Clinical trial NCT05543187
Conditions: Progressive Familial Intrahepatic Cholestasis (PFIC)
Sponsor: Takeda
Start date: 2023-01-10; Completion date: 2025-07-22
Enrollment: 5 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The main aim of the study is to check if TAK-625 improves symptoms of Progressive Familial Intrahepatic Cholestasis (PFIC), side effect from the study treatment or TAK-625, and how much TAK-625 stays in their blood over time. This will help the study sponsor (Takeda) to work out the best dose to give people in the future.

The participants will be treated with TAK-625 for up to the end of study (about 34 months).

Participants will visit their study clinic 15 times from the start of study. After 15 times visits, participants will visit their study clinic every 12 weeks up to the end of study.

Detailed description:

Arms: arm 1: TAK-625 orally, twice daily (BID) for 4 weeks as Dose Escalation Period. The dose in Dose Escalation Period will be increased weekly, 150 mcg/kilograms (kg), 300 mcg/kg, 450 mcg/kg, and 600 mcg/kg. After Dose Escalation Period, TAK-625 600 mcg/kg (or maximum tolerated dose \[MTD\]), orally, BID up to study completion. arm 2: TAK-625 orally, twice daily (BID) for 4 weeks as Dose Escalation Period. The dose in Dose Escalation Period will be increased weekly, 150 mcg/kilograms (kg), 300 mcg/kg, 450 mcg/kg, and 600 mcg/kg. After Dose Escalation Period, TAK-625 600 mcg/kg (or maximum tolerated dose \[MTD\]), orally, BID up to study completion.
Interventions: intervention 1: TAK-625
Intervention descriptions: intervention 1: TAK-625 orally, twice daily (BID)

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
NCT Number: NCT05543187 
Title: An Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-625 in 
the Treatment of Subjects with Progressive Familial Intrahepatic Cholestasis 
Study Number: TAK-625-3002 
Document Version and Date: Amendment 2 / 08-Dec-2022 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 


TAKEDA PHARMACEUTICALS 
PROTOCOL 
An Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-625 in the 
Treatment of Subjects with Progressive Familial Intrahepatic Cholestasis  
Short Title  
TAK-625 for the Treatment of Progressive Familial Intrahepatic Cholestasis (PFIC) 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka, Japan 540-8645
Study Number: 
TAK-625-3002
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
TAK-625 
Date: 
08 Dec 2022 
Version/Amendment 
Number: 
Amendment 02 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
08 Dec 2022 
02 
Substantial 
All sites 
15 Jul 2022 
01 
Nonsubstantial 
All sites 
19 Apr 2022 
Initial version 
Not applicable 
All sites 
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TAK-625 
Study No. TAK-625-3002 
Page 2 of 115 
Protocol Amendment 02 
08 Dec 2022 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
A separate contact information list will be provided to each site (see the annexes). 
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TAK-625 
Study No. TAK-625-3002 
Page 3 of 115 
Protocol Amendment 02  
08 Dec 2022 
1.2 
Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual subjects in accordance 
with the requirements of this study protocol and also in accordance with the following: 
•
The ethical principles that have their origin in the Declaration of Helsinki.
•
International Council for Harmonisation (ICH) E6 (R2) Good Clinical Practice (GCP):
Consolidated Guideline.
•
All applicable laws and regulations, including, without limitation, data privacy laws, clinical
trial disclosure laws, and regulations.
•
“Ministerial Ordinance Concerning the Standards for the Conduct of Clinical Trials of
Medicinal Products” (Ministry of Health, Labour and Welfare [MHLW] Ordinance No. 28,
27 March 1997; hereinafter referred to as “the GCP Ordinance”).
•
“Ministerial Ordinance that Partially Revises the Ministerial Ordinance Concerning the
Standards for the Conduct of Clinical Trials of Medicinal Products” (hereinafter referred to
as “the revised GCP Ordinance”).
•
Pharmaceutical Affairs Law.
After the marketing approval of TAK-625 is obtained in Japan, this study can be continued as a 
post-marketing clinical study in accordance with Good Post-marketing Study Practice for 
medical products (MHLW Ordinance No. 171, 20 December 2004) 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 are provided on the last page of this document. 
Date 
Date 
Date 
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TAK-625 
Study No. TAK-625-3002 
Page 4 of 115 
Protocol Amendment 02  
08 Dec 2022 
INVESTIGATOR AGREEMENT 
I confirm that I have read and understand this protocol, the investigator’s brochure, prescribing 
information, and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and also to protect the rights, life, 
dignity, integrity, confidentiality of personal information, safety, privacy, and well-being of 
study participants in accordance with the following: 
•
The ethical principles that have their origin in the Declaration of Helsinki.
•
International Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use Good Clinical Practice.
•
All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.
•
Regulatory requirements for reporting serious adverse events as defined in this protocol.
•
Terms outlined in the clinical study site agreement.
•
Responsibilities of the investigator as described in this protocol.
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a potential participant to obtain their informed consent to 
participate. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the sponsor. 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Province) 
Location of Facility (Country) 
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TAK-625 
Study No. TAK-625-3002 
Page 5 of 115 
Protocol Amendment 02  
08 Dec 2022 
1.3 
Protocol Amendment 02 Summary of Changes 
This section describes the changes in the protocol amendment 02. 
The primary reasons for this amendment are to: 
•
Revise the lower age limit for enrollment in this study from 1 year of age to 1 month of age
based on the results of an interim analysis of Study MRX-801.
•
Provide the status and results of an interim analysis of Study MRX-801 in subjects
<12 months of age with Alagille syndrome (ALGS) or PFIC.
•
Provide the detailed information on the administration of concomitant sodium
phenylbutyrate.
•
Provide the exceptions in procedures of blood sampling for subjects who are too small to
collect enough amount of blood.
•
Update the table of sample daily exposure.
•
Provide the procedures of dilution of study drug for infants with a body weight <5 kg.
•
Clarify the fasting time before blood sampling.
•
Clarify the procedures of clinical laboratory tests.
•
Add vitamin K to clinical symptoms of lipid soluble vitamin (LSV) deficiency.
•
Any minor changes (grammatical and editorial changes, correction of inconsistencies,
clerical errors, and typographical errors) are included for clarification purposes only.
The following is a summary of the changes made in this amendment. 
Protocol Amendment 02 
Summary of Changes 
Sections (on the current version) 
Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
•
Section 4.1.3 Key Clinical
Experience
Updated the text “one study, 
MRX-501, completed and the other, 
MRX-502 is ongoing outside Japan” 
to “mainly one phase 2 study, 
MRX-501, has been completed and the 
other, one phase 3 study, MRX-502, is 
ongoing outside Japan”. 
Description adjustment: to 
clarify the status/situation of 
clinical experiences. 
•
Section 4.1.3 Key Clinical
Experience
Added the text “In addition, one phase 
2 study, MRX-801, is ongoing outside 
Japan for patients <12 months of age 
with ALGS or PFIC.” 
To provide the information 
on Study MRX-801 for 
patients <12 months of age 
with ALGS or PFIC. 
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TAK-625 
Study No. TAK-625-3002 
Page 7 of 115 
Protocol Amendment 02  
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Protocol Amendment 02 
Summary of Changes 
Sections (on the current version) 
Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
•
Section 6.2 Justification for
Study Design, Dose, and
Endpoints (Justification for
Study Population)
Added the text “Although the safety of 
TAK-625 was confirmed in subjects 
<12 months of age with ALGS with 
moderate to severe cholestasis enrolled 
in Study MRX-801, the lower age 
limit for enrollment in this study is set 
to be 1 month of age, in consideration 
of preventing the patients from being 
exposed to the amount of PG in 
TAK-625 over the maximum daily 
dose limit of PG specified in the 
guidance by the EMA.” 
To revise the lower age limit 
for enrollment (inclusion 
criteria) based on the results 
of an interim analysis of 
Study MRX-801. 
•
Section 6.2 Justification for
Study Design, Dose, and
Endpoints (Justification for
Dose and Regimen of Study
Drug)
Removed the words “(ie, µg/kg)” from 
the text “TAK-625 is provided as an 
oral solution that is dosed on a weight 
basis (ie, µg/kg)”. 
Description adjustment. 
•
Section 6.2 Justification for
Study Design, Dose, and
Endpoints (Justification for
Dose and Regimen of Study
Drug)
Updated the wording “1 year of age” 
to “12 months of age” before the 
words “on treatment for over 5 years”. 
Description adjustment. 
•
Section 6.2 Justification for
Study Design, Dose, and
Endpoints (Justification for
Dose and Regimen of Study
Drug)
Added the text “Although the efficacy 
results in infants <12 months of age 
with PFIC are not yet available, 
improvements in pruritus and sBA 
were observed and the safety of 
TAK-625 was confirmed in infants 
<12 months of age with ALGS in the 
ongoing Study MRX-801, in which 
infants <12 months of age with ALGS 
or PFIC had been enrolled.” 
To provide the results of an 
interim analysis of Study 
MRX-801 and to clarify that 
the results in subjects with 
PFIC in Study MRX-801 are 
not yet available. 
•
Section 6.2 Justification for
Study Design, Dose, and
Endpoints (Justification for
Dose and Regimen of Study
Drug)
•
Updated the weight range from
“5 to 70 kg” to “3 to 70 kg” in the
text referencing Table 6.a.
•
Added sample daily exposure for
weight of 3 kg in Table 6.a.
To provide the sample daily 
exposure for weight of 3 kg 
based on the revision of 
inclusion criteria #2 of this 
study. 
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TAK-625 
Study No. TAK-625-3002 
Page 8 of 115 
Protocol Amendment 02  
08 Dec 2022 
Protocol Amendment 02 
Summary of Changes 
Sections (on the current version) 
Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
•
Section 7.1 Inclusion Criteria
(Inclusion Criteria #2)
•
Section 2.0 Study Summary
(Main Criteria for Inclusion)
•
Revised the lower weight limit
from ≥5 kg to ≥3 kg.
•
Revised the lower age limit from
≥1 year of age to ≥1 month of age.
•
Added the text that defined the
gestational age and postmenstrual
age for subjects <12 months of age.
•
To revise the lower
weight limit for
enrollment in this study
from ≥5 kg to ≥3 kg.
•
To revise the lower age
limit for enrollment in
this study from ≥1 year
of age to ≥1 month of
age.
•
To provide the gestational
age and postmenstrual age
for subjects <12 months
of age.
•
Section 7.1 Inclusion Criteria
(Inclusion Criteria #4)
•
Section 2.0 Study Summary
(Main Criteria for Inclusion)
•
Section 9.1.2 Eligibility
Assessment
•
Section 9.3.1 Screening
Period
Added the text “Since it is difficult to 
evaluate pruritus in infants, subjects 
<12 months of age at screening whose 
pruritus is unavoidably difficult to be 
evaluated are not necessarily required 
to meet the above score.” 
To revise the lower age limit 
for enrollment in this study 
from ≥1 year of age to 
≥1 month of age. 
•
Section 7.1 Inclusion Criteria
(Inclusion Criteria #6)
•
Section 2.0 Study Summary
(Main Criteria for Inclusion)
Added the note “(*≤6 months is 
acceptable for subjects <12 months of 
age)” to the words “Chronic 
cholestasis as manifested by persistent 
(>6 months) pruritus”. 
To clarify the exception for 
period of persistence of 
pruritus for patients 
<12 months of age. 
•
Section 7.5.1.2 Permitted
Concomitant Medications,
Procedures, and Treatments
Added the information on the 
temporary dose adjustments and dose 
adaptations of sodium phenylbutyrate. 
To provide the detailed 
information on the 
administration of 
concomitant sodium 
phenylbutyrate. 
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TAK-625 
Study No. TAK-625-3002 
Page 11 of 115 
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CONFIDENTIAL 
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 .........................................................................................3 
1.3 
Protocol Amendment 02 Summary of Changes.............................................................5 
2.0 
STUDY SUMMARY.........................................................................................................18 
3.0 
LIST OF ABBREVIATIONS ............................................................................................23 
3.1 
Corporate Identification ...............................................................................................26 
3.2 
Study Definitions .........................................................................................................26 
4.0 
INTRODUCTION .............................................................................................................27 
4.1 
Background ..................................................................................................................27 
Drug Overview ....................................................................................................27 
Disease Background ............................................................................................27 
Key Clinical Experience ......................................................................................28 
4.1.3.1 
Pharmacokinetics in Clinical Studies ..........................................................28 
4.1.3.2 
Study MRX-501 (Phase 2 Study) ................................................................29 
4.1.3.3 
Study MRX-801 (Phase 2 Study) ................................................................30 
4.1.3.4 
Study MRX-502 (Phase 3 Study) ................................................................31 
4.2 
Rationale for the Proposed Study ................................................................................32 
4.3 
Benefit/Risk Profile .....................................................................................................32 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................33 
5.1 
Objectives ....................................................................................................................33 
Primary Objectives ..............................................................................................33 
Secondary Objectives ..........................................................................................33 
Additional Objectives ..........................................................................................33 
5.2 
Endpoints .....................................................................................................................33 
Primary Endpoint .................................................................................................33 
Secondary Endpoints ...........................................................................................33 
5.2.2.1 
Key Secondary Endpoints ...........................................................................33 
5.2.2.2 
Secondary Endpoints ...................................................................................33 
Safety Endpoints ..................................................................................................34 
 
PK Endpoint ........................................................................................................34 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................35 
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6.1 
Study Design ................................................................................................................35 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................38 
6.3 
Premature Termination or Suspension of Study or Study Site ....................................40 
Criteria for Premature Termination or Suspension of the Study .........................40 
Criteria for Premature Termination or Suspension of Study Sites ......................40 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) ...............................................................................40 
Duration of an Individual Subject’s Study Participation .....................................40 
End of Study/Study Completion Definition and Planned Reporting...................40 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............41 
7.1 
Inclusion Criteria .........................................................................................................41 
7.2 
Exclusion Criteria ........................................................................................................43 
7.3 
Excluded Medications ..................................................................................................44 
Justification of Excluded Medications ................................................................44 
7.4 
Excluded Procedures and Treatments ..........................................................................45 
Justification of Excluded Procedures and Treatments .........................................45 
7.5 
On Study Restrictions ..................................................................................................45 
Concomitant Medications, Procedures, and Treatments .....................................45 
7.5.1.1 
Prohibited Concomitant Medications, Procedures, and Treatments ...........45 
7.5.1.2 
Permitted Concomitant Medications, Procedures, and Treatments ............45 
7.5.1.3 
LSVs ............................................................................................................46 
Diet, Fluid, and Activity Control .........................................................................46 
7.6 
Criteria for Discontinuation or Withdrawal of a Subject .............................................47 
7.7 
Procedures for Discontinuation or Withdrawal of a Subject .......................................48 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT .......................................................48 
8.1 
Study Drug and Materials ............................................................................................48 
Dosage Form, Manufacturing, Packaging, and Labeling ....................................48 
8.1.1.1 
Study Drug ..................................................................................................48 
8.1.1.2 
Packaging ....................................................................................................49 
8.1.1.3 
Labeling.......................................................................................................49 
Storage .................................................................................................................49 
Dose and Regimen ...............................................................................................49 
Stopping Criteria of Dosing .................................................................................51 
Overdose and Medication Error ..........................................................................51 
8.2 
Study Compliance ........................................................................................................52 
8.3 
Study Drug Assignment and Dispensing Procedures ..................................................52 
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8.4 
Accountability and Destruction of Sponsor-Supplied Drugs.......................................53 
9.0 
STUDY PLAN ...................................................................................................................53 
9.1 
Study Procedures .........................................................................................................53 
Informed Consent Procedure ...............................................................................53 
Eligibility Assessment .........................................................................................54 
Demographics, Medical History, Disease History, and Medication 
History/Prior Treatment Procedure .....................................................................54 
Physical Examination Procedure .........................................................................54 
Weight, Height, and BMI ....................................................................................55 
Vital Sign Procedure ............................................................................................55 
Primary Efficacy Measurement ...........................................................................55 
9.1.7.1 
eDiary ..........................................................................................................55 
9.1.7.2 
Serum Bile Acids and Other Cholestasis Biomarkers.................................56 
Other Efficacy Measurement ...............................................................................57 
Documentation of Concomitant Medications ......................................................58 
Documentation of Concurrent Medical Conditions (Complication) ...................58 
Procedures for Clinical Laboratory Samples .......................................................58 
Pregnancy Test ....................................................................................................61 
Contraception and Pregnancy Avoidance Procedure ..........................................61 
9.1.13.1 Male Subjects and Their Female Partners ...................................................61 
9.1.13.2 Female Subjects and Their Male Partners ...................................................61 
9.1.13.3 Definitions and Procedures for Contraception and Pregnancy 
Avoidance ...................................................................................................61 
9.1.13.4 General Guidance with Respect to the Avoidance of Pregnancy ...............63 
Pregnancy ............................................................................................................63 
ECG Procedure ....................................................................................................64 
Ultrasound Liver Imaging ...................................................................................64 
AE Collection ......................................................................................................64 
Other Safety Evaluation ......................................................................................64 
Genetic Testing (PFIC Genotype) .......................................................................65 
PK Sample Collection and Analysis ....................................................................65 
9.1.20.1 Collection of Blood for PK Sampling .........................................................65 
Documentation of Screen Failure ........................................................................66 
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Protocol Amendment 02  
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Documentation of Study Entrance .......................................................................66 
9.2 
Monitoring Subject Treatment Compliance.................................................................66 
9.3 
Schedule of Observations and Procedures ...................................................................67 
Screening Period ..................................................................................................67 
Dose Escalation Period ........................................................................................69 
9.3.2.1 
Visits in the Dose Escalation Period ...........................................................69 
9.3.2.2 
Phone Calls in the Dose Escalation Period .................................................70 
Stable Dosing Period ...........................................................................................70 
9.3.3.1 
Visits in the Stable Dosing Period ..............................................................70 
9.3.3.2 
Phone Calls the Stable Dosing Period .........................................................71 
ET ........................................................................................................................71 
Follow-up Dosing Period ....................................................................................72 
Safety Follow-up .................................................................................................73 
Post Study Care ...................................................................................................73 
Alternative Approaches to Study Procedures and Data Collection Due to 
Coronavirus Disease 2019 ...................................................................................73 
9.4 
Biological Sample Retention and Destruction .............................................................75 
10.0 
AES ....................................................................................................................................75 
10.1 
Definitions....................................................................................................................75 
Pretreatment Events .............................................................................................75 
AEs ......................................................................................................................76 
Additional Points to Consider for AEs ................................................................76 
SAEs ....................................................................................................................78 
AECIs ..................................................................................................................78 
Intensity of AEs ...................................................................................................78 
Causality of AEs ..................................................................................................79 
Relationship to Study Procedures ........................................................................79 
Start Date .............................................................................................................79 
Stop Date .............................................................................................................80 
Frequency ............................................................................................................80 
Action Concerning Study Drug ...........................................................................80 
Outcome ..............................................................................................................80 
10.2 
Procedures ....................................................................................................................81 
Collection and Reporting of AEs ........................................................................81 
10.2.1.1 AE Collection Period ..................................................................................81 
10.2.1.2 AE Reporting ..............................................................................................81 
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Collection and Reporting of SAEs ......................................................................82 
10.3 
Follow-up of SAEs ......................................................................................................83 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities ................83 
10.4 
Safety Monitoring Rules ..............................................................................................83 
General Guidelines ..............................................................................................83 
Close Monitoring Criteria for Liver Parameters .................................................84 
Guidelines for Interruption of Study Drug for Specific Liver Parameters ..........85 
Rules for Study Drug Discontinuation Following Abnormalities of Liver 
Parameters ...........................................................................................................86 
Safety Monitoring for LSVs ................................................................................87 
Safety Monitoring for Coagulation Panel Results ...............................................88 
Study Medication Discontinuation Rules for Diarrhea .......................................88 
10.5 
Product Complaints ......................................................................................................88 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................88 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................88 
12.1 
eCRFs ...........................................................................................................................88 
12.2 
Record Retention .........................................................................................................89 
13.0 
STATISTICAL METHODS ..............................................................................................90 
13.1 
Statistical and Analytical Plans ....................................................................................90 
Analysis Sets .......................................................................................................90 
Analysis of Demographics and Other Baseline Characteristics ..........................90 
Efficacy Analysis .................................................................................................90 
13.1.3.1 Primary Endpoint ........................................................................................91 
13.1.3.2 Key Secondary Endpoints ...........................................................................91 
13.1.3.3 Secondary Endpoint ....................................................................................91 
 
13.1.3.5 Methods of Data Transformation and Handling of Missing Data...............91 
13.1.3.6 Significance Level and Confidence Coefficient ..........................................92 
PK Analysis .........................................................................................................92 
Safety Analysis ....................................................................................................92 
13.1.5.1 TEAEs .........................................................................................................92 
13.1.5.2 Clinical Laboratory Results, Vital Signs, ECGs, and Physical 
Examination Findings (Including Body Weight, Height, and BMI) ...........93 
13.2 
Interim Analysis ...........................................................................................................93 
13.3 
Determination of Sample Size .....................................................................................93 
13.4 
Other Statistical Considerations ...................................................................................93 
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Protocol Amendment 02  
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................93 
14.1 
Study-Site Monitoring Visits .......................................................................................93 
14.2 
Protocol Deviations ......................................................................................................94 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................94 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................94 
15.1 
IRB Approval ...............................................................................................................95 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................95 
15.3 
Subject Confidentiality ................................................................................................97 
15.4 
Clinical Trial Disclosures and Publication ..................................................................97 
Clinical Trial Registration and Results Disclosure .............................................97 
Publication ...........................................................................................................97 
15.5 
Insurance and Compensation for Injury .......................................................................98 
16.0 
DISSEMINATION OF NEW INFORMATION ...............................................................98 
17.0 
REFERENCES ..................................................................................................................99 
18.0 
APPENDIX ......................................................................................................................100 
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TAK-625 
Study No. TAK-625-3002 
Page 17 of 115 
Protocol Amendment 02  
08 Dec 2022 
LIST OF IN-TEXT TABLES 
Table 6.a 
Sample Daily Exposure (mg/day) in Subjects .......................................................39 
Table 9.a 
Clinical Laboratory Tests .......................................................................................60 
Table 10.a 
Close Monitoring Criteria for Treatment-Emergent Elevated ALT and TSB .......84 
Table 10.b 
Guidelines for Interruption of Study Drug for Specific Liver Parameters ............86 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................37 
LIST OF APPENDICES 
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TAK-625 
Study No. TAK-625-3002 
Page 18 of 115 
Protocol Amendment 02  
08 Dec 2022 
2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Pharmaceutical Company Limited 
Compound: 
TAK-625 
Title of Protocol: An Open-Label, Phase 3 Study to 
Evaluate the Efficacy and Safety of TAK-625 in the 
Treatment of Subjects with Progressive Familial 
Intrahepatic Cholestasis 
IND No.:  
Not Applicable. 
EudraCT No.: 
Not Applicable. 
Study Number: TAK-625-3002 
Phase: 3 
Study Design: 
This is a phase 3, multicenter, open-label, uncontrolled study to evaluate the efficacy and safety of TAK-625 in 
the treatment of Japanese subjects with progressive familial intrahepatic cholestasis (PFIC).  
•
Screening Period (up to 6 weeks prior to the Study Administration):
In the screening period, for subjects who do not have documentation of mutation related with PFIC, a blood 
sample will be obtained for genotyping. Subjects diagnosed with PFIC2 (non-truncating PFIC2 [nt-PFIC2]) will 
be enrolled in the primary cohort and those with other types of PFIC will be enrolled in the supplemental cohort. 
The electronic Diary (eDiary) for assessing pruritus with the Itch Reported Outcome (ItchRO) instrument will be 
dispensed and subjects and caregivers will undergo training during the screening visit.  
•
Dose Escalation Period: (4 weeks [up to 6 weeks]: Week 0 to 4 [6]):
In the dose escalation period, at the baseline visit (Week 0/Visit 2), subjects will be assessed to confirm 
continued study eligibility and undergo a physical examination including body weight, height, body mass index 
(BMI), and vital signs, and have urine and blood samples taken for hematology, chemistry, fasting lipid panel, 
baseline levels of serum bile acid (sBA) and other cholestasis biochemical markers. Compliance with ItchRO 
will be assessed. Study drug will be supplied at each visit (Week 0/Visit 2, Week 2/Visit 3, and Week 4/Visit 4). 
The subject contacts (phone calls) will be conducted at Weeks 1 and 3. The dose is increased weekly, 150 μg/kg, 
300 μg/kg, 450 μg/kg, and 600 μg/kg, twice daily (BID).  
Dose escalation should occur in the absence of major safety (eg, liver parameters and lipid soluble vitamin [LSV] 
deficiency) or tolerability concerns (eg, gastrointestinal [GI]-related TEAEs) related or possibly related to study 
drug. Subjects with such safety concerns can be down-titrated to a lower, previously tolerated dose level for 
1 week before continuing dose escalation. The minimum dose to continue in the study will be 150 μg/kg, BID; 
subjects who cannot tolerate this dose will be discontinued from the study. The dose escalation period is allowed 
to be extended up to 6 weeks depending on the safety or tolerability concerns. 
•
Stable Dosing Period (44 weeks: Week 5 to 48):
After the dose escalation period, each subject will continue dosing with study drug at the Week 4 or Week 6 dose 
level (the maximum tolerated dose [MTD] level) in the stable dosing period. Subjects will return to the study site 
at Weeks 6, 10, 14, 18, 22, 26, 28, 32, 36, 40, 44, and 48 and undergo physical examinations. Subject contacts 
(phone calls) will be conducted as appropriate throughout the stable dosing period. Subjects and caregivers will 
continue twice daily completion of their ItchRO throughout the period.  
•
Follow-up Dosing Period (after Week 48):
Additionally, in the follow-up dosing period, each subject will continue dosing with study drug. The safety 
evaluation will be performed in all the subjects every 12 weeks from Week 48 visit until TAK-625 is approved or 
available in Japan commercially, or if the subject withdraws from the study, or if the investigator determines the 
subject’s discontinuation, or if the sponsor stops the program or development in this indication. Bile acids and 
ItchRO will be measured to evaluate the long-term effectiveness of TAK-625. For subjects discontinuing early, 
safety follow-up will be conducted. 
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TAK-625 
Study No. TAK-625-3002 
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Protocol Amendment 02  
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•
Safety Follow-up (after Final Visit/Early Termination [ET]):
Subjects/caregivers will have a final safety follow-up subject contact (phone call) 7 days after the final study visit 
or ET visit (except for screen failure). 
Primary Objectives: 
•
To evaluate the efficacy of TAK-625 in the primary cohort.
•
To evaluate the safety of TAK-625 in subjects with PFIC.
Secondary Objectives: 
•
To evaluate the efficacy of TAK-625 in subjects with PFIC.
•
To evaluate the pharmacokinetics (PK) of TAK-625 in subjects with PFIC.
Subject Population: Japanese subjects with PFIC who are 1 month of age or older. Subjects diagnosed with 
PFIC2 due to adenosine triphosphate (ATP) Binding Cassette Subfamily B Member 11 (ABCB11) mutation that 
predicts residual bile salt excretion pump (BSEP) function (nt-PFIC2) will be enrolled in the primary cohort. 
Subjects with other PFIC subtypes (eg, truncating PFIC2 [t-PFIC2], PFIC1/3/4, or other PFIC mutation variants) 
or postsurgical subjects (eg, internal or external biliary diversion surgery) will be enrolled in the supplemental 
cohort. 
Number of Subjects: 
The primary cohort (nt-PFIC2): up to approximately 
3 subjects. 
The supplemental cohort (other types of PFIC): up to 
approximately 6 subjects. 
Number of Sites:  
Estimated total: approximately 10 sites in Japan. 
Dose Levels: 
•
Dose Escalation period:
The dose escalation period will consist of the
following weekly steps:
–
Dose level 1: 150 μg/kg TAK-625, BID for
1 week
–
Dose level 2: 300 μg/kg TAK-625, BID for
1week
–
Dose level 3: 450 μg/kg TAK-625, BID for
1 week
–
Dose level 4: 600 μg/kg TAK-625, BID for the
remaining duration of the study
•
Stable Dosing Period:
After the dose escalation period, each subject will
continue dosing with study drug at the Week 4 or
Week 6 dose level (the MTD level) in the stable
dosing period.
•
Follow-up Dosing Period:
After the stable dosing period, each subject will
continue dosing with study drug at the Week 4 or
Week 6 dose level (the MTD level).
Route of Administration: 
Oral 
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Study No. TAK-625-3002 
Page 20 of 115 
Protocol Amendment 02  
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Duration of Treatment: 
•
Dose Escalation Period: 4 weeks (up to 6 weeks).
The dose escalation period is allowed to be extended
up to 6 weeks depending on the safety or tolerability
concerns.
•
Stable Dosing Period: 44 weeks.
•
Follow-up Dosing Period: until TAK 625 is
approved or available in Japan commercially, or if
the subject withdraws from the study, or if the
investigator determines the subject’s
discontinuation, or if the sponsor stops the program
or development in this indication.
Period of Evaluation: 
•
Screening Period: up to 6 weeks.
•
Dose Escalation Period: 4 weeks (up to
6 weeks). 
•
Stable Dosing Period: 44 weeks.
•
Follow-up Dosing Period: every 12 weeks after
the stable dosing period until TAK 625 is
approved or available in Japan commercially, or
if the subject withdraws from the study, or if the
investigator determines the subject’s
discontinuation, or if the sponsor stops the
program or development in this indication.
•
Safety Follow-up (phone call): 7 days after the
final study visit or ET visit (except for screen
failure).
Main Criteria for Inclusion: 
The main criteria for inclusion in this study are as follows: 
•
The subject is Japanese male or female with a body weight ≥3.0 kg and who is ≥1 month of age at the time
of informed consent.
For subjects <12 months of age, gestational age ≥36 weeks at birth. For subjects born with gestational age
between 32 and 36 weeks, a postmenstrual age of ≥36 weeks is required. Postmenstrual age is defined as the
time elapsed between the first day of the last menstrual period and birth plus the time elapsed after birth.
•
The subject has a cholestasis as manifested by total sBA ≥3× upper limit of the normal range (ULN) (applies
to the primary cohort only).
•
The subject has an average morning observer-reported Itch Reported Outcome (ItchRO [Obs]) score ≥1.5
during 4 consecutive weeks of the screening period, leading to the baseline visit (Week 0/Visit 2). Since it is
difficult to evaluate pruritus in infants, subjects <12 months of age at screening whose pruritus is
unavoidably difficult to be evaluated are not necessarily required to meet the above score.
•
The caregiver has completed at least 21 valid* morning ItchRO (Obs) entries during 4 consecutive weeks of
the screening period, leading to the baseline visit (Week 0/Visit 2) (*valid=completed and not answered as “I
don’t know”; the maximum allowed invalid reports=7, no more than 2 invalid reports during the last 7 days
before the baseline visit [Week 0/Visit 2]).
•
The subject has a diagnosis of PFIC based on:
Chronic cholestasis as manifested by persistent (>6 months*) pruritus in addition to biochemical
abnormalities and/or pathological evidence of progressive liver disease (*≤6 months is acceptable for
subjects <12 months of age).
And
Primary cohort:
–
The subject has a genetic testing result consistent with disease-causing variation in ABCB11 (PFIC2),
based on a genotyping.
Supplemental cohort: 
–
The subject has a genetic testing results consistent with disease causing variation in ATPase
Phospholipid Transporting 8B1 (ATP8B1) (PFIC1), ATP Binding Cassette Subfamily B Member 4
(ABCB4) (PFIC3), or tight junction protein 2 gene (TJP2) (PFIC4), based on a genotyping.
–
The subject has a PFIC phenotype without a known mutation or with another known mutation not
described above.
–
The PFIC subject has internal or external biliary diversion surgery history, and the internal or external
biliary diversion surgery was reversed.
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Study No. TAK-625-3002 
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Main Criteria for Exclusion: 
The main criteria for exclusion in this study are as follows: 
•
The diagnosed with PFIC2 due to ABCB11 mutation that predicts complete absence of BSEP function due
to the type of ABCB11 mutation (t-PFIC2), based on a genotyping (applies to the primary cohort only). The
subject may enter the study in the supplemental cohort.
•
The subject has a diagnosis of benign recurrent intrahepatic cholestasis indicated by a history of intermittent
cholestasis with no disease progression.
•
The subject has a current or recent history (<1 year) of atopic dermatitis or other non-cholestatic diseases
associated with pruritus.
•
The subject has a previous history of surgical interruption of the enterohepatic circulation (applies to the
primary cohort only).
•
The subject with chronic diarrhea requiring intravenous (IV) fluid or nutritional intervention and/or its
sequelae at screening or during the 6 months prior to screening.
•
The subject has a history of liver transplant or currently requires imminent liver transplant.
•
The subject with decompensated cirrhosis (international normalized ratio [INR] >1.5, and/or albumin
<30 g/L, history, or presence of clinically significant ascites, and/or variceal hemorrhage, and/or
encephalopathy).
•
The subject has an alanine aminotransferase (ALT) or total serum bilirubin (TSB) level >15× ULN at
screening.
•
The subject has other liver disease.
•
The subject has any other disease or condition known to interfere with the absorption, distribution,
metabolism, or excretion of drugs, including bile salt metabolism in the intestine (eg, inflammatory bowel
disease), per investigator discretion.
•
The subject has received bile acid, lipid binding resins or ileal bile acid transporter (IBAT) inhibitors within
28 days prior to screening and throughout the trial.
•
The subject who has received sodium phenylbutyrate for less than 6 months at the initiation of screening.
Main Criteria for Evaluation and Analyses: 
The primary endpoint for this study is change in the average morning ItchRO (Obs) severity score between 
baseline and average of Week 15 through Week 26. Key secondary endpoints for this study are change in the 
average morning ItchRO (Obs) frequency score between baseline and average of Week 15 through Week 26, and 
change in total sBA between baseline and Week 26. Secondary endpoints for this study are proportion of subjects 
who experience an sBA control (defined as a reduction to <102 μmol/L, or a reduction of >75%, or 
normalization) from baseline through Week 26, and change in the ItchRO (Obs) weekly average severity (based 
on daily maximum of morning and evening severity scores) between baseline and average of Week 15 through 
Week 26. 
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TAK-625 
Study No. TAK-625-3002 
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Statistical Considerations: 
The primary, key secondary and other secondary endpoints will be mainly evaluated in the primary cohort. 
Analytical Methods for Primary Endpoint 
Primary Analysis: Descriptive statistics and two-sided 95% confidence interval (CI) of mean will be provided on 
the primary cohort in the intention-to-treat set (ITT). 
Secondary Analysis: For supportive analysis, the same analysis as the primary analysis will be performed on the 
primary cohort in the per protocol analysis set (PPS) to confirm robustness of the results.  
Other Analysis: The same analysis as the primary analysis will also be performed in the ITT population 
separately on the overall supplemental cohort, all cohorts combined, and in the PFIC1 and PFIC3 sub-cohorts 
(separately) given sufficient sample size. 
Analytical Methods for Key Secondary Endpoints 
Descriptive statistics and two-sided 95% CI of mean will be provided on the primary cohort in the ITT. For 
supportive analysis, the same analysis as the above analysis will be performed on the primary cohort using the 
PPS to confirm robustness of the results. 
The same analysis as the above analysis will also be performed in the ITT population separately on the overall 
supplemental cohort, all cohorts combined, and in the PFIC1 and PFIC3 sub-cohorts (separately) given sufficient 
sample size. 
Analytical Methods for Secondary Endpoints 
For continuous endpoints, descriptive statistics and two-sided 95% CI of mean will be provided on the primary 
cohort in the ITT. For binary endpoints, frequency distribution will be provided on the primary cohort in the ITT 
with proportion and the two-sided 95% CI. 
The same analysis as the above analysis will also be performed in the ITT population separately on the overall 
supplemental cohort, all cohorts combined, and in the PFIC1 and PFIC3 sub-cohorts (separately) given sufficient 
sample size. 
Sample Size Justification: 
PFIC is a rare disease. The targeted sample size of the primary cohort is approximately 3 subjects, and that of the 
supplemental cohort is approximately 6 subjects, based on enrollment feasibility of this population in Japan, 
rather than power calculation. 
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Study No. TAK-625-3002 
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3.0 
LIST OF ABBREVIATIONS 
ABCB4 
ATP Binding Cassette Subfamily B Member 4 
ABCB11 
ATP Binding Cassette Subfamily B Member 11 
AE 
adverse event 
AECI 
adverse event of clinical interest  
AFP 
α-fetoprotein 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ALGS 
Alagille syndrome  
ANA 
antinuclear antibody 
APRI 
AST to platelet ratio index  
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
ATP8B1 
ATPase Phospholipid Transporting 8B1 
AUC 
area under the curve 
7αC4 
7α-hydroxy-4-cholesten-3-one  
β-hCG 
β-human chorionic gonadotropin 
BID 
twice daily 
BMI 
body mass index 
BSEP 
bile salt excretion pump  
BUN 
blood urea nitrogen  
CBC 
complete blood count 
CI 
confidence interval 
Cmax 
maximum drug concentration 
CMV IgM 
cytomegalo virus immunoglobulin M 
COA 
clinical outcomes assessment 
COVID-19 
coronavirus disease 2019 
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CSR 
clinical study report 
 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug-induced livery injury 
DMC 
Data Monitoring Committee  
DSMB 
Data Safety Monitoring Board  
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
EDC 
electronic data capture 
eDiary 
electronic diary 
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Protocol Amendment 02  
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EMA 
European Medicines Agency 
EOT 
end of treatment 
ET 
early termination 
EU 
European Union  
fBA 
fecal bile acid 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor 19  
FIB-4 
fibrosis-4  
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HAV IgM 
hepatitis A virus immunoglobulin M 
HBs Ag 
hepatitis B virus surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein-cholesterol 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
IB 
investigator’s brochure 
IBAT 
ileal bile acid transporter 
IC50 
half maximal (50%) inhibitory concentration 
ICH 
International Council for Harmonisation 
ID 
identification 
INR 
international normalized ratio 
IRB 
institutional review board 
IRT 
Interactive Response Technology 
ItchRO 
Itch Reported Outcome 
ItchRO (Obs) 
Observer-reported Itch Reported Outcome 
Itch Reported Outcome (Observer)  
(Observer-reported outcome, observer rated Itch Reported Outcome) 
ItchRO (Pt) 
Patient-reported Itch Reported Outcome 
Itch Reported Outcome (Patient)  
(Patient-reported outcome, patient rated Itch Reported Outcome) 
ITT 
intention-to-treat set  
IUD 
intrauterine device 
IV 
intravenous 
LC-MS 
liquid chromatography-mass spectrometry  
LC-MS/MS 
liquid chromatograph-tandem mass spectrometer 
LDH 
lactate dehydrogenase 
LDL-C 
low density lipoprotein-cholesterol 
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TAK-625 
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Protocol Amendment 02  
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LOQ 
lower limit of quantification 
LSV 
lipid soluble vitamin  
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labour and Welfare 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MYO5B 
myosin VB 
NR1H4 
nuclear receptor subfamily 1 group H member 4 
nt-PFIC2 
non-truncating PFIC2  
PEBD 
partial external biliary diversion  
 
 
PET 
polyethylene terephthalate  
PFIC 
progressive familial intrahepatic cholestasis  
PG 
propylene glycol 
PK 
pharmacokinetics 
PMDA 
Pharmaceuticals and Medical Devices Agency  
PPS 
per protocol analysis set  
PRO 
patient reported outcome 
PT 
prothrombin time 
q12h 
every 12 hours 
QD 
once a day  
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
RBP 
retinol binding protein 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBA 
serum bile acid  
SD 
standard deviation 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TBili 
total bilirubin  
TEAE 
treatment-emergent adverse event 
TG 
triglycerides  
TJP2 
tight junction protein 2 gene 
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Protocol Amendment 02  
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t-PFIC2
truncating PFIC2 
TSB
total serum bilirubin 
UK
United Kingdom 
ULN
upper limit of the normal range 
US
United States  
WBC
white blood cell 
WHO
World Health Organization 
WOCBP
woman/women of childbearing potential 
3.1 
Corporate Identification 
TDC Japan 
Takeda Development Center Japan 
TDC Asia 
Takeda Development Center Asia, Pte Ltd 
TDC Europe 
Takeda Development Centre Europe Ltd. 
TDC Americas 
Takeda Development Center Americas, Inc. 
TDC 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
Takeda 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
3.2 
Study Definitions 
Terms 
Definitions 
Duration of Treatment 
and Duration of 
Follow-up 
The study will be continued until TAK-625 is approved or available in Japan 
commercially, or if the subject withdraws from the study, or if the investigator 
determines the subject’s discontinuation, or if the sponsor stops the program or 
development in this indication. 
End-of-Trial 
The study completion date is defined as the date when the final subject, across all sites, 
completes their final protocol-defined assessment. 
Primary cohort 
Subjects diagnosed with progressive familial intrahepatic cholestasis 2 (PFIC2) due to 
adenosine triphosphate (ATP) Binding Cassette Subfamily B Member 11 (ABCB11) 
mutation that predicts residual bile salt excretion pump (BSEP) function 
(non-truncating PFIC2 [nt-PFIC2]) will be enrolled in the primary cohort.  
(Subjects diagnosed with PFIC2 due to ABCB11 mutation that predicts complete 
absence of BSEP function [truncating PFIC2; t-PFIC2] are excluded from the primary 
cohort and can be enrolled only in the supplemental cohort.) 
Supplemental cohort 
Subjects diagnosed with other PFIC subtypes (eg, t-PFIC2, PFIC1/3/4, or other PFIC 
mutation variants) or postsurgical subjects (eg, internal or external biliary diversion 
surgery) will be enrolled in the supplemental cohort. 
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Study No. TAK-625-3002 
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Protocol Amendment 02  
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4.0 
INTRODUCTION 
4.1 
Background 
Drug Overview 
Ileal bile acid transporter (IBAT) is a transmembrane protein localized on the luminal surface of 
enterocytes in the terminal ileum and plays a key role in the enterohepatic circulation of bile 
acids by reabsorbing bile acids. TAK-625 (maralixibat) was designed to be minimally absorbed, 
therefore maximizing the local exposure of the molecule to the receptor and minimizing systemic 
exposure of the drug and limiting drug-drug interactions and systemic toxicity. These 
characteristics include a high molecular weight of 710 Da and the addition of a positively 
charged quaternary amino moiety that can interact with the negatively charged surface of the 
enterocyte cell membrane and prevent absorption. TAK-625, a highly potent and selective IBAT 
inhibitor (half maximal (50%) inhibitory concentration [IC50]=0.3 nmol/L), inhibits intestinal 
bile acids reabsorption, thereby increasing fecal bile acid (fBA) excretion and lowering serum 
bile acid (sBA) levels without systemic exposure.  
By virtue of its ability to interrupt enterohepatic circulation by inhibiting bile acid absorption, 
TAK-625 is being developed as a therapeutic agent for signs and symptoms of cholestatic liver 
disease. In September 2021, TAK-625 was approved in the United States (US) for the treatment 
of pruritus associated with Alagille syndrome (ALGS). Clinical studies for progressive familial 
intrahepatic cholestasis (PFIC) and biliary atresia are currently ongoing outside Japan. 
TAK-625 is provided as an oral solution and will be prescribed to a given subject based on body 
weight (µg/kg). This is the standard dosing regimen for pediatric patients and is supported by 
clinical experience in development programs for pediatric cholestatic liver disease.  
Disease Background 
PFIC is an autosomal recessive liver disorder characterized by intrahepatic cholestasis due to 
defects in bile transportation from hepatocytes to bile canaliculi. Its estimated prevalence is 
between 1/50,000 and 1/100,000 births [1]. In Japan, only about 5 patients are newly enrolled for 
PFIC in the Medical Aid Program for Chronic Pediatric Diseases of Specified Categories each 
year [2].  
PFIC is categorized into several subtypes, including the main subtypes PFIC1, PFIC2, and 
PFIC3, caused by mutations in the genes adenosine triphosphatease (ATPase) Phospholipid 
Transporting 8B1 (ATP8B1), ATP Binding Cassette Subfamily B Member 11 (ABCB11), and 
ATP Binding Cassette Subfamily B Member 4 (ABCB4), respectively [3]. Five/ten-year native 
liver survival was 73/51% in PFIC1 and 61/45% in PFIC2 patients. Also, in patients with PFIC2, 
native liver survival is only 33% at 18 years, overall [4].  
PFIC2 is further categorized into non-truncating PFIC2 (nt-PFIC2) with residual bile salt 
excretion pump (BSEP; protein encoded by ABCB11) function and truncating PFIC2 (t-PFIC2) 
with no residual BSEP function. In a previous study, MRX-501, TAK-625 was effective in 
subjects with nt-PFIC2. 
 
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Among clinical symptoms of PFIC, pruritus can be severe, even in the absence of jaundice. 
Elevation of sBA is frequently accompanied by pruritus, and a causal association between 
pruritus and bile acids is suggested by the following: (1) pruritus can be induced in volunteers by 
applying topical unconjugated bile acids, deoxycholate and chenodeoxycholate to the skin; and 
(2) pruritus can be relieved by surgical interruption of the enterohepatic circulation, which
dramatically lowers sBA.
Intractable and pharmacologically recalcitrant pruritus is one of the major morbidities afflicting 
children with PFIC. Treatment with anti-pruritics and bile salt resins may provide partial relief of 
pruritus for children with PFIC, but currently available pharmacologic approaches are of limited 
value. Interruption of the entero-hepatic circulation of bile acids through partial external biliary 
diversion (PEBD) surgery can lead to promising results with respect to pruritus, jaundice, and 
histology, both in patients with PFIC1 and PFIC2. Schukfeh, et al. reported a dramatic 
improvement in 1-year outcome in patients undergoing PEBD with 13/21 (62%) of patients 
normalizing sBAs and liver function [5]. 
In July 2021, odevixibat (IBAT inhibitor) was approved in the European Union (EU) and the US 
for the treatment of pruritus in patients with PFIC. There is no other drug approved for PFIC at 
this time in the EU or the US. Importantly, there are no approved drugs for PFIC in Japan. Since 
reduction in bile acid concentrations with PEBD has been shown to be associated with 
improvement in cholestatic pruritus in PFIC, pharmacological diversion of bile acids with an 
IBAT inhibitor could be an attractive alternative to surgical intervention in PFIC without surgical 
complications. TAK-625 potentially reduces cholestasis due to PFIC and the related effects of 
cholestatic pruritus, xanthomas, and growth deficiency by above mechanism. 
Key Clinical Experience 
For subjects with PFIC, mainly one phase 2 study, MRX-501, has been completed and the other, 
one phase 3 study, MRX-502, is ongoing outside Japan. In addition, one phase 2 study, 
MRX-801, is ongoing outside Japan for patients <12 months of age with ALGS or PFIC. 
4.1.3.1 
Pharmacokinetics in Clinical Studies 
In clinical studies evaluating pharmacokinetics (PK), TAK-625 is minimally absorbed, with little 
detectable unchanged TAK-625 in plasma (lower limit of quantification [LOQ] 0.25 ng/mL) 
after multiple dosing with TAK-625 at doses ≤ 20 mg. In addition, the mean (standard deviation 
[SD]) 2.5 hours after dosing TAK-625 concentration was 0.54 (0.62) ng/mL in subjects 
<12 months of age with ALGS. This low TAK-625 concentraion result is consistent with 
previous result in subjects ≥12 months of age who were administered TAK-625. 
Concomitant administration of a high-fat meal with a single oral dose of TAK-625 decreased 
both the rate and extent of absorption. Area under the curve (AUC) and maximum drug 
concentration (Cmax) of TAK-625 values in the fed state were 64.8% to 85.8% lower relative to 
oral administration of 30 or 45 mg in fasted conditions.  
Fecal excretion was found to be the major route of elimination. Following a single oral dose of 
5 mg [14C] TAK-625, the majority was recovered in feces, with recovery in whole blood, plasma, 
 
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or urine accounting for <1%. Three metabolites were detected in feces, but these accounted for 
<3% of total fecal radioactivity. The remainder of the fecal radioactivity (>94%) was associated 
with unchanged TAK-625. 
4.1.3.2 
Study MRX-501 (Phase 2 Study) 
The efficacy of TAK-625 was assessed in Study MRX-501, which was an open-label phase 2 
study in pediatric subjects (aged 12 months to 18 years) with PFIC1 or PFIC2 designed to 
evaluate the safety and efficacy of TAK-625. Subjects were initially treated with doses up to 
280 μg/kg, once a day (QD) until Protocol Amendment 4 (after Week 72), which allowed partial 
responders and nonresponders (n=10) to be treated with doses up to 280 μg/kg, twice daily 
(BID). The primary efficacy evaluation for this study was the change from baseline to Week 48 
in fasting sBA level.  
The following is a summary of Study MRX-501 results through Week 72: 
Efficacy Results: 
In the primary endpoint of change from baseline to Week 13/early termination (ET) in sBA, 
numerical improvement was observed in subjects with PFIC2 (mean [SD] change from baseline, 
-38 [177.7] μmol/L) but not in subjects with PFIC1. In the overall study population, the mean
(SD) change from baseline was -23 (161.0) μmol/L.
In the secondary endpoints of change from baseline to endpoint (Week 13/ET), numerical 
improvements were observed in the overall study population in mean (SD) the observer-reported 
Itch Reported Outcome (ItchRO [Obs]) 4-week average morning score (-0.7 [0.65]), the 
patient-reported Itch Reported Outcome (ItchRO [Pt]) 4-week average morning score 
(- 0.6 [0.57]), alanine aminotransferase (ALT) (-9 [61.8] U/L), total bilirubin (TBili) 
(- 0.2 [1.65] mg/dL), and direct bilirubin (-0.1 [1.12] mg/dL). Numerical improvements in each 
of the parameters listed above were noted in subjects with PFIC2 and PFIC1. 
In the endpoints of change from baseline to endpoint (Week 72/ET), numerical improvements 
were observed in the overall study population in mean (SD) sBA (-2 [146.0] μmol/L) and ALT 
(- 12 [59.6] μmol/L). Numerical improvements were noted in sBA (Mean [SD], 
- 10 [162.8] μmol/L) and ALT (mean [SD], -19 [65.0] U/L) in subjects with PFIC2, but not
subjects with PFIC1.
In the endpoints of change from baseline to endpoint (Week 48/ET), numerical improvements 
were observed in the overall study population in ItchRO (Obs) 4-week average morning score 
(mean [SD], -0.9 [0.94]) and ItchRO (Pt) 4-week average morning score (mean [SD], 
- 1.0 [0.69]). Numerical improvements were noted in ItchRO (Obs) 4-week average morning
score (mean [SD], -1.0 [0.96]) and ItchRO (Pt) 4-week average morning score (mean [SD],
- 1.0 [0.80]) in subjects with PFIC2. Numerical improvements in ItchRO (Obs) and ItchRO (Pt)
were also observed in subjects with PFIC1.
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TAK-625 
Study No. TAK-625-3002 
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Safety Results: 
Treatment-emergent adverse events (TEAEs) related to study drug were experienced by 
23 subjects (69.7%) overall, with a lower incidence in subjects with PFIC1 (3 subjects [37.5%]) 
compared with subjects with PFIC2 (20 subjects [80.0%]). Gastrointestinal events (from the 
Gastrointestinal [GI] disorders system organ class [SOC]) were the most frequently reported 
treatment-related TEAEs (18 subjects [54.5%]).  
Serious adverse events (SAEs) were experienced by 14 subjects (42.4%) overall, including 
4 subjects (50.0%) with PFIC1 and 10 subjects (40.0%) with PFIC2. Gastrointestinal events 
(from the GI disorders SOC) were the most frequently reported SAEs (6 subjects [18.2%]). The 
only SAEs reported for more than 1 subject were abdominal pain and diarrhea, each experienced 
by 2 subjects (6.1%). SAEs potentially related to study drug were experienced by 5 subjects 
(15.2%) overall, with a similar incidence in subjects with PFIC1 (1 subject [12.5%]) and PFIC2 
(4 subjects [16.0%]). The treatment-related SAEs were reported for 1 subject each and included 
abdominal pain, abdominal pain upper, diarrhea, pancreatitis, blood bilirubin increased, and 
international normalized ratio (INR) increased. 
A total of 5 subjects (15.2%) experienced TEAEs that led to permanent treatment 
discontinuation, including disease progression (2 subjects [6.1%]), blood bilirubin increased 
(2 subjects [6.1%]), and pancreatitis (1 subject [3.0%]). Of the TEAEs that led to permanent 
treatment discontinuation, only the TEAE of pancreatitis was considered potentially related to 
study drug. All of the TEAEs that led to permanent treatment discontinuation were experienced 
by subjects with PFIC2. No deaths were reported during the conduct of the study. 
4.1.3.3 
Study MRX-801 (Phase 2 Study) 
Currently, Study MRX-801, which is an open-label, multicenter, phase 2 study in pediatric 
subjects (<12 months of age) with ALGS or PFIC designed to evaluate the safety and tolerability 
of TAK-625, is ongoing. ALGS or PFIC subjects receive TAK-625 over a 13-week treatment 
period (core study period) that includes dose escalation and stable dosing. Stable dosing occurs 
at 400 μg/kg once daily (QD; for ALGS) and at 600 μg/kg twice daily (BID; for PFIC), or at the 
highest tolerated dose. For subjects <1 month of age, the dose for both ALGS and PFIC is 
75 μg/kg QD for the duration of treatment below this age boundary. 
The interim analyses were planned when at least 6 subjects had completed the 13-week core 
study period for each study cohort (ALGS and PFIC). 
The following is a summary of the results for the ALGS cohort as of 4 May 2022: 
A total of 8 subjects (<12 months of age [2-10 months]) with ALGS were enrolled in the study. 
All subjects successfully escalated to the proposed label dose of 400 µg/kg/day with the 
proposed single drug-escalation step. Overall, 7 subjects completed the 13-week core study 
period, and 1 subject discontinued during the 13-week core study period. 
 
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Study No. TAK-625-3002 
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Efficacy Results: 
Improvements in pruritus and sBA were observed, as indicated by decreases in Clinician Scratch 
Scale (CSS) scores and sBA levels over time with treatment with TAK-625.  
The mean (SD) change in sBA from baseline at Week 13 was -88.91 (113.35) μmol/L. There 
were decreases in sBA from baseline to Week 3, 10, and 13. 
The mean (SD) change from baseline to Week 13 for CSS score was -0.2 (1.91) and ranged from 
-3 to 3. The mean change from baseline for CSS score decreased from baseline to Week 6 and
Week 13.
Safety Results: 
TAK-625 was well tolerated. A total of 7 subjects (87.5%) experienced at least 1 TEAE, 
2 subjects (25.0%) had a TEAE related to the study drug (both events were Grade 1 diarrhea), 
and 4 subjects (50.0%) had a Grade ≥3 TEAE, none of which were considered to be related to 
the study drug. The most frequent TEAEs were nasopharyngitis, abdominal pain, diarrhea, 
teething, and pyrexia. These events were in all cases self-limiting and resolved with no drug 
interruption or change in dose. Most TEAEs were Grade 1 in severity. Four subjects (50.0%) had 
7 SAEs, none of which were considered to be related to the study drug. No TEAE led to study 
discontinuation or death.  
Most subjects had fluctuations in liver chemistry (ALT, aspartate aminotransferase [AST]), and 
total bilirubin) from baseline to each time point; however, 4 subjects (50.0%) had a decrease 
from baseline in total bilirubin, indicating improvement over time. Most subjects maintained or 
had mild increases in lipid soluble vitamin (LSV) levels from baseline to each time point, 
consistent with standard-of-care vitamin supplementation administered to subjects with ALGS. 
4.1.3.4 
Study MRX-502 (Phase 3 Study) 
Currently, Study MRX-502, which is a 6-month, international, multicenter, randomized, 
double-blind, placebo-controlled phase 3 study in subjects with PFIC, is ongoing. The study will 
be followed by the long-term extension study MRX-503, during which all subjects who complete 
Study MRX-502 will have the opportunity to be treated continuously with TAK-625. Subjects 
will be randomized in a 1:1 ratio to the TAK-625 or placebo treatment groups, respectively, 
stratified by cohort (Primary cohort: up to 30 subjects with nt-PFIC2, Supplemental cohort: up to 
60 subjects with other PFIC subtypes). Subjects are treated with doses up to 600 μg/kg, BID with 
4-step dose escalation. The primary efficacy evaluation for this study is the mean change in the 
average morning ItchRO (Obs) severity score between baseline and Week 15 through Week 26. 
The secondary endpoints are 1) the mean change in the average morning ItchRO (Obs) frequency 
score between baseline and Week 15 through Week 26; 2) the mean change in total sBA between 
baseline and Week 26; 3) Proportion of subjects who experience an sBA control (defined as a 
reduction to <102 μmol/L or a reduction of >75%, or normalization) from baseline through 
Week 26.
 
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TAK-625 
Study No. TAK-625-3002 
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4.2 
Rationale for the Proposed Study 
TAK-625 has never been used in Japan, although Study MRX-501 suggested that TAK-625 was 
safe and effective for nt-PFIC2 and the effect sustained in long-term period in subjects with 
nt-PFIC2. In this study, efficacy, safety, and PK profile of TAK-625 will be evaluated in 
Japanese subjects with PFIC. Because all treatment responders in Study MRX-501 were subjects 
with PFIC2, the primary cohort will include subjects with PFIC2, and the supplemental cohort 
will include subjects with PFIC other than PFIC2. This protocol was developed to confirm the 
similarity to Study MRX-502 by comparing the results between Japanese data and overseas data. 
TAK-625 was well tolerated in subjects <12 months of age with ALGS with moderate to severe 
cholestasis in Study MRX-801. Given the clinical outcomes associated with PFIC and ALGS, 
including the negative impact on patients’ and caregivers’ quality of life and the fact that there 
are currently no or limited approved treatments for patients <12 months of age, there is a high 
unmet medical need for a novel treatment for these diseases. Thus, patients <12 months of age 
will be enrolled as well as patients ≥12 months of age in this study. Study MRX-801 was 
designed to enroll patients ≥0 days of age with PFIC; however, from the age of onset of PFIC, it 
is assumed that the administration of TAK-625 would not be started before 1 month after birth. 
Therefore, patients ≥1 month of age was planned to be enrolled in this study, in consideration of 
preventing the patients from being exposed to the amount of propylene glycol (PG) in TAK-625 
over the maximum daily dose limit of PG specified in the guidance by the European Medicines 
Agency (EMA). 
In Japan, a diagnosis of PFIC is made comprehensively with symptoms such as jaundice and 
intense pruritus, as well as characteristic findings in liver biopsy (cholestasis in the bile 
canaliculus and giant cell hepatitis), immunostaining of BSEP. The gene analysis is also 
considered when the diagnosis is difficult [6], like in overseas. Regarding the current treatments 
for patients with PFIC, there are only symptomatic medicines. Also, the overall process from 
diagnosis to treatment is not different in Japan and overseas. These support the rationale for 
comparison between data in Japanese subjects and data in non-Japanese subjects. However, since 
it is not feasible to include a placebo arm considering the extreme rarity of PFIC, the 
randomized, double-blind, placebo-controlled drug withdrawal period will not be used in this 
study. LSV deficiency will be monitored regularly for a long-term as a potential adverse event 
(AE) based on the mechanism of action.
4.3 
Benefit/Risk Profile 
The proposed study is designed to evaluate the efficacy, safety, and PK profile of TAK-625 in 
Japanese patients with PFIC.  
As previously stated in Section 4.1.3, the safety and efficacy profile of TAK-625 in 
non-Japanese subjects with nt-PFIC2 has been confirmed in Study MRX-501, though TAK-625 
has never been used in Japan. The long-term efficacy has been also confirmed in Study 
MRX-501. 
 
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TAK-625 
Study No. TAK-625-3002 
Page 33 of 115 
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Based on clinical study data, diarrhoea and abdominal pain have been classified as identified risk 
and transaminases increased has been classified as potential risk of TAK-625. The majority of 
reported severities of diarrhoea and abdominal pain in clinical studies were mild or moderate.  
Therefore, TAK-625 has a positive benefit-risk profile in the treatment to PFIC. 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
Primary Objectives 
•
To evaluate the efficacy of TAK-625 in the primary cohort.
•
To evaluate the safety of TAK-625 in subjects with PFIC.
Secondary Objectives 
•
To evaluate the efficacy of TAK-625 in subjects with PFIC.
•
To evaluate the PK of TAK-625 in subjects with PFIC.
Additional Objectives 
•
To evaluate primary, secondary, and exploratory endpoints in the supplemental cohort.
5.2 
Endpoints 
Primary Endpoint 
•
Change in the average morning ItchRO (Obs) severity score between baseline and average of
Week 15 through Week 26.
Secondary Endpoints 
5.2.2.1 
Key Secondary Endpoints 
•
Change in the average morning ItchRO (Obs) frequency score between baseline and average
of Week 15 through Week 26.
•
Change in total sBA between baseline and Week 26.
5.2.2.2 
Secondary Endpoints 
•
Proportion of subjects who experience an sBA control (defined as a reduction to
<102 μmol/L, or a reduction of >75%, or normalization) from baseline through Week 26.
•
Change in the ItchRO (Obs) weekly average severity (based on daily maximum of morning
and evening severity scores) between baseline and average of Week 15 through Week 26.
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TAK-625 
Study No. TAK-625-3002 
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Safety Endpoints 
•
Incidence of AEs including SAEs, related to study drug, leading to study drug
discontinuation, and AEs of clinical interest (AECIs).
AECIs include the following:
–
LSV deficiency events.
–
Liver parameter disruption.
•
Change from baseline in clinical laboratory values (hematology, chemistry, urinalysis, and
others), physical examination findings (including body weight, height, and body mass index
[BMI]), vital signs, and electrocardiogram (ECG) parameters.
PK Endpoint 
•
Plasma levels of TAK-625 at predose and approximately 2.5 hours after the morning dose at
Week 10.
•
Plasma levels of TAK-625 at predose (optional) and approximately 30 minutes after the
morning dose at Week 14 (or any visit up to Week 26).
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TAK-625 
Study No. TAK-625-3002 
Page 35 of 115 
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a phase 3, multicenter, open-label, uncontrolled study to evaluate the efficacy and safety 
of TAK-625 in the treatment of Japanese subjects with PFIC.  
Study Population: 
The study population is defined as “Japanese patients with PFIC who are 1 month of age or 
older”. Subjects diagnosed with PFIC2 due to ABCB11 mutation that predicts residual BSEP 
function (nt-PFIC2) will be enrolled in the primary cohort. Subjects with other PFIC subtypes 
(eg, t-PFIC2, PFIC1/3/4, or other PFIC mutation variants) or postsurgical subjects (eg, internal 
or external biliary diversion surgery) will be enrolled in the supplemental cohort. (Subjects 
diagnosed with PFIC2 due to ABCB11 mutation that predicts complete absence of BSEP 
function [t-PFIC2] are excluded from the primary cohort and can be enrolled only in the 
supplemental cohort. PFIC subtypes should be determined by a genotyping [refer to 
Section 7.1]).  
Study Period (Screening, Treatment [Dose Escalation, Stable Dosing, and Follow-Up Dosing], 
and Safety Follow-Up Period): 
This study consists of the screening period (up to 6 weeks prior to the study administration), 
4-week (up to 6-week) dose escalation period (doses up to 600 μg/kg, BID, as tolerated),
44-week stable dosing period, and follow-up dosing period (until TAK-625 is approved or 
available in Japan commercially, or if the subject withdraws from the study, or if the investigator 
determines the subject’s discontinuation, or if the sponsor stops the program or development in 
this indication).
1. Screening Period (up to 6 Weeks prior to the Study Administration):
In the screening period, for subjects who do not have documentation of mutation related with 
PFIC, a blood sample will be obtained for genotyping. Subjects diagnosed with PFIC2 
(nt-PFIC2) will be enrolled in the primary cohort and those with other types of PFIC will be 
enrolled in the supplemental cohort. The electronic Diary (eDiary) for assessing pruritus with the 
Itch Reported Outcome (ItchRO) instrument will be dispensed and subjects and caregivers will 
undergo training during the screening visit.  
2. Dose Escalation Period (4 weeks [up to 6 weeks]: Week 0 to 4 [6]):
In the dose escalation period, at the baseline visit (Week 0/Visit 2), subjects will be assessed to 
confirm continued study eligibility and undergo a physical examination including body weight, 
height, BMI, and vital signs, and have urine and blood samples taken for hematology, chemistry, 
fasting lipid panel, baseline levels of sBA and other cholestasis biochemical markers. 
Compliance with ItchRO will be assessed. Study drug will be supplied at each visit 
(Week 0/Visit 2, Week 2/Visit 3, and Week 4/Visit 4). The subject contacts (phone calls) will be 
conducted at Weeks 1 and 3. The dose is increased weekly, 150 μg/kg, 300 μg/kg, 450 μg/kg, 
and 600 μg/kg, BID.  
 
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TAK-625 
Study No. TAK-625-3002 
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Dose escalation should occur in the absence of major safety (eg, liver parameters and LSV 
deficiency) or tolerability concerns (eg, GI-related TEAEs) related or possibly related to study 
drug. Subjects with such safety concerns can be down-titrated to a lower, previously tolerated 
dose level for 1 week before continuing dose escalation. The minimum dose to continue in the 
study will be 150 μg/kg, BID; subjects who cannot tolerate this dose will be discontinued from 
the study. The dose escalation period is allowed to be extended up to 6 weeks depending on the 
safety or tolerability concerns (refer to Section 8.1.3). 
3. Stable Dosing Period (44 weeks: Week 5 to 48):
After the dose escalation period, each subject will continue dosing with study drug at the Week 4 
or Week 6 dose level (the maximum tolerated dose [MTD] level) in the stable dosing period. 
Subjects will return to the study site at Weeks 6, 10, 14, 18, 22, 26, 28, 32, 36, 40, 44, and 48 and 
undergo physical examinations. Subject contacts (phone calls) will be conducted as appropriate 
throughout the stable dosing period. Subjects and caregivers will continue twice daily 
completion of their ItchRO throughout the period.  
4. Follow-up Dosing Period (after Week 48):
Additionally, in the follow-up dosing period, each subject will continue dosing with study drug. 
The safety evaluation will be performed in all the subjects every 12 weeks from Week 48 visit 
until TAK-625 is approved or available in Japan commercially, or if the subject withdraws from 
the study, or if the investigator determines the subject’s discontinuation, or if the sponsor stops 
the program or development in this indication. Bile acids and ItchRO will be measured to 
evaluate the long-term effectiveness of TAK-625. For subjects discontinuing early, safety 
follow-up will be conducted. 
5. Safety Follow-up (after Final Visit/ET):
Subjects/caregivers will have a final safety follow-up subject contact (phone call) 7 days after the 
final study visit or ET visit (except for screen failure). 
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A. 
 
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TAK-625 
Study No. TAK-625-3002 
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Figure 6.a 
Schematic of Study Design 
BID=twice daily; SCR=screening; W=Week; wks=weeks. 
a The dose escalation period is allowed to be extended up to 6 weeks depending on the safety or tolerability 
concerns. 
Endpoint: 
Primary endpoint is change in the average morning ItchRO (Obs) severity score between 
baseline and the average of Week 15 through Week 26. Key secondary endpoints are change in 
the average morning ItchRO (Obs) frequency score between baseline and the average of 
Week 15 through Week 26, and change in total sBA between baseline and Week 26. 
Sample Size: 
The primary cohort (nt-PFIC2): up to approximately 3 subjects. The supplemental cohort (other 
types of PFIC): up to approximately 6 subjects. 
Sites and Regions: 
The study will be conducted in approximately 10 sites in Japan. 
Duration of Treatment:  
The study will be continued until TAK-625 is approved or available in Japan commercially, or if 
the subject withdraws from the study, or if the investigator determines the subject’s 
discontinuation, or if the sponsor stops the program or development in this indication. A subject 
will be considered as having completed the study if the subject has not withdrawn early from the 
study for any reason prior to completing the end of treatment (EOT) visit. 
If TAK-625 is approved for marketing by authorities during the study, the study can be shifted to 
a post-marketing study after the approval. In that case this protocol will continuously be used. 
 
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TAK-625 
Study No. TAK-625-3002 
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“Clinical Study” mentioned in the protocol will be read as “Post-marketing Study” as 
appropriate. 
6.2 
Justification for Study Design, Dose, and Endpoints 
TAK-625 has never been used in Japan, although Study MRX-501 suggested that TAK-625 was 
safe and effective for nt-PFIC2 and the effect sustained in long-term period in subjects with 
nt-PFIC2. In this study, efficacy, safety, and PK profile of TAK-625 will be evaluated. This 
protocol was developed to confirm the similarity to Study MRX-502 by comparing the results 
between Japanese data and overseas data. 
Justification for Study Population: 
Limiting the analysis to subjects with PFIC2 (primary cohort) is based on the following:(1) All 
responders in Study MRX-501 are subjects with PFIC2; (2) PFIC2 patients most commonly lack 
extrahepatic abnormalities; and (3) PFIC2 represents the most prevalent subgroup of PFIC 
patients and, therefore, constitutes the biggest unmet need. Although the safety of TAK-625 was 
confirmed in subjects <12 months of age with ALGS with moderate to severe cholestasis 
enrolled in Study MRX-801, the lower age limit for enrollment in this study is set to be 1 month 
of age, in consideration of preventing the patients from being exposed to the amount of PG in 
TAK-625 over the maximum daily dose limit of PG specified in the guidance by the EMA. 
Justification for Dose and Regimen of Study Drug: 
The TAK-625 up to 600 μg/kg, orally BID dosing regimen was selected based on international 
phase 2 and phase 3 clinical trials of TAK-625 (Study MRX-501 and Study MRX-502). 
TAK-625 is provided as an oral solution that is dosed on a weight basis. In phase 2 studies, 
TAK-625 has been administered to 119 pediatric subjects with cholestatic liver disease (33 with 
PFIC and 86 with ALGS; >12 months of age) at doses up to a maximum daily dose of 
800 µg/kg/day. Dosing of 400 and 800 µg/kg/day (Study LUM001-304) and 280 and 
560 µg/kg/day (Study MRX-501) demonstrated a consistent safety profile. No MTD has been 
determined at single doses up to 7000 µg/kg and multiple doses up to 1400 µg/kg/day. 
Furthermore, no dose-related safety findings have been identified to date.  
Effective and clinically relevant inhibition of the IBAT using TAK-625 has been demonstrated 
by durable reductions in sBA and pruritus levels in children with PFIC and ALGS ≥12 months of 
age on treatment for over 5 years. Although the efficacy results in infants <12 months of age 
with PFIC are not yet available, improvements in pruritus and sBA were observed and the safety 
of TAK-625 was confirmed in infants <12 months of age with ALGS in the ongoing Study 
MRX-801, in which infants <12 months of age with ALGS or PFIC had been enrolled. Evidence 
from Study MRX-501 indicates that higher doses and BID regimens may improve the responder 
rate to TAK-625 treatment in PFIC. These data led to the dose selection for Study MRX-502, an 
ongoing Phase 3 randomized double blinded, placebo-controlled study, investigating the safety 
and efficacy of higher doses up to 600 µg/kg BID in subjects with PFIC. The 600 µg/kg BID 
dosing regimen is further supported by documentation of dose-dependent increase in fBA 
excretion, the direct pharmacodynamic marker of IBAT inhibition, up to total daily doses of 
 
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TAK-625 
Study No. TAK-625-3002 
Page 39 of 115 
Protocol Amendment 02  
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TAK-625 100 mg (weight-based equivalent of 1400 µg/kg/day). In a dose-finding phase 1 study 
(SHP625-101) conducted in overweight and obese adults, BID dosing (50 mg BID; 700 µg/kg 
BID equivalent) led to higher fBA excretion compared to 100 mg QD (1400 µg/kg QD 
equivalent). The safety profile was comparable across the tested dose range, except for increased 
stool frequency at higher doses.  
Doses of TAK-625 up to 1200 µg/kg/day (600 µg/kg BID) are expected to be safe in children 
with cholestatic liver disease and will be evaluated in Japanese subjects with PFIC for efficacy 
and safety in this study with the same dose escalation step as that in Study MRX-502. 
Sample daily exposure (mg-day) across proposed dose levels for subjects ranging in weight from 
3 to 70 kg is provided in Table 6.a. 
Table 6.a 
Sample Daily Exposure (mg/day) in Subjects 
Weight 
(kg) 
Daily Exposure of TAK-625 (mg) 
Dose Level 1 
(150 μg/kg, BID) 
Dose Level 2 
(300 μg/kg, BID) 
Dose Level 3 
(450 μg/kg, BID) 
Dose Level 4 
(600 μg/kg, BID) 
3 
0.9 
1.8 
2.7 
3.6 
5 
1.5 
3.0 
4.5 
6.0 
10 
3.0 
6.0 
9.0 
12.0 
20 
6.0 
12.0 
18.0 
24.0 
30 
9.0 
18.0 
27.0 
36.0 
40 
12.0 
24.0 
36.0 
48.0 
50 
15.0 
30.0 
45.0 
60.0 
60 
18.0 
36.0 
54.0 
72.0 
70 
21.0 
42.0 
63.0 
84.0 
BID=twice daily. 
Justification for Endpoint: 
The primary and secondary endpoints in this study are similar those in the previous clinical 
studies with TAK-625 in PFIC subjects (Study MRX-502) to compare the results between 
Japanese data and overseas data.  
The primary endpoint is the change in the average morning ItchRO (Obs) severity score between 
baseline and the average of Week 15 through Week 26. The selection of ItchRO (Obs) as the 
primary endpoint of therapeutic response to TAK-625 treatment was based on the clinically 
significant improvements observed in Study MRX-501. 
 
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6.3 
Premature Termination or Suspension of Study or Study Site 
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 ET of the study. 
•
New information or other evaluation regarding the safety or efficacy of the study drug that
indicates a change in the known risk/benefit profile for the TAK-625, such that the risk
/benefit is no longer acceptable for subjects participating in the study.
•
Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve
the primary study objectives or compromises subject safety.
Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
ET or suspension will be provided by the sponsor; the procedure will be followed by applicable 
study sites during the course of termination or study suspension. 
Duration of an Individual Subject’s Study Participation 
Subjects, including those who achieve a clinical response, may receive TAK-625 until TAK-625 
is approved or available in Japan commercially, or if the subject withdraws from the study, or if 
the investigator determines the subject’s discontinuation, or if the sponsor stops the program or 
development in this indication. Subjects will discontinue treatment if they have an unacceptable 
TAK-625-related toxicity. 
Subjects will be followed for 7 days after the final study visit or ET visit to permit the detection 
of any delayed treatment-related AEs. 
End of Study/Study Completion Definition and Planned Reporting 
End of Study:  
The study will be continued until TAK-625 is approved or available in Japan commercially, or if 
the subject withdraws from the study, or if the investigator determines the subject’s 
discontinuation, or if the sponsor stops the program or development in this indication. A subject 
will be considered as having completed the study if the subject has not withdrawn early from the 
study for any reason prior to completing the EOT visit. 
 
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TAK-625 
Study No. TAK-625-3002 
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If TAK-625 is approved for marketing by authorities during the study, the study can be shifted to 
a post-marketing study after the approval. 
Study Completion: 
The study completion date is defined as the date the final subject, across all sites, completes his 
or her final protocol-defined assessment. Note that this includes the follow-up visit or contact, 
whichever comes later (refer to Section 9.3.6 for the defined follow-up period for this protocol) 
but not the long-term clinical follow-up of persistent safety findings. 
Subjects who discontinue at any time during the treatment period will have a final safety 
follow-up subject contact (phone call) 7 days after the ET visit (see Section 9.3.6). Subjects who 
discontinue from the study for safety reasons are followed as long as clinically indicated or until 
no further improvement with an adverse outcome is expected. 
Analysis Points: 
Interim analysis will be performed at Week 26 and Week 48. Final clinical study report (CSR) 
will be prepared at the end of the study. 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed before first dose. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria before study entry: 
1.
The subject signs and dates an informed consent form/assent (as applicable) and any
required privacy authorization prior to the initiation of any study procedures.
If the subjects are under 18 years of age, the investigator is responsible for obtaining written
informed consent not only from the under-aged subjects, but also from their legally
acceptable representatives.
2.
The subject is Japanese male or female with a body weight ≥3.0 kg and who is ≥1 month of
age at the time of informed consent.
For subjects <12 months of age, gestational age ≥36 weeks at birth. For subjects born with
gestational age between 32 and 36 weeks, a postmenstrual age of ≥36 weeks is required.
Postmenstrual age is defined as the time elapsed between the first day of the last menstrual
period and birth plus the time elapsed after birth.
3.
The subject has a cholestasis as manifested by total sBA ≥3× upper limit of the normal range
(ULN) (applies to the primary cohort only).
4.
The subject has an average morning ItchRO (Obs) score ≥1.5 during 4 consecutive weeks of
the screening period, leading to the baseline visit (Week 0/Visit 2). Since it is difficult to
evaluate pruritus in infants, subjects <12 months of age at screening whose pruritus is
unavoidably difficult to be evaluated are not necessarily required to meet the above score.
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5.
The caregiver has completed at least 21 valid* morning ItchRO (Obs) entries during
4 consecutive weeks of the screening period, leading to the baseline visit (Week 0/Visit 2)
(*valid=completed and not answered as “I don’t know”; the maximum allowed invalid
reports=7, no more than 2 invalid reports during the last 7 days before the baseline visit
[Week 0/Visit 2]).
6. The subject has a diagnosis of PFIC based on:
Chronic cholestasis as manifested by persistent (>6 months*) pruritus in addition to
biochemical abnormalities and/or pathological evidence of progressive liver disease
(* ≤6 months is acceptable for subjects <12 months of age).
And
Primary cohort:
a) The subject has a genetic testing result consistent with disease-causing variation in
ABCB11 (PFIC2), based on a genotyping.
Supplemental cohort: 
a) The subject has a genetic testing results consistent with disease causing variation in
ATP8B1 (PFIC1), ABCB4 (PFIC3), or tight junction protein 2 gene (TJP2) (PFIC4),
based on a genotyping.
b) The subject has a PFIC phenotype without a known mutation or with another known
mutation not described above.
c) The PFIC subject has internal or external biliary diversion surgery history, and the
internal or external biliary diversion surgery was reversed.
7. The subject is a male or female of non-childbearing potential. A male and non-pregnant,
non-lactating female of childbearing potential who is sexually active must agree to use
acceptable methods of contraception during the study and 30 days following the last dose of
the study drug. A female of childbearing potential must have a negative pregnancy test result.
Definitions and highly effective methods of contraception are defined in 
Section 9.1.13 and reporting responsibilities are defined in Section 9.1.14. 
8. The subject (whenever possible) and caregiver are able to be contacted by phone for
scheduled remote visits (subject contacts [phone calls]).
9. Both a caregiver and subject above the age of assent are capable of reading and
understanding the questionnaires.
10. The same caregiver should be contacted during this study.
The ItchRO (Obs) should be completed by the same caregiver for consistency during this
study, even if the subject is an adult (over 18 years old).
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7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The diagnosed with PFIC2 due to ABCB11 mutation that predicts complete absence of BSEP
function due to the type of ABCB11 mutation (t-PFIC2), based on a genotyping (applies to
the primary cohort only). The subject may enter the study in the supplemental cohort (based
on inclusion criteria 6.b) or 6.c) (refer to Section 7.1 for details).
2. The subject has a diagnosis of benign recurrent intrahepatic cholestasis indicated by a history
of intermittent cholestasis with no disease progression.
3. The subject has a current or recent history (<1 year) of atopic dermatitis or other
non-cholestatic diseases associated with pruritus.
4. The subject has a previous history of surgical interruption of the enterohepatic circulation
(applies to the primary cohort only).
5. The subject with chronic diarrhea requiring intravenous (IV) fluid or nutritional intervention
and/or its sequelae at screening or during the 6 months prior to screening.
6. The subject has a history of liver transplant or currently requires imminent liver transplant.
7. The subject with decompensated cirrhosis (INR >1.5, and/or albumin <30 g/L, history, or
presence of clinically significant ascites, and/or variceal hemorrhage, and/or
encephalopathy).
8. The subject has an ALT or total serum bilirubin (TSB) level >15× ULN at screening.
9. The subject has other liver disease.
10. The subject has any other disease or condition known to interfere with the absorption,
distribution, metabolism, or excretion of drugs, including bile salt metabolism in the intestine
(eg, inflammatory bowel disease), per investigator discretion.
11. The subject has a possible malignant liver mass in imaging, including screening ultrasound.
12. The subject has a history of human immunodeficiency virus (HIV) infection.
13. The subject has been diagnosed with any cancer (except for in situ carcinoma) within 5 years
before the screening visit (Visit 1).
14. The subject has a history of drug abuse (substance abuse) or a history of alcohol abuse.
15. The subject has received bile acid, lipid binding resins or IBAT inhibitors within 28 days
prior to screening and throughout the trial (refer to Section 7.3).
16. The subject who has received sodium phenylbutyrate for less than 6 months at the initiation
of screening (refer to Section 7.3 and Section 7.5.1.2).
17. The subject participated in another clinical study within 28 days or 5 half-lives (whichever is
longer) prior to screening.
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18. The subject is judged by the investigator or sponsor medical monitor, as being ineligible for
any other reason (eg, history of nonadherence to medical regimens, unreliability, medical
condition, mental instability, or cognitive impairment) that could compromise the validity of
informed consent, compromise the safety of the subject, or lead to nonadherence with the
study protocol or inability to conduct the study procedures.
19. The subject has a history of hypersensitivity to TAK-625 or any of its components.
7.3 
Excluded Medications 
The following medications are prohibited during TAK-625 treatment and within the provided 
timeframe prior to screening. 
Prior Therapy 
Time Restriction 
Bile acid/Lipid binding resins 
Within 28 days prior to screening and throughout the trial. 
IBAT inhibitors 
Within 28 days prior to screening and throughout the trial. 
Sodium phenylbutyrate 
If the subject has received sodium phenylbutyrate for less than 6 months at 
the initiation of screening, the subject cannot be enrolled. 
(If the subject has received sodium phenylbutyrate for 6 months or more at 
the initiation of screening, the medication is permitted; however, the dose 
of sodium phenylbutyrate should not be changed during the study [refer to 
Section 7.5.1.2].) 
IBAT=ileal bile acid transporter.
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator. 
Justification of Excluded Medications 
•
Bile acids/Lipid binding resins: Since bile acids/lipid binding resins have been used for
treatment of pruritus, these medications are excluded to avoid any influence on the efficacy
results of TAK-625.
•
IBAT inhibitors: Since the mechanism of action of IBAT inhibitors is similar to that of
TAK-625, these medications are excluded to avoid any influence on the safety and efficacy
results of TAK-625.
•
Sodium phenylbutyrate: If the subject has received sodium phenylbutyrate for less than
6 months at the initiation of screening, the subject cannot be enrolled; since sodium
phenylbutyrate has been shown to influence pruritus due to cholestatic diseases, the
medication is excluded to avoid any influence on efficacy results of TAK-625. Meanwhile, if
the subject has received sodium phenylbutyrate for 6 months or more at the initiation of
screening, the medication is permitted, because the drug's effect is considered to have
reached a plateau.
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7.4 
Excluded Procedures and Treatments 
The subject with a history of surgical interruption of the enterohepatic circulation or liver 
transplant should not be included in the study. 
Justification of Excluded Procedures and Treatments 
•
Surgical interruption of the enterohepatic circulation: The surgical interruption of the
enterohepatic circulation is excluded from the study due to its significant impact on bile acid
homeostasis.
•
Liver transplant: The liver transplant is excluded from the study since this is considered as a
curable treatment for PFIC.
7.5 
On Study Restrictions 
Concomitant Medications, Procedures, and Treatments 
A subject should not be instructed to discontinue use of any medication or treatment to 
participate in this study until informed consent (or assent as applicable) has been obtained. 
Concomitant treatment refers to all treatment, including concomitant therapies, as well as herbal 
treatments, vitamins, behavioral treatment, non-pharmacological treatment, such as 
psychotherapy, taken between the dates of the first dose of study drug and the end of the 
subject’s participation in the study. Concomitant treatment information must be recorded in the 
subject’s source document.  
7.5.1.1 
Prohibited Concomitant Medications, Procedures, and Treatments 
The prohibited concomitant medications, procedures and treatment are described in Section 7.3 
and Section 7.4. 
7.5.1.2 
Permitted Concomitant Medications, Procedures, and Treatments 
The following medications to treat cholestasis/pruritus are allowed during the study if the subject 
has been on a stable dosing regimen (ie, same dose and frequency in the 30 days prior to the 
screening visit [Visit 1]) and will continue this dosing regimen throughout study participation. 
The investigator must contact the medical monitor to discuss any changes to and introduction of 
concomitant treatments to treat cholestasis/pruritus not listed here that could impact the outcome 
of the study. Dose adaptations to body weight changes are allowed. 
•
Ursodeoxycholic, cholic acid, chenodeoxycholic acid or dehydrocholic acid.
•
Antihistamines.
•
Nalfurafine.
•
Phenobarbital.
•
Rifampicin.
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•
Naloxone.
Administration of sodium phenylbutyrate is permitted only under the conditions below. 
However, the dose of sodium phenylbutyrate should not be changed during the study; temporary 
dose adjustments for safety concerns or dose adaptations to body weight changes are permitted at 
the discretion of the investigator. 
1. Stable dosing for 6 months or more at the initiation of screening; temporary dose adjustments
for safety concerns or dose adaptations to body weight changes are permitted at the discretion
of the investigator.
2. Assessed to be in a stable condition (no more improvement will be expected) by the
investigator.
7.5.1.3 
LSVs 
The investigators must ensure that subjects receive LSV supplements, as needed, for the duration 
of the study. 
Diet, Fluid, and Activity Control 
•
The morning dose should be administered approximately 30 minutes before breakfast and the
evening dose approximately 30 minutes before the main evening meal. The doses will be
administered prior to meals rather than every 12 hours (q12h) in order to better cover the
luminal bile acid release associated with meals. The last meal time prior to blood sampling
will be recorded on the source document and electronic case report form (eCRF) at each visit.
For infants with a body weight <5 kg, at-home dilution will be required (refer to
Section 8.1.3).
For PK plasma samples at approximately 30 minutes (±15 minutes) after morning dose at
Week 14 (or any visit up to Week 26), the PK sampling should be conducted before
breakfast. Study drug should be administered approximately at the same time each day
throughout the study.
•
Blood samples for the analysis of cholestasis biomarkers, lipid panel, and LSV should be
drawn prior to administration of vitamin supplementation and as much as possible after
6 hours or more of the last food or formula (water intake is permitted if necessary but not
recommended). For subjects <12 months of age, samples should be taken before feeding,
after 2 hours or more of the last food or formula, and before administration of vitamin
supplementation, when possible (water intake, excluding milk, is allowed when required)
(refer to Appendix A).
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7.6 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the eCRF using the following categories. For screen failure subjects, refer 
to Section 9.1.21. 
1. AEs.
2. Protocol deviation. The discovery after the first dose of study drug that the subject did not
meet protocol entry criteria or did not adhere to protocol requirements, and continued
participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not attend visits and attempts to contact the subject were
unsuccessful. Attempts to contact the subject must be documented in the subject’s source
documents.
4. Withdrawal by subject. The subject (or subject’s legally acceptable representative) wishes to
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to
an AE should not be recorded in the “voluntary withdrawal” category. Similarly, lack of
efficacy should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The
procedure is described in Section 9.1.14.
7. 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.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF. (eg, “The
minimum dose to continue in the study will be 150 μg/kg TAK-625, BID; subjects who
cannot tolerate this dose will be discontinued from the study” or “Over 56 days [both
morning and evening dose] of cumulative dose interruption during the stable dosing period
(to Week 26); administration of the study drug will continue unless the subject meets this
discontinuation criteria”).
If subjects discontinue from the study due to disease progression and require rescue therapy
with either surgical interruption of the enterohepatic circulation or listing for liver transplant,
both the reason for discontinuation and outcome (ie, PEBD, cholecystostomy tube, ileal
exclusion, liver transplant, or listed for liver transplant) should be recorded in the subject’s
source document. If known, the date of the future scheduled procedure should also be
recorded. The information regarding surgical interruption of the enterohepatic circulation,
liver transplant, or listing for transplant will be collected in the eCRF at the time the subject
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completes/early terminates from the study (EOT/ET) until the completion of the safety 
follow-up period. 
7.7 
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 7.6. 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 ET visit.  
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
This section contains information regarding all medications and materials provided directly by 
the sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material. 
8.1 
Study Drug and Materials 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study drug refers to any of the drugs defined in Section 8.1.1.1. 
For details and the handling of the study drug, refer to the “Investigator’s Brochure (IB)” and 
“Pharmacy Manual”.
8.1.1.1 
Study Drug 
The doses described in this study protocol are for maralixibat chloride (not free base) but are 
written as “TAK-625”. For example, 400 µg/kg of maralixibat chloride is equivalent to 
380 µg/kg of TAK-625 free base but is referred to as 400 µg/kg of TAK-625 in this study 
protocol (the latest TAK-625 IB).  
The study drug of this study is TAK-625 (formerly maralixibat, SHP625, LUM001), which will 
be provided as an oral solution form (eg, 5, 10, 15, and 20 mg/mL) along with either 0.5, 1.0, or 
3.0-mL sized oral dosing dispensers. Equipment for at-home dilution will also be supplied where 
required. 
TAK-625 are presented in 30-mL volumes packaged in an amber colored polyethylene 
terephthalate (PET) bottles equipped with a child resistant cap and require refrigerated storage 
conditions (2°C to 8°C).  
One of the excipients in the TAK-625 oral solution is PG; in order to limit subject exposure to 
PG, a specific strength of oral solution will be prescribed to a given subject based on body 
weight and target dose. The dosing plan will limit PG exposure to ≤26 mg/kg/day and, at the 
same time, will provide reasonable (not too high or too low) dosing volumes to ensure accurate 
dosing. 
 
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Further details are described separately in a “Pharmacy Manual”. 
8.1.1.2 
Packaging 
Study drug will be provided with primary packaging and labelling only (no secondary 
packaging/secondary labeling). Study drug is packaged in the following labeled containers: 
•
Ready-to-use oral solution of TAK-625 5 mg/mL.
•
Ready-to-use oral solution of TAK-625 10 mg/mL.
•
Ready-to-use oral solution of TAK-625 15 mg/mL.
•
Ready-to-use oral solution of TAK-625 20 mg/mL.
The sponsor or designee will provide 0.5, 1.0, and 3.0 mL sized oral dosing dispensers to study 
sites. Bottle adapters and equipment for at-home dilution will also be supplied where required. 
Changes to sponsor-supplied packaging may not occur without full agreement in advance by the 
sponsor. 
8.1.1.3 
Labeling 
All study drug is labeled according to Japan requirements. 
Japanese label is used for TAK-625 oral solution in Japan. Further details are described 
separately in a “Pharmacy Manual”. 
Storage 
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. TAK-625 must be stored at refrigerated storage 
conditions (2ºC to 8ºC). A daily temperature log of the drug storage area must be maintained 
every working day. Further details are described separately in a “Pharmacy Manual”. 
Dose and Regimen 
Route of Administration: oral 
Subjects will be administered (or will self-administer) varying volumes of ready-to-use oral 
solution study drug at each dosing visit, starting with the baseline visit (Week 0/Visit 2). The 
dosing volume is determined based on the individual body weight, the dose level according to 
the dose escalation plan (150, 300, 450 or 600 μg/kg), and the strength of solution being 
administered (5, 10, 15, or 20 mg/mL). For infants with a body weight <5 kg, at-home dilution 
will be required. This will include a 5-fold dilution of assigned TAK-625 with a predefined 
quantity of water. Refer to the “Pharmacy Manual” for a dosing table with the dilution scheme. 
Dose Regimen: 
Study drug administration will take place during the dose escalation, stable dosing, and 
follow-up dosing periods of the study based on a BID regimen (up to 1200 μg/kg/day). 
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Subjects will take the first dose of study drug at the baseline visit (Week 0/Visit 2) after all of the 
exam procedures were performed under the supervision of the investigator or trained staff. 
The morning dose should be administered approximately 30 minutes before breakfast and the 
evening dose approximately 30 minutes before the main evening meal. The doses will be 
administered prior to meals rather than q12h in order to better cover the luminal bile acid release 
associated with meals. Study drug should be administered approximately at the same time each 
day throughout the study.
The interval between administration of study drug and any concomitant treatment should not 
change during the study.  
The dose may be down-titrated throughout the study, at the investigator’s discretion and in 
consultation with the medical monitor, for subjects experiencing intolerance (eg, GI symptoms 
such as diarrhea, abdominal pain, cramping) to a given dose. Subjects who were down-titrated 
after the stable dosing period may be rechallenged after discussion with the medical monitor. 
However, it is preferable to administer the study drug at a stable dose as much as possible until 
Week 26. 
1. Dose Escalation period (4 weeks [up to 6 weeks]: Week 0 to 4 [6]):
The dose escalation period will consist of the following weekly steps:
Dose level 1 
150 μg/kg TAK-625, BID for 1 week 
Dose level 2 
300 μg/kg TAK-625, BID for 1week 
Dose level 3 
450 μg/kg TAK-625, BID for 1 week 
Dose level 4 
600 μg/kg TAK-625, BID for the remaining duration of the study 
BID= twice daily. 
Dose escalation should occur in the absence of major safety (eg, liver parameters and LSV 
deficiency) or tolerability concerns (eg, GI-related TEAEs) related or possibly related to study 
drug. Subjects with such safety concerns can be down-titrated to a lower, previously tolerated 
dose level for 1 week before continuing dose escalation. The minimum dose to continue in the 
study will be 150 μg/kg, BID; subjects who cannot tolerate this dose will be discontinued from 
the study. The dose escalation period is allowed to be extended up to 6 weeks depending on the 
safety or tolerability concerns. 
The investigators should also review study drug compliance during the dose escalation period to 
ensure that subjects have adequate exposure to study drug to assess safety and tolerability. Any 
compliance concerns should be discussed with the medical monitor. 
2. Stable Dosing Period (44 weeks: Week 5 to 48):
After the dose escalation period, each subject will continue dosing with study drug at the Week 4 
or Week 6 dose level (the MTD level) in the stable dosing period.  
 
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The investigators have until Week 6 to determine the MTD; if re-challenges or further dose 
escalations fail, the subject will remain on the MTD level for the remainder of the stable dosing 
period to complete up to 44 weeks of stable dosing.  
Dose reductions are allowed for the above-mentioned safety or tolerability reasons down to a 
minimum level of 150 μg/kg, BID. Subjects who cannot tolerate this dose will be discontinued 
from the study. 
During the stable dosing period (to Week 26), subjects will be allowed a maximum of 28 days 
(both morning and evening dose missed) of cumulative dose interruption. During the 12 weeks 
of the stable dosing period (Weeks 15 to 26), subjects will be allowed a maximum of 17 days 
(both morning and evening dose) of cumulative dose interruption but not more than 7 
consecutive days. Subjects may remain on study during dose interruptions and should continue to 
complete all regularly scheduled subject study visits and assessments. After dose interruption, 
subjects will reinitiate dosing at their MTD. Any dose interruptions longer than the maximum 
allowed will be documented as protocol deviations. 
Any subject who has over 56 days (both morning and evening dose) of cumulative dose 
interruption during the stable dosing period (to Week 26) should be discontinued from the study. 
3. Follow-up Dosing Period (after Week 48):
Additionally, in the follow-up dosing period, each subject will continue dosing with study drug 
at the Week 4 or Week 6 dose level (the MTD level) from Week 48 visit until TAK-625 is 
approved or available in Japan commercially, or if the subject withdraws from the study, or if the 
investigator determines the subject’s discontinuation, or if the sponsor stops the program or 
development in this indication.  
Dose reductions are allowed for the above-mentioned safety or tolerability reasons down to a 
minimum level of 150 μg/kg, BID. Subjects who cannot tolerate this dose will be discontinued 
from the study. 
Stopping Criteria of Dosing 
Subject dosing must be suspended until the retest results are available. Refer to Sections 10.4.3, 
10.4.5, 10.4.6, and 10.4.7. 
Overdose and Medication Error 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol. 
A medication error is defined as an error made in prescribing, dispensing, administration, and/or 
use of a study medication. For studies, medication errors are reportable to the sponsor only as 
defined below. 
 
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Cases of subjects missing doses of the study medication are not considered reportable as 
medication errors. The administration and/or use of the unassigned or expired study medication 
is/are always reportable as a medication error. 
All cases of overdose or medication error (with or without associated AEs) will be documented. 
Cases of overdose or medication error without manifested signs or symptoms are not considered 
AEs. AEs associated with an overdose or a medication error will be documented on AE eCRFs 
according to Section 10.0. 
SAEs associated with overdose or medication error should be reported according to the 
procedure outlined in Section 10.2.2. 
In the event of drug overdose or medication error, the subject should be treated by the 
investigator based on symptoms.  
8.2 
Study Compliance 
Subject compliance with study procedures and treatment compliance will be assessed at each 
treatment visit by the site staff. 
Dose Escalation Period: 
During the dose escalation period, subject compliance will be reviewed as part of the dose 
escalation assessment. Any concerns with compliance should be discussed with the medical 
monitor. 
Stable Dosing Period: 
During the stable dosing period (to Week 26), subjects will be allowed a maximum of 28 days 
(both morning and evening dose missed) of cumulative dose interruption. During the 12 weeks 
of the stable dosing period (Weeks 15 to 26), subjects will be allowed a maximum of 17 days 
(both morning and evening dose) of cumulative dose interruption but not more than 7 
consecutive days. Subjects may remain on study during dose interruptions and should continue to 
complete all regularly scheduled subject study visits and assessments. After dose interruption, 
subjects will reinitiate dosing at their MTD. Any dose interruptions longer than the maximum 
allowed will be documented as protocol deviations. 
Any subject who has over 56 days (both morning and evening dose) of cumulative dose 
interruption during the stable dosing period (to Week 26) should be discontinued from the study. 
Procedures outlined in Section 9.3.4 should be followed for any subject who is discontinued 
early from the study. 
8.3 
Study Drug Assignment and Dispensing Procedures 
Subjects will receive treatment according to the study schedule. 
The investigator or designee will utilize Interactive Response Technology (IRT) at screening to 
register the subject into the study and obtain an enrollment number/subject number to identify 
the subject throughout the study. During this contact, the investigator or designee will provide 
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the necessary subject-identifying information, including the subject identification (ID) number. 
The medication ID number of the study drug to be dispensed will then be provided by the IRT
as well as at subsequent visits. If sponsor-supplied drug is lost or damaged, the site can request a 
replacement from IRT. Refer to IRT manual provided separately. The medication ID number 
will be entered onto the eCRF.  
A study manual/user manual with specific functions and instructions for the IRT will be provided 
to the site, and site personnel will receive training. Please refer to the study manual/user manual 
for additional details regarding the IRT.  
8.4 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee. 
The on-site pharmacist (site designee) will receive the pharmacy manual created by the sponsor, 
according to which the site designee will appropriately manage the sponsor-supplied drug. The 
investigator will also receive those procedures from the sponsor. The procedures include those 
for ensuring appropriate receipt, handling, storage, management, dispensation of the 
sponsor-supplied drug, and collection of medications from the subject as well as return of them to 
the sponsor or destruction of them.  
The on-site pharmacist (site designee) will immediately return unused study drugs to the sponsor 
after the study is closed at the study site. 
Refer to “Pharmacy Manual” for detailed and additional instructions. 
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. 
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 ID number (subject number) will be assigned to each subject at the time that 
informed consent is obtained. This subject number will be used throughout the study. 
If the subjects are under 18 years of age, the investigator is responsible for obtaining written 
informed consent not only from the under-aged subjects, but also from their legally acceptable 
representatives. 
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Eligibility Assessment 
The investigator should confirm the subject’s eligibility at the screening and prior the first 
administration (Visit 1 and Visit 2). Subjects who meet eligibility criteria after completion of all 
screening assessments will enter the dose escalation period. 
The screening period will last at a minimum 4 weeks to confirm the average morning ItchRO 
(Obs) score ≥1.5 and completion of at least 21 valid morning ItchRO (Obs) and will allow for the 
evaluation of each subject’s eligibility for inclusion into the study. Since it is difficult to evaluate 
pruritus in infants, subjects <12 months of age at screening whose pruritus is unavoidably 
difficult to be evaluated are not necessarily required to meet the above score. The requirements 
of Itch Reported Outcome (ItchRO™) are described in Section 9.1.7.1.1.  
Demographics, Medical History, Disease History, and Medication History/Prior 
Treatment Procedure 
Demographics: 
Subject demographic information including sex, date of birth, and race will be collected at the 
screening visit (Visit 1). Variance in pediatric age-related reference ranges is significant, and the 
date of birth is required to ensure correct interpretation of the laboratory report. 
Medical History: 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved within 1 year prior to 
signing of informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.10). 
Disease History: 
During the screening, the investigator will record PFIC disease history. 
Medication History/Prior Treatment: 
Medication history/prior treatment information to be obtained includes any medication/treatment 
relevant to eligibility criteria and efficacy/safety evaluation stopped at or within 3 months prior 
to signing of informed consent. 
Physical Examination Procedure 
Abnormalities identified at the screening visit (Visit 1) and the baseline (Week 0/Visit 2) will be 
documented in the subject’s source documents. Significant changes after the screening visit 
(Visit 1) or the baseline (Week 0/Visit 2) should be assessed as pretreatment events. Refer to 
Section 10.0 for additional details. 
Physical examination assessments should also include specific assessments for signs of 
hepatomegaly, splenomegaly, edema, ascites, jaundice, and scleral icterus. 
 
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Weight, Height, and BMI 
Weight will be assessed at the screening visit (Visit 1), the baseline (Week 0/Visit 2), and at the 
site visits during the treatment period, and recorded to the nearest 0.1 kg, using a balance or 
electronic scale (children who can stand on their own, generally ≥ 2 years of age) or infant scale 
(generally <2 years of age). 
Height will be collected at the screening visit (Visit 1), the baseline (Week 0/Visit 2), and at all 
site visits during the treatment period. Height will be measured by trained site staff in children 
who can stand on their own (generally ≥ 2 years of age) or not (generally < 2 years of age) using 
a stadiometer or headboard, respectively, via 2 independent measurements, recorded to the 
nearest 0.1 cm (and a third measurement if values differ by > 0.5 cm). The same stadiometer 
should be used for all study visit measurements. The detailed procedure will be provided in the 
“Height and Weight Guidance”. 
BMI is calculated using metric units with the formula provided below: Height is recorded in 
centimeters without decimal places. Weight is collected in kilograms (kg) with 1 decimal place. 
BMI should be derived as: 
BMI=weight (kg)/height (m)2
Vital Sign Procedure 
Vital signs include blood pressure, heart rate, temperature, and respiration rate. Blood pressure 
should be determined by cuff using the same method, the same arm, and the same position, 
following 5 minutes of rest throughout the study. Any deviations of vital signs from the 
screening visit (Visit 1) or the baseline (Week 0/Visit 2) vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE. 
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. 
Primary Efficacy Measurement 
9.1.7.1 
eDiary 
Subjects and caregivers will be trained on the use of the eDiary during the screening visit 
(Visit 1). Pruritus will be assessed and recorded twice daily, via ItchROTM, beginning with the 
day after the screening visit (Visit 1) and every day throughout the duration of the study, as 
described in Appendix A. 
Throughout the duration of the study, subjects/caregivers will be required to submit twice daily 
(morning and evening) assessments using the eDiary.  
9.1.7.1.1 
Itch Reported Outcome (ItchRO™) 
Pruritus will be assessed using the Itch caregiver/patient reported outcome (PRO) measure 
(ItchRO™) administered as a twice daily eDiary as described in Appendix D. Caregivers for all 
subjects will complete the Observer instrument: ItchRO (Obs). The ItchRO (Obs) should be 
 
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completed by the same caregiver for consistency, whenever possible. The caregivers should 
assess subject’s pruritus and record it, even if the subject is an adult (over 18 years old). 
The ItchRO (Obs) eligibility must be determined after a minimum of 4 weeks of ItchRO (Obs) 
twice daily diary entry. If the subject does not meet eligibility after 4 weeks, ItchRO (Obs) 
eligibility should be re-assessed at Week 5, and also at Week 6 if eligibility is not met at Week 5. 
A maximum of 3 attempts can be made to determine ItchRO (Obs) eligibility during the 
screening period. 
Only subjects ≥ 9 years of age at the screening visit (Visit 1) will complete the patient 
instrument: ItchRO (Pt). If a subject turns 9 years of age at any point after the screening visit 
(Visit 1), they will not complete the ItchRO (Pt). Due to the expected low number of subjects old 
enough to rate ItchRO (Pt), this measure will only be analyzed as an exploratory outcome. 
ItchRO (Obs)TM 
The severity of pruritus will be measured by the completion of the first question in the ItchRO 
(Obs) (how severe were your child’s itch-related symptoms). The frequency of pruritus will be 
measured by completion of the third question in the ItchRO (Obs) (how much of the time was 
your child rubbing or scratching). Caregivers will rate the severity and frequency of pruritus 
using 5 choices to describe their pruritus condition. The sixth choice, “I don’t know” will not 
count toward their severity or frequency score (categorized as missing data) and is included to 
account for rare occasions that the designated caregiver cannot observe the child, or the child 
could not communicate the severity or frequency of their pruritus condition. Capturing “I don’t 
know” should be kept at an absolute minimum, as this will lead to missing data. 
ItchRO (Pt)TM 
The severity of pruritus will be measured by the completion of the first question in the ItchRO 
(Pt) (how itchy did you feel). The frequency of pruritus will be measured by completion of the 
third question in the ItchRO (Pt) (how much of last night/today did feeling itchy make you rub or 
scratch). Subjects will rate the severity and frequency of pruritus using 5 choices to describe their 
pruritus condition. 
9.1.7.2 
Serum Bile Acids and Other Cholestasis Biomarkers 
Blood samples will be collected as described in Appendix A and to measure levels of cholestasis 
biomarkers including total sBA, sBA subspecies, 7αC4, FGF-19*, and autotaxin* as well as 
liver-related parameters. Subjects ≥12 months of age are encouraged to fast at least 6 hours prior 
to collection (water intake is permitted if necessary but not recommended). Subjects <12 months 
of age are encouraged to fast at least 2 hours prior to collection (water intake, excluding milk, is 
allowed when required). 
* FGF-19 and autotaxin are not mandatory, if the subjects are too small to collect enough amount 
of blood.
Total sBA and sBA subspecies will be quantified with liquid chromatography-mass 
spectrometry (LC-MS) methodology for assessments. In addition, screening total sBA will be 
 
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assessed with an enzymatic assay for inclusion criteria evaluation. 7αC4, a key intermediate in 
the pathway for bile acid synthesis from cholesterol, will be determined by a validated liquid 
chromatograph-tandem mass spectrometer (LC-MS/MS) method. 
Other Efficacy Measurement 
 
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Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the sponsor. At each study visit, subjects will be asked whether they have taken 
any medication other than the study drug (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. 
The investigators must ensure that subjects receive LSV supplements, as needed, for the duration 
of the study.
Documentation of Concurrent Medical Conditions (Complication) 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at screening/baseline examination, according to the 
judgment of the investigator. The condition (ie, diagnosis) should be described. 
Procedures for Clinical Laboratory Samples 
Clinical laboratory evaluations will be performed according to the central laboratory manual. If 
possible, reference ranges are to be supplied by the laboratory and will be used to assess the 
clinical laboratory data for clinical significance and out-of-range pathological changes. The 
investigator must assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved. 
Clinical laboratory assessments will be performed as listed in Table 9.a. 
The sBA (LC-MS) and PK samples must be examined at central laboratory, in all subjects. In 
addition, screening total sBA (enzymatic assay) for inclusion criteria evaluation must be 
examined at central laboratory, in all subjects. The samples for chemistry panel, LSV, cholestasis 
biomarkers, lipid panel, complete blood count (CBC), coagulation, α-fetoprotein (AFP), and 
serum storage samples could be examined at study sites, if the subjects are too small to collect 
enough amount of blood for the central laboratory, depending on the investigator’s decision. For 
each subject, the blood samples should be examined at the same laboratory throughout the study 
once the laboratory is determined by the investigator, as much as possible. 
A serum storage sample will be collected as a back-up sample in case re-analysis is needed. 
According to the Ethical Considerations for Clinical Trials on Medicinal Products Conducted 
with the Paediatric Population, the volume of blood drawn from a subject should not exceed 3% 
of the total blood volume during a period of four weeks and should not exceed 1% at any single 
time [8]. Should the volume of blood required for a single visit or a 30-day period exceed the 
maximum allowable amount, the investigator will draw blood in the priority order listed in 
 
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Appendix B until the maximum amount has been reached. Laboratory draws missing due to the 
maximum allowable amount being reached will not be considered protocol deviations. Further 
instructions will be provided in the “Guidance on Maximum Volume of Blood Draws”. 
When the laboratory data has not been collected electronically, the investigator or designee is 
responsible for transcribing laboratory results to the eCRF. The investigator will maintain a copy 
of the laboratory accreditation and the reference ranges for the laboratory used. 
Unscheduled assessments (eg, laboratory values) are not required to be collected in the eCRF 
except for those that are directly relevant to the monitoring of an AE/SAE; collection of other 
values may be requested by the sponsor. 
Anion gap and osmolar gap as well as corrected sodium, α-Tocopherol/Total Lipids Ratio, 
Retinol/retinol binding protein (RBP) Molar Ratio, FIB-4 and APRI will be calculated. 
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Table 9.a 
Clinical Laboratory Tests 
Hematology (CBC with Differential) 
Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
MCV, MCH, MCHC 
Red blood cells 
Platelets 
White blood cells 
WBC Differential (% and absolute) 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Albumin 
ALP 
Amylase 
ALT (SGPT) 
AST (SGOT) 
Bicarbonate 
Bilirubin, direct (conjugated) 
TSB 
BUN 
Calcium 
Chloride 
Creatinine 
GGT 
Glucose 
Lipase 
Phosphate 
Potassium 
Sodium 
Total protein 
Total sBA (enzymatic assay) 
Uric Acid 
Measured serum Osmolality 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Occult blood and cells 
Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic examination 
Oxalate 
Urinary creatinine 
Other: 
Coagulation 
aPTT (sec) 
INR 
PT (sec) 
Lipid Panel 
Total cholesterol 
LDL-C (direct) 
HDL-C 
TG 
Cholestasis Biomarkers 
sBA (LC-MS) 
sBA subspecies 
7αC4 
FGF-19 a 
Autotaxin a 
Lipid Soluble Vitamins 
25-hydroxy vitamin D
Retinol
RBP b
α-Tocopherol
TAK-625 Levels 
TAK-625 in plasma 
Marker of HCC 
AFP 
Urine 
β-hCG (for pregnancy) 
AFP=α-fetoprotein; ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time;  
AST=aspartate aminotransferase; BUN=blood urea nitrogen; 7αC4=7α-hydroxy-4-cholesten-3-one; β-hCG=β-human chorionic gonadotropin; 
CBC=complete blood count; FGF-19=fibroblast growth factor 19; GGT=gamma-glutamyl transferase; HCC=hepatocellular carcinoma;  
HDL-C=high density lipoprotein-cholesterol; INR=international normalized ratio; LC-MS=liquid chromatography-mass spectrometry; 
LDL-C=low density lipoprotein-cholesterol; LSV=lipid soluble vitamin; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular 
hemoglobin concentration; MCV=mean corpuscular volume; PT=prothrombin time; RBP=retinol binding protein; sBA=serum bile acid; 
SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; TG=Triglycerides; TSB=total serum bilirubin; 
WBC=white blood cell.  
a)
FGF-19 and autotaxin are not mandatory, if the subjects are too small to collect enough amount of blood. 
b)
Performed when clinically indicated or in case of low retinol levels for subjects <12 months of age. 
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The central/local laboratory will perform laboratory tests for hematology, chemistry, urinalysis, 
and others. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results. 
Pregnancy Test 
A urine pregnancy test is performed on all female subjects of childbearing potential prior to 
dispensing study drug at study visits as outlined in Appendix A, or if pregnancy is suspected or 
on withdrawal of the subject from the study. 
Contraception and Pregnancy Avoidance Procedure 
9.1.13.1 
Male Subjects and Their Female Partners 
From signing of informed consent, throughout the duration of the study, and for 30 days after the 
last dose of study drug, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with or without 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period. Females of childbearing potential who are partners of male subjects are also advised to 
use additional contraception as shown in the list containing highly effective/effective 
contraception below (from the list in Section 9.1.13.3). 
9.1.13.2 
Female Subjects and Their Male Partners 
From signing of informed consent, throughout the duration of the study, and for 30 days after last 
dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use a highly effective/effective method of contraception (from 
the list in Section 9.1.13.3).  
In addition, they must be advised not to donate ova during this period. 
9.1.13.3 
Definitions and Procedures for Contraception and Pregnancy Avoidance 
The following definitions apply for contraception and pregnancy avoidance procedures. 
* A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range
(FSH >40 IU/L) may be used to confirm a postmenopausal state in younger women (eg, those 
<45-year-old) or women who are not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.
** Sterilized males should be at least 1-year post-bilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy. 
 
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The following procedures apply for contraception and pregnancy avoidance. 
1. Acceptable and available methods of contraception in Japan are shown in this section. A
male subject who is non-sterilized and sexually active with a female partner of childbearing
potential must use male condom. Females of childbearing potential who are partners of male
subjects are also advised to, or a female subject of childbearing potential who is sexually
active with a nonsterilized male partner must use the method of contraception below.
•
Intrauterine devices (IUDs).
•
Bilateral tubal interruption/tubal ligation.
•
A Male partner who is the only partner of the subject and was postvasectomy and have
confirmed that they have obtained documentation of the absence of sperm in the
ejaculate.
•
Progestin/Estrogen mixed preparation for inhibition of ovulation initiated at least
3 months prior to the first dose of study drug OR combined with a barrier method (male
condom, female condom† or diaphragm†) if for shorter duration until she has been on
contraceptive for 3 months.
2. Unacceptable methods of contraception are:
•
Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).
•
Spermicides† only.
•
Withdrawal.
•
No method at all.
•
Use of female† and male condoms together.
•
Cap†/diaphragm†/sponge†without spermicide and without condom.
•
Sexual abstinence is NOT an acceptable method of contraception.
† These contraception methods and pregnancy avoidance procedures are not approved or 
certificated in Japan. 
3. Subjects will be provided with information on highly effective/effective methods of
contraception as part of the subject informed consent process and will be asked to sign a
consent form stating that they understand the requirements for avoidance of pregnancy,
donation of ova, and sperm donation during the course of the study.
4. During the course of the study, regular urine β-human chorionic gonadotropin (β-hCG)
pregnancy tests will be performed only for females of childbearing potential and all subjects
(male and female) will receive continued guidance with respect to the avoidance of
pregnancy and sperm donation as part of the study procedures. Such guidance should include
a reminder of the following:
a) Contraceptive requirements of the study.
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b) Reasons for use of barrier methods (ie, condom) in males with pregnant partners.
c) Assessment of subject compliance through questions such as:
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles a
pregnancy test must be performed if the answer is “yes”).
iv. Is there a chance you could be pregnant?
5.
In addition to a negative urine β-hCG pregnancy test at screening, female subjects of
childbearing potential must also have confirmed menses in the month before first dosing (no
delayed menses), a negative urine β-hCG pregnancy test at Visit 1 and Visit 2.
9.1.13.4 
General Guidance with Respect to the Avoidance of Pregnancy 
From signing of informed consent and throughout the duration of the study and for 30 days after 
the last dose, 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, throughout the duration of the study, and for 30 days after last dose, 
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 
during the course of the study. During the course of the study, regular urine β-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 urine β-hCG pregnancy test at screening period, subjects also must have 
a negative urine β-hCG pregnancy test on the day of the first dose of study drug (predose), before 
to receiving any dose of study drug. 
In addition, male subjects must be advised not to donate sperm from signing of informed consent 
to 30 days after the last dose of study drug.
Pregnancy 
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 30 days after the last dose, should also be 
recorded following authorization from the subject’s partner.  
If the pregnancy occurs during administration of study drug or within 30 days of the last dose of 
study drug, the pregnancy should be reported immediately, using a pregnancy notification form, 
to the contact listed in the annex. 
 
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If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received. 
All pregnancies, including female partners of male subjects, in subjects on study drug will be 
followed up to final outcome, using the pregnancy form. Pregnancies will remain blinded to the 
study team. The outcome, including any premature termination, must be reported to the sponsor. 
An evaluation after the birth of the child will also be conducted. 
ECG Procedure 
The following parameters will be collected: heart rate, RR interval, PR interval, QRS duration, 
uncorrected QT interval, rhythm (sinus or specify other rhythm), ECG normal or abnormal (if 
abnormal specify abnormality). 
QT interval corrected using both Bazett’s and Fridericia’s formula (QTcB and QTcF) will be 
derived from data collected in the eCRF. 
ECGs should be recorded in the supine position, if possible after at least 10 minutes rest to 
ensure a stable baseline. A standard 12-lead ECG will be performed at the screening (Visit 1) 
and other visits as outlined in Appendix A. ECGs will be recorded locally in source documents 
and results captured in the eCRF. 
Ultrasound Liver Imaging 
An abdominal ultrasound will be performed at the screening (Visit 1) and other visits as outlined 
in Appendix A to determine the presence of any liver mass. A screening ultrasound is not 
required if the results of an ultrasound or liver magnetic resonance imaging (MRI) completed in 
the last 6 months are available, and the clinical status of the subject has not changed significantly 
since the time of the test. 
AE Collection 
At each study visit and subject contact, subjects or their caregivers will be questioned in a 
general way to ascertain if AEs have occurred since the previous visit (eg, “Have you had any 
health problems since your last visit?”). AEs will be collected from the time informed consent is 
signed (refer to Section 10.0). 
Other Safety Evaluation 
Safety will be evaluated based on the occurrence of all AEs, SAEs, AECIs, physical examination 
findings, vital signs (blood pressure, heart rate, temperature, and respiration rate), clinical 
laboratory parameters (hematology, chemistry, urinalysis, and others).  
AECIs include the following: 
•
LSV deficiency events.
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•
Liver parameter disruption.
Safety laboratory tests to be performed at site visits and processed by a central laboratory. 
However, these could be processed at sites, if the subjects are too small to collect enough amount 
of blood for the central laboratory, depending on the investigator’s decision. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Additional evaluations may be 
performed at the discretion of the investigator in consultation with the medical monitor or 
designee. 
Stopping Rule Guidance: Subject dosing must be suspended until the retest results are available. 
If any of the stopping criteria described in Section 10.4.3 and Section 10.4.6 is confirmed, the 
investigator in consultation with the medical monitor (or appropriately qualified designee) will 
permanently discontinue the subject from further treatment with study drug. 
Genetic Testing (PFIC Genotype) 
ATP8B1 (PFIC1), ABCB11 (PFIC2), ABCB4 (PFIC3), TJP2 (PFIC4), nuclear receptor 
subfamily 1 group H member 4 (NR1H4) (PFIC5) and other genes such as myosin VB 
(MYO5B) are reported to be predictive of PFIC. The cohort assignment will be determined by 
the investigator with the genotyping results. If there are only genotyping results obtained as a 
clinical research, additional genotyping analysis by a registered clinical laboratory or a hospital 
(e.g., Kazusa DNA Research Institute) should be performed. For the confirmation, the genotype 
expert reviews the genotyping results for cohort assignment during screening period. If the 
investigator’s determination and the expert’s confirmation does not match, the investigator, the 
expert and the sponsor will discuss the appropriateness of the cohort assignment. The details of 
the confirmation procedure are described in the genotype confirmation manual.  
PK Sample Collection and Analysis 
9.1.20.1 
Collection of Blood for PK Sampling 
Blood samples (one sample per scheduled time) for serum TAK-625 concentration will be 
collected according to the Schedule of Study Procedures (Appendix A).
Plasma PK samples at predose and approximately 2.5 hours (±30 minutes) after morning dose at 
Week 10 and at predose and approximately 30 minutes (±15 minutes) after morning dose at 
Week 14 will be collected. If sample collections at Week 14 are difficult, PK samples can be 
collected at any visit up to Week 26. Additionally, predose at Week 14 is optional. Postdose PK 
samples should be collected in preference to predose PK samples, if the subjects are too small to 
collect enough amount of blood. 
The actual dates and times of PK sample collection, the last dose of study drug before the 
predose PK sample collection and the postdose PK sample collection, and the last meal of each 
PK sample collection will be recorded on the source document and eCRF. 
 
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Instructions for collecting, processing, and shipping of PK samples are provided in the laboratory 
manual. 
 
Documentation of Screen Failure 
The investigators must account for all subjects who sign informed consent. 
If the subject is withdrawn at the screening visit, the investigator should complete the eCRF. The 
IRT should be contacted as a notification of screen failure. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
•
AE.
•
Screen failure (Did not meet inclusion criteria or did meet exclusion criteria <specify
reason>).
•
Protocol deviation.
•
Lost to follow-up.
•
Pregnancy.
•
Withdrawal by subject <specify reason>.
•
Study termination.
•
Other <specify reason>.
Subject ID numbers assigned to subjects who fail screening should not be reused.
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 dose escalation period. 
If the subject is found to be not eligible for treatment phase, the investigator should record the 
primary reason for failure on the applicable eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
The study drug administration will be recorded in the eCRF/eDiary. 
When administration of a study drug was inappropriately conducted, the dosage and the reasons 
will be recorded in the eCRF/eDiary. 
Subjects will be required to bring study drug containers/unused study drugs to each dispensing 
site visit. All study drugs administered to the subject will be recorded on the eCRFs.  
During the dose escalation period, subject compliance will be reviewed as part of the dose 
escalation assessment. Any concerns with compliance should be discussed with the medical 
monitor. 
 
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During the stable dosing period (to Week 26), subjects will be allowed a maximum of 28 days 
(both morning and evening dose missed) of cumulative dose interruption. During the 12 weeks 
of the stable dosing period (Weeks 15 to 26), subjects will be allowed a maximum of 17 days 
(both morning and evening dose) of cumulative dose interruption but not more than 
7 consecutive days. Subjects may remain on study during dose interruptions and should continue 
to complete all regularly scheduled subject study visits and assessments. After dose interruption, 
subjects will reinitiate dosing at their MTD. Any dose interruptions longer than the maximum 
allowed will be documented as protocol deviations. 
Any subject who has over 56 days (both morning and evening dose) of cumulative dose 
interruption during the stable dosing period (to Week 26) should be discontinued from the study. 
Procedures outlined in Section 9.3.4 should be followed for any subject who is discontinued 
early from the study. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or designee must obtain written informed consent (or assent as applicable) from the 
subject (as per local requirements). For information about informed consent process see 
Section 15.2. 
Enrollment numbers /subject numbers are assigned to all subjects as they consent to take part in 
the study. 
Within each site, the subject number is assigned to subjects according to the sequence of 
presentation for study participation. 
The investigator will utilize IRT at screening to register the subject into the study and obtain an 
enrollment number/subject number to identify the subject throughout the study. 
Screening Period 
The screening period starts when informed consent (or assent as applicable) is signed. The 
duration of the screening period is up to 6 weeks during which all procedures listed for the 
screening visit (Visit 1) in Appendix A must be completed.  
The screening period will last at a minimum 4 weeks to confirm the average morning ItchRO 
(Obs) score ≥1.5 and with completion of at least 21 valid morning ItchRO (Obs) and will allow 
for the evaluation of each subject’s eligibility for inclusion into the study. Since it is difficult to 
evaluate pruritus in infants, subjects <12 months of age at screening whose pruritus is 
unavoidably difficult to be evaluated are not necessarily required to meet the above score. If the 
subject does not meet eligibility after 4 weeks, ItchRO (Obs) eligibility should be re-assessed at 
Week 5, and also at Week 6 if eligibility is not met at Week 5. A maximum of 3 attempts can be 
made to determine ItchRO (Obs) eligibility during the screening period and will allow for the 
 
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evaluation of each subject’s eligibility for inclusion into the study. The requirements of 
ItchRO™ are described in Section 9.1.7.1.1. 
Subjects who meet eligibility criteria after completion of all screening assessments will enter the 
dose escalation period. This period should not commence until all screening assessments 
required to confirm eligibility for administering of study drug and the PFIC genotype results 
have been confirmed by sponsor or designee. 
If the subject does not meet eligibility criteria following completion of screening assessments, 
the investigator or designee will document the subject as a screen failure in the IRT. A screen 
failure is a subject who has given informed consent and failed to meet the inclusion and/or met at 
least 1 of the exclusion criteria and has not been administered study drug. 
In exceptional cases, subjects who initially fail to meet all eligibility criteria may be re-screened 
at a later timepoint, after consultation with the medical monitor. 
Screen failure subject numbers cannot be reassigned to other subjects. 
A 5-day visit window will be permitted in the case the 42-day screening period needs to be 
extended. This window will allow for blood sample retesting at the investigator's discretion. 
Procedures to be completed at the screening visit include: 
•
Informed consent/assent.
•
Eligibility assessment based on inclusion/exclusion criteria.
•
Demographics, medical history, disease history (including complication), and
medication/treatment history.
•
Physical examination, vital signs, weight, height, and BMI.
•
12-lead ECG.
•
Liver ultrasound.
•
Pregnancy test (urine, for females of childbearing potential).
•
Confirming PFIC genotype based on a genotyping (for subjects who do not have
documentation of mutation related with PFIC).
•
eDiary supply and instructions.
•
•
•
Screening clinical laboratory tests (blood).
•
AE assessment.
•
Concomitant medications (including confirmation of the need to administer LSV
supplements).
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•
Access IRT to obtain subject number.
Dose Escalation Period 
Subjects who continue to meet all eligibility criteria will receive TAK-625 as described in 
Appendix A at the baseline visit (Week 0/Visit 2).  
The dose escalation period will comprise of 4 weeks. All assessments and procedures listed for 
visits and subject contacts (phone calls) from Week 0 to Week 4 (Visits 2 to Visit 4) in 
Appendix A should be completed during this period.  
The dose escalation period is allowed to be extended up to 6 weeks depending on the safety or 
tolerability concerns (refer to Section 8.1.3). 
9.3.2.1 
Visits in the Dose Escalation Period 
During the dose escalation period, a ±2-day visit window will be permitted, unless otherwise 
specified. Visit dates and acceptable windows are calculated from the baseline visit 
(Week 0/Visit 2). 
Procedures to be completed in the dose escalation visit include: 
•
Eligibility assessment based on inclusion/exclusion criteria (only at Week 0).
•
Physical examination, vital signs, weight, height, and BMI.
•
12-lead ECG (only at Week 0).
•
Pregnancy test (urine, for females of childbearing potential) (at Weeks 0 and 4).
•
•
•
•
Clinical laboratory tests (blood) (at Weeks 0 and 2).
•
Clinical laboratory tests (urine) (only at Week 0).
•
Blood collection for serum storage (at Weeks 0 and 2).
•
eDiary review.
•
Study drug compliance review.
•
Study drug supply and return.
•
AE assessment.
•
Concomitant medications (including confirmation of the need to administer LSV
supplements).
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9.3.2.2 
Phone Calls in the Dose Escalation Period 
During the dose escalation period, subjects/caregivers will receive subject contacts (phone calls) 
on Weeks 1 and 3 to review the use of concomitant treatments, study drug compliances, and AEs 
as outlined in Appendix A.  
For subject contacts (phone calls) of Weeks 1 and 3, a ±2-day window will be permitted. Contact 
dates and acceptable windows are calculated from the baseline visit (Week 0/Visit 2). 
Procedures to be completed in the subject contacts (phone calls) include: 
•
Study drug compliance review.
•
AE assessment.
•
Concomitant medications (including confirmation of the need to administer LSV
supplements).
Stable Dosing Period 
After the dose escalation period, each subject will continue dosing with study drug at the Week 4 
or Week 6 dose level (the MTD level) in the stable dosing period.  
The stable dosing period will comprise of 44 weeks. All assessments and procedures listed for 
visits and subject contacts (phone calls) from Week 5 to Week 48 in Appendix A should be 
completed during this period.  
9.3.3.1 
Visits in the Stable Dosing Period 
During the stable dosing period, for Weeks 6 and 28, a ±2-day visit window will be permitted. 
From Week 10 to 26 and Week 32 to 48, a ±5-day visit window will be permitted. Visit dates 
and acceptable windows are calculated from the baseline visit (Week 0/Visit 2). 
Procedures to be completed in the stable dosing visit include: 
•
Physical examination, vital signs, weight, height, and BMI.
•
12-lead ECG (at Weeks 10, 26 and 48).
•
Liver ultrasound (at Weeks 26 and 48).
•
Pregnancy test (urine, for females of childbearing potential) (at Weeks 10, 18, 26 and 48).
•
•
•
•
Clinical laboratory tests (blood).
•
Clinical laboratory tests (urine) (at Weeks 6, 10, 18, 26, 32, 40, and 48).
•
Blood collection for PK (at Weeks 10 and 14).
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•
Blood collection for serum storage.
•
eDiary review.
•
Study drug compliance review.
•
Study drug supply and return.
•
AE assessment.
•
Concomitant medications (including confirmation of the need to administer LSV
supplements).
9.3.3.2 
Phone Calls the Stable Dosing Period 
During the stable dosing period, subjects/caregivers will receive subject contacts (phone calls) on 
Weeks 5, 8, 12, 16, 20, 24, 27, 30, 34, 38, 42, and 46 to review the use of concomitant 
treatments, study drug compliances, and AEs as outlined in Appendix A.  
For subject contacts (phone calls) at Weeks 5 and 27, a ±2-day window will be permitted. From 
Week 8 to 24 and Week 30 to 46, a ±5-day visit window will be permitted. Contact dates and 
acceptable windows are calculated from the baseline visit (Week 0/Visit 2). 
Procedures to be completed in the subject contacts (phone calls) include: 
•
Study drug compliance review.
•
AE assessment.
•
Concomitant medications (including confirmation of the need to administer LSV
supplements).
ET 
Subjects will return to the study site for ET and the procedures and assessments outlined in 
Appendix A will be performed. 
If study drug is permanently discontinued early, regardless of the reason, the subject will be 
discontinued from the study (refer to Section 7.6), and the evaluations listed for the ET are to be 
performed. The subject should undergo the ET assessments at the visit during which study drug 
was discontinued, or the subject should be scheduled for an additional ET visit as soon as 
possible, if study drug was discontinued between visits. 
Subjects who discontinue prematurely at any time during the treatment period will have a final 
safety follow-up subject contact (phone call) 7 days after the ET visit.  
•
Physical examination, vital signs, weight, height, and BMI.
•
12-lead ECG.
•
Liver ultrasound.
•
Pregnancy test (urine, for females of childbearing potential).
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•
•
•
•
Clinical laboratory tests (blood).
•
Clinical laboratory tests (urine).
•
Blood collection for serum storage.
•
eDiary review.
•
Study drug compliance review.
•
AE assessment.
•
Concomitant medications (including confirmation of the need to administer LSV
supplements).
Follow-up Dosing Period 
Additionally, in the follow-up dosing period, each subject will continue dosing with study drug. 
The safety evaluation will be performed every 12 weeks from Week 48 visit until TAK-625 is 
approved or available in Japan commercially, or if the subject withdraws from the study, or if the 
investigator determines the subject’s discontinuation, or if the sponsor stops the program or 
development in this indication. 
Procedures to be completed in the follow-up dosing visit include: 
•
Physical examination, vital signs, weight, height, and BMI.
•
12-lead ECG.
•
Liver ultrasound.
•
Pregnancy test (urine, for females of childbearing potential).
•
•
•
•
Clinical laboratory tests (blood).
•
Clinical laboratory tests (urine).
•
Blood collection for serum storage.
•
eDiary review.
•
Study drug compliance review.
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•
Study drug supply and return.
•
AE assessment.
•
Concomitant medications (including confirmation of the need to administer LSV
supplements).
Safety Follow-up 
The safety follow-up period for this protocol is 7 days from the final study visit or ET visit. 
Subjects/caregivers will have a final safety follow-up subject contact (phone call) 7 days after 
the final study visit or ET visit (except for screen failure).  
Subjects who discontinue at any time during the treatment period will have a final safety 
follow-up subject contact (phone call) 7 days after the ET visit. 
Subjects who discontinue from the study for safety reasons are also followed-up as long as 
clinically indicated or until no further improvement with an adverse outcome is expected. All 
AEs and SAEs that are not resolved at the time of this contact will be followed to closure by 
the site (see Section 10.0). 
Post Study Care 
The study will be continued until TAK-625 is approved or available in Japan commercially, or if 
the subject withdraws from the study, or if the investigator determines the subject’s 
discontinuation, or if the sponsor stops the program or development in this indication. A subject 
will be considered as having completed the study if the subject has not withdrawn early from the 
study for any reason prior to completing the EOT visit. 
If TAK-625 is approved for marketing by authorities during the study, the study can be shifted to 
a post-marketing study after the approval. 
Alternative Approaches to Study Procedures and Data Collection Due to 
Coronavirus Disease 2019 
In unavoidable circumstances that impact the study site’s ability to conduct study procedures 
according to the Schedule of Study Procedures (Appendix A), in particular during the 
coronavirus disease 2019 (COVID-19) pandemic, contingency measures may be implemented. 
The following information provides guidance regarding changes to the study procedures that 
could be implemented for study subjects or study sites that are affected by the COVID-19 public 
health emergency. This guidance is aligned with the current guidance from global health 
authorities on the conduct of clinical studies during the COVID-19 pandemic. 
As the COVID-19 pandemic may peak in different regions at different times, and as restrictions 
implemented by local laws and recommendations may vary, any decision on procedural changes 
should be made on a case-by-case basis by the principal investigator in consultation with the 
sponsor or designee, while maintaining subject safety and confidentiality as the priority. 
 
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The principal investigator should also notify the local IRB, as appropriate, of any deviation for 
temporary use of alternative methods for conducting subject visits (eg, video conferencing, 
telephone visits) in the event of restrictive measures due to the COVID-19 pandemic, per local 
requirements. 
Procedural changes due to COVID-19 may include the following: 
•
No routine COVID-19 testing is required during the study unless the subject has signs or
symptoms of COVID-19-related disease or COVID-19 pneumonia in the opinion of the
investigator, or the subject has been identified by national or local public health authority as a
close contact of a probable or confirmed case of COVID-19. The decision to have the subject
tested for COVID-19 is left to the subject and the investigator unless required by the health
authority.
•
Subjects who discontinued from screening due to COVID-19-related factors but were
otherwise qualified to participate in the study may be re-screened if the sponsor or designee
agrees.
•
All attempts should be made to perform the assessments with the subject present at the site
using the visit windows. Exceptions may be granted for alternative approaches to study
procedures and data collection through approval by the sponsor or designee. Such instances
must be documented in the study records and may include the following:
–
Sites impacted by the COVID-19 pandemic must contact the sponsor or designee to
discuss individual subject and site circumstances to obtain approval for use of alternative
approaches to study procedures and data collection.
–
Sites may seek approval from the medical monitor to continue subjects in the study despite
departure from the Schedule of Study Procedures. Principal investigators are expected to
evaluate the impact to the safety of the study subjects and site personnel for subjects to
continue. In evaluating such requests, the sponsor or designee will give the highest priority
to the safety and welfare of the subjects. Subjects must be willing and able to continue
taking study medication and remain compliant with the protocol.
•
Informed Consent Procedure: If necessary, informed consent from a potential or current
study subject’s parent or guardian may be obtained via verbal consent when these individuals
are unable to travel to the site. Informed consent forms will be signed once the subject and
his/her parent, or guardian can return in person to the study site.
•
Visits: All visits must be done with the subject present at the study site.
–
Protocol Deviations: Any deviations from the protocol-specified procedures due to
COVID-19 will be recorded as related to COVID-19.
–
Visit Window Extension: Sites may seek approval from the sponsor or designee to extend
a visit window in order to conduct an on-site visit. Assessments that cannot be completed
during the protocol-specified window will be recorded as a protocol deviation, and such
deviations will be recorded in the study records as related to COVID-19.
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–
Local laboratory test may be appliable for assessing clinical chemistry and hematology
•
EOT/ET visit: The EOT/ET visit should be performed with the subject present at the study
site. Sites may seek approval from the sponsor or designee to extend a visit window in order
to conduct an on-site visit. If the visit cannot be conducted on-site within the visit window
granted by the sponsor or designee, sites may conduct EOT/ET visit procedures remotely as
is feasible, including using local laboratories for assessment of biochemistry, hematology,
and urinalysis (as specified in Appendix A). Assessments that cannot be completed during
the protocol-specified window will be recorded as a protocol deviation, and such deviations
will be recorded in the study records as related to COVID 19.
•
When a physical examination or other in-person procedure is needed in response to an AE,
the subject should be evaluated in-person at the site per protocol if possible. If the subject
cannot visit the site due to COVID-19, the site should contact the Medical Monitor.
•
Discontinuation or Withdrawal from the Study or Study Medication: If a subject chooses to
withdraw from the study or study medication due to personal concerns related to the
COVID-19 pandemic (other than a COVID-19-related AE), this must be specified as the
reason for subject withdrawal in the eCRF.
•
Allow transfer of study subjects to study sites away from risk zones or closer to their home to
sites already participating in the study or new ones.
•
For subjects who are impacted by certain factors, any alternative approaches to study
procedures (ie, procedures not conducted per the Schedule of Study Procedures) due to the
COVID-19 pandemic must be documented in the study records as related to COVID 19. Data
collected using alternative methods may be handled differently in the final data analyses.
This will be documented in the statistical analysis plan (SAP).
9.4 
Biological Sample Retention and Destruction 
The additional blood samples collected for this study will be stored at its affiliated companies
for up to 15 years from when the study results are reported or if less, the maximum period 
permitted under applicable law or until consent is withdrawn. 
10.0 
AEs 
10.1 
Definitions 
Pretreatment Events 
A pretreatment event is defined as any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study but before administration of 
any study drug; it does not necessarily have to have a causal relationship with study 
participation. 
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AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. This includes any newly occurring event or a 
previous condition that has increased in severity or frequency since the administration of study 
drug. 
 
Additional Points to Consider for AEs 
An untoward finding generally may: 
•
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent
events for pre-existing conditions or underlying disease should not be considered AEs.)
•
Necessitate therapeutic intervention.
•
Require an invasive diagnostic procedure.
•
Require discontinuation or a change in dose of study drug or a concomitant medication.
•
Be considered unfavorable by the investigator for any reason.
Diagnoses vs signs and symptoms:
•
Each event should be recorded to represent a single diagnosis. Accompanying signs
(including abnormal laboratory values or ECG findings) or symptoms should NOT be
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be
recorded appropriately as an AE(s).
Laboratory values and ECG findings: 
•
Changes in laboratory values or ECG findings are only considered to be AEs if they are
judged to be clinically significant (ie, if some action or intervention is required or if the
investigator judges the change to be beyond the range of normal physiologic fluctuation). A
laboratory or ECG re-test and/or continued monitoring of an abnormal value or finding are
not considered an intervention. In addition, repeated or additional noninvasive testing for
verification, evaluation or monitoring of an abnormality is not considered an intervention.
•
If abnormal laboratory values or ECG findings are the result of pathology for which there is
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be
reported appropriately as an AE.
Pre-existing conditions: 
•
Pre-existing conditions (present at the time of signing of informed consent) are considered
concurrent medical conditions and should NOT be recorded as AEs. Baseline evaluations
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(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, the worsening or complication should be recorded 
appropriately as an AE. The investigators should ensure that the event term recorded captures 
the change in the condition (eg, “worsening of…”). 
•
If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy)
any occurrence of an episode should only be captured as an AE if the condition becomes
more frequent, serious, or severe in nature. The investigators should ensure that the AE term
recorded captures the change in the condition from baseline (eg, “worsening of…”).
•
If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid
arthritis), worsening of the condition should only be recorded as an AE if occurring to a
greater extent to that which would be expected. The 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 any change in study
drug, the worsening or complication should be recorded as a new AE. The investigators
should ensure that the AE term recorded captures the change in the condition (eg, “worsening
of…”).
Changes in intensity of AEs: 
•
If the subject experiences changes in intensity of an AE, the event should be captured once
with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions): 
•
Preplanned procedures (surgeries or therapies) that were scheduled 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
of the condition should be recorded as an AE. Complications resulting from any planned
surgery should be reported as AEs.
Elective surgeries or procedures: 
•
Elective procedures performed where there is no change in the subject’s medical condition
should not be recorded as AEs but should be documented in the subject’s source documents.
Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy): 
•
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as
an AE. The investigator must make the distinction between exacerbation of pre-existing
illness and lack of therapeutic efficacy.
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Overdose and medication error: 
•
Cases of overdose or medication error with any medication without manifested side effects
are NOT considered AEs, but instead will be documented as overdose or medication error
separately. Any manifested side effects will be considered AEs and will be recorded on the
AE page of the eCRF.
 
SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH.
2. Is LIFE THREATENING.
•
The term “life threatening” refers to an event in which the subject was at risk of death at
the time of the event; it does not refer to an event that hypothetically might have caused
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
•
May require intervention to prevent items 1 through 5 above.
•
May expose the subject to danger, even though the event is not immediately life
threatening or fatal or does not result in hospitalization.
AECIs 
An AECI (serious or non-serious) is one of scientific and medical concern specific to the 
compound or program, for which ongoing monitoring may be appropriate. Such events may 
require further investigation in order to characterize and understand them. 
In this study AECIs include the following: 
•
LSV deficiency events.
•
Liver parameter disruption.
 
Intensity of AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
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Causality of AEs 
The relationship of each AE to study drug(s) will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications, and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications, and concurrent treatments. 
 
Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related.  
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
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/diseases 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 values or findings showed previous values or findings, or the onset 
time can be estimated. 
Worsening or complication of 
concurrent medical conditions or 
any signs/symptoms/diseases before 
treatment 
The date that a worsening or complication of the condition was noted first 
by the subject and/or the investigator should be recorded. 
The examination after start of the 
study drug showed abnormal 
values/findings. 
The date of examination when an abnormal value or findings that was 
judged to be clinically significant was noted should be recorded. 
The examination at the start of the 
study drug showed abnormal 
values/findings and the subsequent 
examinations showed worsening of 
the symptoms. 
The date of examination when apparent elevation, reduction, increase, or 
decrease was confirmed in judgment according to the trends in those 
values or findings should be recorded. 
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Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
Frequency 
Episodic AEs (eg, vomiting) or those that occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous. 
Action Concerning Study Drug 
•
Drug withdrawn – a study drug is stopped due to the particular AE.
•
Dose not changed – the particular AE did not require stopping a study drug.
•
Unknown – only to be used if it has not been possible to determine what action has been
taken.
•
Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the
study has been terminated, the subject died, dosing with study drug was already stopped
before the onset of the AE.
•
Dose Reduced – the dose was reduced due to the particular AE.
•
Dose Increased – the dose was increased due to the particular AE.
•
Dose Interrupted – the dose was interrupted due to the particular AE.
Outcome 
•
Recovered/Resolved – Subject returned to first assessment status with respect to the AE.
•
Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or
signs/symptoms has almost disappeared; the abnormal laboratory value improved but has not
returned to the normal range or to baseline; the subject died from a cause other than the
particular AE with the condition remaining “recovering/resolving”.
•
Not recovered/not resolved – there is no change in the diagnosis, signs, or symptoms; the
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the
observed study period has got worse than when it started; is an irreversible congenital
anomaly; the subject died from another cause with the particular AE state remaining “Not
recovered/not resolved”.
•
Resolved with sequelae – the subject recovered from an acute AE but was left with
permanent/significant impairment (eg, recovered from a cardiovascular accident but with
some persisting paresis.
•
Fatal – the AEs that are considered as the cause of death.
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•
Unknown – the course of the AE cannot be followed up due to hospital change or residence
change at the end of the subject’s participation in the study.
10.2 
Procedures 
Collection and Reporting of AEs 
10.2.1.1 
AE Collection Period 
Collection of AEs will commence from the time that the subject signs the informed consent and 
will continue until the end of safety follow-up.  
10.2.1.2 
AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious AE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event: 
1. Event term.
2. Start and stop date and time.
3. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of
study drug(s) (related or not related).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details
of the suspected procedure.
7. Action concerning study drug.
8. Outcome of event.
9. Seriousness.
Patient eDiary/equestionnaire 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 
these instruments, then proper follow-up with the subject for medical evaluation should be 
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undertaken. Through this follow-up if it is determined that an AE not previously reported has 
been identified, normal reporting requirements should be applied. 
Collection and Reporting of SAEs 
All AEs spontaneously reported by the subject or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the appropriate page of the eCRF (see Section 10.2.1 for the period of 
observation). Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as a single comprehensive event. 
An SAE should be reported by the investigator to the sponsor within 24 hours/1 business day of 
the SAE occurrence, along with any relevant information. This will be done by transmitting an 
electronic data capture (EDC) SAE report. If transmission of an EDC SAE report is not feasible 
within 24 hours/1 business day of the SAE occurrence, the completed Takeda paper-based SAE 
form should be submitted to the sponsor/the Emergency Reception Center for Safety Information 
appropriate personnel (see annexes) 24 hours/1 business day of the SAE occurrence. 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 ID number.
•
Investigator’s name.
•
Name of the study drug(s).
•
Causality assessment.
If paper-based SAEs are submitted, EDC/RAVE must be updated as soon as possible with the 
appropriate information. 
•
When reporting SAEs or pregnancy, SAE report form or pregnancy report form those are
provided by the sponsor or by the institutions must be used.
•
After the initial information of SAEs is reported to the sponsor, the initial SAE report form
(original wet-ink) must be submitted to the sponsor in Japan. Also, if applicable, copy of
related documents should be submitted to the sponsor as soon as possible, once they are
available. The investigator should report detailed information without delay after notification
of initial information. Additional detailed follow-up data surrounding the SAEs that becomes
available following the initial report should be communicated through the same channels as
outlined above.
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•
An operator of the Emergency Center for Safety Information is available for contact 24 hours
a day and 365 days a year.
Emergency Center for Safety Information (available 24 hours 365 days) 
BELLSYSTEM24, Inc. 
 
 
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator will transmit a follow-up EDC SAE report or a paper-based SAE form in an EDC 
SAE report is not feasible (copy) or provide other written documentation and transmit 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. 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, IRBs, and the 
head of the study site, as applicable, in accordance with national regulations in the countries 
where the study is conducted. Relative to the first awareness of the event by/or further provision 
to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory authorities as 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events, unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of a study drug/sponsor supplied drug or that would be sufficient to consider changes 
in the study drug/sponsor supplied drug administration or in the overall conduct of the trial. The 
study site also will forward a copy of all expedited reports to his or her IRB. 
10.4 
Safety Monitoring Rules 
 
General Guidelines 
The following guidelines are provided for the monitoring of selected laboratory parameters. 
Confirmation Guidance: At any time during the study, the initial clinical laboratory results 
meeting the safety monitoring criteria presented below must be confirmed by performing 
measurements on new specimens (retest). 
 
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Retests should be conducted by the central laboratory. Retests at a local laboratory are acceptable 
on an as-needed basis. Local laboratory results are sent to the investigator and medical monitor 
of the sponsor for review (these should include the normal range of the local laboratory).  
Retest collection should take place within 48 to 72 hours of the availability of the initial findings 
of potential concern. The results from the retest must be available prior to the next scheduled 
study visit or subject contact. 
The baseline values for the purpose of the safety monitoring are the average between the value 
obtained during the screening visit (Visit 1) and the baseline visit (Week 0/Visit 2), unless a 
confounder (eg, intercurrent illness) causes variability outside what is expected for the 
underlying disease based on the investigator's judgment (in which case a third value will need to 
be obtained). 
If the confirmed laboratory results or the symptom meets the criteria written in Sections 10.4.3, 
10.4.5, 10.4.6 and 10.4.7, administration of study drug should be interrupted. Once the symptom 
is improved, administration of study drug may be restarted at the MTD after consultation with 
the medical monitor. Unless otherwise specified, there is no maximum number of restart. If the 
investigator has concerns about restarting at the MTD, dose reduction is allowed after discussion 
with the medical monitor. 
 
Close Monitoring Criteria for Liver Parameters 
Table 10.a provides the criteria for close monitoring of liver parameters. 
Table 10.a 
Close Monitoring Criteria for Treatment-Emergent Elevated ALT and TSB 
Parameter 
Baseline Value 
Close Monitoring Criteria 
ALT 
<30 U/L 
≥100 U/L 
>30 to ≤150 U/L
>3× BL or ≥250 U/L
whichever comes first
>150 to ≤450 U/L
≥(BL + 100 U/L) 
TSB 
Any 
≥(BL + 3 mg/dL) 
ALT=alanine aminotransferase; BL=baseline; TSB=total serum bilirubin. 
Frequency of Repeat Measurements: Subjects with a confirmed ALT or TSB level that is 
continuing to rise after meeting the close monitoring criteria should have their liver chemistry 
retested as clinically indicated, until levels stabilize or begin to recover. 
Further Investigation into Liver Chemistry Elevations: For subjects with a confirmed increase in 
ALT or TSB level, meeting the close monitoring criteria, the following investigations should be 
considered, as clinically indicated: 
 
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•
Close and frequent monitoring of liver enzyme and serum bilirubin tests as clinically
indicated. Frequency of retesting can decrease if abnormalities stabilize, recover, or the study
drug has been interrupted or discontinued and the subject has no symptomatic manifestations
of hepatitis or immunological reaction.
•
Symptoms as well as prior, current, and intercurrent diseases/illnesses.
•
Use of or recent change in use of concomitant treatment (including non-prescription
medications, herbal and dietary supplement preparations), alcohol use, recreational drug use,
and special diets.
•
History for exposure to environmental chemical agents and travel.
•
Serology for viral hepatitis (hepatitis A virus immunoglobulin M [HAV IgM], hepatitis B
virus surface antigen [HBs Ag], hepatitis C virus [HCV] antibody, HCV ribonucleic acid
[RNA], cytomegalo virus immunoglobulin M [CMV  IgM], and Epstein-Barr virus [EBV]
antibody panel).
•
Serology for autoimmune hepatitis (eg, antinuclear antibody [ANA]).
•
AST, creatine phosphokinase (CPK), and lactate dehydrogenase (LDH).
•
CBC with differential blood count (eosinophils).
•
Reticulocyte count, prothrombin time (PT)/INR.
Additional investigations of liver parameters, including gastroenterology/hepatology 
consultations, and/or hepatic imaging, may be performed at the discretion of the investigator, in 
consultation with the medical monitor. 
Guidelines for Interruption of Study Drug for Specific Liver Parameters 
If the confirmed laboratory results meet any of the criteria below and the event is without an 
alternative explanation (ie, intercurrent illness, disease progression, natural history of the 
disease), interruption of study drug should be considered: 
1. The close monitoring criteria of both ALT and TSB are met simultaneously
OR
2. An increase of ALT or TSB is accompanied by signs and symptoms (eg,
nausea/vomiting, right upper quadrant pain) or an immunological reaction (eg,
rash, >5% eosinophilia, fever).
3. The following thresholds are met for either ALT or TSB (see Table 10.b).
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Table 10.b 
Guidelines for Interruption of Study Drug for Specific Liver Parameters 
Parameter 
Baseline value 
Observed change threshold 
ALT 
<30 U/L 
≥300 U/L 
>30 to ≤150 U/L
>(5× BL AND 300 U/L) OR 
≥450 U/L 
whichever comes first 
>150 to ≤450 U/L
≥(BL + 300 U/L) 
TSB 
Any 
≥(BL + 5 mg/dL) 
ALT=alanine aminotransferase; BL=baseline; TSB=total serum bilirubin. 
Frequency of Repeat Measurements: Subjects with a confirmed ALT or TSB level meeting 
interruption criteria should have their liver chemistry tests retested every 72 hours or as clinically 
indicated, until levels stabilize or begin to recover. 
Further Investigation for Increased Liver Chemistry Results: For subjects with a confirmed 
increase in ALT or TSB level above the threshold, the investigations outlined in Section 10.4.2 
should be considered, as clinically indicated. 
Study drug may be re-started as long as the subject does not meet the dosing interruption criteria 
based on retest, does not meet criteria outlined in Section 10.4.4, liver parameters have returned 
to or near baseline, and an alternative explanation was found for the increased liver parameter 
(ie, intercurrent illness, disease progression, or natural history of the underlying disease). The 
investigator and the medical monitor or qualified designee should confer as to whether additional 
close monitoring is needed.  
Rules for Study Drug Discontinuation Following Abnormalities of Liver 
Parameters 
Study drug should not be restarted: 
•
If the subject had a probable Drug-induced Livery Injury (DILI) in the opinion of the
investigator and medical monitor.
•
If the subject reports signs/symptoms of acute hepatitis, liver decompensation (ie, variceal
hemorrhage, ascites, hepatic encephalopathy) or hypersensitivity reaction.
•
If the subject had liver parameters elevations meeting criteria in Section 10.4.3 without
alternative explanations or that are inconsistent with the natural history of the disease.
•
After meeting stopping criteria subsequent to a re-challenge (ie, meeting stopping criteria
after re-introduction of study drug) that is likely related to study drug.
•
After two previous interruptions for safety reasons, unless there is a compelling reason why
the subject should continue with dosing (ie, interruptions were due to disease progression,
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natural history, intercurrent illness) and provided that the subject is still compliant with the 
study protocol as per Section 8.2. 
If study drug is permanently discontinued, the subject will be discontinued from the study and 
will be expected to complete the ET study procedures. 
Safety Monitoring for LSVs 
The LSV status will be assessed at every study visit per the schedule of assessments (refer to 
Appendix A); blood samples will be obtained at the study visit before the daily dose of vitamins 
is administered (refer to Appendix B). 
In subjects with LSV deficiency, study drug must be interrupted if clinical symptoms of 
deficiency occur. Clinical symptoms include, but are not limited to: 
•
Vitamin A: Night blindness, degeneration of the retina, xerophthalmia, follicular
hyperkeratosis, keratomalacia, or Bitot’s spots.
•
Vitamin D: Rickets, osteomalacia, costochondral beading, epiphyseal enlargement, cranial
bossing, bowed legs.
•
Vitamin E: Numbness/tingling, decreased deep tendon reflexes, hemolytic anemia, limited
extraocular movements, especially upward gaze.
•
Vitamin K: Easy bruising, excessive bleeding (eg, epistaxis), blood in the urine or stool,
anemia.
Subjects may restart dosing once clinical symptoms resolve and LSV levels begin to improve 
unless the subject has been previously discontinued for the same symptomatic LSV deficiency. 
Each subject may be re-challenged after symptomatic LSV deficiency only twice. 
In the event of a confirmed level that falls either below the subject’s baseline or below the lower 
limit of normal (refer to central laboratory manual), whichever is lower, for a vitamin 
(25-hydroxy vitamin D, retinol, retinol binding protein, α-tocopherol), or INR (as a proxy for 
vitamin K status), without clinical symptoms of deficiency, the investigator should make the 
appropriate modification to the subject’s vitamin supplementation regimen (see also
Section 10.4.6 for INR monitoring). 
Doses should be increased, as clinically indicated, to optimize the LSV levels. Parenteral 
formulations should be used (where available) if enteral supplements are unsuccessful at 
improving LSV deficiency. 
The response to the change in regimen will be assessed at the next scheduled on-site study visit. 
LSV supplements are escalated in monthly intervals over a 3-month period. If during this period 
the LSV levels are persistently below the subject’s baseline value or the lower limit of normal, 
whichever is lower, and there is an absence of clinical symptoms, the investigator will be given 
the option of permanent withdrawal of the subject from the study. 
 
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Safety Monitoring for Coagulation Panel Results 
In the event of a confirmed laboratory result for INR >1.5 despite adequate vitamin K 
supplementation, the investigator and the medical monitor may consider a temporary interruption 
of study drug. Dosing may resume when the INR falls below 1.5 or returns to the subject’s 
baseline level. 
Study Medication Discontinuation Rules for Diarrhea 
Study drug should be discontinued if a subject has severe diarrhea that requires hospitalization 
and/or an IV or nutritional supplementation or leads to severe electrolyte disturbances. 
10.5 
Product Complaints 
Product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided in the “Pharmacy Manual”. 
11.0 
STUDY-SPECIFIC COMMITTEES 
Because it is an unblinded, small-scale, and late phase clinical study conducted with thorough 
safety information available in advance, Data Safety Monitoring Board (DSMB)/Data 
Monitoring Committee (DMC) and other review committees will not be established for this 
study. 
12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary/ Japanese 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 access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
ID of the person making the correction, the date the correction was made, and the reason for 
change. Reasons for significant corrections should additionally be included.  
The principal investigator must review the eCRFs for completeness and accuracy and must 
e-sign the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
 
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The following data will not be recorded into the eCRFs: 
1. BMI.
2. Laboratory test values (except urine pregnancy test).
These samples could be examined at sites, if the subjects are too small to collect enough
amount of blood for the central laboratory, depending on the investigator’s decision (refer to
Appendix B).
3. Serum concentrations of TAK-625.
4. Itch Reported Outcome.
5. Drug Compliance.
After the lock of the study database, any change of, modification of or addition to the data on the 
eCRFs should be made by the investigator with use of change and modification records of the 
eCRFs/eCRFs (Data Clarification Form) provided by the sponsor. The principal investigator 
must review the data change for completeness and accuracy, and must sign, or sign and seal, and 
date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. 
The completed eCRFs are the sole property of the sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor.  
Unscheduled assessments (eg, laboratory values) are not required to be collected in the eCRF 
except for those that are directly relevant to the monitoring of an AE/SAE; collection of other 
values may be requested by the sponsor. 
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 ID log of all participating subjects, medical records, all original signed and dated 
informed consent forms, electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees.  
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 
TAK-625 in Japan, the term of record retention shall expire on the day when a reexamination or 
reevaluation of TAK-625 is completed, instead of the day specified as of 1) and 2), if the study is 
shifted to a post-marketing study. 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.  
 
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1. The day on which marketing approval of the study drug 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 ET or completion of the 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.  
13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A SAP will be prepared and finalized prior to database lock. This document will provide further 
details regarding the definition of analysis endpoints and analysis methodology to address all 
study objectives.  
Statistical analyses will be performed using all subjects’ data at Week 26 after the data are 
locked for marketing application. Additionally, statistical analyses will also be performed for 
marketing application at the time when the data are locked after all subjects complete Week 48, 
using all subjects’ data at Week 48. Furthermore, statistical analyses will also be performed 
using all subjects' data at the end of the study after the data are locked. 
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. 
Analysis Sets 
Three kinds of analysis sets are defined in this study. The intention-to-treat set (ITT), the main 
analysis set used for primary efficacy endpoint, will be defined as below. 
•
ITT: all subjects who received at least one dose of study drug.
•
Per protocol analysis set (PPS): all ITT subjects who did not have any of the major protocol
deviations and whose primary endpoint was evaluable.
•
Safety analysis set: all subjects who received at least one dose of study drug.
The primary and supplemental cohort are defined in Section 7.1.
Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized in the ITT population 
separately on the primary cohort, the overall supplemental cohort, and all cohorts combined. 
Efficacy Analysis 
The primary, key secondary and other secondary endpoints will be mainly evaluated in the 
primary cohort. 
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13.1.3.1 
Primary Endpoint 
Primary Analysis: 
Descriptive statistics and two-sided 95% confidence interval (CI) of mean will be provided on 
the primary cohort in the ITT. 
Secondary Analysis: 
For supportive analysis, the same analysis as the primary analysis will be performed on the 
primary cohort in the PPS to confirm robustness of the results.  
Other Analysis: 
The same analysis as the primary analysis will also be performed in the ITT population 
separately on the overall supplemental cohort, all cohorts combined, and in the PFIC1 and PFIC3 
sub-cohorts (separately) given sufficient sample size. 
13.1.3.2 
Key Secondary Endpoints 
Descriptive statistics and two-sided 95% CI of mean will be provided on the primary cohort in 
the ITT. For supportive analysis, the same analysis as the above analysis will be performed on 
the primary cohort using the PPS to confirm robustness of the results. 
The same analysis as the above analysis will also be performed in the ITT population separately 
on the overall supplemental cohort, all cohorts combined, and in the PFIC1 and PFIC3 
sub-cohorts (separately) given sufficient sample size. 
13.1.3.3 
Secondary Endpoint 
For continuous endpoints, descriptive statistics and two-sided 95% CI of mean will be provided 
on the primary cohort in the ITT. For binary endpoints, frequency distribution will be provided 
on the primary cohort in the ITT with proportion and the two-sided 95% CI. 
The same analysis as the above analysis will also be performed in the ITT population separately 
on the overall supplemental cohort, all cohorts combined, and in the PFIC1 and PFIC3 
sub-cohorts (separately) given sufficient sample size. 
13.1.3.5 
Methods of Data Transformation and Handling of Missing Data 
The derivation method for the primary endpoint will be described below.  
•
Baseline average morning ItchRO (Obs) severity score is defined as the 4-week (28 days)
average morning ItchRO (Obs) severity score prior to the first dose of study medication.
Average morning ItchRO (Obs) severity score will be calculated as the sum of the morning
severity scores divided by the number of non-missing morning severity scores.
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•
For Weeks 18 (Weeks 15-18), Week 22 (Weeks 19-22), and Week 26 (Weeks 23-26),
post-baseline average morning ItchRO (Obs) severity scores will be calculated as the sum of
the morning ItchRO (Obs) severity scores divided by the number of morning ItchRO (Obs)
severity scores for the 4-week (28 days) time periods (i.e., Weeks 15-18, 19-22, and 23-26).
•
After the above derivations, each subject will have a baseline average morning ItchRO (Obs)
severity score and have post-baseline average morning ItchRO (Obs) severity scores at
Weeks 18, Week 22, and Week 26. For each subject, change in the average morning ItchRO
(Obs) severity score between baseline and post-baseline visit can be calculated at Weeks 18,
Week 22, and Week 26. Hence, the primary efficacy endpoint for each subject can be
calculated as an average of the changes in the average morning ItchRO (Obs) severity score
from Week 15 through Week 26.
•
If 25% or more morning ItchRO (Obs) severity scores for the 4-week treatment period before
a given study visit are missing, the average morning ItchRO (Obs) severity score at that visit
will be treated as missing. The restriction is not set for the baseline average morning ItchRO
(Obs) severity score.
13.1.3.6 
Significance Level and Confidence Coefficient 
•
Significance Level: 5% (two-sided test).
•
Confidence coefficient: 95% (two-sided).
PK Analysis 
The following analysis will be performed in the safety analysis set separately on the primary 
cohort, the overall supplemental cohort, and all cohorts combined. 
Plasma concentrations of TAK-625 will be summarized by each scheduled sampling time and 
visit using descriptive statistics. 
Safety Analysis 
The following analysis will be performed in the safety analysis set separately on the primary 
cohort, the overall supplemental cohort, and all cohorts combined. 
13.1.5.1 
TEAEs 
A TEAE is defined as an AE whose date of onset occurs on or after the start of study drug. 
TEAEs will be coded using the MedDRA dictionary. The frequency distribution will be provided 
using the SOC and the preferred term as follows: 
•
The frequency of all TEAEs.
•
The frequency of drug-related TEAEs.
•
The frequency of TEAEs by intensity.
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•
The frequency of drug-related TEAEs by intensity.
•
The frequency of TEAEs leading to study drug discontinuation.
•
The frequency of serious TEAEs.
•
The frequency of TEAEs of clinical interest.
13.1.5.2 
Clinical Laboratory Results, Vital Signs, ECGs, and Physical Examination Findings 
(Including Body Weight, Height, and BMI) 
For continuous endpoints, 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 endpoints, shift tables showing the number of subjects in each category at 
baseline and each post-baseline visit will be provided. 
13.2 
Interim Analysis 
This study has no criteria for ET (i.e., neither efficacy nor futility stop). 
Statistical analyses will be performed using all subjects' data at Week 26 and at Week 48 after 
the completion of the planned enrollment period (approximately 10 months) and the database 
lock for marketing application. Additionally, statistical analyses will also be performed using all 
subjects' data at the end of the study after the data are locked. All enrolled subjects at the 
completion of the enrollment period will be included in each of the interim / final analysis (1 or 
more subjects for the primary cohort to be necessary). 
13.3 
Determination of Sample Size 
PFIC is a rare disease. The targeted sample size of the primary cohort (nt-PFIC2) is 
approximately 3 subjects, and that of the supplemental cohort (other types of PFIC) is 
approximately 6 subjects, based on enrollment feasibility of this population in Japan, rather than 
power calculation. 
13.4 
Other Statistical Considerations 
Other details (eg, methods of data transformation, handling of missing data, and so on) will be 
described in the SAP. 
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. 
 
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The investigator and the study site/head of the study site guarantee access to source documents 
by the sponsor or its designee (Contract Research Organization [CRO]) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information 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. 
Alternative approaches may be used to ensure data quality, data integrity, and subject safety (eg, 
remote source data review/source data verification via phone or video) as permitted by regional 
and local regulations. Additional details are in the monitoring plan. 
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 principal investigator should notify the sponsor and the head of the study site of the deviation 
or change and its reason in a written form, and then retain a copy of the written form. When 
necessary, the principal 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 US Food and Drug Administration [FDA], the 
United Kingdom (UK) Medicines and Healthcare products Regulatory Agency [MHRA], the 
Pharmaceuticals and Medical Devices Agency [PMDA] of Japan). If the study site is contacted 
for an inspection by a regulatory body, the sponsor should be notified immediately. The 
investigator and study site/head of the study site guarantee access for quality assurance auditors 
to all study documents as described in Section 14.1. 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Council for Harmonisation (ICH) Harmonised Tripartite 
 
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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 H. The principles of Helsinki 
are addressed through the protocol and through appendices containing requirements for informed 
consent and investigator responsibilities. 
15.1 
IRB Approval 
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 must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity/signing a contract for the clinical study). 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. If required by country or 
regional regulations or procedures, approval from the competent regulatory authority will be 
obtained before commencement of the study or implementation of a substantial amendment. The 
sponsor will ship drug/notify site once the sponsor has confirmed the adequacy of site regulatory 
documentation. Until the site receives drug/notification no protocol activities, including 
screening may occur. 
Study 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 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, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study, including the use of electronic devices and associated 
technologies (if applicable). The informed consent form and the subject information sheet (if 
applicable) further explain the nature of the study, its objectives, and potential risks and benefits, 
and the date informed consent is given. The informed consent form will detail the requirements 
 
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of the subject 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 and if applicable, the subject authorization form. The informed consent form, 
subject authorization form (if applicable), and subject information sheet (if applicable) must be 
approved by both the IRB and the sponsor before use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB.  
If the subjects are under 18 years of age, the investigator is responsible for obtaining written 
informed consent not only from the under-aged subjects, but also from their legally acceptable 
representatives. If the subject is not capable of rendering adequate written informed consent, then 
the subject’s legally acceptable representative may provide such consent for the subject in 
accordance with applicable laws and regulations.  
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and 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 a ballpoint pen with either blue or black ink in the case of written 
informed consent. The investigator must also sign and date the informed consent form and 
subject authorization (if applicable) at the time of consent or after receipt of subject signature 
and before the subject enters the study. 
Once signed, the original informed consent form, or certified copy (if applicable), subject 
authorization form (if applicable), and subject information sheet (if applicable) will be 
maintained by the study site. 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, 
the signed subject authorization form (if applicable), and subject information sheet (if applicable) 
shall be provided 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. 
 
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15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject ID 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 ID number. 
In the event that a serious data breach is detected, the sponsor or its designee and the investigator 
(as applicable) will take appropriate corrective and preventative actions in response. These 
actions will be documented, and the relevant regulatory agency(ies) will be notified as 
appropriate. Where appropriate, the relevant individuals materially affected by the breach would 
also be notified; in the case of study subjects, this would be done through the investigator. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit the monitor or the sponsor’s designee, representatives 
from any regulatory authority (eg, FDA, UK 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, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Clinical Trial Disclosures and Publication 
Clinical Trial Registration and Results Disclosure 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum, register all 
interventional clinical trials before study start and disclose the results of those trials in a manner 
and timeframe compliant with Takeda policy and all applicable laws and regulations. Clinical 
trial registration and results disclosures will occur on ClinicalTrials.gov, other clinical trial 
registries/databases as required by law, and on Takeda’s corporate website(s). 
Publication 
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.  
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication venue (eg, congress, journal) will appropriately 
reflect contributions to the production, review, and approval of the document.  
 
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15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
subjects. Refer to the study site agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 
16.0 
DISSEMINATION OF NEW INFORMATION 
When new information important to the proper conduct of the clinical study becomes available, 
such as on diseases, impairment, and deaths suspected to be due to the effect of the study drug, 
onset of infections suspected to be due to the use of the study drug, and other information related 
to study drug quality, efficacy, and safety, the sponsors will inform the investigators and heads of 
study sites in writing in a timely manner. 
When the investigator receives information which the investigator judges may affect the 
intention of subjects to continue participation in the clinical study, the investigator will make 
available this information immediately to subjects and their legally acceptable representative, to 
be recorded in writing, and confirm whether the subject will continue to participate in the study. 
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17.0 
REFERENCES 
1. Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic
cholestasis. Orphanet J Rare Dis. 2009 8;4:1.
2. Sumazaki R, Toyoichiro K. Comparative study on the number of cases of pediatric chronic
gastrointestinal diseases using the registry data of Research into Treatment for Specific
Pediatric Chronic Diseases (Alagille syndrome). Public welfare labor science research
expense subsidy [in Japanese]. 2011;177-82.
3. Amer S, Hajira A. A Comprehensive Review of Progressive Familial Intrahepatic
Cholestasis (PFIC): Genetic Disorders of Hepatocanalicular Transporters. Gastroenterology
Res. 2014;7(2):39-43.
4. Van Wessel D, Thompson R, Grammatikopoulos T, Kadaristiana A, Jankowska I, Lipinski P,
et al. The natural course of FIC1 deficiency and BSEP deficiency: Initial results from the
NAPPED-consortium (Natural course and Prognosis of PFIC and Effect of biliary
Diversion). J Hepatol. 2018;68(1):S626-S627.
5. Schukfeh N, Metzelder ML, Petersen C, Reismann M, Pfister ED, Ure BM, et al.
Normalization of serum bile acids after partial external biliary diversion indicates an
excellent long-term outcome in children with progressive familial intrahepatic cholestasis. J
Pediatr Surg. 2012;47(3):501-5.
6. Mizutani A, Nakano S, Hayashi H. Familial intrahepatic cholestasis [in Japanese]. Japanese
journal of pediatrics. 2020;73(5):772-6.
7.
8. Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the
Paediatric Population. 2008. Available from: https://ec.europa.eu/health/system/files/2016-
11/ethical_considerations_en_0.pdf [Accessed 09 March 2022].
9. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of
intractable pruritus associated with intrahepatic cholestasis. Gastroenterology.
1988;95(1):130-6.
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SAP_001.pdf: 
Statistical Analysis Plan 
NCT Number: NCT05543187 
Title: An Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-625 in 
the Treatment of Subjects with Progressive Familial Intrahepatic Cholestasis 
Study Number: TAK-625-3002 
Document Version and Date: Version: 2.0 / 10-Nov-2023 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 


STATISTICAL ANALYSIS PLAN for Week 26 
Study Number: TAK-625-3002 
Study Title: An Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-625 in 
the Treatment of Subjects with Progressive Familial Intrahepatic Cholestasis 
Phase: 3 
Version: 2.0 
Date: 10-Nov-2023 
Prepared by: 
 
Based on: 
Protocol Version: Amendment 2 
Protocol Date: 08-Dec-2022 
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Statistical Analysis Plan 2.0 
10Nov2023
 
REVISION HISTORY 
Version 
Approval Date 
Primary Rationale for Revision 
1.0 
01-Jul-2022 
Not Applicable 
2.0 
 
See Section 9.1 
 
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Statistical Analysis Plan 2.0 
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TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................9 
1.1 
Objectives ......................................................................................................................9 
1.1.1 
Primary Objective ..................................................................................................9 
1.1.2 
Secondary Objective(s) .........................................................................................9 
1.1.3 
Additional Objective(s) .........................................................................................9 
1.2 
Endpoints .......................................................................................................................9 
1.2.1 
Primary Endpoint(s) ..............................................................................................9 
1.2.2 
Secondary Endpoint(s) ..........................................................................................9 
1.2.2.1 
Key Secondary Endpoints(s) .........................................................................9 
1.2.2.2 
Secondary Endpoint(s) ..................................................................................9 
 
 
1.2.4 
Safety Endpoints ..................................................................................................10 
1.2.5 
Other Endpoints ...................................................................................................11 
1.2.5.1 
PK Endpoint ................................................................................................11 
1.3 
Estimand(s) ..................................................................................................................11 
2.0 
STUDY DESIGN...............................................................................................................11 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................13 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................13 
5.0 
ANALYSIS SETS .............................................................................................................13 
5.1 
All Subjects Who Signed the Informed Consent Form ...............................................13 
5.2 
All Subjects Who Did Not Enter the Treatment Period ...............................................13 
5.3 
Safety Analysis Set ......................................................................................................14 
5.4 
Intention-to-treat set (ITT) ...........................................................................................14 
5.5 
Per-Protocol Analysis Set (PPS) ..................................................................................14 
6.0 
STATISTICAL ANALYSIS .............................................................................................14 
6.1 
General Considerations ................................................................................................14 
6.2 
Analysis Approach .......................................................................................................16 
6.2.1 
Analysis Cohort ...................................................................................................16 
6.2.2 
Analysis Approach for Continuous Efficacy Endpoints .....................................17 
6.2.3 
Analysis Approach for Binary Efficacy Endpoints .............................................17 
6.2.4 
Analysis Approach for Time-to-Event Efficacy Endpoints ................................17 
6.3 
Disposition of Subjects ................................................................................................17 
6.3.1 
Study Information ................................................................................................17 
6.3.2 
Screen Failures ....................................................................................................18 
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6.3.3 
Subject Eligibility ................................................................................................18 
6.3.4 
Number of Subjects Who Entered the Treatment Period by Site ........................18 
6.3.5 
Disposition of Subjects ........................................................................................19 
6.3.6 
Protocol Deviations and Analysis Sets ................................................................19 
6.3.6.1 
Significant Protocol Deviations ..................................................................19 
6.3.6.2 
Analysis Sets ...............................................................................................20 
6.4 
Demographic and Other Baseline Characteristics .......................................................20 
6.4.1 
Demographic and Baseline Characteristics .........................................................20 
6.4.2 
Medical History and Concurrent Medical Conditions .........................................23 
6.5 
Medication History and Concomitant Medications .....................................................23 
6.6 
Extent of Exposure and Compliance ............................................................................24 
6.7 
Efficacy Analysis .........................................................................................................24 
6.7.1 
Primary Endpoint Analysis ..................................................................................24 
6.7.1.1 
Primary Analysis .........................................................................................24 
6.7.1.2 
Sensitivity Analysis .....................................................................................24 
6.7.1.3 
Supplementary Analyses .............................................................................25 
6.7.2 
Secondary Endpoints Analysis ............................................................................25 
6.7.2.1 
Key Secondary Endpoints ...........................................................................25 
6.7.2.2 
Sensitivity Analysis .....................................................................................26 
6.7.2.3 
Secondary Endpoints ...................................................................................26 
6.7.4 
Subgroup Analysis ...............................................................................................28 
6.8 
Safety Analysis ............................................................................................................29 
6.8.1 
Adverse Events ....................................................................................................29 
6.8.1.1 
Overview of Treatment-Emergent Adverse Events ....................................29 
6.8.1.2 
Displays of Treatment-Emergent Adverse events.......................................30 
6.8.1.3 
Displays of Pretreatment Events .................................................................32 
6.8.2 
Clinical Laboratory Evaluations ..........................................................................32 
6.8.2.1 
Laboratory Tests other than Urinalysis .......................................................32 
6.8.2.2 
Urinalysis ....................................................................................................33 
6.8.3 
Vital Signs, Weight and Height ...........................................................................33 
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6.8.4 
ECGs ....................................................................................................................34 
6.8.5 
Displays of Treatment-Emergent Adverse Events (Japanese) ............................35 
6.9 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses .................................35 
6.9.1 
Pharmacokinetic Analysis ...................................................................................35 
6.9.1.1 
Plasma Concentrations ................................................................................35 
6.10 
Other Analyses .............................................................................................................35 
6.10.1 
Analyses for Overall Supplemental Cohort .........................................................35 
6.10.2 
Analyses for All Cohorts Combined ...................................................................35 
7.0 
REFERENCES ..................................................................................................................36 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................36 
9.0 
APPENDIX ........................................................................................................................36 
9.1 
Changes From the Previous Version of the SAP .........................................................36 
9.2 
Data Handling Conventions .........................................................................................49 
9.2.1 
Definition of Study Days .....................................................................................49 
9.2.2 
Definition of Study Visit Windows .....................................................................50 
9.2.2.1 
Endpoints other than ItchRO Scores and PK Samples ...............................50 
9.2.2.2 
PK Samples .................................................................................................53 
9.2.2.3 
Average ItchRO Scores ...............................................................................54 
9.2.3 
Partial Date Conventions .....................................................................................55 
9.3 
Derivation of Endpoints ...............................................................................................56 
9.3.1 
Primary Efficacy Endpoints ................................................................................56 
9.3.2 
Average ItchRO Scores 
 .....................................56 
9.3.3 
Responder Endpoints ...........................................................................................57 
 
 
9.3.5 
Z-scores ...............................................................................................................58 
9.3.6 
Lists of Laboratory Tests .....................................................................................59 
9.3.7 
Table for AECI ....................................................................................................59 
9.3.8 
Significance Level and Confidence Coefficient ..................................................59 
9.4 
Analysis Software ........................................................................................................59 
 
LIST OF IN-TEXT TABLES 
Table 9.1 
Visit Window of sBA, sBA subspecies, C4, Serum Storage Sample ....................50 
Table 9.2 
Visit Window of Vital Signs, Weight and Height, Clinician Scratch Scale, 
Shiratori severity scores for pruritus ......................................................................51 
Table 9.3 
Urinalysis, Cholestasis Biomarkers (FGF19) ........................................................51 
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Table 9.4 
Lipid Panel, Lipid Soluble Vitamins .....................................................................51 
Table 9.5 
CBC, Coagulation, Chemistry Panel .....................................................................52 
Table 9.6 
Visit Window of ECGs, AFP .................................................................................52 
 
 
Table 9.8 
Visit Window of PK...............................................................................................54 
Table 9.9 
Visit Window of Average ItchRO Score ...............................................................55 
 
LIST OF IN-TEXT FIGURES 
Figure 2.a 
Schematic Study Design ........................................................................................13 
 
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ABBREVIATIONS 
AE 
adverse event 
AECI 
adverse event of clinical interest 
AFP 
alpha-fetoprotein 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
APRI 
AST to platelet ratio index 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
7αC4 
7α-hydroxy-4-cholesten-3-one 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CI 
confidence interval 
 
 
ECG 
Electrocardiogram 
FGF-19 
fibroblast growth factor 19 
FIB-4 
fibrosis-4 
GGT 
gamma-glutamyl transferase 
HCC 
hepatocellular carcinoma 
HDL-C 
high density lipoprotein-cholesterol 
HRQoL 
health-related quality of life 
ItchRO(Obs) 
ItchRO Observer 
ItchRO(Pt) 
ItchRO Patient 
ITT 
intention-to-treat set 
KM 
Kaplan-Meier 
LDL-C 
low density lipoprotein-cholesterol 
LLN 
lower limit of normal 
LOCF 
last observation carried forward 
LS means 
least square means 
LSV 
lipid soluble vitamin 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intention-to-treat set 
PEBD 
partial external biliary diversion 
 
 
PFIC 
progressive familial intrahepatic cholestasis 
PK 
pharmacokinetic 
PPS 
per-protocol analysis set 
PRO 
patient-reported outcomes 
PT 
preferred term  
Q1 
25th percentile 
Q3 
75th percentile 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
QOL 
quality-of-life 
RBP 
retinol binding protein 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBA 
serum bile acid 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SOC 
system organ class 
TEAE  
treatment-emergent adverse event 
TG 
triglycerides 
TSB 
total serum bilirubin 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHODrug 
World Health Organization Drug Dictionary 
 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
• To evaluate the efficacy of TAK-625 in the primary cohort. 
• To evaluate the safety of TAK-625 in subjects with PFIC. 
1.1.2 
Secondary Objective(s) 
• To evaluate the efficacy of TAK-625 in subjects with PFIC. 
• To evaluate the PK of TAK-625 in subjects with PFIC. 
1.1.3 
Additional Objective(s) 
• To evaluate primary, secondary, and exploratory endpoints in the supplemental cohort 
1.2 
Endpoints 
1.2.1 
Primary Endpoint(s) 
• Change in the average morning ItchRO (Obs) severity score between baseline and average 
of Week 15 through Week 26. 
1.2.2 
Secondary Endpoint(s)  
1.2.2.1 
Key Secondary Endpoints(s) 
• Change in the average morning ItchRO (Obs) frequency score between baseline and average 
of Week 15 through Week 26. 
• Change in total sBA between baseline and Week 26 
1.2.2.2 
Secondary Endpoint(s) 
• Proportion of subjects who experience an sBA control (defined as a reduction to <102 
μmol/L, or a reduction of >75%, or normalization) from baseline through Week 26. 
• Change in the ItchRO (Obs) weekly average severity (based on daily maximum of morning 
and evening severity scores) between baseline and average of Week 15 through Week 26. 
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1.2.4 
Safety Endpoints 
• Incidence of AEs including SAEs, related to study drug, leading to study drug 
discontinuation, and AEs of clinical interest (AECIs). 
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AECIs include the following: 
 LSV deficiency events. 
 Liver parameter disruption. 
• Change from baseline in clinical laboratory values (hematology, chemistry, urinalysis, and 
others), physical examination findings (including body weight, height, and body mass index 
[BMI]), vital signs, and electrocardiogram (ECG) parameters 
1.2.5 
Other Endpoints 
1.2.5.1 
PK Endpoint 
• Plasma levels of TAK-625 at predose and approximately 2.5 hours after the morning dose at 
Week 10. 
• Plasma levels of TAK-625 at predose (optional) and approximately 30 minutes after morning 
dose at Week 14 (or any visit up to Week 26). 
1.3 
Estimand(s) 
Not Applicable. 
2.0 
STUDY DESIGN 
This is a phase 3, multicenter, open-label, uncontrolled study to evaluate the efficacy and safety 
of TAK-625 in the treatment of Japanese subjects with PFIC. 
Study Population: 
The study population is defined as “Japanese patients with PFIC who are 1 year of age or 
older”. Subjects diagnosed with PFIC2 due to ABCB11 mutation that predicts residual BSEP 
function (nt-PFIC2) will be enrolled in the primary cohort. Subjects with other PFIC subtypes 
(eg, t-PFIC2, PFIC1/3/4, or other PFIC mutation variants) or postsurgical subjects (eg, internal 
or external biliary diversion surgery) will be enrolled in the supplemental cohort. (Subjects 
diagnosed with PFIC2 due to ABCB11 mutation that predicts complete absence of BSEP 
function [t-PFIC2] are excluded from the primary cohort and can be enrolled only in the 
supplemental cohort. PFIC subtypes should be determined by a genotyping [refer to Protocol  
Section 7.1]). 
Study Period (Screening, Treatment [Dose Escalation, Stable Dosing, and Follow-Up Dosing], 
and Safety Follow-Up Period): 
This study consists of the screening period (up to 6 weeks prior to the study administration), 
4 week dose escalation period (doses up to 600 μg/kg, BID, as tolerated), 44-week stable dosing 
period, and follow-up dosing period (until TAK-625 is approved or available in Japan 
commercially, or if the subject withdraws from the study, or if the investigator determines the 
subject’s discontinuation, or if the sponsor stops the program or development in this indication). 
1. Screening Period (up to 6 Weeks prior to the Study Administration): 
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In the screening period, for subjects who do not have documentation of mutation related with 
PFIC, a blood sample will be obtained for genotyping. Subjects diagnosed with PFIC2 (nt-
PFIC2) will be enrolled in the primary cohort and those with other types of PFIC will be 
enrolled in the supplemental cohort. The electronic Diary (eDiary) for assessing pruritus with 
the Itch Reported Outcome (ItchRO) instrument will be dispensed and subjects and caregivers 
will undergo training during the screening visit. 
2. Dose Escalation Period (4 weeks [up to 6 weeks]: Week 0 to 4 [6]): 
In the dose escalation period, at the baseline visit (Week 0/Visit 2), subjects will be assessed to 
confirm continued study eligibility and undergo a physical examination including body weight, 
height, BMI, and vital signs, and have urine and blood samples taken for hematology, chemistry, 
fasting lipid panel, baseline levels of sBA and other cholestasis biochemical markers. 
Compliance with ItchRO will be assessed. Study drug will be supplied at each visit (Week 0/Visit 
2, Week 2/Visit 3, and Week 4/Visit 4). The subject contacts (phone calls) will be conducted at 
Weeks 1 and 3. The dose is increased weekly, 150 μg/kg, 300 μg/kg, 450 μg/kg, and 600 μg/kg, 
BID. 
Dose escalation should occur in the absence of major safety (eg, liver parameters and LSV 
deficiency) or tolerability concerns (eg, GI-related TEAEs) related or possibly related to study 
drug. Subjects with such safety concerns can be down-titrated to a lower, previously tolerated 
dose level for 1 week before continuing dose escalation. The minimum dose to continue in the 
study will be 150 μg/kg, BID; subjects who cannot tolerate this dose will be discontinued from 
the study. The dose escalation period is allowed to be extended up to 6 weeks depending on the 
safety or tolerability concerns (refer to Protocol Section 8.1.3). 
3. Stable Dosing Period (44 weeks: Week 5 to 48): 
After the dose escalation period, each subject will continue dosing with study drug at the Week 4 
or Week 6 dose level (the maximum tolerated dose [MTD] level) in the stable dosing period. 
Subjects will return to the study site at Weeks 6, 10, 14, 18, 22, 26, 28, 32, 36, 40, 44, and 48 and 
undergo physical examinations. Subject contacts (phone calls) will be conducted as appropriate 
throughout the stable dosing period. Subjects and caregivers will continue twice daily 
completion of their ItchRO throughout the period. 
4. Follow-up Dosing Period (after Week 48): 
Additionally, in the follow-up dosing period, each subject will continue dosing with study drug. 
The safety evaluation will be performed in all the subjects every 12 weeks from Week 48 visit 
until TAK-625 is approved or available in Japan commercially, or if the subject withdraws from 
the study, or if the investigator determines the subject’s discontinuation, or if the sponsor stops 
the program or development in this indication. Bile acids and ItchRO will be measured to 
evaluate the long-term effectiveness of TAK-625. For subjects discontinuing early, safety follow-
up will be conducted. 
5. Safety Follow-up (after Final Visit/ET): 
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Subjects/caregivers will have a final safety follow-up subject contact (phone call) 7 days after 
the final study visit or ET visit (except for screen failure). 
A schematic of the study design is included as Figure 2.a. A schedule of assessments is listed in 
Protocol Appendix A. 
Figure 2.a 
Schematic Study Design 
 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES  
Not Applicable. 
4.0 
SAMPLE-SIZE DETERMINATION 
PFIC is a rare disease. The targeted sample size of the primary cohort is approximately 3 
subjects, and that of the supplemental cohort is approximately 6 subjects, based on enrollment 
feasibility of this population in Japan, rather than power calculation. 
5.0 
ANALYSIS SETS 
5.1 
All Subjects Who Signed the Informed Consent Form 
All subjects who signed the informed consent form. 
5.2 
All Subjects Who Did Not Enter the Treatment Period 
All subjects who did not enter the treatment period. 
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5.3 
Safety Analysis Set 
All subjects who received at least one dose of study drug. 
5.4 
Intention-to-treat set (ITT) 
All subjects who received at least one dose of study drug. 
5.5 
Per-Protocol Analysis Set (PPS) 
All ITT subjects who did not have any of the following major protocol deviations and whose 
primary endpoint was evaluable. 
• Subjects who did not meet inclusion criteria #3, 4, 5, 6. 
• Subjects who met exclusion criteria #1,2, 3, 4, 5, 6, 7, 9, 15, 16, 17, 19. 
6.0 
STATISTICAL ANALYSIS  
Statistical analyses will be performed using all subjects' data up to Week 26 (i.e., up to Day 197) 
after the data are locked. PK analysis will be performed using all subjects' data up to Week 10 
after the data are locked. 
6.1 
General Considerations 
The following definitions and calculation formulas will be used. 
• 
Treatment-emergent adverse event (TEAE): An adverse event whose date of onset occurs 
on or after the start of study drug. TEAEs whose date of onset occurred on or before Week 
26 visit (i.e. the latest visit by Day 197), will be summarized. 
• 
Pretreatment event (PTE): Any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study but prior to administration 
of study drug. 
• 
Concomitant medication: Concomitant medications whose start date occurred on or before 
Week 26 visit (i.e. the latest visit by Day 197), will be summarized. 
• 
Descriptive statistics for endpoints other than PK: Number of subjects, mean, standard 
deviation, standard error, maximum, minimum, and quartiles (Q1, median, and Q3). 
• 
Descriptive statistics for PK: Number of subjects, mean, standard deviation, maximum, 
median, minimum, coefficient of variation, and geometric mean. 
• 
Duration of exposure to study drug (days): {Date of last dose of study drug or Week 26 
visit (i.e. the latest visit by Day 197) which comes faster - date of first dose of study drug} + 
1. 
• 
Duration of study after baseline (days): {Date of last visit/contact or Week 26 visit (i.e. 
the latest visit by Day 197) which comes faster - date of first dose of study drug} + 1. 
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• 
Study drug compliance (%): Number of study drugs taken / (duration of exposure to study 
drug * 2) * 100 (rounded to 1 decimal place). 
• 
Dose Level (μg/kg): Strength of study drug taken (mg) / (last available body weight (kg) 
prior to or on the day of study drug taken) * 1000. 
• 
Dose Level Categories for PK (μg/kg): Categorize by following below calculation rule.  
If Min <= dose level < 225 μg/kg, then dose level category = 150 μg/kg; if 225 μg/kg <= 
dose level < 375 μg/kg, then dose level ＞category = 300 μg/kg; if 375 μg/kg <= dose level 
< 525 μg/kg, then dose level category = 450 μg/kg; if  525 μg/kg <= dose level <= Max, then 
dose level category = 600 μg/kg. 
• 
Total Drug Exposure (μg/kg): Sum of {number of study drugs taken * dose level received 
(μg/kg)}. 
• 
Average Daily Dose (μg/kg/day): Total Drug Exposure (μg/kg) / Duration of exposure to 
study drug (days). 
• 
ItchRO (Obs/Pt) Daily Maximum of Morning and Evening Scores: Maximum of 
morning and evening severity scores for each day. The morning and evening severity scores 
of the same day should be used for the calculation. Both the morning and evening ItchRO 
reports have a minimum score of 0 and a maximum score of 4, with 4 representing more 
severe (Item 1) itching. 
• 
Time to liver-associated events: PEBD surgery, listing for liver transplantation, liver 
decompensation [hepatic encephalopathy, variceal bleeding, ascites, and spontaneous 
bacterial peritonitis] events, hepatocellular carcinoma (HCC), death, and other. 
• 
Estimated Total Lipids (mg/dL): Cholesterol (mg/dL) + Triglycerides (mg/dL) 
• 
Ratio of Alpha-tocopherol to Estimated Total Lipids (mg/g): 1000 * Alpha-tocopherol 
(mg/dL) / Estimated Total Lipids (mg/dL). For Alpha-tocopherol concentrations reported as 
below the minimum quantitation limit, half of the minimum quantitation limit is used in the 
calculation. 
• 
Corrected Sodium (mEq/L): sodium (mEq/L) + (0.002 * Triglycerides (mg/dL)). 
• 
FIB-4: (Age (years) * AST (U/L)) / (platelet count (10^9/L) * sqrt(ALT(U/L))) 
 Age (years) is years at sample collection visit. 
• 
APRI: 100 * (AST (U/L) / AST ULN(U/L)) / (platelet count (10^9/L)) 
 ULN is upper limit normal 
• 
Significant Protocol Deviation: Deviation defined in the PDMP as “Important PD” whose 
Severity Classifications is “major” or “critical”. 
• 
Time since original diagnosis of PFIC (months): (date of first dose – date of original 
diagnosis of PFIC + 1) / 30.4375. 
When reporting derived values or parameters, following presenting rules will be applied. 
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• For sBA, ItchRO: For rules on rounding and decimal presentation of these statistics, along 
with the rules for presenting certain derived values see below. 
 For measures of median and mean, use 3 decimal places. 
 For measures of standard deviation, standard error of the mean and CI, use 4 decimal 
places. 
 For measures of minimum and maximum values as well as observed value (for Listing), 
use 2 decimal places. 
 >=5 is rounded up away from zero, whereas <5 is rounded down toward zero, to account 
for rounding of negative numbers. 
 For p-values use 3 decimal places. 
 Presentation of p-values display p-values that would round to 0.000 as <0.001. 
• Other than sBA, and ItchRO: For rules on rounding and decimal presentation of these 
statistics, along with the rules for presenting certain derived values see below. 
 For measures of median and mean, use 1 decimal place beyond those used for the 
measurement. 
 For measures of standard deviation, standard error of the mean and CI, use 2 decimal 
places beyond those used for the measurement. 
 For measures of minimum and maximum values, use the same number of decimal places 
as those used for the measurement. 
 >=5 is rounded up away from zero, whereas <5 is rounded down toward zero, to account 
for rounding of negative numbers. 
 For p-values use 3 decimal places. 
 Presentation of p-values display p-values that would round to 0.000 as <0.001. 
 BMI should be rounded to 1 decimal place for reporting. 
 Derived questionnaire scores, and other similar efficacy parameters recorded as integers, 
should be rounded to 1 decimal place for reporting. 
 Averaged lab results (e.g. Diastolic/Systolic Blood Pressure and Pulse [when taken in 
triplicate]) should be rounded to 1 decimal place for reporting. 
6.2 
Analysis Approach 
6.2.1 
Analysis Cohort 
Analyses described in section 6.3 ~ 6.9 will be performed for primary cohort. 
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6.2.2 
Analysis Approach for Continuous Efficacy Endpoints 
For efficacy endpoints, all continuous endpoints in this trial will use the analysis method below 
unless stated otherwise in the section specific to an endpoint. 
• Descriptive statistics and two-sided 95% confidence interval of mean will be provided for 
observed values (baseline and post-baseline visits) and changes from baseline (each post-
baseline visit - baseline). For endpoint with multiple visits, these will be provided by visit. 
6.2.3 
Analysis Approach for Binary Efficacy Endpoints 
For efficacy endpoints, all binary endpoints in this trial will use the analysis method below 
unless stated otherwise in the section specific to an endpoint. 
• Frequency distribution will be provided by visit, with proportion and the two-sided 95% 
confidence interval. For endpoint with multiple visits, these will be provided by visit. 
6.2.4 
Analysis Approach for Time-to-Event Efficacy Endpoints 
For efficacy endpoints, all time-to-event endpoints in this study will use the analysis method 
below unless stated otherwise in the section specific to an endpoint. 
• The event-free survival rate and the two-sided 95% confidence intervals will be provided 
using the Kaplan-Meier method. The event-free survival rate will also be plotted. 
Time to event will be defined as the date of first dose of study drug to the event which comes 
fastest. For subjects without an event, time to event will be defined as the date of first dose of 
study drug to the censoring date, which is the date of the last study visit/contact. 
6.3 
Disposition of Subjects 
6.3.1 
Study Information 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Endpoint(s) : 
Date First Subject Signed Informed Consent Form 
 
Date of Last Subject’s Last Visit/Contact 
 
MedDRA Dictionary Version 
 
WHO Drug Dictionary Version 
 
SAS Version Used for Creating the Datasets 
Analytical Method(s) : (1) Study Information 
Study information shown in the analysis endpoints section will be 
provided. 
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6.3.2 
Screen Failures 
Analysis Set: 
All Subjects Who Did Not Enter the Treatment Period 
Analysis Endpoint(s) : 
Age (years)  
 
 
Gender 
[Male, Female] 
Analytical Method(s) : (1) Screen Failures 
Frequency distributions for categorical endpoints and descriptive 
statistics for continuous endpoints will be provided. 
6.3.3 
Subject Eligibility 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Endpoint(s) : 
Eligibility Status 
[Eligible for Entrance into the 
Treatment Period, Not Eligible for 
Entrance into the Treatment Period] 
 
Primary Reason for Subject 
Not Being Eligible 
[AE, Screen Failure (Did not meet 
inclusion criteria or did meet 
exclusion criteria), Protocol 
Deviation, Lost to Follow-up, 
Pregnancy, Withdrawal by Subject, 
Study Terminated by Sponsor, Other] 
Analytical Method(s) : (1) Eligibility for Entrance into the Treatment Period 
Frequency distributions will be provided. When calculating 
percentages for the primary reasons for subject not being eligible, the 
total number of ineligible subjects will be used as the denominator. 
6.3.4 
Number of Subjects Who Entered the Treatment Period by Site 
Analysis Set: 
ITT 
Analysis Endpoint(s) : 
Status of Entrance into the 
Treatment Period 
[Entered] 
Stratum: 
Site 
[Site numbers will be used as 
categories] 
Analytical Method(s) : (1) Number of Subjects Enrolled by Site 
Frequency distribution will be provided for each stratum. 
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6.3.5 
Disposition of Subjects 
Analysis Set: 
ITT 
Analysis Endpoint(s) : 
Study Drug Completion 
Status 
[Ongoing, Completed Study Drug, 
Prematurely Discontinued Study 
Drug] 
 
Reason for Discontinuation 
of Study Drug 
[AE, Protocol Deviation, Lost to 
Follow-up, Withdrawal by Subject, 
Study Terminated by Sponsor, 
Pregnancy, Lack of Efficacy, Other] 
 
Completion Status of All 
Planned Study Visits 
[Ongoing, Completed Study, 
Prematurely Discontinued Study] 
 
Reason for Discontinuation 
of Study 
[AE, Protocol Deviation, Lost to 
Follow-up, Withdrawal by Subject, 
Study Terminated by Sponsor, 
Pregnancy, Lack of Efficacy, Other] 
Analytical Method(s) : (1) Disposition of Subjects 
Frequency distributions will be provided. When calculating 
percentages for the reasons for discontinuation, the total number of 
subjects who prematurely discontinued will be used as the 
denominator. 
6.3.6 
Protocol Deviations and Analysis Sets 
6.3.6.1 
Significant Protocol Deviations 
Analysis Set: 
ITT 
Analysis Endpoint(s) : 
Significant Protocol Deviation [Informed Consent and Process, 
Inclusion Criteria, Exclusion Criteria, 
Concomitant Medication, Laboratory 
Assessment, Study Procedures (not 
safety and efficacy related), Safety, 
Visit Schedule, IP conditions, IP 
preparation, IP administration, 
Subject IP Compliance, Efficacy, 
Subject Discontinuation, 
Administrative, Patient Reported 
Outcomes, PK/PD, Other Criteria] 
Analytical Method(s) : (1) Protocol Deviations 
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Frequency distribution will be provided for each deviation category. 
A subject who has several deviations will be counted once in each 
appropriate category. A subject who has several deviations that can be 
classified into the same category will be counted only once. 
6.3.6.2 
Analysis Sets 
Analysis Set: 
ITT 
Analysis Endpoint(s) : 
 
Handling of Subjects 
 
[Categories are based on the definitions in 
Section 5.0] 
 
Analysis Sets 
ITT 
PPS 
Safety Analysis Set 
 
[Included] 
[Included] 
[Included] 
Analytical Method(s) : (1) Subjects Excluded from Analysis Sets 
(2) Analysis Sets 
Frequency distributions will be provided. For (1), a subject who has 
several reasons for exclusion will be counted once in each appropriate 
category. A subject who has several reasons for exclusion that can be 
classified into the same category will be counted only once. 
6.4 
Demographic and Other Baseline Characteristics 
6.4.1 
Demographic and Baseline Characteristics 
Analysis Set: 
ITT 
Analysis Endpoint(s) : 
Age (years) 
[Min<= - < 9, 9<= - <=18, 18< - 
<=Max]  
[Min<= - <7, 7<= - <=Max] 
 
Gender 
[Male, Female] 
 
Height (cm) 
 
Weight (kg) 
 
BMI (kg/m2) 
 
Height z-score 
 
 
Weight z-score 
 
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BMI z-score 
 
 
Time Since Original 
Diagnosis of PFIC, in 
Months 
 
 
Used Anything to Treat Itch 
in the Past 
[Yes, No] 
 
Type of Therapy Used to 
Treat Itch in the Past 
(multiple count) 
    Topical 
    Oral 
    Other 
 
 
Specific Therapy Used to 
Treat Itch in the Past 
    Topical Corticosteroids 
    Topical Calcineurin 
Inhibitors 
Topical Antihistamines 
Menthol 
Capsaicin 
Salicylic acid 
Local Anesthetics 
Androgens 
Anticholestatic Agents 
Anticonvulsants 
Antidepressants 
Antihistamines 
Anti-Oxidants 
Binding Resins 
Colchicine 
 
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Cannabinoid Agonist 
Enzyme Inducers 
Immunosuppressants 
Opiate Antagonists 
Serotonin Antagonists 
Ursodeoxycholic Acid 
IBAT Inhibitors 
Surgical Interruption of the 
Enterohepatic Circulation 
Phototherapy 
Hemofiltration 
Plasmapheresis 
Nasal Biliary Drainage 
Other 
 
ItchRO(Obs) 4-week 
Morning 
Average Severity (Item 1) 
Score 
 
 
ItchRO(Obs) 4-week 
Morning 
Average Frequency (Item 3) 
Score 
 
 
Clinician Scratch Scale Score [0, 1, 2, 3, 4] 
 
sBA (LC MS) 
 
 
PFIC Subtype 
[PFIC1, PFIC2, PFIC3, PFIC4, 
PFIC5, PFIC6] 
Analytical Method(s) : (1) Demographics and Baseline Characteristics 
Frequency distributions for categorical endpoints and descriptive 
statistics for continuous endpoints will be provided. PFIC subtype will 
be provided in Section 6.10.1 and 6.10.2 only. 
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6.4.2 
Medical History and Concurrent Medical Conditions 
Analysis Set: 
ITT 
Analysis Endpoint(s) : 
Medical History 
 
Concurrent Medical Conditions 
Analytical Method(s) : (1) Medical History by System Organ Class and Preferred Term 
(2) Concurrent Medical Conditions by System Organ Class and 
Preferred Term 
Frequency distributions will be provided. MedDRA dictionary will be 
used for coding. Summaries will be provided using SOC and PT, 
where SOC will be sorted alphabetically and PT will be sorted in 
decreasing frequency.  
A subject with multiple occurrences of medical history or concurrent 
medical condition within a SOC will be counted only once in that 
SOC. A subject with multiple occurrences of medical history or 
concurrent medical condition within a PT will be counted only once in 
that PT. 
6.5 
Medication History and Concomitant Medications  
Analysis Set: 
ITT 
Analysis Endpoint(s) : 
Medication History 
 
Concomitant Medications 
Analytical Method(s) : (1) Medication History by Anatomical Therapeutic Chemical Level 2 
and Preferred Medication Name 
(2) Concomitant Medications That Started and Stopped Prior to 
Baseline by Anatomical Therapeutic Chemical Level 2 and 
Preferred Medication Name 
(3) Concomitant Medications That Started Prior to and Were 
Ongoing at Baseline as well as Those That Started After Baseline 
by Anatomical Therapeutic Chemical Level 2 and Preferred 
Medication Name 
Frequency distributions will be provided. WHO Drug dictionary will 
be used for coding. Summaries will be provided using anatomical 
therapeutic chemical level 2 and preferred medication names and 
sorted in decreasing frequency based on the number of reports. A 
subject who has been administered several medications with the same 
preferred medication names will be counted only once for that 
preferred medication names. For anatomical therapeutic chemical 
level 2, same manners in counting frequency.  
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6.6 
Extent of Exposure and Compliance 
Analysis Set: 
ITT 
Analysis Endpoint(s) : 
Duration of Exposure to 
Study Drug (days) 
[0<= - <= 28, 29 <= - <= Max] 
 
Study Drug Compliance (%) 
[Min<= - < 80, 80 <= - <= 100, 100< - 
<=Max] 
 
Total Drug Exposure (μg/kg)  
 
Average Daily Dose 
(μg/kg/day) 
 
Analytical Method(s) : (1) Study Drug Exposure, Compliance, Total Drug Exposure and 
Average Daily Dose 
Frequency distributions for categorical endpoints and descriptive 
statistics for continuous endpoints will be provided. 
6.7 
Efficacy Analysis 
6.7.1 
Primary Endpoint Analysis 
6.7.1.1 
Primary Analysis 
Analysis Set: 
ITT 
Analysis Endpoint(s): 
Change in the average morning ItchRO (Obs) severity score between 
baseline and average of Week 15 through Week 26 
Analytical Method(s): 
See Section 6.2.2. 
6.7.1.2 
Sensitivity Analysis 
Analysis Set: 
PPS 
Analysis Endpoint(s): 
Change in the average morning ItchRO (Obs) severity score between 
baseline and average of Week 15 through Week 26 
Analytical Method(s): 
See Section 6.2.2. For supportive analysis the same analysis as the 
primary analysis will be performed using the PPS to confirm 
robustness of the results. 
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6.7.1.3 
Supplementary Analyses 
Analysis Set: 
ITT 
Analysis Endpoint(s): 
Change in the average morning ItchRO (Obs) severity score between 
baseline and average of Week 15 through Week 26 
Analytical Method(s): 
If possible, the endpoint will be analyzed using a MMRM model. The 
repeated measures include post-baseline visits (i.e., Week 6, 10, 14, 
18, 22, and 26), with change from baseline in the 6- or 4-week 
average morning ItchRO(Obs) severity score as the response. The 
MMRM will also include visit, baseline and baseline-by-visit 
interaction as fixed effects. LS means and the two-sided 95% 
confidence intervals will be provided using the contrast across the last 
12 weeks of the study (i.e., Weeks 18, 22, and 26 combined). In other 
words, the analytical solution from the MMRM is an equally weighted 
average of the 3 individual visit-specific estimates over the time 
period of interest (i.e., Weeks 18, 22, and 26).  
The unstructured variance/covariance matrix will be used to model the 
variances and covariances. However, if the numerical algorithm for 
estimation of the mixed model fails to converge, the alternative 
variance/covariance matrix structures will be used (e.g., 
heterogeneous autoregressive of order 1). The Kenward-Roger 
approximation will be used to estimate denominator degrees of 
freedom. 
6.7.2 
Secondary Endpoints Analysis 
6.7.2.1 
Key Secondary Endpoints 
Analysis Set: 
ITT 
Analysis Endpoint(s): 
• Change in the average morning ItchRO (Obs) frequency score 
between baseline and average of Week 15 through Week 26 
• Change in total sBA between baseline and Week 26 
Analytical Method(s): 
See Section 6.2.2. 
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6.7.2.2 
Sensitivity Analysis 
Analysis Set: 
PPS 
Analysis Endpoint(s): 
• Change in the average morning ItchRO (Obs) frequency score 
between baseline and average of Week 15 through Week 26 
• Change in total sBA between baseline and Week 26 
Analytical Method(s): 
See Section 6.2.2. For supportive analysis the same analysis as the 
primary analysis will be performed using the PPS to confirm 
robustness of the results. 
6.7.2.3 
Secondary Endpoints 
Analysis Set: 
ITT 
Analysis Endpoint(s): 
• Proportion of subjects who experience an sBA control 
• Change in the ItchRO (Obs) weekly average severity (based on 
daily maximum of morning and evening severity scores) between 
baseline and average of Week 15 through Week 26 
Analytical Method(s): 
See Section 6.2.2 ~ 6.2.3. 
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6.7.4 
Subgroup Analysis 
Analysis Set: 
ITT 
Analysis Endpoint(s): 
• Change in the average morning ItchRO (Obs) severity score 
between baseline and average of Week 15 through Week 26 
• Change in the average morning ItchRO (Obs) frequency score 
between baseline and average of Week 15 through Week 26 
• Change in total sBA between baseline and Week 26 
Subgroup(s): 
Age 
[Min<= - <7, 7<= - <=Max] 
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Gender 
[Male, Female] 
Analytical Method(s): 
Descriptive statistics will be provided for above each subgroup.  
6.8 
Safety Analysis 
6.8.1 
Adverse Events 
6.8.1.1 
Overview of Treatment-Emergent Adverse Events 
Analysis Set: 
Safety Analysis Set 
Analysis Endpoint(s) : 
TEAE 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analytical Method(s) : The following summaries will be provided. 
 
(1) Overview of Treatment-Emergent Adverse Events 
 
1) All Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects)  
 
2) Relationship of Treatment-Emergent Adverse Events to study 
drug (number of events, number and percentage of subjects)  
 
3) Intensity of Treatment-Emergent Adverse Events (number of 
events, number and percentage of subjects)  
 
4) Treatment-Emergent Adverse Events leading to study drug 
discontinuation (number of events, number and percentage of 
subjects)  
 
5) Serious Treatment-Emergent Adverse Events (number of 
events, number and percentage of subjects)  
 
6) Relationship of serious Treatment-Emergent Adverse Events 
to study drug (number of events, number and percentage of 
subjects)  
 
7) Serious Treatment-Emergent Adverse Events leading to study 
drug discontinuation (number of events, number and 
percentage of subjects)  
 
8) Treatment-Emergent Adverse Events resulting in death 
(number of events, number and percentage of subjects)  
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TEAEs will be counted according to the rules below. 
Number of subjects 
• Summaries for 2) and 6)  
A subject with occurrences of TEAE in both categories (i.e., 
Related and Not Related) will be counted once in the Related 
category. 
• Summary for 3)  
A subject with multiple occurrences of TEAE will be counted 
once for the TEAE with the maximum intensity. 
• Summaries other than 2), 3) , and 6)  
A subject with multiple occurrences of TEAE will be counted 
only once. 
Number of events 
For each summary, the total number of events will be calculated. 
6.8.1.2 
Displays of Treatment-Emergent Adverse events 
Analysis Set: 
Safety Analysis Set 
Analysis Endpoint(s) : 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
 
Time of Onset (day)  
[1 – 28, 29 - Max] 
Analytical Method(s) : The following summaries will be provided using frequency 
distribution. 
TEAEs will be coded using the MedDRA and will be summarized 
using SOC and PT. 
SOC will be sorted alphabetically and PT will be sorted in decreasing 
frequency for tables provided by SOC and PT. SOC and PT will be 
sorted in decreasing frequency for tables provided by System Organ 
Class only or PT only. 
 
(1) Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
 
(2) Treatment-Emergent Adverse Events by System Organ Class 
 
(3) Treatment-Emergent Adverse Events by Preferred Term 
 
(4) Drug-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
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(5) Intensity of Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
 
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events 
by System Organ Class, and Preferred Term 
 
(7) Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term 
 
(8) Serious Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(9) Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term Over Time 
 
(10) Treatment-Emergent Adverse Events of Clinical Interest by 
System Organ Class and Preferred Term 
 
(11) Drug-Related Treatment-Emergent Adverse Events of Clinical 
Interest by System Organ Class and Preferred Term 
 
The frequency distribution will be provided according to the rules 
below. 
Number of subjects 
• Summary tables other than (5), (6) and (9) 
A subject with multiple occurrences of TEAE within a SOC will 
be counted only once in that SOC. A subject with multiple 
occurrences of TEAE within a PT will be counted only once in 
that PT. Percentages will be based on the number of subjects in 
the safety analysis set. 
• Summary tables for (5) and (6)  
A subject with multiple occurrences of TEAE within a SOC or a 
PT will be counted only once for the TEAE with the maximum 
intensity. Percentages will be based on the number of subjects in 
the safety analysis set. 
• Summary table for (9)  
A subject with a TEAE that occurs in more than one interval is 
counted in all the intervals that the TEAE occurs. For each time 
interval, a subject with multiple occurrences of TEAE within a 
SOC or a PT will be counted only once in that SOC or PT. 
When calculating percentages for each time interval, the number 
of subjects at risk (i.e., subjects who either have an exposure or 
have an occurrence of TEAE, during or after the corresponding 
time interval) will be used as the denominator. The number of 
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subjects whose onset of any one of the TEAEs is within the time 
interval will be used as the numerator. 
6.8.1.3 
Displays of Pretreatment Events 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Endpoint(s) : 
PTE 
Analytical Method(s) : The following summaries will be provided using frequency 
distribution. 
PTEs will be coded using the MedDRA and will be summarized using 
SOC and PT. SOC will be sorted alphabetically and PT will be sorted 
in decreasing frequency. 
 
(1) Pretreatment Events by System Organ Class and Preferred Term 
(2) Serious Pretreatment Events by System Organ Class and 
Preferred Term 
 
The frequency distribution will be provided according to the rules 
below. 
Number of subjects 
A subject with multiple occurrences of PTE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences 
of PTE within a PT will be counted only once in that PT. 
6.8.2 
Clinical Laboratory Evaluations 
6.8.2.1 
Laboratory Tests other than Urinalysis 
Analysis Set: 
Safety Analysis Set 
Analysis Endpoint(s) : 
See Section 9.3.6. 
Visit: 
Using the visits (Baseline to Week 26) of the visit window defined in 
Section 9.2.2. 
Analytical Method(s) : For each endpoint, summaries (1) to (3) will be provided. 
 
(1) Summary of Laboratory Test Results and Change from Baseline 
by Visit 
Descriptive statistics for observed values and changes from 
baseline (each post-baseline visit - Baseline) will be provided for 
each visit. 
 
(2) Case Plots 
Plots over time for each subject will be presented. 
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(3) Summary of Shifts of Laboratory Test Results 
Shift tables showing the number of subjects in each category at 
baseline and each post-baseline visit will be provided. 
For each laboratory test, the laboratory values will be classified as 
"Low", "Normal" or "High" relative to the normal reference range 
provided by the central laboratory. The shift tables will be based 
on these classifications. 
6.8.2.2 
Urinalysis 
Analysis Set: 
Safety Analysis Set 
Analysis Endpoint(s) : 
See Section 9.3.6. 
Visit: 
Using the visits (Baseline to Week 26) of the visit window defined in 
Section 9.2.2. 
Analytical Method(s) : For pH and specific gravity, summaries (1) , (2) and (4) will be 
provided. 
For each endpoint other than pH and specific gravity, summaries (3) 
and (4) will be provided. 
 
(1) Summary of Urine Laboratory Test Results and Change from 
Baseline by Visit 
Descriptive statistics for observed values and changes from 
baseline (each post-baseline visit - Baseline) will be provided for 
each visit. 
 
(2) Case Plots 
Plots over time for each subject will be presented. 
 
(3) Number of Subjects in Categories of Urine Laboratory Test 
Results 
Shift tables showing the number of subjects in each category at 
baseline and each post-baseline visit will be provided. 
 
(4) Summary of Shifts of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at 
baseline and each post-baseline visit will be provided. 
For each urine laboratory test, the laboratory values will be 
classified as "Low", "Normal" or "High" relative to the normal 
reference range provided by the central laboratory. The shift 
tables will be based on these classifications. 
6.8.3 
Vital Signs, Weight and Height 
Analysis Set: 
Safety Analysis Set 
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Analysis Endpoint(s) : 
Systolic Blood Pressure 
Diastolic Blood Pressure 
 
Heart Rate 
Body Temperature  
 
Weight 
Height 
 
BMI 
Respiration Rate 
Visit: 
Using the visits (Baseline to Week 26) of the visit window defined in 
Section 9.2.2. 
Analytical Method(s) : For each endpoint, summaries (1) and (2) will be provided. 
 
(1) Summary of Vital Signs, Weight and Height, and Change from 
Baseline by Visit 
Descriptive statistics for observed values and changes from 
baseline (each post-baseline visit - Baseline) will be provided for 
each visit. 
 
(2) Case Plots 
Plots over time for each subject will be presented. 
6.8.4 
ECGs 
Analysis Set: 
Safety Analysis Set 
Analysis Endpoint(s) : 
Heart Rate 
 
 
RR Interval 
 
 
PR Interval 
 
 
QRS Interval 
 
 
QT Interval 
 
 
QTcF Interval 
 
 
Interpretation 
[Within Normal Limits, Abnormal but not 
Clinically Significant, Abnormal and 
Clinically Significant] 
Visit: 
Using the visits (Baseline to Week 26) of the visit window defined in 
Section 9.2.2. 
Analytical Method(s) : For each endpoint other than 12-lead ECG interpretations, summaries 
(1) and (2) will be provided. 
For ECG interpretation, summary (3) will be provided. 
 
(1) Summary of ECG Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from 
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baseline (each post-baseline visit - Baseline) will be provided for 
each visit. 
 
(2) Case Plots 
Plots over time for each subject will be presented. 
 
(3) Summary of Shift of ECG Interpretation 
Shift table showing the number of subjects in each category at 
baseline and each post-baseline visit will be provided. 
6.8.5 
Displays of Treatment-Emergent Adverse Events (Japanese) 
Analysis Set: 
Safety Analysis Set 
Analysis Endpoint(s) : 
TEAE 
Analytical Method(s) : TEAEs will be summarized in the same way as in Section 6.8.1.2. All 
summaries will be presented in Japanese. 
6.9 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
6.9.1 
Pharmacokinetic Analysis 
6.9.1.1 
Plasma Concentrations 
Analysis Set: 
Safety Analysis Set 
Analysis Endpoint(s) : 
Plasma concentrations of TAK-625 
Visit: 
Using the visits of the visit window defined in Section 9.2.2.2 
Analytical Method(s) : The following summaries will be provided. 
 
(1) Summary of Plasma Concentrations by Visit 
Descriptive statistics will be provided by visit by dose level 
categories administered just before sample collection. 
6.10 
Other Analyses 
6.10.1 
Analyses for Overall Supplemental Cohort 
Cohort: 
Overall Supplemental Cohort 
Analytical Method(s) : The same analyses in section 6.3 ~ 6.9 will be performed for overall 
supplemental cohort. 
6.10.2 
Analyses for All Cohorts Combined 
Cohort: 
All Cohorts Combined 
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Analytical Method(s) : The same analyses in section 6.3 ~ 6.9 will be performed for all 
cohorts combined. 
7.0 
REFERENCES 
[1] World Health Organization (WHO) growth charts "A SAS Program for the WHO Growth 
Charts (ages 0 to < 2 years)" 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas-who.htm 
[2] Centers for Disease Control (CDC) growth charts "A SAS Program for the 2000 CDC 
Growth Charts (ages 0 to < 20 years)" 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
There was no change to the protocol planned analyses. 
9.0 
APPENDIX  
9.1 
Changes From the Previous Version of the SAP 
From the SAP version 1.0, the major updates except minor updates like error correction were 
following parts. 
 
Section 
  
Before the change 
Not applicable. 
After the change 
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Reason for the change  
Some exploratory endpoints were added when protocol had been amended. 
 
Section 6.0 STATISTICAL ANALYSIS 
Before the change 
Not applicable. 
After the change 
Statistical analyses will be performed using all subjects' data up to Week 26 (i.e., up to Day 197) 
after the data are locked. PK analysis will be performed using all subjects' data up to Week 10 
after the data are locked. 
Reason for the change  
To make the target range of the Interim analysis clear. 
 
Section 6.1 General Considerations 
Before the change 
• 
Descriptive statistics: Number of subjects, mean, standard deviation, standard error, 
maximum, minimum, and quartiles (Q1, median, and Q3). 
• 
Duration of exposure to study drug (days): Date of last dose of study drug - date of first 
dose of study drug + 1. 
• 
Duration of study after baseline (days): Date of last visit/contact - date of first dose of 
study drug + 1. 
… 
• 
Time to liver-associated events: PEBD surgery, listing for liver transplantation, liver 
decompensation [hepatic encephalopathy, variceal bleeding, ascites, and spontaneous 
bacterial peritonitis] events, hepatocellular carcinoma (HCC), death. 
After the change 
• 
Descriptive statistics for endpoints other than PK: Number of subjects, mean, standard 
deviation, standard error, maximum, minimum, and quartiles (Q1, median, and Q3). 
• 
Descriptive statistics for PK: Number of subjects, mean, standard deviation, maximum, 
median, minimum, coefficient of variation, and geometric mean. 
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• 
Duration of exposure to study drug (days): {Date of last dose of study drug or Week 26 
visit (i.e. the latest visit by Day 197) which comes faster - date of first dose of study drug} + 
1. 
• 
Duration of study after baseline (days): {Date of last visit/contact or Week 26 visit (i.e. 
the latest visit by Day 197) which comes faster - date of first dose of study drug} + 1. 
… 
• 
Dose Level (μg/kg): Strength of study drug taken (mg) / (last available body weight (kg) 
prior to or on the day of study drug taken) * 1000. 
• 
Dose Level Categories for PK (μg/kg): Categorize by following below calculation rule.  
If Min <= dose level < 225 μg/kg, then dose level category = 150 μg/kg; if 225 μg/kg <= 
dose level < 375 μg/kg, then dose level ＞category = 300 μg/kg; if 375 μg/kg <= dose level 
< 525 μg/kg, then dose level category = 450 μg/kg; if  525 μg/kg <= dose level <= Max, then 
dose level category = 600 μg/kg. 
• 
Total Drug Exposure (μg/kg): Sum of {number of study drugs taken * dose level received 
(μg/kg)}. 
• 
Average Daily Dose (μg/kg/day): Total Drug Exposure (μg/kg) / Duration of exposure to 
study drug (days). 
… 
• 
Time to liver-associated events: PEBD surgery, listing for liver transplantation, liver 
decompensation [hepatic encephalopathy, variceal bleeding, ascites, and spontaneous 
bacterial peritonitis] events, hepatocellular carcinoma (HCC), death, and other. 
… 
• 
Corrected Sodium (mEq/L): sodium (mEq/L) + (0.002 * Triglycerides (mg/dL)). 
• 
FIB-4: (Age (years) * AST (U/L)) / (platelet count (10^9/L) * sqrt(ALT(U/L))) 
 Age (years) is years at sample collection visit. 
• 
APRI: 100 * (AST (U/L) / AST ULN(U/L)) / (platelet count (10^9/L)) 
 ULN is upper limit normal 
• 
Significant Protocol Deviation: Deviation defined in the PDMP as “Important PD” whose 
Severity Classifications is “major” or “critical”. 
• 
Time since original diagnosis of PFIC (months): (date of first dose – date of original 
diagnosis of PFIC + 1) / 30.4375. 
Reason for the change  
Some calculation rules and definitions were added and updated. 
 
Section 6.1 General Considerations 
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Before the change 
Not applicable. 
After the change 
When reporting derived values or parameters, following presenting rules will be applied. 
• For sBA, ItchRO: For rules on rounding and decimal presentation of these statistics, along 
with the rules for presenting certain derived values see below. 
 For measures of median and mean, use 3 decimal places. 
 For measures of standard deviation, standard error of the mean and CI, use 4 decimal 
places. 
 For measures of minimum and maximum values as well as observed value (for Listing), 
use 2 decimal places. 
 >=5 is rounded up away from zero, whereas <5 is rounded down toward zero, to account 
for rounding of negative numbers. 
 For p-values use 3 decimal places. 
 Presentation of p-values display p-values that would round to 0.000 as <0.001. 
• Other than sBA, and ItchRO: For rules on rounding and decimal presentation of these 
statistics, along with the rules for presenting certain derived values see below. 
 For measures of median and mean, use 1 decimal place beyond those used for the 
measurement. 
 For measures of standard deviation, standard error of the mean and CI, use 2 decimal 
places beyond those used for the measurement. 
 For measures of minimum and maximum values, use the same number of decimal places 
as those used for the measurement. 
 >=5 is rounded up away from zero, whereas <5 is rounded down toward zero, to account 
for rounding of negative numbers. 
 For p-values use 3 decimal places. 
 Presentation of p-values display p-values that would round to 0.000 as <0.001. 
 BMI should be rounded to 1 decimal place for reporting. 
 Derived questionnaire scores, and other similar efficacy parameters recorded as integers, 
should be rounded to 1 decimal place for reporting. 
 Averaged lab results (e.g. Diastolic/Systolic Blood Pressure and Pulse [when taken in 
triplicate]) should be rounded to 1 decimal place for reporting. 
Reason for the change  
Presenting rules in TLF were added. 
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Section 6.3.2 Screen Failures  
Before the change 
Analysis Endpoint(s): Age (months) 
After the change 
Not applicable. 
Reason for the change  
No infant subjects who failed screening. 
 
Section 6.3.5 Disposition of Subjects 
Before the change 
Analysis Endpoint(s) : Study Drug Administration Status, [Eligible but Not Treated] 
Reason for Not Being Treated, [AE, Screen Failure (Did not meet inclusion criteria or did meet 
exclusion criteria), Protocol Deviation, Lost to Follow-up, Pregnancy, Withdrawal by Subject, 
Study Terminated by Sponsor, Other] 
Study Drug Completion Status, [Completed Study Drug, Prematurely Discontinued Study Drug] 
Completion Status of All Planned Study Visits, [Completed Study, Prematurely Discontinued 
Study] 
Analytical Method(s): Frequency distributions will be provided. When calculating percentages 
for the reasons for not being treated, the total number of subjects not treated by the study drug 
will be used as the denominator. When calculating percentages for the reasons for 
discontinuation, the total number of subjects who prematurely discontinued will be used as the 
denominator. 
After the change 
Analysis Endpoint(s) :  
Study Drug Completion Status, [Ongoing, Completed Study Drug, Prematurely Discontinued 
Study Drug] 
Completion Status of All Planned Study Visits, [Ongoing, Completed Study, Prematurely 
Discontinued Study] 
Analytical Method(s): Frequency distributions will be provided. When calculating percentages 
for the reasons for discontinuation, the total number of subjects who prematurely discontinued 
will be used as the denominator. 
Reason for the change  
These analysis endpoints were not appropriate for ITT population. The category of “Ongoing” 
was added because this SAP is for Interim analysis. 
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Section 6.3.6.1 Significant Protocol Deviations 
Before the change 
Analysis Endpoint(s): Significant Protocol Deviations, [AE, Screen Failure (Did not meet 
inclusion criteria or did meet exclusion criteria), Protocol Deviation, Lost to Follow-up, 
Pregnancy, Withdrawal by Subject, Study Terminated by Sponsor, Other] 
After the change 
Analysis Endpoint(s): Significant Protocol Deviations, [Informed Consent and Process, Inclusion 
Criteria, Exclusion Criteria, Concomitant Medication, Laboratory Assessment, Study Procedures 
(not safety and efficacy related), Safety, Visit Schedule, IP conditions, IP preparation, IP 
administration, Subject IP Compliance, Efficacy, Subject Discontinuation, Administrative, 
Patient Reported Outcomes, PK/PD, Other Criteria] 
Reason for the change  
Change it from CRF category to CTMS category. 
 
Section 6.4.1 Demographic and Baseline Characteristics 
Before the change 
Analysis Endpoint(s): Age (years), [Min<= - < 9, 9<= - <=18, 18< - <=Max]  
After the change 
Analysis Endpoint(s): Age (years), [Min<= - < 9, 9<= - <=18, 18< - <=Max]  
[Min<= - <7, 7<= - <=Max] 
Reason for the change  
Added CTD analysis category. 
 
Section 6.6 Extent of Exposure and Compliance 
Before the change 
Analysis Endpoint(s) : Not applicable. 
Analytical Method(s) : (1) Study Drug Exposure and Compliance 
After the change 
Analysis Endpoint(s) : Total Drug Exposure (μg/kg), Average Daily Dose (μg/kg/day) 
Analytical Method(s) : (1) Study Drug Exposure, Compliance, Total Drug Exposure and 
Average Daily Dose 
Reason for the change  
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Added additional endpoints. 
 
Section 
 
Before the change 
Analysis Endpoint(s): 
… 
… 
After the change 
Analysis Endpoint(s): 
… 
Reason for the change  
Added new exploratory endpoints when protocol had been amended. 
 
Section 6.7.3.3 Responder Analysis 
Before the change 
Not applicable. 
After the change 
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Analysis Set:, ITT 
Reason for the change  
Added new exploratory endpoints when protocol had been amended. 
 
Section 6.7.4 Subgroup Analysis 
Before the change 
Subgroup(s): Age, [Min<= - < 9, 9<= - <=18, 18< - <=Max] 
After the change 
Subgroup(s): Age, [Min<= - <7, 7<= - <=Max] 
Reason for the change  
To be consistent with CTD analysis. 
 
Section 6.9.1.1 Plasma Concentrations 
Before the change 
Analytical Method(s) : The following summaries will be provided. 
(1) Summary of Plasma Concentrations by Visit Descriptive statistics will be provided. 
After the change 
Analytical Method(s) : The following summaries will be provided. 
(1) Summary of Plasma Concentrations by Visit Descriptive statistics will be provided by visit 
by dose level categories administered just before sample collection. 
 
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Reason for the change  
To incorporate new Clinical pharmacology insight. 
 
Section 9.2.1 Definition of Study Days 
Before the change 
The following definitions and calculation formulas will be used. 
• Study Day: The day before the first dose of the study drug will be defined as Study Day -1 
and the day of the first dose will be defined as Study Day 1. If the date of the observation is 
on the same date or after the day of the first dose, Study Day will be calculated relative to 
Study Day 1. Otherwise, Study Day will be calculated relative to Study Day -1. 
• Follow-up Day: The day after the last dose of the study drug will be defined as Follow-up 
Day 1. Follow-up Day will be calculated relative to Day 1. 
After the change 
The following definitions and calculation formulas will be used. 
• Study Day: The day before the first dose of the study drug will be defined as Study Day -1 
and the day of the first dose will be defined as Study Day 1. If the date of the observation is 
on the same date or after the day of the first dose, Study Day will be calculated relative to 
Study Day 1. Otherwise, Study Day will be calculated relative to Study Day -1. 
• Follow-up Day: The day after the last dose of the study drug will be defined as Follow-up 
Day 1.  
Reason for the change  
Error correction. 
 
Section 9.2.2.1 Endpoints other than ItchRO Scores and PK Samples 
Before the change 
For each visit, observation obtained in the corresponding time interval will be used. If more than 
one observation lies within the same visit window, the observation with the closest Study Day to 
the scheduled Study Day will be used. If there are two observations equidistant to the scheduled 
Study Day, the later observation will be used.  
After the change 
For each visit, observation obtained in the corresponding time interval will be used. If more than 
one observation lies within the same visit window, the observation with the closest Study Day to 
the scheduled Study Day will be used. If there are two observations equidistant to the scheduled 
Study Day, the later observation will be used. For laboratory test data, if there are two 
observations of both central laboratory sample and local sample on the same date, central 
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  (      medication end year    = TAK-625 start year  and 
    . < medication end month < TAK-625 start month) or 
  (      medication end year    = TAK-625 start year  and 
         medication end month = TAK-625 start month and 
    . < medication end date    < TAK-625 start date ) then "(2) Concomitant Medication" ; 
else "(3) Concomitant Medication" ; 
Reason for the change  
To make it clear how to handle partial date. 
 
Section 9.3.2 Average ItchRO Scores 
Before the change 
Both the morning and evening ItchRO reports have a minimum score of 0 and a maximum score 
of 4, with 4 representing more severe (Item 1) or more frequent (Item 3) itching. After the 
derivation described in section 9.2.2.3, the following endpoints will be derived the same 
procedures as section 9.3.1. 
• 
Change in the average evening ItchRO (Obs/Pt) severity score between baseline and 
average of Week 15 through Week 26. 
• 
Change in the average ItchRO (Obs/Pt) severity (based on daily maximum of morning 
and evening severity scores) 
• 
Change in the average morning ItchRO (Obs/Pt) frequency score between baseline and 
average of Week 15 through Week 26. 
• 
Change in the average evening ItchRO (Obs/Pt) frequency score between baseline and 
average of Week 15 through Week 26. 
After the change 
For ItchRO scores, both the morning and evening ItchRO reports have a minimum score of 0 and 
a maximum score of 4, with 4 representing more severe (Item 1) or more frequent (Item 3) 
itching. After the derivation described in section 9.2.2.3, the following endpoints will be derived 
the same procedures as section 9.3.1. 
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• 
Change in the average evening ItchRO (Obs/Pt) severity score between baseline and 
average of Week 15 through Week 26. 
• 
Change in the average ItchRO (Obs/Pt) severity and frequency (based on daily 
maximum of morning and evening severity scores) between baseline and average of 
Week 15 through Week 26. 
• 
Change in the average morning ItchRO (Obs/Pt) frequency score between baseline and 
average of Week 15 through Week 26. 
• 
Change in the average evening ItchRO (Obs/Pt) frequency score between baseline and 
average of Week 15 through Week 26. 
Reason for the change  
Added new exploratory endpoints when protocol had been amended. 
 
Section 9.3.3 Responder Endpoints 
Before the change 
• Subjects who experience an sBA control: subjects with a reduction to <102 μMol/L, or a 
reduction of >75%, or normalization) from baseline through Week 26 
After the change 
• Subjects who experience an sBA control: subjects with a reduction to <102 μMol/L, or a 
reduction of >75%, or normalization) from baseline through Week 26 
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Reason for the change  
Added new exploratory endpoints when protocol had been amended. 
 
Section 9.3.6 Lists of Laboratory Tests 
Before the change  
Not applicable. 
After the change  
Total sBA (enzymatic assay) 
Reason for the change  
Error correction. 
 
9.2 
Data Handling Conventions 
9.2.1 
Definition of Study Days 
The following definitions and calculation formulas will be used. 
• 
Study Day: The day before the first dose of the study drug will be defined as Study Day -1 
and the day of the first dose will be defined as Study Day 1. If the date of the observation is 
on the same date or after the day of the first dose, Study Day will be calculated relative to 
Study Day 1. Otherwise, Study Day will be calculated relative to Study Day -1. 
• 
Follow-up Day: The day after the last dose of the study drug will be defined as Follow-up 
Day 1.  
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9.3 
Derivation of Endpoints 
9.3.1 
Primary Efficacy Endpoints 
Both the morning and evening ItchRO reports have a minimum score of 0 and a maximum score 
of 4, with 4 representing more severe (Item 1) itching. The derivation method for the primary 
efficacy endpoint will be described below.  
After the derivation described in section 9.2.2.3, each subject will have a baseline (Week 0) 
average morning ItchRO (Obs) severity score, and have post-baseline average morning ItchRO 
(Obs) severity scores at Weeks 18, Week 22, and Week 26. For each subject, change in the 
average morning ItchRO (Obs) severity score between baseline and post-baseline visit can be 
calculated at Weeks 18, Week 22, and Week 26. Hence, the primary efficacy endpoint for each 
subject can be calculated as an average of the changes in the average morning ItchRO (Obs) 
severity score from Week 15 through Week 26 (i.e., the sum of the average morning ItchRO 
(Obs) severity scores divided by the number of non-missing morning severity scores). 
9.3.2 
Average ItchRO Scores 
 
For ItchRO scores, both the morning and evening ItchRO reports have a minimum score of 0 and 
a maximum score of 4, with 4 representing more severe (Item 1) or more frequent (Item 3) 
itching. After the derivation described in section 9.2.2.3, the following endpoints will be derived 
the same procedures as section 9.3.1. 
• 
Change in the average evening ItchRO (Obs/Pt) severity score between baseline and 
average of Week 15 through Week 26. 
• 
Change in the average ItchRO (Obs/Pt) severity and frequency (based on daily 
maximum of morning and evening severity scores) between baseline and average of 
Week 15 through Week 26. 
• 
Change in the average morning ItchRO (Obs/Pt) frequency score between baseline and 
average of Week 15 through Week 26. 
• 
Change in the average evening ItchRO (Obs/Pt) frequency score between baseline and 
average of Week 15 through Week 26. 
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9.3.3 
Responder Endpoints 
• Subjects who experience an sBA control: subjects with a reduction to <102 μMol/L, or a 
reduction of >75%, or normalization) from baseline through Week 26 
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9.3.5 
Z-scores 
Z-scores of weight, height and BMI are based on a subject’s gender and age at each scheduled 
visit. For subjects less than 24 months of age, the World Health Organization (WHO) growth 
charts are recommended by the Centers for Disease Control (CDC) and will be used to derive z-
scores. For subjects at least 24 months of age, the CDC growth charts will be used to derive z-
scores. 
Age at which height and weight were measured should be used for calculating z-scores, not using 
age at baseline. 
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9.3.6 
Lists of Laboratory Tests 
Hematology (CBC with 
Differential) 
Hematocrit 
Hemoglobin 
MCV, MCH, MCHC 
Red blood cells 
Platelets 
White blood cells 
WBC Differential (% and 
absolute) 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
 
Coagulation 
aPTT (sec) 
INR 
PT (sec) 
Chemistry 
Albumin 
ALP 
Amylase 
ALT (SGPT) 
AST (SGOT) 
Bicarbonate 
Bilirubin, direct 
(conjugated) 
TSB 
BUN 
Calcium 
Chloride 
Creatinine 
GGT 
Glucose 
Lipase 
Phosphate 
Potassium 
Sodium 
Corrected Sodium 
Total protein 
Total sBA (enzymatic 
assay) 
Uric Acid 
Measured serum 
Osmolality 
Lipid Panel 
Total cholesterol 
LDL-C (direct) 
HDL-C 
TG 
 
Cholestasis Biomarkers 
sBA (LC-MS) 
sBA subspecies 
7alpha-hydroxy-4-
cholesten-3-one (C4) 
FGF-19 
Autotaxin 
 
Lipid Soluble 
Vitamins 
25-hydroxy vitamin D 
Retinol 
RBP 
Alpha-tocopherol 
Estimated Total Lipids 
Ratio of Alpha-tocopherol 
to Estimated Total Lipids 
Urinalysis 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Occult blood and cells 
Nitrite 
Urobilinogen 
Leukocyte esterase 
Microscopic examination 
Oxalate 
Urinary creatinine 
 
9.3.7 
Table for AECI 
The categories of AECI will follow ones in CRF. 
9.3.8 
Significance Level and Confidence Coefficient 
• Significance level: 5% (two-sided) 
• Confidence coefficient: 95% (two-sided) 
9.4 
Analysis Software  
SAS (version 9.4) 
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