Postauthorization Safety Study of the Long-Term Safety and Efficacy of Repeat Administration of Darvadstrocel in Patients With Crohn's Disease and Complex Perianal Fistula
Phase: PHASE4
Conditions: Crohn's Disease, Complex Perianal Fistula
Sponsor: Takeda

For non-commercial use only

 
 
TAKEDA PHARMACEUTICALS 
PROTOCOL 
Postauthorization Safety Study of the Long-Term Safety and Efficacy of Repeat Administration 
of Darvadstrocel in Patients With Crohn’s Disease and Complex Perianal Fistula 
Short Title 
Postauthorization Safety Study of Darvadstrocel Repeat Administration 
Sponsor: 
Takeda Development Center Americas, Inc. 
95 Hayden Avenue 
Lexington, MA 02421 USA 
Study Number: 
Alofisel-4001 
IND Number: 
17707 
Abbreviated EU CT 
Number: 
2022-503014-23 
EUPAS number: 
EUPAS31439 
Compound: 
Darvadstrocel 
Expanded human allogeneic mesenchymal adult stem cells extracted 
from adipose tissue (expanded adipose stem cells) 
Date: 
29 April 2024 
Amendment Number: 4 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
29 April 2024 
Amendment 4 
Nonsubstantial 
Global 
11 October 2023 
Amendment 3 
Nonsubstantial 
Global 
04 August 2021 
Amendment 2 
Substantial 
Global 
01 July 2020 
Amendment 1 
Nonsubstantial 
Global 
22 May 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 2.1 and relevant guidelines 
provided to the site. 
Contact Type/Role 
European/Rest of World Contact 
Serious adverse event, special situation reports, and 
pregnancy reporting 
Fax: +1-224-554-1052 
Email: PharmacovigilanceMailbox@Takeda.com 
Responsible Medical Officer  
(carries overall responsibility for the conduct of the study) 
(Refer to the contact information list) 
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1.2 
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Conference for Harmonization E6 Good Clinical Practice: Consolidated 
Guideline. 
• 
All applicable laws and regulations (eg, European Union Clinical Trials Regulations), 
including, without limitation, data privacy laws, clinical trial disclosure laws, and 
regulations. 
 
ESignatures may be found on the last page of this document. 
 
SIGNATURES 
 
, PhD 
, Statistics 
Date 
, MD 
 
Pharmacovigilance 
Date 
, MD 
, Clinical 
Science 
Date 
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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. 
• 
International Conference on Harmonization, E6 Good Clinical Practice: Consolidated 
Guideline. 
• 
All applicable laws and regulations (eg, European Union Clinical Trials Regulations), 
including, without limitation, data privacy laws and regulations. 
• 
Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
• 
Terms outlined in the study site agreement. 
• 
Responsibilities of the Investigator (Appendix D). 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix F 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 4 Summary of Changes 
Protocol Amendment 4 Summary and Rationale: 
This document describes the changes to the protocol incorporating Amendment 4.  
The primary purpose of this amendment is to update the protocol to clarify informed consent for 
future use of exploratory biological samples. 
In addition, minor grammatical, editorial, formatting, and administrative changes not affecting 
the conduct of the study are applied throughout the document for clarification and administrative 
purposes. 
The protocol amendment history for previous amendments is located in Appendix G. 
Protocol Amendment 4 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1. 
Section 9.1.11.1 
Collection, Storage, and 
Future Use of 
Biological Samples 
From Clinical Study 
Subjects 
Added a statement that participation 
in future use of samples for 
exploratory biomarker research is 
voluntary, and subjects may decline 
to consent to future use of these 
samples while still participating in 
the main study. 
To clarify that allowing biomarker 
samples to be retained for future 
use is not required for study 
participation.  
 
 
 
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE ...........................................................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 4 Summary of Changes...............................................................5 
2.0 
STUDY REFERENCE INFORMATION .........................................................................11 
2.1 
Study-Related Responsibilities ....................................................................................11 
2.2 
Principal Investigator/Coordinating Investigator .........................................................11 
2.3 
List of Abbreviations ...................................................................................................12 
3.0 
STUDY SUMMARY.........................................................................................................13 
4.0 
INTRODUCTION .............................................................................................................19 
4.1 
Background ..................................................................................................................19 
4.2 
Rationale for the Proposed Study ................................................................................19 
4.3 
Benefit-Risk Profile .....................................................................................................20 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................20 
5.1 
Objectives ....................................................................................................................20 
5.1.1 
Primary Objective ................................................................................................20 
5.1.2 
Secondary Objective ............................................................................................20 
5.1.3 
Exploratory Objectives ........................................................................................21 
5.2 
Endpoints .....................................................................................................................21 
5.2.1 
Primary Endpoint .................................................................................................21 
5.2.2 
Secondary Endpoints ...........................................................................................21 
5.2.3 
Exploratory Endpoints .........................................................................................22 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................22 
6.1 
Study Design ................................................................................................................22 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................24 
6.3 
Study Start Definition ..................................................................................................25 
6.4 
End of Study/Study Completion Definition .................................................................25 
6.5 
Premature Termination or Suspension of Study or Study Site ....................................25 
6.5.1 
Criteria for Premature Termination or Suspension of the Study .........................25 
6.5.2 
Criteria for Premature Termination or Suspension of Study Sites ......................25 
6.5.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites .................................................................................25 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............26 
7.1 
Inclusion Criteria .........................................................................................................26 
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7.2 
Exclusion Criteria ........................................................................................................27 
7.3 
Criteria for Discontinuation or Withdrawal of a Subject .............................................28 
7.4 
Procedures for Discontinuation or Withdrawal of a Subject .......................................29 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT .......................................................29 
8.1 
Study Drug and Materials ............................................................................................29 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ....................................29 
8.1.1.1 
Study Drug ..................................................................................................30 
8.1.1.2 
Sponsor-Supplied Drug ...............................................................................30 
8.1.1.3 
Packaging and Labeling ..............................................................................30 
8.1.2 
Storage and Handling of Study Medication ........................................................31 
8.1.3 
Dose and Regimen ...............................................................................................31 
8.1.4 
Overdose ..............................................................................................................31 
8.2 
Study Drug Assignment and Dispensing Procedures ..................................................31 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs.......................................32 
9.0 
STUDY PLAN ...................................................................................................................33 
9.1 
Study Procedures .........................................................................................................33 
9.1.1 
Informed Consent Procedure ...............................................................................33 
9.1.2 
Demographics, Medical History, and Medication History Procedure ................33 
9.1.3 
Physical Examination Procedure .........................................................................34 
9.1.4 
Height and Weight ...............................................................................................34 
9.1.5 
Vital Sign Procedure ............................................................................................34 
9.1.6 
Primary Safety Measurement ..............................................................................34 
9.1.7 
Efficacy Measurements .......................................................................................34 
9.1.7.1 
Fistula Clinical Assessment ........................................................................35 
9.1.7.2 
Fistula MRI Assessment .............................................................................35 
9.1.7.3 
PDAI ...........................................................................................................35 
9.1.7.4 
PRO-2 ..........................................................................................................35 
9.1.8 
Exploratory Biomarker Assessments ..................................................................35 
9.1.9 
Documentation of Prior and Concomitant Medications ......................................36 
9.1.10 
Documentation of Concurrent Medical Conditions ............................................36 
9.1.11 
Procedures for Clinical Laboratory Samples .......................................................36 
9.1.11.1 Collection, Storage, and Future Use of Biological Samples From 
Clinical Study Subjects ...............................................................................37 
9.1.12 
Contraception and Pregnancy Avoidance Procedure ..........................................38 
9.1.12.1 Male Subjects and Their Female Partners ...................................................38 
9.1.12.2 Female Subjects and Their Male Partners ...................................................38 
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9.1.12.3 Definitions and Procedures for Contraception and Pregnancy 
Avoidance ...................................................................................................38 
9.1.12.4 General Guidance with Respect to the Avoidance of Pregnancy ...............40 
9.1.13 
Pregnancy ............................................................................................................41 
9.1.14 
Documentation of Study Entrance .......................................................................41 
9.2 
Monitoring Subject Treatment Compliance.................................................................41 
9.3 
Schedule of Observations and Procedures ...................................................................41 
9.3.1 
Baseline Visit .......................................................................................................42 
9.3.2 
Preparation Visit (Visit 0) ...................................................................................44 
9.3.3 
Repeat Administration (Visit 1) ..........................................................................45 
9.3.4 
6 Weeks Following Repeat Administration (Visit 2/Week 6 ± 8 days) ..............46 
9.3.5 
6 Months Following Repeat Administration (Visit 3/Week 24 ± 15 days) .........46 
9.3.6 
12 Months Following Repeat Administration (Visit 4/Week 52 ± 15 days) .......47 
9.3.7 
24 Months Following Repeat Administration (Visit 5/Week 104 ± 30 days) .....47 
9.3.8 
36 Months Following Repeat Administration (Visit 6/156 Weeks ± 30 days, 
Final Visit) ...........................................................................................................48 
9.3.9 
Early Termination Visit .......................................................................................48 
9.3.10 
Unscheduled Visit ...............................................................................................49 
9.3.11 
Unscheduled Telephone Call Visit ......................................................................49 
10.0 
ADVERSE EVENTS .........................................................................................................50 
10.1 
Definitions....................................................................................................................50 
10.1.1 
AEs ......................................................................................................................50 
10.1.2 
SAEs ....................................................................................................................50 
10.1.3 
AESIs ...................................................................................................................51 
10.1.4 
SSRs ....................................................................................................................51 
10.1.5 
Causality of AEs ..................................................................................................52 
10.1.6 
Severity of AEs ....................................................................................................52 
10.1.7 
Relationship to Study Procedures ........................................................................52 
10.1.8 
Start Date .............................................................................................................52 
10.1.9 
Stop Date .............................................................................................................52 
10.1.10 Frequency ............................................................................................................52 
10.1.11 Action Concerning Study Drug ...........................................................................53 
10.1.12 Outcome ..............................................................................................................53 
10.2 
Procedures ....................................................................................................................53 
10.2.1 
Collection and Reporting of AEs ........................................................................53 
10.2.1.1 AE Collection Period ..................................................................................53 
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10.2.1.2 AE Reporting ..............................................................................................53 
10.2.1.3 AESIs ..........................................................................................................54 
10.2.2 
Collection and Reporting of SAEs ......................................................................55 
10.3 
Follow-up of SAEs ......................................................................................................55 
10.3.1 
SSRs ....................................................................................................................56 
10.3.2 
Pregnancy ............................................................................................................56 
10.3.3 
Summary of Safety Reporting .............................................................................56 
10.3.4 
Safety Reporting to Investigators, IECs, and Regulatory Authorities .................56 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................57 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................57 
12.1 
eCRFs ...........................................................................................................................57 
12.2 
Record Retention .........................................................................................................57 
13.0 
STATISTICAL METHODS ..............................................................................................58 
13.1 
Statistical and Analytical Plans ....................................................................................58 
13.1.1 
Analysis Sets .......................................................................................................58 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ..........................58 
13.1.3 
Efficacy Analysis .................................................................................................59 
13.1.4 
Safety Analysis ....................................................................................................59 
13.1.5 
Other Analysis .....................................................................................................59 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................60 
13.3 
Determination of Sample Size .....................................................................................60 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................60 
14.1 
Study-Site Monitoring Visits .......................................................................................60 
14.2 
Protocol Deviations ......................................................................................................60 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................61 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................61 
15.1 
IEC Approval ...............................................................................................................62 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................62 
15.3 
Subject Confidentiality ................................................................................................63 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................64 
15.4.1 
Publication and Disclosure ..................................................................................64 
15.4.2 
Clinical Trial Registration ...................................................................................64 
15.4.3 
Study Registration and Results Disclosure ..........................................................65 
15.5 
Insurance and Compensation for Injury .......................................................................65 
16.0 
REFERENCES ..................................................................................................................65 
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LIST OF IN-TEXT TABLES 
Table 8.a 
Study Medications .................................................................................................30 
Table 9.a 
Clinical Laboratory Tests .......................................................................................37 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Study Schematic.....................................................................................................24 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ...............................................................................67 
Appendix B 
Anal Clock .............................................................................................................71 
Appendix C 
PRO-2 Scoring .......................................................................................................72 
Appendix D 
Responsibilities of the Investigator ........................................................................73 
Appendix E 
Elements of the Subject Informed Consent ...........................................................75 
Appendix F 
Investigator Consent to Use of Personal Information ............................................78 
Appendix G 
Protocol History .....................................................................................................79 
 
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2.0 
STUDY REFERENCE INFORMATION 
2.1 
Study-Related Responsibilities  
The sponsor will perform all study-related activities except for those identified in the 
study-related responsibilities template. The vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor. 
2.2 
Principal Investigator/Coordinating Investigator  
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the drug used in the study, 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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2.3 
List of Abbreviations 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AOR 
acknowledgment of receipt 
AST 
aspartate aminotransferase 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index  
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CTA 
Clinical Trials Regulations 
DSA 
donor-specific antibodies 
eASC 
expanded adipose stem cells  
ECG 
electrocardiogram 
eCRF 
electronic case report form  
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IWRS 
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MRI 
magnetic resonance imaging 
PASS 
postauthorization safety study 
PCR 
polymerase chain reaction 
PDAI 
Perianal Disease Activity Index 
PRO-2 
patient reported outcome score-2 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SSR 
special situation report 
TNF-α 
tumor necrosis factor-alpha 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
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3.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Development Center Americas, 
Inc. 
Compound: 
Darvadstrocel 
Title of Protocol:  
Postauthorization Safety Study of the 
Long-Term Safety and Efficacy of Repeat 
Administration of Darvadstrocel in Patients 
With Crohn’s Disease and Complex Perianal 
Fistula 
IND No.: 17707 
Abbreviated EU CT 
Number: 
2022-503014-23 
EUPAS number: 
EUPAS31439 
Study Number: Alofisel-4001 
Phase: 4 
Study Design: 
This is a postauthorization safety study (PASS) to investigate the long-term safety and efficacy of a repeat 
administration with darvadstrocel in subjects with Crohn’s disease (CD) and complex perianal fistula. 
The study is a single-arm clinical study in subjects with CD and complex perianal fistulas, aged 18 years or 
older, who have previously been administered darvadstrocel (Alofisel) and repeat administration is planned by 
their physician. The study will be performed in countries where darvadstrocel is currently marketed. 
The decision to retreat with darvadstrocel is taken at the discretion of the treating physician. Subjects are 
recruited into the study only after the physician and subject have decided to proceed with darvadstrocel repeat 
administration of the original fistula tract or initial treatment of a new complex perianal fistula tract. Only 1 
repeat administration of darvadstrocel is permitted during study. If the subject has previously participated in a 
darvadstrocel study and it was not clear if they received darvadstrocel, the subject will not be eligible for 
inclusion in this study. 
Baseline information will be collected on demographics, clinical characteristics and CD clinical history, 
treatment history (including details of first administration of darvadstrocel), fistula history (prior procedures for 
perianal disease), and comorbidities/concomitant medications. In addition, a pelvic magnetic resonance imaging 
(MRI) will be performed and used to document fistula characteristics before repeat administration at the baseline 
visit. An MRI will also be performed post repeat administration at Week 24 to assess fistula characteristics and 
for the presence or absence of collection(s) >2 cm (in at least 2 dimensions) and at Week 156 to assess fistula 
characteristics and for the presence or absence of collection(s) >2 cm (in at least 2 dimensions). If subjects 
display significant new perianal symptoms, the subject will have an unscheduled visit and an MRI will be 
performed. Central reading of pelvic MRIs will be performed. All local MRIs will be assessed centrally by 2 
imaging readers (or 3 readers if adjudication is needed). 
Subjects will be assessed before repeat administration at the preparation visit, treatment visit and at Weeks 6 
(±8 days), 24 (±15 days), 52 (±15 days), 104 (±30 days), and 156 (±30 days) following repeat administration. 
The Week 6 assessment will be primarily to capture immunogenicity/donor-specific antibody (DSA)/soluble 
factors. 
Blood samples for central laboratory tests and plasma samples for DSA levels and exploratory immunogenicity 
testing will be collected at specific time points in the study. Blood samples for these tests will be analyzed in 
batches as the study progresses; however, if there is a confirmed serious allergic reaction following the 
administration of darvadstrocel, then DSA testing will be done as soon as logistically possible and data on DSA 
will be assessed in conjunction with serious adverse events (SAEs) reported in these subjects. 
Benefit-Risk Profile: 
The decision to proceed with darvadstrocel repeat administration will be taken at the discretion of the treating 
physician before the subject enters the study; therefore, subject treatment will not be altered by their participation 
in this study.  
The additional diagnostic and monitoring procedures conducted in this study pose minimal additional risk and 
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burden to the safety of the subjects compared with usual practice (blood extraction for immunologic analysis and 
contrast-enhanced MRI performance). 
Darvadstrocel was safe and well tolerated. Overall, the data available to date present a positive benefit-risk 
profile for darvadstrocel.  
Primary Objective: 
To evaluate the long-term safety of repeat administration of darvadstrocel in subjects with CD and complex 
perianal fistula by evaluation of adverse events (AEs), SAEs, adverse events of special interest (AESIs), and 
pregnancy. 
Secondary Objective: 
To evaluate the long-term efficacy of repeat administration of darvadstrocel in subjects with CD and complex 
perianal fistula. 
Exploratory Objectives: 
• 
To characterize the immunogenicity of darvadstrocel (DSA) and the impact of immunogenicity on safety 
and clinical response. 
 
 
 
Subject Population: 
Subjects with CD aged 18 years or older, with complex perianal fistulas who have previously received treatment 
with darvadstrocel and a repeat administration of darvadstrocel for the original fistula tract or for a new complex 
perianal fistula tract is planned by their physician. 
Number of Subjects: 
50 subjects 
Number of Sites:  
Approximately 20 to 30 sites 
Dose Level: 
Darvadstrocel (120 million cells) 
Route of Administration: 
Intralesional injection 
Duration of Treatment: 
Single dose  
Period of Evaluation: 
156 weeks after darvadstrocel repeat administration 
Main Criteria for Inclusion: 
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 signs and dates a written, informed consent form (ICF) and any required privacy authorization 
before the initiation of any study procedures. 
3. The subject is male or female and aged 18 years or older. 
4. The subject has complex perianal fistula(s) with a maximum of 2 internal openings and a maximum of 3 
external openings based on clinical assessment and a reading of a locally performed contrast enhanced 
(gadolinium) pelvic MRI. Fistula(s) must have been draining for at least 6 weeks prior to baseline visit. A 
complex perianal fistula is defined as a fistula that meets 1 or more of the following criteria: 
a) High inter-sphincteric, high trans-sphincteric, extra-sphincteric or suprasphincteric. 
b) Presence of ≥2 external openings. 
c) Associated perianal abscess(es). Note: Abscesses that are larger than 2 cm in at least 2 dimensions 
on MRI must be confirmed to have been drained adequately by the surgeon during the preparation 
curettage in order to be eligible. 
5. The subject has already received treatment with darvadstrocel for a complex perianal fistula at least 6 
months prior to baseline visit for retreatment, and their physician has planned a repeat treatment 
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administration for the original tract (full remission not obtained or relapse of fistula draining) or for a new 
complex perianal fistula tract. 
6. The subject has controlled or mildly active CD (defined as patient reported outcomes measure derived from 
Crohn’s Disease Activity Index patient reported outcome score-2 score <14). 
7. A male subject who is nonsterilized and sexually active with a female partner of childbearing potential 
agrees to use barrier method of contraception (eg, condom with or without spermicide) from signing of 
informed consent and until 1 year after repeat administration. 
8. A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to 
use a highly effective/effective method of contraception from signing of informed consent and until 1 year 
after repeat administration. 
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Main Criteria for Exclusion: 
A subject will not be included in the study if he/she meets ANY of the following criteria: 
1. The subject has lack of clinical response to prior treatment with darvadstrocel, where clinical response is 
defined as closure of at least 50% of all treated external fistula openings that were draining at baseline 
despite gentle finger compression or in the case of a unique fistula, a partial closure of the fistula. 
2. The subject has a history of hypersensitivity or allergies to darvadstrocel or related compounds. 
3. The subject has a history of hypersensitivity or allergies to penicillin or to aminoglycosides; Dulbecco 
modified eagle medium; bovine serum; local anesthetics, or gadolinium. 
4. The subject is currently participating in a double-blind clinical study with darvadstrocel. Subjects 
participating in the ongoing INSPIRE (Alofisel-5003) registry study would need to withdraw from that study 
in order to enroll in this study. 
5. The subject is currently receiving or has received any other investigational medicinal product (IMP) within 
the last 3 months or at least 5 times the respective elimination half-life time, whichever is longer, before 
signing the ICF. 
6. The subject has known or suspected coronavirus disease 2019 (COVID-19) by the investigator within the 
past 2 months (additional testing may be performed at the discretion of the investigator). Positive antibody 
testing for COVID without other evidence of current or recent active infection does not exclude 
participation. 
• Subjects who were in screening at the time that COVID 19–related factors resulted in discontinuation 
may also be rescreened with approval of the sponsor or designee. 
7. The subject has major alterations in any of the following laboratory tests: 
a) Serum creatinine levels >1.5 times the upper limit of normal (ULN). 
b) Total bilirubin >1.5 × ULN.  
c) Aspartate aminotransferase or alanine aminotransferase >3.0 × ULN. 
d) Hemoglobin <10.0 g/dL. 
e) Platelets <75.0 × 109/L. 
f) Albumin <3.0 g/dL. 
8. The subject has an increased risk for a surgical procedure. 
9. The subject has a known chronically active hepatopathy of any origin, including cirrhosis and subjects with 
persistent positive hepatitis B surface antigen and quantitative hepatitis B virus polymerase chain reaction 
(PCR) or positive serology for hepatitis C virus (HCV) and quantitative HCV PCR within 6 months prior to 
the baseline visit. 
10. If female, the subject is pregnant or breastfeeding, or intending to become pregnant before participating in 
this study, during the study, or intending to donate ova during such time period. 
11. If male, the subject intends to donate sperm during this study. 
12. The subject has a contraindication to MRI scan (eg, due to the presence of pacemaker, hip replacement, 
severe claustrophobia, or renal insufficiency as defined by local clinical guidelines). 
13. The subject has a contraindication to the anesthetic procedure. 
14. The subject has severe rectal and/or anal stenosis that would make it impossible to follow the surgery 
procedure. 
15. The subject has severe proctitis (rectal ulcers >0.5 cm) that would make it impossible to follow the surgery 
procedure. 
16. The subject has any prior invasive malignancy diagnosed within the last 3 years before the baseline visit. 
Subjects with basal cell carcinoma of the skin completely resected outside the perineal region can be 
included. 
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17. The subject has a current or recent (within 6 months before the baseline visit) history of severe, progressive, 
and/or uncontrolled hepatic, hematologic, gastrointestinal (other than CD), renal, endocrine, pulmonary, 
cardiac, neurologic, or psychiatric disease that may result in subject’s increased risk from study participation 
and/or lack of compliance with study procedures. 
18. The subject has had major surgery of the gastrointestinal tract within 6 months before baseline, or any minor 
surgery of the gastrointestinal tract 3 months before the baseline visit. 
19. The subject has had local major perianal surgery and/or treatment with darvadstrocel within 6 months before 
the baseline visit. The abscess drainage, cleaning surgery, or seton placement are not considered as “local 
major surgery” in this protocol. 
20. The subject does not wish to or cannot comply with study procedures. 
Main Criteria for Evaluation and Analyses: 
Primary Endpoint: 
The primary objective of safety will be assessed by evaluating the following safety parameters: 
• 
Treatment-emergent AEs. 
• 
Treatment-emergent SAEs. 
• 
 Pregnancy. 
• 
Specific treatment-emergent AESIs: 
– 
Immunogenicity/alloimmune reactions. 
– 
Hypersensitivity.  
– 
Transmission of infectious agents. 
– 
Tumorgenicity, applying to malignant tumors only. 
– 
Ectopic tissue formation. 
– 
Medication errors (reported to the pharmacovigilance department as special situation reports). 
Secondary Endpoints: 
Efficacy will be assessed by evaluating the following endpoints: 
• 
Proportion of subjects who achieve combined remission of perianal fistula(s) at Weeks 24 and 156 after 
darvadstrocel repeat administration, where combined remission is defined as: 
- 
The closure of all treated external openings that were draining at baseline, 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 MRI assessment. 
• 
Proportion of subjects who achieve clinical remission at Weeks 6, 24, 52, 104, and 156 after darvadstrocel 
repeat administration. 
- 
Clinical remission is defined as closure of all treated external fistula openings that were draining at 
baseline despite gentle finger compression. 
• 
Proportion of subjects who achieve clinical response at Weeks 6, 24, 52, 104, and 156 after darvadstrocel 
repeat administration. 
- 
Clinical response is defined as closure of at least 50% of all treated external fistula openings that were 
draining at baseline despite gentle finger compression. 
• 
Proportion of subjects with relapse from Week 24 combined remission, where relapse is defined as: 
- 
Reopening of any of the treated fistula(s) external openings with active draining as clinically assessed, 
that were in combined remission at Week 24,  
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OR 
- 
The development of a collection >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) 
confirmed by centrally read MRI assessment. 
• 
Time to reopening of any of the treated external openings with active drainage as clinically assessed, 
measured in days relative to Week 24. 
• 
Proportion of subjects with new perianal abscess in treated fistula.  
• 
Change from baseline to Weeks 6, 24, 52, 104, and 156 after darvadstrocel repeat administration in scores of 
discharge and pain items of Perianal Disease Activity Index (PDAI) score. 
Exploratory Endpoints: 
• 
Immunogenicity responses as measured by DSA levels. 
 
 
 
Statistical Considerations: 
Descriptive analysis of subject demographics and other baseline characteristics including CD characteristics and 
concurrent medications will be presented. 
The safety analysis set will include all subjects retreated with darvadstrocel. Count and percentage of subjects 
with AEs, SAEs (defined as any SAE, regardless of relationship to study drug), and AESIs 
(immunogenicity/alloimmune reactions, hypersensitivity, tumorgenicity (applying to malignant tumors only), 
transmission of infectious agents, ectopic tissue formation, and medication errors) will be summarized 
descriptively by system organ class and preferred term. SAEs will also be summarized by severity and by 
relationship to study drug. 
Categorical efficacy endpoints, including combined remission, clinical remission, clinical response, relapse, and 
new perianal abscess in the treated fistula will be summarized by visit.  
Change from baseline in PDAI subscore (discharge and pain) will be summarized descriptively by visit. 
The probability of reopening of any of the treated external openings with active drainage across time among 
subjects who achieve remission will be estimated using the Kaplan-Meier estimator.  
Full details of the statistical analysis will be provided in the statistical analysis plan. 
Sample Size Justification:  
Complex perianal fistula is a rare disease, with orphan disease designation granted by the European Commission. 
This study will plan to enroll approximately 50 subjects as part of a regulatory commitment, who have received 
previous darvadstrocel treatment and need to be re-treated for the same fistula tract or a new complex perianal 
fistula tract according to their physician. 
 
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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. 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 darvadstrocel (Cx601) was well tolerated in 
the study population (Panes et al. 2016). 
The repeat use of darvadstrocel was investigated in study Cx601-0101 where subjects received a 
single intralesional administration of darvadstrocel (20 million cells) and were followed-up for 
24 weeks. Subjects who had incomplete fistula closure at Week 12 following first administration 
of darvadstrocel were administered a second dose (40 million cells). Twenty-four subjects 
initially received 20 million cells and 15 (65%) subjects received a second dose of darvadstrocel 
(repeat dose). Subjects who received a repeat dose showed comparable results in fistula healing 
compared with subjects who received a single dose. The adverse event (AE) profile following 
single dose and repeat dose was comparable. The generation of donor-specific antibodies (DSA) 
after a second administration of darvadstrocel was assessed. The evaluation of the impact of 
DSA generation on efficacy or safety of darvadstrocel was limited in this study due to the low 
number of subjects. However, no obvious detrimental effect of DSA on the efficacy and safety of 
darvadstrocel was observed (de la Portilla et al. 2013). 
4.2 
Rationale for the Proposed Study 
This postauthorization safety study (PASS) is being undertaken to investigate the long-term 
safety and efficacy of a repeat administration with darvadstrocel in concordance with the 
condition approved in the market authorization: subjects with CD and complex perianal fistula.  
The aim of this study is to generate descriptive data of 3 years follow-up to gain insight into the 
safety and efficacy of a repeat administration of darvadstrocel. Such information will be helpful 
to health authorities, payors, and physicians for the future use of darvadstrocel. 
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4.3 
Benefit-Risk Profile 
The decision to proceed with darvadstrocel repeat administration will be taken at the discretion 
of the treating physician before the subject enters the study, therefore subject treatment will not 
be altered by their participation in this study.  
The additional diagnostic and monitoring procedures conducted in this study pose minimal 
additional risk and burden to the safety of the subjects compared with usual practice (blood 
extraction for immunologic analysis and contrast-enhanced magnetic resonance imaging (MRI) 
performance).  
In clinical studies conducted to date, darvadstrocel appeared to be, overall, well tolerated up to 
120 million cells per administration. No dose-dependent safety concern or toxicity has been 
identified to date. No ectopic tumor formation or hypersensitivity concerns have emerged to 
date. Overall, the data available to date presents a positive benefit-risk profile for darvadstrocel. 
As with any other product containing human blood or plasma product, there is a theoretical 
possibility for transmission of viral agents, despite all controls performed by the manufacturer.  
There are potential complications that may occur during surgery and/or on the days after the 
procedure and are related to the surgical procedure (eg, bleeding, wound infection, and 
procedural pain). Adverse reactions that were associated with the conditioning of the subject 
(curettage) or the surgical administration procedure included: proctalgia, procedural pain, 
postprocedural inflammation, and anal (perianal) abscess. 
Known adverse drug reactions with darvadstrocel include proctalgia, anal abscess, and anal 
fistula. 
There is currently limited experience in the efficacy and safety of repeat administration of 
darvadstrocel. Although subjects included in this study may not receive any benefit from their 
participation, the study will provide data on repeat administration that will be useful for 
maximizing the safe and effective use of darvadstrocel in the future. 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
• 
To evaluate the long-term safety of repeat administration of darvadstrocel in subjects with 
CD and complex perianal fistula by evaluation of AEs, serious adverse events (SAEs), 
adverse events of special interest (AESIs), and pregnancy. 
5.1.2 
Secondary Objective 
• 
To evaluate the long-term efficacy of repeat administration of darvadstrocel in subjects with 
CD and complex perianal fistula. 
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5.1.3 
Exploratory Objectives  
• 
To characterize the immunogenicity of darvadstrocel (DSA) and the impact of 
immunogenicity on safety and clinical response. 
 
 
 
5.2 
Endpoints 
5.2.1 
Primary Endpoint 
The primary endpoint of the study will include assessment of the following safety parameters: 
• Treatment-emergent AEs. 
• Treatment-emergent SAEs. 
• Pregnancy. 
• Specific treatment-emergent AESIs, including: 
- 
Immunogenicity/alloimmune reactions. 
- 
Hypersensitivity. 
- 
Transmission of infectious agents. 
- 
Tumorgenicity, applying to malignant tumors only. 
- 
Ectopic tissue formation. 
- 
Medication errors (reported to the pharmacovigilance department as special situation 
reports [SSRs]). 
5.2.2 
Secondary Endpoints 
Efficacy will be assessed by evaluating the following endpoints: 
• Proportion of subjects who achieve combined remission of perianal fistula(s) at Weeks 24 
and 156 after darvadstrocel repeat administration, where combined remission is defined as: 
- 
The closure of all treated external openings that were draining at baseline, despite gentle 
finger compression, 
AND 
- 
Absence of collection(s) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) 
confirmed by central MRI assessment. 
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• Proportion of subjects who achieve clinical remission at Weeks 6, 24, 52, 104, and 156 after 
darvadstrocel repeat administration. 
- 
Clinical remission is defined as closure of all treated external fistula openings that were 
draining at baseline despite gentle finger compression. 
• Proportion of subjects who achieve clinical response at Weeks 6, 24, 52, 104, and 156 after 
darvadstrocel repeat administration. 
- 
Clinical response is defined as closure of at least 50% of all treated external fistula 
openings that were draining at baseline despite gentle finger compression. 
• Proportion of subjects with relapse from Week 24 combined remission, where relapse is 
defined as: 
- 
Reopening of any of the treated fistula(s) external openings with active drainage as 
clinically assessed that were in combined remission at Week 24, 
OR 
- 
The development of a collection >2 cm (in at least 2 dimensions) of the treated perianal 
fistula(s) confirmed by centrally read MRI assessment. 
• Time to reopening of any of the treated external openings with active drainage as clinically 
assessed, measured in days relative to Week 24. 
• Proportion of subjects with new perianal abscess in treated fistula.  
• Change from baseline to Weeks 6, 24, 52, 104, and 156 after darvadstrocel repeat 
administration in scores of discharge and pain items of Perianal Disease Activity Index 
(PDAI) score. 
5.2.3 
Exploratory Endpoints 
• Immunogenicity responses as measured by DSA levels. 
 
 
 
6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a PASS to investigate the long-term safety and efficacy of a repeat administration with 
darvadstrocel in subjects with CD and complex perianal fistula. 
This study is a single-arm clinical study of adult (aged 18 years or older) subjects with CD and 
complex perianal fistulas who have previously been administered darvadstrocel (Alofisel) and 
whose physician determines that repeat administration is indicated. The study will be performed 
in countries where darvadstrocel is currently marketed. A study schematic is presented in 
Figure 6.a. 
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The decision to perform repeat administration with darvadstrocel is taken at the discretion of the 
treating physician. Subjects are recruited into the study only after the physician and subject have 
decided to proceed with darvadstrocel repeat administration of the original fistula tract or initial 
treatment of a new complex perianal fistula tract. Only 1 repeat administration of darvadstrocel 
is permitted during study. If the subject previously participated in a darvadstrocel study and was 
not clear if they received darvadstrocel, the subject will not be eligible for inclusion in this study. 
Baseline information will be collected on demographics, clinical characteristics and CD clinical 
history, treatment history (including details of first administration of darvadstrocel), fistula 
history (prior procedures for perianal disease), and comorbidities/concomitant medications. In 
addition, a pelvic MRI will be performed and used to document fistula characteristics before 
repeat administration at the baseline visit. An MRI will also be performed post repeat 
administration at Week 24 to assess fistula characteristics and for the presence or absence of 
collection(s) >2 cm (in at least 2 dimensions) and performed at Week 156 to assess fistula 
characteristics and for the presence or absence of collection(s) >2 cm (in at least 2 dimensions). 
If subjects display significant new perianal symptoms, the subject will have an unscheduled visit 
and an MRI will be performed. Central reading of pelvic MRIs will be performed. All local 
MRIs will be assessed centrally by 2 imaging readers (or 3 readers if adjudication is necessary). 
Subjects will be clinically assessed before repeat administration at the preparation visit, 
treatment visit and at Weeks 6 (±8 days), 24 (±15 days), 52 (±15 days), 104 (±30 days), and 156 
(±30 days) following repeat administration. The Week 6 assessment will be used primarily to 
capture immunogenicity/DSA/soluble factors. 
Sites will employ all efforts to see subjects in the clinic for assessments. In unavoidable 
circumstances, such as the COVID-19 pandemic, exceptions may be granted for alternative 
methods for conducting subject visits with approval by the medical monitor and/or sponsor. Such 
instances will be documented in the study records. These data collected with alternative methods 
may be handled differently in the final data analysis, with this documented in the statistical 
analysis plan. 
Blood samples for central laboratory tests and plasma samples for immunogenicity and DSA 
testing and exploratory biomarker analyses will be collected at the time points specified in 
Appendix A. Blood samples for these tests will be analyzed in batches as the study progresses; 
however, if there is a confirmed serious allergic reaction following the administration of 
darvadstrocel, then DSA testing will be done as soon as logistically possible. Data on DSA will 
be assessed in conjunction with SAEs reported in these subjects. Blood samples may be tested at 
a local laboratory for safety evaluation if it is not possible to have them tested at the central 
laboratory. The results of the laboratory tests will be returned to the investigator, who is 
responsible for reviewing and filing these results. 
A schedule of assessments is listed in Appendix A.  
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Figure 6.a 
Study Schematic 
 
DSA: donor-specific antibody; ICF: informed consent form; MRI: magnetic resonance imaging; V0: Visit 0; V1: 
Visit 1; V2: Visit 2; V3: Visit 3; V4: Visit 4; V5: Visit 5; V6: Visit 6. 
Early termination visit can occur at any point of the study. 
* Sample collection for DSA and MRI scan will take place after the subject has signed the ICF. 
** Baseline visit will take place 8 weeks prior to repeat administration (may be longer if repeat administration needs 
to be rescheduled). 
*** Preparation visit (Visit 0) will take place within a minimum of 2 weeks and a maximum of 3 weeks before the 
repeat administration visit. If there is any problem administering darvadstrocel at Visit 1, the visit will need to be 
rescheduled within a minimum of 2 weeks and a maximum of 3 weeks of the original Visit 1. 
 
6.2 
Justification for Study Design, Dose, and Endpoints 
There is currently limited experience of the efficacy and safety of repeat administration of 
darvadstrocel. This study is being conducted as a PASS to evaluate the long-term safety and 
efficacy of a repeat administration with darvadstrocel in the treatment of complex perianal fistula 
in subjects with CD. To be eligible for this study, subjects must have previously been 
administered darvadstrocel, and their physician must be planning repeat administration.  
Repeat administration is intended for patients who have 1 or more fistula tracks previously 
treated with darvadstrocel (who had a clinical response but did not achieve complete remission 
or who had a relapse of fistula draining after experiencing combined remission) or for patients 
who develop a new complex perianal fistula tract after prior administration of darvadstrocel. 
Repeat administration is not intended for patients who have received prior treatment with 
darvadstrocel resulting in lack of clinical response (treatment failure). 
MRI will be used to delineate the classification of the location and fistula characteristics and to 
longitudinally assess the presence and size of collections and assess for absence of 
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collection(s) >2 cm (in at least 2 dimensions). This will enable comparison of the efficacy of 
repeat administration to initial darvadstrocel treatment. 
The long-term follow-up of 3 years permits to have an evaluation of the maintenance of the 
efficacy and safety of this repeat administration. 
Immunogenicity of repeat administration will be assessed on an ongoing basis, and data on 
DSAs will be assessed in conjunction with SAEs reported in these subjects to investigate any 
impact on the safety of darvadstrocel. 
The endpoints used in this study are generally accepted as standard indicators of safety and 
disease activity in complex perianal fistulas in subjects with CD.  
6.3 
Study Start Definition 
The study start date is the date when the first subject signs the informed consent form (ICF).  
6.4 
End of Study/Study Completion Definition 
The study end date is the date when the last subject completes the last study visit.  
6.5 
Premature Termination or Suspension of Study or Study Site 
6.5.1 
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 
balance is no longer acceptable to include subjects in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 
6.5.2 
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. 
6.5.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites 
If the sponsor, 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 signs and dates a written, ICF and any required privacy authorization before the 
initiation of any study procedures. 
3. The subject is male or female and aged 18 years or older. 
4. The subject has complex perianal fistula(s) with a maximum of 2 internal openings and a 
maximum of 3 external openings based on clinical assessment and a reading of a locally 
performed contrast enhanced (gadolinium) pelvic MRI. Fistula(s) must have been draining 
for at least 6 weeks prior to baseline visit. A complex perianal fistula is defined as a fistula 
that meets 1 or more of the following criteria: 
a) High inter-sphincteric, high trans-sphincteric, extra-sphincteric or suprasphincteric. 
b) Presence of ≥2 external openings. 
c) Associated perianal abscess(es). Note: Abscesses that are larger than 2 cm in at least 
2 dimensions on MRI must be confirmed to have been drained adequately by the surgeon 
during the preparation curettage in order to be eligible.  
5. The subject has already received treatment with darvadstrocel for a complex perianal fistula 
at least 6 months prior to baseline visit for retreatment, and their physician has planned a 
repeat treatment administration for the original tract (full remission not obtained or relapse of 
fistula draining) or for a new complex perianal fistula tract. 
6. The subject has controlled or mildly active CD (defined as patient reported outcomes 
measure derived from Crohn’s Disease Activity Index [CDAI] patient reported outcome 
score-2 [PRO-2] score <14).  
7. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential agrees to use barrier method of contraception (eg, condom with or 
without spermicide)* from signing of informed consent and until 1 year after repeat 
administration.  
8. A female subject of childbearing potential* who is sexually active with a nonsterilized male* 
partner agrees to use a highly effective/effective method of contraception* from signing of 
informed consent and until 1 year after repeat administration.  
*Definitions and highly effective/effective methods of contraception are defined in 
Section 9.1.12 and reporting responsibilities are defined in Section 9.1.13. 
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7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. The subject has lack of clinical response to prior treatment with darvadstrocel, where clinical 
response is defined as closure of at least 50% of all treated external fistula openings that were 
draining at baseline despite gentle finger compression or in the case of a unique fistula, a 
partial closure of the fistula. 
2. The subject has a history of hypersensitivity or allergies to darvadstrocel or related 
compounds. 
3. The subject has a history of hypersensitivity or allergies to penicillin or to aminoglycosides; 
Dulbecco modified eagle medium; bovine serum; local anesthetics or gadolinium. 
4. The subject is currently participating in a double-blind clinical study with darvadstrocel. 
Subjects participating in the ongoing INSPIRE1 registry (Alofisel-5003) study would need to 
withdraw from that study in order to enroll in this study. 
5. The subject is currently receiving or has received any other IMP within the last 3 months or 
at least 5 times the respective elimination half-life time, whichever is longer, before signing 
the ICF. 
6. The subject has known or suspected COVID-19 by the investigator within the past 2 months 
(additional testing may be performed at the discretion of the investigator). Positive antibody 
testing for COVID without other evidence of current or recent active infection does not 
exclude participation. 
a) Subjects who were in screening at the time that COVID-19–related factors resulted in 
discontinuation may also be rescreened with approval of the sponsor or designee. 
7. The subject has major alterations in any of the following laboratory tests: 
a) Serum creatinine levels >1.5 times the upper limit of normal (ULN). 
b) Total bilirubin >1.5 × ULN.  
c) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3.0 × ULN. 
d) Hemoglobin <10.0 g/dL. 
e) Platelets <75.0 × 109/L. 
f) Albumin <3.0 g/dL. 
8. The subject has an increased risk for a surgical procedure. 
9. The subjects has a known chronically active hepatopathy of any origin, including cirrhosis 
and subjects with persistent positive hepatitis B surface antigen and quantitative hepatitis B 
 
1 The INSPIRE study is an observational postmarketing registry on effectiveness and safety of darvadstrocel in 
patients with Crohn’s disease and complex perianal fistula. 
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virus polymerase chain reaction (PCR) or positive serology for hepatitis C virus (HCV) and 
quantitative HCV PCR within 6 months before the baseline visit. 
10. If female, the subject is pregnant or breastfeeding, or intending to become pregnant before 
participating in this study, during the study, or intending to donate ova during such time 
period. 
11. If male, the subject intends to donate sperm during this study. 
12. The subject has a contraindication to MRI scan (eg, due to the presence of pacemaker, hip 
replacement, severe claustrophobia, or renal insufficiency as defined by local clinical 
guidelines). 
13. The subject has a contraindication to the anesthetic procedure. 
14. The subject has severe rectal and/or anal stenosis that would make it impossible to follow the 
surgery procedure. 
15. The subject has severe proctitis (rectal ulcers >0.5 cm) that would make it impossible to 
follow the surgery procedure. 
16. The subject has any prior invasive malignancy diagnosed within the last 3 years before 
baseline visit. Subjects with basal cell carcinoma of the skin completely resected outside the 
perineal region can be included. 
17. The subject has a current or recent (within 6 months before the baseline visit) history of 
severe, progressive, and/or uncontrolled hepatic, hematologic, gastrointestinal (other than 
CD), renal, endocrine, pulmonary, cardiac, neurologic, or psychiatric disease that may result 
in subject’s increased risk from study participation and/or lack of compliance with study 
procedures. 
18. The subject has had major surgery of the gastrointestinal tract within 6 months before 
baseline or any minor surgery of the gastrointestinal tract 3 months before baseline. 
19. The subject has had local major perianal surgery and/or treatment with darvadstrocel within 
6 months before baseline. The abscess drainage, cleaning surgery, or seton placement are not 
considered as “local major surgery” in this protocol. 
20. The subject does not wish to or cannot comply with study procedures. 
7.3 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study include: 
1. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s 
source documents.  
2. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
electronic case report form (eCRF). 
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Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to 
an AE should not be recorded in the “voluntary withdrawal” category).  
3. Study termination. The sponsor, IEC, or regulatory agency terminates the study. 
4. Physician’s decision based on subject’s well-being. 
5. Other. 
Note: The specific reason(s) should be recorded in the “specify” field of the eCRF. 
All efforts should be made to keep the subject in the study for safety assessments. 
7.4 
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.  
The eCRF must indicate the study completion visit, the date of termination, and the unique 
reason for discontinuing the study, with all data corresponding to a formal visit filled in the early 
termination visit. 
All information already collected as part of the study will be retained for analyses. A subject that 
discontinues from the study will not be replaced. No further efforts will be made to obtain or 
record additional information regarding the subject and outcomes.  
If a subject withdraws before completing the study follow-up period, the primary reason for 
discontinuation or withdrawal of the subject from the study or study drug should be recorded in a 
subject’s medical record and in the eCRF. 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
8.1 
Study Drug and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study drug or IMP refers to all or any of the drugs defined below. 
Darvadstrocel (Cx601) is a 24 mL suspension of human expanded adipose stem cells (eASCs) of 
allogeneic origin in aseptic buffered human albumin solution presented in disposable vials with 
no preservative agents. The cells will be given at a dose of 120 million cells (5 million cells/mL) 
for local injection in the fistula. 
Cells are obtained through lipoaspiration from healthy individuals and expanded ex vivo. 
Darvadstrocel for clinical use is supplied as a sterile, clear, white to yellowish suspension for 
local injection, provided in 4 × 6 mL vials (suspension of 5 million eASC per mL of Dulbecco 
modified eagle medium with human serum albumin).  
Additional reference information and administration instructions can be found in the IMP 
handling instructions and surgery procedure manual. 
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8.1.1.1 
Study Drug 
The drug being administered in this study is darvadstrocel. 
8.1.1.2 
Sponsor-Supplied Drug 
Darvadstrocel will be supplied by the sponsor. Details about the study medications are provided 
in Table 8.a. 
Table 8.a 
Study Medications 
Drug Name (Identification in the Protocol) 
Alofisel 
Product Class 
Stem cell therapies 
Designation 
IMP  
Marketing Authorization 
Yes 
Used Within Marketing Authorization 
Yes 
ATC Code 
L04AX08 
Route of Administration 
Perilesional injection 
Active Substance 
Darvadstrocel 
Dosage Level(s) 
120 million cells (5 million cells/mL) 
Dose Regimen 
Single, open-label darvadstrocel dose 
Duration 
Single dose 
Arm (Subjects Receiving the Medicinal Product) 
Single-arm study 
Dose Formulation 
Darvadstrocel (24 mL cell suspension containing 120 
million cells of eASCs): 5 million cells/mL 
Dose Strength(s) 
5 million cells/mL 
Sourcing 
Provided centrally/locally by the sponsor 
ATC: Anatomical Therapeutic Chemical; eASC: expanded adipose stem cells. 
 
8.1.1.3 
Packaging and Labeling 
Packaging and labelling of the study drugs will be performed by Takeda in Europe according to 
Good Manufacturing Practice principles and local regulation. 
The product, darvadstrocel (cell suspension), is supplied in duly labeled glass vials, tightly 
closed with rubber stoppers, and sealed with an aluminum cap. 
The packaging material comprises: 
• Immediate package: type 1 glass sterile vials with sterile rubber stopper and aluminium seal. 
• Labels of white polyethylene printed in black ink by thermal transfer printer. 
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• Secondary packaging: cardboard box with corporate design.  
“IMP Handling Instructions,” a printed document in which the product characteristics, 
indication, and method for use are described, is also enclosed with each product batch. 
8.1.2 
Storage and Handling of Study Medication 
Darvadstrocel product will be shipped under temperature-controlled conditions, using 
appropriate transport for biological samples. Shipping material is also duly labeled and has an 
attached package content list and instructions for use ‘see the label on the investigational product 
for expiration date and time’. 
Specific instructions will be provided within a separate study manual. 
Study medication will be shipped by specialized couriers to the hospital pharmacy or the 
corresponding operating room where the study treatment administration will be performed, 
according to local practice and regulations.  
The investigator or designee will maintain adequate records of the receipt and disposition of 
study drug shipment to the site. All used and unused vials of study drug must be recorded and 
tracked until data are monitored. Vials then should be destroyed locally, and destruction will be 
documented as appropriate. 
Study drug administration must be performed by authorized personnel with appropriate protocol 
training. 
A specific surgery procedure manual will be provided to the site as a separate document, 
ensuring appropriate training. 
8.1.3 
Dose and Regimen 
Subjects will receive a single open-label darvadstrocel dose of 120 million cells (5 million 
cells/mL) for local injection in the fistula as presented in Figure 6.a. 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol. 
All cases of overdose (with or without associated AEs) will be documented as a medication error 
on the AESI page of the eCRF and reported to safety on a paper SSR form. 
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2. 
8.2 
Study Drug Assignment and Dispensing Procedures 
Subjects will receive open-label darvadstrocel dose of 120 million cells (5 million cells/mL) for 
local injection in the fistula as presented in Figure 6.a. The subject identification number will be 
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entered onto the eCRF. Sponsor-supplied drug will be shipped from the manufacturing site upon 
request from the investigator according to the separately specified procedures and delivered to 
the study site on the day of administration or the previous day. 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dispensed only to subjects enrolled in the study. The investigator or 
designee will maintain adequate records of the receipt and disposition of study drug shipment to 
the site. All used and unused vials of study drug must be recorded and tracked until data are 
monitored by the contract research organization (CRO) monitor. Vials should then be destroyed 
locally, and destruction will be documented as appropriate. The only exception would be if a 
site’s standard operating procedure does not allow for the used drug vials to be kept on site after 
surgery. The method for verifying the drug accountability and destruction will be clearly 
documented in the site initiation visit report and the monitor will review all detailed records at 
the next site visit. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment. If there are any discrepancies between 
the packing list versus the actual product received, Takeda must be contacted to resolve the 
issue. The packing list should be filed in the investigator’s essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to: 
• Continuously monitoring expiration dates if expiry date/retest date is provided to the 
investigator or designee.  
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for the drug lot/medication identification (ID)/job number 
used to prepare each dose. 
• Verifying that all containers used are documented accurately on the log. 
• Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The investigator or designee must record the current inventory of all sponsor-supplied drugs on a 
sponsor-approved drug accountability log. Drug accountability will be performed at the site. All 
used vials will be stored at site until the local monitor has performed the corresponding 
documented reconciliation and drug accountability. Any dosage deviation should be clearly 
documented. The corresponding destruction will be documented as per local procedures and 
regulations (eg, destruction certificate issued and filed in the corresponding study files). 
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Before site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are destroyed locally, unless a site’s SOP prohibits the used drug vials from being stored 
locally until the monitors visit. The investigator or designee will retain a copy of the 
documentation regarding sponsor-supplied drug accountability, return and/or destruction, and a 
copy will be sent to the sponsor or designee. 
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. 
When the decision of a repeat administration with darvadstrocel has been made by the treating 
physician, eligible subjects will be informed about the study and given the opportunity to consent 
and enroll in this study.  
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 enters the study and before any 
protocol-directed procedures are performed. For any subject not meeting eligibility criteria at the 
baseline and/or preparation visits, and receives sponsor approval to rescreen, the subject will be 
asked to reconsent into the study. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time of enrollment; this subject number will be used throughout the study. 
9.1.2 
Demographics, Medical History, and Medication History Procedure 
Demographic information will be obtained at the baseline visit. 
Medical history to be obtained will include history of CD, fistulizing CD and assessment of 
severity and history of cancer, including anal canal and colorectal malignancy, any 
transplantation or blood transfusion, any prior surgeries, and number of pregnancies. Medical 
history will also include determining whether the subject has any significant conditions or 
diseases relevant or severe at study entry. Other ongoing conditions will be considered 
concurrent medical conditions (see Section 9.1.10). 
Medication history information to be documented in the eCRF includes all prior treatments 
received within 2 years before the baseline visit, including but not limited to medications for the 
treatment of CD or perianal fistulas, including details on first darvadstrocel administration and 
immunosuppressive agents including, but not limited to azathioprine, mercaptopurine, or 
methotrexate, tumor necrosis factor-alpha (TNF-α) antagonist, vedolizumab or ustekinumab, 
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including induction or maintenance, and if any, inadequate response, loss of response of perianal 
fistulas, or intolerance to each of these previous specific treatments. 
9.1.3 
Physical Examination Procedure 
A baseline physical examination (defined as the assessment before first dose of study drug) will 
consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) nervous system; (10) lymph nodes; (11) genitourinary system; and 
(12) other. 
All subsequent physical examinations should assess clinically significant changes from the 
assessment before the first dose examination.  
Any physical examination finding that is assessed by the investigator as a clinically significant 
worsening compared with a baseline value will be considered an AE and will be recorded and 
monitored as described in Section 10.2. 
9.1.4 
Height and Weight 
Height and weight will be measured wearing indoor clothing and with shoes off. Height will be 
measured at the baseline visit only. Weight will be measured at all visits. 
9.1.5 
Vital Sign Procedure 
Vital signs will include body temperature (oral, rectal, tympanic, or temporal measurement), 
sitting/supine blood pressure (systolic and diastolic, resting more than 5 minutes), and pulse 
(beats per minute). 
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw. 
9.1.6 
Primary Safety Measurement  
The long-term safety of repeat administration of darvadstrocel will be assessed in CD subjects 
with complex perianal fistula by collection of AEs, SAEs, pregnancies, and AESIs. Specific 
AESIs assessed will include immunogenicity/alloimmune reactions (including assessment of 
DSA formation and the impact of immunogenicity on safety and clinical response), 
hypersensitivity, ectopic tissue formation, medication errors, tumorgenicity (applying to 
malignant tumors only), and transmission of infectious agents. 
9.1.7 
Efficacy Measurements 
Note: in acknowledgement of hospital, local, state, or national government restrictions or other 
site-related factors caused by unavoidable circumstances such as the COVID-19 pandemic, it 
may be necessary to administer clinical interviews and assessments using alternative approaches 
(see Section 9.3). Such approaches could involve site staff visiting the subject’s residence, and 
remote assessments, which may incorporate audio or video recording. In some cases, audio 
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and/or video recording of subject interviews may not be possible. This will be documented in the 
study records. 
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 or to be 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. 
9.1.7.2 
Fistula MRI Assessment 
A pelvic MRI with and without intravenous contrast material will be performed at the baseline 
visit, Week 24, Week 156, early termination visit, and at any unscheduled visits.  
The MRI central readers will report fistula characteristics and measurements of collection(s) 
greater than 1 cm in at least 2 dimensions. Analysis will also include assessment of 
collections >2 cm, (in at least 2 dimensions). Results will not be sent to study sites. 
9.1.7.3 
PDAI 
The PDAI is a scoring system to evaluate the severity of perianal CD (Irvine 1995). From the 
5-item instrument, discharge and pain will be assessed. 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. 
This assessment will take place at all visits except for the preparation visit. 
9.1.7.4 
PRO-2 
PRO-2 includes 2 predictor variables of the CDAI (number of liquid stools and the abdominal 
pain) (Khanna et al. 2015). PRO-2 combines the average daily liquid or soft stools frequency and 
the average daily abdominal pain severity. PRO-2 score to be collected at baseline to confirm no 
or mildly active CD (score <14) and will be calculated by the investigator before the preparation 
visit using the subject’s diary according to the scoring in Appendix C. The PRO-2 will be 
provided to the subject at each visit for their completion at home and is to be completed 7 days 
before the next visit and the total score will be calculated by the investigator at each visit. 
9.1.8 
Exploratory Biomarker Assessments 
Blood will be taken for exploratory biomarker analysis with the goal of identifying markers of 
response or nonresponse to darvadstrocel. These exploratory biomarkers include 
 
immunogenicity responses, 
. 
Immunogenicity assessment will be conducted by analyzing plasma samples collected at the time 
points specified in Appendix A. Samples will be analyzed via a central laboratory. Results on the 
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presence and titer of DSA will be transferred for their integrated interpretation with potential 
interactions on safety or impact on efficacy. 
 
 
 
 
9.1.9 
Documentation of Prior and Concomitant Medications 
Prior medications are all medications received within 2 years before the baseline visit, including 
but not limited to medications for the treatment of CD or perianal fistulas.  
Concomitant medications are all medications taken on or after the date of baseline including 
those started before treatment administration (Visit 1) and that the subject is continuing to take 
on Visit 1. These may be prescribed by a physician or obtained by the subject over the counter. 
Concomitant medication is not provided by the sponsor. At each study visit, subjects will be 
asked whether they have taken any medication other than the study drug (used from signing of 
the ICF through the end of the study), and all medication including vitamin supplements, 
over-the-counter medications, and oral herbal preparations, must be recorded in the eCRF. 
The study follows an add-on design, thus, any ongoing treatments for CD (ie, 
immunosuppressants and/or biologics: anti-TNF, anti-integrin, or anti-interleukin 12/23) at the 
time of baseline shall continue throughout the study. Any change in medication dose (decrease, 
increase or suspension of medication) will be allowed and will be captured at the eCRF. 
9.1.10 
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, 
electrocardiogram (ECG), or physical examination abnormalities noted at baseline examination, 
according the judgment of the investigator. The condition (ie, diagnosis) should be described and 
recorded as medical history. 
9.1.11 
Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures and analyzed 
via a central laboratory. Details of these procedures and required safety monitoring will be 
provided in the laboratory manual. The laboratory manual describes procedures for specimen 
handling. 
Blood samples for central laboratory tests will be collected at the time points specified in 
Appendix A. 
Table 9.a lists the tests that will be obtained for each laboratory specimen. 
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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Hemoglobin 
Hematocrit 
Erythrocytes 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Leukocytes 
Lymphocytes 
Monocytes 
Neutrophils 
Eosinophils 
Basophils 
Platelet count 
C-reactive protein 
Urea 
Creatinine 
Glucose 
AST 
ALT 
Albumin 
Total bilirubin (direct bilirubin if total bilirubin is 
above the ULN) 
Potassium 
Sodium 
Chloride 
Serum 
Urine 
Beta hCG (for pregnancy) 
hCG (for pregnancy) 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; hCG: human chorionic gonadotropin; ULN: 
upper limit of normal. 
 
The central laboratory will perform laboratory tests for hematology and serum chemistries (tests 
may be performed at local laboratories for safety evaluation if it is not possible to have them 
performed at the central laboratory). The results of laboratory tests will be returned to the 
investigator, who is responsible for reviewing and filing these results. In avoidable circumstances 
such as the COVID-19 pandemic, laboratory tests may be performed by local laboratories where 
possible, upon sponsor approval and in compliance with local regulations. 
Plasma samples for DSA levels and exploratory immunogenicity testing will be collected at the 
time points specified in Appendix A. Plasma samples for these tests will be analyzed in batches 
as the study progresses; however, if there is a confirmed serious allergic reaction following the 
administration of darvadstrocel then DSA testing will be done as soon as logistically possible, 
and data on DSAs will be assessed in conjunction with SAEs reported in these subjects.  
9.1.11.1 
Collection, Storage, and Future Use of Biological Samples From Clinical Study 
Subjects 
The blood samples for standard clinical tests and biomarker analysis will be consumed or 
destroyed at or before the end of the study when all the test data have been analyzed. The blood 
samples collected for the biomarker exploratory research part of this study will be assessed or 
stored by the sponsor with its long-term storage partners for up to 15 years from the end of the 
study. After that time, the samples will be destroyed. Participation in future use of samples for 
exploratory biomarker research is voluntary, and subjects may decline to consent to future use of 
these samples while still participating in the main study. 
Archived samples from those subjects who provided consent may be used for future research—
including the study of diseases, conditions, or drugs that may not be included in the study—and 
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may inform the efficacy, design, and methods of future studies. These archived samples may also 
be shared with researchers collaborating with the sponsor.  
Data generated with subject samples will be coded and, if shared with Takeda collaborators, will 
be anonymized. Personal information will never be shared with outside parties.  
9.1.12 
Contraception and Pregnancy Avoidance Procedure 
9.1.12.1 
Male Subjects and Their Female Partners 
From signing of informed consent, and until 1 year after repeat administration, nonsterilized* 
male subjects who are sexually active with a female partner of childbearing potential** must use 
barrier contraception (eg, condom with or without spermicidal cream or jelly). In addition, they 
must be advised not to donate sperm during this period. Women of childbearing potential 
(WOCBP) who are partners of male subjects are also advised to use additional contraception as 
shown in the list containing highly effective/effective contraception below. 
9.1.12.2 
Female Subjects and Their Male Partners 
From signing of informed consent, and until 1 year after repeat administration, WOCBP** who 
are sexually active with a nonsterilized male partner* must use a highly effective/effective 
method of contraception (from the list below).  
In addition, they must be advised not to donate ova during this period. 
9.1.12.3 
Definitions and Procedures for Contraception and Pregnancy Avoidance 
The following definitions apply for contraception and pregnancy avoidance procedures. 
* Sterilized males should be at least 1-year postbilateral vasectomy and have documentation of 
either the absence of sperm in the ejaculate or record of bilateral orchiectomy. 
** A woman is considered to be a WOCBP (ie, fertile) following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level 
in the postmenopausal range (FSH >40 IU/L) may be used to confirm a postmenopausal state in 
younger women (eg, those <45 years old) or women who are not using hormonal contraception 
or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
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The following procedures apply for contraception and pregnancy avoidance. 
1. Highly effective methods2 of contraception are defined as those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, 
the only acceptable methods of contraception are:  
• Nonhormonal methods:  
– Intrauterine device. 
– Bilateral tubal occlusion.  
– Vasectomized partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success).  
• Hormonal methods: Hormonal contraception may be susceptible to interaction with 
concomitant medications, which may reduce the efficacy of the contraception method 
(evaluate on compound-by-compound and protocol-by-protocol basis and obtain clinical 
pharmacology justification). 
– Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of study drug, 
OR combined with a barrier method (male condom, female condom, or diaphragm) if 
for shorter duration, until she has been using the contraceptive for 3 months: 
• 
Oral. 
• 
Intravaginal (eg, ring). 
• 
Transdermal.  
– Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of study drug, OR combined with a 
barrier method (male condom, female condom, or diaphragm) if shorter duration, 
until she has been using the contraceptive for 3 months: 
• 
Oral.  
• 
Injectable. 
• 
Implantable. 
 
2 Reproductive and developmental toxicity studies have not been performed for darvadstrocel because nonclinical 
biodistribution studies indicated no migration and integration of darvadstrocel into reproductive organs following 
administration of darvadstrocel via different routes. Darvadstrocel is, therefore, unlikely to cause genotoxicity, 
teratogenicity, or embryotoxicity; however, the use of highly effective contraception has been included in this study 
as a conservative approach to contraception management. 
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2. If the investigational drug, comparator, background therapy or standard of care medications 
are unlikely to cause genotoxicity, teratogenicity, or embryotoxicity, effective methods of 
contraception (potential failure rate >1%) are:  
• Double-barrier method (contraceptive sponge, diaphragm, or cervical cap with 
spermicidal jellies or creams PLUS male condom). 
• Progestogen-only hormonal contraception in which inhibition of ovulation is not the 
primary mode of action, PLUS condom with or without spermicide. 
3. Unacceptable methods of contraception are: 
• Periodic sexual abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods). 
• Spermicides only. 
• Withdrawal. 
• No method at all. 
• Use of female and male condoms together. 
• Cap/diaphragm/sponge without spermicide and without condom. 
4. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the study. 
5. During the course of the study, regular urine human chorionic gonadotropin (hCG) 
pregnancy tests will be performed only for WOCBP, and all subjects (male and female) will 
receive continued guidance with respect to the avoidance of pregnancy and sperm donation 
as part of the study procedures (see Section 9.1.12.4).  
6. In addition to a negative serum hCG pregnancy test at baseline, WOCBP must have a 
negative urine hCG pregnancy test before receiving the medication. 
9.1.12.4 
General Guidance with Respect to the Avoidance of Pregnancy 
Such guidance should include a reminder of the following: 
• Contraceptive requirements of the study. 
• Reasons for use of barrier methods (ie, condom) in males with female partners with 
childbearing potential. 
• Assessment of subject compliance through questions such as: 
– Have you used the contraception consistently and correctly since the last visit? 
– Have you forgotten to use contraception since the last visit?  
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– Are your menses late (even in women with irregular or infrequent menstrual cycles, a 
pregnancy test must be performed if the answer is “yes”). 
– Is there a chance you could be pregnant? 
9.1.13 
Pregnancy 
Pregnant or breastfeeding women are excluded from the study. 
In addition, any pregnancies in the partner of a male subject during the study should also be 
recorded following authorization from the subject’s partner. If the pregnancy occurs during the 
study, the pregnancy should be reported immediately, using a pregnancy notification form, to the 
contact listed in Section 1.0. Refer to Section 10.3.2 for details on reporting pregnancy. 
9.1.14 Documentation of Study Entrance  
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into this study. 
9.2 
Monitoring Subject Treatment Compliance 
The volume of study drug administered will be recorded in the eCRF. 
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. 
In acknowledgement of hospital, local, state or national government restrictions or other site 
related factors caused by unavoidable circumstances (ie, COVID-19 pandemic), which may 
prevent investigators from conducting the study according to the schedule of procedures at the 
clinical study site, investigators may seek approval from the medical monitor to continue 
subjects in the study despite departure from the schedule of procedures. Investigators are 
expected to evaluate the impact to the safety of the study participants and site personnel for 
subject to continue. In evaluating such requests, the medical monitor will give the highest 
priority to the safety and welfare of the subjects. Subjects must be willing to remain compliant 
with the protocol. For subjects who are impacted, any procedures not conducted per the original 
study plan will be documented in the study records. 
When a subject has to miss an in-person study visit, a health care provider will speak directly 
with the subject by telephone or other medium (eg, a computer-based video communication) 
during each visit window to assess subject safety and overall clinical status. During this contact 
with the subject, the study qualified site staff should also at minimum conduct the following 
assessments: assessments of AEs, review and record concomitant medication, and a remote 
evaluation of the fistula. Other study assessments may be collected remotely by telephone. 
Additionally, sites may have study personnel see the subject outside of the on-site clinic to 
conduct study assessments contingent upon local regulations. Assessments that cannot be 
completed during the protocol specified window will be considered missing data and such 
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departures will be recorded in the study records, Alternatively, sites may seek approval to extend 
the visit window in order to conduct an on-site visit. 
Visits at baseline, preparation, treatment administration, Weeks 24, and Week 156 should be 
performed in person. Alternative methods of data collection may be considered for the final visit 
(Week 156) when it is not possible for the subject to come to the study site. Under such 
circumstances, a preferred alternative to the final visit would be for a medical professional to go 
to the subject’s residence and conduct the protocol-specified procedures in that location. 
Assessments collected at subjects’ residence should comply with applicable local regulations. 
9.3.1 
Baseline Visit 
Subjects will be screened and enrolled in accordance with predefined eligibility criteria as 
described in Section 7.0. From the baseline visit to the preparation visit, there will be a 
maximum of 5 weeks. 
• ICF signature. 
• Enter subject into interactive web response system (IWRS) and obtain subject identification 
number. 
• Inclusion/exclusion criteria check. 
• Demographics, including weight, height, and lifestyle (smoking history and alcohol use).  
• Medical history. 
• Prior and repeated darvadstrocel administration. 
• Physical examination with vital signs. 
• History of CD and perianal fistula (date of diagnosis, perianal fistula [start and stop dates of 
previous perianal fistulas, start date of perianal fistula ongoing at baseline visit]) number and 
type of previous surgical procedures including previous administration of darvadstrocel.  
• Target fistula(s) information (clinical characteristics, including date of onset, number of other 
fistulas, localization, and clock position [see Appendix B]), including whether fistula to be 
treated was previously treated with darvadstrocel or if it is a new fistula.  
• Serum pregnancy test for WOCBP. 
• Comorbidities of interest. 
• Central laboratory tests: 
- 
Hematology: hemoglobin, hematocrit, erythrocytes, mean corpuscular volume, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, leukocytes, 
lymphocytes, monocytes, neutrophils, eosinophils, basophils, and platelet count. 
- 
Serum biochemistry: C-reactive protein, urea, creatinine, glucose, AST, ALT, albumin, 
total bilirubin (direct bilirubin if total bilirubin is above the ULN), potassium, sodium, 
chloride. 
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• Plasma sample for DSA and immunogenicity. 
 
 
• Previous medications.  
- 
Review and record previous medication within 2 years before the baseline visit, including 
but not limited to the treatment of CD, treatment of perianal fistulas and perianal 
abscesses. The information about inadequate response, loss of response or intolerance to 
immunosuppressants or biologics will be recorded for perianal fistula. 
• Concomitant medications, including all medications taken by the subject at the time of 
baseline. 
• Clinical evaluation of fistula(s) in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, and suspicion of perianal abscess. The tracts and external 
opening(s) must be clearly identified in the eCRF to ensure the same tracts are assessed 
during the study period. A detailed diagram is included in Appendix B to locate the external 
opening and draining status.  
• Pelvic MRI (performed locally). A quality copy will be sent to the central imaging laboratory 
for central MRI reading. The MRI central readers will report fistula characteristics. Analysis 
will also include assessment of collections >2 cm, (in at least 2 dimensions). 
• PRO-2 score.  
• If available, check and record luminal disease activity involving the rectum (within 6 months 
prior to repeat administration). 
• Assessment of AEs/SAEs, pregnancy, and SSRs. 
• Schedule preparation visit (Visit 0). 
For any subject not meeting eligibility criteria at the baseline and/or preparation visit, or if there 
are unavoidable circumstances (such as the COVID-19 pandemic, etc.) it may be possible to 
rescreen the subject later upon the sponsor’s approval. Subject ID numbers assigned to subjects 
who fail screening should not be reused. Subjects who are screen failures and are approved to 
rescreen must repeat all assessments for screening, with the exception of an MRI, if it was 
previously completed within 3 months of the rescreen visit and the clinical condition remains 
unchanged. 
For those subjects who require a rescreening due to an out-of-window preparation visit, and upon 
sponsors approval, the following procedures will need to be repeated and the preparation visit 
rescheduled based on protocol timelines: 
• Reconsent for informed consent. 
• Enter subject in IWRS and obtain a new subject identification number. 
• Inclusion/exclusion criteria check. 
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• Physical examination including weight and vital signs. 
• Central laboratory tests. 
• Serum pregnancy test for WOCBP. 
• Clinical assessment of perianal fistulas and CD (including the presence or absence of 
proctitis, localization, fistula draining status, and pattern of disease). 
• Pelvic MRI: The repeated pelvic MRI scan could be waived if it was previously completed 
within 3 months of the rescreen visit and the clinical condition remains unchanged. 
9.3.2 
Preparation Visit (Visit 0) 
A preparation visit will take place within a minimum of 2 weeks and a maximum of 3 weeks of 
the repeat administration visit. Darvadstrocel will need to be preordered and, thus, this supply 
request at the preparation visit will act as a trigger to start the manufacturing process of 
darvadstrocel for the subject. 
Procedures to be completed at the preparation visit include: 
• Study visit entered in IWRS. 
• Inclusion/exclusion criteria check. 
• Physical examination including weight and vital signs. 
• Urine pregnancy test for WOCBP. 
• Review and record concomitant medications taken since the last visit. 
• Clinical evaluation of fistula(s) in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, and suspicion of perianal abscess before preparation 
procedures. The tracts and external opening(s) must be clearly identified in the eCRF to 
ensure the same tracts are assessed during the study period. 
• Fistula preparation consisting of an examination under anesthesia (EUA), curettage and seton 
placement by the surgeon according to the surgery procedure manual.  
• Mandatory antibiotics coverage will be administered during at least 7 days following the 
fistula curettage (ciprofloxacin and/or metronidazole are recommended). 
• PRO-2 score.  
• Assessment of AEs/SAEs, pregnancy, and SSRs. 
• Schedule repeat administration visit (Visit 1). Date and time of visit to be recorded.  
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9.3.3 
Repeat Administration (Visit 1) 
Repeat administration visit will take place within a minimum of 2 weeks and a maximum of 
3 weeks of the preparation visit. Procedures to be completed at repeat administration include: 
• Study visit entered in IWRS. 
• Physical examination including weight and vital signs. 
• Urine pregnancy test for WOCBP. 
• Plasma sample for DSA and immunogenicity. 
 
 
• Review and record concomitant medications taken since the last visit. 
• Clinical evaluation of fistula(s) in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, and suspicion of perianal abscess before repeat administration. 
The tracts and external opening(s) must be clearly identified in the eCRF to ensure the same 
tracts are assessed during the study period. 
• Identification of number and location of fistula tracts to be treated. 
• IMP preparation and administration will be performed according to the surgery procedure 
manual. All setons must be withdrawn, fistula curettage should be performed, placing 
stitches to close each internal opening before treatment administration in accordance with the 
surgical procedure manual (provided as a separate document). 
• PDAI score. 
• PRO-2 score. 
• Assessment of AEs/SAEs, AESIs, pregnancy, and SSRs, including AEs concerning surgical 
procedures and postsurgery complication status (including any CD-related surgery). 
• Schedule Visit 2/Week 6 (±8 days). 
• 
At the end of treatment, subjects will be observed after their surgical procedure until full 
recovery, with special attention to signs and symptoms of potential allergic reactions. 
Instructions for the immediate treatment of any acute anaphylaxis according to standard of 
care will be provided in the surgery procedure manual. 
• 
If there is any problem administering darvadstrocel at the repeat administration visit (Visit 1), 
the visit will need to be rescheduled within a minimum of 2 weeks and to a maximum of 
3 weeks from the date of the original Visit 1. It will not be necessary to repeat the preparation 
visit, the setons will be maintained until the rescheduled repeat administration visit and will 
be withdrawn just before the administration of darvadstrocel. All procedures required for 
repeat administration visit are to be repeated. 
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9.3.4 
6 Weeks Following Repeat Administration (Visit 2/Week 6 ± 8 days) 
The following procedures will be performed at Visit 2, Week 6: 
• Study visit entered in IWRS. 
• Physical examination including weight and vital signs. 
• Urine pregnancy test for WOCBP. 
• Plasma sample for DSA and immunogenicity. 
 
 
• Review and record concomitant medications taken since last visit. 
• Clinical evaluation of the fistula(s) in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, suspicion of perianal abscess (fistula identification). 
• PDAI score. 
• PRO-2 score. 
• Assessment of AEs/SAEs, AESIs, pregnancy, and SSRs.  
• Schedule Visit 3/Week 24 (± 15 days). 
9.3.5 
6 Months Following Repeat Administration (Visit 3/Week 24 ± 15 days)  
The following procedures will be performed at Visit 3, Week 24: 
• Study visit entered in IWRS. 
• Physical examination including weight and vital signs. 
• Urine pregnancy test for WOCBP. 
• Central laboratory tests. 
• Plasma sample for DSA and immunogenicity. 
 
 
• Review and record concomitant medications taken since last visit. 
• Clinical evaluation of the fistula(s) in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, suspicion of perianal abscess (fistula identification). 
• Pelvic MRI (performed locally). A quality copy will be sent to the central imaging laboratory 
for central MRI reading. The MRI central readers will report fistula characteristics. Analysis 
will also include assessment of collections >2 cm, (in at least 2 dimensions). 
• PDAI score. 
• PRO-2 score. 
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• Assessment of AEs/SAEs, AESIs, pregnancy, and SSRs. 
• Schedule Visit 4/Week 52 (± 15 days). 
9.3.6 
12 Months Following Repeat Administration (Visit 4/Week 52 ± 15 days)  
The following procedures will be performed at Visit 4, Week 52: 
• Study visit entered in IWRS. 
• Physical examination including weight and vital signs. 
• Urine pregnancy test for WOCBP. 
• Review and record concomitant medications taken since last visit. 
• Clinical evaluation of the fistula(s) in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, suspicion of perianal abscess (fistula identification). 
• PDAI score. 
• PRO-2 score. 
• Assessment of AEs/SAEs, AESIs, pregnancy, and SSRs. 
• Schedule Visit 5/Week 104 (± 30 days). 
9.3.7 
24 Months Following Repeat Administration (Visit 5/Week 104 ± 30 days)  
The following procedures will be performed at Visit 5, Week 104: 
• Study visit entered in IWRS. 
• Physical examination including weight and vital signs. 
• Urine pregnancy test for WOCBP. 
• Review and record concomitant medications taken since last visit. 
• Clinical evaluation of the fistula(s) in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, suspicion of perianal abscess (fistula identification). 
• PDAI score. 
• PRO-2 score. 
• Assessment of AEs/SAEs, AESIs, pregnancy, and SSRs. 
• Schedule Visit 6/Week 156 (± 30 days). 
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9.3.8 
36 Months Following Repeat Administration (Visit 6/156 Weeks ± 30 days, Final 
Visit) 
The following procedures will be performed at Visit 6, Week 156: 
• Study visit entered in IWRS. 
• Physical examination including weight with vital signs. 
• Urine pregnancy test for WOCBP. 
• Central laboratory tests. 
• Review and record concomitant medications taken since last visit. 
• Clinical evaluation of the fistula(s) in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, suspicion of perianal abscess (fistula identification). 
• Pelvic MRI (performed locally). A quality copy will be sent to the central imaging laboratory 
for central MRI reading. The MRI central readers will report fistula characteristics. Analysis 
will also include assessment of collections >2 cm, (in at least 2 dimensions). 
• PDAI score. 
• PRO-2 score. 
• Assessment of AEs/SAEs, AESIs, pregnancy, and SSRs. 
9.3.9 
Early Termination Visit 
All efforts should be made to keep the subjects in the study. If the subject decides to withdraw 
from the study, the following procedures will be performed and documented ±30 days of the 
early termination visit: 
• Study visit entered in IWRS. 
• Physical examination including weight and vital signs. 
• Urine pregnancy test for WOCBP. 
• Central laboratory tests. 
• Plasma sample DSA and immunogenicity (sample does not need to be taken if the early 
termination visit takes place after the Week 24 visit).  
 
 
 
• Review and record concomitant medications taken since last visit. 
• Clinical evaluation of the fistula(s) in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, suspicion of perianal abscess (fistula identification). 
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• Pelvic MRI (performed locally). A quality copy will be sent to the central imaging laboratory 
for central MRI reading. The MRI central reader will report fistula characteristics. Analysis 
will also include assessment of collections >2 cm, (in at least 2 dimensions). 
• PDAI score. 
• PRO-2 score. 
• Assessment of AEs/SAEs, AESIs, pregnancy, and SSRs. 
9.3.10 
Unscheduled Visit 
Subjects who experience significant new perianal symptoms will attend an unscheduled visit. 
The following assessments will take place at an unscheduled visit: 
• Physical examination including weight and vital signs. 
• Urine pregnancy test for WOCBP. 
• Review and record concomitant medications taken since last visit. 
• Clinical evaluation of the fistula(s) in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, suspicion of perianal abscess (fistula identification). 
• Pelvic MRI (performed locally), if the unscheduled visit is due to significant new perianal 
symptoms. A quality copy will be sent to the central imaging laboratory for central MRI 
reading, along with the scheduled MRI when all the visits have been completed. The MRI 
central readers will report fistula characteristics. Analysis will also include assessment of 
collections >2 cm, (in at least 2 dimensions). 
• PDAI score. 
• PRO-2 score. 
• Assessment of AEs/SAEs, AESIs, pregnancy, and SSRs. 
9.3.11 
Unscheduled Telephone Call Visit 
Unscheduled telephone calls are proposed for safety follow-up in case the subject cannot attend 
the site for a visit or for any contact requested by the subject between scheduled visits. The 
following information will be recorded: 
• Date and reason for unscheduled phone-call. 
• Remote evaluation of the fistula. 
• Review and record concomitant medications taken since last visit. 
• Assessment of AEs/SAEs, AESIs, pregnancy, and SSRs. 
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
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 an IMP 
drug whether or not it is considered related to the IMP. 
• Medical disorders, including concomitant diseases present at the time of signing the informed 
consent, are only considered AEs if they worsen after this time. All baseline conditions 
should be recorded as part of medical history. 
• Changes in laboratory parameters (biochemistry, hematology), as well as abnormal results of 
other tests (worsening results), detected after the administration of study medication and that 
the investigator considers to be clinically relevant should be recorded as AEs or SAEs, 
provided that the definitions given in this section and in Section 10.1.2 are met, respectively. 
In contrast, clinically significant changes in laboratory parameters or other tests that are 
associated to the disease under study will not be rated as AEs or SAEs, unless the 
investigator judges them to be more serious than expected based on the subject condition. 
• Fluctuations or reoccurrences of the disease under study (CD) that are considered normal for 
the subject are recorded in the medical history and need not be reported as an AE. However, 
if the condition were to deteriorate (worsening) during the study, this would then be recorded 
as an AE. 
• For the purpose of this study, drainage of the treated fistula(s) and abscess(es) will not be 
captured as an AE unless there is evidence suggesting a causal relationship between the IMP 
or the administration procedure. New fistula(s) identified during the course of the study, not 
previously treated by darvadstrocel, will be captured as an AE. 
10.1.2 
SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
Note that death is an outcome of an event. The event(s) causing death should be recorded. 
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. 
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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 infection. 
10.1.3 
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 as such would be described in protocols and instructions 
to investigators for how and when they should be reported to Takeda. 
Refer to Section 10.2.1.3 for a list of known AESIs.  
10.1.4 
SSRs 
SSRs are defined as medication errors, and uses outside what is foreseen in the protocol, 
including overdose, misuse, and abuse of the product. SSRs may or may not be associated with 
an AE/SAE.  
Definitions: 
• 
Abuse: Persistent or sporadic, intentional excessive use of medicinal products, which is 
accompanied by harmful physical or phycological effects. 
• 
Misuse: Situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
• 
Medication error: An unintentional error in the drug treatment process (prescribing, 
dispensing or administration, including incorrect dose or poor-quality administration) of a 
medicinal product while in the control of the investigator, site staff, or patient that leads 
to harm or has the potential to lead to harm. 
• 
Overdose: The administration of a quantity of medicinal product given per administration 
or per day, which is above the maximal recommended dose according to the protocol. 
Note: Abuse, misuse, and overdose are not applicable as the subject will not be 
self-administrating this treatment. 
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10.1.5 
Causality of AEs 
The relationship of each AE to study drug(s) will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which possible 
involvement of the drug cannot be ruled out, although factors other than the 
drug, such as underlying diseases, complications, concomitant medications and 
concurrent treatments, may also be responsible. 
Not related: 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained by other 
factors, such as underlying diseases, complications, concomitant medications 
and concurrent treatments. 
10.1.6 
Severity of AEs 
Severity of the adverse events will be recorded at the time they occur and will be rated according 
to the following criteria: 
•  Mild (asymptomatic): An event easily tolerated by the subject, causing minimal 
discomfort that does not prevent the subject from fulfilling daily activities. 
•  Moderate: Symptomatic, but does not significantly interfere with function. 
• 
 Severe: Causes a significant interference with function. 
10.1.7 
Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all AEs. 
The relationship should be assessed as “related” if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as “not related.”  
10.1.8 
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator. 
10.1.9 
Stop Date  
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died. 
10.1.10 Frequency  
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous. 
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10.1.11 Action Concerning Study Drug 
Not applicable.  
10.1.12 Outcome 
• Recovered/resolved: The subject returned to first assessment status with respect to the AE. 
• Recovering/resolving: The intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE with the condition remaining “recovering/resolving.” 
• Not recovered/not resolved: There is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.” 
• Resolved with sequelae: The subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis). 
• Fatal: The AE was considered to be the cause of death.  
• Unknown: The course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study. 
10.2 
Procedures 
10.2.1 
Collection and Reporting of AEs 
10.2.1.1 
AE Collection Period 
Collection of AEs will commence from the time the subject signs the ICF. Routine collection of 
AEs will continue until final visit/early termination. 
10.2.1.2 
AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study.  
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event: 
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1. Event term. 
2. Start and stop date and time. 
3. Frequency. 
4. Intensity. 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study drug(s) (related or not related). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
7. Action concerning study drug. 
8. Outcome of event. 
9. Seriousness. 
PDAI questionnaire will not be used as a primary means to collect AEs. However, should the 
investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up, if it is determined that an AE not previously reported has been 
identified, normal reporting requirements should be applied. 
10.2.1.3 
AESIs  
AESIs must be recorded as AEs in the eCRF. 
If the AESI occurs during the treatment period or follow-up period and is considered to meet the 
seriousness criteria listed in Section 10.1.2, the SAE form should be completed. The completed 
SAE form should be reported to the pharmacovigilance department of the sponsor or sponsor 
designee as listed in Section 1.1 within 24 hours. The investigator should submit the original 
copy of the SAE form to the sponsor.  
A medication error should be recorded as an AESI and reported as an SSR. See Section 10.3.1 
for reporting SSRs. 
AESIs include:  
• Immunogenicity/alloimmune reactions. 
• Hypersensitivity. 
• Ectopic tissue formation.  
• Medication errors. 
• Tumorgenicity, applying to malignant tumors only. 
• Transmission of infectious agents. 
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10.2.2 
Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period, it should be reported according to the 
following procedure: 
A Takeda SAE form must be completed, in English, and signed by the investigator immediately 
or within 24 hours of awareness of the event. The information should be completed as fully as 
possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study drug(s). 
• Causality assessment. 
The SAE form should be transmitted within 24 hours of awareness of the event 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. 
The paper SAE forms should be submitted via fax (preferred method). In case of fax, site 
personnel need to confirm successful transmission of all pages and include an email address on 
the fax cover sheet so that an acknowledgment of receipt (AOR) can be returned via email within 
1 business day. 
Email submission of SAE forms with a PDF attachment should only be used in the case where 
fax is not possible within 24 hours of receiving the event. In case of email, site personnel need to 
confirm successful transmission by awaiting an AOR via email within 1 business day. 
If SAE forms are submitted via fax or email, a confirmation of receipt will be sent to the sites 
indicating that the SAE has been received. It is the site’s responsibility to ensure an AOR has 
been obtained when email or fax are used. If AOR is not received within 1 business day, site 
should escalate it immediately to their clinical research assistant. 
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 or within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
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10.3.1 
SSRs 
All SSRs must be reported to the sponsor on a paper SSR form within 7 calendar days of 
awareness irrespective of whether the SSR is associated with an AE/SAE.  
If the special situation is associated with an SAE, a separate SAE form must also be submitted to 
the sponsor within 24 hours of awareness in addition to the SSR form. All nonserious AEs 
associated with SSRs should be recorded in the eCRF as well as noted on the SSR form. 
10.3.2 
Pregnancy 
Pregnancies must be reported to the sponsor on a paper pregnancy report form immediately or 
within 24 hours of awareness. 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 male subject was participating in a 
clinical study at the time she became pregnant and provide details of the study drug the subject 
received. 
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.  
10.3.3 
Summary of Safety Reporting 
Safety Event 
How to Report Event to Sponsor 
Pharmacovigilance 
Reporting Timelines to Sponsor 
(from time of awareness) 
SAEs 
Complete and send paper SAE form to 
Sponsor Pharmacovigilance. 
Within 24 hours  
AESI 
Complete AE eCRF (if electronic data 
capture is down, submit paper SAE 
from) 
Within 24 hours  
 
Pregnancy 
Complete and submit paper pregnancy 
form  
24 hours  
SSRs  
Complete and submit paper SSR form   7 calendar days 
 
Contacts for SAE reporting can be found in Section 1.1. 
10.3.4 
Safety Reporting to Investigators, IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, including the European Medicines 
Agency, investigators, and IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, all suspected unexpected serious adverse 
reactions will be submitted to the regulatory authorities as an expedited report within 7 days for 
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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 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, 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 or 
its designee 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 entry on each form, system logic checks will fire queries as soon as you save 
the form in case of inconsistent entries, ie, dates, missing data, and questionable values. Manual 
queries may also be issued by sponsor personnel (or designees) to 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 designee. The sponsor or designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. 
The completed eCRFs are the sole property of the sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor.  
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.0 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
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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 trails, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities, the sponsor, or its designees. Any source documentation printed on 
degradable thermal-sensitive paper should be photocopied by the site and filed with the original 
in the subject’s chart to ensure long-term legibility. Furthermore, International Conference for 
Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to retain essential documents 
specified in ICH E6 (Section 8) until at least 2 years after the last approval of a marketing 
application for a specified drug indication being investigated or, if an application is not 
approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained 
until an amount of time specified by applicable regulatory requirements or for a time specified in 
the clinical study site agreement between the investigator and sponsor. 
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents. 
13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized as early as possible after 
finalization of the study protocol. This document will provide further details regarding the 
definition of analysis variables and analysis methodology to address all study objectives. 
13.1.1 
Analysis Sets 
The primary analysis set for this study will be the safety analysis set, which will consist of all 
subjects who enroll in the study and receive treatment with darvadstrocel. The safety analysis set 
will be the primary analysis set to be used for all statistical analysis of the demographic and 
baseline characteristics, as well as safety and efficacy analysis. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects in the safety 
analysis set. 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. 
Individual subject demographic and baseline characteristic data will be provided in the data 
listings. 
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13.1.3 
Efficacy Analysis 
The proportion of subjects with each of the following outcomes, along with 2-sided 95% 
confidence intervals will be provided by visit: 
• Combined remission. 
• Clinical remission. 
• Clinical response. 
• Relapse. 
• New perianal abscess in treated fistula. 
In addition to providing the proportion of subjects with each outcome at each of the scheduled 
assessments (Week 24, Week 52, Week 104, and Week 156), the proportion of subjects who 
changed in status with respect to each outcome since the previous assessment will be provided.  
Change from baseline in PDAI discharge and pain subscores will be summarized descriptively 
by visit. 
Among subjects who achieve combined remission, probability of reopening of any of the treated 
external openings with active drainage across time will be estimated using the Kaplan-Meier 
estimator. 
Full details on the statistical analysis will be provided in the SAP. 
13.1.4 
Safety Analysis 
Safety analysis will be performed on the safety analysis set.  
Count and percentage of subjects with AEs, SAEs (defined as any SAE, regardless of 
relationship to study drug), and AESIs (immunogenicity/alloimmune reactions, hypersensitivity, 
transmission of infectious agents, tumorgenicity (applying to malignant tumors only), ectopic 
tissue formation, and medication errors) will be summarized descriptively by system organ class 
and preferred term using MedDRA terminology. Treatment-emergent adverse events and SAEs 
will also be summarized by severity, by relationship to study drug, and by outcome. In addition, 
treatment-emergent adverse events and SAEs leading to study withdrawal and fatal treatment-
emergent SAEs will be summarized. 
Clinical laboratory values will be summarized according to Common Terminology Criteria for 
Adverse Events criteria. 
Change from baseline in vital signs will be summarized by study visit.  
Full details of the statistical analysis will be provided in the SAP. 
13.1.5 
Other Analysis 
The association of DSA levels, 
, and key safety and efficacy 
variables will be explored. The details of this exploratory analysis will be provided in the SAP. 
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13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned for this study. 
13.3 
Determination of Sample Size 
Complex perianal fistula is a rare disease, with orphan disease designation granted by the 
European Commission. 
This study will plan to enroll approximately 50 subjects as part of a regulatory commitment, who 
have received previous darvadstrocel treatment and need to be re-treated for the same fistula tract 
or a new complex perianal fistula tract according to their physician. 
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 
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 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, ICF documentation, documentation of subject authorization to use personal health 
information if separate from the ICFs, and review of eCRFs and associated source documents. It 
is important that the investigator and other study personnel are available during the monitoring 
visits and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
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require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and 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 institutional 
review board 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. 
The sponsor will assess any protocol deviation; if it is likely to affect, to a significant degree, the 
safety and rights of a subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol. 
The sponsor will notify concerned EU Member States of any serious breach of EU CTR or the 
applicable protocol version through the EU portal no later than 7 days after becoming aware of 
the breach. In this instance a “serious breach” is one likely to affect, to a significant degree, the 
safety and rights of a subject or the reliability and robustness of study data. 
All parties involved in the conduct of the clinical study must immediately report any events they 
encounter that might meet the definition of a serious breach to the contact point designated in the 
study manual. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the Food and Drug Administration [FDA], the 
United Kingdom Medicines and Healthcare products Regulatory Agency, or 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 participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonized 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 A. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities. 
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15.1 
IEC Approval 
IECs must be constituted according to the applicable requirements of each participating region. 
The sponsor or designee will require documentation noting all names and titles of members who 
make up the respective IEC. If any member of the 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 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 IEC for 
approval. The 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 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 or 
designee will notify site once the sponsor or designee has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor (or designee) has received 
permission from competent authority to begin the study. Until the site receives notification no 
protocol activities, including screening at the baseline visit may occur. 
Study sites must adhere to all requirements stipulated by their respective IEC. This may include 
notification to the 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 IEC, and 
submission of the investigator’s final status report to IEC. All 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 IEC and sponsor or designee. 
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 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 the 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 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 ICF 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 IECs to review the subject’s original medical records (source data or documents), 
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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). 
If a serious data breach affecting personal data is detected, the sponsor or its designee and the 
investigator (as applicable) will take appropriate corrective and preventive actions in response. 
These actions will be documented, and the relevant regulatory agency(ies) will be notified as 
appropriate. Where appropriate, the relevant individuals materially affected by the breach would 
also be notified; in the case of study subjects, this would be done through the investigator. 
Takeda applies certain measures to protect subjects’ personal data and prevent data breaches, 
detailed in a separate document (Compliance with National Requirements on Data Protection). 
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 publication. 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 US investigators), country, and 
recruiting status will be registered and available for public viewing.  
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting study 
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information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the study. The investigative sites are encouraged to handle the study 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of study enrollment, they should be referred to the sponsor.  
Any investigator who objects to the sponsor providing this information to callers must provide 
the sponsor with a written notice requesting that their information not be listed on the registry 
site.  
15.4.3 
Study Registration and 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. 
Public registration and disclosure of the study will be via electronic postauthorization study 
register maintained by the European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance (ENCePP). At a minimum, a summary of the study design/methods and a 
summary of results will be provided along with the contact details of the study sponsor 
representative. 
Once subjects receive investigator contact information, they may call the site requesting 
enrollment into the study. The investigative sites are encouraged to handle the study inquiries 
according to their established subject screening process. If the caller asks additional questions 
beyond the topic of study enrollment, they should be referred to the sponsor. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
subjects. Refer to the study site agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 
16.0 
REFERENCES 
de la Portilla, F., Alba, F., Garcia-Olmo, D., Herrerias, J. M., Gonzalez, F. X. and Galindo, A. 
2013. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of 
complex perianal fistula in Crohn's disease: results from a multicenter phase I/IIa clinical 
trial. Int J Colorectal Dis, 28(3), 313-23. 
Irvine, E. J. 1995. Usual therapy improves perianal Crohn's disease as measured by a new 
disease activity index. McMaster IBD Study Group. J Clin Gastroenterol, 20(1), 27-32. 
Khanna, R., Zou, G., D'Haens, G., Feagan, B. G., Sandborn, W. J., Vandervoort, M. K., et al. 
2015. A retrospective analysis: the development of patient reported outcome measures for 
the assessment of Crohn's disease activity. Aliment Pharmacol Ther, 41(1), 77-86. 
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 
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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 
Assessment 
Baseli
ne 
Visit a 
Preparat
ion 
Visit 
to Visit 1 
b 
Repeat 
Administra
tion 
6 
Wee
ks 
±8 
days 
24 
Wee
ks 
±15 
days 
c 
52 
Wee
ks  
±15 
days 
c 
104 
Wee
ks  
±30 
days 
c 
156 
Wee
ks 
±30 
days 
c 
Early 
Terminat
ion Visit 
Unschedu
led Visit d 
Visit 0 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Enrollment e 
- 
X 
 
 
 
 
 
 
 
 
ICF 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria check 
X 
X 
 
 
 
 
 
 
 
 
IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics, height and lifestyle f 
X 
 
 
 
 
 
 
 
 
 
Weight  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history g 
X 
 
 
 
 
 
 
 
Prior and repeated darvadstrocel administration 
X 
 
 
 
 
 
 
 
 
 
Physical examination with vital signs h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CD history, fistula history, and treatment history i 
X 
 
 
 
 
 
 
 
 
 
Target fistula(s) information (new fistula or 
previously treated fistula) j 
X 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
X l 
X 
X 
X 
X 
X 
X 
X 
Comorbidities of interest 
X 
 
 
 
 
 
 
 
Central laboratory tests k 
X 
 
 
 
X 
 
 
X 
X 
 
Plasma sample for DSA and immunogenicity 
X 
 
X l 
X 
X 
 
 
 
X m 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fistula preparation n 
 
X 
 
 
 
 
 
 
 
 
Mandatory antibiotic prescription o 
 
X 
 
 
 
 
 
 
 
 
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Appendix A Schedule of Study Procedures 
Assessment 
Baseli
ne 
Visit a 
Preparat
ion 
Visit 
to Visit 1 
b 
Repeat 
Administra
tion 
6 
Wee
ks 
±8 
days 
24 
Wee
ks 
±15 
days 
c 
52 
Wee
ks  
±15 
days 
c 
104 
Wee
ks  
±30 
days 
c 
156 
Wee
ks 
±30 
days 
c 
Early 
Terminat
ion Visit 
Unschedu
led Visit d 
Visit 0 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Fistula treatment p 
 
 
X 
 
 
 
 
 
IMP administration q 
 
 
X 
 
 
 
 
 
 
 
Fistula clinical assessment r 
X s 
X  
X 
X 
X 
X 
X 
X 
X 
X 
Pelvic MRI t 
X 
 
 
 
X 
 
X 
X 
X 
PDAI score  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
PRO-2 score u 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
If available, luminal disease activity involving the 
rectum v 
X 
 
 
 
 
 
 
 
 
 
All AEs/SAEs, pregnancy, AESIs, and SSRs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5-ASA: 5-aminosalicylate; 6-MP: 6-mercaptopurine; AE: adverse event; AESI: adverse event of special interest; ALT: alanine aminotransferase; AST: aspartate 
aminotransferase; AZA: azathioprine; CD: Crohn’s disease; COVID-19: coronavirus disease 2019; CRP: C-reactive protein; DSA: donor-specific antibodies; eCRF: 
electronic case report form; ICF: informed consent form; IMP: investigational medicinal product; IWRS: interactive web response system; MCH: mean corpuscular 
hemoglobin; MCHC: mean corpuscular hemoglobin concentration; MCV: mean corpuscular volume; MRI: magnetic resonance imaging; PDAI: Perianal Disease 
Activity Index; PRO-2: patient-reported outcome-2; SAE: serious adverse event; SSR: special situation report; TNF-α: tumor necrosis factor-alpha; ULN: upper limit 
of normal. 
a Repeat administration (Visit 1) should take place within 8 weeks of the baseline visit (may be longer if repeat administration needs to be rescheduled). There will be 
a maximum of 5 weeks from the baseline visit to the preparation visit.  
b From preparation visit to repeat administration (Visit 1) there will be a minimum of 2 weeks and maximum of 3 weeks (necessary to have darvadstrocel treatment 
ready for administration). If there is any problem administering darvadstrocel during Visit 1, the visit will need to be rescheduled within a minimum of 2 weeks and a 
maximum of 3 weeks of the original Visit 1. 
c Due to unavoidable circumstances (ie, COVID-19 pandemic), the Week 24 visit may be conducted within 60 days of the scheduled visit. Visits at Weeks 52, 104, 
and 156 may be conducted within 90 days of the scheduled visit. 
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Appendix A Schedule of Study Procedures 
Assessment 
Baseli
ne 
Visit a 
Preparat
ion 
Visit 
to Visit 1 
b 
Repeat 
Administra
tion 
6 
Wee
ks 
±8 
days 
24 
Wee
ks 
±15 
days 
c 
52 
Wee
ks  
±15 
days 
c 
104 
Wee
ks  
±30 
days 
c 
156 
Wee
ks 
±30 
days 
c 
Early 
Terminat
ion Visit 
Unschedu
led Visit d 
Visit 0 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
d The unscheduled visit can take place in the form of a telephone-call in case the subject cannot attend the site for a visit or for any contact requested by the subject 
between scheduled visits. The following information will be recorded: date and reason for unscheduled telephone call; assessment of AEs/SAEs, pregnancy, 
AESIs, and SSRs; review and record concomitant medications taken since the last visit; remote evaluation of the fistula. 
e Subjects will be enrolled once the physician has decided to readminister darvadstrocel and all study entrance criteria has been met at the preparation visit. 
f Including age, sex, country, smoking history, and alcohol use. 
g Including number of pregnancies, history of blood transfusions, transplantation, and anal canal or colorectal malignancy. Prior medication to include specific drug 
used, indication, dose received, route of administration, and start/end dates, within the last 2 years of use and may include the following: darvadstrocel, systemic 
antibiotics, systemic corticosteroids, immunomodulators including, but not limited to 6-MP, AZA, methotrexate, anti-TNF-α agents, vedolizumab, ustekinumab, 5-
ASAs, narcotic (opioid) analgesics, antidiarrheals (loperamide, diphenoxylate). 
h Physical examination and vital signs (temperature, heart rate, and blood pressure) will be recorded.  
i Including family history, age at onset, medical and surgical history for any CD-related surgery, and surgeries to treat relapse of treated perianal fistula and new 
perianal fistula; preparation surgery will be completed before darvadstrocel administration. 
j Target fistula information (clinical characteristics including date of onset, number of other fistulas, localization, and clock position [see Appendix B], including 
whether fistula to be treated was previously treated with darvadstrocel or if it is a new fistula). 
k Hematology: hemoglobin, hematocrit, erythrocytes, MCV, MCH, MCHC, leukocytes, lymphocytes, monocytes, neutrophils, eosinophils, basophils, and platelet 
count. 
Biochemistry: CRP, urea, creatinine, glucose, AST, ALT, albumin, total bilirubin (direct bilirubin if total bilirubin is above the ULN), potassium, sodium and 
chloride. 
l Samples to be taken before repeat administration. 
m Plasma samples do not need to be taken if the early termination visit takes place after the Week 24 visit. 
n Fistula preparation will consist of examination under anesthesia, curettage, and seton placement. Seton placement/removal and curettage will be performed by the 
surgeon according to the surgery procedure manual (provided as a separate document).  
o Mandatory antibiotics coverage will be administered during at least 7 days following the fistula curettage (ciprofloxacin and/or metronidazole are recommended). 
p Identification of number and location of fistula tracts to be treated. 
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Appendix A Schedule of Study Procedures 
Assessment 
Baseli
ne 
Visit a 
Preparat
ion 
Visit 
to Visit 1 
b 
Repeat 
Administra
tion 
6 
Wee
ks 
±8 
days 
24 
Wee
ks 
±15 
days 
c 
52 
Wee
ks  
±15 
days 
c 
104 
Wee
ks  
±30 
days 
c 
156 
Wee
ks 
±30 
days 
c 
Early 
Terminat
ion Visit 
Unschedu
led Visit d 
Visit 0 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
q All procedures should be performed before darvadstrocel administration. If there is any problem administering darvadstrocel at the repeat administration visit, the 
visit should be rescheduled within a minimum of 2 weeks and a maximum of 3 weeks of the original Visit 1. It is not necessary to repeat the preparation visit, the 
setons will be maintained until the rescheduled treatment visit and will be withdrawn just before the administration of darvadstrocel. All repeat administration 
procedures are to be repeated, see Section 9.3.3. Details of darvadstrocel repeat administration will also be captured in the eCRF. 
r Clinical response defined as closure of at least 50% of all treated external fistula openings that were draining at baseline, despite gentle finger compression. Clinical 
remission defined as closure of all treated external fistula openings that were draining at baseline despite gentle finger compression.  
s Fistula must be actively draining for at least 6 weeks prior to the baseline visit. 
t All MRI scans will be assessed centrally by 2 imaging readers (or 3 readers if adjudication is needed). 
u PRO-2 score to be collected at baseline to confirm no or mildly active CD (score <14). The PRO-2 will be provided to the subject at each visit for their completion at 
home and is to be completed 7 days prior to the next visit. 
v If available, check and record luminal disease activity involving the rectum (within 6 months prior to repeat administration). 
 
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Appendix B Anal Clock 
Note that the anal clock is represented in a lithotomy position (gynecological). 
 
 
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Appendix C PRO-2 Scoring 
 
Adapted from Khanna et al, 2015 (Khanna et al. 2015). 
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Appendix D Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following: 
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 IEC that conform to 
ICH, and local regulatory requirements. 
6. Ensure that the IEC will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the 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 IEC and 
issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met. 
8. Obtain valid informed consent from each subject who participates in the study and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the 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. 
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
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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 E 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), 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 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) 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 subjects, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies; 
d) That subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 
e) That the subject’s identity will remain confidential in the event that study results are 
published. 
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from screening throughout the duration of the study. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject 
is found to be pregnant during study, study drug will be discontinued. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study. If the partner or wife 
of the subject is found to be pregnant during the study, the investigator will offer the subject 
the choice to receive treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov. 
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Appendix F Investigator Consent to Use of Personal Information  
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other personally identifiable information. In addition, the 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. 
• IECs. 
The investigator’s personal information may be retained, processed, and transferred by Takeda 
and these other parties for research purposes including the following: 
• Assessment of the suitability of 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. 
The investigator’s personal information may be transferred to other countries that do not have 
data protection laws that offer the same level of protection as data protection laws in 
investigator’s own country. 
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above. 
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Appendix G Protocol History 
Date 
Amendment Number 
Amendment Type 
Region 
29 April 2024 
Amendment 4 
Nonsubstantial 
Global 
11 October 2023 
Amendment 3 
Nonsubstantial 
Global 
04 August 2021 
Amendment 2 
Substantial 
Global 
01 July 2020 
Amendment 1 
Nonsubstantial 
Global 
22 May 2019 
Initial protocol 
- 
Global 
Rationale for Amendment 3 
The primary purpose of this amendment was to update the protocol to align with the guidelines 
and requirements of the new European Union Clinical Trials Regulations (EU CTR). 
In addition, minor grammatical, editorial, formatting, and administrative changes not affecting 
the conduct of the study were applied throughout the document for clarification and 
administrative purposes. 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1. 
Title page, 
Section 3.0 Study 
Summary 
Replaced EudraCT number by 
Abbreviated EU CT number. 
To comply with new European 
Union Clinical Trials Regulations 
(EU CTR) guidelines and 
requirements. 
2. 
Section 3.0 Study 
Summary  
Section 5.1.1 Primary 
Objective 
Section 5.2.1 Primary 
Endpoint 
Section 9.3 Schedule of 
Observations and 
Procedures, 
Appendix A Schedule 
of Study Procedures 
Replaced evaluation of special 
situation reports (SSRs) by that of 
pregnancy and added it to be 
recorded at all visits along with all 
adverse events (AEs) and SSRs etc. 
Also added pregnancy to be 
recorded for unscheduled visit in 
footnote d of the Schedule of Study 
Procedures. 
To provide clarity and additional 
details regarding SSRs and 
pregnancy due to the new EU CTR 
guidelines and requirements. 
3. 
Section 3.0 Study 
Summary 
Section 5.1.3 
Exploratory Objectives 
Section 5.2.3 
Exploratory Endpoints 
Rephrased the biomarker objective 
and endpoint for updating the 
word/phrase 
 
 
 
 
 
 
 
Clarification 
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Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
4. 
Section 3.0 Study 
Summary 
Section 5.2.1 Primary 
Endpoint 
Removed the phrase “Incidence of” 
from all safety parameters. 
Updated adverse events of special 
interest (AESIs) to treatment-
emergent AESIs. 
Updated medication errors to specify 
that these are medication errors 
reported to the pharmacovigilance 
department as SSRs. 
Updated for consistency with other 
studies in the darvadstrocel 
program. 
5. 
Section 3.0 Study 
Summary 
Section 5.2.2 Secondary 
Endpoints 
Updated the phrase “after 
darvadstrocel administration” to 
“after darvadstrocel repeat 
administration”. 
Minor correction because in this 
study, subjects receive a repeat 
dose of study drug. 
6. 
Section 3.0 Study 
Summary 
Section 6.1 Study 
Design 
Appendix A Schedule 
of Study Procedures 
Updated the number of MRI readers 
in case of adjudication. 
To clarify the number of readers in 
case of adjudication. 
7. 
Section 3.0 Study 
Summary 
New section added: Benefit-Risk 
Profile 
To comply with new EU CTR 
guidelines and requirements. 
8. 
Section 4.3 Benefit-
Risk Profile 
Updated the section with safety 
details. 
Updated the language with details 
on the known adverse drug 
reactions since the previous 
version of the protocol. 
9. 
Section 6.3 Study Start 
Definition, 
Section 6.4 End of 
Study/Study 
Completion Definition 
New sections added. 
To comply with new EU CTR 
guidelines and requirements. 
10. 
Section 8.1.1.2 
Sponsor-Supplied Drug 
New table added with details of 
study medications. 
To comply with new EU CTR 
guidelines and requirements. 
11. 
Section 8.1.4 Overdose 
Added detail for overdose to be 
reported on paper SSR form. 
To align with new EU CTR 
guidelines. 
12. 
Section 9.1.7.2 Fistula 
MRI Assessment 
Updated the MRI reporting with 
respect to fistula dimensions. 
To provide more details on the 
circumstances under which 
measurements of collections will 
be made by central MRI readers. 
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Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
13. 
Section 9.1.8 
Exploratory Biomarker 
Assessments 
Updated text for immunogenicity 
assessment 
 
 
Removed the subheadings for this 
section and their text. 
Clarification and simplification of 
details. 
14. 
Section 9.1.11.1 
Collection, Storage, and 
Future Use of 
Biological Samples 
From Clinical Study 
Subjects 
New section added. 
To comply with new EU CTR 
guidelines and requirements. 
15. 
Section 9.1.13 
Pregnancy 
Removed pregnancy reporting 
details and added reference to newly 
added section. 
To harmonize the details in 1 
section. 
16. 
Section 10.1.4 SSRs 
Updated section to remove 
pregnancy and created a dedicated 
pregnancy section. 
Added definitions of abuse, misuse, 
medication error, and overdose. 
To comply with new EU CTR 
guidelines and requirements. 
17. 
Section 10.1.6 Severity 
of AEs 
New section added with details on 
AE severity assessment. 
To clarify with details for the 
severity classifications. 
18. 
Section 10.2.1.1 AE 
Collection Period 
Corrected the start date of AE 
collection. 
Correction to align with the 
Appendix A Schedule of Study 
Procedures. 
19. 
Section 10.2.1.3 AESIs 
Deleted the details about an AESI 
form and added a statement for 
medication error to be captured both 
as an AESI and reported as an SSR. 
To align with the EU CTR 
guidelines for reporting SSRs, and 
to clarify how to handle reports of 
medications errors defined as an 
AESI as well as an SSR. 
20. 
Section 10.2.2 
Collection and 
Reporting of SAEs 
Updated the serious adverse event 
(SAE) reporting to start from 
“awareness” instead of “first onset 
or notification”. 
To clarify the timing of SAE 
reporting language more 
accurately. 
21. 
Section 10.3.1 SSRs 
New section added with details 
about SSR reporting. 
To comply with new EU CTR 
guidelines and requirements. 
22. 
Section 10.3.2 
Pregnancy 
New section added with details 
about pregnancy reporting. 
To comply with new EU CTR 
guidelines and requirements. 
23. 
Section 10.3.3 
Summary of Safety 
Reporting 
New section added with details 
about reporting timelines and 
methods. 
To comply with new EU CTR 
guidelines and requirements. 
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Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
24. 
Section 13.1.1 Analysis 
Sets 
Updated definition of the safety 
analysis set. 
Correction 
25. 
Section 13.1.4 Safety 
Analysis 
Updated the text for analysis of 
treatment-emergent adverse events 
and SAEs. 
Clarification on further safety 
analyses. 
26. 
Section 14.2 Protocol 
Deviations 
Updated to include information on 
reporting requirements in the event 
of any serious breach of EU CTR 
regulations. 
To comply with new EU CTR 
guidelines and requirements. 
27. 
Section 15.3 Subject 
Confidentiality 
Updated to include information on 
reporting requirements in the event 
of a serious breach of personal data. 
To comply with new EU CTR 
guidelines and requirements. 
 
Rationale for Amendment 2 
The primary reasons for this amendment were to: 
• 
Legal entity change from Millennium Pharmaceuticals, Inc to Takeda Development Center 
Americas, Inc. 
• 
Provide improved clarity to the eligibility criteria and study procedures. 
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 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1. 
Title Page 
Section 3.0 Study Summary 
Update to the sponsor from 
Millennium 
Pharmaceuticals, Inc to 
Takeda Development 
Center Americas, Inc. 
Sponsor was updated. 
2. 
Title Page 
Section 3.0 Study Summary 
Added EUPAS number. 
To provide EUPAS number. 
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Protocol Amendment 2 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
3. 
Section 3.0 Study Summary 
Section 5.2.1 Primary Endpoint 
Section 9.1.6 Primary Safety 
Measurement 
Section 10.2.1.3 AESIs 
Section 13.1.4 Safety Analysis. 
Update to adverse event of 
special interest (AESI) 
details. 
This section has been 
updated to further clarify 
that the specific AESI of 
tumorgenicity applies to 
malignant tumors only. 
4. 
Section 3.0 Study Summary 
Section 5.2.2 Secondary Endpoints 
Removal of wording 
“baseline visit” from the 
combined remission 
definition. 
To provide flexibility, since 
it is possible the active 
draining fistula could be 
draining weekly, not daily 
and may not drain on the 
day of baseline visit. 
5. 
Section 3.0 Study Summary 
Section 5.2.2 Secondary Endpoints 
Added the wording “of the 
treated perianal fistula(s)” 
to the relapse definition. 
To provide clarity. 
6. 
Section 3.0 Study Summary 
Section 5.2.2 Secondary Endpoints 
Update of wording “IMP” 
to “darvadstrocel”. 
To provide clarity. 
7. 
Section 3.0 Study Summary 
Section 6.1 Study Design 
Section 6.2 Justification for Study 
Design, Dose, and Endpoints 
Section 7.1 Inclusion Criteria (criterion 
5) 
Section 13.3 Determination of Sample 
Size. 
Update of wording “new 
fistula tract” to “new 
complex perianal fistula 
tract”. 
To provide clarity and 
additional details on new 
fistula. 
8. 
Section 3.0 Study Summary 
Section 7.1 Inclusion Criteria 
Update to inclusion 
criterion 4. 
A reading of a locally 
performed contrast enhanced 
(gadolinium) pelvic 
magnetic resonance imaging 
(MRI) has been added. In 
addition updates have been 
made to define complex 
perianal fistula. 
9. 
Section 3.0 Study Summary 
Section 7.1 Inclusion Criteria 
Update to inclusion 
criterion 5. 
To clarify that the subject 
has already received 
treatment with darvadstrocel 
for a complex perianal 
fistula at least 6 months 
prior to baseline visit for 
retreatment are eligible to 
enter the study. 
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Protocol Amendment 2 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
10. 
Section 3.0 Study Summary 
Section 7.2 Exclusion Criteria 
Update to exclusion 
criterion 4. 
To add the study number, 
remove the wording 
“PASS”, update the wording 
of the footnote to clarify the 
description of INSPIRE 
study, and minor editorial 
updates for clarification. 
11. 
Section 3.0 Study Summary 
Section 7.2 Exclusion Criteria 
Update to exclusion 
criterion 19. 
To clarify that abscess 
drainage, cleaning surgery, 
or seton placement are not 
considered as “local major 
surgery” in this protocol. 
12. 
Section 9.1.1 Informed Consent 
Procedure 
Section 9.3.1 Baseline Visit 
Section 9.3.2 Preparation Visit (Visit 0) 
Appendix A 
Update to informed 
consent, preparation visit 
procedure. 
To clarify that eligibility 
criteria will be confirmed at 
preparation visits. 
13. 
Section 9.3.2 Preparation Visit (Visit 0) 
Appendix A 
Update to preparation visit 
procedure. 
To clarify that 
inclusion/exclusion criteria 
check will be done at 
preparation visits 
14. 
Section 9.1.5 Vital Sign Procedure 
Update to vital sign 
procedure. 
To clarify types of 
measurements for body 
temperature. 
15. 
Section 9.3.1 Baseline Visit 
Update to rescreening 
requirement for screen 
failures. 
To clarify that screen 
failures must repeat all 
assessments with exception 
to pelvic MRI which could 
be waived if it was 
previously completed within 
3 months of the rescreen 
visit and the clinical 
condition remains 
unchanged. 
16. 
Section 9.3.2 Preparation Visit (Visit 0) 
Section 9.3.3 Repeat Administration 
(Visit 1) 
Appendix A 
Clinical fistula assessment 
was added at preparation 
visit and repeat 
administration. 
In line with the actual 
conduct, at both visit 
investigator requires to 
perform clinical fistula 
assessment before they 
perform the procedure. 
To be consistent with other 
Alofisel protocols. 
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CONFIDENTIAL 
Protocol Amendment 2 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
17. 
Section 9.3.10 Unscheduled Visit 
Added text for MRI central 
reader at unscheduled visit. 
To clarify that a quality copy 
will be sent to the central 
imaging laboratory for 
central MRI reading, along 
with the scheduled MRI 
when all the visits have been 
completed 
18. 
Section 10.1.2 SAEs 
Editorial update to serious 
adverse event (SAE) 
definition. 
To clarify that death should 
have been an outcome of an 
event and that the event(s) 
causing death should be 
recorded. 
19. 
Section 10.1.2 SAEs 
Removal of the Takeda 
Medically Significant 
adverse event (AE) list. 
In line with updated internal 
process, the EudraVigilance 
Expert Working Group 
Important Medical Event 
Terms list will now be 
implemented. 
20. 
Section 3.0 Study Summary 
Section 13.1.3 Efficacy Analysis 
“Combined remission” 
was moved up in the order 
of the list. 
To be consistent within the 
protocol (secondary 
endpoints). 
21. 
Section 3.0 Study Summary 
Section 13.1.3 Efficacy Analysis 
Update of wording 
“relapse” to “reopening of 
any of the treated external 
openings with active 
drainage”. 
To be consistent within the 
protocol (secondary 
endpoints). 
22. 
Section 13.1.4 Safety Analysis 
Added text “Clinical 
laboratory values will be 
summarized according to 
Common Terminology 
Criteria for Adverse 
Events criteria”. 
To be consistent with other 
Alofisel studies. 
23. 
Appendix A 
Update to enrollment. 
To clarify that enrollment 
will be done at preparation 
visit instead of baseline visit. 
 
Rationale for Amendment 1 
The primary reasons for this amendment were to: 
• 
Provide improved clarity and completeness to the eligibility criteria and assessments that are 
to be conducted. 
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CONFIDENTIAL 
• 
Describe how to manage study procedures during unavoidable circumstances such as the 
coronavirus disease 2019 (COVID-19) pandemic.  
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study were included for clarification and administrative purposes 
only. 
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  
Section 5.1.3 Exploratory 
Objectives  
Section 3.0 Study Summary 
Section 9.3.1 Baseline Visit 
Section 9.3.2 Preparation Visit 
(Visit 0) 
Section 9.3.3 Repeat 
Administration (Visit 1) 
Section 9.3.4 6 Weeks Following 
Repeat Administration (Visit 
2/Week 6 ± 8 days) 
Section 13.1.5 Other Analysis 
Appendix A Schedule of Study 
Procedures 
Removal of stool and fistula swab 
microbiome analysis from 
exploratory objectives. In line with 
this update, Section 9.1.7.5 
Exploratory Biomarker Samples, 
which described the microbiome 
assessments, has also been 
removed. 
The exploratory objective to 
characterize microbiome diversity 
has been removed to avoid any 
additional burden on participants.  
Section 5.2.2 Secondary Endpoints 
Section 3.0 Study Summary 
The definition of the relapse 
endpoint has been corrected and an 
editorial update made. 
The definition of relapse was 
corrected as follows “Reopening of 
any of the treated fistula(s) external 
openings with active drainage as 
clinically assessed that were in 
combined remission at Week 24, 
OR 
The development of a collection >2 
cm (in at least 2 dimensions) 
confirmed by centrally read MRI 
assessment”. 
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CONFIDENTIAL 
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  
Section 5.2.2 Secondary Endpoints 
Section 3.0 Study Summary 
Week 6 assessment added to 
secondary endpoints to assess 
proportion of subjects who achieve 
clinical remission and clinical 
response. 
A fistula clinical assessment was 
added to Week 6 in order to allow the 
capture of clinical response or 
clinical remission at that time point. 
Section 5.2.2 Secondary Endpoints 
Section 3.0 Study Summary 
Editorial update to the secondary 
endpoint: time to reopening of any 
treated external openings with 
active drainage. 
To improve endpoint definition and 
clarify the time point for assessment. 
Section 5.2.3 Exploratory 
Endpoints 
Section 3.0 Study Summary 
Revised exploratory endpoints. 
For improved clarity in the definition 
of the exploratory endpoints relating 
to plasma sample biomarker analysis 
(donor-specific antibody [DSA], 
immunogenicity, 
 
). 
Section 6.1 Study Design 
Section 3.0 Study Summary 
Update to the description of the 
study to include where the study 
will be conducted. 
To clarify that the study will be 
conducted in countries where 
darvadstrocel is currently marketed. 
Section 6.1 Study Design 
Section 3.0 Study Summary 
Appendix A Schedule of Study 
Procedures 
Revised wording for magnetic 
resonance imaging (MRI) 
assessment.  
To clarify that MRI will be assessed 
by 2 imaging readers. 
Section 6.1 Study Design 
Sections 9.3.3 Repeat 
Administration (Visit 1)  
Appendix A Schedule of Study 
Procedures 
Details added on the requirements 
for rescheduling of the repeat 
administration visit. 
To provide clarity on the procedure 
for rescheduling of the repeat 
administration visit. 
Section 6.1 Study Design 
Section 9.1.7 Efficacy 
Measurements 
Section 9.1.11 Procedures for 
Clinical Laboratory Samples 
Section 9.3 Schedule of 
Observations and Procedures 
Appendix A Schedule of Study 
Procedures 
Explicitly stated where study 
procedures are to be conducted and 
how to manage alternative 
strategies for collecting data and 
conducting study procedures 
during the coronavirus disease 
2019 (COVID-19) pandemic.  
The COVID-19 pandemic means that 
subjects may not be able to attend 
study visits as planned. Therefore it 
is necessary to clarify alternative 
arrangements for data collection and 
study procedures during unavoidable 
circumstances such as the COVID-19 
pandemic. 
Section 6.2 Justification for Study 
Design, Dose, and Endpoints 
Details added to clarify the criteria 
for darvadstrocel repeat 
administration. 
To provide further details and 
improved clarity on the criteria for 
receiving darvadstrocel repeat 
administration. 
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CONFIDENTIAL 
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  
Section 7.1 Inclusion Criteria 
Section 3.0 Study Summary 
Addition of inclusion Criterion 4. 
To clearly specify the maximum 
number of internal and external 
openings in line with the 
darvadstrocel Summary of Product 
Characteristics. 
Section 7.1 Inclusion Criteria 
Section 3.0 Study Summary 
Addition of inclusion Criterion 5 
to specify entry requirements for 
subjects who have previously 
received darvadstrocel. 
To provide clarity on entry 
requirements. 
Section 7.1 Inclusion Criteria 
Section 3.0 Study Summary 
Update to inclusion Criterion 6.  
 
To provide clarity on entry 
requirements. 
Section 7.2 Exclusion Criteria 
Section 3.0 Study Summary 
Update to exclusion Criterion 1 to 
specify a unique fistula. 
To clarify subjects with a unique 
fistula must have a partial closure. 
Section 7.2 Exclusion Criteria 
Section 3.0 Study Summary 
Update to exclusion Criterion 4 
and inclusion of footnote to 
describe the INSPIRE study. 
To provide clarity on the eligibility 
criteria for subjects participating in 
the INSPIRE registry study. 
Section 7.2 Exclusion Criteria 
Section 3.0 Study Summary 
Update to exclusion Criterion 5. 
To provide the maximum elimination 
half-life for other IMPs the subject 
may have received before study 
enrollment. 
Section 7.2 Exclusion Criteria 
Section 3.0 Study Summary 
Addition of exclusion Criterion 6 
To exclude subjects with known or 
suspected COVID-19. 
Section 7.2 Exclusion Criteria 
Section 3.0 Study Summary 
Addition of laboratory parameters 
exclusion Criterion 7. 
Laboratory tests will be conducted at 
the baseline visit. Subjects meeting 
the listed laboratory values will not 
be eligible for inclusion in the study.  
Section 7.2 Exclusion Criteria 
Section 3.0 Study Summary 
Addition of exclusion Criterion 8  
To exclude subjects at increased risk 
of surgical procedures. 
Section 7.2 Exclusion Criteria 
Section 3.0 Study Summary 
Addition of exclusion Criterion 9 
to define entry requirements for 
subjects with active hepatopathy. 
To provide improved clarity on 
subject entry requirements. 
Section 7.2 Exclusion Criteria 
Section 3.0 Study Summary 
Update to exclusion Criterion 18 to 
define entry requirements for 
subjects who have had 
major/minor surgery of the 
gastrointestinal tract. 
To provide improved clarity on 
subject entry requirements. 
Section 7.2 Exclusion Criteria 
Section 3.0 Study Summary 
Update to exclusion Criterion 19 to 
define entry requirements for 
subjects who have had perianal 
surgery. 
To provide improved clarity on 
subject entry requirements. 
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CONFIDENTIAL 
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  
Section 7.3 Criteria for 
Discontinuation or Withdrawal of 
a Subject 
The primary reason for 
discontinuation or withdrawal was 
updated to include ‘Physician’s 
decision based on subject’s 
well-being’. 
Update made for completeness. 
Section 7.4 Procedures for 
Discontinuation or Withdrawal of 
a Subject 
Updated to clarify the details to be 
included in the electronic case 
report form for discontinuation or 
withdrawal of subject. 
For improved clarity on reporting 
procedures. 
Section 8.1.2 Storage and 
Handling of Study Medication 
Text added to specify where 
expiration date and time for the 
investigational medicinal product 
can be found. 
Editorial change made for 
completeness. 
Section 8.3 Accountability and 
Destruction of Sponsor-Supplied 
Drugs 
Editorial updates and additions on 
drug accountability. 
To improve clarity on the procedure 
for drug accountability. 
Section 9.1.1 Informed Consent 
Procedure 
Inclusion of reconsent for subjects. 
For any subject not meeting the 
eligibility criteria at the baseline visit 
and receives sponsor approval to 
rescreen, the subject will be asked to 
reconsent into the study. 
Section 9.1.2 Demographics, 
Medical History, and Medication 
History Procedure 
Appendix A Schedule of Study 
Procedures 
Update to medical history and 
medication history. 
To provide improved clarity on the 
information to be collected for 
medical history. 
Section 9.1.3 Physical 
Examination Procedure 
Update to physical examination 
section. 
To provide a complete list of all body 
systems that will be assessed during 
physical examination and 
clarification provided on adverse 
event (AE) reporting for worsening 
of physical examination findings. 
Section 9.1.7.2 Fistula MRI 
Assessment 
Revised wording for fistula MRI 
assessment. 
To improve clarity on the procedural 
requirements for pelvic MRI 
assessment. 
Section 9.1.7.3 PDAI 
Appendix A Schedule of Study 
Procedures 
Removal of assessment from the 
preparation visit. 
Update made for correctness. 
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CONFIDENTIAL 
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  
Section 9.1.7.4 PRO-2 
Appendix A Schedule of Study 
Procedures 
Added Section 9.1.7.4 PRO-2 
To include details on the patient-
reported outcome-2 (PRO-2) 
assessment. 
Additional time points included for 
PRO-2 assessment. 
Section 9.1.8.1 Immunologic Tests 
Section 9.3.1 Baseline Visit 
Section 9.3.4 6 Weeks Following 
Repeat Administration (Visit 
2/Week 6 ± 8 days) 
Section 9.3.5 6 Months Following 
Repeat Administration (Visit 
3/Week 24 ± 15 days) 
Section 9.3.8 36 Months 
Following Repeat Administration 
(Visit 6/156 Weeks ± 30 days, 
Final Visit) 
Section 9.3.9 Early Termination 
Visit 
Appendix A Schedule of Study 
Procedures 
Removal of analysis of peripheral 
blood mononuclear cells. 
To avoid any additional burden on 
participants 
Section 9.1.9 Documentation of 
Prior and Concomitant 
Medications 
Update to concomitant 
medications for completeness and 
clarity. 
To provide clarity on the definitions 
for prior medication and concomitant 
medication, including reporting time 
frames. In addition, a paragraph was 
added to provide details on the add-
on study design for completeness. 
Section 9.1.12.3 Definitions and 
Procedures for Contraception and 
Pregnancy Avoidance 
Inclusion of new footnote. 
To clarify the reason for including 
the use of highly effective 
contraception by subjects 
participating in the study. 
Section 9.3.1 Baseline Visit 
Editorial change for clarity. 
Removal of the word enrollment in 
combination with the word baseline 
throughout the protocol as they are 
synonymous. 
Section 9.3.1 Baseline Visit 
Appendix A Schedule of Study 
Procedures 
Removal of inclusion and 
exclusion criteria check at the 
preparation visit. 
This check will only take place at the 
baseline visit. 
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Protocol Incorporating Amendment No. 4 
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CONFIDENTIAL 
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  
Section 9.3.1 Baseline Visit – 
Section 9.3.10 Unscheduled Visit 
Appendix A Schedule of Study 
Procedures 
Addition of interactive web 
response system (IWRS) at each 
visit. 
For completeness to list of 
procedures required to be performed 
at each visit. 
Section 9.3.1 Baseline Visit 
Appendix A Schedule of Study 
Procedures 
Editorial changes to provide clarity 
on study assessments. 
To provide clarity on study 
assessments for history of Crohn’s 
disease (CD) and perianal fistula, 
previous medications, concomitant 
medications, clinical evaluation of 
fistula, PRO-2 score, and 
colonoscopy information. 
Section 9.3.1 Baseline Visit 
Appendix A Schedule of Study 
Procedures 
Inclusion of fistula clinical 
assessment procedure. 
This assessment was included at the 
preparation visit in the initial 
protocol and has now been corrected 
to take place at the baseline visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
To avoid any additional burden on 
participants. 
Section 9.3.2 Preparation Visit 
(Visit 0) 
Appendix A Schedule of Study 
Procedures 
Inclusion of assessment: review 
and record concomitant 
medications taken since the last 
visit. 
Assessment added for completeness. 
Section 9.3.2 Preparation Visit 
(Visit 0) 
Appendix A Schedule of Study 
Procedures 
Inclusion of mandatory antibiotic 
administration after fistula 
preparation. 
Mandatory antibiotics have been 
included as this is a procedure 
already in place in most hospitals 
after an exploration under anesthesia 
with curettage as prophylaxis of 
infections in the area. 
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29 April 2024 
 
CONFIDENTIAL 
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  
Sections 9.3.3 Repeat 
Administration (Visit 1)  
Section 9.3.4 6 Weeks Following 
Repeat Administration (Visit 
2/Week 6 ± 8 days)  
Section 9.3.5 6 Months Following 
Repeat Administration (Visit 
3/Week 24 ± 15 days) 
Section 9.3.6 12 Months 
Following Repeat Administration 
(Visit 4/Week 52 ± 15 days)  
Section 9.3.7 24 Months 
Following Repeat Administration 
(Visit 5/Week 104 ± 30 days) 
Section 9.3.8 36 Months 
Following Repeat Administration 
(Visit 6/156 Weeks ± 30 days, 
Final Visit) 
Section 9.3.9 Early Termination 
Visit 
Section 9.3.10 Unscheduled Visit  
Assessments reorganized. 
The order of assessments listed in the 
Schedule of Observations and 
Assessments has been updated to 
match with the order in the Schedule 
of Assessments table. 
Section 9.3 Schedule of 
Observations and Procedures 
Appendix A Schedule of Study 
Procedures 
Removal of Crohn’s Disease 
Activity Index (CDAI) assessment 
throughout the study and replacing 
with PRO-2 score. 
In light of COVID-19, if a subject is 
unable to attend a visit, it is deemed 
more appropriate to replace the 
CDAI assessment (which requires a 
blood sample for hematocrit value) 
with the PRO-2 score, which can still 
measure evolution the of CD in a 
simpler way without requiring 
clinical assessment. 
Section 9.3.9 Early Termination 
Visit 
Wording added to clarify that 
samples for DSA, immunogenicity 
 do not 
need to be taken at the early 
termination visit if the early 
termination visit takes place after 
the Week 24 visit.  
To provide clarity on assessment 
procedures. 
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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  
Section 9.3.10 Unscheduled Visit 
Appendix A Schedule of Study 
Procedures  
Removal of plasma sample 
analysis from the unscheduled 
visit. 
Update made for correctness. 
Section 9.3.11 Unscheduled 
Telephone Call Visit 
Appendix A Schedule of Study 
Procedures 
Added Section 9.3.11.  
To allow subjects to have the option 
for a telephone call in case they are 
unable to attend the site visit. 
Section 10.1.1 AEs 
Update to AE definition. 
 
A sentence has been added to 
clarify that new fistula(s) 
identified during the course of the 
study will be captured as an AE. 
To reinstate the International 
Conference for Harmonisation 
definition of an AE.  
The worsening of the treated fistula 
will be assessed as efficacy endpoint. 
Only the worsening of the nontreated 
newly developed fistula will be 
collected as an AE. 
Section 10.1.2 SAEs 
Addition of ‘COVID-19 
pneumonia’ and ‘COVID-19-
related disease’ to Takeda 
Medically Significant AE List. 
Update made in line with recent 
industry and sponsor guidance. 
Section 10.1.4 SSRs 
Removal of breastfeeding as 
special situation report (SSR). 
Only pregnancy is considered as an 
SSR and breastfeeding has therefore 
been removed.  
Section 10.2.1.3 AESIs 
Section updated to provide clarity 
on the process for reporting 
adverse event of special interests 
(AESIs) that meet the seriousness 
criteria. 
For improved clarity on the AESI 
reporting procedure. 
Section 10.2.2 Collection and 
Reporting of SAEs 
Section updated to provide details 
on the procedure for reporting 
serious adverse events (SAEs). 
For improved transparency on the 
SAE reporting procedure. 
Section 13.1.3 Efficacy Analysis 
Revised wording for efficacy 
analysis.  
To provide specificity and 
clarification around the efficacy 
analysis. 
Section 13.2 Interim Analysis and 
Criteria for Early Termination 
Section 6.1 Study Design 
Section 9.1.11 Procedures for 
Clinical Laboratory Samples 
Sentence added to clarify that no 
interim analysis is planned for this 
study. 
Update made for clarity to study 
procedures. 
Section 13.3 Determination of 
Sample Size 
Revised wording for determination 
of sample size. 
To improve wording and clearly 
specify the reason for enrolling 50 
subjects.  
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Protocol Incorporating Amendment No. 4 
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CONFIDENTIAL 
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  
Section 9.1.12.4 General Guidance 
with Respect to the Avoidance of 
Pregnancy 
Section 9.3.2 Preparation Visit 
(Visit 0) 
Appendix A Schedule of Study 
Procedures 
Inclusion of urine pregnancy test. 
Serum pregnancy test is only 
required at the baseline visit. Urine 
pregnancy tests will be performed at 
subsequent visits. 
Section 9.3.8 36 Months 
Following Repeat Administration 
(Visit 6/156 Weeks ± 30 days, 
Final Visit) 
Appendix A Schedule of Study 
Procedures 
Removal of plasma samples for 
DSA levels, immunogenicity, 
 
 at 
Week 156. 
The Week 156 exploratory biomarker 
assessments have been removed to 
avoid any additional burden on 
participants. 
Appendix B Anal Clock 
Inclusion of appendix.  
Added for completeness to protocol. 
Appendix C PRO-2 Scoring 
Inclusion of appendix. 
Added for completeness to protocol. 
 
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Signature Page for Alofisel-4001 Protocol Amend 4 2024-04-29
Title: Amendment 4 to Postauthorization Safety Study of the Long-Term Safety and
Document Number: TDN-000333585 v1.0
Approval
Statistics
30-Apr-2024 13:03:06 GMT+0000
Approval
Pharmacovigilance
30-Apr-2024 13:11:38 GMT+0000
Approval
Clinical
30-Apr-2024 13:22:13 GMT+0000
For non-commercial use only