A Phase 3, Multicenter, Open-Label, Uncontrolled Study to Evaluate the Efficacy and Safety of Cx601 in the Treatment of Complex Perianal Fistulas in Adult Patients With Crohn's Disease
Phase: PHASE3
Conditions: Complex Perianal Fistulas in Adult Participants With Crohn's Disease
Sponsor: Takeda

Title: A Phase 3, Multicenter, Open-Label, Uncontrolled Study to Evaluate the Efficacy 
and Safety of Cx601 in the Treatment of Complex Perianal Fistulas in Adult Patients 
with Crohn's Disease 
NCT Number: NCT03706456 
Protocol Approve Date: 13-APR-2021 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered
confidential information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners,
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 

 
 
 
TAKEDA PHARMACEUTICALS 
PROTOCOL 
 
<Title> 
A Phase 3, Multicenter, Open-Label, Uncontrolled Study to Evaluate the Efficacy and 
Safety of Cx601 in the Treatment of Complex Perianal Fistulas in Adult Patients with 
Crohn's Disease 
 
<Short Title> 
Phase 3 Study of Cx601 in Subjects with Complex Perianal Fistulising Crohn's Disease 
 
Sponsor: 
Takeda Pharmaceutical Company Limited,  
1-1, Doshomachi 4-Chome, Chuo-ku, Osaka-shi, Osaka, Japan 
Study Number: 
Darvadstrocel-3002 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Product: 
Cx601 (INN: Darvadstrocel) 
Date: 
13 April 2021 
Amendment Number: 5 
 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
13 April 2021 
Amendment No.5 
Non-substantial 
All sites 
6 October 2020 
Amendment No.4 
Non-substantial 
All sites 
9 October 2019 
Amendment No.3 
- 
All sites 
5 September 2018 
Amendment No.2 
- 
All sites 
27 July 2018 
Amendment No.1 
- 
All sites 
20 April 2018 
Initial Protocol 
Not applicable 
All sites 
Note: After the marketing approval of Cx601 is obtained in Japan, this study will be continued as a post-marketing 
clinical study. This protocol will be continuously used in the post-marketing clinical study by replacing the term 
"study" in this document with "post-marketing clinical study" as appropriate. 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See the Annex 
1.2 
Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline. 
• Good Clinical Practice for regenerative medical products (Ordinance 89 of the Ministry of 
Health, Labour and Welfare [MHLW], 2014) 
• All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
After the marketing approval of Cx601 is obtained in Japan, this study will be continued as a 
post-marketing clinical study in accordance with Good Post-marketing Study Practice for 
regenerative medical products (Ordinance 90 of the MHLW, 2014) in addition to above. 
 
SIGNATURES 
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page. 
Electronic signatures may be found on the last page of this document. 
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: For non-commercial use only and subject to the applicable Terms of Use
PPD

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1.3 
Protocol Amendment No.5 Summary of Changes 
This section describes the changes in reference to the Protocol Amendment No.5. 
The primary purpose of this amendment is to add the procedures for the post-marketing clinical 
study when this study is continued as a post-marketing clinical study after the marketing 
approval of Cx601 is obtained in Japan. 
A summary of the changes made in Amendment No.5 compared with Amendment No.4 is 
described below. 
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.  
Changes in Amendment No.5: 
Protocol Amendment No.5 
Summary of Changes  
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
Cover page 
Added the note that this protocol 
will be continuously used by 
replacing the term "study" with 
"post-marketing clinical study" as 
appropriate after the marketing 
approval of Cx601 in Japan. 
To conduct this study as a post-
marketing clinical study after the 
marketing approval of Cx601 is 
obtained in Japan. 
Section 1.2 Principles of Clinical 
Studies 
Added the description that this 
study will be conducted in 
accordance with Good Post-
marketing Study Practice for 
regenerative medical products after 
the marketing approval of Cx601 in 
Japan. 
To clarify applicable regulations to 
be complied with in the post-
marketing clinical study. 
Section 10.3.1 Safety Reporting to 
Investigators, IRBs and Regulatory 
Authorities 
Added the procedure of safety 
reporting to investigators when an 
SAE which could affect the study 
continuation occurs after the 
marketing approval of Cx601 in 
Japan. 
To define the optimal procedure 
for the post-marketing clinical 
study, taking into account the 
situation that all subjects in the 
study have completed 
administration of Cx601 and 
certain safety assessments have 
been conducted by the time 
marketing approval is obtained. 
Section 12.2 Record Retention 
Added the description that after the 
marketing approval of Cx601 in 
Japan, the term of record retention 
shall expire on the day when a 
reexamination or reevaluation of 
Cx601 is completed. 
To clarify the term of record 
retention in the post-marketing 
clinical study. 
 
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES .............................................................................................................................2 
1.1 
Contacts and Responsibilities of Study-Related Activities ................................... ... ...2 
1.2 
Principles of Clinical Studies ........................................................................... ... .........2 
1.3 
Protocol Amendment No.5 Summary of Changes ......................................... . .............3 
2.0 
STUDY SUMMARY..................................................................................... . ...................9 
3.0 
STUDY REFERENCE INFORMATION ................................................ ........................14 
3.1 
List of Abbreviations ................................................................... . .............................14 
3.2 
Study Definition ........................................................................ ..................................15 
4.0 
INTRODUCTION ................................................................ ..... ......................................16 
4.1 
Background ................................................................. . ..............................................16 
4.1.1 Complex Perianal Fistulising Crohn's Disease . . .................................................16 
4.1.2 Cx601 ......................................................... ...........................................................16 
4.1.3 Main Clinical Studies Results ............... . ..............................................................17 
4.1.3.1 Study Cx601-0101 (Phase 1/2a, Open-Label, Uncontrolled Study) ................17 
4.1.3.2 Study Cx601-0302 (Phase 3, Placebo-controlled Study) .................................18 
4.2 
Rationale for the Proposed Study . .............................................................................19 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................21 
5.1 
Objectives ...................... ... .........................................................................................21 
5.1.1 Primary Objective . . ..............................................................................................21 
5.1.2 Secondary Objectives .............................................................................................21 
5.1.3 Additional Objectives ............................................................................................21 
5.2 
Endpoints .. ..................................................................................................................21 
5.2.1 Primary Endpoint ...................................................................................................21 
5.2.2 Secondary Endpoints .............................................................................................21 
5.2.3 Safety Endpoints ....................................................................................................22 
5 2 4 Additional Endpoints .............................................................................................22 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................23 
6.1 
Study Design ................................................................................................................23 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................24 
6.3 
Premature Termination or Suspension of Study or Study Site ....................................26 
6.3.1 Criteria for Premature Termination or Suspension of the Study ...........................26 
6.3.2 Criteria for Premature Termination or Suspension of Study Sites ........................26 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ....................................................................................26 
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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............28 
7.1 
Inclusion Criteria .........................................................................................................28 
7.2 
Exclusion Criteria ........................................................................................................29 
7.3 
Excluded Medications and Treatments .................................................................. ... .31 
7.4 
Rescue Therapy ................................................................................................ ... .......35 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ............................... . ...........36 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject ................... . .................37 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT................................ ........................38 
8.1 
Study Product and Materials ........................................................ . .............................38 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ... ..................................38 
8.1.2 Storage ...................................................................... ..... ......................................38 
8.1.3 Dose and Regimen ................................................ . ..............................................38 
8.1.4 Overdose ........................................................... . .................................................39 
8.2 
Study Product Dispensing Procedures ............. ...........................................................39 
8.3 
Accountability and Destruction of Sponsor-Supplied Products ..................................39 
9.0 
STUDY PLAN ........................................... . . ...................................................................40 
9.1 
Study Procedures ............................... . .......................................................................40 
9.1.1 Informed Consent Procedure .. .............................................................................40 
9.1.2 Demographics, Medical History, and Medication History Procedure ...................40 
9.1.3 Physical Examination Procedure ...........................................................................40 
9.1.4 Weight and Height . ..............................................................................................40 
9.1.5 Vital Sign Procedure ..............................................................................................41 
9.1.6 Documentation of Concomitant Medications ........................................................41 
9.1.7 Documentation of Concurrent Medical Conditions ...............................................41 
9.1.8 Procedures for Clinical Laboratory Samples .........................................................41 
9.1.9 Contraception and Pregnancy Avoidance Procedure .............................................43 
9.1.10 Pregnancy ...............................................................................................................43 
9 1 11 Rectosigmoidoscopy ..............................................................................................43 
9.1.12 Fistula Clinical Assessment ...................................................................................44 
9.1.13 Fistula MRI Assessment ........................................................................................44 
9.1.13.1 
Van Assche Score ......................................................................................44 
9.1.14 Perianal Crohn's Disease Activity Index (PDAI) ..................................................44 
9.1.15 Crohn's Disease Activity Index (CDAI) ................................................................45 
9.1.15.1 
Patient Diary ..............................................................................................45 
9.1.16 Anti-donor Antibody Test ......................................................................................45 
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9.1.17 Fistula Preparation .................................................................................................45 
9.1.18 Study Product Administration................................................................................46 
9.1.19 Documentation of Subjects Failure ........................................................................46 
9.1.20 Documentation of Study Entrance ................................................................... ... .46 
9.2 
Monitoring Subject Treatment Compliance ..................................................... ... .......47 
9.3 
Schedule of Observations and Procedures ..................................................... . ...........47 
9.3.1 Screening period ................................................................................ . .................47 
9.3.1.1 Screening (Visit 1) .................................................................. ........................47 
9.3.1.2 Preparation (Visit 2) ......................................................... . .............................47 
9.3.1.3 Potential Re-Screening .................................................. ..................................47 
9.3.2 Treatment .................................................................. ..... ......................................47 
9.3.3 Follow-up period ................................................... . ..............................................48 
9.3.4 Long-term Follow-up Period ............................ . .................................................48 
9.3.5 Final Visit or Early Termination ................ ...........................................................48 
9.3.6 Post Study Care ..................................... . ..............................................................48 
10.0 
ADVERSE EVENTS ................................. . . ...................................................................49 
10.1 
Definitions.......................................... . .......................................................................49 
10.1.1 AEs .......................................... .............................................................................49 
10.1.2 Additional Points to Consider for AEs ..................................................................49 
10.1.3 SAEs ........................ ... .........................................................................................51 
10.1.4 AEs of Special Interest...........................................................................................52 
10.1.5 Intensity of AEs . ...................................................................................................53 
10.1.6 Causality of AEs to Study Product(s) ....................................................................53 
10.1.7 Causality of AEs to Study Procedures ...................................................................53 
10.1.8 Start Date ...............................................................................................................53 
10.1.9 End Date.................................................................................................................54 
10.1.10 
Pattern of Adverse Event .................................................................................54 
10.1.11 
Action Taken with Study Treatment ................................................................54 
10.1.12 
Outcome ...........................................................................................................54 
10.1.13 
Causality of AEs to Product Malfunctions ......................................................55 
10.2 
Procedures ....................................................................................................................55 
10.2.1 Collection and Reporting of AEs ...........................................................................55 
10.2.1.1 
AE Collection Period .................................................................................55 
10.2.1.2 
AE Reporting .............................................................................................55 
10.2.1.3 
AEs of Special Interest Reporting..............................................................56 
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10.2.2 Collection and Reporting of SAEs .........................................................................57 
10.2.3 Reporting of Abnormal Liver Function Tests ........................................................57 
10.2.4 Collection and Reporting of Product Malfunctions ...............................................58 
10.2.5 Collection and Reporting of Other Special Situations ..................................... ... .59 
10.3 
Follow-up of SAEs .......................................................................................... ... .......59 
10.3.1 Safety Reporting to Investigators, IRBs and Regulatory Authorities ...... . ...........59 
11.0 
STUDY-SPECIFIC COMMITTEES ............................................................. . .................61 
12.0 
DATA HANDLING AND RECORDKEEPING ..................................... ........................62 
12.1 
eCRFs ........................................................................................... . .............................62 
12.2 
Record Retention ...................................................................... ..................................63 
13.0 
STATISTICAL METHODS ................................................. ..... ......................................64 
13.1 
Statistical and Analytical Plans ................................... . ..............................................64 
13.1.1 Analysis Sets ..................................................... . .................................................64 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................64 
13.1.3 Efficacy Analysis .................................. . ..............................................................64 
13.1.3.1 
Primary Endpoint and Analytical Methods ................................................64 
13.1.3.2 
Secondary Endpoints and Analytical Methods ..........................................65 
13.1.3.3 
Methods of Data Transformation and Handling of Missing Data .............66 
13.1.4 Safety Analysis .............. .......................................................................................66 
13.1.4.1 
AEs ............... ... .........................................................................................66 
13.1.4.2 
Clinical Laboratory Test and Vital Signs ...................................................67 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................67 
13.3 
Determination of Sample Size .....................................................................................67 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................68 
14.1 
Study-Site Monitoring Visits .......................................................................................68 
14.2 
Protocol Deviations ......................................................................................................68 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................68 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................69 
15 1 
IRB Approval ...............................................................................................................69 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................69 
15.3 
Subject Confidentiality ................................................................................................70 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................71 
15.4.1 Publication and Disclosure ....................................................................................71 
15.4.2 Clinical Trial Registration ......................................................................................71 
15.4.3 Clinical Trial Results Disclosure ...........................................................................71 
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15.5 
Insurance and Compensation for Injury .......................................................................71 
16.0 
REFERENCES ..................................................................................................................72 
 
LIST OF IN-TEXT TABLES 
Table 7.a 
Allowed/Excluded Medications and Treatments ...................................... ............33 
Table 9.a 
Clinical Laboratory Tests ..................................................................... .................42 
Table 10.a 
Takeda Medically Significant AE List ......................................... . ....................52 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic Study Design .......................................... ... .........................................24 
 
 
74 
77 
78 
 
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CCI
CCI

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CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Clinical Study Sponsor(s): 
Takeda Pharmaceutical Company Limited 
Product: 
Cx601 
Study Title: 
A Phase 3, Multicenter, Open-label, Uncontrolled 
Study to Evaluate the Efficacy and Safety of Cx601 in 
the Treatment of Complex Perianal Fistulas in Adult 
Patients with Crohn's Disease 
IND No.: 
Not applicable 
EudraCT No.: 
Not applicable 
Study Identifier: Darvadstrocel-3002 
Phase: 3 
Study Design: 
This is a Phase 3, multicenter, open-label, uncontrolled study to evaluate the efficacy and safety of Cx601 in the 
treatment of complex perianal fistulas in adult patients with Crohn's disease. The study will permit continuation 
of baseline treatment for Crohn's disease in an add-on design (ie, biologics, immunosuppressants, etc.). 
This study consists of the screening period (approximately 5 weeks prior to study product administration, 
including the screening visit and the preparation visit), the treatment period (the day of study product 
administration), the follow-up period (approximately 52 weeks after study product administration), and the long-
term follow-up period (from Week 52 to Week 156). Cx601 will be administrated once on Day 1, and the efficacy 
and safety of Cx601 will be mainly evaluated in the subsequent 52-week follow-up period. The primary endpoint 
will be evaluated at Week 24. Additionally, in the long-term follow-up period after Week 52, a safety follow-up 
evaluation will be performed for all subjects every 26 weeks (6 months) until Week 156. 
An overview of study design is illustrated below: 
 
Primary Objective: 
To evaluate the efficacy of Cx601 for the treatment of complex perianal fistulas in adult patients with Crohn's 
disease over 24 weeks. 
Secondary Objectives: 
To evaluate the efficacy of Cx601 for the treatment of complex perianal fistulas in adult patients with Crohn's 
disease over 52 weeks. 
To evaluate the safety of Cx601 for the treatment of complex perianal fistulas in adult patients with Crohn's 
disease over 156 weeks. 
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Subject Population: 
The target population will consist of adult patients with Crohn's disease whose complex perianal fistulas were 
previously treated and refractory (inadequate response, loss of response or intolerance) to at least one of the 
following treatments: antibiotics, immunosuppressants or biologics. Treatment naïve subjects are excluded, and 
those who are refractory to antibiotics only must be less than 25% of all subjects enrolled. 
Planned Number of Subjects: 
20 subjects 
Planned Number of Sites: 
approximately 7 sites in Japan 
Dose Level(s): 
24 mL of cell suspension containing 
120×106 cells of expanded 
allogeneic adipose-derived stem 
cells (eASCs) (5×106 cells/mL) 
Route of Administration: 
Intralesional injection 
A half of the cell suspension will be injected into an adjacent site to the 
internal opening, and the other half into the tract wall along the fistula 
tracts through the external openings, with several micro-blebs forming 
inside the tract wall. If there are 2 internal openings, 6 mL will be injected 
into the adjacent site to each internal opening. The other half of the cell 
suspension (12 mL) will be portioned into all of the tract walls of the 
external openings. 
Duration of Treatment: 
Single dose 
Study Length: 
24 weeks for the primary endpoint evaluation, and 156 weeks for the 
safety follow-up for all subjects. 
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Main Criteria for Inclusion: 
• The subject who was diagnosed with Crohn's disease at least 6 months prior to the screening period according 
to the Diagnostic Criteria for Crohn's Disease issued by the Research Group for Intractable Inflammatory 
Bowel Disease Designated as Specified Disease by the Ministry of Health, Labour and Welfare (MHLW) of 
Japan (revised January 2017). 
• The subject is either a male or female outpatient, aged 18 years or older at the time of signing the informed 
consent form. 
• The subject who has non-active or mildly active Crohn's disease defined by the Crohn's disease activity index 
(CDAI) ≤220 evaluated at any time between Visit 1 and Visit 2. 
• The subject who has complex perianal fistulas with a maximum of 2 internal openings and a maximum of 3 
external openings, confirmed by clinical assessment and magnetic resonance imaging (MRI). All of the 
external openings must connect to internal openings. Fistula must have been draining for at least 6 weeks prior 
to the screening. Complex perianal fistula is defined as the one that meets 1 or more of the following criteria: 
‒ High (ie, above the dentate line) inter-sphincteric or trans-sphincteric fistula, extrasphincteric fistula, or 
supra-sphincteric fistula. 
‒ Presence of ≥2 external openings (tracts). 
‒ Associated fluid collections. 
• The subject whose perianal fistulas were previously treated and have shown an inadequate response (absence 
of closure of part or all fistula tract, or new fistula during induction treatment) or a loss of response (fistula 
relapse after complete closure of initial fistula, or fistula worsening after partial closure of initial fistula during 
maintenance treatment) while they were receiving either immunosuppressants or biologics, or having 
documented intolerance (occurrence, at any time, of an unacceptable level of treatment-related side effects 
that makes necessary treatment discontinuation) to any of these treatments administered at least approved or 
recommended doses during the minimum period mentioned; 
‒ Antibiotics (ciprofloxacin or metronidazole): 1 or more month treatment. 
‒ Immunosuppressants (azathioprine, 6 mercaptopurine or methotrexate): 3 or more months treatment. 
‒ Biologics (anti-TNFs, anti-integrin or anti-IL-12/23): 14 or more weeks (16 or more weeks for anti-IL-
12/23) standard treatment for induction or maintenance. 
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Main Criteria for Exclusion: 
• The subject whose CDAI is >220 at any time between Visit 1 and Visit 2, or who has active Crohn's disease 
requiring a new of escalating immediate therapy. 
• The subject who has concomitant rectovaginal or rectovesical fistulas. 
• The subject who has >2 internal openings or >3 external openings. 
• The subject who is naïve to protocol required treatment for complex perianal fistulising Crohn's disease (ie, 
antibiotics, immunosuppressants or biologics). 
• The subject who has an abscess or collections >2 cm. 
• The subject who has rectal and/or anal stenosis and/or active proctitis, which would restrict the surgical 
procedure. 
• The subject who underwent surgery other than drainage or seton placement for the treated fistula. 
• The subject who has diverting stomas. 
• The subject who was treated with systemic steroids within 4 weeks prior to study product administration. 
• The subject receiving cytapheresis therapy. 
• The subject who requires new treatment with immunosuppressants/biologics/non-tapered systematic steroids 
during the screening period. 
• The subject who has known allergies or hypersensitivity to antibiotics (including but not limited to penicillin, 
streptomycin, gentamicin, aminoglycosides), human serum albumin (HSA), bovine-derived materials, local 
anesthetics or gadolinium (MRI contrast agent). 
• The subject for whom MRI scan is contraindicated (eg, due to the presence of a pacemaker, a history of hip 
replacements, or severe claustrophobia). 
• The subject who has received eASCs in a clinical study conducted in the past or as a therapeutic agent. 
Main Criteria for Evaluation and Analyses: 
• Primary Endpoint: 
Proportion of subjects with combined remission at Week 24 (combined remission is defined as the clinically 
confirmed closure of all treated external openings that were draining at the screening despite gentle finger 
compression, and absence of collections >2 cm in the treated fistulas confirmed by central MRI assessment). 
• Secondary Endpoints: 
Efficacy analysis by Week 24: 
‒ Proportion of subjects with clinical remission at Week 24 (clinical remission is defined as the clinically 
confirmed closure of all treated external openings that were draining at the screening despite gentle finger 
compression)  
‒ Proportion of subjects with response at Week 24 (response is defined as the clinically confirmed closure of 
at least 50% of all treated external openings that were draining at the screening despite gentle finger 
compression). 
‒ Time to clinical remission by Week 24 (defined as the time from the study product administration to the 
first visit by which clinical remission is observed). 
‒ Time to response by Week 24 (defined as the time from the study product administration to the first visit 
by which response is observed). 
‒ Proportion of subjects with relapse at Week 24 in subjects with clinical remission at previous visit (relapse 
is defined as the clinically confirmed reopening of any of the treated external openings with active 
drainage, or the development of a collection >2 cm in the treated fistulas which is confirmed by the central 
MRI assessment). 
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‒ Time to relapse by Week 24 in subjects with clinical remission at previous visit (defined as the time from 
the first visit by which clinical remission is observed to the first visit by which relapse is observed). 
‒ Perianal Disease Activity Index (PDAI) (including total score, discharge sub-score and pain sub-score) up 
to Week 24. 
‒ CDAI score up to Week 24. 
‒ Van Assche score up to Week 24. 
Efficacy analysis by Week 52: 
‒ Proportion of subjects with combined remission at Week 52. 
‒ Proportion of subjects with clinical remission at Week 52. 
‒ Proportion of subjects with Response at Week 52. 
‒ Time to combined remission by Week 52 (defined as time from treatment start to the first visit combined 
remission is observed). 
‒ Time to clinical remission by Week 52. 
‒ Time to Response by Week 52. 
‒ Proportion of subjects with relapse at Week 52 in subjects with combined remission at Week 24. 
‒ Time to relapse by Week 52 in subjects with combined remission at Week 24. 
‒ PDAI score (including total score, discharge sub-score and pain sub-score) up to Week 52. 
‒ CDAI score up to Week 52. 
‒ Van Assche score up to Week 52. 
• Safety Endpoints: 
‒ Adverse events (AEs), including serious adverse events (SAEs) and AEs of special interest. 
‒ Product malfunctions. 
‒ Physical examination findings. 
‒ Vital signs (heart rate, blood pressure, body temperature). 
‒ Clinical laboratory test results (serum chemistry, hematology and urinalysis). 
Statistical Considerations: 
The primary efficacy endpoint is proportion of subjects with combined remission at Week 24. Frequency 
distribution will be provided with proportion and the two-sided confidence intervals (confidence coefficient: 90% 
and 95%). 
Sample Size Justification: 
The planned sample size is 20 based on the feasibility. However, this study has at least 94% probability to show a 
proportion of combined remission of 35% or more given an expected proportion of subjects with combined 
remission of 50% based on Week 24 results in the study Cx601-0302. 
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3.0 
STUDY REFERENCE INFORMATION 
3.1 
List of Abbreviations 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CDAI 
Crohn's Disease Activity Index 
eASC 
expanded allogeneic adipose-derived stem cells 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HSA 
human serum albumin 
ICH 
International Conference on Harmonisation 
IL 
interleukin 
INN 
international nonproprietary name 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intention to treat 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labour and Welfare 
MHRA 
Medicines and Healthcare products Regulatory Agency 
mITT 
modified intention to treat 
MRI 
magnetic resonance imaging 
PCR 
polymerase chain reaction 
PDAI 
Perianal Disease Activity Index 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
per protocol set 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SES-CD 
Simple Endoscopic Score for Crohn's Disease 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent AE 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
WBC 
white blood cell 
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3.2 
Study Definition 
Term 
Definition 
Combined remission 
Defined as the clinically confirmed closure of all treated external openings that 
were draining at the screening despite gentle finger compression, and absence 
of collections >2 cm in the treated fistulas which is confirmed by the central 
MRI assessment. 
Clinical remission 
Defined as the clinically confirmed closure of all treated external openings that 
were draining at the screening despite gentle finger compression  
Response 
Defined as the clinically confirmed closure of at least 50% of all treated 
external openings that were draining at the screening despite gentle finger 
compression. 
Relapse 
Defined as the clinically confirmed reopening of any of the treated external 
openings with active drainage, or the development of a collection >2 cm in the 
treated fistulas confirmed by central MRI assessment. 
Time to combined remission/ 
clinical remission/response 
The time from the study product administration to the first visit by which 
combined remission/clinical remission/response is observed. 
Time to relapse 1) 
The time from the first visit which linical remission is observed to the first 
visit by which relapse is observed. 
1) Time to relapse by Week 52 in subjects who achieved combined remission at Week 24 is defined as “the time 
from the combined remission at Week 24 to the first visit by which relapse is observed.” 
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4.0 
INTRODUCTION 
4.1 
Background 
4.1.1 
Complex Perianal Fistulising Crohn's Disease 
Crohn's disease is a granulomatous inflammatory disease, which occurs predominantly in young 
people. The lesion develops in any part of the gastrointestinal tract from mouth to anus, 
commonly in small intestine and large intestine, with characteristic pathological conditions (eg, 
intestinal stenosis due to edema or ulcer, and fistulas). Clinical symptoms mainly include 
gastrointestinal symptoms such as diarrhea and abdominal pain, systemic symptoms (eg, fever, 
weight loss, malnutrition) and complication-induced symptoms (eg, anemia, arthritis, iritis, skin 
lesions). The etiology of Crohn's disease has not been well elucidated yet, and Crohn's disease is 
designated as the specified rare and intractable disease in Japan. The number of the recipient 
certificates issued for specific disease treatment for Crohn's disease is increasing year by year[1]. 
The number of recipients of the specific medical expense for Crohn's disease (a designated 
intractable disease) in FY2016 is reported to be 42,789 patients[2]. 
Anal lesion is one of characteristic complications of Crohn's disease, and the cumulative 
incidence rates of the disease for 10 years after diagnosis is reported to be 74% to 80%[3]. In 
Japan, the frequency of anal fistula and perianal abscess is especially high[3], and the associated 
pain and drainage markedly deteriorate patients' quality of life (QOL). Futami et al. reported that, 
of 577 patients with Crohn's disease, 367 patients had anal fistula or abscess, of which 166 
patients had complex fistulas with multiple external openings[4]. 
The prognosis of complex perianal fistula with Crohn's disease is poor. Similar to the intestinal 
lesion, recurrence/relapse is repeated. If repeated recurrence/relapse interferes with a patient's 
daily life, a surgical treatment may be selected. Also, a colostomy may be considered for severe 
cases. For simple anal fistula, a radical surgery may be selected, but it may invade the sphincter 
muscle and affect the postoperative anal function. Therefore, for complex perianal fistula, 
considering the high risk of relapse, the seton drainage is usually selected rather than radical 
surgery, in terms of preservation of anal function and alleviation of symptoms. However, the 
seton drainage often requires drainage for more than one year and deteriorate patients' QOL. 
Infliximab (recombinant), a biological product and anti-human tumor necrosis factor-α (TNFα) 
monoclonal antibody, was approved for the treatment of Crohn's disease with external fistula in 
2002. However, in a clinical trial investigating the remission-maintaining effect of Infliximab on 
anal lesions (ACCENT II), the proportion of subjects who achieved fistula closure after 54-week 
treatment remains 36%[5], which suggests that Infliximab is not always effective in all patients. 
Furthermore, immunosuppressants and TNF antagonists may cause side effects associated with 
systemic immunosuppression. Therefore, there exists an unmet medical need in the treatment of 
complex perianal fistula. 
4.1.2 
Cx601 
Cx601 (INN: Darvadstrocel) is a human cell-processed therapeutic product developed by the 
TiGenix S.A.U as a regenerative medical product for treatment of complex perianal fistulas with 
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subjects who achieved complete closures of the external openings of the treated perianal 
fistula was 38.1% (8/21 subjects) at Week 12, and 56.3% (9/16 subjects) at Week 24[6]. 
4.1.3.2 
Study Cx601-0302 (Phase 3, Placebo-controlled Study) 
Study Cx601-0302 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of Cx601 in subjects with complex 
perianal fistulas with Crohn's disease. The target subjects in this study were those with complex 
perianal fistulising Crohn's disease refractory to at least one of the existing treatments (eg, 
antibiotics, immunosuppressants or biologics). A total of 212 subjects were randomized, and 
single dose of Cx601 (120×106 cells of eASCs) or placebo (saline) were administered to 103 of 
107 subjects in the Cx601 group and 102 of 105 subjects in the placebo group, respectively. The 
primary endpoint (proportion of subjects with combined remission) was evaluated at Week 24 
and follow-up was conducted up to Week 104. 
The main results of study Cx601-0302 up to Week 104 are shown below. 
• The 24-week post-treatment evaluation was completed in 171 subjects (80.7%), which 
consisted of 88 subjects (82.2%) in the Cx601 group and 83 subjects (79.0%) in the placebo 
group. The main reasons for withdrawal from the study by Week 24 were adverse event, 
surgical procedure for other reason than fistulas, worsening of Crohn's disease requiring 
change in therapy. The 52-week post-treatment evaluation was completed in 131 subjects 
(61.8%), which consisted of 70 subjects (65.4%) in the Cx601 group and 61 subjects (58.1%) 
in the placebo group. The main reasons for withdrawal from the study during the period 
between Weeks 24 and 52 were the lack of efficacy against fistulas or worsening fistula, 
adverse events, surgical procedure for other reason than fistulas, worsening of Crohn's 
disease requiring change in therapy. The 104-week post-treatment evaluation was completed 
in 37 subjects (17.5%), which consisted of 23 subjects (21.5%) in the Cx601 group and 
14 subjects (13.3%) in the placebo group. The main reasons for withdrawal from the study 
during the period between Weeks 52 and 104 were withdrawal of patient consent to 
participate in the study, or others. 
• The proportion of subjects who achieved combined remission at Week 24, which is the 
primary endpoint, was significantly higher (p=0.024) in the Cx601 group (49.5%) than in the 
placebo group (34.3%). In addition, the secondary endpoints were also superior in the Cx601 
group to the placebo group; the proportion of subjects who achieved clinical remission at 
Week 24 was 53.3% in the Cx601 group and 40.0% in the placebo group (p=0.064), and the 
proportion of subjects who achieved response at Week 24 was 66.4% in the Cx601 group and 
53.3% in the placebo group (p=0.054). 
• The proportion of subjects who achieved combined remission, clinical remission and 
response at Week 24 were all higher in the Cx601 group compared to the placebo group, and 
these trends were observed at Week 52 (the proportion of subjects who achieved combined 
remission at Week 52 [Cx601 vs Placebo] was 54.2% vs 37.1%, the proportion of subjects 
who achieved clinical remission at Week 52 [Cx601 vs Placebo] was 57.0% vs 40.0%, the 
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proportion of subjects who achieved response at Week 52 [Cx601 vs Placebo] was 63.6% vs 
53.3%). 
• In post hoc analyses of clinical remission at Week 104 on observed data, the proportion of 
subjects who achieved clinical remission at Week 104 (Cx601 vs Placebo) was 56.0% vs 
40.0%, a greater proportion of patients in the Cx601 group achieved clinical remission 
compared with placebo group. 
• Total Perianal Disease Activity Index (PDAI) decreased in both treatment groups at all visits 
up to Week 24 and Week 52 with the decrease being slightly greater in the Cx601 treatment 
group compared with the placebo group. Results at Week 104 are aligned. Mean Crohn's 
Disease Activity Index (CDAI) total scores at Week 104 were comparable to those at 
baseline, Weeks 24 and 52. 
• The incidence of TEAEs up to Week 52 was 76.7% (79/103 subjects) in the Cx601 group 
and 72.5% (74/102 subjects) in the placebo group, which was comparable between both 
groups. In addition, the incidence of TEAEs that lead to discontinuation of the study was low 
(8.8% overall) and similar in both groups (8.7% in the Cx601 group and 8.8% in the placebo 
group). The majority of TEAEs observed by Week 52 were mild or moderate in intensity, 
and the incidence of severe TEAEs (10.7% overall) was similar in both groups (9.7% in the 
Cx601 group and 11.8% in the placebo group). Most of the TEAEs reported up to Week 52 
were considered not related to the study treatment, and the treatment-related TEAEs were 
more frequently reported in the placebo group (26.5%) than in the Cx601 group (20.4%). 
• The incidence of serious TEAEs up to Week 52 was slightly higher in the Cx601 group 
(24.3%) than in the placebo group (20.6%). The most common serious TEAE was anal 
abscess, the incidence was slightly higher in the Cx601 group (13.6%) than in the placebo 
group (7.8%). The number of subjects whose anal abscess was considered serious and 
treatment-related was similar in both groups (7 subjects in the Cx601 group, 5 subjects in the 
placebo group). 
• The safety profile of Cx601 up to Week 104 were similar to that up to Week 52. Only 4 new 
serious TEAEs (3 in Cx601 group [fistula discharge, anal fistula/disease recurrence, anal 
abscess/pain/pyrexia] and 1 in placebo group [fistula discharge/anal fistula excision]) were 
reported among the 37 patients who entered the extended follow-up period after Week 52 up 
to Week 104. None were considered related to the treatment administered. No new suspected 
unexpected serious adverse reactions (SUSARs) were reported, thus no apparent new safety 
signals occurred up to 104 weeks follow-up extension. 
4.2 
Rationale for the Proposed Study 
This will be the first study to evaluate the efficacy and safety of Cx601 in Japanese subjects with 
complex perianal fistulas with Crohn's disease. 
The available evidences based on the efficacy and safety data from clinical studies conducted in 
Europe suggest that Cx601 was safe and effective in closing the fistula and the effect sustained 
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up to Week 52 in subjects with complex perianal fistula refractory to at least one of existing 
treatments (ie, antibiotics, immunosuppressants or TNF antagonists). 
However, Cx601 has never been administered to Japanese, and no definite conclusion has been 
drawn from previous clinical studies on that there might be ethnic differences in the efficacy and 
safety of Cx601. Cx601 is allogeneic adipose tissue-derived mesenchymal stem cells, and the 
direct injection of Cx601 into the target lesion promotes the healing of the perianal tissue with 
fistula, so that there may be no ethnic differences in pharmacokinetics that may influence clinical 
outcome. There are no major differences in diagnosis and treatment of complex perianal 
fistulising Crohn's disease between Japan and foreign countries when comparing the Japanese 
guidelines for the treatment of perianal lesion of Crohn's disease (revised January 2016)[7], with 
the American Gastroenterological Association (AGA) guideline published in 2003[8], and the 
European Crohn's and Colitis Organization (ECCO) guideline published in 2010[9], there are no 
major differences between home and abroad on diagnosis and treatment of complex perianal 
fistulas with Crohn's disease. Considering the above, it is thought that Cx601 will be effective for 
Japanese population, similar to the result of the study Cx601-0302, and this study can be carried 
out safely by appropriate monitoring of safety during the study. 
From the above, this study has been planned because Cx601 could be a new option for the 
treatment of complex perianal fistulas in Japanese patients with Crohn's disease as the current 
treatment options for the disease are limited. 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
• To evaluate the efficacy of Cx601 for the treatment of complex perianal fistulas in adult 
patients with Crohn's disease over 24 weeks. 
5.1.2 
Secondary Objectives 
• To evaluate the efficacy of Cx601 for the treatment of complex perianal fistulas in adult 
patients with Crohn's disease over 52 weeks. 
• To evaluate the safety of Cx601 for the treatment of perianal fistulas in adult patients with 
Crohn's disease over 156 weeks. 
5.1.3 
Additional Objectives 
• To evaluate the absence of clinically relevant alloreactivity. 
• To evaluate the effects of Cx601 on Crohn's disease activity and quality of life. 
5.2 
Endpoints 
5.2.1 
Primary Endpoint 
• Proportion of subjects with combined remission at Week 24. 
5.2.2 
Secondary Endpoints 
Efficacy analysis using data up to Week 24: 
• Proportion of subjects with clinical remission at Week 24. 
• Proportion of subjects with response at Week 24. 
• Time to clinical remission by Week 24. 
• Time to response by Week 24. 
• Proportion of subjects with relapse at Week 24 in subjects with clinical remission at previous 
visit. 
• Time to relapse by Week 24 in subjects with clinical remission at previous visit. 
• PDAI score (including total score, discharge sub-score and pain sub-score) up to Week 24. 
• CDAI score up to Week 24. 
• Van Assche score up to Week 24. 
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Efficacy analysis using data up to Week 52: 
• Proportion of subjects with combined remission at Week 52. 
• Proportion of subjects with clinical remission at Week 52. 
• Proportion of subjects with response at Week 52. 
• Time to combined remission by Week 52. 
• Time to clinical remission by Week 52. 
• Time to response by Week 52. 
• Proportion of subjects with relapse at Week 52 in subjects with combined remission at 
Week 24. 
• Time to relapse by Week 52 in subjects with combined remission at Week 24. 
• PDAI score (including total score, discharge sub-score and pain sub-score) up to Week 52. 
• CDAI score up to Week 52. 
• Van Assche score up to Week 52. 
5.2.3 
Safety Endpoints 
• Adverse events (AEs) including serious adverse events (SAEs) and AEs of special interest. 
• Product malfunctions. 
• Physical examination findings. 
• Vital signs (heart rate, blood pressure, body temperature). 
• Clinical laboratory test results (serum chemistry, hematology and urinalysis). 
5.2.4 
Additional Endpoints 
• Presence/absence of anti-donor antibody. 
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is Phase 3, a multicenter, open-label, uncontrolled study to evaluate the efficacy and safety 
of Cx601 in the treatment of complex perianal fistulas in adult patients with Crohn's disease. 
Subjects with Crohn's disease whose complex perianal fistulas were previously treated and 
refractory (inadequate response, loss of response or intolerance) to at least one of the following 
treatments: antibiotics, immunosuppressants or biologics (anti-TNFs, anti-integrin or anti-IL-
12/23) will be included in the study (See Inclusion Criteria on Section 7.1). Note that those 
subjects who are refractory to antibiotics only will be must be less than 25% of all subjects 
enrolled. 
The study will permit continuation of baseline treatments for Crohn's disease in an add-on design 
(ie, biologics, immunosuppressants, etc.). A total of 20 subjects are planned to be enrolled, and 
study product, cell suspension containing 120×106 cells of eASCs, will be intralesionally 
injected to all participants. Since this is the first study of Cx601 in Japanese subjects, the 
enrollment of at least the first 3 subjects will be adjusted not to be administered the study product 
at the same day. 
This study consists of the screening period (approximately 5 weeks prior to study product 
administration, including the screening visit and the preparation visit), the treatment period (the 
day of study product administration), the follow-up period (approximately 52 weeks after study 
product administration), and the long-term follow-up period (from Week 52 to Week 156). 
Cx601 will be administrated once on Day 1, and the efficacy and safety of Cx601 will be mainly 
evaluated in the subsequent 52-week follow-up period. The primary endpoint will be evaluated at 
Week 24. Additionally, in the long-term follow-up period after Week 52, a safety follow-up 
evaluation will be performed for all subjects every 26 weeks (6 months) until Week 156. 
In the screening period, a screening visit (Visit 1) to determine a subject's eligibility is scheduled 
during the period from Day -39 to the day before VISIT2. All the subjects eligible by the 
screening will receive fistula curettage and seton placement under anesthesia at the preparation 
visit (Visit 2: Day 21, done no later than Day -14). Seton(s) placed will be removed on the day 
of study product administration (Visit 3: Day 1), just before the administration of the study 
product. Appropriate training for the preparation and the administration will be implemented to 
standardize the procedures between study sites. 
The subjects who meet all the eligibility criteria will visit the study site on Day 1, and receive 
fistula curettage under anesthesia and an intralesional injection of cell suspension containing 
120×106 cells of eASCs (Cx601). Thereafter, in follow-up period, the subjects will visit the study 
site for the clinical assessments including fistula closure at Weeks 2, 4, 8, 16, 24, 40 and 52. 
Radiological assessments (MRI) of fistula closure will also be performed at Weeks 24 and 52. 
Additionally, in the long-term follow-up period, the safety follow-up will be performed on all the 
subjects (where possible) every 26 weeks (6 months) from a visit in Week 52 through Week 156. 
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This study will be switched to a post-marketing clinical study if Cx601 is approved before the 
study completion. 
A schematic study design is shown in Figure 6.a. A schedule of assessments is listed in 
Appendix A. 
Figure 6.a 
Schematic Study Design 
 
 
All or some parts of the study results may be used as the data for post-authorization safety 
studies conducted in Europe or long-term evaluation studies planned in the future. 
6.2 
Justification for Study Design, Dose, and Endpoints 
(1) Objectives and target population 
This study has been planned to evaluate the efficacy and safety of Cx601 for the treatment of 
complex perianal fistulas in Japanese patients with Crohn's disease as the current treatment 
options for the disease are limited. 
In the Phase 3 placebo-controlled study conducted overseas (study Cx601-0302), the efficacy of 
Cx601 has been confirmed in subjects with complex perianal fistulising Crohn's disease 
refractory to at least one of existing treatments (ie, antibiotics, immunosuppressants or TNF 
antagonists). Since similar result is expected in the same sub-population in Japanese, the target 
population in this study is defined as Japanese subjects with complex perianal fistulising Crohn's 
disease refractory to at least one of existing treatments (ie, antibiotics, immunosuppressants or 
biologics) as well. 
(2) Study design 
Since the number of patients with complex perianal fistulising Crohn's disease is small in Japan, 
the study design with control-arm is considered to be very difficult to carry out. Considering the 
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feasibility of implementation in small number of subjects, the study is determined to be 
multicenter, open-label, uncontrolled design. 
Considering that the target population is the subjects who failed to achieve complete closure of 
fistulas despite existing treatments and evaluation of complete closure of the fistulas could be 
performed objectively as well as study Cx601-0302, it is thought to be possible to suggest the 
clinical meanings of Cx601 without control group setting. Additionally, considering the results 
of study Cx601-0302, the efficacy and safety of Cx601 in Japanese population can be evaluated 
comprehensively. 
(3) Dose and Regimen 
In the open-label, uncontrolled study conducted overseas (study Cx601-0101), 24 subjects 
received a dose of at least 20×106 cells of eASCs (Cx601), of which 15 subjects with incomplete 
fistula closure at Week 12 received an additional 40×106 cells of eASCs. As a result, proportion 
of subjects with closure of the external opening of the treated perianal fistula at Weeks 12 and 24 
was 38.1% (8/21 subjects) and 41.7% (5/12 subjects), respectively. Although a certain proportion 
of subjects achieved closure of the external opening by the first dosing of 20×106 cells, there was 
similar proportion of subjects who achieved closure of the external opening by additional dose of 
40×106 cells after first dose. From this results, it is considered that the dose of 20×106 cells is not 
always sufficient for all patients. 
Based on the above results, in the study Cx601-0302, considering that the subject has maximum 
3 fistula tracts, 120×106 cells dose, 3-fold higher than 40×106 cells dose showing efficacy for 1 
fistula tract in study Cx601-0101, was selected. And single dose were selected in order to avoid 
fistula curettage in subjects whose fistulas may have partially closed. In these dose and regimen 
settings, the efficacy in the Cx601 group was superior to the placebo group in study Cx601-0302. 
Based on the results of study Cx601-0302, it is considered that a single dose of 120×106 cells 
could be also effective in Japanese, similar to study Cx601-0302. 
(4) Study duration 
Considering the comparability of the results in this study with study Cx601-0302, 24-week 
evaluation period for the primary endpoint, and 52-weeks evaluation period for secondary 
endpoints are defined in this study. 
Furthermore, the evaluation up to Week 104 was included in the study Cx601-0302. Considering 
that this is the first study for Cx601 in Japanese population, and longer-term follow-up is 
important to establish the safety and efficacy profile of Cx601 in the small number of subjects, 
156-week evaluation, exceeding the study Cx601-0302, is defined in this study for the purpose of 
safety follow-up. 
(5) Endpoints 
Considering the comparability of the results in this study with study Cx601-0302, combined 
remission with the same definition as the study Cx601-0302 is selected as the primary endpoint. 
In general, fistula closure (defined as no draining from external openings despite gentle finger 
compression) is a conventional endpoint to determine the response to treatment in clinical 
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studies[10], and it is also used in clinical practice[9]. However, no draining from external 
openings does not always reflect the state of complete closure of the fistula tract. If inflammation 
remains in the fistula tract, there are risks of perianal abscess and fistula recurrence[11]. 
Therefore, in addition to the confirmation of no draining from the external openings despite 
gentle finger compression, when absence of collections >2 cm are confirmed by MRI assessment 
is defined as combined remission, it is thought to be appropriate as the primary endpoint. 
The other secondary endpoints are defined same as the study Cx601-0302 in order to compare 
the efficacy results of this study with those of study Cx601-0302. Because the presence or 
absence of draining is considered an important secondary endpoint in the clinical development 
guideline for the treatment of Crohn's disease published by EMA[12], clinical remission and 
response will be evaluated by confirming absence of draining from external openings despite 
gentle finger compression. In addition, PDAI[13] will be evaluated in this study because the 
above guideline recommends use of PDAI as a secondary endpoint as index of the severity of 
fistula in patients with Crohn's disease and study Cx601-0302 showed improvements in PDAI 
discharge sub-score and pain sub-score as well as PDAI total score. CDAI[14] will be evaluated 
because it is commonly used in clinical studies as an index of severity of Crohn's disease. Van 
Assche[15] will be evaluated because it is a useful to evaluate the severity of fistula in patients 
with Crohn's disease by MRI. 
6.3 
Premature Termination or Suspension of Study or Study Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of the study product that 
indicates a change in the known risk/benefit profile for the product, such that the risk/benefit 
is no longer acceptable for subjects participating in the study. 
• Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety. 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the study 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. 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
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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. 
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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to study product 
administration. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to study product 
administration: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
the protocol requirements. 
2. The subject or, when applicable, the subject's legally acceptable representative signs and 
dates a written, informed consent form and any required privacy authorization prior to the 
initiation of any study procedures. 
3. The subject who was diagnosed with Crohn's disease at least 6 months prior to the screening 
period according to the Diagnostic Criteria for Crohn's Disease issued by Research Group for 
Intractable Inflammatory Bowel Disease Designated as Specified Disease by the MHLW of 
Japan (revised January 2017). 
4. The subject is either a male or female outpatient, aged 18 years or older at the time of signing 
the informed consent form. 
5. The subject who has non-active or mildly active Crohn's disease defined by the CDAI ≤220 
evaluated at any time between Visit 1 and Visit 2. 
6. The subject who has complex perianal fistulas with a maximum of 2 internal openings and a 
maximum of 3 external openings, confirmed by clinical assessment and MRI. All of the 
external openings must connect to internal openings. Fistula must have been draining for at 
least 6 weeks prior to the screening. Complex perianal fistula is defined as the one that meets 
1 or more of the following criteria: 
– High (ie, above the dentate line) inter-sphincteric or trans-sphincteric fistula, 
extrasphincteric fistula, or supra-sphincteric fistula. 
– Presence of ≥2 external openings (tracts). 
– Associated fluid collections. 
7. The subject whose perianal fistulas were previously treated and have shown an inadequate 
response (absence of closure of part or all fistula tract, or new fistula during induction 
treatment) or a loss of response (fistula relapse after complete closure of initial fistula, or 
fistula worsening after partial closure of initial fistula during maintenance treatment) while 
they were receiving either immunosuppressants or biologics, or having documented 
intolerance (occurrence, at any time, of an unacceptable level of treatment-related side 
effects that makes necessary treatment discontinuation) to any of these treatments 
administered at least approved or recommended doses during the minimum period 
mentioned; 
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– Antibiotics (ciprofloxacin or metronidazole): 1 or more month treatment. 
– Immunosuppressants (azathioprine, 6-mercaptopurine or methotrexate): 3 or more 
months treatment. 
– Biologics (anti-TNFs, anti-integrin or anti-IL-12/23): 14 or more weeks (16 or more 
weeks for anti-IL-12/23) standard treatment for induction or maintenance. 
8. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential* agrees to use adequate contraception* from signing of informed 
consent up to Week 52 of the study. 
9. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent up 
to Week 52 of the study. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.9 and reporting responsibilities are defined in Section 
9.1.10. 
 
Justification for Inclusion Criteria 
1 and 2: Are the basic criteria for conducting a clinical study. 
3: Is the criterion for ensuring the diagnosis of Crohn's disease. 
4: Is defined because Crohn's disease can occur in both men and women, and often in younger 
people. And it is also appropriate to enroll outpatients as the study subjects in consideration of 
the severity of Crohn's disease. 
5 to 7: Are the criteria for identifying the pathological conditions of Crohn's disease and complex 
perianal fistulas in this study  
8 and 9: Are included in consideration of the risks of pregnancy. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject whose CDAI is >220 at any time between Visit 1 and Visit 2, or who has active 
Crohn's disease requiring a new of escalating immediate therapy. 
2. The subject who has concomitant rectovaginal or rectovesical fistulas. 
3  The subject who has >2 internal openings of >3 external openings. 
4. The subject who is naïve to protocol required treatment for complex perianal fistulising 
Crohn's disease (ie, antibiotics, immunosuppressants or biologics). 
5. The subject who has an abscess or collections >2 cm. 
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6. The subject who has rectal and/or anal stenosis and/or active proctitis, which would restrict 
the surgical procedure. 
7. The subject who underwent surgery other than drainage or seton placement for the to be 
treated fistula. 
8. The subject who has diverting stomas. 
9. The subject who was treated with systemic steroids in the 4 weeks prior to study product 
administration. 
10. The subject receiving cytapheresis therapy. 
11. The subject who requires new treatment with immunosuppressants/biologics/non-tapered 
systematic steroids during the screening period. 
12. The subject who has renal impairment defined by creatinine clearance below 60 mL/min 
calculated using Cockcroft-Gault formula or by serum creatinine ≥1.5 × upper limit of 
normal (ULN). 
13. The subject who has hepatic impairment defined by both total bilirubin ≥1.5 × ULN, and 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥2.5 × ULN. 
14. The subject who has history of abuse of alcohol or other addictive substances in the 6 months 
prior to the screening period. 
15. The subject who has malignant tumour or who has a history of malignant tumour, including 
any type of fistula carcinoma. 
16. The subject who has abnormal, severe, progressive, uncontrolled hepatic, hematological, 
gastrointestinal (except Crohn's disease), endocrine, pulmonary, cardiac, neurological, 
psychiatric, or cerebral disease, or the subject who developed any of the above diseases 
within 3 months prior to the screening period. 
17. The subject who has congenital or acquired immunodeficiency, including subjects known to 
be HIV carriers. 
18. The subject who has clinically significant chronically active hepatopathy of any origin, 
including hepatic cirrhosis, and subjects who is persistent positive for hepatitis B virus 
(HBV) surface antigen (HBsAg) and quantitative HBV polymerase chain reaction (PCR), or 
positive serology for hepatitis C virus (HCV) and quantitative HCV-PCR within 6 months 
prior to the screening period. 
19. The subject who has known allergies or hypersensitivity to antibiotics (including but not 
limited to penicillin, streptomycin, gentamicin, aminoglycosides), Human Serum Albumin 
(HSA), bovine-derived materials, local anesthetics or gadolinium (MRI contrast agent). 
20. The subject for whom MRI scan is contraindicated (eg, due to the presence of a pacemaker, a 
history of hip replacements, or severe claustrophobia). 
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21. The subject who has major surgery (eg, surgery under general anesthesia, laparotomy, 
thoracotomy, craniotomy) or severe trauma within 6 months prior to the screening period. 
22. The female subject who is pregnant, or is lactating. 
23. The subject who has received any investigational drug within 12 weeks (84 days) prior to the 
screening. 
24. The subject who has received eASC in a previous clinical study or as a therapeutic agent. 
25. The subject who needs perianal surgery other than fistulas preparation required by the 
protocol during the screening, or the subject who will receive a perianal surgery within 
24 weeks after study product administration. 
26. The subject for whom anesthesia is contraindicated. 
27. The subject who received excluded medications or treatment listed in Section 7.3. 
Justification of Exclusion Criteria 
1 to 5: These subject were not the target population of this study. 
6: These conditions could restrict the procedures for the study treatment. 
7, 9, 10, 11, 21, 23 to 25, 27: These conditions could influence the evaluation of efficacy and 
safety. 
8: This condition could make it impossible to evaluate perianal fistulas. 
12 to 18: These conditions could influence the safety of the subjects, and because it could 
influence the evaluation of study product. 
19, 26: These were set with respect to the safety of the subjects exposed to the ingredients/drugs, 
which are contained in study product or used for procedure prior to the administration of study 
product. 
20: This condition could make it impossible to perform MRI scan required for the primary 
endpoint. 
22: To ensure the safety of pregnant women and fetuses, or nursing infants. 
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 particular restrictions for medications and 
treatments after Week 52, but follow the rules set before Week 52, as far as possible. In there are 
any questionable medications or treatments, the sponsor or its designee should be contacted. 
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If a subject received any excluded medications or treatments, the subject may continue to 
participate in the study as long as the risk is considered acceptable by the investigator. 
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Table 7.a 
Allowed/Excluded Medications and Treatments 
Medications/Treatment 
Period from start of 
screening period to study 
product administration 
Period from study 
product 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 prior to start of 
screening period.) 
NOT Allowed 
These 
medications/treatments are 
excluded in consideration 
of any influences on the 
efficacy and safety 
evaluation of the study 
product. 
Antibiotics 
(including but not 
limited to ciprofloxacin 
and/or metronidazole) 
Allowed 
(Continuous use of 
antibiotics must be up to 
4 weeks.) 
Allowed 
(Continuous use of 
antibiotics must be up to 
4 weeks, including the 
period before the study 
product administration.) 
These medications are 
allowed with the 
restriction of dosing period 
because long-term use 
beyond clinical standard 
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 
the study product. 
Topical steroid 
Inhalatory steroids 
Allowed 
Allowed 
These medications are 
allowed because they have 
less effect on the efficacy 
and safety evaluation of 
the study product. 
Immunosuppressants 
(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 
the study product. 
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Table 7.a 
Allowed/Excluded Medications and Treatments (Cont.) 
Medications/Treatment 
Period from start of 
screening period to study 
product administration 
Period from study 
product administration 
to Week 52 
Justification 
Biologics 
(anti-TNF, anti-integrin, 
anti-IL-12/23) 
Allowed 
(Continuous use of biologics 
is allowed if it showed no 
response to complex 
perianal fistulas despite at 
least 14-week treatment 
[16 weeks for anti-IL-12/23] 
prior to 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 
the study product. 
Systematic steroids 
Rectal steroids 
Allowed 
(These medications should 
be tapered and discontinued 
within 4 weeks prior to 
study product 
administration.) 
NOT Allowed 
(These medication are 
allowed as a rescue 
therapy only when Crohn's 
disease worsened. See 
Section 7.4.) 
These medications are 
excluded in consideration 
of any influences on the 
efficacy and safety 
evaluation of the study 
product. Use for a rescue 
therapy is allowed in 
consideration of the safety 
of subjects. 
Enteral nutrition 
Allowed 
Allowed 
These medications are 
allowed because they have 
less effect on the efficacy 
and safety evaluation of 
the study product. 
Central venous nutrition 
Enteral total nutrition 
NOT Allowed 
NOT Allowed 
(These treatments are 
allowed to use as a rescue 
therapy only when Crohn's 
disease worsened. See 
Section 7.4.) 
These treatments are 
excluded in consideration 
of any influences on the 
efficacy and safety 
evaluation of the study 
product. Use for a rescue 
therapy is allowed in 
consideration of the safety 
of subjects. 
Cytapheresis 
NOT Allowed 
NOT Allowed 
These medications are 
excluded in consideration 
of any influences on the 
efficacy and safety 
evaluation of the study 
product. 
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Table 7.a 
Allowed/Excluded Medications and Treatments (Cont.) 
Medications/Treatment 
Period from start of 
screening period to study 
product administration 
Period from study 
product administration 
to Week 52 
Justification 
Medications/treatments 
for Crohn's disease not 
including the above 
Allowed 
Allowed 
These medications are 
allowed because they have 
less effect on the efficacy 
and safety evaluation of 
the study product. 
Oral anticoagulants 
NOT Allowed 
(If an anticoagulant has been 
used before screening period 
and required continuous use, 
it should switch 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 in 
preparation and study 
product administration. 
Medications/treatments 
for a disease other than 
Crohn's disease, not 
including the above 
Allowed 
Allowed 
These medications are 
allowed because they have 
less effect on the efficacy 
and safety evaluation of 
the study product. 
7.4 
Rescue Therapy 
If worsening of Crohn's disease is observed within 52 weeks after study product administration, 
the following treatments will be permitted as a rescue therapy. In the applicable case, the subject 
should continue the study according to the study schedule. 
• A steroid course starting at 40 mg or less dose (as prednisolone or equivalent, 9 mg for 
Budesonide) and tapering over 12 weeks, or 
• Central venous nutrition/enteral total nutrition (allowed until a flare improves). 
If a subject receive an excluded medication or treatment for rescue (eg, commencement of a new 
dosing with an immunosuppressant/biologics, or a dose increase in a concomitant medications 
which has been used at the baseline of the study), the subject must be treated as a non-responder 
(See Section 13.1.3.3). Then, the subject may continue to participate in the study as long as the 
risk is considered acceptable by the investigator. 
If a deterioration of the complex perianal fistulising Crohn's disease or a complication (such as 
abscess, sepsis, etc.) is observed, the subject should receive an appropriate treatment depending 
on the symptom. If a subject receive medications which could affect fistula closure directly, the 
subject must be treated as a non-responder (See Section 13.1.3.3).Then, the subject may continue 
to participate in the study as long as the risk is considered acceptable by the investigator. 
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7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study should be 
recorded in the electronic case report form (eCRF) using the following categories. For subject 
failure, refer to Section 9.1.19. 
1. Death. The subject died on study. 
Note: If the subject dies on study, the event will be considered as SAE. See Section 10.2.2 
for the reporting procedures. 
2. Adverse event (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. 
• 
Liver Function Test Abnormalities. 
Appropriate clinical follow-up (including repeat laboratory tests, until a subject's laboratory 
profile has returned to normal/baseline status, See Section 9 1.8) will be conducted, if the 
following circumstances occur at any time during study treatment: 
– ALT or AST >8 × ULN, or 
– ALT or AST >5 × ULN and persists for more than 2 weeks, or 
– ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
3. Protocol deviation. The discovery after the dose of study product that the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject's health. 
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject's 
source documents. 
5. Withdrawal by subject. The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to 
an AE or lack of efficacy). 
6. Study terminated by sponsor. The sponsor terminates the study. 
7. Pregnancy. The subject is found to be pregnant, and continued participation imposes an 
unacceptable risk to the subject's health. 
Note: If the subject is found to be pregnant before Week 52, the subject must be withdrawn 
immediately. If the subject is found to be pregnant after Week 52, the subject may continue 
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to participate in the study as long as the risk is considered acceptable by the investigator. The 
procedure when a pregnancy occurs is described in Section 9.1.10. 
8. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
study treatment; and, continued participation would pose an unacceptable risk to the subject. 
9. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
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 termination 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. 
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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
8.1 
Study Product and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
The study product is a human cell-processed product defined as following: 
Study product name: 
Code name: Cx601 
INN: Darvadstrocel 
Product substance, excipients, strength and formulation 
Cx601 is a cell suspension containing eASCs, which original allogeneic adipose tissue is 
obtained from a healthy donor and expanded ex vivo. 
Cx601 is supplied as a white to yellowish homogeneous suspension of 5×106 eASCs per mL of 
Dulbecco Modified Eagle's Medium with 5% HSA. 
Packaging, Labeling, Manufacturing 
Study product is provided as 4 glass vials containing 6 mL of eASC suspension each, duly 
labelled, tightly closed with rubber stoppers and sealed with an aluminium cap. The disposable 
vials are packaged in a carton box with its corresponding labeling. 
The labels will contain, but will not be limited the following: study product name, product 
identification number, protocol number, sponsor's name and address, and state that the drug is for 
study use only. 
Study products are manufactured by TiGenix S.A.U. 
Additional reference information can be found in the manual. 
8.1.2 
Storage 
The study product will be shipped directly from the manufacturing site to each study site under 
temperature-controlled conditions, using an appropriate transportation method. The study 
product must be stored under the storage conditions specified in the manual, and be remained in 
the original container until dispensed. 
8.1.3 
Dose and Regimen 
In this study, 24 mL of cell suspension containing 120×106 cells of eASC (5×106 cells/mL) will 
be given to all subjects as a single intralesional dose according to the study schedule. 
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A half of the cell suspension will be injected into an adjacent site to the internal opening, and the 
other half into the tract wall along the fistula tracts through the external openings, with several 
micro-blebs forming inside the tract wall. If there are 2 internal openings, 6 mL will be injected 
into the adjacent site to each internal opening. The other half of the cell suspension (12 mL) will 
be portioned into all of the tract walls of the external openings. 
The details of procedures for study product administration are specified in the manual  
Prior to the first administration of the study product, 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 product, to or 
by a study subject, at a dose above that which is assigned to that individual subject according to 
the study protocol. 
All cases of overdose (with or without associated AEs) will be recorded on an Overdose page of 
the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be recorded on an AE page of the eCRF 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 Product Dispensing Procedures 
The study products will be shipped from the manufacturing site upon request from the 
investigator according to the separately specified procedures, and delivered to the study site on 
the day of study product administration or the previous day. The investigator or the designee will 
record the product identification number on eCRF. 
8.3 
Accountability and Destruction of Sponsor-Supplied Products 
The site designee will receive the procedure manual for handling, storage and management of 
study products created by the sponsor, according to which the site designee will appropriately 
manage the sponsor-supplied product. The investigator will also receive those procedures from 
the sponsor. The procedure manual includes those for ensuring appropriate receipt, handling, 
storage, management, dispensation of the sponsor-supplied product, and return of unused 
products to the sponsor or destruction of them. See the procedure manual for details of these 
procedures. 
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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A. 
9.1.1 
Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is explained; this subject number will be used throughout the study. 
9.1.2 
Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, and smoking 
classification of the subject. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the target disease (complex perianal fistulising Crohn's disease) 
that stopped prior to signing of informed consent. Ongoing conditions are considered concurrent 
medical conditions (See Section 9.1.7). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation stopped at or within 6 months prior to signing of informed 
consent. Previous treatment for Crohn's disease or associated complex perianal fistulas are 
included. 
9.1.3 
Physical Examination Procedure 
A baseline physical examination (defined as the assessment prior to dose of study product) 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) other. All subsequent 
physical examinations should assess clinically significant changes from the assessment prior to 
dose examination. 
9.1.4 
Weight and Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The Takeda standard for collecting height is centimeters without decimal places and for 
weight it is kilograms (kg) with 1 decimal place. 
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9.1.5 
Vital Sign Procedure 
Vital signs will include body temperature (axilla measurement), sitting blood pressure (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 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study product. These may be 
prescribed by a physician or obtained by the subject over the counter. Agents to be used for 
fistulas preparation (9.1.17) are not included. At each study visit, subjects will be asked whether 
they have taken any medication (used from signing of informed consent through the end of the 
study), and all medication including vitamin supplements, over-the-counter medications, and oral 
herbal preparations, must be recorded in the eCRF. 
9.1.7 
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory or physical 
examination abnormalities noted at start of screening period. The condition (ie, diagnosis) should 
be described. 
9.1.8 
Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. Samples will 
be collected after fasting at least 8 hour, if possible. The maximum volume of blood collected for 
clinical laboratory tests at each visit is provided in the procedure manual. 
The items of clinical laboratory tests are shown in Table 9.a. 
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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Hemoglobin 
Hematocrit 
Red blood cells count 
Mean Corpuscular Volume 
Mean Corpuscular Hemoglobin 
Mean Corpuscular Hemoglobin 
Concentration 
White blood cells (WBC) count 
differential WBC (neutrophils, basophils, 
eosinophils, lymphocytes, monocytes) 
Platelet count 
C-reactive protein 
ALT 
AST 
Alkaline phosphatase (ALP) 
Gamma-glutamyl transpeptidase (GGT) 
Total bilirubin 
Total protein 
Glucose 
Creatinine 
Creatine phosphokinase 
Blood urea nitrogen 
Potassium 
Sodium 
Chloride 
pH 
Specific gravity 
Qualitative tests for 
glucose, protein, 
occult blood, ketone 
body, bilirubin, 
urobilinogen 
Tests performed only for eligibility assessment: 
Serum immunology tests 
Tests performed only for women of childbearing 
potential: 
Pregnancy Tests 
HBsAg, HBV-PCR, HCV antibody, HCV-PCR,  
HIV antigen/antibody 
hCG (for pregnancy)* 
*Serum hCG pregnancy test will be performed at Visit 1 (Screening), Visit 8 (Week 24), Visit 10 (Week 52), or 
Early Termination Visit in follow-up period. Urine hCG pregnancy test will be performed at Visit 3 (Day 1) before 
study product administration. 
 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
serum immunology tests, and serum hCG pregnancy tests. Each study site will perform urine 
hCG pregnancy tests. The results of laboratory tests will be returned to the investigator, who is 
responsible for reviewing and filing these results. 
If subjects experience ALT or AST >3 × ULN, follow-up laboratory tests (at a minimum, serum 
ALP, ALT, AST, total bilirubin, GGT, and INR) should be performed within a maximum of 
7 days and preferably within 48-72 hours after the abnormality was noted. 
(Please refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 × ULN 
in conjunction with total bilirubin >2 × ULN.) 
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator 
must contact the study monitor for consideration of additional testing, close monitoring, 
discussion of the relevant subject details and possible alternative etiologies. The abnormality 
should be recorded as an AE (please refer to Section 10.2.3). 
The investigator will maintain a copy of the reference ranges for the laboratory used. 
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9.1.9 
Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent up to Week 52 of the study, female subjects of childbearing 
potential (ie, nonsterilized, premenopausal female subjects) who are sexually active must use 
acceptable methods of contraception. Also from signing of informed consent up to Week 52 of 
the study, nonsterilized male subjects who are sexually active with a female partner of 
childbearing potential must use contraception. Such subjects will be provided with information 
on acceptable methods of contraception as part of the subject informed consent process, and will 
be asked to sign a consent form stating that they understand the requirements for avoidance of 
pregnancy from signing of informed consent up to Week 52 of the study. During the course of 
the study, regular serum/urine human chorionic gonadotropin (hCG) pregnancy tests will be 
performed, and subjects will receive continued guidance with respect to avoiding pregnancy as 
part of the study procedures (Appendix A). 
In addition to a negative serum hCG pregnancy test at screening, subjects also must have a 
negative urine hCG pregnancy test on the day of the dose of study product, prior to receiving any 
dose of study product. 
In addition, male subjects must be advised not to donate sperm from signing of informed consent 
up to Week 52 of the study. 
9.1.10 
Pregnancy 
If a female subject is found to be pregnant before Week 52, the subject should be withdrawn. If a 
female subject is found to be pregnant after Week 52, the subject may continue to participate in 
the study as long as the risk is considered acceptable by the investigator. In addition, any 
pregnancies in the partner of a male subject during the study, should also be recorded following 
authorization from the subject's partner. 
If the pregnancy occurs after the study product administration, eg, after Visit 3, the pregnancy 
should be reported immediately, using a pregnancy notification form, to the contact listed in 
Annex. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the subject/female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of treatment the subject received. 
All pregnancies in subjects on active study product will be followed up to final outcome, using 
the pregnancy form. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted. 
9.1.11 
Rectosigmoidoscopy 
Rectosigmoidoscopy will be performed to evaluate endoscopic disease activity in the rectum and 
sigmoid colon using the Simple Endoscopic Score for Crohn’s Disease (SES-CD) score. SES-
CD includes 4 variables: size of ulcers, ulcerated surface, affected surface, presence of 
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narrowings. Each variable can be assigned a score of 0 to 3. Each item score will be recorded in 
the eCRF. 
Rectosigmoidoscopy will not be required in case that the SES-CD is evaluable by using the data 
of previous rectosigmoidoscopy performed within 4 weeks before start of screening period. Also 
in case of re-screening, both rectosigmoidoscopy and SES-CD evaluation will not be required. 
9.1.12 
Fistula Clinical Assessment 
For the fistula tract treated or to be treated, the presence of spontaneous drainage from the 
external openings or the presence of drainage from the external openings after gentle finger 
compression will be confirmed. The same fistula tracts will be assessed throughout the study 
period. Number of external openings, location of each external opening, and presence or absence 
of drainage from each external opening will be recorded in the eCRF  
Appropriate training for gentle finger compression to confirm presence or absence of drainage 
will be implemented before the first assessment is performed to standardize the procedure 
between evaluators. 
9.1.13 
Fistula MRI Assessment 
A pelvic MRI will be performed on the fistula tracts treated or to be treated at each study site. 
The MRI data will be evaluated by a designated MRI central laboratory and the investigator. 
MRI assessments include the confirmation of the presence or absence of collections >2 cm (3-
dimensional evaluation) in the fistula tracts treated or to be treated, and the presence or absence 
of new fistula tracts. The results of these assessments made by the central laboratory will be 
provided to the sponsor directly, and the results of assessments made by the investigator will be 
recorded in eCRF. 
The MRI results assessed at screening will also be used by a surgeon for the preparation and 
study product administration. 
9.1.13.1 Van Assche Score 
The Van Assche score represents the MRI-based severity of perianal lesion associated with 
Crohn's disease  Based on MRI data, the number, location and extension of fistula tracts, 
hyperintensity on T2-weighted images, presence or absence of collections (cavities >3 mm in 
diameter), and rectal wall involvement will be evaluated. A higher score means more severe 
disease. The Van Assche score will be assessed by the designated MRI central laboratory, and 
the results will be provided to the sponsor directly. 
9.1.14 
Perianal Crohn's Disease Activity Index (PDAI) 
The PDAI is a scoring system to evaluate the severity of perianal lesion associated with Crohn's 
disease. It includes the following 5 items: (a) Discharge; (b) Pain; (c) Restriction of sexual 
activity; (d) Type of perianal disease; and (e) Degree of induration. Each item is graded on a 5-
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point scale ranging from no symptoms (score of 0) to severe symptoms (score of 4); a higher 
score means more severe disease. Each item score will be recorded in the eCRF. 
9.1.15 
Crohn's Disease Activity Index (CDAI) 
CDAI score is calculated from the following 8 items: (a) Number of liquid or very soft stools; (b) 
Abdominal pain; (c) General wellbeing; (d) Extraintestinal complications; (e) Antidiarrhoeal 
drugs; (f) Abdominal mass; (g) Hematocrit; and (h) Body weight. Scores of some items in CDAI 
are calculated based on patient diary. 
In CDAI evaluation between Visit 1 and Visit 2 to determine subject eligibility, a hematocrit 
value which is tested at each study site on the day of CDAI evaluation will be used. In other 
CDAI evaluations, a hematocrit value obtained the most recently from the central laboratory will 
be used. 
Each item score will be recorded in the eCRF. 
9.1.15.1 Patient Diary 
For CDAI evaluations, subjects will be required to complete the following 5 items each day 
before going to bed in principle: (1) Number of liquid or very soft stools; (2) Score of abdominal 
pain (0 = none, 1 = mild, 2 = moderate, 3 = severe); (3) Score of general wellbeing (0 = general 
well, 1 = slightly below par, 2 = poor, 3 = very poor, 4 = terrible); (4) Evening body temperature 
(axillary); (5) Use of antidiarrheal drug (yes/no). 
Subjects will be instructed to record the diary every day until Week 52 (Visit 10) and bring it 
with them at the next visit. After Week 52, subjects will be instructed to record the diary for at 
least 10 days before CDAI evaluation visit and bring it with them at the visit. 
9.1.16 
Anti-donor Antibody Test 
Presence/absence of anti-donor antibodies will be investigated. A 3 mL of whole blood sample 
will be collected from each subject at each time point. The procedures for handling and delivery 
of samples are provided in a separately created manual. 
Anti-HLA antibodies in each blood sample will be determined by 
 
 in the laboratory for anti-donor 
antibody test. For anti-HLA antibody-positive samples except for baseline sample, donor specific 
antibodies will be determined using 
 
 
9.1.17 
Fistula Preparation 
As the fistula preparation, all subjects will receive examination under anesthesia, fistula 
curettage and seton placement at the preparation visit (Visit 2: Day -21, done no later than Day -
14). At least 7-day treatment with antibiotics (ciprofloxacin and/or metronidazole are 
recommended unless intolerance to these drugs is observed or these drugs are contraindicated) 
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after the fistula curettage is mandatory. Seton(s) placed will be removed on the day of study 
product administration, just before the administration. 
Appropriate training for the preparation procedure will be implemented before the first 
preparation is performed to standardize the procedures between study sites. A manual for fistula 
preparation will be provided to each study site. Only the personnel who completed the training 
will perform the preparation. 
9.1.18 
Study Product Administration 
The study product will be given at Visit 3 (Day 1). Seton(s) placed will be removed on the day of 
study product administration, just before the administration. Subjects will receive fistula 
curettage under anesthesia and subsequently study product. See Section 8.1.3 for dose regimen. 
Appropriate training for the administration procedures will be implemented before the first 
administration is performed to standardize the procedures between study sites. A manual for the 
administration procedures will be provided to each study site. Only the personnel who completed 
the training will perform the study product administration. 
9.1.19 
Documentation of Subjects Failure 
Investigators must account for all subjects who sign informed consent. 
If the subject is found to be not eligible before study product administration, the investigator 
should complete the eCRF. 
The primary reason for subject failure is recorded in the eCRF using the following categories: 
• Death. 
• Adverse event. 
• Screen failure (failed inclusion criteria or did meet exclusion criteria). 
• Protocol deviation. 
• Lost to follow up. 
• Withdrawal by subject <specify reason>. 
• Study terminated by sponsor. 
• Pregnancy. 
• Other <specify reason>. 
Subject numbers assigned to subjects who fail screening should not be reused. 
9.1.20 
Documentation of Study Entrance 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the treatment period. 
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If the subject is found to be not eligible for the treatment period, the investigator should record 
the primary reason for failure on the applicable eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
Treatment compliance will be assured because treatment will be directly given by site staff at 
Visit 3 (Day 1). The dates and times of study product administration, infused volume, and 
injection site will be recorded in the eCRF. 
When injection of a study product was not completed, the reason for dose incompletion will be 
recorded in the eCRF. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related examinations/observations/assessments are shown in 
Appendix A. The examinations, observations and assessments listed below should be performed 
at scheduled visit/time point(s). 
9.3.1 
Screening period 
9.3.1.1 
Screening (Visit 1) 
For the screening test (Visit 1), subjects will visit the study site during the period between Day -
39 and the day before VISIT2, and the examinations, observations and assessments shown in 
Appendix A will be performed. Subject eligibility will be determined according to the 
inclusion/exclusion criteria shown in Section 7.0. The procedures for documenting subject 
failures during screening period including Visit 1 are shown in Section 9.1.19. 
9.3.1.2 
Preparation (Visit 2) 
For fistulas preparation (Visit 2), subjects will visit the study site on Day -21 (no later than Day -
14) and receive the examinations, observations and assessments shown in Appendix A. Subject 
eligibility will be determined according to the inclusion/exclusion criteria shown in Section 7.0. 
The procedures for documenting subject failures during screening period including Visit 2 are 
shown in Section 9.1.19. 
9.3.1.3 
Potential Re-Screening 
For those subjects needing a re-screening due to an out-of-window of Visit 1 and/or Visit 2 
caused by re-scheduling Visit 3 because of any problem on study product administration at 
Visit 3, Visit 1 and/or Visit 2 will need to be re-scheduled based on protocol timelines, and 
applicable examinations, observations and assessments will be repeated. 
9.3.2 
Treatment 
For study product administration (Visit 3), subjects will visit the study site on Day 1 and receive 
the examinations, observations and assessments shown in Appendix A. Subject eligibility will be 
determined according to the inclusion/exclusion criteria shown in Section 7.0, and those who met 
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all of the inclusion criteria and none of the exclusion criteria will be enrolled in the study. The 
procedures for documenting subject failures before study product administration are shown in 
Section 9.1.19. 
If there is any problem on study product administration at Visit 3, the visit will need to be re-
scheduled. The seton(s) will be maintained until the re-scheduled Visit 3. The time frame for the 
re-scheduled Visit 3 should be a minimum of 2 weeks from the date of the original Visit 3, but if 
re-screening will be needed due to an out-of-window of Visit 1 and/or Visit 2, the re-scheduled 
Visit 3 should be after the re-screening. All procedures for Visit 3 will be repeated at the re-
scheduled Visit 3. 
9.3.3 
Follow-up period 
For the evaluation in the follow-up period (Visits 4 to 10), subjects will visit the study site 
according to the schedule shown in Appendix A, and receive examinations, observations and 
assessments scheduled for each visit. 
9.3.4 
Long-term Follow-up Period 
For the evaluation in the long-term follow-up period (Visit 11 to Visit 14), subjects will visit the 
study site according to the schedule shown in Appendix A, and receive examinations, 
observations and assessments scheduled for each visit. 
9.3.5 
Final Visit or Early Termination 
The final visit will be performed on Visit 14 (Week 156). 
If a subject will withdraw from the study earlier than Visit 14 (Week 156), the examinations, 
observations and assessments for early termination shown in Appendix A will be performed 
immediately. 
For all subjects who received study product administration, the investigator must complete the 
Subject Status eCRF page. 
9.3.6 
Post Study Care 
After the study, subjects will return to their primary care physicians to receive the previous 
standard care. 
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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 who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with this treatment or study participation. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the study 
participation whether or not it is considered related to the product or study procedures. 
An AE includes any unfavorable and unintended sign, symptom, or disease temporally 
associated with the collection of cells or tissues for manufacturing the product. 
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 product 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. 
Diagnoses vs signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or electrocardiogram [ECG] findings) or symptoms 
should NOT be recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) 
should be recorded appropriately as an AE(s). 
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters 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 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 ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE. 
Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing the informed consent form) are 
considered concurrent medical conditions and should NOT be recorded as AEs. The first 
evaluations after signing of informed consent (eg, laboratory tests, ECG, 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 is 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 condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”). 
• If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be captured as an AE if occurring to a 
greater extent to that which would be expected. Again, investigators should ensure that the 
AE term recorded captures the change in the condition (eg, “worsening of…”). 
Worsening of AEs: 
• If the subject experiences a worsening or complication of an AE after starting administration 
of the study product, the worsening or complication should be recorded appropriately as a 
new 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 
product, 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 that are not related to starting the 
study product or changing in the dose or regimen, the event should be captured once with the 
maximum intensity recorded. 
Preplanned procedures (surgeries or therapies): 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening 
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of the condition should be captured appropriately as an AE. Complications resulting from 
any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject's medical condition 
should not be recorded as AEs, but should be documented in the subject's source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy. 
Overdose: 
• Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be recorded 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. 
Product malfunctions: 
• In cases of product malfunctions that caused AEs, the product malfunctions will be recorded 
on the Product malfunction page of the eCRF, and AEs will be recorded on the AE page of 
the eCRF. 
• In cases of product malfunctions that would lead to any health injuries but actually no AEs 
occurred, the product malfunctions and assumed health injuries will be recorded on the 
Product malfunction page of the eCRF. 
10.1.3 
SAEs 
A SAE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study: 
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. 
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• 
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
• 
Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a). 
Table 10.a 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Hepatic necrosis 
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia 
Acute liver failure 
Anaphylactic shock 
Malignant hypertension 
Acute renal failure 
Convulsive seizure 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis 
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson syndrome 
Confirmed or suspected transmission of infectious agent 
by a medicinal product 
COVID-19-related disease* 
Neuroleptic malignant syndrome/malignant hyperthermia 
COVID-19 pneumonia* 
Spontaneous abortion/stillbirth and fetal death 
*Asymptomatic positive COVID-19 test is not considered as medically important event. 
10.1.4 
AEs of Special Interest 
An AE of Special Interest (treatment-emergent only, serious or non-serious) is one of scientific 
and medical concern specific to the product 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. How and when they should be 
reported to Takeda is described in Section 10.2.1.3. 
AEs of special interest in this study include the following: 
• Ectopic tissue formation. 
• Hypersensitivity. 
• Transmission of infectious agents. 
• Immunogenicity. 
• Alloimmune reactions. 
• Medication errors. 
• Tumorigenicity. 
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10.1.5 
Intensity of AEs 
The different categories of intensity are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject's usual activities. 
Severe: 
The event causes considerable interference with the subject's usual activities. 
10.1.6 
Causality of AEs to Study Product(s) 
The causality of each AE to study product(s) will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a product (including the 
course after withdrawal of the product), or for which possible involvement of the product is at least a 
reasonable possibility, ie, the relationship cannot be ruled out, although factors other than the product, 
such as underlying diseases, complications, concomitant drugs and concurrent treatments, may also be 
responsible. 
Not 
related: 
An AE that does not follow a reasonable temporal sequence from administration of a product and/or that 
can reasonably be explained by other factors, such as underlying diseases, complications, concomitant 
drugs and concurrent treatments. 
10.1.7 
Causality of AEs to Study Procedures 
The causality of each AE to study procedures will be assessed. 
The causality 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 causality should be assessed 
as Not Related. 
10.1.8 
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
the investigator. 
The start date of AEs will be determined using the following criteria; 
AEs 
Start Date 
Any signs/symptoms/diseases 
(diagnosis) 
The date that the first signs/symptoms were noted by the subject and/or the 
investigator should be recorded. 
Asymptomatic diseases 
The date when examination was performed for diagnosis and diagnosis 
was confirmed should be recorded. 
The date when diagnosis was confirmed should also be recorded even 
when laboratory findings showed previous findings or the onset time can 
be estimated. 
Worsening of concurrent medical 
conditions or any 
signs/symptoms/diseases before 
treatment from signing of informed 
consent 
The date that a worsening of disease and symptom was noted first by the 
subject and/or the investigator should be recorded. 
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AEs 
Start Date 
The first examination after signing 
of informed consent or the 
examination right before the start of 
the study product showed abnormal 
findings 
The date of examination when an abnormal value that was judged to be 
clinically significant was noted should be recorded. 
The first examination after signing 
of informed consent or the 
examination right before the study 
product showed abnormal findings, 
and the subsequent examinations 
showed worsening of the symptoms 
The date of examination when apparent elevation, reduction, increase or 
decrease was confirmed in medical judgment according to the trends in 
laboratory values should be recorded. 
10.1.9 
End Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
10.1.10 Pattern of Adverse Event 
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous. 
10.1.11 Action Taken with Study Treatment 
• Drug withdrawn – a study product is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study product. 
• Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
• Not Applicable – a study product was stopped for a reason other than the particular AE eg, 
the study has been terminated, the subject died, dosing with study product was already 
stopped before the onset of the AE, the AE that occurred before the study product 
administration  
10.1.12 Outcome 
• Recovered/Resolved – Subject returned to first assessment status with respect to the AE. 
• Recovering/Resolving – the intensity is lowered by one 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”. 
• Recovered/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. 
10.1.13 Causality of AEs to Product Malfunctions 
The causality of each AE to product malfunctions will be assessed. 
If the AE is related to product malfunctions, the details of the product malfunction will be 
recorded on the Product malfunction page of the eCRF. The procedures for collection and 
reporting of product malfunction are described in Section 10.2.4. 
10.2 
Procedures 
10.2.1 
Collection and Reporting of AEs 
10.2.1.1 AE Collection Period 
Collection of AEs will commence from the time the subject signs the informed consent. Routine 
collection of AEs will continue until Visit 14 (Week 156) or 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 that occurs prior to the first exposure to study product 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. Non-serious AEs that occur prior to 
the first exposure to study product, related or unrelated to the study procedure, need not to be 
followed up for the purposes of the protocol. 
All subjects experiencing AEs after the first exposure to study product, whether considered 
associated with the use of the study product 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 recorded in the AE 
page of the eCRF, whether or not the investigator concludes that the event is related to the 
product treatment. The following information will be documented for each event: 
1. Event term. 
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2. Start and end date. 
3. Pattern. 
4. Intensity. 
5. Investigator's opinion of the causality between the event and administration of study 
product(s). 
6. Investigator's opinion of the causality to study procedure(s), including the details of the 
suspected procedure. 
7. Action taken with study treatment (not applicable for the AE that occurred before the study 
product administration). 
8. Outcome of event. 
9. Seriousness. 
10. Treatment emergent. 
11. Investigator's opinion of the causality between the event and product malfunction(s). 
Patient diary will not be used as a primary means to collect AEs. However, should the 
investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been identified, 
normal reporting requirements should be applied. 
10.2.1.3 AEs of Special Interest Reporting 
If an AE of special interest in this study (See section 10.1.4) occurs during AEs collection 
period, it should be reported by the investigator to the Emergency Reception Center for Safety 
Information (see annex) immediately or within 1 business day of first onset or subject's 
notification of the event  An AE of special interest Form or SAE Form should be completed, 
signed and/or sealed by the principal investigator, and reported to appropriate personnel in the 
separate contact information list within 10 calendar days. 
The AE of special interest have to be recorded as AEs in the eCRF. An evaluation form along 
with all other required documentation must be submitted to the sponsor. 
The AEs of special interest in this study include the following. If any other AEs which may be 
specific to the product or program occur, consider handling of AE of special interest. 
• Ectopic tissue formation:  
Evidence of new masses or new lesions with calcifications in the area of the fistula which 
were not present before study treatment will be collected. 
• Hypersensitivity:  
Hypersensitivity or AEs related to hypersensitivity. 
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• Transmission of infectious agents:  
Any suspected transmission of an infectious agent via the study product or AEs related to 
transmission of infectious agents. 
• Immunogenicity:  
The investigators will not be required to reported since the sponsor will evaluate based on 
anti-donor antibody test results. However, a suspected severe allergic reaction following the 
administration of the study product must be reported as hypersensitivity. 
• Alloimmune reactions:  
The AEs related to Type III immune complex mediated reaction, immune-mediated adverse 
reaction, rash, pyrexia and anaphylactic reaction, which are suspected to be alloimmune 
reactions. 
• Medication errors:  
Medication errors are defined as an unintended failure in the drug treatment process that 
leads to, or has the potential to lead to, harm to the patient  
• Tumorigenicity:  
Occurrence of anal canal or colorectal malignancy will be collected. 
10.2.2 
Collection and Reporting of SAEs 
When a SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A SAE should be reported by the investigator to the Emergency Reception Center for Safety 
Information (see annex) within 24 hours after first onset or subject's notification of the event. 
The principal investigator should submit the completed SAE form within 10 calendar days. 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. 
• Study product name. 
• Product identification number. 
• Causality assessment. 
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
10.2.3 
Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST >3 × ULN and total bilirubin >2 × ULN for which an 
alternative etiology has not been identified, the event should be recorded as a SAE and reported 
as per Section 10.2.2. The investigator must contact the study monitor for discussion of the 
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relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.8 must also be performed. 
10.2.4 
Collection and Reporting of Product Malfunctions 
All product malfunctions (eg, a functional failure in the study product), regardless of presence or 
absence of AEs, will be recorded in the Product Malfunction page of the eCRF. The following 
information will be documented for each event: 
• Product identification number. 
• Event term. 
• Date observed by the investigator. 
• Presence or absence of AEs due to the malfunction. 
• Presence or absence of a potential risk of health injury due to the malfunction (not applicable 
if any AEs have already occurred) 
• Presence or absence of a potential risk that would lead to deaths1 or SAEs2 due to the 
malfunction (If there is such a risk, assumed health injury name must be provided. It is not 
applicable if any AEs have already occurred) 
If a SAE occurred due to product malfunction, the SAE and the product malfunction should be 
reported as per section 10.2.2 and the following procedure. If a product malfunction that may 
lead to death or SAE occurred without actual AE, it should be also reported according to the 
following procedure: 
A product malfunction should be reported by the investigator to the Emergency Reception 
Center for Safety Information (see annex) within 1 business day of first onset or subject's 
notification of the event, such as SAE or product malfunction that may lead to death or SAE. The 
principal investigator should submit the completed report form within 10 calendar days. The 
information should be completed as fully as possible but contain, at a minimum: 
• A short description of the event. 
• Subject identification number. 
• Investigator's name. 
• Study product name 
• Presence or absence of AEs 
                                                 
1 Including deaths and life threatening cases 
2 Including: cases that would require inpatient hospitalization or prolongation of existing hospitalization; cases that 
would lead to a persistent or significant disability/incapacity; other serious cases second to these cases or deaths/life 
threatening cases; and cases that would lead to a congenital anomaly/birth defect in later generation. 
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The sponsors also evaluate whether there is a risk that would lead to deaths or SAEs due to the 
malfunction. As a result of the evaluation, the sponsor may ask the investigator for additional 
investigation. If additional investigation is required, the principal investigator should submit the 
completed report form within 10 calendar days after the sponsor's request. 
10.2.5 
Collection and Reporting of Other Special Situations 
The following information, regardless of presence or absence of AEs, should be reported to the 
sponsor if it occurs: 
• Breastfeeding: infant exposure from breast milk. 
• Drug abuse, misuse or medication error: all information on medicinal product abuse, misuse, 
or medication error (potential or actual). 
• Occupational exposure. 
• Use of falsified medicinal product. 
The investigator should contact the study monitor for the reporting of those cases immediately. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately. Copies of any relevant data from the hospital notes (eg, ECGs, laboratory 
tests, discharge summary, postmortem results) should be sent to the addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 
Safety Reporting to Investigators, IRBs and Regulatory Authorities 
The sponsor will be responsible for reporting all SUSARs, any other applicable SAEs, and 
product malfunctions that have risks that would lead to deaths or SAEs to regulatory authorities, 
investigators and IRBs /the head of the study site in accordance with the applicable local 
requirements. 
Relative to the first awareness of the event by/or further provision to the sponsor or sponsor's 
designee, SUSARs will be submitted to the regulatory authorities as expedited report within 7 
days for fatal and life-threatening events and 15 days for other serious events, unless otherwise 
required by national regulations. The sponsor will also prepare an expedited report for other 
safety issues where these might materially alter the current benefit-risk assessment of a study 
product/sponsor supplied product or that would be sufficient to consider changes in the study 
product/sponsor supplied product administration or in the overall conduct of the trial. The 
sponsor will also prepare an expedited report for product malfunctions in accordance with 
applicable regulations. 
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If a SAE reported from this study in accordance with Section 10.2.2 is considered as “The safety 
information that could affect study continuation” by the sponsor, the information will be reported 
to the investigators in this study within 24 hours after the sponsor's receipt of the information. 
Safety information that could affect study continuation in relation to a SAE reported from 
clinical studies of Cx601 conducted in foreign countries will also be reported to investigators in 
this study within 24 hours after the sponsor's receipt of the information. After the marketing 
approval of Cx601 is obtained in Japan, the timeframe of 24 hours after the sponsor's receipt of 
the information will not be applied, but the sponsor will be responsible for reporting the 
information to the investigators in this study in accordance with the applicable regulations. 
The study site also will forward a copy of all expedited reports to his or her IRB. 
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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 
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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs and medical history including concurrent 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. 
The sponsor or its designee will supply study sites with 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. Data are transcribed directly onto eCRFs. 
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 study site. 
Corrections 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 sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
The following data will not be recorded into the eCRFs: 
• Clinical laboratory test results (excluding urine pregnancy test results) 
• Fistula MRI assessment results by the designated MRI central lab 
• Van Assche scores 
• Anti-donor antibody test results 
After the lock of the clinical 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 (Data Clarification Form) provided by the sponsor. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject's medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor. 
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12.2 
Record Retention 
The investigator and the head of the study site agree to keep the records stipulated in Section 
12.1 and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as thermal 
sensitive paper, source worksheets, all original signed and dated informed consent forms, subject 
authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of eCRFs, including the audit trail, and detailed records 
of product 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, the investigator and the head of the study site are required to retain 
essential relevant documents until the day specified as 1) or 2) below, whichever comes later. 
After the marketing approval of Cx601 in Japan, the term of record retention shall expire on the 
day when a reexamination or reevaluation of Cx601 is completed, instead of the day specified as 
of 1) and 2). However, if the sponsor requests a longer time period for retention, the head of the 
study site should discuss how long and how to retain those documents with the sponsor. 
1) The day on which marketing approval of the study product is obtained (or the day 3 years 
after the date of notification in the case that the investigation is discontinued.) 
2) The day 3 years after the date of early termination or completion of the clinical study. 
In addition, the investigator and the head of the study site should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. Statistical analyses will be performed using all 
subjects' data up to Week 24 after the data are locked. Furthermore, statistical analyses will also 
be performed at the time when the data are locked after all subjects complete Week 52 and 
Week 156, using all subjects' data up to Week 52 and overall data respectively. 
A data review will be conducted prior to database lock. This review will assess the accuracy and 
completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods. 
13.1.1 
Analysis Sets 
Four kinds of analysis sets are defined in this study: 
• Intention to treat (ITT):  
All subjects who have enrolled into treatment period. 
• Modified intention to treat (mITT):  
All subjects who have received the study treatment and whose primary efficacy endpoint is 
evaluable. 
• Per protocol set (PPS):  
All subjects who have completed the minimum protocol-specified procedures without any 
major protocol deviations. 
• Safety analysis set:  
All subjects who have received the study treatment. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. If necessary, the SAP will be 
supplemented and finalized with new handling rules that were not discussed at the planning 
stage. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized using the ITT population. 
13.1.3 
Efficacy Analysis 
13.1.3.1 Primary Endpoint and Analytical Methods 
[Primary endpoint] 
• Proportion of subjects with combined remission at Week 24. 
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[Primary analysis] 
The following analysis will be performed for the ITT population. 
For combined remission at Week 24, frequency distribution will be provided with proportion and 
the two-sided confidence intervals (confidence coefficient: 90% and 95%). 
[Secondary analysis] 
For sensitivity point of view, the same analysis as the primary analysis will be performed for the 
mITT population and PPS to confirm robustness of the results. 
13.1.3.2 Secondary Endpoints and Analytical Methods 
[Secondary endpoints] 
Efficacy analysis using data up to Week 24: 
• Proportion of subjects with clinical remission at Week 24  
• Proportion of subjects with response at Week 24. 
• Time to clinical remission by Week 24. 
• Time to response by Week 24. 
• Proportion of subjects with relapse at Week 24 in subjects with clinical remission at previous 
visit. 
• Time to relapse by Week 24 in subjects with clinical remission at previous visit. 
• PDAI score (including total score, discharge sub-score and pain sub-score) up to Week 24. 
• CDAI score up to Week 24  
• Van Assche score up to Week 24. 
Efficacy analysis using data up to Week 52: 
• Proportion of subjects with combined remission at Week 52. 
• Proportion of subjects with clinical remission at Week 52. 
• Proportion of subjects with response at Week 52. 
• Time to combined remission by Week 52. 
• Time to clinical remission by Week 52. 
• Time to response by Week 52. 
• Proportion of subjects with relapse at Week 52 in subjects with combined remission at 
Week 24. 
• Time to relapse by Week 52 in subjects with combined remission at Week 24. 
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• PDAI score (including total score, discharge sub-score and pain sub-score) up to Week 52. 
• CDAI score up to Week 52. 
• Van Assche score up to Week 52. 
[Analytical Methods] 
For proportion of subjects with clinical remission at Week 24 and proportion of subjects with 
response at Week 24, the same analysis for the primary endpoint will be performed. 
For other secondary endpoints, details will be described in the SAP. 
13.1.3.3 Methods of Data Transformation and Handling of Missing Data 
For the primary and secondary analyses of the primary endpoint, the last observation carried 
forward (LOCF) from the latest earlier post-baseline visit (including an Early Termination Visit 
prior to Week 24, if applicable) will apply in case of missing clinical assessment at Week 24. In 
case of missing MRI data at Week 24, LOCF from an Early Termination Visit prior to Week 24 
will apply if applicable. In case of no MRI data by Week 24 or no post-baseline clinical 
assessment, non-response will be imputed. 
If rescue therapy which is not allowed in section 7.4 or medications which could affect fistula 
closure directly occur prior to Week 24, non-response will be imputed overriding all other 
imputation conventions. 
Details will be described in the SAP. 
13.1.4 
Safety Analysis 
The following analysis will be performed for the safety analysis set. 
13.1.4.1 AEs 
A TEAE is defined as an adverse event whose date of onset occurs on or after receiving study 
treatment. TEAEs will be coded using the MedDRA dictionary. The frequency distribution will 
be provided using the system organ class and the preferred term as follows: 
• All TEAEs. 
• Study treatment-related TEAEs. 
• Intensity of TEAEs. 
• Intensity of study treatment-related TEAEs. 
• Serious TEAEs. 
• TEAEs of special interest. 
• Product malfunction-related TEAEs. 
• TEAEs over time. 
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13.1.4.2 Clinical Laboratory Test and Vital Signs 
For continuous variables, the observed values and the changes from baseline will be summarized 
for each visit using descriptive statistics. Case plots will also be presented for the observed 
values. 
For categorical variables, shift tables showing the number of subjects in each category at 
baseline and each post-baseline visit will be provided. 
13.2 
Interim Analysis and Criteria for Early Termination 
There will not be any interim analysis. Note, the analysis using data up to Week 24 is the 
primary analysis for marketing application. Additionally, separate analyses using data up to 
Week 52 and overall data will be performed after all subjects complete Week 52 and Week 156 
respectively. 
13.3 
Determination of Sample Size 
The planned sample size is 20 based on feasibility. However, this study has at least 94% 
probability to show a proportion of subjects with combined remission of 35% or more given an 
expected proportion of subjects with combined remission of 50% based on Week 24 results in 
the Cx601-0302 study. 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the head of the study site guarantee access to source documents by the 
sponsor or its designee and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee, including but not limited to the Investigator's Binder, study product, subject medical 
records, informed consent documentation, and review of eCRFs and associated source 
documents. It is important that the investigator and other study personnel are available during the 
monitoring visits and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written 
agreement with the sponsor or a prior approval from IRB. In the event of a deviation or change, 
the investigator should notify the sponsor and the head of the study site of the deviation or 
change as well as its reason in a written form, and then retain a copy of the written form. When 
necessary, the investigator may consult and agree with the sponsor on a protocol amendment. If 
the protocol amendment is appropriate, the amendment proposal should be submitted to the head 
of the study site as soon as possible and an approval from IRB should be obtained. 
The investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the Food and Drug Administration [FDA], the 
United Kingdom Medicines and Healthcare products Regulatory Agency [MHRA], the 
Pharmaceuticals and Medical Devices Agency of Japan [PMDA]). If the study site is contacted 
for an inspection by a regulatory body, the sponsor should be notified immediately. The 
investigator and institution guarantee access for quality assurance auditors to all study documents 
as described in Section 14.1. 
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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix 
B. The principles of Helsinki are addressed through the protocol and through appendices 
containing requirements for informed consent and investigator responsibilities. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable 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. If any member of the IRB has direct participation in 
this study, written notification regarding his or her abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol's review and approval. This protocol, the Investigator's Brochure, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB for approval. The IRB's written approval of the protocol and subject 
informed consent form must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before study specific screening activity). The IRB approval 
must refer to the study by exact protocol title, number, and version date; identify versions of 
other documents (eg, informed consent form) reviewed; and state the approval date. The sponsor 
will notify site once the sponsor has confirmed the adequacy of site regulatory documentation. 
Until the site receives notification no protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator's final status report to IRB. All IRB 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 and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form describe the planned and permitted 
uses, transfers, and disclosures of the subject's personal and personal health information for 
purposes of conducting the study. The informed consent form further explain the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is 
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given. The informed consent form will detail the requirements of the participant and the fact that 
he or she is free to withdraw at any time without giving a reason and without prejudice to his or 
her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form. The informed consent form must be approved by both the IRB and the sponsor 
prior to use. 
The informed consent form must be written in a language fully comprehensible to the 
prospective subject. It is the responsibility of the investigator to explain the detailed elements of 
the informed consent form to the subject. Information should be given in both oral and written 
form whenever possible and in the manner deemed appropriate by the IRB. 
The subject, or the subject's legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject's legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form must be signed and dated by the subject, 
or the subject's legally acceptable representative, at the time of consent and prior to the subject 
entering into the study. The subject or the subject's legally acceptable representative should be 
instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. The 
investigator must also sign and date the informed consent form at the time of consent and prior to 
subject entering into the study. 
Once signed, the original informed consent form will be stored in the investigator's site file. The 
investigator must document the date the subject signs the informed consent in the subject's 
medical record. Copies of the signed informed consent form shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject's legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject's medical 
record, and the subject should receive a copy of the revised informed consent form. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject's right to protection 
against invasion of privacy. Throughout this study, a subject's source data will only be linked to 
the sponsor s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth may be used to verify the subject and accuracy of the subject's unique identification 
number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee's monitor, representatives 
from any regulatory authority (eg, FDA, MHRA, PMDA), the sponsor's designated auditors, and 
the appropriate IRBs 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. 
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Access to a subject's original medical records requires the specific authorization of the subject as 
part of the informed consent process (See Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject's eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 
Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results is the 
sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. 
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association. 
15.4.2 
Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with the study sites' name and location (ie, city, state [for Americas 
investigators], country), and recruiting status will be registered and available for public viewing. 
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
study 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. 
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16.0 
REFERENCES 
[1] Japan Intractable Diseases Information Center: Number of certified recipients for specific 
disease treatment [Internet]. cited Apr 20, 2018.  
Available from: http://www.nanbyou.or.jp/entry/1356#p09. 
[2] Japan Intractable Diseases Information Center: Number of certified recipients of the specific 
medical expense for designated intractable diseases [Internet]. cited Apr 20, 2018.  
Available from: http://www.nanbyou.or.jp/entry/5354. 
[3] Maeda N. Complications of Crohn's disease: 1. Intestinal complication. Crohn's Disease - 
New Diagnosis and Treatment -. Diagnosis and treatment company, Inc. 2011. p162-170. 
[4] Futami K, Higashi D, Egawa Y, Ishibashi Y, Maekawa T. Surgical treatment of 
inflammatory bowel disease: Treatment for perianal Crohn's disease. Nihon Rinsho. 
2012;70(Suppl 1):437-42. 
[5] Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. 
Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 
2004;350(9):876-85. 
[6] De la Portilla F, Alba F, García-Olmo D, Herrerías JM, González FX, Galindo A. 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. 
2013;28(3):313-23. 
[7] Research Group for Intractable Inflammatory Bowel Disease (Suzuki Group). Guideline for 
Treatment of Perianal lesion of Crohn's Disease (revised January 2016). MHLW Grant-in-
Aid for Scientific Research on Overcoming intractable diseases: Annual report for research 
on intractable intestinal inflammatory bowel disorders in FY2016, supplementary volume. 
2017. p26-27. 
[8] American Gastroenterological Association Clinical Practice Committee. American 
Gastroenterological Association medical position statement: perianal Crohn's disease. 
Gastroenterology. 2003;125(5):1503-7. 
[9] Van Assche G, Dignass A, Reinisch W, van der Woude CJ, Sturm A, De Vos M, et al. The 
second European evidence-based Consensus on the diagnosis and management of Crohn's 
disease: Special situations. J Crohns Colitis. 2010;4(1):63-101. 
[10] Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, et al. 
Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 
1999;340(18):1398-405. 
[11] Horsthuis K, Ziech ML, Bipat S, Spijkerboer AM, de Bruine-Dobben AC, Hommes DW, et 
al. Evaluation of an MRI-based score of disease activity in perianal fistulising Crohn's 
disease. Clin Imaging. 2011;35(5):360-5. 
[12] European Medicines Agency. Guideline on the development of new medical products for 
the treatment of Crohn's Disease (CPMP/EWP/2284/99 Rev.1). 2008. 
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[13] Irvine EJ. Usual therapy improves perianal Crohn's disease as measured by a new disease 
activity index. J Clin Gastroenterol. 1995;20(1):27-32. 
[14] Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn's Disease Activity 
Index. National Cooperative Crohn's Disease Study. Gastroenterology. 1976;70(3):439-44. 
[15] Van Assche G, Vanbeckevoort D, Bielen D, Coremans G, Aerden I, Noman M, et al  
Magnetic resonance imaging of the effects of infliximab on perianal fistulising Crohn's 
disease. Am J Gastroenterol. 2003;98(2):332-9. 
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