An Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-625 in the Treatment of Subjects With Alagille Syndrome
Phase: PHASE3
Conditions: Alagille Syndrome (ALGS)
Sponsor: Takeda

 
 
Clinical Study Protocol 
 
NCT Number: NCT05543174 
Title: An Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-625 in 
the Treatment of Subjects with Alagille Syndrome 
Study Number: TAK-625-3001 
Document Version and Date: Amendment 02 / 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 Alagille Syndrome 
Short Title 
TAK-625 for the Treatment of Alagille Syndrome (ALGS) 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka, Japan 540-8645
Study Number: 
TAK-625-3001
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 
18 Apr 2022 
Initial version 
Not applicable 
All sites 
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TAK-625 
Study No. TAK-625-3001 
Page 2 of 114 
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-625-3001 
Page 3 of 114 
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-625-3001 
Page 4 of 114 
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-625-3001 
Page 5 of 114 
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 ALGS or familial intrahepatic cholestasis (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.
•
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
Added the text “For subjects with 
ALGS, mainly 5 phase 2 studies, 
LUM001-301, LUM001-302, 
LUM001-303, LUM001-304, and 
LUM001-305, have been 
completed outside Japan.” 
Description adjustment: to 
elaborate the status/situation 
of clinical experiences. 
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TAK-625 
Study No. TAK-625-3001 
Page 6 of 114 
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 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. 
•
Section 4.1.3.1
Pharmacokinetics in Clinical
Studies
Added the text “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.” 
To provide the PK result in 
subjects <12 months of age 
with ALGS enrolled in Study 
MRX-801. 
•
Section 4.1.3.2 Study
LUM001-304 (Phase 2 Study)
Added the words “(Phase 2 Study)” 
to the section title. 
Description adjustment: to 
clarify the phase of study. 
•
Section 4.1.3.3 Study MRX-
801 (Phase 2 Study)
Added a section to describe the 
results summary of an interim 
analysis of Study MRX-801. 
To provide the results of an 
interim analysis of Study 
MRX-801. 
•
Section 4.2 Rationale for the
Proposed Study
Added descriptions on the rationale 
for the enrollment of patients 
≥1 month of age in this study. 
To revise the lower age limit 
for enrollment (inclusion 
criteria) based on the results of 
an interim analysis of Study 
MRX-801. 
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TAK-625 
Study No. TAK-625-3001 
Page 8 of 114 
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 6.2 Justification for
Study Design, Dose, and
Endpoints (Justification for
Study Population)
Removed the words “, based on the 
fact that the GI tract is fully mature 
at 1 year in humans and higher 
plasma exposures were observed in 
rats with immature GI tracts in 
juvenile toxicokinetic studies”. 
To remove the redundant 
explanation. 
•
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 “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 (the 
efficacy results in subjects 
<12 months of age with PFIC are 
not yet available).” 
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 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.
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TAK-625 
Study No. TAK-625-3001 
Page 11 of 114 
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 
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TAK-625 
Study No. TAK-625-3001 
Page 12 of 114 
Protocol Amendment 02 
08 Dec 2022 
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.........................................................................................................19 
3.0 
LIST OF ABBREVIATIONS ............................................................................................24 
3.1 
Corporate Identification ...............................................................................................27 
3.2 
Study Definitions .........................................................................................................27 
4.0 
INTRODUCTION .............................................................................................................28 
4.1 
Background ..................................................................................................................28 
4.1.1 
Drug Overview ....................................................................................................28 
4.1.2 
Disease Background ............................................................................................28 
4.1.3 
Key Clinical Experience ......................................................................................29 
4.1.3.1 
Pharmacokinetics in Clinical Studies ..........................................................29 
4.1.3.2 
Study LUM001-304 (Phase 2 Study) ..........................................................30 
4.1.3.3 
Study MRX-801 (Phase 2 Study) ................................................................31 
4.2 
Rationale for the Proposed Study ................................................................................32 
4.3 
Benefit/Risk Profile .....................................................................................................33 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................33 
5.1 
Objectives ....................................................................................................................33 
5.1.1 
Primary Objectives ..............................................................................................33 
5.1.2 
Secondary Objectives ..........................................................................................33 
5.2 
Endpoints .....................................................................................................................34 
5.2.1 
Primary Endpoint .................................................................................................34 
5.2.2 
Secondary Endpoints ...........................................................................................34 
5.2.2.1 
Key Secondary Endpoints ...........................................................................34 
5.2.2.2 
Secondary Endpoints ...................................................................................34 
5.2.3 
Safety Endpoints ..................................................................................................34 
5.2.5 
PK Endpoint ........................................................................................................36 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................36 
6.1 
Study Design ................................................................................................................36 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................39 
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6.3 
Premature Termination or Suspension of Study or Study Site ....................................40 
6.3.1 
Criteria for Premature Termination or Suspension of the Study .........................40 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites ......................40 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) ...............................................................................41 
6.3.4 
Duration of an Individual Subject’s Study Participation .....................................41 
6.3.5 
End of Study/Study Completion Definition and Planned Reporting...................41 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............42 
7.1 
Inclusion Criteria .........................................................................................................42 
7.2 
Exclusion Criteria ........................................................................................................43 
7.3 
Excluded Medications ..................................................................................................45 
7.3.1 
Justification of Excluded Medications ................................................................45 
7.4 
Excluded Procedures and Treatments ..........................................................................45 
7.4.1 
Justification of Excluded Procedures and Treatments .........................................45 
7.5 
On Study Restrictions ..................................................................................................46 
7.5.1 
Concomitant Medications, Procedures, and Treatments .....................................46 
7.5.1.1 
Prohibited Concomitant Medications, Procedures, and Treatments ...........46 
7.5.1.2 
Permitted Concomitant Medications, Procedures, and Treatments ............46 
7.5.1.3 
LSVs ............................................................................................................47 
7.5.2 
Diet, Fluid, and Activity Control .........................................................................47 
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 .......................................................49 
8.1 
Study Drug and Materials ............................................................................................49 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ....................................49 
8.1.1.1 
Study Drug ..................................................................................................49 
8.1.1.2 
Packaging ....................................................................................................49 
8.1.1.3 
Labeling.......................................................................................................50 
8.1.2 
Storage .................................................................................................................50 
8.1.3 
Dose and Regimen ...............................................................................................50 
8.1.4 
Stopping Criteria of Dosing .................................................................................51 
8.1.5 
Overdose and Medication Error ..........................................................................51 
8.2 
Study Compliance ........................................................................................................52 
8.3 
Study Drug Assignment and Dispensing Procedures ..................................................52 
8.4 
Accountability and Destruction of Sponsor-Supplied Drugs.......................................52 
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9.0 
STUDY PLAN ...................................................................................................................53 
9.1 
Study Procedures .........................................................................................................53 
9.1.1 
Informed Consent Procedure ...............................................................................53 
9.1.2 
Eligibility Assessment .........................................................................................53 
9.1.3 
Demographics, Medical History, Disease History, and Medication 
History/Prior Treatment Procedure .....................................................................54 
9.1.4 
Physical Examination Procedure .........................................................................54 
9.1.5 
Weight, Height, and BMI ....................................................................................54 
9.1.6 
Vital Sign Procedure ............................................................................................55 
9.1.7 
Primary Efficacy Measurement ...........................................................................55 
9.1.7.1 
eDiary ..........................................................................................................55 
9.1.7.2 
Serum Bile Acids and Other Cholestasis Biomarkers.................................56 
9.1.8 
Other Efficacy Measurement ...............................................................................56 
9.1.9 
Documentation of Concomitant Medications ......................................................58 
9.1.10 
Documentation of Concurrent Medical Conditions (Complication) ...................58 
9.1.11 
Procedures for Clinical Laboratory Samples .......................................................58 
9.1.12 
Pregnancy Test ....................................................................................................61 
9.1.13 
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 
9.1.14 
Pregnancy ............................................................................................................63 
9.1.15 
ECG Procedure ....................................................................................................64 
9.1.16 
Ultrasound Liver Imaging ...................................................................................64 
9.1.17 
AE Collection ......................................................................................................64 
9.1.18 
Other Safety Evaluation ......................................................................................65 
9.1.19 
Genetic Testing (ALGS Genotype) .....................................................................65 
9.1.20 
PK Sample Collection and Analysis ....................................................................65 
9.1.20.1 Collection of Blood for PK Sampling .........................................................65 
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9.1.21 
Documentation of Screen Failure ........................................................................66 
9.1.22 
Documentation of Study Entrance .......................................................................66 
9.2 
Monitoring Subject Treatment Compliance.................................................................66 
9.3 
Schedule of Observations and Procedures ...................................................................67 
9.3.1 
Screening Period ..................................................................................................67 
9.3.2 
Dose Escalation Period ........................................................................................69 
9.3.2.1 
Visit in the Dose Escalation Period .............................................................69 
9.3.2.2 
Phone Calls in the Dose Escalation Period .................................................70 
9.3.3 
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 
9.3.4 
ET ........................................................................................................................71 
9.3.5 
Follow-up Dosing Period ....................................................................................72 
9.3.6 
Safety Follow-up .................................................................................................73 
9.3.7 
Post Study Care ...................................................................................................73 
9.3.8 
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 ....................................................................................................................................76 
10.1 
Definitions....................................................................................................................76 
10.1.1 
Pretreatment Events .............................................................................................76 
10.1.2 
AEs ......................................................................................................................76 
10.1.3 
Additional Points to Consider for AEs ................................................................76 
10.1.4 
SAEs ....................................................................................................................78 
10.1.5 
AECIs ..................................................................................................................78 
10.1.6 
Intensity of AEs ...................................................................................................79 
10.1.7 
Causality of AEs ..................................................................................................79 
10.1.8 
Relationship to Study Procedures ........................................................................79 
10.1.9 
Start Date .............................................................................................................79 
10.1.10 Stop Date .............................................................................................................80 
10.1.11 Frequency ............................................................................................................80 
10.1.12 Action Concerning Study Drug ...........................................................................80 
10.1.13 Outcome ..............................................................................................................81 
10.2 
Procedures ....................................................................................................................81 
10.2.1 
Collection and Reporting of AEs ........................................................................81 
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10.2.1.1 AE Collection Period ..................................................................................81 
10.2.1.2 AE Reporting ..............................................................................................81 
10.2.2 
Collection and Reporting of SAEs ......................................................................82 
10.3 
Follow-up of SAEs ......................................................................................................83 
10.3.1 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities ................83 
10.4 
Safety Monitoring Rules ..............................................................................................84 
10.4.1 
General Guidelines ..............................................................................................84 
10.4.2 
Close Monitoring Criteria for Liver Parameters .................................................84 
10.4.3 
Guidelines for Interruption of Study Drug for Specific Liver Parameters ..........86 
10.4.4 
Rules for Study Drug Discontinuation Following Abnormalities of Liver 
Parameters ...........................................................................................................87 
10.4.5 
Safety Monitoring for LSVs ................................................................................87 
10.4.6 
Safety Monitoring for Coagulation Panel Results ...............................................88 
10.4.7 
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 ...........................................................................................................................89 
12.2 
Record Retention .........................................................................................................90 
13.0 
STATISTICAL METHODS ..............................................................................................90 
13.1 
Statistical and Analytical Plans ....................................................................................90 
13.1.1 
Analysis Sets .......................................................................................................91 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ..........................91 
13.1.3 
Efficacy Analysis .................................................................................................91 
13.1.3.1 Primary Endpoint ........................................................................................91 
13.1.3.2 Key Secondary Endpoints and Other Secondary Endpoints .......................91 
13.1.3.4 Significance Level and Confidence Coefficient .........................................91 
13.1.4 
PK Analysis .........................................................................................................92 
13.1.5 
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) ...........92 
13.2 
Interim Analysis ...........................................................................................................92 
13.3 
Determination of Sample Size .....................................................................................93 
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13.4 
Other Statistical Considerations ...................................................................................93 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................93 
14.1 
Study-Site Monitoring Visits .......................................................................................93 
14.2 
Protocol Deviations ......................................................................................................93 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................94 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................94 
15.1 
IRB Approval ...............................................................................................................94 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................95 
15.3 
Subject Confidentiality ................................................................................................96 
15.4 
Clinical Trial Disclosures and Publication ..................................................................97 
15.4.1 
Clinical Trial Registration and Results Disclosure .............................................97 
15.4.2 
Publication ...........................................................................................................97 
15.5 
Insurance and Compensation for Injury .......................................................................97 
16.0 
DISSEMINATION OF NEW INFORMATION ...............................................................97 
17.0 
REFERENCES ..................................................................................................................98 
18.0 
APPENDIX ........................................................................................................................99 
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Study No. TAK-625-3001 
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Protocol Amendment 02 
08 Dec 2022 
LIST OF IN-TEXT TABLES 
Table 9.a 
Clinical Laboratory Tests .......................................................................................60 
Table 10.a 
Close Monitoring Criteria for Treatment-Emergent Elevated ALT and TSB .......85 
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 ....................................................................................38 
LIST OF APPENDICES 
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TAK-625 
Study No. TAK-625-3001 
Page 19 of 114 
Protocol Amendment 02 
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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 Alagille Syndrome  
IND No.:  
Not Applicable. 
EudraCT No.: 
Not Applicable. 
Study Number: TAK-625-3001 
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 Alagille syndrome (ALGS). This study consists of the screening period 
(up to 6 weeks prior to the study administration), 2-week dose escalation period, 46-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). 
•
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 to ALGS (JAGGED-1 
or NOTCH2), genetic testing may be performed, if necessary. 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 (2 Weeks: Week 0 to 2):
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 and have urine and blood samples taken. 
Compliance with ItchRO will be assessed. Study drug for Weeks 1 and 2 will be supplied at the baseline visit to 
eligible subjects. Subjects will receive the study drug, TAK-625, administered orally once a day (QD). The dose 
will be increased weekly over a 2-week period up to 400 μg/kg/day QD as follows: dose level 1, 200 μg/kg/day 
QD for 1 week; and dose level 2, 400 μg/kg/day QD for the remaining duration of the study. 
If an individual subject exhibits a treatment-emergent moderate or severe drug-related gastrointestinal (GI) 
toxicity with 400 μg/kg/day, study drug dose may be lowered to 200 μg/kg/day; later attempts to escalate the 
dose are permitted during the dose escalation period. This decision should be made in consultation with the 
medical monitor. If further dose escalations fail during the dose escalation period, the subject will remain on 
200 μg/kg/day for the remainder of the study.  
•
Stable Dosing Period (46 Weeks: Week 3 to 48):
After the dose escalation period, each subject will continue dosing with study drug at the Week 3 dose level, 
which is either 200 or 400 µg/kg/day, in 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):
In the follow-up dosing period, each subject will continue dosing with study drug at the Week 48 dose level, 
which is either 200 or 400 µg/kg/day. 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. 
•
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). 
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TAK-625 
Study No. TAK-625-3001 
Page 20 of 114 
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Primary Objectives: 
•
To evaluate the efficacy and safety of TAK-625 in subjects with ALGS.
Secondary Objectives: 
•
To evaluate the pharmacokinetics (PK) of TAK-625 in subjects with ALGS.
•
To evaluate the efficacy of TAK-625 on biochemical markers of cholestasis and liver disease in subjects
with ALGS.
Subject Population: Japanese patients with ALGS who are 1 month of age or older. 
Number of Subjects: 
In this study, approximately 5 subjects will be enrolled as 
targeted sample size. 
Number of Sites:  
Estimated total: approximately 10 sites in Japan. 
Dose Levels: 
Dose level 1: 200 μg/kg/day QD for 1 week. 
Dose level 2: 400 μg/kg/day QD for the remaining 
duration of the study. 
Route of Administration: 
Oral 
Duration of Treatment: 
•
Dose Escalation Period: 2 weeks.
•
Stable Dosing Period: 46 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: 2 weeks.
•
Stable Dosing Period: 46 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).
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TAK-625 
Study No. TAK-625-3001 
Page 21 of 114 
Protocol Amendment 02 
08 Dec 2022 
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 is diagnosed with ALGS based on the diagnostic criteria outlined below.
Major clinical criteria/features for ALGS include: cholestasis, consistent cardiac, renal, vascular, ocular,
skeletal involvement, or characteristic “Alagille” facies.
ALGS Family History a 
Paucity 
JAGGED1 or  
NOTCH2 Mutation 
Major Clinical Criteria 
Needed for Diagnosis 
Present or Absent 
Present 
Identified b 
Any or no features 
None (proband) 
Absent or unknown 
Identified 
1 or more features 
None (proband) 
Present 
Not identified c 
3 or more features 
None (proband) 
Absent or unknown 
Not identified 
4 or more features 
Present 
Absent or unknown 
Identified 
Any or no features 
Present 
Present 
Not identified 
1 or more features 
Present 
Absent or unknown 
Not identified 
2 or more features 
a Family history=ALGS present in a first degree relative. 
b Identified=JAGGED1 or NOTCH2 mutation identified in clinical laboratory. 
c Not identified=Not identified on screening, or not screened for. 
•
The subject has one or more of the following evidences of cholestasis:
a.
Total serum bile acid (sBA) >3× upper limit of the normal range (ULN) for age.
b.
Direct bilirubin (conjugated) >1 mg/dL.
c.
Lipid soluble vitamin (LSV) deficiency otherwise unexplainable.
d.
Gamma-glutamyl transferase (GGT) >3×ULN for age.
e.
Intractable pruritus explainable only by liver disease.
•
Caregivers (and age-appropriate subjects) must complete at least 10 eDiary reports (morning or evening)
during each of 2 consecutive weeks of the screening period (maximum possible reports=14 per week), even
if the subject is an adult (over 18 years old).
Average daily score >2 on the ItchRO questionnaire (maximum possible daily score of 4) for 2 consecutive
weeks in the screening period, prior to dosing. A daily score is the higher of the scores for the morning and
evening ItchRO. The average daily score is the sum of all daily scores divided by the number of days the
ItchRO was completed. 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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TAK-625 
Study No. TAK-625-3001 
Page 22 of 114 
Protocol Amendment 02 
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Main Criteria for Exclusion: 
The main criteria for exclusion in this study are as follows: 
•
The subject has chronic diarrhea requiring ongoing intravenous (IV) fluid or nutritional intervention.
•
The subject has a previous history of surgical interruption of the enterohepatic circulation.
•
The subject has a previous liver transplant.
•
The subject decompensated cirrhosis (alanine aminotransferase [ALT] >15×ULN, international normalized
ratio [INR] >1.5 [unresponsive to vitamin K therapy], albumin <3.0 g/dL, history or presence of clinically
significant ascites, variceal hemorrhage, and/or encephalopathy).
•
The subject has a history or presence of other concomitant liver disease.
•
The subject has a history or presence of 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).
•
The subject has a history or presence of gallstones or kidney stones.
•
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 the change from Week 18 to 22 of fasting sBA levels. 
Key secondary endpoints are as follows: 
•
Change from baseline to Week 18:
–
Fasting sBA levels.
–
Pruritus as measured by Observer-reported Itch Reported Outcome (ItchRO [Obs]): weekly average
severity (based on daily maximum of morning and evening severity scores).
–
Pruritus as measured by ItchRO (Obs): weekly average morning severity.
•
Change from Week 18 to 22:
–
Pruritus as measured by ItchRO (Obs): weekly average severity (based on daily maximum of morning
and evening severity scores).
–
Pruritus as measured by ItchRO (Obs): weekly average morning severity.
Other secondary endpoints for this study are as follows: 
•
Change from baseline to Week 18:
–
Pruritus as measured by Patient-reported Itch Reported Outcome (ItchRO [Pt]): weekly average severity
(based on daily maximum of morning and evening severity scores).
–
Pruritus as measured by ItchRO (Pt): weekly average morning severity.
–
Liver enzymes (ALT and alkaline phosphatase [ALP]) and bilirubin (total and direct).
•
Change from Week 18 to 22:
–
Pruritus as measured by ItchRO (Pt): weekly average severity (based on daily maximum of morning and
evening severity scores).
–
Pruritus as measured by ItchRO (Pt): weekly average morning severity.
–
Liver enzymes (ALT and ALP) and bilirubin (total and direct).
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TAK-625 
Study No. TAK-625-3001 
Page 23 of 114 
Protocol Amendment 02 
08 Dec 2022 
Statistical Considerations: 
Analytical Methods for Primary Endpoint 
Primary Analysis: Descriptive statistics and two-sided 95% confidence interval (CI) of mean will be provided 
based on the intention-to-treat set (ITT). 
Secondary Analysis: For supportive analysis, the same analysis as the primary analysis will be performed using 
the modified intention-to-treat set (MITT) and the per protocol analysis set (PPS) to confirm robustness of the 
results. 
Analytical Methods for Key Secondary Endpoints 
Descriptive statistics and two-sided 95% CI of mean will be provided based on the ITT. For supportive analysis, 
the same analysis as the above analysis will be performed using the PPS to confirm robustness of the results. 
Analytical Methods for Secondary Endpoints 
Descriptive statistics and two-sided 95% CI of mean will be provided based on the ITT. 
Sample Size Justification: ALGS is a rare disease. The targeted sample size is approximately 5 subjects based 
on enrollment feasibility of this population in Japan, rather than power calculation. 
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TAK-625 
Study No. TAK-625-3001 
Page 24 of 114 
Protocol Amendment 02 
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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
AECI 
adverse event of clinical interest 
AFP 
α-fetoprotein 
ALGS 
Alagille syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibody 
ANCOVA 
analysis of covariance 
 
 
aPTT 
activated partial thromboplastin time 
ARW 
after randomized withdrawal 
AST 
aspartate aminotransferase 
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 
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 
CSS 
Clinician Scratch Scale 
DILI 
drug-induced livery injury 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board  
EAP 
Expanded Access Program 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EMA 
European Medicines Agency 
EOT 
end of treatment 
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Study No. TAK-625-3001 
Page 25 of 114 
Protocol Amendment 02 
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ET 
early termination 
fBA 
fecal bile acid 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor 19 
 
 
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 
LOQ 
lower limit of quantification 
LS 
least squares 
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TAK-625 
Study No. TAK-625-3001 
Page 26 of 114 
Protocol Amendment 02 
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LSV 
lipid soluble vitamin 
LTE 
long-term extension 
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 
MITT 
modified intention-to-treat set 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
OL 
open-label run-in 
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 
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 
RWD 
randomized withdrawal 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sBA 
serum bile acid 
SD 
standard deviation 
SE 
standard error 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TG 
triglycerides 
TSB 
total serum bilirubin 
UK 
United Kingdom 
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TAK-625 
Study No. TAK-625-3001 
Page 27 of 114 
Protocol Amendment 02 
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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. 
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TAK-625 
Study No. TAK-625-3001 
Page 28 of 114 
Protocol Amendment 02 
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4.0 
INTRODUCTION 
4.1 
Background 
4.1.1 
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. 
4.1.2 
Disease Background 
ALGS is a rare genetic, multisystem disease affecting 1 in 100,000 people [1]. In Japan, an 
estimated frequency is 1 in 30,000 people and there are 200 to 300 diagnosed patients reported 
based on national survey [2]. 
In addition to multiple other abnormalities (eg, cardiovascular, skeletal, and ocular), ALGS is 
typically accompanied by cholestatic liver disease and usually associated with severe pruritus 
manifesting during infancy and childhood, jaundice, xanthomas, fat malabsorption, failure to 
thrive, and hepatocellular injury. Debilitating pruritus, xanthomas, and progressive liver disease 
ultimately lead to the need for surgical interventions, including partial external biliary diversion 
(PEBD) or liver transplantation. Transplant-free survival in patients with cholestasis related to 
ALGS was no more than 70% at 10 years and is estimated to be 24% at 18.5 years of age [3]. 
Liver transplant carries the burden of lifelong immunosuppressive therapy and has significant 
morbidity and mortality [4]. Left untreated, patients with ALGS have a median life expectancy 
of approximately 2 decades [1]. 
 
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TAK-625 
Study No. TAK-625-3001 
Page 29 of 114 
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Among clinical symptoms of ALGS, 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 ALGS. Treatment with anti-pruritics and bile salt resins may provide partial relief 
of pruritus for children with ALGS, but currently available pharmacologic approaches are of 
limited value. It has been shown that removing bile with surgical procedures such as PEBD 
substantially reduces pruritus in ALGS [5]. 
To date, no pharmacologic interventions have been approved to treat ALGS or cholestatic 
pruritus associated with ALGS in Japan. Since reduction in bile acid concentrations with PEBD 
has been shown to be associated with improvement in cholestatic pruritus in ALGS, 
pharmacological diversion of bile acids with an IBAT inhibitor could be an attractive alternative 
to surgical intervention in ALGS without surgical complications. TAK-625 potentially reduces 
cholestasis due to ALGS and the related effects of cholestatic pruritus, xanthomas, and growth 
deficiency by above mechanism. 
4.1.3 
Key Clinical Experience 
For subjects with ALGS, mainly 5 phase 2 studies, LUM001-301, LUM001-302, LUM001-303, 
LUM001-304, and LUM001-305, have been completed 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, 
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. 
 
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TAK-625 
Study No. TAK-625-3001 
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4.1.3.2 
Study LUM001-304 (Phase 2 Study) 
For subjects with ALGS, the efficacy of TAK-625 was assessed in Study LUM001-304, which 
was a pivotal study in US Food and Drug Administration (FDA) approval of TAK-625 for the 
treatment of cholestatic pruritus associated with ALGS. Study LUM001-304 consisted of an 
18-week open-label run-in (OL) period (OL phase), a 4-week randomized, double-blind,
placebo-controlled drug-withdrawal period (randomized withdrawal [RWD] phase), a 26-week
stable-dosing period (after randomized withdrawal [ARW] phase), and an optional long-term
treatment period (long-term extension [LTE] phase).
Efficacy Results: 
1. sBA
The primary efficacy endpoint was the change from Week 18 to Week 22 in fasting sBA
levels. A total of 29 subjects (RWD TAK-625, n=13; RWD placebo, n=16) were included in
the intention-to-treat set (ITT), of which 15 subjects (RWD TAK-625, 5 subjects; RWD
placebo, 10 subjects) were included in modified intention-to-treat set (MITT).
Using an analysis of covariance (ANCOVA) model for MITT, subjects in the RWD placebo
group had significant increases in sBA from Week 18 to Week 22, with a least squares (LS)
mean (standard error [SE]) increase of 95.55 (30.488) µmol/L (p=0.0086), while subjects in
the RWD TAK-625 group had no significant change (LS mean [SE] decrease, or
improvement of 21.73 [43.125] µmol/L, p=0.6234), leading to a statistically significant
difference in sBA between the TAK-625 and placebo groups (-117.28 [52.828] µmol/L,
p=0.0464).
Similar results were observed in the ITT, with a significant increase in sBA from Week 18 to
Week 22 in the RWD placebo group (LS mean [SE] increased by 95.21 [31.686] µmol/L,
p=0.0058), but not in the RWD TAK-625 group (LS mean [SE] decreased or improved by
18.74 [35.251] µmol/L, p=0.5995), with a statistically significant difference in sBA between
the TAK-625 and placebo groups (-113.95 [48.032] µmol/L, p=0.0254).
In the ITT, a statistically significant difference was observed in sBA from baseline to
Week 18: mean change from baseline (SD) -87.73 (119.979) µmol/L, p=0.0005.
2. Observer-reported Itch Reported Outcome (ItchRO [Obs]): Weekly Average Morning
Severity Score
Given the subjects’ young age, an observer-reported outcome was used to measure subjects’
pruritus symptoms as observed by their caregiver twice daily (once in the morning and once
in the evening) on the ItchRO (Obs) instrument with scores ranging from 0 (none observed or
reported) to 4 (very severe).
At Week 18, a statistically significant mean (SD) decrease (improvement) from baseline in
ItchRO (Obs) weekly average morning severity scores were identified in the ITT (-1.704
[0.9114], p <0.0001) with similar reductions observed in the TAK-625 and placebo groups
when analyzed separately.
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TAK-625 
Study No. TAK-625-3001 
Page 31 of 114 
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At Week 22, a statistically significant increase (worsening) in mean (SD) change from 
Week 18 in ItchRO (Obs) scores was observed in the placebo group (1.712 [1.0054], 
p <0.0001), while no relevant change was observed in the TAK-625 group (0.201 [0.7551], 
p=0.3754). 
Using an ANCOVA model, a significant increase in ItchRO (Obs) was observed in the RWD 
placebo group from Week 18 to Week 22 (LS mean [SE] increase of 1.700 [0.2031], 
p <0.0001), but not in the RWD TAK-625 group (LS mean [SE] increase of 0.217 [0.2345], 
p=0.3639), with a statistically significant difference in ItchRO (Obs) between the TAK-625 
and placebo groups (-1.483 [0.3103], p <0.0001). 
Safety Results: 
The incidence of treatment-emergent adverse events (TEAEs) was similar during the OL, ARW, 
and LTE phases, with the majority of subjects (86.2%-100%) experienced TEAEs. The most 
frequently reported TEAEs (>30% in at least 1 phase) were abdominal pain, pyrexia, diarrhea, 
nasopharyngitis, vomiting, cough, and pruritus. The incidence of abdominal pain was highest in 
the OL and LTE phases (12 subjects [38.7%] and 12 subjects [52.2%], respectively) and was 
lower in the ARW phase (6 subjects [20.7%]). During the RWD phase, subjects in the RWD 
TAK-625 group had a similar incidence of abdominal pain TEAEs compared with subjects in the 
RWD placebo group (1 subject [7.7%] and 1 subject [6.3%], respectively). 
During the OL and LTE phases, 38.7% and 34.8% of subjects, respectively, experienced TEAEs 
potentially related to the study drug, while only 1 subject (3.4%) experienced such TEAEs 
during the ARW phase. During the RWD phase, subjects in the TAK-625 group had a lower 
incidence of TEAEs and TEAEs potentially related to the study drug (53.8% and 7.7%, 
respectively) compared with subjects in the placebo group (75% and 18.8%, respectively). 
During the RWD phase, serious adverse events (SAEs) were reported for 1 subject each in the 
TAK-625 group and the placebo group. None of the SAEs were considered related to the study 
drug. A total of 6 subjects (2 subjects each in the OL, ARW, and LTE phases) experienced 
TEAEs leading to study drug discontinuation. No deaths occurred during 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 (once a day [QD]; for ALGS) and at 600 μg/kg twice daily (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). 
 
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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. 
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 (alanine aminotransferase [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. 
4.2 
Rationale for the Proposed Study 
TAK-625 has never been used in Japan, although Study LUM001-304 suggested that TAK-625 
was safe and effective and the effect sustained in long-term period in subjects with ALGS. In this 
study, efficacy, safety, and PK profile of TAK-625 will be evaluated. This protocol was 
developed to confirm the similarity to Study LUM001-304 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. 
 
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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 ALGS; however, 
from the age of onset of ALGS, 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). The diagnostic criteria for 
ALGS in Japan are the same as those in overseas countries [6]. Regarding the current treatments 
for potential subjects for this study, who are without surgical treatment, 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 ALGS, 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 ALGS. 
As previously stated in Section 4.1.3, the safety and efficacy profile of TAK-625 in 
non-Japanese subjects with ALGS has been confirmed in Study LUM001-304, though TAK-625 
has never been used in Japan. The long-term efficacy has been also confirmed in Study 
LUM001-304. 
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 ALGS. 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objectives 
•
To evaluate the efficacy and safety of TAK-625 in subjects with ALGS.
5.1.2 
Secondary Objectives 
•
To evaluate the PK of TAK-625 in subjects with ALGS.
•
To evaluate the efficacy of TAK-625 on biochemical markers of cholestasis and liver disease
in subjects with ALGS.
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5.2 
Endpoints 
5.2.1 
Primary Endpoint 
•
The change from Week 18 to 22 of fasting sBA levels.
5.2.2 
Secondary Endpoints 
5.2.2.1 
Key Secondary Endpoints 
•
Change from baseline to Week 18:
–
Fasting sBA levels.
–
Pruritus as measured by ItchRO (Obs): weekly average severity (based on daily
maximum of morning and evening severity scores).
–
Pruritus as measured by ItchRO (Obs): weekly average morning severity.
•
Change from Week 18 to 22:
–
Pruritus as measured by ItchRO (Obs): weekly average severity (based on daily
maximum of morning and evening severity scores).
–
Pruritus as measured by ItchRO (Obs): weekly average morning severity.
5.2.2.2 
Secondary Endpoints 
•
Change from baseline to Week 18:
–
Pruritus as measured by Patient-reported Itch Reported Outcome (ItchRO [Pt]): weekly
average severity (based on daily maximum of morning and evening severity scores).
–
Pruritus as measured by ItchRO (Pt): weekly average morning severity.
–
Liver enzymes (ALT and alkaline phosphatase [ALP]) and bilirubin (total and direct).
•
Change from Week 18 to 22:
–
Pruritus as measured by ItchRO (Pt): weekly average severity (based on daily maximum
of morning and evening severity scores).
–
Pruritus as measured by ItchRO (Pt): weekly average morning severity.
–
Liver enzymes (ALT and ALP) and bilirubin (total and direct).
5.2.3 
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.
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5.2.5 
PK Endpoint 
•
Plasma levels of TAK-625 at predose and approximately 4 hours after the morning dose at
Week 12.
•
Plasma levels of TAK-625 at predose (optional) and approximately 30 minutes after the
morning dose at Week 18 (or any visit up to Week 28).
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 ALGS. 
Study Population: 
The study population is defined as “Japanese patients with ALGS who are 1 month of age or 
older”. 
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), 
2-week dose escalation period (doses up to 400 μg/kg/day, QD, as tolerated), 46-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 to 
ALGS (JAGGED-1 or NOTCH2), genetic testing may be performed, if necessary. 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 (2 Weeks: Week 0 to 2):
In the 2-week 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 for Weeks 1 and 2 
will be supplied at the baseline visit to eligible subjects. Subjects will receive the study drug, 
TAK-625, administered orally QD. The dose will be increased weekly over a 2-week period up 
to 400 μg/kg/day QD as follows: dose level 1, 200 μg/kg/day QD for 1 week; and dose level 2, 
400 μg/kg/day QD for the remaining duration of the study. If an individual subject exhibits a 
treatment-emergent moderate or severe drug-related gastrointestinal (GI) toxicity with 
400 μg/kg/day, study drug dose may be lowered to 200 μg/kg/day; later attempts to escalate the 
 
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dose are permitted during the dose escalation period. This decision should be made in 
consultation with the medical monitor. If further dose escalations fail during the dose escalation 
period, the subject will remain on 200 μg/kg/day for the remainder of the study. The dose should 
be taken at least 30 minutes prior to the first meal of the day. It is recommended that the dose 
should be taken approximately at the same time each day for the duration of the treatment period. 
Subjects will return to the clinic at Week 3 and follow-up phone calls will be made at Weeks 1 
and 2. 
3. Stable Dosing Period (46 Weeks: Week 3 to 48):
After the dose escalation period, each subject will continue dosing with study drug at the Week 3 
dose level, which is either 200 or 400 µg/kg/day, in the stable dosing period. Subjects will visit 
the study site at Weeks 6, 12, 18, 22, 28, 38, 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):
In the follow-up dosing period, each subject will continue dosing with study drug at the Week 48 
dose level, which is either 200 or 400 µg/kg/day. 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/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). 
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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“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 LUM001-304 suggested that TAK-625 
was safe and effective and the effect sustained in long-term period in subjects with ALGS. In this 
study, efficacy, safety, and PK profile of TAK-625 will be evaluated. This protocol was 
developed to confirm the similarity to Study LUM001-304 by comparing the results between 
Japanese data and overseas data. 
Justification for Study Population: 
The study population is defined as Japanese patients with ALGS. 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. 
The diagnostic criteria for ALGS in Japan are the same as those in overseas countries [6]. 
Justification for Dose and Regimen of Study Drug: 
The TAK-625 up to 400 μg/kg/day, orally QD dosing regimen was selected based on 
international phase 2 clinical trial of TAK-625 (Study LUM001-304). 
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 LUM001-501) demonstrated a consistent safety profile. No maximum 
tolerated dose (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. 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 (the 
efficacy results in subjects <12 months of age with PFIC are not yet available). 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, 
with the exception of increased stool frequency at higher doses. In this study, the dose of 
TAK-625 up to 400 µg/kg/day, which is already approved by FDA will be evaluated in Japanese 
subjects with ALGS for efficacy and safety. Regarding dose escalation, the design was to 
escalate the dose of 14 μg/kg/day to 400 μg/kg/day by 1 week in 6 steps. However, the 
 
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FDA-approved commercial dose regimen is to escalate the dose of 200 μg/kg/day to 
400 μg/kg/day by 1 week in 2 steps. A similar two-step dose escalation regimen was adopted in 
the Expanded Access Program (EAP) currently ongoing in the US, where 36 subjects have been 
requested by medical institutions to receive TAK-625 by the data cutoff on May 10, 2021. No 
additional safety concerns were observed in EAP. Therefore, it is considered that the reduction of 
the dose escalation step regimen to 2-step, from 6-step in Study LUM001-304, would not affect 
the safety. The time to the primary endpoint after reaching the therapeutic dose of 400 μg/kg/day 
was 12 weeks in Study LUM001-304 with 6-step escalation and 16 weeks in this study with 
2-step escalation. However, since previous clinical studies suggested that the full treatment
effects were already achieved as early as Week 12, it was considered that this 4-week difference
will not affect the results of the primary endpoint.
Justification for Endpoints: 
The endpoints are set to confirm the similarity to Study LUM001-304 by comparing the results 
between Japanese data and overseas data. The diagnostic criteria for ALGS in Japan are the same 
as those in overseas countries [6]. Regarding the current treatments for potential subjects for this 
study, who are without surgical treatment, 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 ALGS, the randomized, double-blind, placebo-controlled drug withdrawal period will not be 
used in this study.  
6.3 
Premature Termination or Suspension of Study or Study Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or 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.
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
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6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) 
In the event that the sponsor, an institutional review board (IRB), 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. 
6.3.4 
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. 
6.3.5 
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. 
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 Weeks 22 and 48. Final clinical study report (CSR) will be 
prepared at the end of the study. 
 
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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 is diagnosed with ALGS based on the diagnostic criteria outlined below.
Major clinical criteria/features for ALGS include: cholestasis, consistent cardiac, renal,
vascular, ocular, skeletal involvement, or characteristic “Alagille” facies.
ALGS Family History a 
Paucity 
JAGGED1 or  
NOTCH2 Mutation 
Major Clinical Criteria 
Needed for Diagnosis 
Present or Absent 
Present 
Identified b 
Any or no features 
None (proband) 
Absent or unknown 
Identified 
1 or more features 
None (proband) 
Present 
Not identified c 
3 or more features 
None (proband) 
Absent or unknown 
Not identified 
4 or more features 
Present 
Absent or unknown 
Identified 
Any or no features 
Present 
Present 
Not identified 
1 or more features 
Present 
Absent or unknown 
Not identified 
2 or more features 
a Family history=ALGS present in a first degree relative. 
b Identified=JAGGED1 or NOTCH2 mutation identified in clinical laboratory. 
c Not identified=Not identified on screening, or not screened for. 
4. The subject has one or more of the following evidences of cholestasis:
a) Total sBA >3× upper limit of the normal range (ULN) for age.
b) Direct bilirubin (conjugated) >1 mg/dL.
c) LSV deficiency otherwise unexplainable.
d) Gamma-glutamyl transferase (GGT) >3×ULN for age.
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e) Intractable pruritus explainable only by liver disease.
5. 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. 
6. The subject is expected to have a consistent caregiver(s) for the duration of the study.
7. The subject has an access to phone for scheduled calls from study site.
8. Both a caregiver and subject above the age of assent are capable of reading and
understanding the questionnaires.
9. Caregivers (and age-appropriate subjects) must be willing and able to use an eDiary device
during the study.
10. Caregivers (and age-appropriate subjects) must complete at least 10 eDiary reports (morning
or evening) during each of 2 consecutive weeks of the screening period (maximum possible
reports=14 per week), even if the subject is an adult (over 18 years old).
Average daily score >2 on the ItchRO questionnaire (maximum possible daily score of 4) for
2 consecutive weeks in the screening period, prior to dosing. A daily score is the higher of
the scores for the morning and evening ItchRO. The average daily score is the sum of all
daily scores divided by the number of days the ItchRO was completed. 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.
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. The subject has chronic diarrhea requiring ongoing intravenous (IV) fluid or nutritional
intervention.
2. The subject has a previous history of surgical interruption of the enterohepatic circulation.
3. The subject has a previous liver transplant.
4. The subject decompensated cirrhosis (ALT >15×ULN, international normalized ratio
[INR] >1.5 [unresponsive to vitamin K therapy], albumin <3.0 g/dL, history or presence of
clinically significant ascites, variceal hemorrhage, and/or encephalopathy).
5. The subject has a history or presence of other concomitant liver disease.
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6. The subject has a history or presence of 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).
7. The subject has a history or presence of gallstones or kidney stones.
8. The subject has a possible malignant liver mass in imaging, including screening ultrasound.
9. The subject has a history of human immunodeficiency virus (HIV) infection.
10. The subject has cancers, except for in situ carcinoma, or cancers treated at least 5 years prior
to screening with no evidence of recurrence.
11. The subject has a recent medical history or current status that suggests that the subject may
be unable to complete the study.
12. The subject is any female who is pregnant or lactating or who is planning to become pregnant
during the study period.
13. The subject has a known history of alcohol or substance abuse.
14. 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).
15. 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).
16. The subject has a known hypersensitivity to TAK-625 or any of its components.
17. The subject participated in another clinical study within 28 days or 5 half-lives (whichever is
longer) prior to screening.
18. The subject has a history of nonadherence to medical regimens, unreliability, mental
instability, or incompetence that could compromise the validity of informed consent or lead
to nonadherence with the study protocol based upon investigator judgment.
19. The subject has any other conditions or abnormalities which, in the opinion of the
investigator or medical monitor, may compromise the safety of the subject, or interfere with
the subject participating in or completing the study.
20. The subject is judged by the investigator as being ineligible for any other reason.
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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. 
7.3.1 
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.
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. 
7.4.1 
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.
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•
Liver transplant: The liver transplant is excluded from the study since this is considered as a
curable treatment for ALGS.
7.5 
On Study Restrictions 
7.5.1 
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 treatments 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.
•
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. 
 
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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. 
7.5.2 
Diet, Fluid, and Activity Control 
•
The dose should be taken at least 30 minutes prior to the first meal of the day. It is
recommended that the dose should be taken approximately at the same time each day
throughout the study. 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 18 (or any visit up to Week 28), the PK sampling should be conducted before
breakfast.
•
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
4 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).
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.
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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.
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
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. 
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8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
This section contains information regarding all medications and materials provided directly by 
the sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material. 
8.1 
Study Drug and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study drug refers to 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 (10 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. 
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 10 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. 
 
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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”. 
8.1.2 
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”. 
8.1.3 
Dose and Regimen 
Route of Administration: oral 
Dose Regimen:  
Subjects will receive TAK-625 (up to 400 μg/kg/day), orally QD. 
The dose should be taken at least 30 minutes prior to the first meal of the day. It is recommended 
that the dose should be taken approximately at the same time each day throughout the study. 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. 
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 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 22. 
1. Dose Escalation Period (2 weeks: Week 0 to 2):
The dose will be increased weekly over a 2-week period up to 400 μg/kg/day QD as follows:
The dose escalation period will consist of the following weekly steps: 
Dose level 1: 200 μg/kg/day QD for 1 week 
Dose level 2: 400 μg/kg/day QD for the remaining duration of the study 
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GI intolerance, as evidenced by diarrhea/loose stools, abdominal pain/cramping, and nausea, is 
expected to be the most frequent manifestation of a lack of tolerability to study drug. If an 
individual subject exhibits a treatment-emergent moderate or severe drug-related GI toxicity with 
400 μg/kg/day, study drug dose may be lowered to 200 μg/kg/day; later attempts to escalate the 
dose are permitted during the dose escalation period. This decision should be made in 
consultation with the medical monitor. If further dose escalations fail during the dose escalation 
period, the subject will remain on 200 μg/kg/day for the remainder of the study. A requirement 
for IV fluids as treatment for diarrhea will lead to discontinuation of study drug. 
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 (46 Weeks: Week 3 to 48):
After the dose escalation period, each subject will continue dosing with study drug at the Week 3 
dose level, which is either 200 or 400 µg/kg/day, in the stable dosing period. 
3. Follow-up Dosing Period (after Week 48):
In the follow-up dosing period, each subject will continue dosing with study drug at the Week 48 
dose level, which is either 200 or 400 µg/kg/day. 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. 
8.1.4 
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. 
8.1.5 
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. 
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 
 
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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. 
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. 
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 
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 
 
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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. 
9.1.1 
Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject 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. 
9.1.2 
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 2 weeks to confirm the average daily score >2 on 
the ItchRO (Obs) and completion of at least 10 eDiary reports, 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. 
 
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9.1.3 
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 ALGS 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. 
9.1.4 
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. 
9.1.5 
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 
 
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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 
9.1.6 
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. 
9.1.7 
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 ItchRO™, 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 
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 2 weeks of ItchRO (Obs) 
twice daily diary entry. If the subject does not meet eligibility after 2 weeks, ItchRO (Obs) 
eligibility should be re-assessed at Week 3, and also at Week 4 if eligibility is not met at Week 3. 
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 
 
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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)™ 
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. 
ItchRO (Pt)™ 
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 4 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 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. 
9.1.8 
Other Efficacy Measurement 
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9.1.9 
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. 
9.1.10 
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. 
9.1.11 
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 4 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 
 
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maximum allowable amount, the investigator will draw blood in the priority order listed in 
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
 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; 7αC4=7α-hydroxy-4-cholesten-3-one; β-hCG=β-human chorionic gonadotropin; BUN=blood urea nitrogen; 
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. 
9.1.12 
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. 
9.1.13 
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.
 
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** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy. 
The following procedures apply for contraception and pregnancy avoidance. 
1. 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
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(male and female) will receive continued guidance with respect to the avoidance of 
pregnancy and sperm donation as part of the study procedures. Such guidance should include 
a reminder of the following: 
a) Contraceptive requirements of the study.
b) Reasons for use of barrier methods (ie, condom) in males with pregnant partners.
c) Assessment of subject compliance through questions such as:
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. 
9.1.14 
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 
 
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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. 
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. 
9.1.15 
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. 
9.1.16 
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. 
9.1.17 
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). 
 
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9.1.18 
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.
•
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. 
9.1.19 
Genetic Testing (ALGS Genotype) 
JAGGED1 and NOTCH2 mutations can be predictive of ALGS. For ALGS subjects who meet 
clinical diagnostic criteria for ALGS (see Section 7.1) but do not have documentation of a 
JAGGED1 or NOTCH2 mutation, the clinical diagnosis of ALGS may be confirmed by 
genotyping, if necessary. Subjects for whom prior genotyping was performed may need to have 
an optional repeat analysis performed if the original information collected at screening was 
insufficient for complete documentation of the diagnosis of ALGS including the type of mutation 
recorded in the source document. For those subjects for which the type of the mutation cannot be 
documented, genetic testing may be performed and the results recorded on the source document 
and eCRF, if necessary. 
9.1.20 
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 4 hours (±30 minutes) after morning dose at 
Week 12 and at predose and approximately 30 minutes (±15 minutes) after morning dose at 
Week 18 will be collected. If sample collections at Week 18 are difficult, PK samples can be 
collected at any visit up to Week 28. Additionally, predose at Week 18 is optional. Postdose PK 
 
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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. 
Instructions for collecting, processing, and shipping of PK samples are provided in the laboratory 
manual. 
9.1.21 
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.
9.1.22 
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. 
 
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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. 
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. 
9.3.1 
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 2 weeks to confirm the average daily score >2 on 
the ItchRO (Obs) score and completion of at least 10 eDiary reports, 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 2 weeks, ItchRO (Obs) eligibility should be re-assessed at Week 3, and 
also at Week 4 if eligibility is not met at Week 3. A maximum of 3 attempts can be made to 
determine ItchRO (Obs) eligibility during the screening period and will allow for the evaluation 
of each subject’s eligibility for inclusion into the study. The requirements of ItchRO™ are 
described in Section 9.1.7.1.1. 
 
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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. 
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 ALGS genotype based on a genotyping (for subjects who do not have
documentation of mutation related with ALGS), if necessary.
•
eDiary supply and instructions.
•
•
•
Screening clinical laboratory tests (blood).
•
AE assessment.
•
Concomitant medications (including confirmation of the need to administer LSV
supplements).
•
Access IRT to obtain subject number.
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9.3.2 
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 2 weeks. All assessments and procedures listed for 
visits and subject contacts (phone calls) from Week 0 to 2 in Appendix A should be completed 
during this period. 
9.3.2.1 
Visit 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 (Week 0) include: 
•
Eligibility assessment based on inclusion/exclusion criteria.
•
Physical examination, vital signs, weight, height, and BMI.
•
12-lead ECG.
•
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.
•
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 2 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 2, 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).
9.3.3 
Stable Dosing Period 
After the dose escalation period, each subject will continue dosing with study drug at the Week 3 
dose level, which is either 200 or 400 µg/kg/day, in the stable dosing period.  
The stable dosing period will comprise of 46 weeks. All assessments and procedures listed for 
visits and subject contacts (phone calls) from Week 3 to 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 3 and 6, a ±2-day visit window will be permitted. 
From Week 12 to 22 and Week 28 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 12, 28, and 48).
•
Liver ultrasound (at Week 48).
•
Pregnancy test (urine, for females of childbearing potential).
•
•
•
•
•
Clinical laboratory tests (blood).
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•
Clinical laboratory tests (urine).
•
Blood collection for PK (at Weeks 12 and 18).
•
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 4, 5, 9, 20, 23, 24, 25, 26, 27, 33, and 43 to review the use of concomitant treatments, 
study drug compliances, and AEs as outlined in Appendix A.  
For subject contacts (phone calls) at Weeks 4 and 5, and from Week 23 to 27, a ±2-day window 
will be permitted. At Weeks 9, 20, 33, and 43, 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).
9.3.4 
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.
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•
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.
•
AE assessment.
•
Concomitant medications (including confirmation of the need to administer LSV
supplements).
9.3.5 
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).
•
•
•
•
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•
Clinical laboratory tests (blood).
•
Clinical laboratory tests (urine).
•
Blood collection for serum storage.
•
eDiary review.
•
Study drug supply and return.
•
Study drug compliance review.
•
AE assessment.
•
Concomitant medications (including confirmation of the need to administer LSV
supplements).
9.3.6 
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). 
9.3.7 
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. 
9.3.8 
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 
 
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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. 
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.
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•
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.
–
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. 
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10.0 
AEs 
10.1 
Definitions 
10.1.1 
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. 
10.1.2 
AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. This includes any newly occurring event or a 
previous condition that has increased in severity or frequency since the administration of study 
drug. 
10.1.3 
Additional Points to Consider for AEs 
An untoward finding generally may: 
•
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent
events for pre-existing conditions or underlying disease should not be considered 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
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laboratory or ECG retest and/or continued monitoring of an abnormal value or finding are not 
considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention. 
•
If abnormal laboratory values or ECG findings are the result of pathology for which there is
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be
reported appropriately as an AE.
Pre-existing conditions: 
•
Pre-existing conditions (present at the time of signing of informed consent) are considered
concurrent medical conditions and should NOT be recorded as AEs. Baseline evaluations
(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.
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Elective surgeries or procedures: 
•
Elective procedures performed where there is no change in the subject’s medical condition
should not be recorded as AEs but should be documented in the subject’s source documents.
Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy): 
•
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as
an AE. The investigator must make the distinction between exacerbation of pre-existing
illness and lack of therapeutic efficacy.
Overdose 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.
10.1.4 
SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH.
2. Is LIFE THREATENING.
•
The term “life threatening” refers to an event in which the subject was at risk of death at
the time of the event; it does not refer to an event that hypothetically might have caused
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
•
May require intervention to prevent items 1 through 5 above.
•
May expose the subject to danger, even though the event is not immediately life
threatening or fatal or does not result in hospitalization.
10.1.5 
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. 
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In this study AECIs include the following: 
•
LSV deficiency events.
•
Liver parameter disruption.
10.1.6 
Intensity of AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
10.1.7 
Causality of AEs 
The relationship of each AE to study drug(s) will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications, and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications, and concurrent treatments. 
10.1.8 
Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all AEs. 
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as Not Related.  
10.1.9 
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator. 
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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. 
10.1.10 Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
10.1.11 Frequency 
Episodic AEs (eg, vomiting) or those that occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous. 
10.1.12 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.
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•
Dose Interrupted – the dose was interrupted due to the particular AE.
10.1.13 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.
•
Unknown – the course of the AE cannot be followed up due to hospital change or residence
change at the end of the subject’s participation in the study.
10.2 
Procedures 
10.2.1 
Collection and Reporting of AEs 
10.2.1.1 
AE Collection Period 
Collection of AEs will commence from the time that the subject 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 
 
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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 
undertaken. Through this follow-up if it is determined that an AE not previously reported has 
been identified, normal reporting requirements should be applied. 
10.2.2 
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.
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•
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.
•
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) 
 
 
 
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. 
10.3.1 
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 
 
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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 
10.4.1 
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). 
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.  
10.4.2 
Close Monitoring Criteria for Liver Parameters 
Table 10.a provides the criteria for close monitoring of liver parameters. 
 
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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 total serum bilirubin 
(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: 
•
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. 
 
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10.4.3 
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):
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 restarted 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. 
 
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10.4.4 
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 2 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,
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. 
10.4.5 
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. 
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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, RBP, 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. 
10.4.6 
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. 
10.4.7 
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 
 
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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.
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.  
 
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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.  
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 up to Week 22 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 up to and including Week 48. Furthermore, statistical analyses will also 
be performed using all subjects' data up to 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. 
 
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13.1.1 
Analysis Sets 
Four kinds of analysis sets are defined in this study. The 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.
•
MITT: all subjects who received study drug through Week 18, and had a reduction from
baseline in sBA levels of ≥50% at the Week 12 or Week 18 measurement.
•
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.
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized using the ITT. 
13.1.3 
Efficacy Analysis 
13.1.3.1 
Primary Endpoint 
Primary Analysis: 
Descriptive statistics and two-sided 95% confidence interval (CI) of mean will be provided based 
on the ITT. 
Secondary Analysis: 
For supportive analysis, the same analysis as the primary analysis will be performed using the 
MITT and the PPS to confirm robustness of the results. 
13.1.3.2 
Key Secondary Endpoints and Other Secondary Endpoints 
Analytical Methods for Key Secondary Endpoints 
Descriptive statistics and two-sided 95% CI of mean will be provided based on the ITT. For 
supportive analysis, the same analysis as the above analysis will be performed using the PPS to 
confirm robustness of the results. 
Analytical Methods for Secondary Endpoints 
Descriptive statistics and two-sided 95% CI of mean will be provided based on the ITT. 
13.1.3.4 
Significance Level and Confidence Coefficient 
•
Significance Level: 5% (two-sided test).
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•
Confidence coefficient: 95% (two-sided).
13.1.4 
PK Analysis 
The following analysis will be performed for the safety analysis set. 
Plasma concentrations of TAK-625 will be summarized by each scheduled sampling time and 
visit using descriptive statistics. 
13.1.5 
Safety Analysis 
The following analysis will be performed for the safety analysis set. 
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 system organ class and the preferred term as follows: 
•
The frequency of all TEAEs.
•
The frequency of drug-related TEAEs.
•
The frequency of TEAEs by intensity.
•
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 up to Weeks 22 and 48 after the 
data are locked for marketing application. Additionally, statistical analyses will also be 
performed using all subjects’ data up to the end of the study after the data are locked. 
 
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13.3 
Determination of Sample Size 
ALGS is a rare disease. The targeted sample size is approximately 5 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. 
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. 
 
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14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the US 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 
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 I. 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 IB, 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, 
 
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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 
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 
 
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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. 
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). 
 
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15.4 
Clinical Trial Disclosures and Publication 
15.4.1 
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). 
15.4.2 
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.  
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. Elisofon SA, Emerick KM, Sinacore JM, Alonso EM. Health status of patients with Alagille
syndrome. J Pediatr Gastroenterol Nutr. 2010;51(6):759-65.
2. Imagawa K, Wada H, Tagawa M, Sumazaki R. Alagille syndrome [in Japanese]. J. New
Rem. & Clin. 2018;67(12):148-52.
3. Kamath BM, Ye W, Goodrich NP, Loomes KM, Romero R, Heubi JE, et al. Outcomes of
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Epidemiology, Natural History, and Burden of Alagille Syndrome. J Pediatr Gastroenterol
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