 days 
before D1.
b Visits should be performed on the scheduled day (as shown) but are allowed ±7 days as indicated for each visit.
c All screening procedures for Part 1 screening must be completed before a subject’s planned surgical procedure occurs. The surgical procedure includes a planned 
laparoscopic ileocecal resection with primary anastomosis. The ileocecal resection is an entry criterion that is not considered a study-related procedure and should 
be completed per an institution’s standard of care. Refer to the study manual for details on collection, processing, storage, and shipment of the resected sample.
d Randomization will be stratified by smoking status (Section 9.3.2) and occurs on D1 within 72 hours after surgery. Other than PK sampling (refer to Appendix B), 
study procedures on D1 should be conducted predose.
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Study Period
Screening a
Study Visits b
ET h
Part 1 c
Part 2
W0 d,e
W3 e,f
W6 e
W12 e
W18 e
W26 e,g
W30 e,g
D1
D21 
±7d
D42 
±7d
D84 
±7d
D126 
±7d
D182 
±7d
D212 
±7d
e Study visits on D1 and W26 are clinic visits; study visits at W3, W6, W12, W18, and W30 may be conducted as clinic or HHC visits. 
f The W3 visit includes a complete PE. A complete PE will include examination of general appearance, skin, head, eyes, ears, nose, throat, neck, lungs, abdomen 
(including liver and spleen), lymph nodes, extremities, cardiovascular system, genitourinary system, musculoskeletal system, neurological system, and weight; 
height will be measured only during screening. HHC visits related to COVID-19 or other similar pandemic may be performed by qualified health care professionals.
g All subjects will have a final study follow-up visit 30 days after their last dose of study drug. For subjects who complete study treatment, the final study visit will 
occur at W30, 30 days after the W26 endoscopy for final study assessments.
h Subjects who terminate study early will have a final follow-up visit 30 days after their last dose of study drug. This will include a targeted PE (see footnote i), vital 
signs, and chemistry/hematology/liver tests.
i A targeted PE will include examination of lungs, abdomen, skin, and cardiovascular system. Body weight measurement should also be collected.
j Vital sign measurements include blood pressure, heart rate, oxygen saturation, respiration rate, and body temperature. On clinic visit days, vital sign measurements 
should be performed before study drug is taken.
k Standard 12-lead ECG.
l Immunodeficiency and hepatitis virus testing are required to be performed only at the screening visit, unless satisfactory documentation of negative results of all 
such tests within 30 days of randomization are available.
m Pregnancy testing will be performed as follows or as otherwise required by local regulations. A serum choriogonadotropin beta pregnancy test will be performed 
only for subjects of childbearing potential during screening. A urine choriogonadotropin beta pregnancy test will be performed only for subjects of childbearing 
potential predose on scheduled study visits at D1, W3, W6, W12, W18, W26, and W30. The results must be negative before subsequent study drug is distributed. 
Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of an IEC/IRB, or if required by local regulations. 
For postmenopausal subjects, FSH screening will be performed and if below 40 IU/L, the need for adequate contraception (Section 9.3.17) should be confirmed 
before study drug is distributed.
n Blood samples should be collected on study visit days (D1 predose, and at W3, W6, W12, W18, and W26) and at W30 and at ET. Refer to the laboratory manual 
for details on collection, processing, storage, and shipment of these samples.
o Urine samples should be collected on study visit days (D1 predose, and at W3, W6, W12, W18, and W26) and at W30 and at ET. Urinalysis is performed centrally 
and includes dipstick for blood, protein, pH, specific gravity, ketones, bilirubin, nitrite, urobilinogen, leukocytes and glucose (microscopic examination, if 
abnormal).
p Blood samples for PK analysis will be collected as shown in Appendix B. Refer to the laboratory manual for details on collection, processing, storage, and 
shipment of plasma PK samples.
q Refer to the laboratory manual for details on collection, processing, storage, and shipment of these samples.
 
 
 
 
 
 
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Appendix B
Schedule of PK Samples 
Study Time 
(Week/Day):
Week 0 / Day 1
Week 3 / Day 21
Week 6 / Day 42
Week 12 / Day 84
Week 18
Week 26
Sampling time
(hr) a:
PK subgroup
Others
PK subgroup
Others
All
All
All
All
Predose
X b
X c
X b
X d
X c
X c
X c
X e
1
X
X
2
X
X
3
X
X
4
X
X
6
X
X
8
X f
X f
12
X f
X f
PK: pharmacokinetics.
Approximately one-third of subjects will participate in the PK subgroup. The actual date and time of the sample collection and the date and time for the last dose on 
the day before the collection day and for the first dose on the collection day should be accurately recorded in the electronic data capture. In addition to the scheduled 
PK sample collections, blood samples to measure TAK-018 plasma concentrations may be obtained during the on-treatment period and within 30 days after the last 
dose of study treatment, if clinically feasible, at the time of an adverse event that is judged by the investigator to be treatment-related. The unscheduled PK 
collections will be left to the discretion of the investigator.
a
PK sampling times are relative to the most recent dose (in hours).
b
PK samples on Day 1 and Week 3 collected 30 minutes predose.
c
One blood sample collected at beginning of study visit and another blood sample collected at the end of the study visit. These 2 collections should be made at 
least 30 minutes apart. 
d
One blood sample collected predose and another blood sample collected between 2 to 4 hours postdose.
e 
One blood sample collected before endoscopy on Week 26.
f
Blood samples for PK should be collected at these times; however, these samples are optional.
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Appendix C
Rutgeerts Grading Scale for Endoscopic Recurrence at the Ileocolonic 
Anastomosis and Preanastomotic Ileum
Rutgeerts Score
Endoscopic Description of Lesions
i0
No lesions.
i1
5 aphthous ulcers.
i2
>5 aphthous ulcers with normal mucosa between lesions or lesions are confined to the 
anastomosis.
i3
Diffuse aphthous ileitis with diffusely inflamed mucosa.
i4
Diffuse inflammation with larger ulcers, nodules, and/or narrowing.
Source: Adapted from Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the postoperative course of 
Crohn’s disease. Gastroenterology. 1990;99(4):956-63. 
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Appendix D
Guidance on Liver Test Abnormality Monitoring, Evaluation, and Follow-up
Investigators must be vigilant for abnormal liver test results in subjects during the clinical study. 
Transient fluctuations in serum aminotransferases occur commonly in clinical study subjects, but 
it is crucial that the investigator identifies and evaluates subjects with possible hepatic injury. This 
guidance is intended to aid investigations of abnormal liver tests in clinical study subjects who had 
no known liver disease and had either normal or near normal baseline liver tests (ie, ALT <2× 
ULN, total bilirubin <1.5× ULN, and ALP <1.5× ULN) at the time of enrollment.
In evaluating study subjects with abnormal liver test results, the investigator should perform 
follow-up laboratory tests to confirm the abnormal test results and monitor the subject. If the 
abnormal liver test results are confirmed, then the subject should be monitored and, if necessary, 
additional diagnostic tests should be performed as shown in Appendix D Figure 1. Suggested 
hepatic investigations are listed in Appendix D Table 1. Criteria for considering discontinuation of 
study drug are shown in Appendix D Figure 2.
Subjects with combined elevations in aminotransferase and bilirubin
If a subject has elevated ALT ≥3× ULN with concurrent elevated total bilirubin >2× ULN or 
elevated INR >1.5, the investigator must contact the sponsor’s medical monitor within 24 hours. 
Hepatic investigations as suggested in Table 1 should be initiated. Any event of elevated ALT ≥3× 
ULN with concurrent elevated total bilirubin >2× ULN or elevated INR >1.5 for which an 
alternative etiology has not been identified must be reported as an SAE.
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Appendix D Table 1: Hepatic Investigation
Characteristic
Recommended Considerations
Medical history

Concomitant medications (including over-the-counter medications such 
as acetaminophen, and herbal supplements)

Medical conditions (eg, ischemia, hypotension, severe hypoxemia, 
congestive heart failure, sepsis)

Alcohol intake

Hepatobiliary disorder

Previous liver disease or metabolic syndrome (eg, obesity, insulin 
resistance, diabetes, or dyslipidemia)

Travel history
Physical examination (symptoms, 
signs, and laboratory results)

General malaise, fatigue, nausea, or vomiting

Right upper quadrant pain or tenderness, fever, jaundice, rash

Eosinophilia >5%
Hepatic/hepatobiliary imaging
Perform as appropriate (eg, abdominal ultrasound, computed tomography, 
magnetic resonance imaging, or other hepatobiliary imaging)
Viral hepatitis serology

Hepatitis A antibody (total and IgM)

Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody 
(anti-HBsAb)), Hepatitis B core antibody (IgM anti-HBc), Hepatitis C 
antibodies (anti-HCV)

Hepatitis E (IgG and IgM)

Consider PCR for Hepatitis B, C, and E

Consider Epstein-Barr virus serology (viral capsid antigen [VCA] 
nuclear antigen [EBNA], early antigen [EA])

Consider cytomegalovirus serology (IgG and IgM)
Autoimmune hepatitis serology

Anti-nuclear antibody (ANA)

Anti-smooth muscle antibody (ASMA)

Anti-liver-kidney-microsomal antibody (anti-LKM)
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Appendix G
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, before 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 
21 Code of Federal Regulations (CFR) Part 56, 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 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix H
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 ICF, the subject 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 
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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 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 ICF or provided as a separate 
document) describing to the subject the contemplated and permissible uses and disclosures of 
the subject’s personal information (including personal health information) for purposes of 
conducting the study. The subject authorization must contain the following statements 
regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from screening throughout the duration of the study, and for a minimum of 40 days 
after last dose. Regular pregnancy tests will be performed throughout the study for all female 
subjects of childbearing potential. If a subject is found to be pregnant during study, study drug 
will be discontinued and the investigator will offer the subject the choice to receive unblinded 
treatment information.
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study, and for a minimum of 
100 days after last dose. If the partner or wife of the subject is found to be pregnant during the 
study, the investigator will offer the subject the choice to receive unblinded treatment 
information.
27. A statement that clinical study information from this study will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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Appendix I
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 
UK, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix J
Protocol History
Date
Amendment Number
Amendment Type
Region
08 October 2021
Amendment 05
Substantial
Global
30 July 2020
Amendment 04
Substantial
Global
14 January 2020
Amendment 03
Substantial
Global
05 December 2019
Amendment 02
Nonsubstantial
France
02 July 2019
Amendment 01
Substantial
Global
01 March 2019
Initial Protocol
Not applicable
Global
Rationale for Amendment 04
This document describes the changes in reference to the protocol incorporating Amendment 04. 
The primary reason for this amendment is to maintain subject safety, confidentiality, and study 
integrity in the context of health care delivery challenges presented by the coronavirus disease 
(COVID-19) pandemic. Amendment 04 provides flexibility to study participants to opt for home 
health care (HHC) solutions as permitted by local regulations. This “hybrid study design” will 
offer study participants the option of in clinic or HHC for study visits. Assessments after surgery 
and endoscopy at Week 26 are conducted at the clinic. All other study visits may be conducted by 
telehealth and HHC.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Changes in Amendment 04:
Protocol Amendment 04
Summary of Changes Compared With TAK-018-2001 Amendment 03
Description of Each Change and Rationale
Section(s) Affected by Change
Description
Rationale 
1
Specification that the surgical 
procedure is a prerequisite for 
enrollment to the study.
To clarify that surgery is not 
considered a study procedure.
Section 2.0 STUDY SUMMARY
Section 6.1 Overview of Study Design
2
Reference to study visits to 
enable distinction between clinic 
(onsite) and home health care 
(HHC) visits.
To provide flexibility to subjects 
as related to a pandemic (eg, 
coronavirus disease [COVID-19]) 
or other future similar unexpected 
public health concerns requiring 
physical distancing resulting in 
subjects missing their visits.
Section 2.0 STUDY SUMMARY
Section 4.3 Benefit/Risk Profile
Section 6.1 Overview of Study Design
Section 9.5 Completion of Study
Section 9.10 Final Visit or ET
Section 9.3.6 Vital Signs
Section 9.3.8.1 
Section 9.3.8.2 
Section 10.2.3.1 Collection Period
Appendix A Schedule of Events 
footnotes g, m, n, o, s
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Protocol Amendment 04
Summary of Changes Compared With TAK-018-2001 Amendment 03
Description of Each Change and Rationale
Section(s) Affected by Change
Description
Rationale 
3
Specification of clinic visits on 
Day 1 (D1) and Week 26 (W26) 
and that study visits at screening 
and on W3, W6, W12, W18, and
W30 may be conducted as clinic 
or HHC visits.
To provide flexibility to subjects 
as related to a pandemic (eg, 
COVID-19) or other future 
similar unexpected public health 
concerns requiring physical 
distancing resulting in subjects 
missing their visits. 
Section 2.0 STUDY SUMMARY
Section 6.1 Overview of Study Design 
and Figure 6.a
Section 9.3.17 Contraception and 
Pregnancy Avoidance Procedure
Appendix A Schedule of Events 
footnote e
4
Clarification regarding study 
drug administration related to 
changes in study procedures 
related to the pandemic.
To provide clarity when study 
drug should be taken relative to 
blood collections on given study 
visits and as related to a pandemic 
(eg, COVID-19) or other future 
similar unexpected public health 
concerns requiring physical 
distancing resulting in subjects 
missing their visits.
Section 8.1 Study Drug Administration
5
Clarification regarding physical 
examination (PE) during HHC 
visits.
To provide an alternative 
approach for PE at HHC visits 
related to a pandemic (eg, 
COVID-19) or other future 
similar unexpected public health 
concerns requiring physical 
distancing resulting in subjects 
missing their visits.
Section 9.3.4 Physical Examination
Appendix A Schedule of Events 
footnote f
6
Clarification regarding where 
pharmacokinetic (PK) sample 
collection times are recorded.
To identify that PK sample 
collection times are recorded in 
the electronic data capture.
Section 9.3.14 PK Sample Collection
Appendix B Schedule of PK Samples
7
Addition of information 
regarding changes to study 
procedures due to the pandemic.
To provide flexibility to subjects 
as related to a pandemic (eg, 
COVID-19) or other future 
similar unexpected public health 
concerns requiring physical 
distancing resulting in subjects 
missing their visits.
Section 9.3.16 Changes to Study 
Procedures Due to a Pandemic
Appendix A Schedule of Events
8
Clarification regarding 
posttreatment follow-up 
assessments for subjects who 
complete the study and for those 
who discontinue early.
To provide clarity concerning the 
timing of the posttreatment 
follow-up assessment for all 
subjects.
Section 9.9 Posttreatment Follow-up 
Assessments 
9
Addition of COVID-19–related 
terms to the Takeda Medically 
Significant Adverse Event list.
To be consistent with health 
authority guidance as related to 
the COVID-19 pandemic.
Section 10.1.1 SAEs Table 10.a
10
Correction that the safety 
To correct a previous error 
Section 13.1.7 Safety Analysis 
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Protocol Amendment 04
Summary of Changes Compared With TAK-018-2001 Amendment 03
Description of Each Change and Rationale
Section(s) Affected by Change
Description
Rationale 
assessment does not include 
electrocardiogram changes from 
baseline.
regarding the planned statistical 
safety analyses.
11
Changes in Appendix A
To provide clarity and flexibility 
regarding study procedures.
Appendix A Schedule of Events
12
Changes in Appendix D
To align with changes made by 
the internal Takeda liver subject 
matter expert guidance and to 
insert a clearer presentation of 
Figure 1. 
Appendix D Guidance on Liver Test 
Abnormality Monitoring, Evaluation, 
and Follow-up
Rationale for Amendment 03
This document describes the changes in reference to the protocol incorporating Amendment 03.
The primary reason for this amendment is to change the protocol design from a safety/proof of 
mechanism study to an early proof of concept study. The original study design presented in 
Amendment 01 was limited by 3-month toxicology coverage, an inadequate dosing interval to 
assess the efficacy of TAK-018 in prevention of endoscopic recurrence. The recent availability of 
favorable long-term toxicology enables a 6-month dosing interval that also aligns with standard of 
care colonoscopy performed by treating physicians 6-months after surgery. Based on the longer 
treatment period, Protocol Amendment 03 contains additional changes to the study design that 
include a change in the primary endpoint to assess efficacy, identification of a safety objective 
distinct from efficacy objectives, clarifications to the secondary 
 
endpoints, and changes in the statistical considerations that include an increase in the number of 
subjects and deletion of the interim analysis. Other changes in Protocol Amendment 03 are made 
to respond to US and European health authorities and ethics committees requests for information 
regarding Study TAK-018-2001, including the addition of the composition of study drug and 
placebo tablets. Updates have also been made to clarify logistical and operational aspects of the 
study.
In addition, minor grammatical, editorial, formatting, and administrative changes not affecting the 
conduct of the study are included for clarification and administrative purposes only.
For specific description of text changes and where the changes are located, see Appendix J. 
Changes in Amendment 03:
1.
Addition of results from the chronic toxicity studies in dogs and rats. 
2.
Updated information for the phase 1b Study EBFIM117.
3.
Changes to the primary, safety, secondary, and exploratory objectives.
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30. Corrections to the statistical analyses sections.
31. Updates to Appendix A, Schedule of Events (and footnotes), to align with changes in the text.
32. Corrections and clarifications made to Appendix C.
Rationale for Amendment 02
This document describes the changes in reference to the protocol incorporating Amendment 02.
The primary reason for this amendment is to include revisions in response to feedback on the 
protocol from the French Comité de Protection des Personnes (CPP), central ethics committee. A 
summary of the changes incorporated in this amendment is outlined below and detailed in 
Appendix J.
In addition, minor grammatical, editorial, formatting, and administrative changes not affecting the 
conduct of the study are included for clarification and administrative purposes only.
For specific description of text changes and where the changes are located, see Appendix J. 
Changes in Amendment 02:
1. Clarification of the primary endpoint.
2. Clarification of the duration of the study.
3. Clarification of the exclusion criteria.
Rationale for Amendment 01
This document describes the changes in reference to the protocol incorporating Amendment 01.
The primary reason for this amendment is to include study stoppage criteria based on Common 
Terminology Criteria for Adverse Events (CTCAE) grading, inclusion of details relating to subject 
discontinuation, early termination, and to replace adverse event (AE) assessment terminology with 
the CTCAE, Version 5 scale. These revisions are being incorporated in response to feedback on 
the protocol from the United States (US) Food and Drug Administration (FDA). Updates have also 
been made to clarify logistical and operational aspects of the study.
In addition, minor grammatical, editorial, formatting, and administrative changes not affecting the 
conduct of the study are included for clarification and administrative purposes only.
For specific description of text changes and where the changes are located, see Appendix J. 
Changes in Amendment 01:
1. Update to include descriptive information on nonclinical findings relating to rat specific renal 
tubular degeneration to align with the investigator brochure (IB).
2. Update to clarify when study drug should be taken in relation to meal consumption and 
clarification regarding when treatment will start.
3. Update that subjects who terminate early from the study will have a final visit 30 days after 
their last dose of study drug. 
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1.1
APPROVAL SIGNATURES
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 Harmonization E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
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
INTRODUCTION...........................................................................................................8
5.0
OBJECTIVES .................................................................................................................8
5.1
Primary Objective......................................................................................................8
5.2
Safety Objective ........................................................................................................8
5.3
Secondary Objectives.................................................................................................8
5.4
Exploratory Objectives ..............................................................................................8
5.5
Study Design .............................................................................................................9
6.0
STUDY ENDPOINTS...................................................................................................10
6.1
Primary Endpoint.....................................................................................................10
6.2
Safety Endpoint .......................................................................................................10
6.3
Secondary Endpoints ...............................................................................................10
6.4
Exploratory Endpoints .............................................................................................11
7.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
8.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
8.1
General Considerations............................................................................................11
8.1.1
Statistics and Precision................................................................................11
8.1.2
Definition of Study Day and Visit Windows................................................12
8.2
Important Protocol Deviations .................................................................................12
8.3
Analysis Sets ...........................................................................................................13
8.4
Disposition of Subjects ............................................................................................14
8.5
Demographic and Baseline Characteristics...............................................................14
8.6
Disease Characteristics ............................................................................................14
8.7
Medical History and Concurrent Medical Conditions...............................................14
8.8
Medication/Procedure History and Concomitant Medications/Procedures................15
8.9
Study Drug Exposure and Compliance.....................................................................15
8.10
Primary and Secondary Efficacy Analyses...............................................................16
8.10.1
Primary Efficacy Analyses..........................................................................16
8.10.1.1
Sensitivity Analyses ...............................................................................17
8.10.2
Secondary Efficacy Analyses ......................................................................17
8.11
Pharmacokinetic Analyses .......................................................................................18
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
BID
twice daily
BLQ
below the limit of quantification
BMI
body mass index
BUN
blood urea nitrogen
CD
Crohn’s disease
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CTCAE
common terminology criteria for adverse events
CV
coefficient of variation
eCRF
electronic case report form
D1
Day 1
ET
early termination
ERR
endoscopic recurrence rate
FAS
full analysis set
FCP
fecal calprotectin
FCS
fully conditional specification
GLMM
generalized linear mixed model
HHC
home health care
IBD
inflammatory bowel disease
ICH
International Conference on Harmonization
ICF
informed consent form
IMP
investigational medical product
LLN
lower limit of normal
LLOQ
lower limit of quantitation
LOCF
last observation carried forward
LS
least squares
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MOA
mechanism of action
OC
observed case
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PCS
potentially clinically significant
PE
physical examination
PK
pharmacokinetics
PPS
per protocol set
Q1
lower quartile
Q3
upper quartile
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SD
standard deviation
SE
standard error
SI unit
international system of units
SOC
system organ class
TBILI
total bilirubin
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
VAS
visual analog score
WBC
white blood cell
WHO
World Health Organization
W3
Week 3
W6
Week 6
W12
Week 12
W18
Week 18
W26
Week 26
W30
Week 30
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4.0
INTRODUCTION
This document describes the statistical analyses to be performed and data presentations to be 
produced for this randomized, double-blinded, placebo-controlled, phase 2a study to evaluate the 
safety, tolerability, and Early Proof of Concept of TAK-018 for the prevention of postoperative 
Crohn’s Disease (CD) recurrence in subjects who are undergoing a planned laparoscopic 
ileocecal resection with primary anastomosis.
The purpose of this statistical analysis plan (SAP) is to ensure the credibility of the study 
findings by specifying the statistical approaches to the analyses of the double-blinded data prior 
to database lock. This SAP was developed based on the International Conference on 
Harmonization (ICH) E3 and E9 Guidelines and in reference to the following document:

Protocol TAK-018-2001 Amendment 05 dated 08 October 2021.
Any deviations during the analysis and reporting process from the current statistical analysis plan 
will be described and justified in the final report. Analysis issues that suggest changes to the 
principal features stated in the protocol will be documented in a protocol amendment. Otherwise, 
the statistical analysis plan will be updated through an amendment in which the changes in the 
analysis will be documented.
5.0
OBJECTIVES
5.1
Primary Objective

To evaluate the efficacy of TAK-018 in reducing endoscopic recurrence of intestinal 
inflammation in postoperative subjects with CD after planned laparoscopic ileocecal 
resection with primary anastomosis.
5.2
Safety Objective

To assess the safety and tolerability of TAK-018 in postoperative subjects with CD after 
planned laparoscopic ileocecal resection with primary anastomosis.
5.3
Secondary Objectives

To evaluate the effect of TAK-018 on intestinal inflammation based on serial fecal 
calprotectin measurements. 

To characterize the pharmacokinetics (PK) of TAK-018 in postoperative subjects with CD 
after planned laparoscopic ileocecal resection with primary anastomosis. 
5.4
Exploratory Objectives
 
. 
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Table 8.a
Analysis Visit Window
Visit
Scheduled
Day
Safetya
ECG
Endoscopy
/
FCP
Baseline
Day 1
≤1
≤1
≤1
≤1
W3
Day 21
2-32
2-53
NA
2-32
W6
Day 42
33-63
NA
NA
33-63
W12
Day 84
64-105
54-133
NA
64-105
W18
Day 126
106-154
NA
NA
106-154
W26
Day 182
155-196
134-196
≥91
155-196
W30
Day 212
≥197
≥197
NA
≥197
a Safety analyses parameters including safety labs, vital signs, and urinalysis. 
8.3
Analysis Sets
The following analysis sets will be used:

Full analysis set (FAS) will include all subjects to whom study treatment have been assigned 
by randomization and received at least 1 dose of study drug. Subjects in this set will be 
analyzed by the treatment arm to which the subjects were randomized.

Per protocol set (PPS) will include all FAS subjects who had no important protocol deviation 
that could confound the interpretation of the primary analyses based on the FAS. Subjects 
with any of the following protocol deviations will be excluded from the FAS to form the 
PPS. 
–
Subject do not have a documented diagnosis of CD confirmed by endoscopic biopsy 
before resection or by tissue obtained at resection.
–
Non-evaluable ileocolonoscopic score at W26 (with the analysis visit window in 
Table 8.a applied).
–
Subjects received wrong treatment during study.
The PPS will be used as a supplemental analysis for the primary efficacy endpoint.

Response-evaluable set will include all randomized subjects who received at least 1 dose of 
study drug and had an evaluable ileocolonoscopic score at W26. Subjects in this set will be 
analyzed by the treatment arm to which the subjects were randomized.

Safety analysis set (SAS) will include all randomized subjects who receive at least 1 dose of 
study drug. Subjects in this set will be analyzed according to the treatment received.

PK analysis set: Subjects from the safety analysis set with at least 1 reported PK 
concentration. Subjects in this set will be analyzed according to the treatment received.
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8.4
Disposition of Subjects
A subject disposition summary presented by treatment group and overall will be provided for all 
randomized subjects. The categories will include all subjects who were randomized, subjects 
who were not treated, subjects who discontinued from the study categorized by reason, and 
subjects who completed the study. Post-randomization discontinuation reasons will include all 
categories collected on the eCRF. A listing will be presented to describe study treatment, date of 
first dose, date of last dose, date of completion or early withdrawal, and the reason for early 
discontinuation for each subject.
A summary of screening failures and listings of inclusion/exclusion criteria responses for 
subjects with protocol deviations will also be provided.
8.5
Demographic and Baseline Characteristics
Demographic, baseline characteristics including sex, age, race, height, weight, body mass index 
(BMI), and smoking status will be listed and summarized for each treatment group and overall. 
These summaries will be based on FAS.
Height and weight values will be presented in metric units (cm and kg respectively). BMI is 
calculated as [weight (kg)/height (m) 2], using the weight collected prior to first dose date. 
All individual demographic and baseline data will be listed by treatment, study center and 
subject number.
8.6
Disease Characteristics
Crohn’s Disease characteristics including family history of inflammatory bowel disease (IBD), 
time from diagnosis until randomization (months), number of acute exacerbations during the last 
12 months, location and extent of the disease, prior interventions and prior therapies related to 
the disease will be summarized for each treatment group and overall. These summaries will be 
based on FAS.
All individual disease-related data will be listed by treatment, study center and subject number.
8.7
Medical History and Concurrent Medical Conditions
Medical history refers to significant conditions/diseases that stopped at or prior to Screening 
(time of informed consent). Concurrent medical conditions are those significant ongoing 
conditions/diseases present at Screening (time of informed consent).
Medical history and concurrent medical conditions will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) latest version and will be summarized by treatment group and 
overall using System Organ Class (SOC) and MedDRA preferred term based on FAS. The table 
will include number and percentages of subjects and will be sorted in alphabetical order by 
system organ class and preferred term. A subject will only be counted once within a particular 
class even if he/she has multiple conditions/symptoms. 
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All medical history and concurrent medical condition data will be listed by treatment, study 
center and subject number.
8.8
Medication/Procedure History and Concomitant Medications/Procedures
The medication/procedure history and concomitant medications/procedures are defined as 
follows:

Medication/procedure history refers to the medication/procedure that the study subjects 
stopped taking within 30 days prior to randomization.

Concomitant medication/procedure is defined as medication/procedure that the study subjects 
continued taking or started after randomization.
In the case of missing or partial dates, the rules of imputation are defined in Appendix C. 
Medication history and concomitant medications will be coded using the latest version of the 
World Health Organization (WHO) Drug Dictionary and summarized by treatment group and 
overall using preferred term within each anatomical therapeutic class, with anatomical 
therapeutic class and medications in each class sorted in alphabetical order based on FAS. If a 
subject reports taking more than one drugs belonging to the same class, he/she will only be 
counted once within that class. 
All prior and concomitant medications will be listed by treatment, study center and subject 
number. The listings will contain subject identifier, WHO Drug preferred term and reported 
term, dose, unit, route, frequency, the indication for which the medication was being taken, start 
date, whether start date was before or after signing informed consent, stop date, and whether the 
medication was ongoing.
All prior and concomitant procedures will be listed by treatment, study center, and subject 
number. The listings will contain subject identifier, category of procedure, procedure name, the 
indication for which the procedure was being taken, start date, whether start date was before or 
after signing informed consent, stop date, and whether the medication was ongoing.
8.9
Study Drug Exposure and Compliance
The summary of study drug exposure and compliance will be based on the safety analysis set.
The duration of exposure (weeks) to study medications is defined as (date of last dose – date of 
first dose +1)/7. Treatment duration will be summarized using descriptive statistics (n, mean, SD, 
median, Q1, Q3, minimum, and maximum). In addition, the number and percentage of subjects 
in each duration category (≤4 weeks, 4 - ≤8 weeks, 8 - ≤12 weeks, 12 - ≤16 weeks, 
16 - ≤20 weeks, 20 - ≤26 weeks, and >26 weeks) will be summarized by treatment group and 
overall. 
Percent of study drug compliance is defined as (number of tablets dispensed – number of tablets 
returned)/[(date of last dose – date of first dose +1)*6]*100%. If a value for the number of 
returned tablets is missing or the return date is missing, then 100% compliance will be assigned 
for each day up to number of tablets dispensed or up to the date of return whichever is earlier.
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The number and percentage of subjects in each compliance category (<80% and ≥80%) will be 
summarized by treatment group and overall. Study medication compliance will also be 
summarized as a continuous variable using descriptive statistics (n, mean, SD, median, Q1, Q3, 
minimum, and maximum) by treatment group and overall.
All study drug administration and accountability data will be listed by treatment, study site, and 
subject number. The following variables will be listed: subject identifier, visit number, first and 
last dose dates, medication identification number, date dispensed and returned, number of tablets 
dispensed and returned, and percent compliance. 
8.10
Primary and Secondary Efficacy Analyses
All efficacy endpoints will be analyzed by placebo arm, TAK-018 dose arms, and TAK-018 
pooled using the FAS.
8.10.1
Primary Efficacy Analyses
The number and percentage of subjects with evaluable ileocolonoscopic score at W26 will be 
summarized by the ordinal Rutgeerts score of endoscopic lesions (Appendix A) and treatment 
arm (ie, placebo arm, TAK-018 dose arms, and TAK-018 pooled) based on FAS.
The endoscopic recurrence is defined as a subject with Rutgeerts score of endoscopic lesions 
being graded equal to or higher than the ordinal Rutgeerts score i2 at W26. The 
Cochran-Mantel-Haenszel (CMH) test using the randomization stratification factor (smoking 
status) will be used for the comparison of the endoscopic recurrence rate (ERR) between 
TAK-018 dose arms (ie, two TAK-018 dose arms and TAK-018 pooled) and placebo arm. In the 
case of small cell sizes (ie, <5), the Fisher’s exact test will be used instead of the CMH test. The 
estimate of ERR of each treatment arm and its 95% CI will be reported (the exact 
Clopper-Pearson CI will be reported if Fisher’s exact test are used). The estimates of the 
difference in ERR between TAK-018 dose arms and placebo arm and their 80% and 95% CIs 
(the exact Clopper-Pearson CI will be reported if Fisher’s exact test are used) will be provided as 
well. In addition, the nominal two-sided p-values for testing the differences in ERR between the 
TAK-018 dose arms (ie, two TAK-018 dose arms, and TAK-018 pooled) and placebo arm will 
be reported. 
The primary efficacy analysis will be conducted using both local and central reads of the 
endoscopic results. Analysis results based on local and central reads will be reported separately. 
In the primary efficacy analysis, missing data will be handled using non-responder (worst-case) 
imputation, ie, subjects will be classified as endoscopic recurrence (ie, ordinal Rutgeerts score is 
i2 or higher) at W26 if no endoscopy was performed at W26 or if the ileocolonoscopic score was 
unevaluable at W26.
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8.10.1.1
Sensitivity Analyses
To assess the robustness of the primary efficacy analysis, the following additional sensitivity
analyses will be performed for the primary efficacy endpoint:

The primary efficacy analysis described in section 8.10.1, will be repeated using the 
response-evaluable set.

The primary efficacy analysis described in section 8.10.1, will be repeated using the PPS.
The sensitivity analysis will be conducted using both local and central reads of the endoscopic 
results. Analysis results based on local and central reads will be reported separately.
8.10.2
Secondary Efficacy Analyses
The actual values of fecal calprotectin (FCP) in stool sample will be summarized by treatment 
arms (ie, placebo arm, TAK-018 dose arms, and TAK-018 pooled) and scheduled visits 
(ie, Baseline, W3, W6, W12, W18, W26, and W30) using descriptive statistics (n, mean, SD, 
median, Q1, Q3, minimum, and maximum) based on FAS. In addition, the number and 
percentage of subjects with FCP level >135 µg/g, >250 µg/g, and <100 µg/g will be summarized 
respectively by treatment arms (ie, placebo arm, TAK-018 dose arms, and TAK-018 pooled) and 
scheduled visits (ie, Baseline, W3, W6, W12, W18, W26, and W30) based on FAS.
The generalized mixed-effects model (GLMM) will be applied to analyze the secondary efficacy 
endpoints (ie, rates of FCP level >135 µg/g, >250 µg/g, and <100 µg/g, respectively) observed at 
visits of W3, W6, W12, W18, and W26 to assess the treatment difference between TAK-018 
dose arms and placebo. In GLMM, the missing continuous values of FCP at visits of W3, W6, 
W12, W18, and W26 will be handled using multiple imputation (MI), ie, the missing FCP value 
(based on log-10 transformation) will be imputed by treatment group, smoking status at 
randomization, and baseline FCP value (on a log-10 transformation) via a multivariate step-wise 
approach using fully conditional specification (FCS) regression method. Twenty-five (25) 
complete datasets will be computed and analyzed by using GLMM, as the relative efficiency is 
sufficiently high with the expected fraction of missing information is 65%.The results from the 
25 complete datasets will be combined for the GLMM inference following Rubin’s rule.
The GLMM will have FCP level >135 µg/g, >250 µg/g, and <100 µg/g as response variable, 
respectively, with treatment group, visit, treatment and visit interaction, smoking status at 
randomization, and baseline FCP value (on log-10 transformation) as fixed effects, and subject 
as random effect. The estimate of the FCP rate of each treatment arm at each visit (ie, W3, W6, 
W12, W18, and W26) and its 95% CI will be reported. The estimates of the difference in FCP 
rates and the odds ratio between TAK-018 dose arms and placebo at each visit, and its associated 
95% CIs and nominal two-sided p-values based on the GLMM will be reported as well.
Among the 25 complete datasets from MI procedure, if less than 15 (<60%) datasets analyzed by 
using GLMM converge after database lock, other analyses, such as the GLMM without adjusting 
for smoking status at randomization, the chi-squared test or the Fisher’s exact test in the case of 
small cell sizes at each scheduled visits, will be explored. 
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receiving the last dose of study drug (AE start date - last dose date ≤30). A TEAE may also be a 
pretreatment adverse event or a concurrent medical condition diagnosed prior to the date of first 
dose of study drug that increases in severity after the start of dosing. Adverse events data with 
onset occurring more than 30 days after last dose of study drug (AE start date - last dose date 
>30) will be listed, but not included in the summary tables. In the case of missing or partial 
dates, the rules of imputation are defined in Appendix C. 
Serious adverse events (SAEs) with onset that occurs after receiving study drug (AE start date 
≥first dose date) and within 30 days after receiving the last dose of study drug (AE start 
date - last dose date ≤30) will be summarized.
At the adverse event level, the summary tables will present the number of subjects reporting each 
of these MedDRA events, ie, the number of subjects reporting 1 or more events that map to the 
given MedDRA term.
At the SOC level, the summary tables will present the number of subjects reporting 1 or more 
events that map to the given SOC. That is, the number of subjects reported at the SOC level will 
be less than or equal to the sum of the subject counts across all adverse events within that SOC.
In selected summaries (TEAEs overview, and TEAEs by SOC and preferred term), adverse 
events will be summarized by Placebo, TAK-018 dose arms, TAK-018 pooled, and Overall using 
the number and percentage of subjects with events.
For the summary of TEAEs by SOC, preferred term and maximum intensity, if a subject 
experiences more than 1 episode of a particular coded adverse event, the subject will be counted 
only once by the maximum intensity of the episode (preferred term). Similarly, if a subject has 
more than 1 adverse event within an SOC, the subject will be counted only once by the 
maximum intensity in that SOC. Adverse events with missing severity will be classified as 
having the highest severity. Similarly, adverse events with missing relationship will be classified 
as having the highest relationship to study drug.
The following summaries will be presented:

Overview of TEAEs during the study - number and percentage of subjects.

TEAEs by SOC and preferred term - number and percentage of subjects.

TEAEs by SOC and preferred term by sex (male and female) - number and percentage of 
subjects.

TEAEs by SOC and preferred term by age group (≤65, >65) - number and percentage of 
subjects.

TEAEs with grade 3 or higher by SOC and preferred term - number and percentage of 
subjects.

Treatment-related TEAEs by SOC and preferred term - number and percentage of subjects.

Treatment-related TEAEs with grade 3 or higher by SOC and preferred term - number and 
percentage of subjects.
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
TEAEs leading to study discontinuation by SOC and preferred term - number and percentage 
of subjects.

Treatment-emergent SAEs by SOC and preferred term - number and percentage of subjects.

Treatment-related treatment-emergent SAEs by SOC and preferred term - number and 
percentage of subjects.

Most frequent non-serious TEAEs (>5% in any treatment arm) by preferred term - number 
and percentage of subjects
SOCs will be sorted by alphabetical order. Within a SOC, adverse events will be sorted in 
descending order of total number of subjects with preferred term among all the treatment groups.
All adverse events will be listed by treatment, study center, subject number and onset date of the 
adverse event. The listing will contain subject identifier, age, sex, body weight, race, adverse 
event (preferred term and reported term), SOC, onset date, end date or whether the event was 
ongoing, duration, frequency, intensity (mild, moderate or severe), action taken concerning study 
drug, causality to study drug, the outcome, and whether the adverse event was an SAE. 
8.13.2
Clinical Laboratory Evaluations
The summaries will include all clinical laboratory assessments collected no later than 30 days 
after the last administration of study treatment. All laboratory assessments will be listed and 
those collected later than 30 days after the last treatment date will be flagged in the listings.
Laboratory data will be classified into CTC grades according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0. For laboratory tests where grades are not defined by 
CTCAE, results will be graded by the low/normal/high classifications based on laboratory 
normal ranges.
For each laboratory parameter, the following will be displayed for each scheduled time point
(each visit and end of study).

Summary statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) by Placebo, 
TAK-018 dose arms, TAK-018 pooled, and Overall for the actual values and change from 
Baseline values.

Shift tables using CTCAE grades to compare baseline to the worst post-baseline value will be 
produced for hematology and chemistry laboratory parameters with CTCAE grades.

Shift tables for the change from Baseline to each post-baseline time point will be presented. 
For these tables each subject will be categorized as low, normal, or high for the baseline 
value, and low, normal, or high for each post-Baseline time point, according to the central 
laboratory reference ranges. The number of subjects in each of the combinations of shifts will 
be presented.

Potentially clinically significant (PCS) laboratory values, as defined in Appendix A, will be 
summarized by treatment group and overall. The number and percentage of subjects with 
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PCS values observed post-Baseline in each of the applicable laboratory parameters will be 
presented.

For liver function tests, the number and percentages of subjects with the worst post-baseline 
values that fall in each of the listed categories will be summarized by Placebo, TAK-018 
dose arms, TAK-018 pooled, and Overall:
–
ALT:
‒
>3 × upper limit of normal (ULN);
‒
>5 × ULN;
‒
>8 × ULN;
‒
>20.0 × ULN.
–
AST:
‒
>3 × ULN;
‒
>5 × ULN;
‒
>8 × ULN;
‒
>20 × ULN.
–
ALT or AST:
‒
ALT >3 × ULN or AST >3 × ULN;
‒
ALT >5 × ULN or AST >5 × ULN;
‒
ALT >8 × ULN or AST >8 × ULN;
‒
ALT >20 × ULN or AST >20 × ULN.
–
ALT/AST and Total Bilirubin (TBILI):
‒
ALT >3 × ULN AND TBILI >2 × ULN;
‒
AST >3 × ULN AND TBILI >2 × ULN;
‒
(ALT >3 × ULN or AST >3 × ULN) AND TBILI >2 × ULN.
A listing of all laboratory data will be provided. Laboratory data outside of the normal reference 
range will be flagged on the listing along with values meeting PCS criteria. The listing will also 
include the age (at consent) and sex of the subject. Listings of PCS laboratory values will also be 
presented. 
Summaries and listings of laboratory data will be presented in conventional units.
8.13.3
Vital Signs and Weight
Vital signs and weight at scheduled visits and their changes from Baseline will be summarized 
by Placebo, TAK-018 dose arms, TAK-018 pooled, and Overall using descriptive statistics by 
visit and end of study. The number and percentage of subjects with at least one post-Baseline 
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PCS vital sign value during the double-blind treatment period will be presented by Placebo, 
TAK-018 dose arms, TAK-018 pooled, and Overall for each variable over all visits. A listing of 
PCS vital signs values will also be presented. The criteria for identification of PCS vital signs 
values are given in Appendix A.
8.13.4
Physical Examinations
All physical examination findings, if applicable, will be listed by treatment, study center and 
subject number. The following variables will be listed: subject identifier, age, sex, study visit, 
visit date, body system, whether there was an abnormality, and, a description of the abnormality.
8.13.5
Pregnancy Test, Urine Drug and Alcohol Screen Test
For females, pregnancy test results will be listed by treatment, study center and subject number.
8.13.6
12-lead ECG
The investigator’s ECG interpretation (ie, with normal limits, abnormal but not clinically 
significant, abnormal and clinically significant, and not evaluable) will be summarized by 
Placebo, TAK-018 dose arms, TAK-018 pooled, and Overall using descriptive statistics by visit 
(Baseline, W3, W12, W26) and end of study based on safety analysis set. 
All ECG data will be presented in the by-subject listing based on safety analysis set.
8.14
Interim Analysis
Not applicable.
8.15
Changes in the Statistical Analysis Plan 
8.15.1
Changes From the Protocol Analysis Plan
Version 
Protocol Version
Changes
Justifications 
1
Amendment 04, 
Protocol Date: 
30 July 2020
Rephrase the definition of the primary 
endpoints
To make the endpoint more clearly 
defined.
Rephrase the definitions of some binary 
secondary 
 endpoints
To make these endpoints to become 
variables defined at a subject level 
instead of summary statistics at a 
population level.
Add the definition of per protocol set.
To provide a sensitivity analysis of 
the primary endpoint based on the 
per protocol set.
Add the option of using the Fisher’s exact 
test as an alternative to the CMH test in the 
case of small cell sizes (ie, the expected 
values of any of the cells of the 
contingency table are below 5).
To make the analysis method more 
robust in case of small cell sizes.
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Appendix A
Rutgeerts Grading Scale for Endoscopic Recurrence at the Ileocolonic 
Anastomosis and Pre-anastomotic Ileum
Rutgeerts Score
Endoscopic Description of Lesions
i0
No lesions.
i1
5 aphthous ulcers.
i2
>5 aphthous ulcers with normal mucosa between lesions or lesions are 
confined to the anastomosis.
i3
Diffuse aphthous ileitis with diffusely inflamed mucosa.
i4
Diffuse inflammation with larger ulcers, nodules, and/or narrowing.
Source: Adapted from Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the postoperative course of 
Crohn’s disease. Gastroenterology. 1990;99(4):956-63.
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Appendix C
Missing/Partial Dates for Adverse Event/Concomitant 
Medication/Procedures
Missing Data Imputation for Start Dates
If the stop date is non-missing and the imputed start date is after the stop date, the stop date will 
be used as the start date.
(1)Missing day only

If the month and year are the same as the month and year of the first dose date, the 
first dose date will be used.

If the month and year are before the month and year of the first dose date, the last day 
of the month will be assigned to the missing day.

If the month and year are after the month and year of the first dose date, the first day 
of the month will be assigned to the missing day.
(2) Missing day and month

If the year is the same as the year of the first dose date, the first dose date will be 
used.

If the year is prior to the year of the first dose date, December 31 will be assigned to 
the missing fields.

If the year is after the year of the first dose date, January 1st will be assigned to the 
missing fields.
(3) Missing day, month, and year

The first dose date will be used.
Missing Data Imputation for Stop Date
If the start date is non-missing and the imputed stop date is before the start date, the start date 
will be used. If the death date is available and the imputed stop date is after the death date, the 
death date will be used.
(1) Missing day only

The last day of the month will be assigned as the missing day.
(2) Missing day and month

December 31 will be assigned to the missing fields.
(3) Missing day, month and year

The event will be regarded as ongoing.
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Appendix D
Criteria for Identification of Potentially Clinically Significant Laboratory 
Values
Parameter
Unit Type
Unit (a)
PCS Definition
Sodium
SI
mmol/L
High: 155, Low: 125
conventional
mEq/L
High: 155, Low: 125
Potassium
SI
mmol/L
High: 5.5, Low: 3.0
conventional
mEq/L
High: 5.5, Low: 3.0
Calcium (total)
SI
mmol/L
High: 3.0, Low: 1.75
conventional
mg/dL
High: 12.0, Low: 7.0
Creatinine
SI
mol/L
High: 175
conventional
mg/dL
High: 2.0
Creatine phosphokinase (CPK)
both
U/L
High: 2ULN
Uric acid
SI
mol/L
High: 1.3ULN, Low: 0.7LLN
conventional
mg/dL
High: 1.3ULN, Low: 0.7LLN
Glucose (non-fasting)
SI
mmol/L
High: 13.9, Low: 2.8
conventional
mg/dL
High: 250, Low: 50
Cholesterol (total)
SI
mmol/L
High: 7.8
conventional
mg/dL
High: 302
Triglycerides
SI
mmol/L
High: 3.40
conventional
mg/dL
High: 301
High density lipoproteins (HDL) 
cholesterol
SI
mmol/L
Low: <0.9
conventional
mg/dL
Low: <35
Low density lipoproteins (LDL) 
cholesterol
SI
mmol/L
High: 5.0
conventional
mg/dL
High: 193
Urinalysis
Glucose
N/A
Protein
N/A
Occult Blood
N/A
Pregnancy
N/A
(a) Systeme International (SI) units, conventional units and conversion factors were obtained from Laposata, 
Michael. SI Unit Conversion Guide. Boston: NEJM Books, 1992.
LLN=lower limit of normal range; N/A=not applicable; PCS=potentially clinically significant; ULN=upper limit of 
normal range.
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Appendix E
Criteria for Identification of Potentially Clinically Significant Vital Signs
Parameter
Unit
PCS Definition (a)
Systolic Blood Pressure
mmHg
180 mmHg and an increase of 20 mmHg or
90 mmHg and a decrease of 20 mmHg
Diastolic Blood Pressure
mmHg
105 mmHg and an increase of 15 mmHg or
50 mmHg and a decrease of 15 mmHg
Pulse
bpm
120 bpm and an increase of 15 bpm or
50 bpm and a decrease of 15 bpm
Weight
kg
Change of 7% body weight
(a) PCS criteria are applied to postbaseline values and changes relative to Baseline values, as appropriate.
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