A Follow-up of a Phase 3 Study to Evaluate the Long-term Safety and Efficacy of Darvadstrocel in the Treatment of Complex Perianal Fistula in Subjects With Crohn's Disease Who Have Participated in ADMIRE II Study
Phase: PHASE3
Conditions: Crohn's Disease, Complex Perianal Fistula
Sponsor: Takeda

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TAKEDA PHARMACEUTICALS
PROTOCOL
A Follow-up of a Phase 3 Study to Evaluate the Long-term Safety and Efficacy of Darvadstrocel 
in the Treatment of Complex Perianal Fistula in Subjects With Crohn’s Disease Who Have 
Participated in ADMIRE II Study
Short Title
Long-term Follow-up Study With Darvadstrocel in the Treatment of Complex Perianal Fistula
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421 USA
Study Number:
Darvadstrocel-3003
IND Number:
017707
EudraCT Number:
2019 000333-39
clinicaltrials.gov:
NCT04075825
Compound:
Darvadstrocel (Cx601)
Expanded human allogeneic mesenchymal adult stem cells extracted from 
adipose tissue (expanded adipose stem cells)
Date:
17 November 2022
Amendment Number:
2
Amendment History:
Date
Amendment Number
Amendment Type
Region
17 November 2022
2
Substantial 
Global
26 January 2022
1
Substantial
Global
22 March 2019
Initial protocol
-
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 
1.1
Contacts 
A separate contact information list will be provided to each site.
Takeda Development Center sponsored investigators per individual country requirements will be 
provided with emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Serious adverse event and pregnancy reporting
Contracted contract research organization’s 
contact
(Refer to the contact information list)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the study)
Contracted contract research organization’s 
contact
(Refer to the contact information list)
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
package insert and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and 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.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.

Regulatory requirements for reporting serious adverse events (SAEs) defined in Section 10.2
of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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1.3
Protocol Amendment 2 Summary of Changes
This document describes the changes to the protocol incorporating Amendment 2. The primary 
reasons for this amendment are to:

Clarify the timing of the baseline assessments that will be used for the study's secondary and
expoloratory analyses.

Include an interim analysis (IA).

Include the option of remote site visits in sites/countries where local legislation allows.

Define the situations in which a subject will be considered a treatment failure.

Define the end of the study.
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.
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Title page
Addition of study's 
clinicaltrials.gov identifier.
Addition made in line with internal 
process.
Section 1.2 Approval
Revision to signatories.
Approvers were updated.
Section 2.0 STUDY SUMMARY
Section 6.1 Study Design
Section 8.0 Clinical Study Material 
Management
Editorial revision. 
To clarify the timing of study 
unblinding. 
Section 2.0 STUDY SUMMARY
Section 6.1 Study Design
Language revision.
To clarify the timing of the study's 
primary efficacy analysis.
Section 2.0 STUDY SUMMARY
Section 5.2.2 Secondary Endpoints
Section 5.2.3 Exploratory 
Endpoints
Section 13.1.3 Efficacy Analysis
Editorial revision.
To clarify the timing of the baseline 
assessments that will be used for the 
study's secondary and exploratory 
analyses.
Section 2.0 STUDY SUMMARY
Section 5.2.2 Secondary Endpoints
Editorial revision.
To clarify the study's definition of 
"relapse".
Section 2.0 STUDY SUMMARY
Section 6.1 Study Design
Section 13.2 Interim Analysis
Addition of IA.
To support the long-term benefit-risk 
profile of darvadstrocel at the time of 
completion of Study Cx601-0303 
ADMIRE-CD II. 
Section 2.0 STUDY SUMMARY
Section 13.1.3 Efficacy Analysis
Language addition.
To specify what is included in the 
study's statistical analysis plan (SAP). 
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Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 6.1 Study Design
Language addition.
To define the situations in which a 
subject will be considered a treatment 
failure.
Section 6.3 End of Study/Study 
Completion Definition
Addition of section. 
To define the end of the study.
Section 13.1 Statistical and 
Analytical Plans
Editorial revision.
To clarify when the SAP for the study 
will be finalized. 
Section 13.1.2 Analysis of 
Demographics and Other Baseline 
Characteristics
Text deleted. 
To remove duplicated text from 
Section 13.1.4.
Section 14.1 Study-Site Monitoring 
Visits
Inclusion of remote site visits.
Remote site visits improve efficiency 
and allow for a continuous verification 
of data. Additionally, some sites have 
restricted on-site monitoring activities 
due to the coronavirus disease 2019 
(COVID-19) pandemic. These remote 
visits will occur only in those 
sites/countries where local legislation 
allows, and not prior to independent 
ethics committee (IEC)/institutional 
review board (IRB) notification.
Appendix E
COVID-19 and COVID-19 
pneumonia Preferred Terms added 
to the list of Takeda medically 
significant adverse events (AEs). 
Addition made to align with Takeda 
data standards. 
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 2 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Coordinating Investigator.........................................................................................15
3.3
List of Abbreviations ...............................................................................................16
3.4
Corporate Identification...........................................................................................16
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rationale for the Proposed Study.............................................................................17
4.3
Benefit/Risk Profile .................................................................................................17
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................18
5.1
Objectives................................................................................................................18
5.1.1
Primary Objective............................................................................................18
5.1.2
Secondary Objective........................................................................................18
5.1.3
Exploratory Objective......................................................................................18
5.2
Endpoints.................................................................................................................18
5.2.1
Primary Endpoint.............................................................................................18
5.2.2
Secondary Endpoints .......................................................................................18
5.2.3
Exploratory Endpoints .....................................................................................19
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................19
6.1
Study Design ...........................................................................................................19
6.2
Justification for Study Design and Endpoints...........................................................21
6.3
End of Study/Study Completion Definition..............................................................22
6.4
Premature Termination or Suspension of Study or Study Site...................................22
6.4.1
Criteria for Premature Termination or Suspension of the Study........................22
6.4.2
Criteria for Premature Termination or Suspension of Study Sites.....................22
6.4.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) ...........................................................................22
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............23
7.1
Inclusion Criteria .....................................................................................................23
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7.2
Exclusion Criteria ....................................................................................................23
7.3
Procedures for Discontinuation or Withdrawal of a Subject......................................23
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................23
9.0
STUDY PLAN ..............................................................................................................24
9.1
Study Procedures.....................................................................................................24
9.1.1
Informed Consent Procedure............................................................................24
9.1.2
Demographics, Medical History, and Medication History Procedure................24
9.1.3
Physical Examination Procedure......................................................................24
9.1.4
Weight and Height...........................................................................................24
9.1.5
Vital Sign Procedure........................................................................................24
9.1.6
Primary Safety Measurement...........................................................................25
9.1.7
Efficacy Measurements....................................................................................25
9.1.7.1
Fistula Clinical Assessment .....................................................................25
9.1.7.2
Fistula MRI Assessment ..........................................................................25
9.1.7.3
PDAI.......................................................................................................25
9.1.7.4
Immunologic Tests ..................................................................................26
9.1.7.5
.........................................................................................26
9.1.8
Documentation of Concomitant Medications/Procedures .................................26
9.1.9
Documentation of Concurrent Medical Conditions...........................................26
9.1.10
Procedures for Clinical Laboratory Samples ....................................................26
9.1.11
Contraception and Pregnancy Avoidance Procedure ........................................26
9.1.12
Pregnancy........................................................................................................27
9.1.13
Documentation of Study Entrance....................................................................27
9.2
Monitoring Subject Treatment Compliance..............................................................27
9.3
Schedule of Observations and Procedures................................................................27
9.3.1
Baseline (Week 52 After Darvadstrocel Treatment) .........................................27
9.3.2
Follow-up Period (Visit 1/Week 104 After Darvadstrocel Treatment)..............28
9.3.3
Final Visit (Visit 2/Week 156 After Darvadstrocel Treatment).........................29
9.3.4
Unscheduled Visit/Early Termination Visit......................................................29
9.3.5
Telephone Visit ...............................................................................................30
10.0
TREATMENT-EMERGENT ADVERSE EVENTS......................................................30
10.1
Definitions...............................................................................................................30
10.1.1
Pretreament Events..........................................................................................30
10.1.2
AEs .................................................................................................................30
10.1.3
Additional Points to Consider for AEs .............................................................30
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10.1.4
SAEs ...............................................................................................................32
10.1.5
AESIs..............................................................................................................33
10.1.6
Intensity of AEs...............................................................................................33
10.1.7
Causality of AEs and SAEs..............................................................................33
10.1.8
Relationship to Study Procedures.....................................................................33
10.1.9
Start Date.........................................................................................................33
10.1.10 Stop Date.........................................................................................................33
10.1.11 Outcome..........................................................................................................34
10.2
Procedures...............................................................................................................34
10.2.1
Collection and Reporting of AEs .....................................................................34
10.2.1.1
AESIs......................................................................................................34
10.2.2
Collection and Reporting of SAEs ...................................................................34
10.2.3
Reporting of Abnormal Liver Function Tests...................................................35
10.3
Follow-up of SAEs ..................................................................................................35
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...35
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................36
12.0
DATA HANDLING AND RECORDKEEPING............................................................36
12.1
eCRFs......................................................................................................................36
12.2
Record Retention .....................................................................................................37
13.0
STATISTICAL METHODS..........................................................................................37
13.1
Statistical and Analytical Plans ................................................................................37
13.1.1
Analysis Sets ...................................................................................................37
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................37
13.1.3
Efficacy Analysis.............................................................................................38
13.1.4
Safety Analysis................................................................................................38
13.1.5
Other Analyses ................................................................................................38
13.2
Interim Analysis ......................................................................................................39
13.3
Determination of Sample Size..................................................................................39
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................39
14.1
Study-Site Monitoring Visits ...................................................................................39
14.2
Protocol Deviations..................................................................................................40
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................40
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................40
15.1
IRB and/or IEC Approval ........................................................................................40
15.2
Subject Information, Informed Consent, and Subject Authorization .........................41
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15.3
Subject Confidentiality ............................................................................................42
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................43
15.4.1
Publication and Disclosure...............................................................................43
15.4.2
Clinical Trial Registration................................................................................43
15.4.3
Clinical Trial Results Disclosure......................................................................43
15.5
Insurance and Compensation for Injury....................................................................43
16.0
REFERENCES..............................................................................................................44
LIST OF IN-TEXT FIGURES
Figure 6.a
Study Schematic ................................................................................................21
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................45
Appendix B
Responsibilities of the Investigator.....................................................................46
Appendix C
Elements of the Subject Informed Consent.........................................................48
Appendix D
Investigator Consent to Use of Personal Information..........................................51
Appendix E
Additional Information for the Investigator........................................................52
Appendix F
Protocol History.................................................................................................53
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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc.
Compound:
Darvadstrocel (Cx601)
Title of Protocol: A Follow-up of a Phase 3 Study to 
Evaluate the Long-term Safety and Efficacy of 
Darvadstrocel in the Treatment of Complex Perianal 
Fistula in Subjects With Crohn’s Disease Who Have 
Participated in ADMIRE II Study
IND No.: 017707
EudraCT No.:
2019-000333-39
Study Number: Darvadstrocel-3003
Phase: 3
Study Design:
This long-term extension (LTE) study is a follow-up of a phase 3 study to evaluate the long-term safety and efficacy 
of darvadstrocel (Cx601) in the treatment of complex perianal fistula in Crohn’s disease (CD). To be eligible for the 
LTE study, subjects will have completed the final Week 52 assessment in the Cx601-0303 ADMIRE-CD II study 
(hereafter referred to as ADMIRE-CD II). Informed consent will be obtained at the Week 52 visit of the ADMIRE-
CD II study or up to 4 weeks after the Week 52 visit. 
For those subjects who have more than a 4-week gap between the Week 52 visit of the ADMIRE-CD II study and 
signing of the informed consent form (ICF) for the LTE study, a re-baseline visit will be scheduled; the re-baseline 
visit will include the same procedures included at the baseline visit with the addition of interval inflammatory bowel 
disease history and medical interventions since the Week 52 visit. Magnetic resonance imaging (MRI) assessment 
will not be included at the re-baseline visit. The re-baseline visit cannot be performed any later than 3 months after 
the Week 52 visit. MRI will be performed in all subjects at the Week 156 visit.
Study visits will take place annually for up to 2 years from enrollment into the LTE of ADMIRE-CD II or 3 years 
following treatment in ADMIRE-CD II. At these visits, clinical assessment of the fistula will be considered for 
clinical remission. Additional telephone call visits will be conducted every 3 months for safety assessments.
In addition, unscheduled visits may be performed for safety follow-up, and for subjects experiencing any clinically 
significant symptoms of perianal disease, an MRI will be performed.
The LTE study will be blinded until unblinding of the original study after final database lock, when all subjects have 
completed their participation at Week 52 of the ADMIRE-CD II study. After unblinding of the ADMIRE-CD II 
study, the LTE study will be conducted as an open-label study. Subjects will remain in the treatment group assigned 
in the ADMIRE-CD II study.
Enrollment into the LTE study will not prevent subjects with ongoing fistulizing disease or luminal CD from 
receiving any additional treatment (including any medical or surgical treatment) prescribed by his/her physician for 
the treatment of CD and/or perianal disease. Subjects who receive surgical and/or biologic treatment for the perianal 
fistulizing disease will be considered treatment failures, but should continue in the study. Those subjects who are 
prescribed darvadstrocel will be withdrawn from the LTE study and complete an early termination visit because the 
study will assess the long-term follow-up of investigational medicinal product (IMP) administration in the 
ADMIRE-CD II study.
ADMIRE-CD II is an ongoing phase 3, randomized, double-blind, parallel-group, placebo-controlled, international, 
multicenter study to assess the efficacy and safety of darvadstrocel, adult allogeneic expanded adipose-derived stem 
cells, for the treatment of complex perianal fistula(s) in subjects with CD over a period of 52 weeks. The primary 
efficacy analysis is to be conducted at Week 24. Thereafter, the double-blind design will be maintained up to Week 
52 to allow for evaluation of longer term (Week 52) efficacy and safety. The study follows an add-on design, with 
subjects receiving any ongoing concomitant medical treatment for CD at stable doses at the time of screening and 
allowed to continue with it throughout the study. Study subjects are allocated to treatment, in a 1:1 ratio. A curettage 
and a seton placement will take place at randomization into ADMIRE-CD II. The study population consists of 
subjects whose perianal fistulas were previously treated and have shown an inadequate response, a loss of response, 
intolerance or contraindication to immunosuppressives or monoclonal antibodies, and subjects with complex 
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Main Criteria for Exclusion:
Subjects will not be eligible for inclusion in the study if:
1.
It has been more than 3 months since the subject completed the ADMIRE-CD II study.
2.
Subjects are currently receiving, have received any investigational drug in the last 3 months before the inclusion 
in the study, or are planning to receive any investigational drug during the duration of this LTE study, except 
for prior participation in the ADMIRE-CD II study.
Main Criteria for Evaluation and Analyses:
Primary Endpoints:

AEs.

SAEs.

Specific AESIs:
–
Immunogenicity/alloimmune reactions.
–
Tumorgenicity.
–
Ectopic tissue formation.
Secondary Endpoints:

Proportion of subjects who achieve clinical remission at Week 104 and Week 156 after IMP administration. 
–
Clinical remission is defined as closure of all treated external fistula openings that were draining at baseline 
of ADMIRE-CD II despite gentle finger compression.

Proportion of subjects who achieve clinical response at Week 104 and Week 156 after IMP administration. 
–
Clinical response is defined as closure of at least 50% of all treated external fistula openings that were 
draining at baseline of ADMIRE-CD II despite gentle finger compression.

Proportion of subjects with a relapse where a relapse is defined as patients who were in combined remission at 
Week 52 of ADMIRE-CD II, and who have either:
–
Reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed, or
–
The development of a perianal fluid collection >2 cm of the treated perianal fistulas confirmed by centrally 
read MRI assessment.

Proportion of subjects who achieve combined remission at Week 156 after IMP administration.
–
Combined remission of complex perianal fistula(s), defined as the clinical assessment of closure of all 
treated external openings that were draining at baseline of ADMIRE-CD II, despite gentle finger 
compression, and 
–
Absence of collection(s) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by 
centrally read blinded MRI assessment.

Proportion of subjects with new anal abscess in treated fistula at Week 156.

Change from baseline of ADMIRE-CD II to Week 104 and Week 156 in scores of discharge and pain items of 
Perianal Disease Activity Index (PDAI) score.
Exploratory Endpoints:
Statistical Considerations:
Demographic and baseline characteristics will be summarized by treatment group and overall based on all enrolled 
subjects. For continuous variables, summary statistics (nonmissing values, mean, median, SD, minimum, and 
maximum) will be generated. For categorical variables, the counts and percentages of each possible value will be 
generated. 
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities except for those identified in the Clinical 
Study Sponsor Supplier list. The identified vendors in the list for specific study-related activities 
will perform these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate 
in the study. Selection criteria for this investigator will include significant knowledge of the 
study protocol, the study medication, their expertise in the therapeutic area and the conduct of 
clinical research as well as study participation. The Signatory Coordinating Investigator will be 
required to review and sign the clinical study report and by doing so agrees that it accurately 
describes the results of the study.
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3.3
List of Abbreviations
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CD
Crohn’s disease
eCRF
electronic case report form
CRO
contract research organization
Cx601
darvadstrocel
DSA
donor specific antibody
ECG
electrocardiogram
EMA
European Medicines Agency
FDA
Food and Drug Administration
GCP
Good Clinical Practice
IBD
inflammatory bowel disease
IA
interim analysis
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
institutional review board
LFT
liver function test
LTE
long-term extension
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
PDAI
Perianal Disease Activity Index
PTE
pretreatment event
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
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
Adipose-derived mesenchymal stem cells are a promising new approach for the treatment of 
complex perianal fistulas because of their anti-inflammatory and immunomodulatory potential. 
Darvadstrocel, which is a suspension of expanded human allogeneic mesenchymal adult stem 
cells extracted from adipose tissue, is a promising new treatment. The current hypothesis is that 
darvadstrocel has immunomodulatory and anti-inflammatory properties resulting in the reduction 
of inflammation, which allows fistulas to heal through homeostatic mechanisms. 
The efficacy of darvadstrocel was assessed in the Cx601-0302 ADMIRE-CD study. This was a 
randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical study to assess 
efficacy and safety of darvadstrocel for the treatment of complex perianal fistula(s) in subjects 
with Crohn’s disease (CD). The study showed that a significantly greater proportion of subjects 
in the darvadstrocel group achieved the primary endpoint of combined remission at Week 24 
compared with placebo. The safety data showed that Cx601 was well tolerated in the study 
population (Panes et al. 2016).
4.2
Rationale for the Proposed Study
This study is an extension of the ongoing phase 3 randomized, double-blind, parallel-group, 
controlled, global, multicenter study to evaluate the efficacy and safety of darvadstrocel in 
subjects with CD and complex perianal fistula(s) over a period of 52 weeks (Cx601-0303 
ADMIRE-CD II). This long-term extension (LTE) study is being undertaken as a 
postauthorization measure for the European Medicines Agency (EMA) to evaluate the long-term 
safety and efficacy of darvadstrocel.
There are limited long-term follow-up data currently available following darvadstrocel injection. 
The longest follow-up conducted to date was up to 104 weeks following darvadstrocel injection 
in the Cx601-0302 study. The results of this follow-up study showed consistency with the 
adverse events (AEs) previously reported up to the Week 52 visit and did not suggest any safety 
concerns; however, since these data were limited to a small sample of subjects, a larger sample 
size is required to evaluate long-term efficacy up to 156 weeks after treatment with 
darvadstrocel.
4.3
Benefit/Risk Profile 
In studies conducted to date, darvadstrocel appeared to be, overall, well tolerated at a dose of up 
to 120 million cells per administration. No dose-dependent safety concern or toxicity has been 
identified to date. No safety concerns have been identified from the small amount of 
postmarketing exposure data. Overall, the data available to date presents a positive benefit-risk 
profile for darvadstrocel.
No additional risks associated with administration of darvadstrocel are anticipated in this LTE 
study as no investigational medicinal product (IMP) is to be administered during the study.
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For those subjects who have more than a 4-week gap between the Week 52 visit of the 
ADMIRE-CD II study and signing of the informed consent form (ICF) for the LTE study, a re-
baseline visit will be scheduled; the re-baseline visit will include the same procedures included at 
the baseline visit with the addition of interval inflammatory bowel disease (IBD) history and 
medical interventions since the Week 52 visit. MRI assessment will not be included at the re-
baseline visit. The re-baseline visit cannot be performed any later than 3 months after the 
Week 52 visit. An MRI will be performed in all subjects at the Week 156 visit.
Study visits will take place annually for up to 2 years from enrollment into the LTE of 
ADMIRE-CD II or 3 years following treatment in ADMIRE-CD II. At these visits, clinical 
assessment of the fistula will be considered for clinical remission. Additional telephone call 
visits will be conducted every 3 months for safety follow-up. In addition, unscheduled visits may 
be performed for safety follow-up, and for subjects experiencing any clinically significant 
symptoms of perianal disease, an MRI will be performed.
The LTE study will be blinded until unblinding of the ADMIRE-CD II study after final database 
lock, when all subjects have completed their participation at Week 52. After unblinding of the 
ADMIRE-CD II study, the LTE study will be conducted as an open-label study. Subjects will 
remain in the treatment group assigned in the ADMIRE-CD II study.
Enrollment into the LTE study will not prevent subjects with ongoing fistulizing disease or 
luminal CD from receiving any additional treatment (including any medical or surgical 
treatment) prescribed by his/her physician for the treatment of CD and/or perianal disease. 
Subjects who receive surgical and/or biologic treatment for the perianal fistulizing disease will 
be considered treatment failures, but should continue in the study. Treatment failure is 
documented for a subject if they require rescue medication(s) or procedure(s), defined as switch 
to or addition of any new monoclonal antibody not ongoing at baseline, increase in dose or 
frequency of any prior ongoing monoclonal antibody in the LTE study, subjects starting any 
investigational drug(s) for CD or any other local investigational treatment(s) in the perianal 
region while participating in the LTE study or any new surgical procedure required in the 
perianal region for the fistula(s) or draining of collections or established abscess(es) or any 
ostomy required due to fistula(s). 
Those subjects who are prescribed darvadstrocel will be withdrawn from the LTE study and 
complete an early termination visit because the study will assess the long-term follow-up of IMP 
administration in the ADMIRE-CD II study.
ADMIRE-CD II is an ongoing phase 3, randomized, double-blind, parallel-group, placebo 
controlled, international, multicenter study to assess the efficacy and safety of darvadstrocel, 
adult allogeneic expanded adipose-derived stem cells, for the treatment of complex perianal 
fistula(s) in subjects with CD over a period of 52 weeks. The primary efficacy analysis is to be 
conducted at Week 24. Thereafter, the double-blind design will be maintained up to Week 52 to 
allow for evaluation of longer term (Week 52) efficacy and safety. The study follows an add-on 
design, with subjects receiving any ongoing concomitant medical treatment for CD at stable 
doses at the time of screening and allowed to continue with it throughout the study. Study 
subjects are allocated to treatment, in a 1:1 ratio. A curettage and a seton placement will take 
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in the Cx601-0302 study. The results of this follow-up study showed consistency with AEs 
previously reported up to the Week 52 visit and did not suggest any safety concerns; however, 
since these data were limited to a small sample of subjects, a larger sample size is required to 
evaluate long-term efficacy up to 156 weeks following treatment with darvadstrocel. The 
availability of a control arm for 2 years during this LTE study will help to identify which AEs 
and other occurrences are due to darvadstrocel, other treatment, or disease progression, which 
contributes to the scientific rigor of the study.
The endpoints in this study are generally accepted as standard indicators of safety and disease 
activity in complex perianal fistulas in subjects with CD.
6.3
End of Study/Study Completion Definition
The end of the study is defined as the last scheduled procedure for the last participant in the 
study.
6.4
Premature Termination or Suspension of Study or Study Site
6.4.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known benefit-risk profile for the product, such that the benefit-risk 
profile is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.4.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.4.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
If the sponsor, an institutional review board (IRB)/independent ethics committee (IEC) or 
regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites 
during termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and 
dates a written ICF and any required privacy authorization before the initiation of any study 
procedures. 
3. The subject has participated in and completed the ADMIRE-CD II study (ie, did not 
discontinue).
7.2
Exclusion Criteria
Subjects will not be eligible for inclusion in the study if:
1. It has been more than 3 months since the subject completed the ADMIRE-CD II study.
2. Subjects are currently receiving, have received any investigational drug in the last 3 months 
before the inclusion in the study, or are planning to receive any investigational drug during 
the duration of this LTE study, except for prior participation in the ADMIRE-CD II study.
7.3
Procedures for Discontinuation or Withdrawal of a Subject
Subjects may withdraw consent and discontinue participation in the study at any time. 
Withdrawal will have no effect on their medical care or access to treatment. 
All information already collected as part of the study will be retained for analyses. A subject who 
discontinues from the study will not be replaced. Follow-up of AEs will be conducted according 
to GCP/Clinical Trial Directives. 
If a subject withdraws before completing the study follow-up period, the primary reason for 
discontinuation or withdrawal of the subject from the study should be recorded in a subject’s 
medical record and in the electronic case report form (eCRF).
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
There will be no IMP administration in this LTE study. This study will be blinded until 
unblinding of the ADMIRE-CD II study after final database lock, when all subjects have 
completed their participation at Week 52.
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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained before the subject entering into the study, and before any 
protocol-directed procedures are performed.
The subject number will be maintained from the ADMIRE-CD II study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information and medical history will be obtained from the Week 52 visit of the 
ADMIRE-CD II study and this data will be used as the baseline of the LTE study.
Medical history will include history of fistulizing CD and assessment of severity and history of 
cancer including anal canal and colorectal malignancy. A targeted questionnaire will be used to 
collect detailed information on all malignancies. Medical history will also include determining 
whether the subject has any significant conditions or diseases relevant to the disease under study 
that resolved at or before signing of the ICF. Ongoing conditions are considered concurrent 
medical conditions (see Section 9.1.9).
Medication history information includes any medication relevant to eligibility criteria and 
efficacy/safety evaluation stopped at or within 52 weeks before signing of the ICF.
9.1.3
Physical Examination Procedure
A physical examination will be performed at the Week 52 visit of the ADMIRE-CD II study and 
this data will be used as the baseline of the LTE study.
9.1.4
Weight and Height
Weight will be obtained from the Week 52 visit of the ADMIRE-CD II study and this data will 
be used as the baseline of the LTE study. Height will be obtained from the screening visit of the 
ADMIRE-CD II study.
9.1.5
Vital Sign Procedure
Vital signs (including temperature, heart rate, and blood pressure) will be obtained from the 
Week 52 visit of the ADMIRE-CD II study and this data will be used as the baseline of the LTE 
study.
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9.1.6
Primary Safety Measurement 
The long-term safety of a single dose of darvadstrocel will be assessed in subjects with CD with 
complex perianal fistula, including assessment of SAEs, and AESIs 
(immunogenicity/alloimmune reactions, tumorgenicity, and ectopic tissue formation).
9.1.7
Efficacy Measurements
9.1.7.1
Fistula Clinical Assessment
Fistula clinical assessment will consist of a physical examination of the fistula by the investigator 
to evaluate the presence of drainage spontaneously or after gentle finger compression through the 
external openings treated. The treated tracts and external openings must be clearly identified in 
the eCRF to ensure the same treated tracts are assessed during the study period.
For the purpose of this study, drainage of the treated fistula and abscesses, will not be captured 
as AEs unless there is evidence suggesting a causal relationship between the IMP or meet the 
seriousness criteria. SAEs will be reported by the sponsor according to International Conference 
on Harmonisation (ICH) guidelines.
9.1.7.2
Fistula MRI Assessment
A central reading MRI will be performed at Week 156 following IMP administration. In 
addition, a pelvic MRI will be conducted at an unscheduled visit for those subjects who 
experience clinically significant symptoms of perianal disease, as assessed by the investigator.
All MRI scans will be assessed centrally by the designated MRI central laboratory in a blinded 
approach including treatment and period. Blinded central MRI results will include number of 
fistulas, location, type, collection in 3 dimensions, if any, with fistula location. Analysis will 
include assessment of collections >2 cm, in 3 axes and directly related to the fistula tracts treated, 
and any new tracts that might appear.
Before the MRI procedure, it would be necessary to confirm that there are no contraindications 
for performing it (eg, hypersensitivity to gadolinium, pacemarker, hip replacement, serum 
creatinine levels >1.5 times upper limit of normal or pregnancy).
9.1.7.3
PDAI
The PDAI is a scoring system to evaluate the severity of perianal CD (Best et al. 1976; Losco et 
al. 2009). From the 5-item instrument, discharge and pain will be used. Each category is graded 
on a 5-point Likert scale ranging from no symptoms (score of 0) to severe symptoms (score of 
4); a higher score indicates more severe disease.
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9.1.12
Pregnancy
If a pregnancy occurs during the study, the pregnancy should be reported immediately, using a 
pregnancy notification form, to the contact listed in Section 1.1.
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.
All pregnancies, including female partners of male subjects, will be followed up to final 
outcome, using the pregnancy form. The outcome, including any premature termination, must be 
reported to the sponsor. 
9.1.13
Documentation of Study Entrance
Only subjects who have attended the final Week 52 visit of the ADMIRE-CD II study and sign 
the ICF to participate in this LTE study will be eligible.
Subjects who have completed their participation in ADMIRE-CD II, can still be invited to enter 
the LTE study. In these subjects, a re-baseline visit will be conducted if there is a gap longer than 
4 weeks from the ADMIRE-CD II Week 52 visit and the signing of the ICF for the LTE. The re-
baseline visit cannot occur more than 3 months after the ADMIRE-CD II Week 52 visit. 
Collection of data at the re-baseline visit will be similar to data collected at the baseline visit 
with the exception of blood samples and MRI assessment.
If the subject is found to be not eligible for this LTE study, or the subject does not wish to 
participate, the investigator should record the primary reason on the applicable eCRF.
Subjects who are pregnant will be allowed to enter the study; however, an MRI must not be 
performed on those subjects.
9.2
Monitoring Subject Treatment Compliance
There will be no IMP administration during this study. 
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time points.
9.3.1
Baseline (Week 52 After Darvadstrocel Treatment)
Where possible, the final visit at Week 52 of the ADMIRE-CD II study will be the baseline visit 
for this LTE study. Informed consent will be obtained at the Week 52 study visit of the 
ADMIRE-CD II study or up to 4 weeks after the Week 52 visit. For subjects who do not wish to 
participate, the reason will be collected in a screening log at the site.
For those subjects who have more than a 4 week gap between the ADMIRE-CD II Week 52 visit 
and signing of the ICF for the LTE study, a re-baseline visit will be scheduled. The re-baseline 
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visit will include the same procedures included at the baseline visit with the addition of interval 
IBD history and medical interventions since the Week 52 visit. The immunologic tests and MRI 
will not be included at re-baseline visit. Re-baseline visit cannot occur more than 3 months after 
the ADMIRE-CD II Week 52 visit.
Baseline data from Week 52 include:

Informed consent: a written informed consent will be obtained from the subject before any 
study procedure is performed.

Demographics and medical history, including history of CD and smoking history.

Physical examination covering all body systems, including weight and height.

Vital signs, including systolic and diastolic blood pressure (mm Hg), heart rate (beats/min), 
and body temperature (°C)

Concomitant medications and procedures.

Clinical evaluation of fistula.

MRI assessment of fistula (central reading).

PDAI 
.

Immunologic tests and T-cell responses.

AE/SAE assessment.

Telephone calls will be made every 3 months for safety follow-up from baseline/re-baseline 
until the next visit.
The procedure for documenting screening failures is provided in Section 9.1.13.
9.3.2
Follow-up Period (Visit 1/Week 104 After Darvadstrocel Treatment)
The following procedures will be performed at Visit 1, LTE Week 52/Week 104 after 
darvadstrocel treatment:

Physical examination covering all body systems, including weight.

Vital signs, including systolic and diastolic blood pressure (mm Hg), heart rate (beats/min), 
and body temperature (°C).

Concomitant medications and procedures since last visit.

Clinical evaluation of fistula.

PDAI score.

Interval IBD history and medical interventions since last visit.
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
Immunologic tests and T-cell responses.

AE/SAE assessment.

Telephone calls will be made for safety follow-up every 3 months from Visit 1 to the next 
visit.
9.3.3
Final Visit (Visit 2/Week 156 After Darvadstrocel Treatment)
The final visit will be performed on Visit 2, LTE Week 104/Week 156 after darvadstrocel 
treatment or at the early termination visit. The following procedures will be performed and 
documented:

Physical examination covering all body systems, including weight.

Vital signs, including systolic and diastolic blood pressure (mm Hg), heart rate (beats/min), 
and body temperature (°C)

Concomitant medications and procedures since last visit.

Clinical evaluation of fistula.

MRI assessment of fistula (central reading).

PDAI score.

Interval IBD history and medical interventions since last visit.

Immunologic tests and T-cell responses.

AE/SAE assessment.
9.3.4
Unscheduled Visit/Early Termination Visit
The unscheduled visit will be conducted for safety follow-up if required, and for subjects 
experiencing clinically significant symptoms of perianal disease, as assessed by the investigator. 
The following procedures will be performed and documented for safety follow-up:

Physical examination covering all body systems, including weight.

Vital signs, including systolic and diastolic blood pressure (mm Hg), heart rate (beats/min), 
and body temperature (°C).

Concomitant medications and procedures since last visit.

Clinical evaluation of fistula.

MRI assessment of fistula only if the subject is experiencing symptoms of perianal disease.

PDAI score.
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
Interval IBD history and medical interventions since last visit.

Immunologic tests and T-cell responses.

AE/SAE assessment.
9.3.5
Telephone Visit
A telephone call for safety follow-up will be made to the subject every 3 months between Week 
52 and Week 156.
10.0
TREATMENT-EMERGENT ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreament Events 
Pretreament events (PTEs) will not be reported in this LTE study.
10.1.2
AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug.
For the purpose of this study, drainage of the treated fistula and abscesses defining the efficacy 
endpoint, will not be captured as AEs unless there is evidence suggesting a causal relationship 
between the IMP or meet the seriousness criteria.
10.1.3
Additional Points to Consider for AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered 
pretreatment events or AEs).

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Be considered unfavorable by the investigator for any reason.
AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a AE.
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Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or electrocardiogram [ECG] findings) or symptoms 
should NOT be recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) 
should be recorded appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be AEs if they are 
judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory or ECG retest and/or continued monitoring of an abnormal value or finding are not 
considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as AEs. However, if the subject 
experiences a worsening or complication of such a concurrent medical condition, the 
worsening or complication should be recorded appropriately as an AE (worsening or 
complication occurs after start of study drug). Investigators should ensure that the event term 
recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) 
any occurrence of an episode should only be captured as an AE if the condition becomes 
more frequent, serious or severe in nature. Investigators should ensure that the AE term 
recorded captures the change in the condition from baseline (eg “worsening of…”).

If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as an AE if occurring to a 
greater extent to that which would be expected. Investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the PTE (eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
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Changes in intensity of AEs:

If the subject experiences changes in intensity of an AE, the event should be captured once 
with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled before signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening 
of the condition should be recorded as an AE. Complications resulting from any planned 
surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy.
10.1.4
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Transmission of infectious agents.
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
Includes any event or synonym described in the Takeda Medically Significant AE List 
(Appendix E).
10.1.5
AESIs
An AESI (serious or nonserious) is one of scientific and medical concern specific to the 
compound or program, for which ongoing monitoring and rapid communication by the 
investigator to Takeda may be appropriate. Such events may require further investigation to 
characterize and understand them and would be described in protocols and instructions provided 
for investigators as to how and when they should be reported to Takeda.
Refer to Section 10.2.1.1 for a list of known AESIs. 
10.1.6
Intensity of AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.7
Causality of AEs and SAEs
The relationship of each AE/SAE to study procedures will be assessed using the following 
categories:
Related:
An AE for which possible involvement of the drug cannot be ruled out, although factors other 
than the drug, such as underlying diseases, complications, concomitant medications and 
concurrent treatments, may also be responsible.
Not Related:
An AE that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications and concurrent treatments.
10.1.8
Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all AEs/SAEs.
The relationship should be assessed as related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure, including treatment 
administration. Otherwise, the relationship should be assessed as not related. 
10.1.9
Start Date
The start date of the AE/SAE is the date that the first signs/symptoms were noted by the subject 
and/or investigator.
10.1.10
Stop Date 
The stop date of the AE/SAE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died.
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10.1.11
Outcome

Recovered/resolved: Subject returned to first assessment status with respect to the AE/SAE.

Recovering/resolving: The intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/SAE with the condition remaining “recovering/resolving”.

Not recovered/not resolved: There is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE/SAE state remaining 
“Not recovered/not resolved”.

Resolved with sequelae: The subject recovered from an acute AE/SAE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal: The AE/SAEs that are considered as the cause of death. 

Unknown: The course of the AE/SAE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1
Collection and Reporting of AEs
10.2.1.1
AESIs
If the AESI/abnormality occurs during the study, it should be recorded in the appropriate AESI 
eCRF page. When an AESI meets the seriousness criteria, it should be reported to the clinical 
contract research organization (CRO)/ pharmacovigilance department within 24 hours as per the 
SAE reporting requirements.
AESI/abnormality criteria include:

Immunogenicity/alloimmune reactions.

Tumorgenicity reactions.

Ectopic tissue formation.
10.2.2
Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
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A Takeda SAE form must be completed, in English, and signed by the investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum:
A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation.
10.2.3
Reporting of Abnormal Liver Function Tests
If a subject is noted to have alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
elevated >3 times the upper limit of normal (ULN) on 2 consecutive occasions, the abnormality 
should be recorded as an AE. In addition, a liver function test (LFT) increases eCRF must be 
completed providing additional information on relevant recent history, risk factors, clinical signs 
and symptoms, and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 × ULN and total bilirubin >2 × ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.10 must also be performed. In addition, an LFT increases eCRF 
must be completed and transmitted with the Takeda SAE form (per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, laboratory tests, discharge summary, postmortem results) should be sent to the addressee, if 
requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the EMA, 
investigators and IRBs or IECs, as applicable, in accordance with national regulations in the 
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countries where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as expedited report within 7 days for fatal and life-threatening events and 15 days for 
other serious events, unless otherwise required by national regulations. The sponsor will also 
prepare an expedited report for other safety issues where these might materially alter the current 
benefit-risk assessment of 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
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs/SAEs, medical history, and concomitant procedures 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 informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff in the use of the eCRF. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. All eCRFs must be completed in English. Data are transcribed into eCRFs 
from source records.
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 sponsor 
personnel (or designees) and will be answered by the site.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered into the eCRFs.
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic 
visits by the study sponsor or its designee. The sponsor or its designee will be permitted to 
review the subject’s medical and hospital records pertinent to the study to ensure accuracy of the 
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. 
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12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original 
in the subject’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires 
the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 
years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Site Agreement between the 
investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. 
The investigator should contact and receive written approval from the sponsor before disposing 
of any such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
The statistical analysis plan (SAP) will be prepared and finalized before interim 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
Safety analysis set: All subjects enrolled in the study, according to the actual treatment they 
received in the ADMIRE-CD II study.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
The safety analysis set will be the primary analysis set to be used for all statistical analysis of the 
demographic and baseline characteristics. Demographic and baseline characteristics will be 
summarized by the treatment group and overall based on all enrolled subjects. For continuous 
variables, summary statistics (nonmissing values, mean, median, SD, minimum, and maximum) 
will be generated. For categorical variables, the counts and percentages of each possible value 
will be generated. 
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13.2
Interim Analysis
IA and reports will be done after ADMIRE-CD II is unblinded to support the long-term benefit-
risk profile of darvadstrocel. The data cutoff date for the IA will be the date of the last ADMIRE-
CD II subject's Week 52 visit. The IA will include safety analyses and selected efficacy analyses 
(such as clinical remission and clinical response, etc.) based on available data. The analysis 
details will be delineated in the SAP.
13.3
Determination of Sample Size
Eligible subjects from the ADMIRE-CD II study will be given the opportunity to participate in 
this long-term safety follow-up study. 
Approximately 150 subjects are expected to enroll into this study from the ADMIRE-CD II 
study. 
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
Designated study personnel will participate in a training program that will encourage consistency 
of process and procedures at the investigative sites and ensure collection of high-quality data for 
this study. All sites will be trained on the protocol, study logistics, and the electronic data capture 
system. Retraining will be conducted as needed. Investigators will be reminded of the processes 
and importance of reporting adverse reactions, SAEs, and other information.
Initial monitoring will be performed to ensure that ICFs have been completed for all enrolled 
subjects. At monitoring visits, the progress of the study and any procedural or data issues will be
discussed with the investigator and/or designee. The investigator will make subject source 
documents available for review and will permit the sponsor, representatives of the sponsor, the 
IRB/IEC, or regulatory authorities to inspect facilities and original records relevant to this study. 
The investigator will allocate adequate time to discuss findings and relevant issues and, after the 
visit, to complete appropriate corrective actions as necessary.
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 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, including but not limited to the Investigator’s Binder, 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.
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The sponsor will employ all efforts to conduct on-site monitoring visits. Per country/site 
regulations, remote monitoring practices may include remote source data verification and remote 
source data review. Any remote montoring practices will be documented in the monitoring plan.
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 (ie, prospectively approved deviations) during study participation.
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the 
sponsor or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
and any other facility used during the study. In addition, there is the possibility that this study 
may be inspected by regulatory agencies, including those of foreign governments (eg, the Food 
and Drug Administration [FDA], the United Kingdom Medicines and Healthcare products 
Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the study 
site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator guarantee access for quality assurance auditors to all study 
documents as described in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual subjects (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
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titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the product package insert, a copy of 
the ICF, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study. The IRB or IEC approval must refer to the study by exact protocol 
title, number, and version date; identify versions of other documents (eg, ICF) reviewed; and 
state the approval date. The sponsor will notify site once the sponsor has confirmed the adequacy 
of site regulatory documentation and, when applicable, the sponsor has received permission from 
competent authority to begin the study. Until the site receives notification no protocol activities, 
including screening may occur.
Study sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the 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 its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The 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, as well as 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.
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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. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the ICF and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the ICF and subject 
authorization (if applicable) at the time of consent and before subject entering into the study; 
however, the sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable law.
Once signed, the original 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 or the relevant subject’s 
legally acceptable representative in the same manner as the original informed consent. The date 
the revised consent was obtained should be recorded in the subject’s medical record, and the 
subject should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit the monitor or the sponsor’s designee, representatives 
from any regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
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documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the study site agreement. In the event of any discrepancy 
between the protocol and the study site agreement, the study site agreement will prevail.
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 all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, 
and recruiting status will be registered and available for public viewing. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly 
accessible websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
subjects. Refer to the study site agreement regarding the sponsor’s policy on subject 
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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
Best, W. R., Becktel, J. M., Singleton, J. W. and Kern, F., Jr. 1976. Development of a Crohn's 
disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology,
70(3), 439-44.
Losco, A., Vigano, C., Conte, D., Cesana, B. M. and Basilisco, G. 2009. Assessing the activity of 
perianal Crohn's disease: comparison of clinical indices and computer-assisted anal 
ultrasound. Inflamm Bowel Dis, 15(5), 742-9.
Panes, J., Garcia-Olmo, D., Van Assche, G., Colombel, J. F., Reinisch, W., Baumgart, D. C., et 
al. 2016. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for 
complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind 
controlled trial. Lancet, 388(10051), 1281-90.
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Appendix A
Schedule of Study Procedures
Visit Number
Baseline
Re-Baseline a
Follow-up Period up to Week 156
Unscheduled 
Visit/Early 
Termination
1 b
2 (Final Visit)
LTE Week
0
0
52
104 
Week after Darvadstrocel Treatment
52
>56 weeks a
104
156
Informed consent
X
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
X
Physical examination including weight
X
X
X
X
X
Vital signs
X
X
X
X
X
Concomitant medications and procedures
X
X
X
X 
X
Fistula clinical assessment
X
X
X
X
X
Fistula MRI assessment
X c
X
X d
PDAI score e
X
X
X
X
X
Interval IBD history and medical 
interventions 
X
X
X
X
Immunologic tests and T-cell responses f
X
X
X
X
AE/SAE assessment g
X
X
X
X
X
Telephone calls h
Every 3 months
AE: adverse event; IBD: inflammatory bowel disease; ICF: informed consent form; LTE: long-term extension; MRI: magnetic 
resonance imaging; PDAI: Perianal Disease Activity Index; SAE: serious adverse event.
a Re-baseline visit will be conducted if there is a gap >4 weeks between ADMIRE-CD II Week 52 visit and signing of ICF for the 
LTE study. The re-baseline visit must take place within 3 months of the ADMIRE-CD II Week 52 visit.
b Visit 1 will be up to 52 weeks after completion of the ADMIRE-CD II study. 
c Baseline MRI for the LTE study is the examination performed at Week 52 of ADMIRE-CD II study.
d Central reading MRI assessment of fistula (performed locally) only if the subject is experiencing symptoms of perianal disease.
e Only the PDAI items of discharge and pain will be used.
f An extra whole blood sample (40 mL) for T-cell responses, extracellular turnover markers, and immunologic tests 
(presence/absence of antidonor specific antibodies) will be obtained at each visit.
g Collection of AEs and SAEs will begin from the time the subject signs the ICF in this study and will continue through final 
visit/early termination; however, any new AEs/SAEs reported during Week 52 ADMIRE-II visit should be recorded as AEs in 
the ADMIRE-II database. Ongoing AEs/SAEs at the completion of the Week 52 ADMIRE-CD II study visit will be kept in the 
ADMIRE-CD II study database. New events or ongoing AEs/SAEs from ADMIRE-CD II that change severity after completion 
of the week 52 ADMIRE-CD II visit will need to be recorded as medical history for this LTE study if they occur before the ICF 
for LTE being signed.
h Telephone call visits will be conducted every 3 months throughout the study for safety follow-up.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, 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 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 ICH and local regulations, are 
met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section 
that describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a subject authorization, then the investigator must obtain a separate subject 
authorization form from each subject or the subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) 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 or
the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any
compensation and an explanation as to whether any medical treatments are available if injury
occurs and, if so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a research-
related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty
or loss of benefits to which the subject otherwise is entitled, and that the subject or the
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subject’s legally acceptable representative may discontinue participation at any time without 
penalty or loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
subject’s willingness to continue participation in the study.
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the 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. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to
regulatory agencies relating to other medications used in other clinical studies that may
contain the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix E
Additional Information for the Investigator
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure 
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome
Confirmed or suspected transmission of infectious agent 
by a medicinal product
COVID-19-related disease
Neuroleptic malignant syndrome/malignant hyperthermia
COVID-19 pneumonia
Spontaneous abortion/stillbirth and fetal death
AE: adverse event; COVID-19: coronavirus disease 2019; SAE: serious adverse event.
Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements. 
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Appendix F
Protocol History
Date
Amendment Number
Amendment Type
Region
17 November 2022
2
Substantial
Global
26 January 2022
1
Substantial
Global
22 March 2019
Initial protocol
-
Global
Rationale for Amendment 1
The primary reason for this amendment was for a legal entity change from Millennium 
Pharmaceuticals, Inc to Takeda Development Center Americas, Inc.
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Title Page
Section 2.0 STUDY SUMMARY
Revision of Millennium 
Pharmaceuticals, Inc to Takeda 
Development Center Americas, Inc.
Sponsor company name and address 
was updated.
Section 1.2 Approval
Revision to signatories
Approvers were updated
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