A Phase 3, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of Darvadstrocel in the Treatment of Complex Perianal Fistula in Pediatric Subjects With Crohn's Disease Over a Period of 24 Weeks and an Extended Follow-up Period for a Total of up to 52 Weeks
Phase: PHASE3
Conditions: Crohn's Disease, Complex Perianal Fistula
Sponsor: Takeda

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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list will be provided to each site. 
Takeda Development Center sponsored investigators per individual country requirements will be 
provided with emergency medical contact information cards to be carried by each subject. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site. 
Contact Type/Role 
European/Rest of World Contact 
Serious adverse event,   
special situation, and pregnancy reporting 
SAEs: Report via EDC and paper SAE form (back-
up method) 
Special situation (including pregnancy) 
 Fax: +1-224-554-1052 
Email: PharmacovigilanceMailbox@Takeda.com 
(Rest of world) 
Email: Takeda@e-medinfo.com (Japan-specific) 
Medical Monitor 
(medical advice on protocol and study drug) 
Medical Director, Clinical Science 
Responsible Medical Officer  
(carries overall responsibility for the conduct of the study) 
Medical Director, Clinical Science 
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CONFIDENTIAL 
1.2 
Approval  
REPRESENTATIVES OF TAKEDA  
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also in accordance with the 
following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference for Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
SIGNATURES 
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page. 
Electronic signatures are provided on the last page of this document. 
, MD 
 Clinical Science 
Date 
 MS 
, Statistical & Quantitative 
Sciences 
Date 
 
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CONFIDENTIAL 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the investigator’s brochure, 
package insert and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and also to protect the rights, safety, 
privacy, and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference for Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
• Terms outlined in the study site agreement. 
• Responsibilities of the Investigator (Appendix H). 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix J 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 3 Summary of Changes 
Protocol Amendment 3 Summary and Rationale: 
This section describes the changes in reference to the protocol incorporating Amendment 3. The 
primary reason for this amendment is to include an interim analysis.  
In addition, minor grammatical, editorial, formatting, and administrative changes not affecting 
the conduct of the study are included 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. 
Section 2.0 STUDY 
SUMMARY 
Section 13.2 Interim 
Analysis and Criteria for 
Early Termination 
Added interim analysis for 
evaluation of safety and 
efficacy. 
Takeda’s internal decision to 
review the safety and efficacy of 
davardstrocel in enrolled 
pediatric patients to support 
future submission to regulatory 
agencies. 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 3 Summary of Changes...............................................................5 
2.0 
STUDY SUMMARY.........................................................................................................11 
3.0 
STUDY REFERENCE INFORMATION .........................................................................17 
3.1 
Study-Related Responsibilities ....................................................................................17 
3.2 
Principal Investigator/Coordinating Investigator .........................................................17 
3.3 
List of Abbreviations ...................................................................................................18 
4.0 
INTRODUCTION .............................................................................................................19 
4.1 
Disease Background.....................................................................................................19 
4.2 
Rationale for the Proposed Study ................................................................................21 
4.3 
Benefit-Risk Profile .....................................................................................................23 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................24 
5.1 
Objectives ....................................................................................................................24 
5.1.1 
Primary Objective ................................................................................................24 
5.1.2 
Secondary Objectives ..........................................................................................24 
5.1.3 
Exploratory Objective .........................................................................................24 
5.2 
Endpoints .....................................................................................................................24 
5.2.1 
Primary Endpoint .................................................................................................24 
5.2.2 
Secondary Endpoints ...........................................................................................25 
5.2.3 
Exploratory Endpoints .........................................................................................26 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................26 
6.1 
Study Design ................................................................................................................26 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................28 
6.3 
Definition of Study Start ..............................................................................................30 
6.4 
Definition of End of Study ...........................................................................................30 
6.5 
Premature Termination or Suspension of Study or Study Site ....................................30 
6.5.1 
Criteria for Premature Termination or Suspension of the Study .........................30 
6.5.2 
Criteria for Premature Termination or Suspension of Study Sites ......................30 
6.5.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) ...............................................................................30 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............31 
7.1 
Inclusion Criteria .........................................................................................................31 
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7.2 
Exclusion Criteria ........................................................................................................32 
7.3 
Excluded Medications and Treatments ........................................................................34 
7.4 
Rescue Therapy ............................................................................................................37 
7.5 
Criteria for Withdrawal of a Subject ............................................................................38 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................39 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT .......................................................39 
8.1 
Study Drug and Materials ............................................................................................39 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ....................................39 
8.1.1.1 
Darvadstrocel ..............................................................................................39 
8.1.1.2 
Study drug ...................................................................................................40 
8.1.1.3 
Sponsor-Supplied Drug ...............................................................................40 
8.1.2 
Storage .................................................................................................................40 
8.1.3 
Dose and Regimen ...............................................................................................41 
8.1.4 
Overdose ..............................................................................................................41 
8.2 
Study Drug Assignment and Dispensing Procedures ..................................................41 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs.......................................42 
8.4 
Continued Access to Study Drug After the End of the Study......................................43 
9.0 
STUDY PLAN ...................................................................................................................43 
9.1 
Study Procedures .........................................................................................................43 
9.1.1 
Informed Consent/Pediatric Assent Procedure ....................................................43 
9.1.2 
Demographics, Medical History, and Surgical History .......................................43 
9.1.3 
Physical Examination Procedure .........................................................................44 
9.1.4 
Weight, Height and Body Mass Index ................................................................44 
9.1.5 
Vital Sign Procedure ............................................................................................44 
9.1.6 
Primary Efficacy Measurements .........................................................................44 
9.1.6.1 
Fistula Clinical Assessment ........................................................................44 
9.1.6.2 
Pelvic MRI ..................................................................................................45 
9.1.7 
Documentation of Concomitant Medications ......................................................45 
9.1.8 
Documentation of Concurrent Medical Conditions ............................................45 
9.1.9 
Procedures for Clinical Laboratory Samples .......................................................45 
9.1.10 
Contraception and Pregnancy Avoidance Procedure ..........................................46 
9.1.10.1 Male Subjects and Their Female Partners ...................................................46 
9.1.10.2 Female Subjects and Their Male Partners ...................................................47 
9.1.10.3 Definitions and Procedures for Contraception and Pregnancy 
Avoidance ...................................................................................................47 
9.1.10.4 General Guidance With Respect to the Avoidance of Pregnancy...............49 
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9.1.11 
Pregnancy ............................................................................................................49 
9.1.12 
Documentation of Screen Failure ........................................................................49 
9.1.13 
Documentation of Study Entrance .......................................................................50 
9.1.14 
Fistula Preparation ...............................................................................................50 
9.1.15 
Clinical Outcome Assessments ...........................................................................51 
9.1.15.1 Clinician-Reported Outcomes .....................................................................51 
9.1.15.2 Patient-Reported Outcomes ........................................................................51 
9.2 
Monitoring Subject Treatment Compliance.................................................................51 
9.3 
Schedule of Observations and Procedures ...................................................................51 
9.3.1 
Screening Visit ....................................................................................................52 
9.3.2 
Potential Rescreening ..........................................................................................53 
9.3.3 
Preparation Visit ..................................................................................................54 
9.3.4 
Treatment Administration Visit (Week 0/Visit 0) ...............................................55 
9.3.5 
Follow-up Period .................................................................................................56 
9.3.5.1 
Week 6/Visit 1.............................................................................................56 
9.3.5.2 
Week 12/Visit 2...........................................................................................56 
9.3.5.3 
Week 24/Visit 3...........................................................................................57 
9.3.5.4 
Week 36/Visit 4...........................................................................................58 
9.3.5.5 
Week 52/Visit 5 (End of Study Visit) .........................................................58 
9.3.6 
Early Termination ................................................................................................59 
9.3.7 
Unscheduled Telephone Follow-up Calls ...........................................................59 
9.3.8 
Remote Visit due to COVID-19 ..........................................................................60 
10.0 
ADVERSE EVENTS .........................................................................................................61 
10.1 
Definitions....................................................................................................................61 
10.1.1 
AEs ......................................................................................................................61 
10.1.2 
Additional Points to Consider for AEs ................................................................61 
10.1.3 
SAEs ....................................................................................................................63 
10.1.4 
AEs of Special Interest ........................................................................................63 
10.1.5 
Special Situation Reports ....................................................................................64 
10.1.6 
Intensity of AEs ...................................................................................................64 
10.1.7 
Causality of AEs ..................................................................................................65 
10.1.8 
Relationship to Study Procedures ........................................................................65 
10.1.9 
Start Date .............................................................................................................65 
10.1.10 Stop Date .............................................................................................................65 
10.1.11 Frequency ............................................................................................................65 
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10.1.12 Outcome ..............................................................................................................65 
10.2 
Procedures ....................................................................................................................66 
10.2.1 
Collection and Reporting of AEs ........................................................................66 
10.2.1.1 AE Collection Period ..................................................................................66 
10.2.1.2 AE Reporting ..............................................................................................66 
10.2.1.3 AESIs ..........................................................................................................67 
10.2.2 
Collection and Reporting of SAEs ......................................................................67 
10.2.3 
Reporting of Abnormal Liver Function Tests .....................................................68 
10.3 
Follow-up of SAEs ......................................................................................................68 
10.3.1 
Collecting and Reporting of SSRs .......................................................................68 
10.3.2 
Collecting and Reporting of Pregnancies ............................................................69 
10.3.3 
Summary of Safety Reporting .............................................................................69 
10.3.4 
Safety Reporting to Investigators, IRBs, IECs, and Regulatory Authorities ......69 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................70 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................70 
12.1 
eCRFs ...........................................................................................................................70 
12.2 
Record Retention .........................................................................................................71 
13.0 
STATISTICAL METHODS ..............................................................................................72 
13.1 
Statistical and Analytical Plans ....................................................................................72 
13.1.1 
Analysis Sets .......................................................................................................72 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ..........................72 
13.1.3 
Efficacy Analysis .................................................................................................72 
13.1.3.1 Primary Efficacy Analysis ..........................................................................72 
13.1.3.2 Secondary Efficacy Endpoints ....................................................................73 
13.1.3.3 
 ......................................................................................73 
13.1.4 
Safety Analysis ....................................................................................................73 
13.1.5 
Exploratory Analyses ..........................................................................................73 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................74 
13.3 
 .....................................................................................74 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................75 
14.1 
Study-Site Monitoring .................................................................................................75 
14.2 
Protocol Deviations ......................................................................................................75 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................76 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................76 
15.1 
IRB and/or IEC Approval ............................................................................................76 
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CONFIDENTIAL 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................77 
15.3 
Subject Confidentiality ................................................................................................78 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................79 
15.4.1 
Publication and Disclosure ..................................................................................79 
15.4.2 
Clinical Trial Registration ...................................................................................79 
15.4.3 
Clinical Trial Results Disclosure .........................................................................79 
15.5 
Insurance and Compensation for Injury .......................................................................80 
16.0 
REFERENCES ..................................................................................................................80 
 
LIST OF IN-TEXT TABLES 
Table 7. a 
Allowed/Excluded Medications and Treatments ...................................................35 
Table 8. a 
Study Medication ...................................................................................................40 
Table 9. a 
Clinical Laboratory Tests .......................................................................................46 
Table 1 
Hepatic Investigation .............................................................................................91 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Study Schematic.....................................................................................................27 
Figure 1 
Liver Test Abnormality Monitoring and Follow-up ..............................................89 
Figure 2 
Liver Test Abnormalities: Considerations for Study Drug Discontinuation .........90 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Study Procedures ...............................................................................83 
Appendix B 
Blood Volume Table ..............................................................................................86 
Appendix C 
Anal Clock .............................................................................................................87 
Appendix D 
Guidance on Liver Test Abnormality Monitoring, Evaluation, and Follow-up ....88 
Appendix E 
PDAI ......................................................................................................................92 
Appendix F 
PCDAI....................................................................................................................93 
Appendix G 
Perianal Pain VAS .................................................................................................94 
Appendix H 
Responsibilities of the Investigator ........................................................................95 
Appendix I 
Elements of the Subject Informed Consent/Pediatric Assent ................................97 
Appendix J 
Investigator Consent to Use of Personal Information ..........................................100 
Appendix K 
Protocol History ...................................................................................................101 
 
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2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Development Center Americas, Inc. 
Compound: 
Darvadstrocel 
Title of Protocol:  
A Phase 3, Open-Label, Multicenter Study to 
Evaluate the Efficacy and Safety of Darvadstrocel in 
the Treatment of Complex Perianal Fistula in 
Pediatric Subjects with Crohn’s Disease over a 
Period of 24 Weeks and an Extended Follow-up 
Period for a Total of up to 52 Weeks. 
IND No.: Not 
applicable 
Abbreviated EU CT No.:  
2023-503973-39 
Study Number: Darvadstrocel-3004 
Phase: 3 
Study Design: 
This is a phase 3, open-label, multicenter study to evaluate the efficacy and safety of darvadstrocel (also known 
as Cx601) in the treatment of complex perianal fistula refractory to therapy in pediatric subjects with Crohn’s 
disease (CD) aged 4 to <18 years. 
At least 20 subjects are planned to be enrolled to receive a single dose of darvadstrocel (24 mL cell suspension 
containing 120 million cells of allogeneic expanded adipose-derived mesenchymal stem cells [eASCs]). The 
study will permit continuation of previous treatment of luminal CD in an add-on study design (ie, anti-tumor 
necrosis factor [TNF] therapy, immunosuppressants etc). Subjects receiving any ongoing concomitant medical 
treatment for CD at stable doses (stable dose is considered either the same dose or same weight-based dose 
adjusted for weight) at the time of the screening visit, will be allowed to continue treatment throughout the study.  
The study consists of a screening period (within a minimum of 4 and a maximum of 5 weeks before the 
preparation visit), preparation visit (within a minimum of 2 and a maximum of 3 weeks before treatment), 
treatment visit (day of study drug administration [Visit 0]), and a follow-up period (for approximately 52 weeks 
after study drug administration). 
After a successful screening period to determine eligibility, subjects will attend a preparation visit before 
receiving a single dose of darvadstrocel at Visit 0. At each visit, a clinical assessment of the fistula(s) will be 
performed. 
A pelvic magnetic resonance imaging (MRI) scan will be performed locally at the screening visit and at Week 24 
to assess fistula characteristics, fistula location, and for the presence or absence of abscesses >2 cm (in at least 2 
dimensions). All MRIs will be assessed centrally by the MRI central reader. 
A follow-up period of an additional 28 weeks after Week 24 (up to a total of 52 weeks) is incorporated into the 
study for continued evaluation of safety and efficacy.  
Sites will employ all efforts to see subjects as described in the clinical assessments. In unavoidable 
circumstances, such as the coronavirus disease 2019 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, and will be documented in the statistical analysis plan. 
Benefit-Risk Profile:  
Because darvadstrocel has not yet been formally evaluated in pediatric subjects, the final benefit-risk assessment 
for the treatment of complex perianal fistula in pediatric patients with CD has not been determined. 
In clinical studies conducted to date, darvadstrocel has been well tolerated in adult patients with complex 
perianal fistula(s) and CD up to 120 million cells per administration. In nonclinical studies conducted to date, no 
dose-dependent safety concern or toxicity, including in juvenile animals, has been identified and no ectopic 
tumor formation or hypersensitivity concerns have emerged. Overall, the data available present a positive 
benefit-risk profile for darvadstrocel. 
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CONFIDENTIAL 
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 for darvadstrocel include proctalgia, anal abscess, and anal fistula.   
Although a rare condition, as with adults there is a significant unmet medical need for treatment of complex 
perianal fistulas in the pediatric population with CD. Taking into consideration that there is no 
pathophysiological difference between perianal fistula in CD in the adult and pediatric populations and that the 
mechanism of action of darvadstrocel does not have any known age-dependent characteristics, based on the 
clinical data in adults, combined with nonclinical data, the benefit-risk balance in pediatric subjects is expected 
to be positive. 
Primary Objective: 
To evaluate the efficacy of darvadstrocel in combined remission at Week 24 for the treatment of complex 
perianal fistula in pediatric subjects with CD aged 4 to <18 years. 
Secondary Objectives: 
To evaluate the efficacy of darvadstrocel in clinical remission at Week 24 and Week 52 for the treatment of 
complex perianal fistula in pediatric subjects with CD aged 4 to <18 years. 
To evaluate the efficacy of darvadstrocel in clinical response at Week 24 and Week 52 for the treatment of 
complex perianal fistula in pediatric subjects with CD aged 4 to <18 years. 
To evaluate the efficacy of darvadstrocel in time to clinical remission up to Week 52 for the treatment of 
complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.  
To evaluate the efficacy of darvadstrocel in time to clinical response up to Week 52 for the treatment of complex 
perianal fistula in pediatric subjects with CD aged 4 to <18 years. 
To evaluate the efficacy of darvadstrocel on relapse by Week 52 in pediatric subjects with combined remission at 
Week 24. 
To evaluate the safety of darvadstrocel for the treatment of complex perianal fistula in pediatric subjects with CD 
aged 4 to <18 years over 52 weeks. 
Subject Population: Pediatric subjects with CD aged 4 to <18 years, with complex perianal fistula(s), whose 
perianal fistulas were previously treated and have shown an inadequate response (ie, a loss of response, 
intolerance or contraindication) to at least one of the following treatments: immunosuppressants, or biologics 
(anti-TNFs, anti-integrin or anti-interleukin [IL] 12/23). 
Number of Subjects: 
At least 20 subjects. 
Number of Sites:  
Estimated total: Approximately 30 sites in European 
Union, Israel, and Japan. 
Dose Level: 
Single administration of 120 million cells of 
darvadstrocel 
(24 mL, 5 million cells/mL) 
Route of Administration: 
Perilesional injection 
Duration of Treatment: 
Single dose at Day 0/Visit 0 
Period of Evaluation: 
Screening period (minimum of 4 and maximum of 5 
weeks before preparation visit), preparation visit 
(minimum of 2 and a maximum of 3 weeks before 
treatment administration), treatment administration 
visit (1 day), follow-up period (for approximately 52 
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weeks after treatment administration). 
Main Criteria for Inclusion: 
The list below includes the main criteria for inclusion. Refer to the main body of the protocol for the complete 
list of inclusion criteria: 
• 
The subject is a male or female aged 4 to <18 years at the time of study treatment administration. 
• 
The subject has a CD diagnosis based on accepted clinical, endoscopic, histological and/or radiologic 
criteria at least 6 months before the screening visit. 
• 
The subject has complex perianal fistula refractory to at least one of the following treatments: 
immunosuppressants, or biologics (anti-TNFs, anti-integrin, or anti-IL 12/23). Fistula(s) refractory to 
therapy are defined in this study as follows: 
– 
Immunosuppressants: Inadequate response after 3 months, based on clinical assessment, or more 
treatment with azathioprine, 6 mercaptopurine or methotrexate. 
– 
Biologics: Inadequate response after 14 weeks (16 weeks for anti-IL 12/23), based on clinical 
assessment, or more standard treatment for induction and maintenance. 
• 
A complex perianal fistula(s) that meets one or more of the following criteria, modified from the American 
Gastroenterological Association (AGA) technical review: 
– 
High intersphincteric, transsphincteric, extrasphincteric, or suprasphincteric as assessed by MRI.  
– 
Presence of 2 or 3 external openings (tracts) as assessed by clinical examination. 
– 
Associated fluid (abscess) collections as determined by MRI. 
This study requires that the subject has complex perianal fistulas with a maximum of 2 internal 
openings and a maximum of 3 external openings, based on clinical assessment. Darvadstrocel treatment 
is targeted for fistulas that connect between internal and external openings. A central reading of a 
locally performed pelvic MRI will be performed to confirm the location of the fistula and potential 
associated perianal abscess(es). Fistulas must have been draining for at least 6 weeks before the 
screening visit. Subjects with actively draining simple subcutaneous fistulas, at the time of the screening 
visit are not allowed in this study. 
• 
The subject has inactive or mildly active luminal CD defined by meeting all of the following criteria: 
a) Colonoscopy, flexible sigmoidoscopy or rectoscopy performed either at screening or within the 6 
months before screening, demonstrating no rectal ulcers larger than 0.5 cm. A subject who has 
documented rectal ulcers larger than 0.5 cm within the 6 months before screening but has undergone 
subsequent treatment may be eligible if there are no rectal ulcers larger than 0.5 cm on a sigmoidoscopy 
or rectoscopy performed after treatment or at the time of screening. 
b) The improvement of or no worsening in stool frequency, sustained for 1 week or more, in the interval 
between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion criteria 5(a) and the 
screening visit. 
c) No initiation or intensification of treatment with corticosteroids, immunosuppressants, or monoclonal 
antibody dose regimen between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion 
criteria 5(a) and the screening visit. 
Main Criteria for Exclusion: 
The list below includes the main criteria for exclusion. Refer to the main body of the protocol for the complete 
list of exclusion criteria: 
• 
The subject has received any investigational compound within 12 weeks/84 days before screening. 
• 
The subject has received darvadstrocel/eASC in a previous clinical study or as a therapeutic agent.  
• 
The subject has a history of hypersensitivity or allergies to darvadstrocel or any of its excipients. 
• 
The subject weighs <10 kg at screening. 
• 
The subject has concomitant perianal fistula(s) with only internal or external opening(s). 
• 
The subject has concomitant internal fistula(s) such as ileo-vesical, rectovaginal or ileo-colonic fistula(s). 
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• 
The subject has an abscess >2 cm, unless resolved in the preparation procedure. 
• 
The subject has rectal and/or anal stenosis, and/or active proctitis, which would restrict the surgical 
procedure. 
• 
The subject underwent surgery for the fistula other than drainage or seton placement. 
• 
The subject has diverting stomas.  
• 
The subject has ongoing systemic corticosteroid treatment or has been treated with systemic corticosteroids 
within 4 weeks before screening. 
• 
The subject requires new treatment with immunosuppressants/anti-TNF agents during the screening period. 
• 
The subject requires surgery in the perianal region for reasons other than fistulas at the time of screening or 
foreseen either during the study and/or during the 24 weeks after treatment administration. 
• 
The subject has known allergies or hypersensitivity to antibiotics (including benzylpenicillin/streptomycin, 
gentamicin [used in the darvadstrocel manufacturing process]) human serum albumin; Dulbecco Modified 
Eagle’s Medium, material of bovine origin, or local anesthetics. 
Main Criteria for Evaluation and Analyses: 
The primary endpoint for this study is the proportion of subjects who achieve combined remission at Week 24, 
where combined remission is defined as: 
a) The closure of all treated external openings that were draining at baseline despite gentle finger 
compression 
AND 
b) Absence of abscess(es) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by 
central MRI assessment. 
Secondary endpoints for this study are: proportion of subjects who achieve clinical remission at Weeks 24 and 
52, time to clinical remission up to Week 52, proportion of subjects with clinical response at Week 24 and 52, 
time to clinical response up to Week 52, and proportion of subjects with relapse by Week 52 in subjects with 
combined remission at Week 24. 
The following safety endpoints will be assessed: adverse events (AEs), serious adverse events (SAEs), adverse 
events of special interest (AESIs), vital signs, and laboratory parameters (biochemistry, hematology, and 
urinalysis). 
The exploratory endpoints are: change from baseline to Week 24 and Week 52 in subscores for discharge and 
pain domains from the Perianal Disease Activity Index (PDAI) scores, change from baseline to Week 24 and 
Week 52 in Pediatric Crohn’s Disease Activity Index (PCDAI) scores, and change from baseline in perianal pain 
visual analog scale (VAS). 
Statistical Considerations: 
Analysis Sets: 
• 
Intent-to-treat (ITT) analysis set: Includes all subjects who undergo the fistula preparation procedure 
regardless of being treated or not. 
• 
 
 
• 
Safety analysis set: Includes all subjects who received the study treatment. 
Interim Analysis: 
An interim analysis (IA) will be conducted to evaluate the safety and efficacy of davardstrocel in enrolled 
subjects. The details of the IA will be described in the statistical analysis plan (SAP). 
Efficacy Analyses:  
Analysis of the primary endpoint will be performed on the ITT 
, with the ITT as the primary 
analysis set. Analysis of the secondary endpoints and the exploratory endpoints will be performed on the ITT 
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analysis set. 
Primary Efficacy Analysis: 
For the primary efficacy analysis, the estimates of the combined remission rate at Week 24 will be provided 
along with the 95% Clopper-Pearson confidence intervals (CI). Counts will be presented along with the 
proportions for the primary endpoint.  
 
 
 
 
 
 
Secondary Endpoint Analysis: 
The binary secondary endpoints are: proportion of subjects who achieve clinical remission at Weeks 24 and 52, 
proportion of subjects with clinical response at Week 24 and 52, and proportion of subjects with relapse by 
Week 52 in subjects with combined remission at Week 24. 
 
 
The time-to-event secondary endpoints (ie, time to clinical remission up to Week 52, and time to clinical 
response up to Week 52). will be analyzed 
 
 
 Subjects without documented event of interest by the end of study (Week 52), will 
be censored at the date of last assessment. 
 
Exploratory Endpoint Analysis: 
The continuous endpoints of change from baseline at each time point (Week 24, Week 52) in PDAI, PCDAI and 
in VAS will be summarized using descriptive statistics at each time point.  
  
 
 
  
Safety Analysis: 
Counts and percentages for subjects with treatment emergent AEs, SAEs (defined as any SAE, regardless of 
relationship to study drug), and AESIs (immunogenicity/alloimmune reactions, hypersensitivity, ectopic tissue 
formation, medication errors, tumorigenicity, and transmission of infectious agents) will be summarized 
descriptively by System Organ Class and Preferred Term using Medical Dictionary for Regulatory Activities 
terminology. 
 Change from baseline 
in vital signs will also be summarized. 
The final analysis will be performed after the data base lock when all subjects have completed the Week 52 visit. 
Further details on all of the above analyses will be provided in the statistical analysis plan. 
 
 
 
  
 
 
 
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3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities  
The sponsor will perform all study-related activities with the exception of those identified in the 
study-related responsibilities template. The vendors identified in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor. 
3.2 
Principal Investigator/Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate 
in the study. Selection criteria for this investigator will include significant knowledge of the 
study protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required 
to review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study. 
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3.3 
List of Abbreviations 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CTR 
Clinical Trials Regulations 
eCRF 
electronic case report form 
EDC 
electronic data capture 
CD 
Crohn’s disease 
COVID-19 
coronavirus disease 2019 
DSMB 
data and safety monitoring board 
eASC 
expanded adipose-derived mesenchymal stem cells 
EMA 
European Medicines Agency 
ESR 
erythrocyte sedimentation rate 
EU 
European Union 
FCA 
fistula clinical assessment 
GCP 
Good Clinical Practice 
hCG 
human chorionic gonadotropin 
IA 
interim analysis 
ICH 
International Conference for Harmonisation 
IEC 
independent ethics committee 
IL 
interleukin 
IRB 
institutional review board 
ITT 
intent-to-treat 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
PCDAI 
Pediatric Crohn's Disease Activity Index 
PDAI 
Perianal Disease Activity Index 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SSR 
special situation report 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WOCBP 
women of childbearing potential 
 
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4.0 
INTRODUCTION 
4.1 
Disease Background 
A perianal fistula is an abnormal connection or passageway that develops between the rectum, ie, 
the end of the large intestine that stores feces, and the skin. The presence of a fistula results in 
abnormal discharge of feces through a skin opening other than the anus. Perianal fistula, 
sometimes called a fistula-in-ano, may be due to noninflammatory causes such as congenital 
abnormalities of the anal crypts and glands or be acquired following trauma, surgery, 
malignancy, or radiation therapy. Perianal fistula may also be the result of a chronic, inflamed 
condition such as a manifestation of perianal Crohn's disease (CD) or an infection in the anal 
glands (cryptoglandular fistulas). 
The incidence of CD in children is increasing worldwide, with an estimate of 2.5 to 11.3 per 
100,000 (Ruemmele et al. 2014); similarly, the incidence rate quantiles of pediatric CD in 
European countries were estimated to be 1.2 to 13.9 per 100,000 (Benchimol et al. 2011). 
Perianal fistulas are a common feature in patients with CD. The cumulative incidence of perianal 
fistula in patients with CD is estimated to range from 23% to 38% in population-based studies 
(Marzo et al. 2015). The risk of perianal fistula correlates with the duration after diagnosis of 
CD, with an estimated risk of 15% at 5 years, 22% at 10 years, and 26% at 20 years (Schwartz et 
al. 2002; Tozer et al. 2011; Zhao et al. 2019). With limited pediatric data, the incidence of 
perianal fistula in pediatric patients with CD has been estimated to be between 13.6% to 62% 
(Keljo et al. 2009). In contrast to adult patients, childhood CD is associated with more aggressive 
perianal fistula development with fistula occurrence in 20% to 31% of children within 5 to 7 
years after diagnosis of CD (Adler et al. 2017; Kugathasan et al. 2003; Vernier-Massouille et al. 
2008). In one large cohort of pediatric CD, the age of diagnosis for perianal fistulas occurred 
mainly after 12 years (Herman et al. 2017). Based on a national population-based study, there are 
estimated to be more than 10,000 children with perianal fistula due to CD in the United States 
(Kappelman et al. 2013), however, there is no population-based study estimating the burden of 
pediatric fistulizing CD in Europe. 
Based on the Parks classification (Parks et al. 1976), perianal fistulas can also be classified into 
2 main categories; simple and complex: 
• Simple perianal fistulas are anatomically low (superficial, low intersphincteric or low 
transsphincteric), have a single external opening, and are not associated with perianal 
abscess, connection to the vagina or bladder, or anal stenosis.  
• A complex perianal fistula is anatomically high (high intersphincteric or high 
transsphincteric or extrasphincteric or suprasphincteric origin of the fistula tract), may have 
multiple external openings, may be associated with the presence of pain or fluctuation to 
suggest a perianal abscess, may be associated with the presence of a rectovaginal fistula, may 
be associated with the presence of an anorectal stricture, and may be associated with the 
presence of active rectal disease at endoscopy. 
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This classification has greater clinical relevance: simple perianal fistulas respond better to 
treatment whereas complex ones have lower cure rates with medical treatment and an aggressive 
surgical procedure will often lead to incontinence. 
Perianal fistulas in CD are highly complex to treat and usually take a multidisciplinary approach, 
combining pharmacological treatment of the disease with surgery of the fistula to achieve fistula 
healing. The aim of therapy is to alleviate symptoms and treat complications of the disease in 
order to improve the patients’ quality of life. Aggressive treatments such as immunomodulators 
and biologics have aimed to modify the natural course of CD (Lichtenstein et al. 2009). Current 
treatment options mostly focus on surgical closure of the fistula, while maintaining continence 
and resolving the acute ongoing inflammatory process. As pediatric perianal fistulas of any 
origin are rare, treatment for pediatric patients with CD and fistulizing CD usually follows the 
same course as in adult patients (Forsdick et al. 2019).  
Current standard of care for patients with complex perianal fistula consists of pharmacologic 
management with antibiotics (metronidazole or ciprofloxacin) as a first step alongside biologic 
anti-tumor necrosis factor (TNF) agents such as infliximab, although the efficacy of antibiotics 
alone has been doubted due to lack of firm evidence (Crandall et al. 2009; de Zoeten et al. 2013). 
Glucocorticoids have potent anti-inflammatory activity and are often used in the management of 
CD, but have no demonstrated efficacy in treating fistulas (Nielsen et al. 2009). 
5-aminosalicylate have no conclusive benefits to treatment of CD or fistulizing CD (Farrell and 
Peppercorn 2013; Nielsen et al. 2009). 
Immunosuppressants such as azathioprine, are commonly used as second line therapy, but again 
there are no randomized clinical studies assessing the efficacy of this treatment on perianal 
fistula in subjects with CD. Data on efficacy has been derived from post-hoc analyses of 
randomized clinical studies in which immunosuppressants were used for treatment of active 
luminal disease. A meta-analysis of results with immunosuppressants showed efficacy in terms 
of achieving response (closure or reduction in drainage), but no data assessing the recommended 
end point of remission of fistulizing disease could be analyzed (Pearson et al. 1995). 
Several anti-TNF monoclonal antibody treatments have been approved to treat patients with CD. 
To date, only the monoclonal antibody infliximab has demonstrated efficacy for the treatment of 
perianal fistula in patients with CD in an randomized clinical study (Sands et al. 2004). The 
study showed that 69% of patients responded at week 14 and of these 36% were in remission at 
week 54 (25% of the overall randomized population), making this therapy the most effective 
medical treatment in complex perianal fistulas. However, despite these results, a large number of 
patients continue to suffer from disease activity and high relapsing rates (Roumeguere et al. 
2011), whereas only a small percentage of them have complete fistula healing (Alessandroni et 
al. 2011; Bourikas and Koutroubakis 2010). A major disadvantage of anti-TNF therapies is the 
risk for a variety of major adverse events (AEs) such as serious infections, serious infusion 
reactions, hepatitis B virus reactivation, and congestive heart failure. In addition, neutralizing 
antibodies to the monoclonal antibodies can develop and limit or eliminate effectiveness for 
long-term use. To minimize the development of antibody formation, other immunomodulators 
like azathioprine, mercaptopurine, cyclosporine or methotrexate, and corticosteroids are 
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frequently used concomitantly with anti-TNF therapy and adds to the patient's risk of 
experiencing a serious adverse event (SAE). 
Surgical treatment of complex perianal disease aims to control sepsis through abscess drainage 
and intervention in the fistulous tracts, including placement of noncutting setons (van der Hagen 
et al. 2005). Fistulectomy or fistulotomy are now rarely indicated in complex perianal fistulas in 
view of the high rate of incontinence associated with the procedure. In severe cases with high 
fistulas, endorectal flaps are useful. In patients with severe refractory disease, diverting 
colostomy or ileostomy or even proctectomy might be necessary. Other procedures such as those 
involving fibrin glues have been shown to be useful, but only in small uncontrolled series 
In conclusion, although a rare condition, there is a serious unmet medical need for the treatment 
of complex perianal fistulas that can reduce the requirement for debilitating surgery that can 
require a stoma or result in full or partial incontinence in both the adult and pediatric population. 
4.2 
Rationale for the Proposed Study 
Allogeneic expanded adipose-derived mesenchymal stem cells (eASCs) are a promising new 
approach for the treatment of complex perianal fistulas because of their anti-inflammatory and 
immunomodulatory potential. Darvadstrocel is a suspension of eASCs extracted from adipose 
tissue. Darvadstrocel has demonstrated local regenerative, immunomodulatory and 
anti-inflammatory properties resulting in the reduction of inflammation, which allows fistulas to 
heal through homeostatic mechanisms.  
Treatment of pediatric fistulizing CD usually follows the same course as in adult patients. There 
are no known or reported differences in the pathophysiology of perianal fistulas in patients with 
CD between the pediatric and adult populations that may affect the efficacy or safety of 
darvadstrocel or the development of the product in the pediatric population (Abcarian 2011; 
Hadzhiev and Murdjeva 2010; Sandborn et al. 2003). The major difference between the 
2 populations is both the lower incidence of the underlying disease in pediatric patients and the 
lower probability of developing a complex perianal fistula.  
The ultimate therapeutic goal in perianal CD is a complete and sustained closure of the fistulas 
without development of abscesses and thereby avoiding the need for surgical interventions and 
improving the patients’ quality of life. In a high number of patients, complete closure cannot be 
achieved despite medical treatment (including infliximab) and surgery in accordance with 
clinical practice. 
The darvadstrocel clinical development program includes 2 completed studies (a phase 1/2 study 
[Cx601-0101] and a phase 3 study [Cx601-0302]). The available evidence based on the efficacy 
and safety data from these clinical studies suggest that darvadstrocel was well-tolerated and 
effective in closing the fistula, an effect that was sustained up to Week 52 in subjects with 
complex perianal fistula refractory to at least one of existing treatments (ie, antibiotics, 
immunosuppressants, or TNF antagonists). 
The safety of darvadstrocel was initially investigated in a phase 1/2 study (Cx601-0101) where 
subjects received a single perilesional administration of darvadstrocel (20 million cells) and were 
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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 AE profile 
following single dose and repeat dose was comparable. The generation of donor-specific 
antibodies after a second administration of darvadstrocel was assessed. No obvious detrimental 
effect of donor-specific antibodies on the efficacy and safety of darvadstrocel was observed (de 
la Portilla et al. 2013). 
The efficacy and safety of darvadstrocel was assessed in the pivotal phase 3, randomized, 
double-blind, placebo-controlled Cx601-0302 study for the treatment of complex perianal 
fistula(s) in subjects with CD. Darvadstrocel was administered as a single perilesional dose of 
120 million cells and it demonstrated efficacy across a range of endpoints. 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 
120 million cells of darvadstrocel was well-tolerated in the study population (Panes et al. 2016). 
These data were submitted to the European Medicines Agency (EMA) in March 2016 to support 
Marketing Approval Authorisation to demonstrate that darvadstrocel treatment effectively 
induces fistula closure, an effect that is maintained for up to 52 weeks, in adult subjects with 
complex perianal fistulas that have shown an inadequate response to at least one conventional or 
biologic therapy. Marketing approval was granted by the EMA on 23 March 2018. Marketing 
Authorisation Applications have also been granted for Switzerland (30 December 2018) and 
Israel (22 January 2019). 
Darvadstrocel is being investigated and developed in the adult population for the treatment of 
complex perianal fistula in patients with CD in 2 completed studies (a global phase 3 study 
[Cx601-0303] and a Japan phase 3 study [Darvadstrocel-3002]) intended to support future 
marketing applications in other regions. A total of 552 subjects had received double-blind 
treatment in the Cx601-0303 study. Results from the final analysis of Study Cx601-0303 showed 
that, although darvadstrocel demonstrated a safety profile consistent with that observed in other 
darvadstrocel studies, Study Cx601-0303 did not achieve statistical significance for its primary 
and key secondary efficacy endpoints. There were no new safety signals identified in the study. 
In the completed Study Darvadstrocel-3002, in which 22 Japanese subjects received open-label 
darvadstrocel treatment, darvadstrocel showed benefits in terms of combined remission at 
Week 24, and the benefits of darvadstrocel appear to be maintained from Week 24 to Week 156. 
Safety data up to Week 156 showed that darvadstrocel was well tolerated and no major safety 
concerns were identified in the 156-week study. The current study (Darvadstrocel-3004) will be 
the first to investigate the efficacy and safety of darvadstrocel in pediatric subjects with complex 
perianal fistulas due to CD.  
In conclusion, darvadstrocel has been demonstrated to be well-tolerated and efficacious in the 
treatment of complex perianal fistula in adults and can avoid some of the disadvantages 
associated with surgery and systemic treatments and may have the potential to address the unmet 
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medical need of pediatric patients with complex perianal fistulas due to CD. In addition, taking 
into consideration that there is no pathophysiological difference between perianal fistula in CD 
in the adult and pediatric population, and that the mechanism of action of darvadstrocel does not 
have any known age-dependent characteristics, the aim is to extrapolate efficacy data, while 
collecting safety data in the pediatric population.  
4.3 
Benefit-Risk Profile  
Because darvadstrocel has not yet been formally evaluated in pediatric subjects, the final benefit-
risk assessment for the treatment of complex perianal fistula in pediatric patients with CD has 
not been determined. 
In clinical studies conducted to date, darvadstrocel has been well tolerated in adult patients with 
complex perianal fistula(s) and CD up to 120 million cells per administration. In nonclinical 
studies conducted to date, no dose-dependent safety concern or toxicity, including in juvenile 
animals, has been identified and no ectopic tumor formation or hypersensitivity concerns have 
emerged. Overall, the data available present 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 for darvadstrocel include proctalgia, anal abscess, and anal fistula.  
Although a rare condition, as with adults there is a significant unmet medical need for treatment 
of complex perianal fistulas in the pediatric population with CD. Taking into consideration that 
there is no pathophysiological difference between perianal fistula in CD in the adult and pediatric 
populations and that the mechanism of action of darvadstrocel does not have any known 
age-dependent characteristics, based on the clinical data in adults, combined with nonclinical 
data, the benefit-risk balance in pediatric subjects is expected to be positive. 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
To evaluate the efficacy of darvadstrocel in combined remission at Week 24 for the treatment of 
complex perianal fistula in pediatric subjects with CD aged 4 to <18 years. 
5.1.2 
Secondary Objectives 
To evaluate the efficacy of darvadstrocel in clinical remission at Week 24 and Week 52 for the 
treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years. 
To evaluate the efficacy of darvadstrocel in clinical response at Week 24 and Week 52 for the 
treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years. 
To evaluate the efficacy of darvadstrocel in time to clinical remission up to Week 52 for the 
treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.  
To evaluate the efficacy of darvadstrocel in time to clinical response up to Week 52 for the 
treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years. 
To evaluate the efficacy of darvadstrocel on relapse by Week 52 in pediatric subjects with 
combined remission at Week 24. 
To evaluate the safety of darvadstrocel for the treatment of complex perianal fistula in pediatric 
subjects with CD aged 4 to <18 years over 52 weeks. 
5.1.3 
Exploratory Objective 
To evaluate the impact of darvadstrocel on perianal disease activity. 
5.2 
Endpoints 
5.2.1 
Primary Endpoint 
Efficacy Endpoint 
Proportion of subjects who achieve combined remission at Week 24, where combined remission 
is defined as: 
a) The closure of all treated external openings that were draining at baseline despite gentle 
finger compression 
AND 
b) Absence of abscess(es) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) 
confirmed by central MRI assessment.  
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5.2.2 
Secondary Endpoints 
Efficacy at Week 24 
1. Proportion of subjects who achieve clinical remission at Week 24, where clinical remission 
is defined as the closure of all treated external openings that were draining at baseline 
despite gentle finger compression. 
2. Proportion of subjects with clinical response at Week 24, where clinical response is defined 
as closure of at least 50% of all treated external openings that were draining at baseline 
despite gentle finger compression. 
Efficacy at Week 52 
1. Proportion of subjects who achieve clinical remission at Week 52, where clinical remission 
is defined as the closure of all treated external openings that were draining at baseline 
despite gentle finger compression. 
2. Time to clinical remission (weeks) assessed at each clinic visit up to Week 52. This is 
defined as the time from treatment start to first visit at which clinical remission is observed 
before Week 52; where clinical remission is said to occur if a clinical assessment shows 
closure of all treated external openings that were draining at baseline despite gentle finger 
compression.  
3. Proportion of subjects with clinical response at Week 52, where clinical response is defined 
as closure of at least 50% of all treated external openings that were draining at baseline 
despite gentle finger compression.  
4. Time to clinical response (weeks) assessed at each clinic visit up to Week 52. This is defined 
as the time from treatment start to first visit at which clinical response is observed before 
Week 52; where clinical response is said to occur if a clinical assessment shows closure of at 
least 50% of all treated external openings that were draining at baseline despite gentle finger 
compression.  
5. Proportion of subjects with relapse by Week 52, in subjects with combined remission at 
Week 24, where relapse is defined as reopening of any of the treated fistula(s) external 
openings with active drainage as clinically assessed in subjects who were in combined 
remission at Week 24. 
Safety Endpoints 
1. AEs. 
2. SAEs. 
3. AEs of special interest (AESIs). 
4. Vital signs. 
5. Laboratory parameters (biochemistry, hematology, and urinalysis). 
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5.2.3 
Exploratory Endpoints 
1. Change from baseline in subscale scores for discharge and pain domains from the Perianal 
Disease Activity Index (PDAI) scores. 
2. Change from baseline in PCDAI scores. 
3. Change from baseline in perianal pain visual analog scale (VAS). 
6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a phase 3, open-label, multicenter study to evaluate the efficacy and safety of 
darvadstrocel (also known as Cx601) in the treatment of complex perianal fistula refractory to 
therapy in pediatric subjects with CD aged 4 to <18 years. 
At least 20 subjects are planned to be enrolled to receive a single dose of darvadstrocel (24 mL 
cell suspension containing 120 million cells of allogeneic eASCs). The study will permit 
continuation of previous treatment of luminal CD in an add-on study design (ie, anti-TNF 
therapy, immunosuppressants, etc.): subjects receiving any ongoing concomitant medical 
treatment for CD at stable doses (stable dose is considered either the same dose or same 
weight-based dose adjusted for weight) at the time of the screening visit, will be allowed to 
continue treatment throughout the study.  
The study consists of a screening period (within a minimum of 4 and a maximum of 5 weeks 
before the preparation visit), preparation visit (within a minimum of 2 and a maximum of 
3 weeks before treatment), treatment visit (day of study drug administration), and a follow-up 
period (for approximately 52 weeks after study drug administration). 
After a successful screening period to determine eligibility, subjects will attend a preparation 
visit before receiving a single dose of darvadstrocel at Visit 0. At least 2 to 3 weeks before the 
treatment administration day, the investigator will perform a preparatory surgery (under 
anesthesia) comprising exploration of fistula anatomy, topography, assessment for potential 
associated complications, and fistula curettage. The location of the internal openings should be 
identified using only an injection of a sodium chloride 9 ng/mL (0.9%) solution through the 
external openings until it exits through the internal openings. In case of an abscess, incision and 
drainage will be performed, and setons should be placed, if appropriate, in accordance with 
routine surgical procedures. Mandatory antibiotic coverage for all subjects will be administered 
for at least 7 days following the fistula curettage (ciprofloxacin and/or metronidazole are 
recommended unless there is documented previous intolerance or contraindication to both). 
Subjects who fulfill the eligibility criteria at the preparation visit will be enrolled into the study. 
Before scheduling darvadstrocel administration, the surgeon must ensure that no abscesses are 
present. Seton(s) placed will be removed on the day of darvadstrocel administration. Appropriate 
training for preparation and darvadstrocel administration will be implemented to standardize the 
procedures between study sites. 
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b Study drug administration at Visit 0 must be performed within a minimum of 2 weeks and a maximum of 3 weeks 
of the preparation visit. Once the date for treatment administration surgery is set it cannot be moved due to the 
darvadstrocel preparation procedure and the limited window of manufacturing, shipment and study drug viability. 
6.2 
Justification for Study Design, Dose, and Endpoints 
Study Design 
This study is planned to evaluate the efficacy and safety of darvadstrocel in the treatment of 
complex perianal fistulas in pediatric patients with CD. 
The efficacy of darvadstrocel has been demonstrated in the pivotal phase 3, randomized, 
placebo-controlled study (Cx601-0302) in adult subjects with complex perianal fistula due to CD 
refractory to at least one standard of care therapy (ie, antibiotics, immunosuppressants, or 
biologics) (Panes et al. 2016).  
Since the frequency of complex perianal fistulizing CD in pediatric patients is very low 
compared to adults and the pathophysiology of complex perianal fistula due to CD is similar 
among adults and pediatric patients, at least 20 subjects are planned to be enrolled into this study 
in an open-label, uncontrolled design. 
Dose Selection 
The planned dose to be administered to pediatric patients is 120 million cells of darvadstrocel by 
local perilesional injection. This dose is approved in Europe for use in adults and is the same 
dose that was used in the completed pivotal global phase 3 study (Cx601-0303) in adult subjects 
with complex perianal fistula in CD and the completed Japan phase 3 study 
(Darvadstrocel-3002). Any adjustments to dose made by the surgeon (eg, due to unavoidable 
resistance at the injection site) will be recorded in the electronic case report form (eCRF). 
The rationale for this dose is based on 1) nonclinical data and clinical data, including results 
from the completed phase 3 Cx601-0302 study which showed that this dose was efficacious and 
safe (Panes et al. 2016); 2) data showing that characteristics of complex perianal fistulas in 
pediatric patients are similar to those of adults; 3) published literature and feedback received 
from pediatric gastroenterologists and surgeons, and scientific advice from the EMA and the 
Pharmaceuticals and Medical Devices Agency, Japan. 
Clinical Data 
In the earlier phase 1/2 study for Cx601 (Study Cx601-0101) and in the clinical studies 
conducted during the development of an autologous product, Cx401, the pivotal phase 3 study 
(Cx401/FATT1) and the phase 1 study (Study Cx401[fCFIS]), the dose for a single fistula tract 
(out of up to 3 tracts) was 20 million cells followed by the administration of a further 40 million 
cells after 8 to 12 weeks in cases where the fistula was not completely closed. 
To administer the 40 million cell dose, the fistula had to undergo another full curettage and 
debridement whereby any partially closed fistula was re-opened returning the fistula to baseline 
conditions. These studies supported that this dose was safe and efficacious for a single fistula 
tract but might not be adequate to treat a complex perianal fistula with multiple tracts, leading to 
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the proposal to use 120 million cells as a dose likely to be efficacious and safe for a complex 
fistula with multiple tracts. 
In the pivotal phase 3 study (Cx601-0302), a dose of 120 million eASCs was shown to be 
efficacious and safe in the treatment of complex perianal fistula (Panes et al. 2016). In the 
completed phase 3 studies (Cx601-0303 and Darvadstrocel-3002) of complex perianal fistula in 
adults using the dose of 120 million cells, no new safety signals have emerged. 
Published Clinical Data 
A number of clinical studies in adults have demonstrated the efficacy and safety of stem cell 
therapy. The stem cell doses for fistulizing CD are variable and range from 3 million to 
120 million cells per dose (Ciccocioppo and Corazza 2016).  
Similarity in the Characteristics of Complex Perianal Fistula in Adult and Pediatric Populations 
Pediatric patients with CD who develop perianal fistulas are typically adolescents, with the 
median age in reported studies ranging from 11.5 to 14.6 years (Adler et al. 2017; Herman et al. 
2017; Keljo et al. 2009). Data show complex perianal fistula in pediatric patients and adults have 
similar characteristics on MRI, including similar fistula tract number, similar dominant fistula 
length, and similar anatomic location (Shenoy-Bhangle et al. 2014). The similarity of pediatric 
and adult complex perianal fistulas data support use of the same dose of 120 million cells. 
Nonclinical Studies 
Nonclinical safety studies conducted support the use of darvadstrocel in pediatric patients. 
Biodistribution, toxicity, and tumorigenicity studies in immunocompromised animals confirm 
darvadstrocel has a low order of toxicity. The safety of eASC was investigated in toxicology 
studies in animals with doses up to 2.5 million cells/animal (perianal maximum feasible dose) 
and 10 million cells/animal (subcutaneous) with follow-up out to 6 months post administration. 
Biodistribution studies in juvenile athymic rats (at least 5 weeks of age) confirmed a short 
persistence of eASC (maximal persistence of <14 days via intravaginal and <91 days via 
intravenous or perianal/intrarectal routes), and local distribution of eASCs and repeat-dose 
toxicity studies in rodents of eASCs up to 2.5 million cells (perianal maximum feasible dose) 
were well-tolerated. The nonclinical program did not reveal any sign of tumor promotion, tumor 
formation, or ectopic tissue formation. In vivo tumorigenicity assays in nude mice administered 
by subcutaneous injection (10 million cells/mouse) identified no evidence of tumor formation in 
studies with darvadstrocel. In vitro assays showed that tumorigenicity risk of the product is low.  
Summary 
The available evidence to date from clinical studies as well as limited postmarketing experience 
demonstrates that darvadstrocel is well tolerated up to 120 million cells per administration in 
adults. No dose-dependent safety concern or toxicity has been identified and no ectopic tumor 
formation concerns have emerged. Overall, the data available presents a positive benefit-risk 
profile for darvadstrocel. 
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Endpoints 
The purpose of this study is to demonstrate comparability in safety and efficacy of darvadstrocel 
between adult and pediatric subjects, therefore the same primary endpoint and similar secondary 
endpoints will be used in this study as those used in the phase 3 studies (Cx601-0302, 
Cx601-0303, and Darvadstrocel-3002). 
Given the similar pathophysiology, clinical course, and treatment of complex perianal fistulas 
related to CD and that the mechanism of action of darvadstrocel does not have any known 
age-dependent characteristics, partial extrapolation of efficacy from the adult population is 
appropriate and will be further supported by using very similar inclusion and exclusion criteria 
and the same combined remission primary endpoint as used in the adult studies. 
6.3 
Definition of Study Start  
The study start date is the date when the first subject signs the informed consent/pediatric assent 
form.  
6.4 
Definition of End of Study 
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 darvadstrocel, such that the benefit-
risk is no longer acceptable for subjects participating in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 
• Subject enrollment is unsatisfactory. 
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 Site(s) 
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of a 
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study site, a study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable study sites during the course of 
termination or study suspension. 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed before study drug administration.  
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject, or when applicable, the subject’s legally acceptable representative, signs and 
dates a written, informed consent/pediatric assent form and any required privacy 
authorization before the initiation of any study procedures. 
3. The subject is male or female aged 4 to <18 years at the time of study treatment 
administration. 
4. The subject has a CD diagnosis based on accepted clinical, endoscopic, histological and/or 
radiologic criteria at least 6 months before the screening visit. 
5. The subject has complex perianal fistula refractory to at least one of the following treatments: 
immunosuppressants or biologics (anti-TNFs, anti-integrin, anti-interleukin [IL] 12/23). 
Fistula(s) refractory to therapy are defined in this study as follows: 
• Immunosuppressants: Inadequate response after 3 months, based on clinical assessment, 
or more treatment with azathioprine, 6-mercaptopurine or methotrexate. 
• Biologics: Inadequate response after 14 weeks (16 weeks for anti-IL 12/23), based on 
clinical assessment, or more standard treatment for induction and maintenance. 
6. A complex perianal fistula(s) that meets one or more of the following criteria, modified from 
the American Gastroenterological Association (AGA) technical review (Sandborn et al. 
2003): 
• High intersphincteric, transsphincteric, extrasphincteric, or suprasphincteric as assessed 
by MRI.  
• Presence of 2 or 3 external openings (tracts) as assessed by clinical examination. 
• Associated fluid (abscess) collections as determined by MRI. 
This study requires that the subject has complex perianal fistulas with a maximum of 
2 internal openings and a maximum of 3 external openings, based on clinical assessment. 
Darvadstrocel treatment is targeted for fistulas that connect between internal and external 
openings. A central reading of a locally performed pelvic MRI will be performed to 
confirm the location of the fistula and potential associated perianal abscess(es). Fistulas 
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must have been draining for at least 6 weeks before the screening visit. Subjects with 
actively draining simple subcutaneous fistulas, at the time of the screening visit, are not 
allowed in this study. 
7. The subject has inactive or mildly active luminal CD defined by meeting all of the following 
criteria: 
a) Colonoscopy, flexible sigmoidoscopy or rectoscopy performed either at screening or 
within the 6 months before screening, demonstrating no rectal ulcers larger than 0.5 cm. A 
subject who has documented rectal ulcers larger than 0.5 cm within the 6 months before 
screening but has undergone subsequent treatment may be eligible if there are no rectal 
ulcers larger than 0.5 cm on a sigmoidoscopy or rectoscopy performed after treatment or 
at the time of screening. 
b) The improvement of, or no worsening in stool frequency, sustained for 1 week or more, in 
the interval between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion 
criteria 7(a) and the screening visit. 
c) No initiation or intensification of treatment with corticosteroids, immunosuppressants, or 
monoclonal antibody dose regimen between the colonoscopy, flexible sigmoidoscopy or 
rectoscopy in inclusion criteria 7(a) and the screening visit.  
8. 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 the time of signing of informed consent/pediatric assent 
throughout the duration of the study. The female partner of a male subject should also be 
advised to use a highly effective method of contraception. 
9. A female subject of childbearing potential* who is sexually active with a nonsterilized male 
partner agrees to use a highly effective method of contraception* from the time of signing of 
informed consent/pediatric assent throughout the duration of the study. 
*Definitions and highly effective methods of contraception are defined in Section 9.1.10 and 
reporting responsibilities are defined in Section 9.1.11. 
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 received any investigational compound within 12 weeks/84 days before 
screening. 
2. The subject has received darvadstrocel/eASC in a previous clinical study or as a therapeutic 
agent.  
3. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling), or may consent under duress. 
4. The subject weighs <10 kg at screening. 
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5. The subject has, in the judgment of the investigator, clinically significant abnormal 
hematological parameters of hemoglobin, hematocrit, or erythrocytes at screening. 
6. The subject has a history of hypersensitivity or allergies to darvadstrocel or any of its 
excipients. 
7. The subject takes or is required to take excluded medications listed in Table 7. a. 
8. The subject has concomitant perianal fistula(s) with only internal or external opening(s). 
9. The subject has concomitant internal fistula(s) such as ileo-vesical, rectovaginal or 
ileo-colonic fistula(s). 
10. The subject has an abscess >2 cm, unless resolved in the preparation procedure. 
11. The subject has rectal and/or anal stenosis, and/or active proctitis, which would restrict the 
surgical procedure. 
12. The subject underwent surgery for the fistula other than drainage or seton placement. 
13. The subject has diverting stomas.  
14. The subject has ongoing systemic corticosteroid treatment or has been treated with systemic 
corticosteroids within 4 weeks before screening. 
15. The subject requires new treatment with immunosuppressants/anti-TNF agents during the 
screening period. 
16. 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. 
• 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. 
17. The subject requires surgery in the perianal region for reasons other than fistulas at the time 
of screening or foreseen either during the study and/or during the 24 weeks after treatment 
administration. 
18. The subject has a serum creatinine ≥2 × upper limit of normal (ULN). 
19. The subject has hepatic impairment defined by both of the following laboratory ranges: 
a) Total bilirubin ≥1.5 × ULN. 
b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥2 × ULN. 
20. The subject has known history of abuse of alcohol or other addictive substances in the 
6 months before screening. 
21. The subject has malignant tumor or a prior history of any malignant tumor, including any 
type of fistula carcinoma. 
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22. The subject has current or recent (within 3 months before the screening) history of abnormal, 
severe, progressive, uncontrolled hepatic, hematologic, gastrointestinal (except CD), 
endocrine, pulmonary, cardiac, neurological, psychiatric, or cerebral disease. 
23. The subject has either congenital or acquired immunodeficiencies, including subjects known 
to be HIV carriers or subjects with, in the judgment of the investigator, are suspected to have 
monogenic inflammatory bowel disease. 
24. The subject has a known clinically significant 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, or positive serology for hepatitis C 
virus (IgG) and quantitative hepatitis C virus polymerase chain reaction at the screening visit. 
25. The subject has known allergies or hypersensitivity to antibiotics (including 
benzylpenicillin/streptomycin, gentamicin [used in the darvadstrocel manufacturing process]) 
human serum albumin; Dulbecco Modified Eagle’s Medium, material of bovine origin, or 
local anesthetics. 
26. The subject has previously received a bone marrow transplant. 
27. The subject has a contraindication to MRI scan, or other planned study procedures. 
28. The subject has a contraindication to the anesthetic procedure. 
29. The subject had major surgery or severe trauma within 6 months before the screening visit. 
30. A female subject who is pregnant or is lactating or intending to become pregnant before 
participating in this study or during the study; or intending to donate ova during such time 
period. 
31. If male, the subject intends to donate sperm during the course of this study.  
32. The subject does not wish to or cannot comply with study procedures. 
7.3 
Excluded Medications and Treatments  
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator. 
The details of allowed/excluded medications or treatments during the period from start of 
screening period to study product administration, and from the study product administration to 
Week 52 are summarized in Table 7. a. There are no restrictions for medications and treatments 
after Week 52. If there are any questionable medications or treatments, the sponsor or its 
designee should be contacted. 
If a subject received any excluded medications or treatments, the subject may continue to 
participate in the study if the risk is considered acceptable by the investigator and sponsor. 
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Table 7. a 
Allowed/Excluded Medications and Treatments 
Medications/ 
Treatment 
From Start of Screening 
Period to Darvadstrocel 
Administration 
From Darvadstrocel 
Administration to 
Week 52 
Justification 
Any investigational 
drugs or other local 
investigational 
treatments for the 
perianal region 
NOT Allowed 
Should be excluded from 
84 days before start of 
screening period. 
NOT Allowed 
These 
medications/treatments 
are excluded in 
consideration of any 
influences on the efficacy 
and safety evaluation of 
darvadstrocel. 
Antibiotics 
(including but not 
limited to ciprofloxacin 
and/or metronidazole) 
Allowed 
Continuous use of 
antibiotics must be up to a 
maximum of 4 weeks. 
Allowed 
Continuous use of 
antibiotics must be up to a 
maximum of 4 weeks, 
including the period 
before the study product 
administration. 
These medications are 
allowed with the 
restriction following the 
dosing period because 
long-term use beyond 
clinical standards may 
jeopardize the safety of 
the subject. 
5-aminosalicylic acid 
Allowed 
Allowed 
A stable dose should be 
given after the study 
product administration. 
Only dose reduction from 
the initial dose will be 
allowed. 
These medications are 
allowed with the 
restriction to avoid any 
influences on the efficacy 
and safety evaluation of 
darvadstrocel. 
Topical steroid 
(nonrectal) 
Inhalatory steroids 
Allowed 
Allowed 
These medications are 
allowed because they 
have less effect on the 
efficacy and safety 
evaluation of 
darvadstrocel. 
Immunosuppressants 
(eg, azathioprine, 
6-mercaptoprine, 
methotrexate, 
tacrolimus) 
Allowed 
Continuous use of 
immunosuppressants is 
allowed if it has been used 
at stable dose for more than 
3 months before start of 
screening period. 
Allowed 
A stable dose should be 
given after the study 
product administration. 
Dose reduction or 
discontinuation of 
immunosuppressants will 
be allowed only if adverse 
reactions associated with 
immunosuppressants are 
observed. 
These medications are 
allowed with the 
restriction to avoid any 
influences on the efficacy 
and safety evaluation of 
darvadstrocel. 
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Table 7. a 
Allowed/Excluded Medications and Treatments 
Medications/ 
Treatment 
From Start of Screening 
Period to Darvadstrocel 
Administration 
From Darvadstrocel 
Administration to 
Week 52 
Justification 
Biologics 
(anti-TNF, anti-integrin, 
anti-IL-12/23) 
Allowed 
Continuous use of biologics 
is allowed if complex 
perianal fistulas showed no 
response despite at least 
14-week treatment 
(16 weeks for anti-IL-
12/23) before start of 
screening period, OR 
complex perianal fistulas 
recurred after achieving 
closure of fistulas. 
Allowed 
A stable dose should be 
given after the study 
product administration. 
These medications are 
allowed with the 
restriction to avoid any 
influences on the efficacy 
and safety evaluation of 
darvadstrocel. 
Janus kinase (JAK) 
inhibitors 
Allowed 
Continuous use of JAK 
inhibitors is allowed if the 
complex perianal fistula(s) 
showed no response despite 
at least 16-week treatment. 
Allowed 
A stable dose should be 
given after the study 
product administration. 
These medications are 
allowed with the 
restriction to avoid any 
influences on the efficacy 
and safety evaluation of 
darvadstrocel. 
Systematic steroids 
Rectal steroids 
Allowed 
These medications should 
be tapered and discontinued 
at least 4 weeks before 
study product 
administration. 
NOT Allowed 
These medications are 
allowed as a rescue 
therapy only when CD 
worsens. 
These medications are 
excluded in consideration 
of any influences on the 
efficacy and safety 
evaluation of 
darvadstrocel. Use for a 
rescue therapy is allowed 
in consideration of the 
safety of subjects. 
Enteral nutrition/ 
exclusive enteral 
nutrition 
Allowed 
No new treatment with total 
enteral nutrition therapy 
will be allowed. 
Allowed 
Stable therapy allowed. 
This treatment can be 
used as a rescue therapy 
only when CD worsens, 
see Section 7.4. 
This therapy is allowed 
because it has less effect 
on the efficacy and safety 
evaluation of 
darvadstrocel. 
Parenteral nutrition 
NOT Allowed 
NOT Allowed 
These treatments can be 
used as a rescue therapy 
only when CD worsens, 
see Section 7.4. 
These treatments are 
excluded in consideration 
of any influences on the 
efficacy and safety 
evaluation of 
darvadstrocel. Use for a 
rescue therapy is allowed 
in consideration of the 
safety of subjects. 
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Table 7. a 
Allowed/Excluded Medications and Treatments 
Medications/ 
Treatment 
From Start of Screening 
Period to Darvadstrocel 
Administration 
From Darvadstrocel 
Administration to 
Week 52 
Justification 
Cytapheresis 
NOT Allowed 
NOT Allowed 
These medications are 
excluded in consideration 
of any influences on the 
efficacy and safety 
evaluation of 
darvadstrocel. 
Oral anticoagulants 
NOT Allowed 
If an anticoagulant has been 
used before screening 
period and required 
continuous use, it should be 
switched to appropriate 
dose of low molecular 
weight heparin. 
NOT Allowed 
For 2 weeks after study 
product administration 
These medications are 
restricted in consideration 
of the safety risk of 
possible bleeding 
during/following the 
preparation surgery and 
study product 
administration. 
Anesthesia/sedation 
during MRI 
NOT Allowed 
 
NOT Allowed 
 
This therapy is not 
allowed in consideration 
of the safety risk 
associated with 
anesthesia. 
NSAIDS 
Allowed 
Allowed 
These medications are 
allowed because they 
have less effect on the 
efficacy and safety 
evaluation of 
darvadstrocel. 
CD: Crohn’s disease; IL: interleukin; MRI: magnetic resonance imaging; NSAID: nonsteroidal anti-inflammatory 
drug; TNF: tumor necrosis factor. 
For medications dosed using weight-based dosing: if a subject gains significant weight during the study, the 
investigator is permitted to adjust the dose to maintain a stable weight-based dose to account for the subject’s 
weight gain. 
7.4 
Rescue Therapy 
The need for rescue therapy for complex perianal fistula will be determined, for a safety concern, 
at the discretion and clinical judgment of the site investigator when the condition of complex 
perianal fistula deteriorates and requires further treatment immediately. The criteria for rescue 
medication or interventions are applicable from the time it occurs until Week 52. Examples of 
subjects that fulfill the need for rescue treatment include (but are not limited to): 
• Subject requires add-on treatment for complex perianal fistula with a new 
immunosuppressant, biologic, or Janus kinase inhibitor, or requires higher doses compared to 
the baseline therapy documented at screening. 
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• Subjects starting any other investigational drug for complex perianal fistula or any other local 
investigational treatment in the perianal region while participating in the study. 
• Any new surgical procedure required in the perianal region for the fistula(s) or draining of 
abscess(es) or established abscess(es).  
• Prolonged use of systemic antibiotics (more than 2 weeks) to treat perianal disease after the 
treatment administration visit. 
Rescue therapy, including medications and/or surgical procedures, for complex perianal fistula 
should follow the local or institutional guidance for standard of care. Subjects requiring any of 
these rescue medications or interventions for complex perianal fistula during the study will be 
considered a treatment failure but will not be withdrawn from the study and will attend further 
visits for safety follow up until Week 52 if the risk is considered acceptable by the investigator. 
7.5 
Criteria for Withdrawal of a Subject 
The primary reason for withdrawal of the subject from the study or study drug should be 
recorded in the eCRF using the following categories.  
1. AE. The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling 
to continue because of the AE. 
2. 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.  
3. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (eg, withdrawal due 
to an AE should not be recorded in the “voluntary withdrawal” category. Similarly, lack of 
efficacy should not be recorded in the “voluntary withdrawal” category). 
4. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study. 
5. Death. 
6. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
For screen failure subjects, refer to Section 9.1.12. 
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7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study withdrawal criteria described in Section 7.5. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. Should a subject’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all 
procedures scheduled for the early termination visit. Discontinued or withdrawn subjects will not 
be replaced. 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
This section contains information regarding all medications and materials provided directly by 
the sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material. 
8.1 
Study Drug and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study drug refers to all or any of the drugs defined below. 
8.1.1.1 
Darvadstrocel 
Study sites will be supplied by the sponsor with the following medication for local perilesional 
injection around the internal opening(s) and into the tissue walls along the fistula tract(s): 
• Darvadstrocel (code name: Cx601) will be supplied as a white-to-yellowish suspension for 
local perilesional injection, provided in 4 × 6 mL type I glass vials (suspension of 5 million 
eASCs per mL [30 million cells per vial and 120 million cells per dose] of Dulbecco 
Modified Eagle’s Medium with human serum albumin). The disposable vials are packaged in 
a carton box with its corresponding 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 packaging material comprises: 
• Immediate package: type I glass sterile vials, each of 9 mL volume capacity (filled up to 
6 mL each) with chlorobutyl sterile rubber stopper and aluminum seal (not in contact with 
the product). 
• Labels of white polyethylene printed in black ink by thermal transfer printer. 
• 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. 
Refer to preparation and administration instructions in the pharmacy manual.  
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Additional reference information and administration instructions can be found in the 
investigational medicinal product handling instructions and surgery procedure manual. 
8.1.1.2 
Study drug 
The drug being administered in this study is darvadstrocel. 
8.1.1.3 
Sponsor-Supplied Drug 
Darvadstrocel will be supplied by the sponsor. Details about the study medication are provided 
in Table 8. a. 
Table 8. a 
Study Medication 
Drug Name (Identification in the Protocol) 
Darvadstrocel 
Product Class 
Stem cell therapies 
Designation 
IMP  
Marketing Authorization 
Yes (centralized): Alofisel 
Used Within Marketing Authorization 
No 
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; IMP: investigational medicinal 
product. 
8.1.2 
Storage 
Study drug must be kept in an appropriate, limited-access, secure place until it is used or ready 
for destruction. Study drug must be stored under the conditions specified on the label and remain 
in the original container until dispensed. A daily temperature log of the drug storage area must be 
maintained every working day. 
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Darvadstrocel will be shipped under temperature-controlled conditions, using appropriate 
transport for biological samples. Shipping material is also duly labelled and has an attached 
package content list and instructions for use. 
Specific instructions will be provided within a separate study manual. The study medication must 
be stored under the storage conditions specified in the manual. 
8.1.3 
Dose and Regimen 
Darvadstrocel will be administered via perilesional injection as a single dose at Day 0/Visit 0 
(see Appendix A). The study drug will be administered by the investigator at the study site. 
A single dose of darvadstrocel (120 million cells of eASCs) is supplied in 4 vials. Each vial 
contains 30 million cells in 6 mL of suspension. The full content of the 4 vials must be 
administered for the treatment of up to 2 internal openings and/or up to 3 external openings. 
Details on the procedure for study product administration will be specified in the surgical 
procedure manual. 
All subjects will receive the same dose, however if the surgeon is unable to inject the full dose 
(eg, due to unavoidable resistance at the injection site), a reduced dose (<120 million cells 
[<24 mL]) will be administered and recorded as a protocol deviation. The adjusted dose (mL) 
will be recorded in the eCRF and the subject will be able to continue in the study. 
Before administration of the study drug, appropriate training will be implemented at each study 
site. Only personnel who completed the training can administer the study product. 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
the investigator/surgeon, 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 Pharmacovigilance on a paper SSR form. AEs 
associated with an overdose will be documented on AE CRF(s) according to Section 10.0. 
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 treatment according to the study schedule. The enrollment number will be 
entered onto the eCRF. 
Subjects will be assigned to receive the next available medication ID number allocated to each 
study site. The tear-off portion of the medication label will be affixed to the dispensing log. The 
medication ID Number will be entered onto the eCRF. 
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8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug accountability will be performed at the site. The investigator or designee will maintain 
adequate records of the receipt of study drug shipment to the site. All used and unsed vials of 
study drug must be recorded and tracked. 
All used darvadstrocel vials will be stored at the site until the local monitor has performed the 
corresponding documented reconciliation and drug accountability. Any dosage deviation should 
be clearly noted in site source documentation. The corresponding destruction will be documented 
as per local procedures and regulations (eg, destruction certificate issued and filed in the 
corresponding study files). 
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance 
with the protocol and is dosed only to subjects enrolled in the study. To document appropriate 
use of sponsor-supplied drug, the investigator or designee must maintain records of all 
sponsor-supplied drug delivery to the site, administration to subject, and vial destruction. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and faxing per instructions provided on the form. If there are any discrepancies between the 
packing list versus the actual product received, Takeda must be contacted to resolve the issue. 
The packing list should be filed in the investigator’s essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dosed during his or her entire participation in the study. Proper drug accountability 
includes, but is not limited to: 
• Continuously monitoring expiration dates.  
• Verifying that the log is completed for the drug lot/medication ID/job number/other 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 dosing errors or discrepancies are discovered, the sponsor must be notified immediately. 
The investigator or designee must record all sponsor-supplied drugs on a sponsor-approved drug 
accountability log. The following information will be recorded at a minimum: protocol number 
and title, name of investigator, site identifier and number, description of sponsor-supplied drugs, 
expiry date, and date and amount dosed including initials, seal, or signature of the person 
dispensing the drug. The log should include all required information as a separate entry for each 
subject to whom sponsor-supplied drug is dosed.  
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 available for destruction. The investigator or designee will retain a copy of the 
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documentation regarding sponsor-supplied drug accountability, return, and/or destruction, and 
originals will be sent to the sponsor or designee. 
8.4 
Continued Access to Study Drug After the End of the Study 
No aftercare is planned for this study. The study drug will not be available upon completion of 
the subject’s participation in the study. The subject should be returned to the care of a physician 
and standard therapies as required. 
9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. 
The schedule of study procedures is located in Appendix A. 
9.1.1 
Informed Consent/Pediatric Assent Procedure 
The requirements of the informed consent/pediatric assent are described in Section 15.2. 
Informed consent/pediatric assent must be obtained before the subject entering into the study, 
and before any protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent/pediatric assent is obtained/explained; this subject number will be 
used throughout the study. 
9.1.2 
Demographics, Medical History, and Surgical History 
Demographic information to be obtained will include date of birth or age, sex, race as described 
by the subject, height, weight, and smoking status of the subject at screening.  
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing of 
informed consent/pediatric assent. Ongoing conditions are considered concurrent medical 
conditions (see Section 9.1.8). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 2 years before signing of informed 
consent/pediatric assent. 
Surgical history will be obtained to document any significant procedures performed before the 
signing of informed consent. In particular, prior surgical procedures related to the fistula will be 
recorded on the specific eCRF. 
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9.1.3 
Physical Examination Procedure 
A baseline physical examination (defined as the assessment before the study drug administration) 
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 
examination prior to study drug administration. 
9.1.4 
Weight, Height and Body Mass Index 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. 
The body mass index (BMI) is calculated using metric units with the formula provided below: 
Height is recorded in centimeters without decimal places. Weight is collected in kilograms (kg) 
with 1 decimal place. BMI should be derived as: 
Metric: 
BMI = weight (kg)/height (m)2 
Note that although height is reported in centimeters, the formula uses meters for height; meters 
can be determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.6 kg/m2 
The values should be reported to 1 decimal place by rounding. Thus, in the above example BMI 
would be reported as 25.6 kg/m2.  
9.1.5 
Vital Sign Procedure 
Vital signs will include body temperature (oral measurement), blood pressure (systolic and 
diastolic, resting more than 5 minutes), and heart rate (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 Efficacy Measurements 
9.1.6.1 
Fistula Clinical Assessment 
Primary efficacy assessments will be based on clinical evaluation of fistula(s) in terms of 
drainage at the external opening(s) after gentle finger compression, anal pain, suspicion of 
perianal abscess (fistula identification). The fistula(s) must have been draining for at least 
6 weeks before screening. The clinical assessment will consist of a physical examination of the 
fistula(s) by an investigator to evaluate the presence of drainage spontaneously or after gentle 
finger compression through the external openings. The tracts and external openings must be 
clearly identified in the eCRF in order to ensure the same tracts are assessed during the study 
period. 
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9.1.6.2 
Pelvic MRI 
A pelvic MRI scan will be performed locally at baseline (screening visit), Week 24, and early 
termination visit before Week 24 to assess for fistula characteristics, fistula location and the 
presence or absence of abscess(es) >2 cm (in at least 2 dimensions). A quality copy will be sent 
to the central imaging laboratory for reading as detailed in the specific MRI manual. 
At screening, central MRI results reporting fistula characteristics, fistula location and 
abscess(es), if any will be communicated to the investigator and the surgeon before the 
preparation visit. The baseline MRI (at screening) can be obtained within a minimum of 4 and a 
maximum of 5 weeks before the preparation visit before the preparation visit to determine 
eligibility. 
At Week 24 or early termination (if applicable), copies of the MRIs performed locally will be 
sent to the central imaging laboratory for central MRI reading. MRI assessments at Week 24 will 
include evaluation of presence of any abscess(es) directly related to the treated fistula tracts, and 
any new tracts that might appear. 
All MRI scans, including MRI scans available from initial treatment, will be assessed centrally 
by the MRI central reader. The MRI central reader will report fistula characteristics, fistula 
location, and measurements of any abscess(es) >2 cm (in at least 2 dimensions).  
Refer to the specific MRI manual for further details. 
9.1.7 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the sponsor. At each study visit, subjects will be asked whether they have taken 
any medication other than the study drug (used from signing of informed consent/pediatric assent 
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. 
9.1.8 
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent/pediatric assent. This includes clinically significant 
laboratory or physical examination abnormalities noted at screening examination, according the 
judgment of the investigator. The condition (ie, diagnosis) should be described. 
9.1.9 
Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. The 
maximum volume of blood at any single study visit is approximately 7.5 mL, and the 
approximate total volume of blood for the entire study duration is 30 mL (see Appendix B). 
Details of these procedures and required safety monitoring will be provided in the laboratory 
manual. The laboratory manual describes procedures for specimen handling. 
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Blood samples for central laboratory tests will be collected at the timepoints specified in 
Appendix A. Table 9. alists the tests that will be obtained for each laboratory specimen. 
Table 9. a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Hemoglobin 
Hematocrit 
MCV 
MCH 
MCHC 
Erythrocytes 
Leukocytes 
Lymphocytes 
Monocytes 
Neutrophils 
Eosinophils 
Basophils 
Platelet count 
ESR a 
ALT 
AST 
Albumin 
Total bilirubin 
CRP 
Creatinine 
Urea 
Creatine kinase 
Potassium 
Sodium 
Chloride 
pH 
Specific gravity 
Protein 
Sugar 
Ketones 
Bilirubin 
Urobilinogen 
Blood (Red blood cells) 
White blood cells 
Epithelial cells 
Nitrites/Leukocyte esterase 
Casts 
Crystals 
Bacteria 
Serum 
Urine 
Female subjects who are menstruating or aged ≥11 years, 
whichever is younger: 
Female subjects only who are menstruating 
or aged ≥11 years, whichever is younger: 
Beta hCG (for pregnancy) 
Beta hCG (for pregnancy) 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CRP: C-reactive protein; ESR: erythrocyte 
sedimentation rate; hCG: human chorionic gonadotropin; MCH; mean corpuscular hemoglobin; MCHC; mean 
corpuscular hemoglobin concentration; MCV: mean corpuscular volume. 
a ESR will be analyzed by a local laboratory. 
 
The central laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results. In unavoidable 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. 
For subjects with treatment-emergent ALT elevations ≥3 × ULN, see Appendix D for additional 
monitoring, evaluation, and follow-up recommendations. 
9.1.10 
Contraception and Pregnancy Avoidance Procedure 
9.1.10.1 
Male Subjects and Their Female Partners 
From signing of informed consent/pediatric assent, throughout the duration of the study, 
nonsterilized** male subjects who are sexually active with a female partner of childbearing 
potential* must use barrier contraception (eg, condom with or without spermicidal cream or 
jelly). In addition, they must be advised not to donate sperm during this period. Females of 
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childbearing potential who are partners of male subjects are also advised to use additional 
contraception as shown in the list containing highly effective contraception below. 
9.1.10.2 
Female Subjects and Their Male Partners 
From signing of informed consent/pediatric assent, throughout the duration of the study, female 
subjects of childbearing potential* who are sexually active with a nonsterilized male partner** 
must use a highly effective form of contraception (from the list below).  
In addition, they must be advised not to donate ova during this period. This will apply to female 
subjects of childbearing potential who have reached menarche prior to or during the study. 
9.1.10.3 
Definitions and Procedures for Contraception and Pregnancy Avoidance 
The following definitions apply for contraception and pregnancy avoidance procedures. 
* A woman is considered a woman of childbearing potential (WOCBP) as follows: fertile, 
following menarche or aged ≥11 years, whichever is younger. 
** Sterilized males should be at least 1-year post-bilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy. 
The following procedures apply for contraception and pregnancy avoidance. 
1. Highly effective methods of contraception are defined as “those, alone or in combination, 
that result in a low failure rate (ie, less than 1% failure rate per year when used consistently 
and correctly). In this study, where medications and devices containing hormones are 
included, the only acceptable methods of contraception are:  
– Non-hormonal methods:  
• Intrauterine device.  
• Bilateral tubal occlusion.  
• Vasectomized partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomized partner has received medical assessment of 
the surgical success). 
• True sexual abstinence, only if this is in line with the preferred and usual lifestyle 
of the subject. True abstinence is defined as refraining from heterosexual 
intercourse during the entire period of the study, from signing of informed 
consent/pediatric assent. 
– Hormonal methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method. 
• Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of study 
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drug OR combined with a barrier method (male condom, female condom or 
diaphragm) if for shorter duration until she has been on contraceptive for 
3 months; 
• Oral.  
• Intravaginal (eg, ring). 
• Transdermal.  
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before study drug administration OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has 
been on contraceptive for 3 months; 
• Oral.  
• Injectable. 
• Implantable. 
2. Unacceptable methods of contraception are: 
– Periodic 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. 
3. Subjects will be provided with information on highly effective methods of contraception as 
part of the subject informed consent/pediatric assent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, ova 
donation, and sperm donation during the course of the study. 
4. During the course of the study, regular urine human chorionic gonadotropin (hCG) 
pregnancy tests will be performed only for female subjects following menarche or aged 
≥11 years, whichever is younger. All subjects (male and female) will receive continued 
guidance with respect to the avoidance of pregnancy and sperm donation as part of the study 
procedures. Such guidance should include a reminder of the following: 
a) Contraceptive requirements of the study. 
b) Reasons for use of barrier methods (ie, condom) in males with pregnant partners. 
c) Assessment of subject compliance through questions such as 
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i. Have you used the contraception consistently and correctly since the last 
visit? 
ii. Have you forgotten to use contraception since the last visit?  
iii. Are your menses late (even in women with irregular or infrequent 
menstrual cycles a pregnancy test must be performed if the answer is 
“yes”) 
iv. Is there a chance you could be pregnant? 
5. In addition to a negative serum pregnancy test at screening, female subjects of childbearing 
potential must also have confirmed menses in the month before first dosing (no delayed 
menses), a negative urine hCG pregnancy test before receiving study medication and at the 
visits specified in Appendix A. 
9.1.10.4 
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?  
– 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? 
9.1.11 
Pregnancy 
Pregnant or breastfeeding women are excluded from study entry. If any subject is found to be 
pregnant during the study, the pregnancy should be reported immediately using a pregnancy 
notification form to the contact listed in Section 1.1. 
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. 
See Section 10.3.2 for details on reporting pregnancy. 
9.1.12 
Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent/pediatric assent. 
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If the subject is withdrawn during the screening period, the investigator should complete the 
eCRF. The primary reason for screen failure is recorded in the eCRF using the following 
categories: 
• AE. 
• Did not meet inclusion criteria or did meet exclusion criteria (specify reason). 
• Significant protocol deviation. 
• Lost to follow-up. 
• Voluntary withdrawal (specify reason). 
• Study termination. 
• Pregnancy. 
• Death. 
• Other (specify reason), including unavoidable circumstances such as the COVID-19 
pandemic. 
Subject identification numbers assigned to subjects who fail screening should not be reused. 
9.1.13 
Documentation of Study Entrance 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for treatment. 
If the subject is found to be not eligible for treatment, the investigator should record the primary 
reason for failure on the applicable eCRF. 
9.1.14 
Fistula Preparation 
Fistula preparation will consist of preparatory surgery (under anesthesia) comprising exploration 
of fistula anatomy, topography, assessment for potential associated complications, and vigorous 
curettage, with special emphasis on the internal opening(s). Before scheduling darvadstrocel 
administration, the surgeon must ensure that no abscesses are present. If there is an abscess 
present, incision and drainage must be performed in accordance with routine surgical procedures. 
Loose seton placement will be required for all subjects. Mandatory antibiotic coverage for all 
subjects will be administered for at least 7 days following the fistula curettage (ciprofloxacin 
and/or metronidazole are recommended unless there is documented previous intolerance or 
contraindication to both). 
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9.1.15 
Clinical Outcome Assessments 
9.1.15.1 
Clinician-Reported Outcomes 
PDAI 
The PDAI score (Appendix E) is a scoring system to evaluate the severity of perianal CD 
(Sandborn et al. 2003). 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. 
PCDAI 
The PCDAI score (Appendix F) was developed and validated as an evaluative multi-item index 
for disease activity of CD in multicenter studies among children and adolescents (Hyams et al. 
1991). The PCDAI score will be evaluated using the subject’s/parent’s or legal guardian’s diary 
entries and laboratory results collected during screening and then at every scheduled visit during 
the study as per Appendix A. 
ESR as part of the PCDAI assessment will be analyzed by a local laboratory. 
9.1.15.2 
Patient-Reported Outcomes 
Perianal Pain VAS 
Pain intensity, recorded using a daily VAS from 0-10 (Appendix G), while standing, sitting, and 
defecating will be recorded by the subjects at home for 2 weeks (14 days) before each visit (or, 
for the screening visit only, for 2 weeks [14 days] starting within 7 days after the screening visit) 
as specified in Appendix A. 
9.2 
Monitoring Subject Treatment Compliance 
The volume (mL) 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 visits.  
In acknowledgement of hospital, local, state or national government restrictions or other site 
related factors caused by unavoidable circumstances (eg, 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 sponsor 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 subjects and site personnel for subjects to continue. In 
evaluating such requests, the sponsor will give the highest priority to the safety and welfare of 
the subjects. For subjects that are impacted, any procedures not conducted per the original study 
plan will be documented in the study records. 
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When approval is given for a subject to miss an in-person study visit, a healthcare 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, the study site physician or other qualified site staff should also at minimum 
conduct the following assessments: AE collection and concomitant medication/procedure 
documentation and a remote evaluation of the fistula. Other study assessments may be collected 
remotely as is feasible and may involve audio or video recording. 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 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 screening, preparation, treatment administration, Week 24, and Week 52 must be done 
with the subject present at the investigative site. Alternative methods of data collection may be 
considered for visits at Weeks 6, 12, and 36 when it is not possible for the subject to attend the 
study site. Under such circumstances, a preferred alternative would be for a qualified medical 
professional delegated by the investigator and authorized to perform assessments for this study 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 
Screening Visit  
Subjects will be screened within a minimum of 4 weeks and a maximum of 5 weeks before the 
preparation visit. Subjects will be screened in accordance with predefined inclusion and 
exclusion criteria as described in Section 7.0. See Section 9.1.12 for procedures on documenting 
screening failures. 
Procedures to be completed at the screening visit include: 
• Informed consent/pediatric assent. 
• Inclusion/exclusion criteria check. 
• Demographics and medical history. 
• Weight, height, and BMI. 
• Physical examination covering all body systems. 
• Vital signs (body temperature, blood pressure, and heart rate).  
• Concomitant medications.  
• Concurrent medical conditions. 
• CD, fistula and treatment history. 
– 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; 
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preparatory surgery will be completed before darvadstrocel administration at the 
preparation visit. 
• Target fistula(s) information (new fistula or previously treated fistula). 
– Fistula clinical assessment (Appendix C): 
– Clinical characteristics, including age of onset, number of other fistulas, localization, 
and clock position. 
– The investigator must also complete the FCA eCRF for screening in addition to the anal 
clock form in Appendix C. 
• Screening clinical laboratory tests (refer to Section 9.1.9) 
– Hematology, serum biochemistry and urinalysis. 
• Serum pregnancy test for WOCBP. A female subject is considered a WOCBP following 
menarche or aged ≥11 years, whichever is younger. 
• Fistula MRI assessment: 
– Pelvic MRI performed locally.  
• PCDAI score. 
– ESR as part of the PCDAI assessment will be analyzed by a local laboratory. 
• PDAI subscale scores. 
• Perianal pain VAS. 
• Luminal disease activity involving the rectum. 
– A colonoscopy or rectoscopy will need to be performed at screening if the subject has not 
had one within the last 6 months of screening. 
• Assessment of AEs/SAEs, AESIs, and SSRs. 
9.3.2 
Potential Rescreening 
For any subject not meeting the eligibility criteria, or if there are unavoidable circumstances such 
as the COVID-19 pandemic, it may be possible to rescreen the subject if they later meet the 
criteria and based upon the sponsor’s approval. 
For subjects who require a rescreening, and upon the sponsor’s approval, the following 
procedures will need to be repeated and the preparation visit rescheduled based on protocol 
timelines: 
• Informed consent. 
• Inclusion/exclusion criteria check. 
• Physical examination.  
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• Weight, height, and BMI.  
• Vital signs. 
• Clinical laboratory tests (hematology, biochemistry, and urinalysis). 
• Serum pregnancy test for WOCBP. A female subject is considered a WOCBP following 
menarche or aged ≥ 11 years, whichever is younger. 
• Clinical assessment of perianal fistulas and CD (including the presence or absence of 
proctitis, localization, fistula draining status, and pattern of disease). 
– The investigator must complete the anal clock form in Appendix C in addition to the 
FCA eCRF for screening. 
• Pelvic MRI: The need to repeat the pelvic MRI scan at the rescreening visit will be 
determined on a case-by-case basis at the investigator’s discretion based on the duration 
between screening and rescreening and the subject's clinical condition.  
• PDAI subscale scores. 
• Perianal pain VAS. 
9.3.3 
Preparation Visit  
The preparation visit will take place within a minimum of 2 weeks and a maximum of 3 weeks 
before the treatment administration visit. Darvadstrocel will need to be preordered and, thus, this 
supply request at the preparatory visit will act as a trigger to start the manufacturing process of 
darvadstrocel for the subject. Subjects must fulfill the eligibility criteria at the preparation visit in 
order to be enrolled into the study. 
The surgeon is to receive the screening MRI to review results before the preparation visit. 
• Prior to fistula preparation: 
– Inclusion/exclusion criteria check, including review of central laboratory results and 
central MRI reading confirmation. 
– Weight, height, and BMI. 
– Physical examination covering all body systems. 
– Vital signs. 
– Review and record concomitant medications. 
– Review and record concurrent medical conditions. 
– Urine pregnancy test for WOCBP. A female subject is considered a WOCBP following 
menarche or aged ≥11 years, whichever is younger. 
• Fistula preparation consisting of examination under anesthesia (including FCA), seton 
placement, and curettage for ALL subjects by the surgeon according to the surgical 
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procedure manual (provided as a separate document). This must be done at least 2 weeks and 
a maximum of 3 weeks before the study treatment administration day. Administration of 
antibiotics is mandatory, and use should be in accordance with standard clinical care 
guidelines for perianal fistulas.  
– The FCA eCRF must be completed by the investigator.  
• Assessment of AEs/SAEs, AESIs, and SSRs. 
9.3.4 
Treatment Administration Visit (Week 0/Visit 0) 
The study treatment administration visit (Visit 0) will take place at a minimum of 2 weeks and a 
maximum of 3 weeks from the preparation visit. Once the date for treatment administration 
surgery is set, it cannot be moved due to the darvadstrocel preparation procedure and the limited 
window of manufacturing, shipment and study drug viability. 
• Before treatment administration: 
– Weight, height, and BMI. 
– Physical examination covering all body systems. 
– Vital signs. 
– Concomitant medications taken since last visit. 
– Concurrent medical conditions. 
– Urine pregnancy test for WOCBP. 
– Fistula clinical assessment in terms of drainage at the external opening(s) after gentle 
finger compression, anal pain, suspicion of perianal abscess (fistula identification). 
– The FCA eCRF must be completed by the investigator. If a new external opening is 
identified during the assessment, the FCA eCRF for new external openings should be 
completed. 
– PDAI subscale scores. 
– Perianal pain VAS. 
• Study treatment administration: 
– Darvadstrocel administration. To 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. 
– Number and location of fistula tracts treated. 
• Assessment of AEs/SAEs, AESIs, including AEs concerning surgical procedures and 
postsurgery complication status (including any CD-related surgery), and SSRs. 
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. 
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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 administration visit, the visit should be 
rescheduled within a minimum of 2 weeks and to a maximum of 3 weeks from the date of the 
original Visit 0. It is not necessary to repeat the preparation visit, the setons will be maintained 
until the rescheduled repeat administration visit and will be withdrawn just before darvadstrocel 
administration. All procedures required for repeat administration visit are to be repeated. 
9.3.5 
Follow-up Period 
Visits at Week 24 and Week 52 should be performed in person. Alternative methods of data 
collection may be considered for visits at Weeks 6, 12, and 36 when it is not possible for the 
subject to attend the study site (see Section 9.3.8). 
9.3.5.1 
Week 6/Visit 1 
• Weight, height, and BMI. 
• Physical examination covering all body systems. 
• Vital signs. 
• Concomitant medications taken since last visit. 
• Concurrent medical conditions. 
• Clinical laboratory tests (hematology, biochemistry, and urinalysis). 
• Urine pregnancy test for WOCBP. A female subject is considered a WOCBP following 
menarche or aged ≥11 years, whichever is younger. 
• Fistula clinical assessment in terms of drainage at the external opening(s) after gentle finger 
compression, anal pain, suspicion of perianal abscess (fistula identification). 
– The FCA eCRF must be completed by the investigator. If a new external opening is 
identified during the assessment, the FCA eCRF for new external openings should be 
completed. 
• PCDAI score. 
– ESR as part of the PCDAI assessment will be analyzed by a local laboratory. 
• PDAI subscale scores. 
• Perianal pain VAS. 
• Assessment of AEs/SAEs, AESIs, and SSRs. 
9.3.5.2 
Week 12/Visit 2 
• Weight, height, and BMI. 
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• Physical examination covering all body systems. 
• Vital signs. 
• Concomitant medications taken since last visit. 
• Concurrent medical conditions. 
• Urine pregnancy test for WOCBP. 
• Fistula clinical assessment in terms of drainage at the external opening(s) after gentle finger 
compression, anal pain, suspicion of perianal abscess (fistula identification). 
– The FCA eCRF must be completed by the investigator. If a new external opening is 
identified during the assessment, the FCA eCRF for new external openings should be 
completed. 
• Assessment of AEs/SAEs, AESIs, and SSRs. 
9.3.5.3 
Week 24/Visit 3 
• Weight, height, and BMI. 
• Physical examination covering all body systems. 
• Vital signs. 
• Concomitant medications taken since last visit. 
• Concurrent medical conditions. 
• Clinical laboratory tests (hematology, biochemistry, and urinalysis). 
• Urine pregnancy test for WOCBP. 
• Fistula clinical assessment in terms of drainage at the external opening(s) after gentle finger 
compression, anal pain, suspicion of perianal abscess (fistula identification). 
– The FCA eCRF must be completed by the investigator. If a new external opening is 
identified during the assessment, the FCA eCRF for new external openings should be 
completed. 
• Fistula MRI assessment: 
– Pelvic MRI performed locally. 
• Perianal pain VAS. 
• PCDAI score. 
– ESR as part of the PCDAI assessment will be analyzed by a local laboratory. 
• PDAI subscale scores. 
• Assessment of AEs/SAEs, AESIs, and SSRs. 
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9.3.5.4 
Week 36/Visit 4 
• Weight, height, and BMI. 
• Physical examination covering all body systems. 
• Vital signs. 
• Concomitant medications taken since last visit. 
• Concurrent medical conditions. 
• Urine pregnancy test for WOCBP. 
• Fistula clinical assessment in terms of drainage at the external opening(s) after gentle finger 
compression, anal pain, suspicion of perianal abscess (fistula identification). 
– The FCA eCRF must be completed by the investigator. If a new external opening is 
identified during the assessment, the FCA eCRF for new external openings should be 
completed. 
• Assessment of AEs/SAEs, AESIs, and SSRs. 
9.3.5.5 
Week 52/Visit 5 (End of Study Visit) 
• Weight, height, and BMI. 
• Physical examination covering all body systems. 
• Vital signs. 
• Concomitant medications taken since last visit. 
• Concurrent medical conditions. 
• Clinical laboratory tests (hematology, biochemistry, and urinalysis). 
• Urine pregnancy test for WOCBP. 
• Fistula clinical assessment in terms of drainage at the external opening(s) after gentle finger 
compression, anal pain, suspicion of perianal abscess (fistula identification). 
– The FCA eCRF must be completed by the investigator. If a new external opening is 
identified during the assessment, the FCA eCRF for new external openings should be 
completed. 
• Perianal pain VAS. 
• PCDAI score. 
– ESR as part of the PCDAI assessment will be analyzed by a local laboratory. 
• PDAI subscale scores. 
• Assessment of AEs/SAEs, AESIs, and SSRs. 
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9.3.6 
Early Termination 
The end of study visit will be performed at Week 52 or at the early termination visit. All efforts 
should be made to keep the subject 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: 
• Weight, height, and BMI. 
• Physical examination covering all body systems. 
• Vital signs. 
• Concomitant medications taken since last visit. 
• Concurrent medical conditions. 
• Clinical laboratory tests (hematology, biochemistry, and urinalysis). 
• Urine pregnancy test for WOCBP. 
• Fistula clinical assessment in terms of drainage at the external opening(s) after gentle finger 
compression, anal pain, suspicion of perianal abscess (fistula identification). 
– The FCA eCRF must be completed by the investigator. If a new external opening is 
identified during the assessment, the FCA eCRF for new external openings should be 
completed. 
• Fistula MRI assessment (only if the early termination visit takes place before the Week 24 
visit). 
– Pelvic MRI performed locally. 
• Perianal pain VAS. 
• PCDAI score. 
– ESR as part of the PCDAI assessment will be analyzed by a local laboratory. 
• PDAI subscale scores. 
• Assessment of AEs/SAEs, AESIs, and SSRs. 
For all subjects receiving study drug, the investigator must complete the end of study eCRF 
page. 
9.3.7 
Unscheduled Telephone Follow-up Calls 
Unscheduled telephone-calls are proposed for safety follow-up for any contact requested by the 
subject between scheduled visits. The following information needs to be recorded: 
• Unscheduled phone-call follow-up date and reason. 
• Concomitant medications and procedures. 
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• Concurrent medical conditions. 
• Remote evaluation of the fistula(s).  
– The items of the FCA form will be assessed by the investigator via telephone call.  
• Review of PDAI and PCDAI questionnaires since last visit by the investigator.  
• Assessment of AEs/SAEs, AESIs, and SSRs. 
9.3.8 
Remote Visit due to COVID-19 
The following assessments are to be performed if the subject cannot attend any interim visits 
(Weeks 6, 12, and 36) due to COVID-19 restrictions: 
• Date of remote visit. 
• Concomitant medications and procedures. 
• Concurrent medical conditions. 
• Remote evaluation of the fistula(s): The items in the FCA form will be assessed by the 
investigator via telephone call. 
• Review of PDAI and PCDAI questionnaires by the site investigator.  
• Clinical laboratory tests (hematology, biochemistry, urinalysis). Tests will be performed at a 
local laboratory if possible. 
• Urine pregnancy test for WOCBP: Test will be performed at a local laboratory if possible.  
• Assessment of AEs/SAEs, AESIs, 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 a drug 
whether or not it is considered related to the drug. 
10.1.2 
Additional Points to Consider for AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition (intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs). 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study drug or a concomitant medication. 
• Be considered unfavorable by the investigator for any reason. 
AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as an AE. 
For the purpose of this study, drainage of the treated fistula and abscesses will not be captured as 
an AE unless there is evidence suggesting a causal relationship between the study drug or the 
administration procedure. New fistula(s) identified during the course of the study, that are not 
treated and evaluated by the study drug, will be captured as an AE. 
Diagnoses vs signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values) or symptoms should NOT be recorded as additional 
AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as 
an AE(s). 
Laboratory values: 
• Changes in laboratory values are only considered to be AEs if they are judged to be clinically 
significant (ie, if some action or intervention is required or if the investigator judges the 
change to be beyond the range of normal physiologic fluctuation). A laboratory re-test and/or 
continued monitoring of an abnormal value or finding are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention. 
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• If abnormal laboratory values or the result of pathology for which there is an overall 
diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be reported 
appropriately as an AE. 
Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing of informed consent/pediatric assent) 
are considered concurrent medical conditions and should NOT be recorded as AEs. The first 
evaluations after signing of informed consent/pediatric assent (eg, laboratory tests, 
electrocardiogram, X-rays etc.) should NOT be recorded as AEs unless related to study 
procedures. However, if the subject experiences a worsening or complication of such a 
concurrent medical condition after informed consent/pediatric assent has been signed, the 
worsening or complication should be recorded appropriately as an AE. Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”). 
• If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) 
any occurrence of an episode should only be captured as an AE if the condition becomes 
more frequent, serious or severe in nature. Investigators should ensure that the AE term 
recorded captures the change in the condition from baseline (e.g. “worsening of…”). 
• If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as an AE if occurring to a 
greater extent to that which would be expected. Investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”). 
Worsening of AEs: 
• If the subject experiences a worsening or complication of an AE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that 
the AE term recorded captures the change in the condition (eg, “worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”). 
Changes in intensity of AEs: 
• If the subject experiences changes in intensity of an AE, the event should be captured once 
with the maximum intensity recorded. 
Preplanned procedures (surgeries or interventions): 
• Preplanned procedures (surgeries or therapies) that were scheduled before signing of 
informed consent/pediatric assent are not considered AEs. However, if a preplanned 
procedure is performed early (eg, as an emergency) due to a worsening of the pre-existing 
condition, the worsening of the condition should be recorded as an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
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Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy. 
Overdose: 
• Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested side 
effects will be considered AEs and will be recorded on the AE page of the eCRF. See 
Section 10.3.1 for reporting overdose to the Takeda Pharmacovigilance Department.  
10.1.3 
SAEs 
An SAE is defined as any untoward medical occurrence in a subject who has signed informed 
consent/pediatric assent to participate in a study that: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
• The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
10.1.4 
AEs of Special Interest  
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 in 
order to characterize and understand them and would be described in protocols and instructions 
provided for investigators as to how and when they should be reported to Takeda. 
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AESIs must be recorded as AEs in the eCRF.  
See Section 10.2.1.3 for information on AESI reporting and a list of known AESIs. 
10.1.5 
Special Situation Reports 
Special situation reports (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 that 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. 
10.1.6 
Intensity of AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual 
activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
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10.1.7 
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. 
10.1.8 
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.  
10.1.9 
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator. 
10.1.10 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. 
10.1.11 Frequency  
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous. 
10.1.12 Outcome 
• Recovered/Resolved – 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 
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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 AEs which are considered as 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 that the subject first signs informed 
consent/pediatric assent. Routine collection of AEs will continue until Visit 6 (Week 52) or the 
early termination visit.  
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. Subjects experiencing a 
serious AE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Nonserious AEs that occur before the first exposure to study drug, related or unrelated to the 
study procedure, need not to be followed-up for the purposes of the protocol. 
All subjects experiencing AEs after exposure to study drug, 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: 
1. Event term. 
2. Start and stop date. 
3. Frequency. 
4. Intensity. 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study drug.  
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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. 
10.2.1.3 
AESIs 
AESIs should 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 10.2.2, 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 of awareness. 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. 
AESI/abnormality criteria include:  
• Immunogenicity/alloimmune reactions. 
• Hypersensitivity. 
• Ectopic tissue formation.  
• Medication errors. 
• Tumorigenicity. 
• Transmission of infectious agents. 
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: 
SAEs should be reported via the SAE eCRF page in electronic data capture (EDC) (RAVE) 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 
• Causality assessment. 
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SAEs should be reported via the SAE eCRF page in electronic data capture (EDC) (RAVE), 
which is the preferred method of reporting SAEs. 
If access to EDC/RAVE is not feasible within 24 hours of awareness of the event, the paper SAE 
forms should be submitted via fax or email to the attention of the contact listed in Section 1.1. 
– 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 can 
be returned via e-mail within 1 business day. 
E-mail submission of SAE forms with a PDF attachment should only be used in the case where 
fax is not possible and EDC is not feasible within 24 hours of receiving the event.  
– In case of e-mail, site personnel need to confirm successful transmission by awaiting an 
acknowledgment of the receipt via email within 1 business day. 
If SAEs are reported via fax or by email, EDC/RAVE must be updated as soon as possible with 
the appropriate information. 
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
10.2.3 
Reporting of Abnormal Liver Function Tests  
For any subject with ALT ≥3 × ULN AND total bilirubin >2 × ULN OR INR >1.5 × ULN for 
which an alternative etiology has not been found, report the event as an SAE, contact the 
sponsor’s medical monitor within 24 hours immediately and follow the additional monitoring, 
10.3 
Follow-up of SAEs 
If information that was not available at the time of the initial report becomes available at a later 
date, the investigator should complete a follow-up SAE form or provide other written 
documentation. This form should be faxed or emailed immediately within 24 hours of receipt. 
Copies of any relevant data from the hospital notes (eg, laboratory tests, discharge summary, 
postmortem results) should be sent to the addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 
Collecting and Reporting of 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.  
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10.3.2 
Collecting and Reporting of Pregnancies 
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 in 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 Timeline to Sponsor (From 
Time of Awareness) 
SAE 
Complete eCRF page in EDC to Sponsor 
Pharmacovigilance. 
Use the paper SAE form only if EDC is 
not available.  
Within 24 hours  
AESI 
Complete AE eCRF for all AESIs. 
Submit the SAE form to Sponsor if AESI 
meets seriousness criteria in 
Section 10.2.2. 
Within 24 hours   
Pregnancy 
Complete and submit paper pregnancy 
form.  
Within 24 hours  
SSR  
Complete and submit paper SSR form.   
If the SSR is associated with an SAE, a 
separate SAE form must also be 
submitted to the sponsor.  
Within 7 calendar days 
SSR associated with SAE: report within 
24 hours of awareness 
AE: adverse event; AESI: adverse event of special interest; eCRF: electronic case report form; EDC: electronic 
data capture; SAE: serious adverse event; SSR: special situation report. 
 
Contacts for SAE, pregnancy, and SSR reporting can be found in Section 1.1. 
10.3.4 
Safety Reporting to Investigators, IRBs, IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, including the EMA, investigators and 
IRBs/the head of the study site or IECs, as applicable, in accordance with national regulations in 
the countries where the study is conducted. Relative to the first awareness of the event by/or 
further provision to the sponsor or sponsor’s designee, suspected unexpected serious adverse 
reactions will be submitted to the regulatory authorities as expedited report within 7 days for 
fatal and life-threatening events and 15 days for other serious events, unless otherwise required 
by national regulations. The sponsor will also prepare an expedited report for other safety issues 
where these might materially alter the current benefit-risk assessment of a study drug/sponsor 
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supplied drug or that would be sufficient to consider changes in the study drug/sponsor supplied 
drug administration or in the overall conduct of the study. The study site also will forward a copy 
of all expedited reports to his or her IRB or IEC in accordance with local regulations. 
11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data and safety monitoring board (DSMB), or clinical endpoint 
committee will be used in this study. 
A DSMB is not planned for this open-label study, given the safety data available from adult 
studies and the tolerability of darvadstrocel for the single administration. Takeda’s standards and 
processes, which include continuous review and evaluation of safety data reported from all 
participating sites through the conduct of the study, are appropriate for the ongoing monitoring 
of subject safety and data integrity. The decision to convene a DSMB could be made at any time 
during the conduct of 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 concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization Drug Dictionary. 
12.1 
eCRFs 
Completed eCRFs are required for each subject who signs an informed consent/pediatric assent. 
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English, if needed. Data are transcribed directly onto 
eCRFs from source records. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.  
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included.  
The principal investigator must review the eCRFs for completeness and accuracy and must 
e-sign the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
After the lock of the study database, any change of, modification of or addition to the data on the 
eCRFs should be made by the investigator with use of change and modification records of the 
eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign, or sign and seal, and date. 
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eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. 
The completed eCRFs are the sole property of the sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor.  
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent/pediatric assent forms, subject 
authorization forms regarding the use of personal health information (if separate from the 
informed consent/pediatric assent forms), electronic copy of eCRFs, including the audit trail, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities, 
the sponsor or its designees. Any source documentation printed on degradable thermal sensitive 
paper should be photocopied by the site and filed with the original in the subject’s chart to ensure 
long term legibility. Furthermore, International Conference 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 study site agreement between 
the investigator and sponsor. 
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
The study SAP will be prepared and finalized prior to database lock. The final analysis for this 
study will be performed after database lock, which will occur when all subjects have completed 
the Week 52 visit. 
13.1.1 
Analysis Sets 
The following analysis sets will be defined: 
• Intent-to-treat (ITT) analysis set: Includes all subjects who undergo the fistula preparation 
procedure regardless of being treated or not. 
 
 
 
• Safety analysis set: Includes all subjects who received the study treatment. 
The main population for the primary and secondary efficacy analysis will be the ITT analysis set. 
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. 
13.1.3 
Efficacy Analysis 
The analyses the primary and secondary endpoints will be performed on the ITT 
 
, with the ITT as the primary analysis set. 
13.1.3.1 
Primary Efficacy Analysis 
The primary efficacy endpoint will be summarized at Week 24. The proportion of subjects who 
achieve combined remission at Week 24 along with 95% 2-sided Clopper-Pearson CIs will be 
provided at Week 24. 
 
 
 
 
 
 
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13.1.3.2 
Secondary Efficacy Endpoints 
The proportion of subjects along with 2-sided 95% Clopper-Pearson CIs will be provided by visit 
for the following proportion-based efficacy endpoints: 
• Clinical remission at Weeks 24 and 52. 
• Clinical response at Weeks 24 and 52. 
• Relapse by Week 52 in subjects who achieve combined remission at Week 24. 
 
 
Time-to-event variables will be assessed 
 
  
Subjects without documented time-to-event of interest by the end of study (Week 52), will be 
censored at the date of last assessment. 
 
 
13.1.3.3 
 
 
 
 
 
13.1.4 
Safety Analysis 
Safety analysis will be performed on the safety analysis set.  
Counts and percentages for subjects with treatment emergent AEs, SAEs (defined as any SAE, 
regardless of relationship to study drug), and AESIs (immunogenicity/alloimmune reactions, 
hypersensitivity, ectopic tissue formation, medication errors, tumorigenicity, and transmission of 
infectious agents) will be summarized descriptively by System Organ Class and Preferred Term 
using MedDRA terminology. 
 
 Change from baseline in vital signs will also be summarized. 
Full details of the statistical analysis will be provided in the SAP. 
13.1.5 
Exploratory Analyses 
The following continuous endpoints will be summarized using descriptive statistics: changes in 
PDAI discharge and pain subscale scores, PCDAI score, and perianal pain VAS. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring 
Monitoring will be completed periodically during the study to ensure that all aspects of the 
protocol are followed. Source documents will be reviewed for verification of data recorded on 
the eCRFs. Source documents are defined as original documents, data, and records. The 
investigator and the study site guarantee access to source documents by the sponsor or its 
designee (clinical research organization) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent/pediatric assent 
documentation, documentation of subject authorization to use personal health information, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during monitoring and that sufficient time is devoted to the 
process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the 
sponsor or designee for any significant deviation from the protocol.  
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 the concerned European Union (EU) Member States of a serious breach 
of EU Clinical Trial Regulation (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 trial 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. 
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14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and study site guarantee access for quality assurance auditors to 
all study documents as described in Section 14.1. 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local and/or regional regulatory requirements and align his or 
her conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix H. The principles of the Declaration of Helsinki are addressed through the protocol 
and through appendices containing requirements for informed consent/pediatric assent and 
investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those Americas sites unwilling to provide names 
and titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal Wide Assurance Number or comparable number assigned by the Department of Health 
and Human Services (for studies including TDC Americas). 
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of 
the informed consent/pediatric assent form, and, if applicable, subject recruitment materials 
and/or advertisements and other documents required by all applicable laws and regulations, must 
be submitted to a central or local IRB or IEC for approval. The IRB’s or IEC’s written approval 
of the protocol and subject informed consent/pediatric assent must be obtained and submitted to 
the sponsor or designee before commencement of the study (ie, before shipment of the sponsor-
supplied drug or study specific screening activity). The IRB or IEC approval must refer to the 
study by exact protocol title, number, and version date; identify versions of other documents 
(eg, informed consent/pediatric assent form) reviewed; and state the approval date. The sponsor 
will ship drug once the sponsor has confirmed the adequacy of site regulatory documentation 
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and, when applicable, the sponsor has received permission from competent authority to begin the 
study.  
Study sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the informed 
consent/pediatric assent form, recruitment materials intended for viewing by subjects, local 
safety reporting requirements, reports and updates regarding the ongoing review of the study at 
intervals specified by the respective IRB or IEC, and submission of the investigator’s final status 
report to IRB or IEC. All IRB and IEC approvals and relevant documentation for these items 
must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent/pediatric assent as 
described in the Declaration of Helsinki and the ICH Guidelines for GCP and will be in 
accordance with all applicable laws and regulations. The informed consent/pediatric assent form, 
subject authorization form (if applicable), and subject information sheet (if applicable) describe 
the planned and permitted uses, transfers, and disclosures of the subject’s personal and personal 
health information for purposes of conducting the study. The informed consent/pediatric assent 
form and the subject information sheet (if applicable) further explain the nature of the study, its 
objectives, and potential risks and benefits, as well as the date informed consent/pediatric assent 
is given. The informed consent/pediatric assent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent/pediatric assent form and if applicable, the subject authorization form. The 
informed consent/pediatric assent form, subject authorization form (if applicable), and subject 
information sheet (if applicable) must be approved by both the IRB or IEC and the sponsor prior 
to use. 
The informed consent/pediatric assent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) must be written in a language fully comprehensible to 
the prospective subject. It is the responsibility of the investigator to explain the detailed elements 
of the informed consent/pediatric assent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) to the subject and to the subject’s parent or legal 
representative. Information should be given in both oral and written form whenever possible and 
in the manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of 
rendering adequate written informed consent/pediatric assent, 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. 
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If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent/pediatric assent form and subject 
authorization form (if applicable) must be signed and dated by the subject, or the subject’s 
legally acceptable representative, at the time of consent and before the subject entering into the 
study. The subject or the subject’s legally acceptable representative should be instructed to sign 
using their legal names, not nicknames, using blue or black ballpoint ink. The investigator must 
also sign and date the informed consent/pediatric assent form and subject authorization (if 
applicable) at the time of consent and before the subject entering into the study; however, the 
sponsor may allow a designee of the investigator to sign to the extent permitted by applicable 
law. 
Once signed, the original informed consent/pediatric assent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) will be stored in the investigator’s site 
file. The investigator must document the date the subject signs the informed consent/pediatric 
assent in the subject’s medical record. Copies of the signed informed consent/pediatric assent 
form, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) will be given to the subject. 
All revised informed consent/pediatric assent forms must be reviewed and signed by relevant 
subjects or the relevant subject’s legally acceptable representative in the same manner as the 
original informed consent/pediatric assent. The date the revised consent was obtained should be 
recorded in the subject’s medical record, and the subject will receive a copy of the revised 
informed consent/pediatric assent form. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit the monitor or the sponsor’s designee, representatives 
from any regulatory authority (eg, Food and Drug Administration, Medicines and Healthcare 
Products Regulatory Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s 
designated auditors, and the appropriate IRBs and IECs to review the subject’s original medical 
records (source data or documents), including, but not limited to, laboratory test result reports, 
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/pediatric assent process (see 
Section 15.2). 
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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). 
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 participants, this would be done through the investigator. 
Takeda applies certain measures to protect participants’ personal data and prevent data breaches, 
detailed in a separate document (Compliance with National Requirements on Data Protection). 
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. 
15.4.2 
Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, 
and recruiting status will be registered and available for public viewing.  
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.  
Any investigator who objects to the sponsor providing this information to callers must provide 
the sponsor with a written notice requesting that their information not be listed on the registry 
site.  
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly 
accessible websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 
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15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to 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 
Abcarian, H. 2011. Anorectal infection: abscess-fistula. Clin Colon Rectal Surg, 24(1), 14-21. 
Adler, J., Dong, S., Eder, S. J., Dombkowski, K. J. and ImproveCareNow Pediatric, I. B. D. L. 
H. S. 2017. Perianal Crohn disease in a large multicenter pediatriccollaborative. J Pediatr 
Gastroenterol Nutr, 64(5), e117-e24. 
Alessandroni, L., Kohn, A., Cosintino, R., Marrollo, M., Papi, C., Monterubbianesi, R., et al. 
2011. Local injection of infliximab in severe fistulating perianal Crohn's disease: an open 
uncontrolled study. Tech Coloproctol, 15(4), 407-12. 
Benchimol, E. I., Fortinsky, K. J., Gozdyra, P., Van den Heuvel, M., Van Limbergen, J. and 
Griffiths, A. M. 2011. Epidemiology of pediatric inflammatory bowel disease: a 
systematic review of international trends. Inflamm Bowel Dis, 17(1), 423-39. 
Bourikas, L. A. and Koutroubakis, I. E. 2010. Anti-TNF and fistulizing perianal Crohn's disease: 
use in clinical practice. Curr Drug Targets, 11(2), 187-97. 
Ciccocioppo, R. and Corazza, G. R. 2016. Mesenchymal stem cells for fistulising Crohn's 
disease. Lancet, 388(10051), 1251-2. 
Crandall, W., Hyams, J., Kugathasan, S., Griffiths, A., Zrubek, J., Olson, A., et al. 2009. 
Infliximab therapy in children with concurrent perianal Crohn disease: observations from 
REACH. J Pediatr Gastroenterol Nutr, 49(2), 183-90. 
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. 
de Zoeten, E. F., Pasternak, B. A., Mattei, P., Kramer, R. E. and Kader, H. A. 2013. Diagnosis 
and treatment of perianal Crohn disease: NASPGHAN clinical report and consensus 
statement. J Pediatr Gastroenterol Nutr, 57(3), 401-12. 
Farrell, R. J. and Peppercorn, M. A. 2013. Overview of the medical management of mild to 
moderate Crohn's disease in adults [Online]. UpToDate.  [Accessed]. 
Forsdick, V. K., Tan Tanny, S. P. and King, S. K. 2019. Medical and surgical management of 
pediatric perianal crohn's disease: A systematic review. J Pediatr Surg, 54(12), 2554-8. 
Hadzhiev, B. D. and Murdjeva, M. A. 2010. Immunopathological characteristics of 
cryptoglandular and Crohn's anorectal fistulas. Folia Med (Plovdiv), 52(4), 5-12. 
Herman, Y., Rinawi, F., Rothschild, B., Nir, O., Shamir, R. and Assa, A. 2017. The 
characteristics and long-term outcomes of pediatric Crohn's disease patients with perianal 
disease. Inflamm Bowel Dis, 23(9), 1659-65. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Darvadstrocel 
 
Study No. Darvadstrocel-3004 
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CONFIDENTIAL 
Hyams, J. S., Ferry, G. D., Mandel, F. S., Gryboski, J. D., Kibort, P. M., Kirschner, B. S., et al. 
1991. Development and validation of a pediatric Crohn's disease activity index. J Pediatr 
Gastroenterol Nutr, 12(4), 439-47. 
Irvine, E. J. 1999. Development and subsequent refinement of the inflammatory bowel disease 
questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel 
disease. J Pediatr Gastroenterol Nutr, 28(4), S23-7. 
Kappelman, M. D., Moore, K. R., Allen, J. K. and Cook, S. F. 2013. Recent trends in the 
prevalence of Crohn's disease and ulcerative colitis in a commercially insured US 
population. Dig Dis Sci, 58(2), 519-25. 
Keljo, D. J., Markowitz, J., Langton, C., Lerer, T., Bousvaros, A., Carvalho, R., et al. 2009. 
Course and treatment of perianal disease in children newly diagnosed with Crohn's 
disease. Inflamm Bowel Dis, 15(3), 383-7. 
Kugathasan, S., Judd, R. H., Hoffmann, R. G., Heikenen, J., Telega, G., Khan, F., et al. 2003. 
Epidemiologic and clinical characteristics of children with newly diagnosed 
inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr, 
143(4), 525-31. 
Lichtenstein, G. R., Hanauer, S. B. and Sandborn, W. J. 2009. Management of Crohn ’s disease 
in adults. American Journal of Gastroenterology, 104(i2), 465-83. 
Marzo, M., Felice, C., Pugliese, D., Andrisani, G., Mocci, G., Armuzzi, A., et al. 2015. 
Management of perianal fistulas in Crohn's disease: an up-to-date review. World J 
Gastroenterol, 21(5), 1394-403. 
Nielsen, O. H., Rogler, G., Hahnloser, D. and Thomsen, O. O. 2009. Diagnosis and management 
of fistulizing Crohn's disease. Nat Clin Pract Gastroenterol Hepatol, 6(2), 92-106. 
Panes, J., Garcia-Olmo, D., Van Assche, G., Colombel, J. F., Reinisch, W., Baumgart, D. C., et 
al. 2016. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for 
complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind 
controlled trial. Lancet, 388(10051), 1281-90. 
Parks, A. G., Gordon, P. H. and Hardcastle, J. D. 1976. A classification of fistula-in-ano. Br J 
Surg, 63(1), 1-12. 
Pearson, D. C., May, G. R., Fick, G. H. and Sutherland, L. R. 1995. Azathioprine and 6-
mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med, 123(2), 132-42. 
Roumeguere, P., Bouchard, D., Pigot, F., Castinel, A., Juguet, F., Gaye, D., et al. 2011. 
Combined approach with infliximab, surgery, and methotrexate in severe fistulizing 
anoperineal Crohn's disease: results from a prospective study. Inflamm Bowel Dis, 17(1), 
69-76. 
Ruemmele, F. M., Veres, G., Kolho, K. L., Griffiths, A., Levine, A., Escher, J. C., et al. 2014. 
Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric 
Crohn's disease. J Crohns Colitis, 8(10), 1179-207. 
Sandborn, W. J., Fazio, V. W., Feagan, B. G., Hanauer, S. B. and American Gastroenterological 
Association Clinical Practice Committee 2003. AGA technical review on perianal 
Crohn's disease. Gastroenterology, 125(5), 1508-30. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Darvadstrocel 
 
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CONFIDENTIAL 
Sands, B. E., Anderson, F. H., Bernstein, C. N., Chey, W. Y., Feagan, B. G., Fedorak, R. N., et 
al. 2004. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med, 
350(9), 876-85. 
Schwartz, D. A., Loftus, E. V., Jr., Tremaine, W. J., Panaccione, R., Harmsen, W. S., 
Zinsmeister, A. R., et al. 2002. The natural history of fistulizing Crohn's disease in 
Olmsted County, Minnesota. Gastroenterology, 122(4), 875-80. 
Shenoy-Bhangle, A., Nimkin, K., Goldner, D., Bradley, W. F., Israel, E. J. and Gee, M. S. 2014. 
MRI predictors of treatment response for perianal fistulizing Crohn disease in children 
and young adults. Pediatr Radiol, 44(1), 23-9. 
Tozer, P. J., Burling, D., Gupta, A., Phillips, R. K. and Hart, A. L. 2011. Review article: medical, 
surgical and radiological management of perianal Crohn's fistulas. Aliment Pharmacol 
Ther, 33(1), 5-22. 
Tsze, D. S., von Baeyer, C. L., Bulloch, B. and Dayan, P. S. 2013. Validation of self-report pain 
scales in children. Pediatrics, 132(4), e971-9. 
van der Hagen, S. J., Baeten, C. G., Soeters, P. B., Beets-Tan, R. G., Russel, M. G. and van 
Gemert, W. G. 2005. Staged mucosal advancement flap for the treatment of complex anal 
fistulas: pretreatment with noncutting Setons and in case of recurrent multiple abscesses a 
diverting stoma. Colorectal Dis, 7(5), 513-8. 
Vernier-Massouille, G., Balde, M., Salleron, J., Turck, D., Dupas, J. L., Mouterde, O., et al. 
2008. Natural history of pediatric Crohn's disease: a population-based cohort study. 
Gastroenterology, 135(4), 1106-13. 
von Baeyer, C. L. 2006. Children's self-reports of pain intensity: scale selection, limitations and 
interpretation. Pain Res Manag, 11(3), 157-62. 
Zhao, M., Lo, B. Z. S., Vester-Andersen, M. K., Vind, I., Bendtsen, F. and Burisch, J. 2019. A 
10-year follow-up study of the natural history of perianal Crohn's disease in a Danish 
population-based inception cohort. Inflamm Bowel Dis, 25(7), 1227-36. 
 
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Appendix A Schedule of Study Procedures 
Visit (Week) 
Screening 
Visit 
(-4 to -5 
weeks) a 
Preparation 
Visit 
(-2 to -3 
weeks) b 
V0 
V1 
(W6) r 
V2 
(W12) r 
V3 
(W24) 
V4 
(W36) r 
V5  
(W52) 
End of 
Study 
Unscheduled 
Phone Call 
Follow-up q 
Early 
Termination 
Study Day (Window) 
NA 
NA 
D0 
D42 
(±8) 
D84  
(±8) 
D168 
(±8) 
D252 
(±15) 
D364 
(±15) 
NA 
(±15) 
Enrollment  
 
X 
 
 
 
 
 
 
 
 
ICF/pediatric assent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria check 
X 
X 
 
 
 
 
 
 
 
 
Demographics, medical and 
surgical history 
X 
 
 
 
 
 
 
 
 
 
Weight, height, and BMI  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs c 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concurrent medical conditions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CD, fistula, and treatment history d 
X 
 
 
 
 
 
 
 
 
 
Target fistula(s) information (new 
fistula or previously treated fistula) 
e 
X 
 
 
 
 
 
 
 
 
 
Hematology & biochemistry f 
X 
 
 
X 
 
X 
 
X 
 
X 
Urinalysis f 
X 
 
 
X 
 
X 
 
X 
 
X 
Serum pregnancy 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy g 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Fistula clinical assessment 
X h 
X 
X 
X 
X 
X 
X 
X 
 
X 
Remote fistula clinical assessment 
 
 
 
 
 
 
 
 
X 
 
Fistula MRI assessment j 
X 
 
 
 
 
X 
 
 
 
X i 
Fistula preparation k 
 
X 
 
 
 
 
 
 
 
 
Perianal pain VAS l 
X 
 
X 
X 
 
X 
 
X 
X 
X 
PCDAI score m 
X 
 
 
X 
 
X 
 
X 
X 
X 
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CONFIDENTIAL 
Visit (Week) 
Screening 
Visit 
(-4 to -5 
weeks) a 
Preparation 
Visit 
(-2 to -3 
weeks) b 
V0 
V1 
(W6) r 
V2 
(W12) r 
V3 
(W24) 
V4 
(W36) r 
V5  
(W52) 
End of 
Study 
Unscheduled 
Phone Call 
Follow-up q 
Early 
Termination 
Study Day (Window) 
NA 
NA 
D0 
D42 
(±8) 
D84  
(±8) 
D168 
(±8) 
D252 
(±15) 
D364 
(±15) 
NA 
(±15) 
PDAI subscores n 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Luminal disease activity involving 
the rectum o 
X 
 
 
 
 
 
 
 
 
 
Treatment administration p 
 
 
X 
 
 
 
 
 
 
 
Number and location of fistula 
tracts treated 
 
 
X 
 
 
 
 
 
 
 
Assessment of 
AEs/SAEs/AESIs/SSRs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE: adverse event; AESI: adverse event of special interest; ALT; alanine aminotransferase; AST: aspartate aminotransferase; BMI: body mass index; CD: Crohn’s disease; 
COVID-19: coronavirus disease 2019; CRP: C-reactive protein; D: day; eCRF: electronic case report form; ESR: erythrocyte sedimentation rate; ICF: informed consent form; 
MCH; mean corpuscular hemoglobin; MCHC; mean corpuscular hemoglobin concentration; MCV: mean corpuscular volume; MRI: magnetic resonance imaging; NA: not 
applicable; PCDAI: Pediatric Crohn’s Disease Activity Index; PDAI: Perianal Disease Activity Index; SAE: serious adverse event; SSR: special situation report; ULN: upper 
limit of normal; V: visit; VAS: visual analog scale; W: week. 
a The screening visit will take place within a minimum of 4 weeks and a maximum of 5 weeks of the preparation visit. For any subject not meeting the eligibility criteria, or if 
there are unavoidable circumstances such as the COVID-19 pandemic, it may be possible to rescreen the subject if they later meet the criteria and based upon the sponsor’s 
approval. The procedures listed in Section 9.3.2 will need to be repeated and the preparation visit rescheduled based on the protocol timelines.  
b From the preparation visit to the treatment administration visit (Visit 0) there will be a minimum of 2 weeks and a maximum of 3 weeks (necessary to have darvadstrocel 
treatment ready for administration). Once the date for treatment administration surgery is set it cannot be moved due to the darvadstrocel preparation procedure and the limited 
window of manufacturing, shipment and study drug viability. 
c Temperature, heart rate, and blood pressure will be recorded.  
d 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; 
preparatory surgery will be completed before darvadstrocel administration. 
e Clinical characteristics including age of onset, number of other fistulas, localization, and clock position (Appendix C). 
f Refer to Section 9.1.9 for clinical laboratory parameters. 
g If the urine pregnancy test is positive, a serum pregnancy test will also be performed. 
h Fistula must have been draining for at least 6 weeks before the screening visit. 
i An MRI will be performed at the early termination visit only if this visit occurs before the Week 24 visit. 
j A pelvic MRI will be performed at baseline (screening visit), Week 24, and early termination visit. An MRI will be obtained at the early termination visit only if the early 
termination visit occurs before Week 24. See Section 9.1.6.2 and the MRI manual for further details. 
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CONFIDENTIAL 
Visit (Week) 
Screening 
Visit 
(-4 to -5 
weeks) a 
Preparation 
Visit 
(-2 to -3 
weeks) b 
V0 
V1 
(W6) r 
V2 
(W12) r 
V3 
(W24) 
V4 
(W36) r 
V5  
(W52) 
End of 
Study 
Unscheduled 
Phone Call 
Follow-up q 
Early 
Termination 
Study Day (Window) 
NA 
NA 
D0 
D42 
(±8) 
D84  
(±8) 
D168 
(±8) 
D252 
(±15) 
D364 
(±15) 
NA 
(±15) 
k Fistula preparation will consist of examination under anesthesia, seton placement and curettage to be performed by the surgeon according to the surgery procedure manual 
(provided as a separate document).  
l The screening perianal pain VAS will be recorded daily by the subjects at home for a 2-week (14-day) period starting within 7 days after the screening visit. For all other 
visits, perianal pain VAS will be recorded daily by the subjects at home for 2 weeks (14 days) before each visit. 
m ESR as part of the PCDAI assessment will be analyzed by a local laboratory. 
n Change in subscale scores for discharge and pain domains. 
o Luminal disease activity involving the rectum, as determined by the presence or absence of proctitis as measured by colonoscopy, flexible sigmoidoscopy or rectoscopy 
performed within 6 months of the screening visit showing absence of rectal ulcers larger than 0.5 cm. A colonoscopy or rectoscopy will need to be performed at screening if the 
subject has not had one within the last 6 months of screening. 
p All study procedures should be performed before darvadstrocel administration. Darvadstrocel administration is to be performed according to the surgery procedure manual. If 
there is any problem administering darvadstrocel on the day of administration, the visit should be rescheduled within a minimum of 2 weeks and a maximum of 3 weeks of 
Visit 0. 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 darvadstrocel 
administration. All procedures which take place on the day of darvadstrocel administration are to be repeated. If the surgeon is unable to inject the full dose of darvadstrocel 
(120 million cells [24 mL]) due to resistance at the injection site, the adjusted dose (mL) will be recorded in the eCRF and the subject will be able to continue in the study. 
q Unscheduled phone-calls are proposed for safety follow-up for any contact requested by the subject between scheduled visits. 
r The assessments listed in Section 9.3.8 are to be performed if the subject cannot attend any interim visits (Weeks 6, 12, and 36) due to COVID restrictions. 
 
 
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CONFIDENTIAL 
Appendix B Blood Volume Table 
Sample 
Type 
Sample 
Volume 
(ml) 
Number of Samples 
Total 
Volume 
(ml) 
Screening 
Visit (up to 
5 weeks) 
Preparation 
Visit (≥2 
weeks to ≤3 
weeks) 
Day 0 
Week 
6 
Week 12 
Week 24 
Week 36 
Week 52 
Unscheduled 
Phone Call 
Follow-up 
Early 
Termination 
 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Clinical 
laboratory 
tests a 
7.5 
X 
 
 
X 
 
X 
 
X 
 
X 
30 
Total Approximate Blood Sampling Volume (ml) 
30 
a Hematology and biochemistry. 
 
 
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Appendix D Guidance on Liver Test Abnormality Monitoring, Evaluation, and Follow-up 
Investigators must be vigilant for abnormal liver test results in subjects during the clinical study. 
Transient fluctuations in serum aminotransferases occur commonly in clinical study subjects, but 
it is crucial that the investigator identifies and evaluates subjects with possible hepatic injury. 
This guidance is intended to aid investigations of abnormal liver tests in clinical study subjects 
who had no known liver disease and had either normal or near normal baseline liver test results 
(ie, ALT <2 × ULN, total bilirubin <1.5 × ULN, and alkaline phosphatase <1.5 × ULN) at the 
time of enrollment). 
In evaluating study subjects with abnormal liver test results, the investigator should perform 
follow-up laboratory tests to confirm the abnormal test results and monitor the subject. If the 
abnormal liver test results are confirmed, then the subject should be monitored and, if necessary, 
additional diagnostic tests should be performed as shown in Figure 1. Suggested hepatic 
investigations are listed in Table 1. Criteria for considering discontinuation of study drug are 
shown in Figure 2. 
Subjects with Combined Elevations in Aminotransferase and Bilirubin 
If a subject has elevated ALT ≥3 × ULN with concurrent elevated total bilirubin >2 × ULN or 
elevated INR >1.5, the investigator must contact the sponsor’s medical monitor within 24 hours. 
Hepatic investigations as suggested in Table 1 should be initiated. Any event of elevated ALT 
≥3 × ULN with concurrent elevated total bilirubin >2 × ULN or elevated INR >1.5 for which an 
alternative etiology has not been identified must be reported as an SAE. 
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CONFIDENTIAL 
Table 1 
Hepatic Investigation 
Medical history  
• 
Concomitant medications (including over-the-counter medications, such 
as acetaminophen, and herbal supplements). 
• 
Medical conditions (eg, ischemia, hypotension, severe hypoxemia, 
congestive heart failure, sepsis).  
• 
Alcohol intake.  
• 
Hepatobiliary disorder. 
• 
Previous liver disease or metabolic syndrome (eg, obesity, insulin 
resistance, diabetes, or dyslipidemia). 
• 
Travel history. 
Physical examination 
(symptoms, signs, and 
laboratory results) 
• 
General malaise, fatigue, nausea, or vomiting. 
• 
Right upper quadrant pain or tenderness, fever, jaundice, rash. 
• 
Eosinophilia >5%. 
Hepatic/hepatobiliary 
imaging 
Perform as appropriate (eg, abdominal ultrasound, computed tomography, 
magnetic resonance imaging, or other hepatobiliary imaging). 
Viral hepatitis serology  
 
• 
Hepatitis A antibody (total and IgM). 
• 
Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody 
(anti-HBs), hepatitis B core antibody (IgM anti-HBc), hepatitis C 
antibodies (anti-HCV). 
• 
Hepatitis E (IgG and IgM). 
• 
Consider polymerase chain reaction for hepatitis B, C, and E. 
• 
Consider Epstein-Barr virus serology (viral capsid antigen [VCA] 
nuclear antigen [EBNA], early antigen [EA]). 
• 
Consider cytomegalovirus serology (IgG and IgM). 
Autoimmune hepatitis 
serology 
• 
Antinuclear antibody (ANA). 
• 
Antismooth muscle antibody (ASMA). 
• 
Anti–liver-kidney microsomal antibody (anti-LKM).  
 
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CONFIDENTIAL 
Appendix E PDAI 
Categories affected by fistulas 
Score 
Discharge 
 
No discharge 
0 
Minimal mucous discharge 
1 
Moderate mucous or purulent discharge 
2 
Substantial discharge 
3 
Gross fecal soiling 
4 
Pain/restriction of activities 
 
No activity restriction 
0 
Mild discomfort, no restriction 
1 
Moderate discomfort, some limitation activities 
2 
Marked discomfort, marked limitation 
3 
Severe pain, severe limitation 
4 
Restriction of sexual activity 
 
No restriction in sexual activity 
0 
Slight restriction in sexual activity 
1 
Moderate limitation in sexual activity 
2 
Marked limitation in sexual activity 
3 
Unable to engage in sexual activity 
4 
Type of perianal disease 
 
No perianal disease/skin tags 
0 
Anal fissure or mucosal tear 
1 
<3 Perianal fistulae 
2 
≥3 Perianal fistulae 
3 
Anal sphincter ulceration or fistulae with significant undermining of skin 
4 
Degree of induration 
 
No induration 
0 
Minimal induration 
1 
Moderate induration 
2 
Substantial induration 
3 
Gross fluctuance/abscess 
4 
Source: Irvine E.J, 1999 (Irvine 1999). 
 
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CONFIDENTIAL 
Appendix H Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations.  
The investigator agrees to assume the following responsibilities: 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent/pediatric assent, as outlined in ICH and local 
regulations, are met. 
8. Obtain valid informed consent/pediatric assent from each subject who participates in the 
study and document the date of consent in the subject’s medical chart. Valid informed 
consent/pediatric assent is the most current version approved by the IRB/IEC. Each informed 
consent/pediatric assent form should contain a subject authorization section that describes the 
uses and disclosures of a subject’s personal information (including personal health 
information) that will take place in connection with the study. If an informed 
consent/pediatric assent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc. and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
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CONFIDENTIAL 
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. *This responsibility lies 
on the appropriate individual, designated by the site in Japan.  
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 I 
Elements of the Subject Informed Consent/Pediatric Assent  
In seeking informed consent/pediatric assent, the following information shall be provided to each 
subject: 
1. A statement that the study involves research. 
2. An explanation of the purposes of the research. 
3. The expected duration of the subject’s participation. 
4. A description of the procedures to be followed, including invasive procedures. 
5. The identification of any procedures that are experimental. 
6. The estimated number of subjects involved in the study. 
7. A description of the subject’s responsibilities. 
8. A description of the conduct of the study. 
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment. 
10. A description of the possible side effects of the treatment that the subject may receive. 
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this. 
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the subject and their important potential risks and benefits. 
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), 
IRB/IEC, and the monitor may inspect the records. By signing a written informed 
consent/pediatric assent form, the subject or the subject’s legally acceptable representative is 
authorizing such access. 
15. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if injury 
occurs and, if so, what they consist of or where further information may be obtained. 
16. The anticipated prorated payment(s), if any, to the subject for participating in the study. 
17. The anticipated expenses, if any, to the subject for participating in the study. 
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a research-
related injury to the subject. 
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CONFIDENTIAL 
19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the subject otherwise is entitled, and that the subject or the 
subject’s legally acceptable representative may discontinue participation at any time without 
penalty or loss of benefits to which the subject is otherwise entitled. 
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject. 
21. A statement that the subject or the subject’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
subject’s willingness to continue participation in the study. 
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so. 
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated. 
24. A written subject authorization (either contained within the informed consent/pediatric assent 
form or provided as a separate document) describing to the subject the contemplated and 
permissible uses and disclosures of the subject’s personal information (including personal 
health information) for purposes of conducting the study. The subject authorization must 
contain the following statements regarding the uses and disclosures of the subject’s personal 
information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies; 
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 
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CONFIDENTIAL 
e) that the subject’s identity will remain confidential in the event that study results are 
published. 
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/pediatric assent) 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, and the investigator will offer the subject the choice to receive treatment 
information. 
26. Male subjects must use highly effective contraception (as defined in the informed 
consent/pediatric assent) from signing the informed consent/pediatric assent 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 J 
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. 
• IRBs and 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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CONFIDENTIAL 
Appendix K Protocol History 
Amendment History: 
Date 
Amendment Number 
Region 
22 May 2024 
Amendment 3 
Global 
12 February 2024 
Amendment 2 
Global 
01 February 2021 
Amendment 1 
Global 
24 June 2020 
Initial protocol 
Global 
 
Protocol Amendment 2 Summary and Rationale:  
This section describes the changes in reference to the protocol incorporating Amendment 2. The 
primary reasons for this amendment are to: 
• Revise the age of subject eligibility to 4 to <18 years at the time of study treatment 
administration. 
• Update the protocol to align with the guidelines and requirements of the European Union 
Clinical Trials Regulations (EU CTR). 
In addition, minor grammatical, editorial, formatting, and administrative changes not affecting 
the conduct of the study are included throughout the document for clarification and 
administrative purposes.  
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 2.0 STUDY 
SUMARY  
Replaced EudraCT number 
with Abbreviated EU CT 
number. 
To comply with new European 
Union Clinical Trials Regulations 
(EU CTR) guidelines and 
requirements. 
2. 
Section 2.0 STUDY 
SUMMARY  
Section 7.1 Inclusion 
Criteria, inclusion criterion 
3 
Revised inclusion criterion 
to require subjects to be 
aged 4 to <18 years at the 
time of study treatment 
administration. 
To align with pediatric age limits 
in the EU, United Kingdom, and 
Japan.   
3. 
Section 2.0 STUDY 
SUMMARY 
Section 5.2.2 Secondary 
Endpoints  
Removed the phrase 
“incidence of” from the 
safety endpoints of adverse 
events (AEs), serious AEs 
(SAEs), and AEs of special 
interest (AESIs). 
 
To update the endpoint language 
for consistency with other studies 
in the darvadstrocel program. 
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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  
4. 
Section 2.0 STUDY 
SUMMARY 
Added new section in the 
Study Summary to include 
the description of the 
benefit-risk profile present 
in Section 4.3. 
To comply with new EU CTR 
guidelines and requirements. 
5. 
Section 2.0 STUDY 
SUMMARY 
Section 13.1.4 Safety 
Analysis  
Corrected the list of AESIs 
in the description of planned 
safety analyses. 
Correction. 
6. 
Section 4.2 Rationale for 
the Proposed Study  
Updated information on 
study status and results from 
Studies Darvadstrocel-3002 
and Cx601-0303.  
To provide updated background 
information on clinical studies of 
darvadstrocel in adults. 
7. 
Section 4.3 Benefit-Risk 
Profile  
Updated the section with 
safety details. 
To update the language with 
details on the known adverse 
drug reactions since the previous 
version of the protocol. 
8. 
Section 5.2.3 Exploratory 
Endpoint  
Removed “at Week 24 and 
Week 52” from the first 
2 exploratory endpoints. 
To ensure consistency across the 
exploratory endpoints and to 
reflect that analysis of change 
from baseline will be conducted 
for all visits at which the 
assessments are performed (ie, 
Week 6, Week 24, and Week 52). 
9. 
Section 6.2 Justification for 
Study Design, Dose, and 
Endpoints  
Updated text to reflect that 
Studies Darvadstrocel-3002 
and Cx601-0303 are 
completed. 
To update justification for study 
design with current study status 
information. 
10. 
Section 6.3 Definition of 
Study Start  
Section 6.4 Definition of 
End of Study  
Added new sections to 
include definitions of study 
start and end of study.  
To comply with new EU CTR 
guidelines and requirements.  
11. 
Section 8.1.1.1 
Darvardstrocel 
Removed “sterile” and 
“clear” from the description 
of darvadstrocel drug 
product. 
Correction. 
12. 
Section 8.1.1.3 Sponsor-
Supplied Drug  
Added new table with 
details of the study 
medication. 
To comply with new EU CTR 
guidelines and requirements. 
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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  
13. 
Section 8.1.4 Overdose 
Added details for overdose 
to be reported in the 
electronic case report form 
(eCRF) as a medication 
error and reported to safety 
on a paper special situation 
report (SSR) form. 
To align with new EU CTR 
guidelines. 
14. 
Section 8.4 Continued 
Access to Study Drug 
After the End of the Study  
Added new section to state 
that no aftercare is planned 
for this study and that the 
subject should be returned 
to the care of a physician 
and standard therapies as 
required. 
To align with new EU CTR 
guidelines requiring clarification 
of whether participation in the 
study will lead to requirements 
for additional care after the study, 
or care that differs from that 
normally expected for their 
medical condition.  
15. 
Section 9.1.11 Pregnancy 
Removed details of 
pregnancy reporting and 
added reference to the new 
location of these details in 
newly added Section 10.3.2. 
To consolidate the description of 
procedures for reporting 
pregnancies in the study. 
16. 
Section 9.1.15.2 Patient-
Reported Outcomes  
Appendix A Schedule of 
Study Procedures, new 
footnote l 
Added clarification that the 
perianal pain visual analog 
scale at the screening visit 
should be collected by the 
subjects at home for 
2 weeks (14 days) starting 
within 7 days after the 
screening visit. 
Clarification 
17. 
Section 9.3 Schedule of 
Observations and 
Procedures  
Appendix A Schedule of 
Study Procedures 
Added assessment of SSRs 
to all study visits.  
To comply with new EU CTR 
guidelines and requirements. 
18. 
Section 10.1.4 AEs of 
Special Interest  
Section 10.2.1.3 AESIs 
Removed statement 
regarding an AESI 
evaluation form. 
To comply with new EU CTR 
guidelines and requirements.  
19. 
Section 10.1.5 Special 
Situation Reports  
Added new section to define 
SSRs.  
To comply with new EU CTR 
guidelines and requirements. 
20. 
Section 10.2.1.3 AESIs 
Added a statement for a 
medication error to be both 
captured as an AESI and 
reported as an SSR. 
To clarify how to handle reports 
of medications errors defined as 
an AESI as well as an SSR. 
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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  
21. 
Section 10.2.2 Collection 
and Reporting of SAEs  
Clarified that SAEs should 
be reported via the SAE 
eCRF page in electronic 
data capture. 
Updated the SAE reporting 
to start from “awareness” 
instead of “first onset or 
notification.” 
To clarify the procedures for SAE 
reporting. 
22. 
Section 10.3.1 Collection 
and Reporting of SSRs 
Added new section with 
details about SSR reporting. 
To comply with new EU CTR 
guidelines and requirements. 
23. 
Section 10.3.2 Collection 
and Reporting of 
Pregnancies  
Added new section with 
details about pregnancy 
reporting. 
To comply with new EU CTR 
guidelines and requirements. 
24. 
Section 10.3.3 Summary of 
Safety Reporting  
Added new section 
summarizing safety 
reporting timelines and 
methods. 
To comply with new EU CTR 
guidelines and requirements. 
25. 
Section 14.2 Protocol 
Deviations  
Updated section 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. 
26. 
Section 15.3 Subject 
Confidentiality  
Updated section 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. 
 
Protocol Amendment 1 Summary and Rationale: 
This section describes the changes in reference to the protocol incorporating Amendment 1. The 
primary reasons for this amendment are to: 
• Remove magnetic resonance imaging (MRI) contrast due to the risks associated in the 
pediatric population. 
• Remove anesthesia for MRI due to the risks associated in the pediatric population. 
• Inclusion of erythrocyte sedimentation rate (ESR) as part of the clinical laboratory tests in 
order to complete the Pediatric Crohn’s Disease Activity Index (PCDAI) assessment. 
• Provide improved clarity to the eligibility criteria and study assessments. 
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CONFIDENTIAL 
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 1 
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 4.2 Rationale for the 
Proposed Study 
Update to the number of 
subjects who have received 
double-blind treatment in the 
Cx601-0303 study. 
To be in line with recent update to 
the Cx601 Investigator's Brochure. 
2. 
Section 6.0 Study Design and 
Description, Figure 6.a 
Section 9.3.4 Treatment 
Administration Visit (Week 
0/Visit 0) 
Section 2.0 STUDY 
SUMMARY 
Appendix A Schedule of 
Study Procedures 
Editorial updates to align the 
study schematic with 
Appendix A and to include 
details on the timing of the 
screening visit in relation to 
the preparation visit and study 
drug administration.  
For improved clarity on the timing 
for study drug administration. 
3. 
Section 7.1 Inclusion Criteria 
Section 7.2 Exclusion 
Criteria 
Section 2.0 STUDY 
SUMMARY 
Appendix A Schedule of 
Study Procedures 
Update to inclusion criterion 
6. 
Update to exclusion criterion 
27. 
The use of magnetic resonance 
imaging (MRI) contrast has been 
removed in recognition of the risks 
associated with the pediatric 
population. In addition, updates 
have been made to clarify 
assessments to be assessed by MRI 
or by clinical examination.  
4. 
Section 7.3 Excluded 
Medications and Treatments 
Table 7.a 
 
Update to allowed/excluded 
medications and treatments 
table. 
Anesthesia/sedation during MRI is 
not allowed in the study in 
consideration of the safety risk 
associated with anesthesia in the 
pediatric population. 
5. 
Section 8.1.3 Dose and 
Regimen 
Section 8.1.4 Overdose 
Editorial updates to dose 
administration. 
Since the drug is administered by 
the investigator/surgeon, the text 
has been updated to reflect this. 
6. 
Section 8.3 Accountability 
and Destruction of Sponsor-
Supplied Drugs 
Editorial updates to correctly 
reflect study procedures. 
Due to the nature of the drug, there 
will be no drug supply stored at the 
site; therefore, there will be no 
inventory at the site. This section 
has been updated to reflect the 
procedures applicable to this study. 
7. 
Section 9.1.6.2 Pelvic MRI 
Inclusion of additional details 
surrounding the pelvic MRI 
assessments. 
This section has been updated to 
improve clarity on the timings and 
assessments related to the MRI 
scan. 
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Protocol Amendment 1 
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  
8. 
Section 9.1.9 Procedures for 
Clinical Laboratory Samples 
Section 9.1.15 Clinical 
Outcome Assessments 
Section 9.3.1 Screening Visit 
Section 9.3.5 Follow-up 
Period 
Section 9.3.6 Early 
Termination 
Appendix A Schedule of 
Study Procedures 
Erythrocyte sedimentation rate 
(ESR) added as part of the 
hematology clinical laboratory 
tests for Pediatric Crohn’s 
Disease Activity Index 
(PCDAI) assessment. 
Analysis of ESR is required as part 
of the PCDAI assessment. Text 
added to clarify that ESR will be 
analyzed by a local laboratory. 
9. 
Section 9.1.9 Procedures for 
Clinical Laboratory Samples 
Section 10.2.3 Reporting of 
Abnormal Liver Function 
Tests 
Editorial update to monitoring 
requirements for alanine 
aminotransferase elevations.  
Text has been replaced with 
reference to Appendix D, which 
includes guidance on liver test 
abnormality monitoring, evaluation, 
and follow-up.  
10. 
Section 9.1.15 Clinical 
Outcome Assessments 
Heading updated to Clinical 
Outcome Assessments. 
To encompass the clinician 
(Perianal Disease Activity Index 
[PDAI] and PCDAI) and patient 
(Perianal Pain visual analog scale 
[VAS]) reported outcomes. 
11. 
Section 9.1.15.1 Clinician-
Reported Outcomes 
New subheading of Clinician-
Reported Outcomes. 
Updated since PDAI and PCDAI 
assessments are clinician-reported 
outcomes.  
12. 
Section 9.1.15.2 Patient-
Reported Outcomes 
New subheading of Patient-
Reported Outcomes. 
Perianal Pain VAS is reported by 
the patient; therefore, the 
subheading has been updated to 
reflect this. 
13. 
Section 9.3 Schedule of 
Observations and Procedures 
Update to wording. 
To clarify that visits at screening, 
preparation, treatment 
administration, Week 24, and 
Week 52 must be done with the 
subject present at the investigative 
site. 
14. 
Section 9.3.1 Screening Visit 
to Section 9.3.6 Early 
Termination 
Editorial update to the fistula 
clinical assessment (FCA). 
To provide clarity on which 
electronic case report forms need to 
be completed by the investigator at 
each visit when performing the 
FCA. 
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Protocol Amendment 1 
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  
15. 
Section 9.3.1 Screening Visit 
Appendix A Schedule of 
Study Procedures 
Editorial update to clarify 
colonoscopy or rectoscopy 
requirements at the screening 
visit. 
A colonoscopy or rectoscopy will 
need to be performed at screening if 
the subject has not had one within 
the last 6 months of screening. 
16. 
Section 9.3.2 Potential 
Rescreening 
Editorial update to clarify 
requirements for repeat MRI 
at the rescreening visit.  
For completeness to study 
procedures at the rescreening visit. 
17. 
Section 9.3.4 Treatment 
Administration Visit (Week 
0/Visit 0) 
Appendix A Schedule of 
Study Procedures 
Removal of PCDAI 
assessment from the treatment 
administration visit. 
Since there will be no clinical 
laboratory tests at the treatment 
administration visit, PCDAI has 
been removed from this visit. 
18. 
Section 9.3.7 Unscheduled 
Telephone Follow-up Calls 
Appendix A Schedule of 
Study Procedures 
Editorial update to provide 
clarity on the unscheduled 
telephone follow-up calls. 
To clarify that subjects will be able 
to contact the investigator between 
scheduled visits or if the subject 
cannot attend an interim visit. 
19. 
Section 9.3.8 Remote Visit 
due to COVID-19 
New section added. 
To allow remote visits in the event 
a subject cannot attend an interim 
visit due to coronavirus disease 
2019. 
20. 
Section 10.1.3 SAEs 
Removal of the Takeda 
Medically Significant AE list. 
In line with updated internal 
process, the EudraVigilance Expert 
Working Group Important Medical 
Event Terms list will now be 
implemented. 
21. 
Section 13.0 STATISTICAL 
Methods 
Section 2.0 STUDY 
SUMMARY 
Editorial updates made. 
For improved clarity and 
completeness to the statistical 
methodology. 
22. 
Appendix D Guidance on 
Liver Test Abnormality 
Monitoring, Evaluation, and 
Follow-up 
Addition of new appendix. 
In line with internal process, this 
appendix has been included to 
provide guidance on reporting liver 
test abnormalities. 
23. 
Appendix G Perianal Pain 
VAS 
Addition of new appendix. 
Added for completeness to 
protocol.  
 
 
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Signature Page for Darvadstrocel-3004 Protocol Amend 3 2024-05-22
Title: A Phase 3, Open-Label, Multicenter Study to Evaluate the Efficacy and Saf
Document Number: TDN-000337912 v1.0
Approval
Statistics
23-May-2024 20:29:37 GMT+0000
Approval
Clinical
23-May-2024 21:53:49 GMT+0000
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