Conditions: Healthy Volunteers
Keywords: Drug Therapy
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 80
Healthy volunteers: yes

Brief summary:
It is hoped that in the future, TAK-105 will be used to help treat people with nausea and vomiting. The main aims of this study are as follows:

* To check for side effects from TAK-105 in healthy adults.
* To learn how much TAK-105 they can receive without getting side effects from it.

Participants will receive either TAK-105 as TAK-105-a or TAK-105-b (depending upon the part they are enrolled in) or a placebo as an injection under the skin (sub-cutaneous injection). A placebo looks like TAK-105-a or TAK-105-b but will not have any medicine in it. Three times as many participants will receive TAK-105-a or TAK-105-b than placebo.

The study will have 6 parts. Each part will have several small groups of participants, called cohorts. Participants will only be in 1 cohort in 1 part of the study.

Part 1: Participants will check into the study clinic to receive a single dose of TAK-105-a or placebo and will stay in the clinic for about 10 days. Then, participants return to the clinic for follow-up visits up to about 60 days after the dose.

Part 2: Participants will check into the study clinic to receive TAK-105-a or placebo once a week for 4 weeks, and will stay in the clinic for about 26 days. Then, participants return to the clinic for follow-up visits up to about 60 days after last dose.

Part 3: Participants will check into the study clinic to receive 2, 3 or 4 weekly doses of TAK-105-a or placebo. Their clinic stay will be for 10 to 24 days depending which cohort they are in. Then, participants return to the clinic for follow-up visits up to about 28 days after last dose.

Part 4: Participants will check into the study clinic to receive 2 doses (once a week for 2 weeks) of TAK-105-a or placebo and will stay in the study clinic for about 12 days. They will return to the clinic later (in about 1-3 weeks) for another (third) dose and will stay for 2 days after the third dose. Then, participants return to the clinic for follow-up visits up to about 3 months after first dose.

Part 5a: Participants will check into the study clinic to receive a single dose of TAK-105-a or placebo and will stay in the clinic for about 10 days. Then, participants return to the clinic for follow-up visits up to about 60 days after the dose.

Part 5b: Participants will check into the study clinic to receive TAK-105-a or placebo once a week for 4 weeks, and will stay in the clinic for about 26 days. Then, participants return to the clinic for follow-up visits up to about 60 days after last dose. Part 5b will be optional, depending on the pharmacokinetic (PK) and safety data observed in Part 2.

Part 6: Participants will check into the study clinic to receive a single dose of TAK-105-b or placebo and will stay in the clinic for about 10 days. Then, participants return to the clinic for follow-up visits up to about 60 days after the dose.

Detailed description:
The drug being tested in this study is called TAK-105. The study will look at the safety, tolerability, and PK of TAK-105-a and TAK-105-b in healthy participants.

Participants in each cohort will be randomized to receive treatment with TAK-105-a or TAK-105-b or matching placebo which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need). The study consists of 6 parts and up to 34 cohorts as mentioned below:

* Part 1 (SRD) will enroll healthy participants in up to 12 cohorts.
* Part 2 (MRD) will enroll healthy participants in up to 5 ascending cohorts.
* Part 3 (Dose titration) will enroll healthy participants in up to 6 multiple-dose cohorts.
* Part 4 (Redosing) will enroll healthy participants in up to 4 redosing cohorts.
* Part 5a (SRD) will enroll healthy Japanese participants in up to 3 cohorts.
* Part 5b (MRD) (optional) will enroll healthy Japanese participants in up to 2 cohorts. The MRD cohorts in Part 5b will be optional, depending on the PK and safety data observed in Part 2 (MRD).
* Part 6 (SRD) will enroll healthy participants in up to 2 cohorts.

Each cohort in all the parts will have 8 randomized participants with 6 participants receiving a single dose of TAK-105-a in Parts 1 to 5 or TAK-105-b in Part 6, and 2 receiving TAK-105-a matching placebo (Parts 1 to 5) or TAK-105-b matching placebo (Part 6) in a 3:1 ratio. This multi-center trial will be conducted in the United States. The overall duration of the study is approximately 18 months.

Arms:
arm 1: TAK-105-a matching-placebo, injection, subcutaneously, once on Day 1. arm 2: TAK-105-a Dose 1, injection, subcutaneously, once on Day 1. arm 3: TAK-105-a Dose 2, injection, subcutaneously, once on Day 1. arm 4: TAK-105-a Dose 3, injection, subcutaneously, once on Day 1. arm 5: TAK-105-a Dose 4, injection, subcutaneously, once on Day 1. arm 6: TAK-105-a Dose 5, injection, subcutaneously, once on Day 1. arm 7: TAK-105-a Dose 6, injection, subcutaneously, once on Day 1. arm 8: TAK-105-a Dose 7, injection, subcutaneously, once on Day 1. arm 9: TAK-105-a matching-placebo, injection, subcutaneously, once weekly for 4 weeks. arm 10: TAK-105-a Dose 1A, injection, subcutaneously, once weekly for up to 4 weeks. arm 11: TAK-105-a Dose 2A, injection, subcutaneously, once weekly for 1 week.

Interventions: intervention 1: TAK-105-a intervention 2: TAK-105-a Placebo
Intervention descriptions: intervention 1: TAK-105-a subcutaneous solution. intervention 2: TAK-105-a placebo-matching solution.

Protocol document:
Prot_000.pdf: 
For non-commercial use only


 
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, Phase 1 Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-105 in Healthy Subjects
Sponsor:
Takeda Development Center Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421 USA
Study Identifier:
TAK-105-1001 
Compound:
TAK-105
Date:
19 December 2022
Version/Amendment 
Number:
Amendment 4
Amendment History:
Date
Amendment Number
Amendment Type
Region
19 December 2022
Amendment 4
Substantial
Global
23 March 2022
Amendment 3
Substantial
Global
09 September 2021
Amendment 2
Substantial
Global
29 July 2021
Amendment 1
Nonsubstantial
Global
27 May 2021
Initial protocol
Not applicable
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ....................................................................................................10
1.1
Protocol Amendment 4 Summary of Changes..........................................................16
2.0
STUDY SCHEMATICS................................................................................................21
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................27
3.1
Part 1 for SRD Cohort 1 to 12..................................................................................27
3.1.1
Part 1 for SRD Cohort 1 to 12 (Days 1 Through 8) ..........................................27
3.1.2
Part 1 for SRD Cohort 1 to 12 (Follow-Up Through ET)..................................31
3.2
Part 2 for MRD Cohorts 13 to 17 .............................................................................33
3.2.1
Part 2 for MRD Cohorts 13 to 17 (Week 1)......................................................33
3.2.2
Part 2 for MRD Cohorts 13 to 17 (Week 2)......................................................37
3.2.3
Part 2 for MRD Cohorts 13 to 17 (Week 3)......................................................39
3.2.4
Part 2 for MRD Cohorts 13 to 17 (Week 4, Follow-Up, and ET)......................41
3.3
Part 3 Dose Titration Cohorts 18 and 19...................................................................44
3.3.1
Part 3 Dose Titration Cohorts 18 and 19 (Week 1)...........................................44
3.3.2
Part 3 Dose Titration Cohorts 18 and 19 (Week 2)...........................................47
3.3.3
Part 3 Dose Titration Cohorts 18 and 19 (Week 3)...........................................49
3.3.4
Part 3 Dose Titration Cohorts (Week 4, Follow-Up, and ET) ...........................51
3.4
Part 3 Dose Titration Cohorts 20 and 21...................................................................54
3.4.1
Part 3 Dose Titration Cohorts 20 and 21 (Week 1)...........................................54
3.4.2
Part 3 Dose Titration Cohorts 20 and 21 (Week 2)...........................................57
3.4.3
Part 3 Dose Titration Cohorts 20 and 21 (Week 3, Follow-Up, and ET)...........59
3.5
Part 3 Dose Titration Cohorts 22 and 23...................................................................61
3.5.1
Part 3 Dose Titration Cohorts 22 and 23 (Week 1)...........................................61
3.5.2
Part 3 Dose Titration Cohorts 22 and 23 (Week 2, Follow-Up, and ET)...........64
3.6
Part 4 Redosing Cohorts 24 Through 27...................................................................66
3.6.1
Part 4 Redosing Cohorts 24 Through 27 (Week 1) ...........................................66
3.6.2
Part 4 Redosing Cohorts 24 Through 27 (Week 2) ...........................................69
3.6.3
Part 4 Redosing Cohorts 24 Through 27 (Third Dose Week, Follow-Up, and 
ET)..................................................................................................................71
3.7.2
Part 5a for Japanese SRD Cohort 28 to 30: Follow-Up Through ET.................78
3.7.4
Part 5b for Japanese MRD Cohorts 31 and 32 (Week 2)...................................83
3.7.5
Part 5b for Japanese MRD Cohorts 31 and 32 (Week 3)...................................85
3.7.6
Part 5b for Japanese MRD Cohorts 31 and 32 (Week 4, Follow-Up, and ET)...87
3.8
Part 6 TAK-105-b New Formulation of Drug Product..............................................90
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3.8.1
Part 6 TAK-105-b Formulation - SRD Cohorts 33 and 34: Days 1 Through 8..90
4.0
INTRODUCTION.........................................................................................................96
4.1
Background .............................................................................................................96
4.2
Rationale for the Proposed Study.............................................................................96
4.3
Benefit/Risk Profile .................................................................................................97
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................98
5.1
Study Objectives......................................................................................................98
5.1.1
Study Primary Objective..................................................................................98
5.1.2
Study Secondary Objective..............................................................................99
5.1.3
Study Exploratory Objectives ........................................................................100
5.2
Endpoints...............................................................................................................100
5.2.1
Primary Endpoint...........................................................................................100
5.2.2
Secondary Endpoints .....................................................................................100
5.2.3
Exploratory Endpoints ...................................................................................101
6.0
STUDY DESIGN AND DESCRIPTION.....................................................................102
6.1
Study Design .........................................................................................................102
6.1.1
Overall Study Design.....................................................................................102
6.1.2
Part 1: SRD Cohorts 1 to 12...........................................................................105
6.1.3
Part 2: MRD Cohorts 13 to 17........................................................................105
6.1.4
Part 3: Dose Titration Cohorts 18 to 23..........................................................106
6.1.4.1
Cohorts 18 and 19..................................................................................107
6.1.4.2
Cohorts 20 and 21 (optional)..................................................................108
6.1.4.3
Cohort 22 and 23 (optional) ...................................................................108
6.1.5
Part 4: Redosing Study Cohorts 24, 25, 26, and 27.........................................108
6.1.5.1
Cohort 24...............................................................................................109
6.1.5.2
Cohorts 25, 26, and 27...........................................................................110
6.1.6
Part 5a/b: SRD and MRD in Japanese Subjects Cohorts 28 to 32 ...................110
6.1.7
Part 6: TAK-105-b New Formulation.............................................................110
6.1.8
Study Drug Administration............................................................................111
6.2
Dose Escalation .....................................................................................................111
6.3
External Safety Adjudication Committee ...............................................................112
6.4
Stopping Rules.......................................................................................................112
6.4.1
Stopping Criteria for Individual Subjects .......................................................112
6.4.2
Criteria for Premature Termination or Suspension of the Study......................112
6.5
Rationale for Study Design, Dose, and Endpoints ..................................................114
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7.4.1.2
Parts 2, 3, 4, and 5b ...............................................................................125
7.4.2
Activity .........................................................................................................126
7.5
Criteria for Discontinuation or Withdrawal of a Subject.........................................126
7.6
Procedures for Discontinuation or Withdrawal of a Subject....................................127
7.7
Subject Replacement..............................................................................................127
8.0
CLINICAL STUDY MATERIAL MANAGEMENT...................................................127
8.1
Clinical Study Drug ...............................................................................................127
8.1.1
Clinical Study Drug Labeling ........................................................................127
8.1.2
Clinical Study Drug Inventory and Storage....................................................128
8.1.3
Clinical Study Drug Blinding.........................................................................128
8.1.4
Randomization Code Creation and Storage....................................................128
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure................................129
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs...........................129
9.0
STUDY PROCEDURES.............................................................................................130
9.1
Administrative Procedures.....................................................................................130
9.1.1
Informed Consent Procedure..........................................................................130
9.1.1.1
Assignment of Screening and Randomization Numbers .........................130
9.1.1.2
Study Drug Assignment.........................................................................130
9.1.2
Inclusion and Exclusion.................................................................................130
9.1.3
Medical History/Demography........................................................................131
9.1.4
Concomitant Medications ..............................................................................131
9.2
Clinical Procedures and Assessments.....................................................................131
9.2.1
Full Physical Exam........................................................................................131
9.2.2
Height and Weight.........................................................................................131
9.2.3
BMI...............................................................................................................131
9.2.4
Vital Signs.....................................................................................................131
9.2.4.1
Orthostatic Measurements......................................................................132
9.2.4.2
Follow-Up Safety Monitoring................................................................133
9.2.5
Glucose .........................................................................................................134
9.2.6
ECG Procedure..............................................................................................134
9.2.6.1
Screening and Safety ECGs ...................................................................134
9.2.6.2
Telemetry ..............................................................................................134
9.2.7
Study Drug Administration............................................................................136
9.2.8
AE Monitoring ..............................................................................................136
9.2.9
Laboratory Procedures and Assessments........................................................136
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9.2.9.1
Hematology...........................................................................................136
9.2.9.2
Chemistry..............................................................................................137
9.2.9.3
Urinalysis ..............................................................................................137
9.2.9.4
Diagnostic Screening.............................................................................138
9.2.10
PK, Immunogenicity, Biomarker, and DNA Samples.....................................138
9.2.10.1
PK Measurements..................................................................................139
9.2.10.2
Urine for PK Measurements...................................................................141
9.2.10.3
Immunogenicity (ADA) Measurements .................................................141
9.2.10.4
Biomarker Measurements ......................................................................142
9.2.10.5
DNA Measurements ..............................................................................142
9.3
Confinement ..........................................................................................................143
9.3.1
SRD (Parts 1, 5a, and 6).................................................................................143
9.3.2
MRD (Parts 2 and 5b)....................................................................................143
9.3.3
Part 3 (Dose Titration) ...................................................................................144
9.3.4
Part 4 (Redosing)...........................................................................................144
9.4
Childbearing Status and Methods of Contraception................................................144
9.4.1
Women of Childbearing Potential..................................................................144
9.4.1.1
Definition of WOCBP ...........................................................................144
9.4.2
Women of Nonchildbearing Potential ............................................................144
9.4.2.1
Contraception for WONCBP .................................................................144
10.0
ADVERSE EVENTS ..................................................................................................144
10.1
Definitions and Elements of AEs ...........................................................................144
10.1.1
SAEs .............................................................................................................147
10.1.2
AEs of Special Interest...................................................................................147
10.2
AE Procedures.......................................................................................................147
10.2.1
Assigning Severity/Intensity of AEs ..............................................................147
10.2.2
Assigning Causality of AEs ...........................................................................148
10.2.3
Start Date.......................................................................................................148
10.2.4
End Date........................................................................................................148
10.2.5
Pattern of AE (Frequency) .............................................................................148
10.2.6
Action Taken With Study Treatment..............................................................149
10.2.7
Outcome........................................................................................................149
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
Liver Function Tests......................................................................................149
10.2.8.1
Collection Period...................................................................................149
10.2.8.2
Reporting AEs.......................................................................................150
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10.2.8.3
Reporting SAEs.....................................................................................150
10.2.8.4
Management of Specific AEs.................................................................151
10.2.8.5
Reporting of Abnormal LFTs.................................................................152
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.152
11.0
STATISTICAL METHODS........................................................................................153
11.1
Statistical and Analytical Plans ..............................................................................153
11.1.1
Analysis Sets .................................................................................................154
11.1.1.1
Safety Analysis Set................................................................................154
11.1.1.2
PK Analysis Set.....................................................................................154
11.1.1.3
Immunogenicity Analysis Set ................................................................154
11.1.2
Analysis of Demography and Other Baseline Characteristics .........................154
11.1.3
PK Analysis...................................................................................................155
11.1.4
Safety Analysis..............................................................................................155
11.1.4.1
AEs .......................................................................................................155
11.1.4.2
Clinical Laboratory Evaluation ..............................................................155
11.1.4.3
Vital Signs.............................................................................................156
11.1.4.4
ECG ......................................................................................................156
11.1.4.5
Other Safety Parameters ........................................................................156
11.1.5
Immunogenicity Analysis ..............................................................................156
11.1.6
Biomarker Analysis .......................................................................................157
11.2
Interim Analysis ....................................................................................................157
11.3
Determination of Sample Size................................................................................157
12.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................157
12.1
Study-Site Monitoring Visits .................................................................................157
12.2
Protocol Deviations................................................................................................158
12.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................158
13.0
ETHICAL ASPECTS OF THE STUDY......................................................................158
13.1
IRB and/or IEC Approval ......................................................................................158
13.2
Subject Information, Informed Consent, and Subject Authorization .......................159
13.3
Subject Confidentiality ..........................................................................................160
13.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................161
13.4.1
Publication and Disclosure.............................................................................161
13.4.2
Clinical Trial Registration..............................................................................161
13.4.3
Clinical Trial Results Disclosure....................................................................162
13.5
Insurance and Compensation for Injury..................................................................162
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.......................................162
14.1
Administrative Information....................................................................................162
14.1.1
Study Contact Information.............................................................................162
14.1.2
Investigator Agreement..................................................................................163
14.1.3
Study-Related Responsibilities.......................................................................164
14.1.4
List of Abbreviations .....................................................................................164
15.0
DATA HANDLING AND RECORDKEEPING..........................................................167
15.1
CRFs (Electronic and Paper)..................................................................................167
15.2
Record Retention ...................................................................................................167
16.0
REFERENCES............................................................................................................168
17.0
APPENDICES.............................................................................................................170
LIST OF IN-TEXT TABLES
Table 3.a
Part 1 for SRD Cohorts 1 to 12: Days 1 Through 8.............................................27
Table 3.b
Part 1 for SRD Cohorts 1 to 12: Follow-Up Through ET....................................31
Table 3.c
Part 2 for MRD Cohorts 13 to 17: Screening Through Day 7 (Week 1) ..............33
Table 3.d
Part 2 for MRD Cohorts 13 to 17: Day 8 Through Day 14 (Week 2) ..................37
Table 3.e
Part 2 for MRD Cohorts 13 to 17: Day 15 Through Day 21 (Week 3) ................39
Table 3.f
Part 2 for MRD Cohorts 13 to 17: Day 22 to 82 (Week 4, Follow-Up, and ET)..41
Table 3.g
Part 3 Dose Titration Cohorts 18 and 19: Screening Through Day 7 (Week 1)....44
Table 3.h
Part 3 Dose Titration Cohorts 18 and 19: Day 8 Through Day 14 (Week 2)........47
Table 3.i
Part 3 Dose Titration Cohorts 18 and 19: Day 15 Through Day 21 (Week 3)......49
Table 3.j
Part 3 for Dose Titration Cohorts 18 and 19: Day 22 to 82 (Week 4, Follow-Up, 
and ET)..............................................................................................................51
Table 3.k
Part 3 Dose Titration Cohorts 20 and 21: Screening Through Day 7 (Week 1)....54
Table 3.l
Part 3 Dose Titration Cohorts 20 and 21: Day 8 Through Day 14 (Week 2)........57
Table 3.m
Part 3 for Dose Titration Cohorts 20 and 21: Day 15 Through Day 17 (Week 3, 
Follow-Up, and ET)...........................................................................................59
Table 3.n
Part 3 for Dose Titration Cohorts 22 and 23: Screening Through Day 7 
(Week 1)............................................................................................................61
Table 3.o
Part 3 for Dose Titration Cohorts 22 and 23: Day 8 Through Day 10 (Week 2), 
Follow-Up, and ET ............................................................................................64
Table 3.p
Part 4 Redosing Study Cohorts 24 Through 27: Screening Through Day 7 
(Week 1)............................................................................................................66
Table 3.q
Part 4 Redosing Study Cohorts 24 Through 27: Day 8 Through Day 10 
(Week 2)............................................................................................................69
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. (TDC Americas)
95 Hayden Avenue
Lexington, Massachusetts USA 02421
Telephone: +1 (617) 679-7000
Compound:
TAK-105
Study Identifier: TAK-105-1001
Phase: 1
Protocol Title: A Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, Phase 1 Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of TAK-105 in Healthy Subjects
Study Design:
This is a phase 1, randomized, double-blind, sponsor-open, placebo-controlled study to evaluate the safety, 
immunogenicity, tolerability, and pharmacokinetics (PK) of TAK-105 in healthy subjects. 
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. The study will be 
conducted sponsor-open. Sponsor discussions with investigators and within the study team will be conducted in a 
blinded manner (ie, no unblinded information will be communicated to blinded investigators, site staff or blinded 
study monitoring personnel).
The study will consist of 6 parts: 

Part 1 is a first-in-human (FIH), randomized, double-blind, sponsor-open, placebo-controlled single-rising dose 
(SRD) design to assess the safety, immunogenicity, tolerability, and PK of TAK-105 in healthy subjects. Part 1 
will consist of up to 12 sequential cohorts with 8 healthy subjects per cohort. Subjects in each cohort will be 
randomly assigned to receive a single dose of TAK-105-a (Process A formulation) or matching placebo via 
subcutaneous (SC) administration in a 3:1 ratio in a double-blind manner.

Part 2 is a randomized, double-blind, sponsor-open, placebo-controlled, multiple-rising dose (MRD) design to 
assess the safety, immunogenicity, tolerability, and PK of TAK-105 in healthy subjects. Part 2 consists of 
sequential dosing in up to 5 ascending cohorts of healthy subjects. In each cohort, 8 healthy subjects will be 
randomly assigned to receive TAK-105-a or matching placebo in a 3:1 ratio in a double-blind manner. 

Part 3 is a randomized, double-blind, sponsor-open, placebo-controlled, multiple-dose, dose titration design to 
assess the safety, immunogenicity, tolerability, and PK of TAK-105 in healthy subjects. Part 3 will consist of up 
to 6 cohorts with 8 healthy subjects per cohort. Subjects will be assigned to receive TAK-105-a or matching 
placebo in a 3:1 ratio in a double-blind manner. The intent of the design of Part 3 is to enable a descriptive 
comparison (ie, without hypothesis testing) of cardiovascular (CV) tolerability profile findings between Part 3 
cohorts and cohorts in Parts 1 and 2 with comparable exposures, to determine whether dose titration results in 
different tolerability in relation to CV observations.

Part 4 is a randomized, double-blind, sponsor-open, placebo-controlled, redosing after a period of withholding 
study drug design to assess the safety, immunogenicity, tolerability, and PK of TAK-105 in healthy subjects. Part 
4 will consist of up to 4 cohorts with 8 healthy subjects per cohort. Subjects will be assigned to receive 
TAK-105-a or matching placebo in a 3:1 ratio in a double-blind manner. The intention of the design of Part 4 is to 
provide an exploratory evaluation to assess the safety and CV tolerability profile of redosing with TAK-105 after 
a period of withholding study drug.

Part 5 is a randomized, double-blind, sponsor-open, placebo-controlled SRD (Part 5a) and MRD (Part 5b 
[optional]) design to assess the safety, immunogenicity, tolerability, and PK of TAK-105 in healthy Japanese 
subjects. Part 5 will consist of up to 5 cohorts (3 SRD and 2 MRD [optional]) with 8 healthy Japanese subjects per 
cohort. Subjects will be assigned to receive TAK-105-a or matching placebo in a 3:1 ratio in a double-blind 
manner. The MRD cohorts in Part 5b will be optional, depending on the PK/safety data observed in Part 2 MRD. 

Part 6 is a randomized, double-blind, sponsor-open, placebo-controlled SRD design to assess the safety, 
immunogenicity, tolerability, and PK of a new formulation of TAK-105 in healthy subjects. Part 6 will consist of 
up to 2 cohorts (1 is optional) with 8 healthy subjects per cohort. Subjects will be assigned to receive TAK-105-b 
(Process B formulation) or matching placebo in a 3:1 ratio in a double-blind manner. The intention of Part 6 is to 
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evaluate safety and PK of the new formulation.
Study drug in Parts 1 to 5 is TAK-105-a (Process A formulation) or matching placebo and in Part 6 is TAK-105-b 
(Process B formulation) or matching placebo, which has improved stability. TAK-105-1001 Parts 1 and 2 will be 
initiated in advance of Parts 3 and 4. Parts 3 and 4 will be conducted at the discretion of the sponsor based on a review 
of available safety and PK data from Parts 1 and 2. At the discretion of the sponsor, Parts 3 and 4 may be initiated 
before completion of all cohorts in Parts 1 and 2 as otherwise permissible in the protocol. Part 5a/b may be performed 
in parallel with Parts 1 and 2 based on the review of safety and PK data at least at the matching dose from the previous 
parts. Part 6 with the new drug formulation of TAK-105 (TAK-105-b) may be performed in parallel with Part 1 
provided that the new formulation is available and after Part 1 SRD data are available. The highest tolerable dose in 
Part 1 will not be exceeded in subsequent parts of the study.
Study Primary Objectives:

Part 1:
–
To characterize the safety and tolerability of single SC doses of TAK-105-a in healthy subjects.

Part 2:
–
To characterize the safety and tolerability of multiple SC doses of TAK-105-a in healthy subjects.

Part 3:
–
To characterize the safety and tolerability of multiple SC dose regimens of TAK-105-a that include titration 
from lower doses in healthy subjects.

Part 4
–
To characterize the safety and tolerability of multiple SC dose regimens of TAK-105-a that include weekly 
dosing, withholding, then redosing in healthy subjects.

Part 5:
–
To characterize the safety and tolerability of single SC doses and of multiple SC doses of TAK-105-a in 
healthy Japanese subjects.

Part 6: 
–
To characterize the safety and tolerability of single SC doses of new formulation TAK 105-b in healthy 
subjects.
Secondary Objectives:

Part 1:
–
To characterize the plasma PK of TAK-105 following a single SC dose of TAK-105-a in healthy subjects.
–
To assess the immunogenicity of TAK-105 following single SC doses in healthy subjects.
–
To characterize the urinary PK of TAK-105 following a single SC dose of TAK-105-a in healthy subjects.

Part 2:
–
To characterize the plasma PK of TAK-105 following multiple SC doses of TAK-105-a in healthy subjects.
–
To assess the immunogenicity of TAK-105 following multiple SC doses in healthy subjects. 
–
To characterize the urinary PK of TAK-105 following multiple SC doses of TAK-105-a in healthy subjects.

Parts 3 and 4: To assess the immunogenicity of TAK-105-a following multiple SC dose regimens that include 
titration from lower doses for Part 3 and weekly dosing, withholding, then redosing for Part 4 in healthy subjects.

Part 5:
–
To characterize the plasma PK of TAK-105 following a single SC dose and multiple SC doses of TAK-105-a 
in healthy Japanese subjects.
–
To assess the immunogenicity of TAK-105-a following single SC doses and multiple SC doses in healthy 
Japanese subjects.
–
To characterize the urinary PK of TAK-105 following a single SC dose and multiple SC doses of TAK-105-a 
in healthy Japanese subjects.

Part 6: 
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–
To characterize the plasma PK of TAK-105 following single SC doses of TAK-105-b in healthy subjects.
–
To assess the immunogenicity of TAK-105 following a single SC dose of TAK-105-b in healthy subjects.
Study Subject Population: Healthy subjects aged 18 to 55 years, inclusive.
Planned Number of Subjects:
Part 1: Up to approximately 96 subjects. 
Part 2: Up to approximately 40 subjects.
Part 3: Up to approximately 48 subjects. 
Part 4: Up to approximately 32 subjects.
Part 5: up to approximately 40 subjects.
Part 6: up to approximately 16 subjects.
Approximate values do not account for potential 
replacement of subjects who withdraw for 
nonsafety reasons.
Planned Number of Sites:
4 sites.
Dose Levels:
The starting dose is 
.
Route of Administration:
SC
Duration of Treatment:
Part 1: 1 day.
Part 2: 4 weeks (once weekly [QW], 4 doses 
total). 
Part 3: 2 to 4 weeks (QW, 2 to 4 doses total).
Part 4: up to 4 weeks (3 doses total).
Part 5a: SRD – 1 day, Part 5b: MRD 4 weeks 
(QW, 4 doses total).
Part 6: 1 day.
Planned Study Duration:
Part 1 will be approximately 89 days (a 28-day screening period, 
a 1-day treatment period, and a follow-up period of 60 days. 
Part 2 will be approximately 110 days (a 28-day screening period, 
a 22-day treatment period, and a follow-up period of 60 days).
Part 3 will be approximately 78 days (a 28-day screening period, 
a varying treatment period of up to 22 days, a follow-up period of 
28 days).
Part 4 will be approximately 85 days (a 28-day screening period, 
a varying treatment period with a maximum of 29 days, and a 
follow-up period of 28 days).
Part 5a will be approximately 89 days (a 28-day screening period, 
a 1-day treatment period, and a follow-up period of 60 days) for 
SRD cohorts and Part 5b will be approximately 110 days (a 
28-day screening period, a 22-day treatment period, and a 
follow-up period of 60 days) for MRD cohorts.
Part 6 will be approximately 89 days (a 28-day screening period, 
a 1-day treatment period, and a follow-up period of 60 days).
Main Criteria for Inclusion:
In order to be eligible for study participation, subjects must: 
For All Cohorts

Be willing and able to comply with all study procedures and restrictions.

Be a healthy male or female of nonchildbearing potential aged 18 to 55 years, inclusive, at the screening visit.

Have a body mass index ≥18 and ≤30.0 (kg/m2) at the screening visit.

Continuous nonsmoker who has not used nicotine- and tobacco-containing products for at least 3 months prior to 
screening and through discharge.

Be judged to be in good health (eg, no evidence of psychiatric, hepatic, renal, pulmonary, or CV disease) by the 
investigator, based on clinical evaluations including laboratory safety tests, medical history, physical 
examination, electrocardiogram (ECG), and vital sign measurements performed at the screening visit and before 
administration of the initial dose of study drug or invasive procedure.
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Additional inclusion criteria for Japanese subjects in Part 5 (Cohorts 28 to 32 only): 

The subject has 2 Japanese parents and 4 Japanese grandparents, as confirmed by interview.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject: 
For All Cohorts

The subject has participated in another investigational study within 4 weeks (or based on local regulations) or 
within 5 half-lives of the investigational product before the screening visit. The 4-week or 5 half-lives window 
will be derived from the date of the last dose and/or adverse event (AE) related to the study procedure in the 
previous study to the screening visit of the current study.

The subject has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or has had an 
anaphylactic reaction or significant intolerance to prescription or nonprescription drugs or food.

The subject has a positive pregnancy test or is lactating or breastfeeding.

The subject is unable to refrain from or anticipates using all medications including herbal medicines beginning 
approximately 7 days before administration of the first dose of study drug, throughout the study until the last 
follow-up visit.

The subject has a known or suspected current coronavirus disease 2019 (COVID-19) infection or is at risk of 
COVID-19 infection as assessed by the investigator.

The subject has a history or presence of: 
–
3 or more incidences of syncope (eg, vasovagal) within the last 5 years prior to screening;
–
A family history of unexplained sudden death or channelopathy;
–
Brugada syndrome (ie, RBBB [right bundle branch block] pattern with ST-elevation in leads V1-V3);
–
CV or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, stroke, sick sinus 
syndrome, pulmonary congestion, symptomatic or significant cardiac arrhythmia, supraventricular or 
ventricular tachycardia, second-degree atrioventricular (AV) block type 2, third degree AV block, prolonged 
QT interval with Fridericia correction method (QTcF) interval, hypokalemia, hypomagnesemia, or 
conduction abnormalities;
–
Risk factors for Torsade de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT 
Syndrome);
–
Any clinically significant ECG findings or medical history including: long or short QTcF (over 450 msec or 
less than 360 msec), bifascicular block or QRS ≥120 msec or PR interval >200 msec at screening or Day 1 
pre-Hour 0;
–
The subject has a documented history of sinus bradycardia (<45 beats per minute [bpm]) based upon vital 
signs assessments, sinoatrial block as evidenced on ECG or sinus pause ≥3 seconds on ECG or predose 
telemetry.

The subject has an average semirecumbent blood pressure (BP) less than 90/60 mm Hg or greater than 140/90 mm 
Hg from screening to predose, inclusive. Any assessments on Day -1, where 2 consecutive timepoint values do 
not meet this criterion, must be discussed with the medical monitor for approval. 

From screening to Day -2, subjects with an average semirecumbent heart rate (HR) <55 or >100 bpm should be 
excluded. From Day -2 to predose, enrollment of subjects with an average HR <55 or >100 bpm will be left to the 
judgment of the investigator, unless HR is <50 bpm, which must be discussed with the medical monitor for 
approval. 

The subject has orthostatic hypotension defined as a decrease in systolic BP (SBP) ≥20 mm Hg or a decrease in 
diastolic BP (DPB) ≥10 mm Hg at approximately 2 minutes of standing when compared with BP from the 
semirecumbent position at screening to predose assessments, inclusive. In asymptomatic subjects, any 
assessments after screening which do not meet this criterion may be repeated after the subject has remained in the 
semirecumbent or supine position for 15 minutes. If the repeat assessment is exclusionary based on the above 
criterion, the subject will not be eligible. If the repeat assessment is not exclusionary, the subject will be eligible.

The subject has postural orthostatic tachycardia, defined as an increase of >30 bpm or HR >120 bpm at 
approximately 2 minutes of standing, at screening to predose assessments, inclusive. 
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Any assessments after screening which do not meet this criterion may be repeated with the subject remaining 
standing for up to a total of 5 minutes, provided that the subject remains asymptomatic. If the repeat assessment 
occurring within 5 minutes is exclusionary based on the above criterion, the subject will not be eligible. A 
confirmed orthostatic increase of >30 bpm, but <40 bpm, on 1 or more Day -1 assessments may not be considered 
exclusionary if not considered clinically significant by the investigator and the medical monitor. Such 
assessments must be discussed with the medical monitor prior to determination that the subject is eligible to 
proceed.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study is:

All parts of the study:
–
The primary endpoint of the study is safety and tolerability as assessed through vital signs, ECG, laboratory 
assessments, and AEs.
The secondary endpoints will be assessed through evaluation of the following parameters: 

Parts 1, 5a, and 6: plasma PK parameters for TAK-105
–
Maximum observed plasma concentration (Cmax).
–
Area under the concentration-time curve from time 0 to infinity (AUC∞).
–
Area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast).
–
Time of first occurrence of Cmax (tmax).
–
Terminal disposition phase half-life (t1/2z).
–
Apparent clearance after extravascular administration (CL/F).
–
Apparent volume of distribution during the terminal elimination phase after extravascular 
administration(Vz/F).

Parts 2 and 5b: plasma PK parameters for TAK-105 on Day 1 (the first dose):
–
Cmax, tmax, and area under the concentration-time curve during a dosing interval, where tau (τ) is the length of 
the dosing interval (AUCτ). 

Parts 2 and 5b: plasma PK parameters for TAK-105 on Day 22 (the fourth dose):
–
AUCτ, Cmax, tmax, t1/2z, CL/F, Vz/F, observed plasma concentration at the end of a dosing interval (Ctrough).

Parts 1, 2, and 5a/b include the following urine PK parameters:
–
Amount of drug excreted in urine from time 0 to time t (Aet). 
–
Amount of drug excreted in urine from time 1 to time 2 (Aet1-t2). 
–
Amount of drug excreted in urine during a dosing interval (τ) after fourth dose (Aeτ).
–
Fraction of administered dose of drug excreted from urine from time 0 to time t (fe,t). 
–
Renal clearance (CLR). 

All parts of the study:
–
Status of subject’s antidrug antibody (ADA) assessment (ie, ADA-negative or transiently and persistently 
ADA-positive, and low or high ADA titer).
Statistical Considerations: 
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This document will provide 
further details regarding the definition of analysis variables and analysis methodology to address all study objectives.
Safety Analysis:
The safety analysis set consists of all subjects who are randomized and receive at least 1 dose of study treatment. 
Subjects will be analyzed according to the study treatment actually received. No formal statistical tests or inference 
will be performed for safety analyses. All safety summary analyses will be performed by treatment arm (TAK-105 or 
placebo) within each part of the study separately. In particular, the safety summary for Parts 5a (SRD) and 5b (MRD) 
will be provided separately. The number and percentage of subjects with at least 1 postdose value meeting the 
sponsor’s markedly abnormal criteria for BP and HR will be provided. All data will be provided in by-subject listings.
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PK Analysis:
The PK analysis set consists of all subjects who receive at least 1 dose of TAK-105 and have at least 1 measurable 
postdose plasma or urine concentration for TAK-105. The plasma (all parts of the study) and urine (Parts 1, 2, and 5 
a/b only) concentrations of TAK-105 will be summarized by treatment arm at each scheduled sampling day/time 
within each part of the study separately, using descriptive statistics based on the PK analysis set. In particular, the 
summary of plasma concentration of TAK-105 for Parts 5a (SRD) and 5b (MRD) will be provided separately, as data 
allows. The plasma PK (all parts of the study) and urine PK (Parts 1, 2, and 5a/b only) parameters of TAK-105 
determined using a noncompartmental analysis approach will be summarized by treatment arm, at each scheduled day 
where appropriate, within each part of the study separately, using descriptive statistics based on the PK analysis set. In 
particular, the summary of PK parameters of TAK-105 for Parts 5a (SRD) and 5b (MRD) will be provided separately. 
Dose proportionality may be assessed graphically (logtransformed dose-normalized Cmax and area under the plasma 
concentration-time curve [AUC] versus dose) and by using a power model within each part of the study separately as 
data allow; no formal statistical comparisons will be conducted. All data will be provided in by-subject listings.
Immunogenicity Analysis:
The immunogenicity analysis set consists of all subjects who receive at least 1 dose of study treatment and have the 
baseline sample and at least 1 postbaseline sample ADA assessment. The number and percentage of subjects in each 
category of the immunogenicity status (ADA-negative or transiently and persistently ADA-positive, and low or high 
ADA titer) will be tabulated by treatment arm at scheduled time points within each part of the study separately. In 
particular, the summary of immunogenicity for Parts 5a (SRD) and 5b (MRD) will be provided separately. The 
relationship between immunogenicity status (ADA-negative or transiently and persistently ADA-positive, and low or 
high ADA titer) and plasma drug concentration and PK parameters, and safety will be explored. All data will be 
provided by-subject listings.
Biomarker Analysis:
Biomarker measurements will be summarized using the safety analysis set. The baseline concentrations of 
 will be summarized using descriptive statistics by 
treatment arm within each part of the study separately. In addition, the number and percentage of subjects within each 
of the 4 categories defined by quartile (ie, 0 to <Q1, Q1 to <median, median to <Q3, ≥Q3) of 
 
 will be presented for each time point by treatment arm within each part of the study separately. The 
change from baseline in the 
, will be summarized using descriptive statistics by 
treatment arm at scheduled time points within each part of the study separately. In particular, the summary of 
biomarker measurements for Parts 5a (SRD) and 5b (MRD) will be provided separately. All data will be provided in 
by-subject listings.
In case a data-dependent decision is needed to inform the subsequent development of TAK-105 prior to database lock 
an interim analysis may be deemed necessary. The details about situations when such a case occurs and associated 
interim analyses will be provided in the SAP. 
Sample Size Justification: 
The selected sample sizes in all parts of the study are considered sufficient for evaluation of safety and tolerability of 
TAK-105 in healthy subjects. No formal statistical hypothesis testing is planned; therefore, no formal power 
calculations were performed in the determination of the sample size for this study. 
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1.1
Protocol Amendment 4 Summary of Changes
Protocol Amendment 4 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 4. The 
primary reasons for this amendment are to: 
1. The protocol title was modified and language was added to modify the study to sponsor-open 
design.
2. Revise study design to add additional cohorts for Japanese subjects to support future studies in 
this population.
3. Revise study design to add additional cohorts for testing a new formulation of TAK-105, 
TAK-105-b, to support the use of this formulation in future studies. Unless specified 
“TAK-105” refers to the TAK-105-a formulation or entity.
4. Provision of an External Safety Adjudication Committee (ESAC) to monitor cardiovascular 
safety throughout the study.
5. Revision of the procedure for measuring orthostatic changes in heart rate (HR) and blood 
pressure (BP).
6. Reformat footnote styles in schedules of assessment tables and address inconsistencies in the 
schedule of study procedures.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
1.
Title Page
Added the sponsor name and address to 
the title page.
Updated for accuracy.
2.
Section 1.0 Study Summary
Updated number of sites.
Updated the number of sites 
to accommodate additional 
new parts added to the 
study.
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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
3.
Section 1.0 Study Summary
Section 2.0 STUDY 
SCHEMATIC
Section 3.7 Part 5 Japanese 
Subjects
Section 4.2 Rationale for the 
Proposed Study
Section 5.0 Trial Objectives 
And Endpoints
Section 6.1 Study Design
Section 6.1.6 Part 5a/b: SRD 
and MRD in Japanese Subjects 
Cohorts 28 to 32 (new section)
Section 6.1.8 Study Drug 
Administration
Section 6.4.2 Criteria for 
Premature Termination or
Suspension of the Study
Section 6.5.1 Rationale of 
Study Design
Section 7.1 Inclusion Criteria
Section 7.4.1 Diet and Fluid
Section 9.2.6.2 Telemetry
Section 9.3 Confinement
Modified Figures 2.a, 2.b (new), 2.c, 
2.d; and Table 6.a.
Updated study design, sample size and 
statistical analyses to include Part 5a/b, 
containing 5 additional cohorts. 
Added Section 3.7 for schedule of study 
procedure tables for Part 5 a/b.
Modified study rationale language to 
clarify inclusion of Japanese 
populations.
Updated objectives and endpoints to 
include Part 5 a/b.
Updated study design text to include 
Part 5a/b cohorts as needed.
Included new section 6.1.6 for new Part 
5 a/b study design.
Added inclusion criteria #9 for Japanese 
subjects.
To assess safety, 
tolerability, and 
pharmacokinetic (PK) in 
healthy Japanese subjects, 
for the determination of 
dose selection for future 
studies in this population.
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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
4.
Section 1.0 Study Summary
Section 2.0 STUDY 
SCHEMATIC
Section 3.0 Schedule of Study 
Procedures
Section 3.8 Part 6 TAK-105-b 
New Formulation of Drug 
Product
Section 4.2 Rationale for the 
Proposed Study
Section 5.0 Trial Objectives 
And Endpoints
Section 6.1 Study Design
Section 6.1.7 Part 6: 
TAK-105-b New Formulation
(new section)
Section 6.1.8 Study Drug 
Administration
Section 6.5.1 Rationale of 
Study Design
Section 7.4.1 Diet and Fluid
Section 8.1 Clinical Study
Drug
Section 9.2.6.2 Telemetry
Section 9.3 Confinement
Modified Figures 2.b and 2.c and Table 
6.a.
Updated study design, sample size, and 
statistical analyses to include additional 
cohorts for Part 6.
Added Section 3.8 for schedule of study 
procedure tables for Part 6.
Modified language to distinguish 
TAK-105-a and TAK-105-b 
formulations, specifically in Tables 3.a 
through 3.r, objectives/endpoints, and 
as needed.
Updated objectives and endpoints to 
include Part 6.
Added text to include Part 6 cohorts as 
needed.
Added TAK-105-b study drug and 
storage information.
Clarified in the footnotes for the 
Schedule of Study Procedure tables, that 
the study drug is either TAK-105-a or 
TAK-105-b, depending on the part of 
the study.
To evaluate the new Process 
B formulation of TAK-105 
(TAK- 105-b), including to 
assess safety and tolerability 
and to support the use of 
TAK-105-b in future 
studies. Included 
clarification of the different 
formulations and storage 
conditions.
5.
Section 3.0 Schedule of Study 
Procedures
Modified the language in footnote ‘r’ of 
Table 3.a and footnote ‘q’ Table 3.c to 
clarify when urine PK samples are 
collected.
Correction.
6.
Section 1.0 Study Summary
Section 5.2.1 Primary 
Endpoint
Removed the word “safety” from the 
primary endpoint bullet.
Correction.
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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
7.
Title page
Section 1.0 Study Summary
Section 6.1 Study Design
Section 6.2 Dose Escalation
Section 6.5.1 Rationale of 
Study Design
Section 6.5.2.6 Rationale for 
MRD Dose Selection
Section 8.1.3 Clinical Study
Drug Blinding
Section 11.2 Interim Analysis
Section 12.1 Study-Site 
Monitoring Visits
Added/modified language to modify the 
study to sponsor open.
The study design is 
modified to sponsor-open to
provide for oversight of the 
study for efficient 
evaluation of study data in 
an unblinded manner. The 
study remains blinded to 
investigators, study site 
staff, and subjects.
8.
Section 6.2 Dose Escalation
Added language that optional cohorts 
may not be enrolled as deemed 
appropriate by the investigator and the 
sponsor.
For clarification.
9.
Section 6.3 External Safety 
Adjudication Committee
Addition of an external safety 
adjudication committee who will 
perform a blinded review of ongoing 
cardiovascular adverse events 
throughout the course of the study.
To monitor cardiovascular 
safety throughout the study.
10.
Section 1.0 Study Summary
Section 7.1 Inclusion Criteria
Section 7.2 Exclusion Criteria
Added subheading for inclusion and 
exclusion criteria.
To clarify that existing 
inclusion and exclusion 
criteria apply to all cohorts. 
11.
Section 1.0 Study Summary
Section 7.2 Exclusion Criteria
Modified language in exclusion criteria 
#14 to “…syncope (eg, vasovagal)…”
Modified language to exclusion criteria 
#16 to include “semirecumbent”.
For clarification.
12.
Section 9.2 Clinical 
Procedures and Assessments
Added text detailing the time window 
for clinical procedures and assessments.
For clarification.
13.
Section 9.2.4 Vital Signs
Section 9.2.4.1 Orthostatic 
Measurements
Section 3.0 Schedule of Study 
Procedures
The modified orthostatic BP and HR 
measurement procedure with orthostatic 
maneuvers has been added.
To improve assessment of 
orthostatic changes and 
safety measures to reduce 
risk of falls and injuries.
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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
14.
Section 9.2.6.2 Telemetry
Real-time actively monitored telemetry 
may be limited to less than 12 leads (ie, 
2 leads for real time alerts).
This change is made to 
accommodate site telemetry
capabilities for Parts 2 to 6 
with additional 
investigational sites.
15.
Section 9.2.9.2 Chemistry
Added a footnote to chemistry 
evaluations table that samples for 
laboratory evaluations are collected at 
specified timepoints or as deemed 
necessary by site investigator.
For clarification for safety 
purposes.
16.
Section 9.2.10.1.1 Plasma for 
PK Measurements and MetID
Section 9.2.10.2 Urine for PK 
Measurements
Clarified language for validated assay.
For clarification.
17.
Section 10.2.8.3 Reporting 
SAEs
Changed “SAE form” to “SAE eCRF 
entry” and
“SAE form” to “SAE information”.
For correction.
18.
Section 1.0 Study Summary
Section 11.1 Statistical and 
Analytical Plans
Section 11.3 Determination of 
Sample Size
Modified analysis plans and sample size 
determination language to include Parts 
5a/b and 6 cohorts.
To modify analysis plans to 
include new cohorts in 
Parts 5a/b and 6.
19.
Section 7.2 Exclusion Criteria
Clarified that subjects with an average 
semirecumbent heart rate (HR) <55 
or >100 beats per minute from 
screening to Day -2, should be 
excluded. From Day -2 to predose, such 
subjects can be enrolled at discretion of 
investigator.
To reflect that the inclusion 
criteria are based on blood 
pressure and HR measured 
on Day -1 and Day -2
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2.0
STUDY SCHEMATICS
Figure 2.a
Study Schematic: Parts 1 to 4
MRD: multiple-rising dose; QW: once weekly.
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Figure 2.b
Study Schematic: Parts 5 and 6
JP: Japanese; MRD: multiple-rising dose; QW: once weekly; SRD: single-rising dose; TBD: to be determined. 
Part 5 will consist of subjects of Japanese origin (see Section 7.1 for details).
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Figure 2.c
Schematic of SRD Study Design: Part 1, Part 5a and Part 6
SRD study design applies to Part 1 cohorts, cohorts 28, 29, and 30 in Part 5a, and Part 6 cohorts.
PBO: placebo; SRD: single-rising dose.
a Subjects are dosed on Day 1 during the confinement period. 
b Subjects are discharged on Day 8. 
c During the follow-up period, subjects return to the clinic for assessments on specified days.
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Figure 2.d
Schematic of MRD Study Design: Part 2 and Part 5b
MRD study design applies to Part 2 cohorts and optional cohorts 31 and 32 in Part 5b.
MRD: multiple-rising dose; PBO: placebo.
a Subjects are dosed on Days 1, 8, 15, and 22 during the confined treatment period. Subjects will be discharged 48 h after the last dose.
b During the follow-up period, subjects return to the clinic for assessments on specified days.
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Figure 2.e
Schematic of Part 3 (Titration) Study Design
CV: cardiovascular; h: hours; PBO: placebo; PK: pharmacokinetic. 
Starting (S), titrated (T), and final (F) doses may vary between cohorts.
a Starting dose for Cohorts 18 and 19 will be the same. 
b Final (F) dose to be determined based on available safety, CV and PK data from Parts 1 and 2.
c Subjects will be confined from Day -1 through 48 hours post last dose (ie, until Day 10, 17, or 24 depending on the cohort assigned).
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Figure 2.f
Schematic of Part 4 (Redosing) Study Design
CV: cardiovascular; h: hours; PBO: placebo; PK: pharmacokinetic. 
a Study day for third dose is variable for Cohorts 25, 26, and 27 depending on CV effects observed in prior cohort. See Section 6.1.5.1 for potential CV effects 
criterion.
b Dose to be determined based on available safety, CV and PK data from Parts 1 and 2.
c Subjects will be confined from Day -1 through 48 hours post second dose, then return to the clinic the day prior to the third dose (redosing day will vary for each 
cohort). Assessments will be performed through 48 hours after the third dose.
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Table 3.b
Part 1 for SRD Cohorts 1 to 12: Follow-Up Through ET
Day 15 ±3 d
Day 29 ±3 d
Day 45 ±3 d
Day 60 ±3 d
ET
ECG: electrocardiogram; ET: early termination; FSH: follicle stimulating hormone; HBsAg: hepatitis B surface antigen; HR: heart rate; LFT: liver function test; 
PK: pharmacokinetic; SBP: systolic blood pressure; SRD: single-rising dose.
a All BP and HR assessments should be made in duplicate, with the subject semirecumbent, and the average of both assessments should be used to calculate the final result. The 
investigator can take a third measurement if there is inconsistency (ie, a difference >10 bpm in HR or a difference >10 mmHg in SBP or DBP) between assessments (see 
Section 9.2.4 for details). On Day 1, vital signs will be time-matched (±5 minutes) to the Day -1 clock time (ie, time-matched baseline). At predose, vital signs will be measured 
within approximately 1 hour before dosing.
b For standing BP and HR assessment, a BP and HR assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should perform the 
modified orthostatic maneuver with measurement of standing BP and HR as detailed in Section 9.2.4.1. Standing assessments must not be performed if semirecumbent SBP is 
<85 mm Hg or if the subject presents with signs or symptoms suggestive of postural hypotension after standing (eg, lightheadedness or dizziness, nausea, blurry vision).
c If CK is elevated in an individual subject after dosing, additional serum samples for CK may be collected at the investigator’s discretion. The medical monitor will be updated 
regularly on any findings of elevated CK and plans for continued monitoring.
d Serum pregnancy test for female subjects only.
e Immunogenicity serum samples for ADA testing will be taken at ET (if applicable), and at follow-up visits on Days 15, 29, 45, and 60. If ADAs are present, subjects may be asked 
to return for additional sample collection. The sampling time points will be same for all subjects dosed with either placebo or study drug.
f
If subjects have provided consent for the optional DNA collection, blood samples should be collected and can be collected at any time on the day of ET (if applicable).
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Table 3.t
Part 5 for Japanese SRD Cohorts 28 to 30: Follow-Up Through ET
Day 15 +3 d
Day 29 ±3 d
Day 45 ±3 d
Day 60 ±3 d
ET
ECG: electrocardiogram; ET: early termination; FSH: follicle stimulating hormone; HBsAg: hepatitis B surface antigen; HR: heart rate; LFT: liver function test; 
PK: pharmacokinetic; SBP: systolic blood pressure; SRD: single-rising dose.
a All BP and HR assessments should be made in duplicate, with the subject semirecumbent, and the average of both assessments should be used to calculate the final result. The 
investigator can take a third measurement if there is inconsistency (ie, a difference >10 bpm in HR or a difference >10 mmHg in SBP or DBP) between assessments (see 
Section 9.2.4 for details). On Day 1, vital signs will be time-matched (±5 minutes) to the Day -1 clock time (ie, time-matched baseline). At predose, vital signs will be measured 
within approximately 1 hour before dosing.
b For standing BP and HR assessment, a BP and HR assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should perform the 
modified orthostatic maneuver with measurement of standing BP and HR as detailed in Section 9.2.4.1. Standing assessments must not be performed if semirecumbent SBP is 
<85 mm Hg or if the subject presents with signs or symptoms suggestive of postural hypotension after standing (eg, lightheadedness or dizziness, nausea, blurry vision).
c If CK is elevated in an individual subject after dosing, additional serum samples for CK may be collected at the investigator’s discretion. The medical monitor will be updated 
regularly on any findings of elevated CK and plans for continued monitoring.
d Serum pregnancy test for female subjects only.
e Immunogenicity serum samples for ADA testing will be taken at ET (if applicable), and at follow-up visits on Days 15, 29, 45, and 60. If ADAs are present, subjects may be asked 
to return for additional sample collection. The sampling time points will be same for all subjects dosed with either placebo or study drug.
f
If subjects have provided consent for the optional DNA collection, blood samples should be collected and can be collected at any time on the day of ET (if applicable).
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Table 3.z
Part 6 for TAK-105-b SRD Cohorts 33 and 34: Follow-Up Through ET
Day 15 +3 d
Day 29 ±3 d
Day 45 ±3 d
Day 60 ±3 d
ET
a All BP and HR assessments should be made in duplicate, with the subject semirecumbent, and the average of both assessments should be used to calculate the final result. The 
investigator can take a third measurement if there is inconsistency (ie, a difference >10 bpm in HR or a difference >10 mmHg in SBP or DBP) between assessments (see 
Section 9.2.4 for details). On Day 1, vital signs will be time-matched (±5 minutes) to the Day -1 clock time (ie, time-matched baseline). At predose, vital signs will be measured 
within approximately 1 hour before dosing.
b For standing BP and HR assessment, a BP and HR assessment will be performed after the duplicate semirecumbent assessment has been completed. . The subject should perform 
the modified orthostatic maneuver with measurement of standing BP and HR as detailed in Section 9.2.4.1. Standing assessments must not be performed if semirecumbent SBP 
is <85 mm Hg or if the subject presents with signs or symptoms suggestive of postural hypotension after standing (eg, lightheadedness or dizziness, nausea, blurry vision).
c If CK is elevated in an individual subject after dosing, additional serum samples for CK may be collected at the investigator’s discretion. The medical monitor will be updated 
regularly on any findings of elevated CK and plans for continued monitoring.
d Serum pregnancy test for female subjects only.
e Immunogenicity serum samples for ADA testing will be taken at ET (if applicable), and at follow-up visits on Days 15, 29, 45, and 60. If ADAs are present, subjects may be asked 
to return for additional sample collection. The sampling time points will be same for all subjects dosed with either placebo or study drug.
f
If subjects have provided consent for the optional DNA collection, blood samples should be collected and can be collected at any time on the day of ET (if applicable).
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
Part 3:
–
Multiple SC dose regimens of TAK-105-a that include titration from lower doses in 
healthy subjects.

Part 4
Multiple SC dose regimens of TAK-105-a that include weekly dosing, withholding, then 
redosing in healthy subjects.

Part 5:
–
Single SC doses and multiple SC doses of TAK-105-a in healthy Japanese subjects.

Part 6: 
–
Single SC doses of new formulation TAK-105-b in healthy subjects.
5.1.2
Study Secondary Objective
The secondary objectives of the study are:

Part 1:
–
To characterize the plasma PK of TAK-105 following a single SC dose of TAK-105-a in 
healthy subjects.
–
To assess the immunogenicity of TAK-105 following single SC doses in healthy subjects.
–
To characterize the urinary PK of TAK-105 following a single SC dose of TAK-105-a in 
healthy subjects.

Part 2:
–
To characterize the plasma PK of TAK-105 following multiple SC doses of TAK-105-a in 
healthy subjects.
–
To assess the immunogenicity of TAK-105 following multiple SC doses in healthy 
subjects. 
–
To characterize the urinary PK of TAK-105 following multiple SC doses of TAK-105-a in 
healthy subjects.

Parts 3 and 4: To assess the immunogenicity of TAK-105 following multiple SC dose 
regimens that include titration from lower doses for Part 3 and weekly dosing, withholding, 
then redosing for Part 4 in healthy subjects. 

Part 5:
–
To characterize the plasma PK of TAK-105 following a single SC dose and multiple SC 
doses of TAK-105-a in healthy Japanese subjects.
–
To assess the immunogenicity of TAK-105 following single SC doses and multiple SC 
doses in healthy Japanese subjects.
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–
To characterize the urinary PK of TAK-105 following a single SC dose and multiple SC 
doses of TAK-105-a in healthy Japanese subjects.

Part 6: 
–
To characterize the plasma PK of TAK-105 following single SC doses of TAK-105-b in 
healthy subjects.
–
To assess the immunogenicity of TAK-105 following a single SC dose of TAK-105-b in 
healthy subjects.
5.1.3
Study Exploratory Objectives 

Parts 3 and 4:
–
To characterize the PK of TAK-105 in plasma following multiple SC dose regimens that 
include titration from lower doses for Part 3 and weekly dosing, withholding, then redosing 
for Part 4 in healthy subjects.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint of the study is:

All parts of the study:
–
The primary endpoint of the study is safety and tolerability as assessed through vital signs, 
ECG, laboratory assessments, and adverse events (AEs).
5.2.2
Secondary Endpoints 
Secondary endpoints include: 

Parts 1, 5a, and 6: plasma PK parameters for TAK-105
–
Maximum observed plasma concentration (Cmax).
–
Area under the concentration-time curve from time 0 to infinity (AUC∞).
–
Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast).
–
Time of first occurrence of Cmax (tmax).
–
Terminal disposition phase half-life (t1/2z).
–
Apparent clearance after extravascular administration (CL/F).
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–
Apparent volume of distribution during the terminal elimination phase after extravascular 
administration(Vz/F).

Parts 2 and 5b: plasma PK parameters for TAK-105 on Day 1 (the first dose):
–
Cmax, tmax, and area under the concentration-time curve during a dosing interval, where tau 
(τ) is the length of the dosing interval (AUCτ). 

Parts 2 and 5b: plasma PK parameters for TAK-105 on Day 22 (the fourth dose):
AUCτ, Cmax, tmax, t1/2z, CL/F, Vz/F, observed plasma concentration at the end of a dosing 
interval (Ctrough).

Parts 1, 2, and 5a/b include the following urine PK parameters:
–
Amount of drug excreted in urine from time 0 to time t (Aet). 
–
Amount of drug excreted in urine from time 1 to time 2 (Aet1-t2). 
–
Amount of drug excreted in urine during a dosing interval (τ) after last dose (Aeτ).
–
Fraction of administered dose of drug excreted from urine from time 0 to time t (fe,t). 
–
Renal clearance (CLR). 

All parts of the study:
–
Status of subject’s ADA assessment (ie, ADA-negative or transiently and persistently 
ADA-positive, and low or high ADA titer).
5.2.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters: 

Parts 3 and 4 include the following plasma PK parameters:
–
AUCτ. 
–
AUClast. 
–
Cmax. 
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
6.1.1
Overall Study Design
This is a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, 
immunogenicity, tolerability, and PK of TAK-105 in healthy subjects. 
The study will consist of 6 parts: 

Part 1 is a FIH, randomized, double-blind, sponsor-open, placebo-controlled SRD design to 
assess the safety, immunogenicity, tolerability, and PK of TAK-105-a in healthy subjects. Up 
to 12 cohorts may be enrolled. 

Part 2 is a randomized, double-blind, sponsor-open, placebo-controlled, MRD design to assess 
the safety, immunogenicity, tolerability, and PK of TAK-105-a in healthy subjects. Up to 
5 cohorts may be enrolled. 

Part 3 is a randomized, double-blind, sponsor-open, placebo-controlled, multiple-dose, dose 
titration design to assess the safety, immunogenicity, tolerability, and PK of TAK-105-a in 
healthy subjects. Up to 6 cohorts may be enrolled. 

Part 4 is a randomized, double-blind, sponsor-open, placebo-controlled, redosing after a period 
of withholding study drug design to assess the safety, immunogenicity, tolerability, and PK of 
TAK-105-a in healthy subjects. Up to 4 cohorts may be enrolled. 

Part 5 is a randomized, double-blind, sponsor-open, placebo-controlled SRD (Part 5a) and 
MRD (Part 5b) design to assess the safety, immunogenicity, tolerability, and PK of 
TAK-105-a in healthy Japanese subjects. Up to 5 cohorts may be enrolled. 

Part 6 randomized, double-blind, sponsor-open, placebo-controlled SRD design to assess the 
safety, immunogenicity, tolerability, and PK of a new formulation of TAK-105-b in healthy 
subjects. Up to 2 cohorts may be enrolled. 
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. The 
study will be conducted sponsor-open. Sponsor discussions with investigators and within the study 
team will be conducted in a blinded manner (ie, no unblinded information will be communicated to 
blinded investigators, site staff or blinded study monitoring personnel).
Study drug in Parts 1 to 5 is TAK-105-a (Process A formulation) or matching placebo and in Part 6 
is TAK-105-b (Process B formulation) or matching placebo, which will be administered SC. 
While Parts 1 (SRD) and 2 (MRD) of TAK-105-1001 are intended to be completed as planned, 
subsequent parts of the study (ie, Parts 3 or 4) may not be conducted at the discretion of the 
sponsor. Parts 1 and 2 will be initiated in advance of Parts 3 and 4. Parts 3 and 4 will be conducted 
at the discretion of the sponsor based on a review of the available safety and PK data from Parts 1 
and 2. At the discretion of the sponsor, Parts 3 and 4 may be initiated before completion of all 
cohorts in Parts 1 and 2 as otherwise permissible in the protocol. Part 5 may be performed in 
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parallel with Parts 1 and 2 based on the review of safety and PK data at least at the matching dose
from the previous parts. Part 6 with the new drug formulation of TAK-105 (TAK-105-b) may be 
performed in parallel with Part 1 provided that the new formulation is available and after Part 1 
SRD data are available. 
Safety will be assessed by monitoring for AEs, vital signs including orthostatic assessments, 
ECGs, telemetry, safety laboratory assessments after each dose, and immunogenicity. PK 
sampling times may vary based on emerging safety, tolerability and PK data, but the maximal 
number of samples will not change. Subjects may not participate in more than 1 part or more than 
1 dosing cohort of the study. 
A schematic of the overall study design is presented in Figure 2.a (Parts 1 to 4) and Figure 2.b
(Parts 5a/b and 6). A schematic of the SRD study design (Parts 1, 5a, and 6), the MRD study design 
(Parts 2 and 5b), Part 3 (titration), and Part 4 (redosing) study designs are presented in Figure 2.c, 
Figure 2.d, Figure 2.e, and Figure 2.f, respectively. 
An overview of treatment cohorts is presented in Table 6.a. Healthy subjects will be enrolled in 
Cohorts 1 to 12 (Part 1), 13 to 17 (Part 2), 18 to 23 (Part 3), 24 to 27 (Part 4), and 33 to 34 (Part 6). 
Healthy Japanese subjects will be enrolled in Cohorts 28 to 30 (Part 5a – SRD), and 31 and 32 
(Part 5b – MRD [optional]). The schedules of study procedures are presented in Section 3.0.
The study may be conducted at 3 phase 1 units to support recruitment of all cohorts.
Table 6.a
Overview of Treatment Cohorts
Cohort
Regimen
TAK-105 formulation
Treatment
TAK-105
Placebo
Part 1
1
SRD
TAK-105-a
6
2
2
6
2
3
6
2
4
6
2
5
6
2
6
6
2
7
6
2
8
6
2
9
6
2
10 
6
2
11
6
2
12
6
2
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Table 6.a
Overview of Treatment Cohorts
Cohort
Regimen
TAK-105 formulation
Treatment
TAK-105
Placebo
Part 2 
13
MRD
TAK-105-a
6
2
14
6
2
15
6
2
16
6
2
17
6
2
Part 3 
18
Dose Titration
TAK-105-a
6
2
19
6
2
20 (optional)
6
2
21 (optional)
6
2
22 (optional)
6
2
23 (optional)
6
2
Part 4
24
Redosing
TAK-105-a
6
2
25
6
2
26 (optional)
6
2
27 (optional)
6
2
Part 5a (Japanese subjects)
28
SRD
TAK-105-a
6
2
29
6
2
30
6
2
Part 5b (Japanese subjects) a
31 (optional)
MRD
TAK-105-a
6
2
32 (optional)
6
2
Part 6
33
SRD
TAK-105-b
6
2
34 (optional)
6
2
MRD: multiple-rising dose; PK: pharmacokinetic; SRD: single-rising dose.
The starting dose in Part 1 (SRD) will be 
. The starting doses of subsequent cohorts in Parts 1, 2, 3, and 4, will be 
determined at the dose escalation meeting based on emerging safety, tolerability, and available PK data. Additional 
cohorts may be included in any part of the study, as determined at the dose escalation meeting based on emerging 
safety, tolerability, and available PK data during the study.
a The MRD cohorts in Part 5b will be optional, depending on the PK/safety data observed in Part 2 MRD.
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The weekly maximum exposure will not exceed an exposure established as tolerated in Part 1. 
Similar to Part 1, a staggered dosing approach may be used for cohorts in Part 2. Part 2 consists of 
sequential dosing in up to 5 ascending cohorts of healthy subjects. In each cohort, 8 healthy 
subjects will be randomly assigned to receive TAK-105-a or matching placebo in a 3:1 ratio in a 
double-blind, sponsor-open manner. Up to approximately 40 healthy subjects may be randomized 
in Part 2 (the number of subjects is approximate and does not account for potential replacement of 
subjects who withdraw for nonsafety reasons). 
The schedule of study assessments for Part 2 (MRD) are presented in Table 3.c (screening through 
Day 7; Week 1), Table 3.d (Days 8 through 14; Week 2), Table 3.e (Days 15 through 21; Week 3), 
and Table 3.f (Days 22 to 82; Week 4, follow-up and ET).
Subjects will be admitted to the study unit on Day -2. Baseline HR and BP assessments will be 
taken on Day -1, and will be time-matched to the Day 1 assessments. Subjects will be dosed on 
Days 1, 8, 15, and 22 in each cohort after a minimum of 8 hours of fasting. Subjects will be 
confined until Day 24, 48 hours after the fourth dose, to assess safety, tolerability, 
immunogenicity, and PK. Assessments of postural hypotension will be measured on Day 1 
predose, and at the time points specified postdose, including at the time-matched time points on 
Day -1. Blood and urine samples for assessment of TAK-105 concentrations and PK will be 
collected predose and at the specified time points postdose as described in schedule of events. 
 
Optional DNA samples will also be collected from subjects that provide consent for collection 
through a separate procedure. Immunogenicity assessments will be assessed predose and prior to 
discharge, and during the specified follow-up visits.
In Part 2, up to 5 tolerated doses 
 
 will be studied in an ascending manner. The weekly maximum exposure in 
Part 2 will not exceed exposures determined to be tolerated in Part 1. Doses in Part 2 are planned 
to be administered SC QW for 4 weeks. Doses will be determined in the dose escalation meeting 
based on emerging safety, tolerability, and available PK data. The sponsor may decide to 
administer lower doses, repeat doses, and cancel cohort(s) if deemed appropriate. 
6.1.4
Part 3: Dose Titration Cohorts 18 to 23
The intent of the design of Part 3 is to enable a descriptive comparison (ie, without hypothesis 
testing) of cardiovascular (CV) tolerability profile findings between Part 3 cohorts and cohorts in 
Parts 1 and 2 with comparable exposures, to determine whether dose titration results in different 
tolerability in relation to CV observations. 
Part 3 may start before the completion of Parts 1 and 2. If Part 3 is started before the completion of 
Part 2, the starting dose will be decided in the dose escalation meeting (see Section 6.2). The 
maximum weekly exposure in Part 3 will be at a total weekly exposure level below or at the 
highest completed cohorts in Parts 1 and 2. The weekly maximum exposure will not exceed an 
exposure established as tolerated in Parts 1 and 2.
Part 3 will consist of up to 6 cohorts with 8 healthy subjects per cohort. Subjects will be assigned to 
receive TAK-105-a or matching placebo in a 3:1 ratio in a double-blind, sponsor-open manner. Up 
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to approximately 48 healthy subjects will be randomized in Part 3 (the number of subjects is 
approximate and does not account for potential replacement of subjects who withdraw for 
nonsafety reasons).
The TAK-105-a doses for Part 3 will consist of a starting low dose (for Cohorts 18 and 19) that will 
be either held constant or titrated for 2 additional doses, followed by a final (fourth) dose, which 
will be determined by the available safety, CV, and PK data from Parts 1 and 2. The starting doses 
will be chosen with the objective of minimizing CV effects and allow for attenuation of CV effects 
following the next titrated dose. The goal is to achieve attenuation of CV effects with the fewest 
doses. Review of the data from Cohorts 18 and 19 will determine which if any of the additional 
optional cohorts with fewer weeks of treatment (ie, 3 weeks for Cohorts 20 and 21 and 2 weeks for 
Cohorts 22 and 23) will be enrolled. As applicable, the CV and available PK data from Cohorts 18 
and 19 will be used to determine starting dose and titrated doses for Cohorts 20 to 23. The starting, 
titrated, and final doses chosen between cohorts may vary based on emerging available PK and CV 
data. 
For cohorts in Part 3, doses will be determined in the dose escalation meeting based on emerging 
safety, tolerability, and available PK data. The sponsor may decide to administer lower doses, 
repeat doses, and cancel cohort(s) if deemed appropriate.
Subjects from each cohort will be admitted into the study unit on Day -2. On Day 1, after 
randomization and all predose procedures have been performed, subjects will be dosed according 
to the cohort, titration schema, and randomized treatment assignment after a minimum of 8 hours 
fasting. Subjects will be confined for the duration of dosing and discharged 48 hours post last dose, 
on Day 10, 17, or 24, depending on the cohort assigned. 
The proposed dose titration design for the 6 cohorts are presented in Figure 2.e and are described 
in the following Sections 6.1.4.1, 6.1.4.2, and 6.1.4.3.
6.1.4.1
Cohorts 18 and 19
After randomization and Day -1 assessments have been performed, Cohorts 18 and 19 will start 
with a low TAK-105 dose on Day 1. Doses for Cohorts 18 and 19 will be based on emerging 
safety, tolerability, and available PK and CV data, but will have a corresponding dose that does not 
exceed the weekly maximum exposure established as tolerated in Parts 1 and 2. The second dose 
on Day 8 will be either the same starting dose (Cohort 18) or a titrated dose (Cohort 19). The 
subjects will receive a third dose on Day 15, which may either be the same starting dose 
(Cohort 18) or a titrated doses (Cohort 19). Subjects will receive a fourth dose (final dose) on Day 
22, which will not exceed the weekly maximum exposure established as tolerated in Parts 1 and 2. 
Subjects will be discharged after 48 hours assessments are taken after the last dose. A follow-up 
visit will occur 28 days after the last dose.
The assessments for Cohorts 18 and 19 will follow the schedule of assessments in Table 3.g
(Week 1), Table 3.h (Week 2), Table 3.i (Week 3), and Table 3.j (Week 4, follow-up, ET). 
The sponsor has the option to add additional cohorts following the same dosing schedule as 
Cohorts 18 and 19, but with modified doses.
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6.1.4.2
Cohorts 20 and 21 (optional)
Cohorts 20 and 21 are optional. After randomization and Day -1 assessments have been 
performed, Cohorts 20 and 21 will begin with a starting dose on Day 1. Doses for these cohorts 
will be determined in the dose escalation meeting before dosing begins and will be based on 
emerging safety, tolerability, and available PK and CV data during the study, but will have a 
corresponding weekly dose that does not exceed the weekly maximum exposure established as 
tolerated in Parts 1 and 2.
The second dose on Day 8 will be a titrated dose. Subjects will receive a third and final dose on 
Day 15, which will not exceed the weekly maximum exposure established as tolerated in 
Parts 1 and 2. Subjects will be discharged after 48 hours assessments are taken after the last dose. 
A follow-up visit will occur 28 days after the last dose for both cohorts.
The assessments for Cohorts 20 and 21 will follow the schedule of assessments in Table 3.k (Week 
1), Table 3.l (Week 2), and Table 3.m (Week 3).
6.1.4.3
Cohort 22 and 23 (optional)
Cohorts 22 and 23 are optional. After randomization and Day -1 assessments have been 
performed, Cohorts 22 and 23 will begin with a starting dose on Day 1. Doses for these cohorts 
will be determined in the dose escalation meeting before dosing begins and will be based on 
emerging safety, tolerability, and available PK and CV data during the study, but will have a 
corresponding dose that does not exceed the weekly maximum exposure established as tolerated in 
Parts 1 and 2.
Subjects will receive a second and final dose on Day 8, which will not exceed the weekly 
maximum exposure established as tolerated in Parts 1 and 2. Subjects will be discharged after 
48 hour assessments are taken. A follow-up visit will occur 28 days after the last dose for both 
cohorts.
The assessments for Cohorts 22 and 23 will follow the schedule of assessments in Table 3.n
(Week 1) and Table 3.o (Week 2, follow-up, and ET). 
6.1.5
Part 4: Redosing Study Cohorts 24, 25, 26, and 27 
The intention of the design of Part 4 is to provide an exploratory evaluation to assess the safety and 
CV tolerability profile of redosing with TAK-105-a after a period of withholding study drug. A 
schematic of the Part 4 study design is presented in Figure 2.f.
Part 4 may start before the completion of Parts 1 and 2, and may start before Part 3 is initiated. If 
Part 4 is started before the completion of Part 2, the starting dose will be decided in the dose 
escalation meeting (see Section 6.2). The maximum weekly exposure in Part 4 will be at a total 
weekly exposure level below or at the highest completed cohort in Parts 1 and 2. The weekly 
maximum exposure will not exceed an exposure established as tolerated in Parts 1 and 2.
Part 4 will consist of up to 4 cohorts with 8 healthy subjects per cohort. Subjects will be assigned to 
receive TAK-105-a or matching placebo in a 3:1 ratio in a double-blind, sponsor-open manner. Up 
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to approximately 32 healthy subjects will be randomized in Part 4 (the number of subjects is 
approximate and does not account for potential replacement of subjects who withdraw for 
nonsafety reasons).
Subjects from each cohort will be admitted into the study unit on Day -2. On Day 1, after 
randomization and all predose procedures have been performed, subjects will be dosed according 
to the cohort and redosing schema they have been randomized to after a minimum of 8 hours 
fasting. Subjects will be confined until Day 10. Subjects will return to the clinic the day prior to the 
third dose and will be confined until 48 hours post third dose. The total duration of confinement is 
14 days.
The proposed redosing study design for the 4 cohorts are presented in Figure 2.f and are as 
described in the following Sections 6.1.5.1 and 6.1.5.2. 
Doses will be determined in the dose escalation meeting based on emerging safety, tolerability, 
and available PK data. The sponsor may decide to administer lower doses, repeat doses, and cancel 
cohort(s) if deemed appropriate.
6.1.5.1
Cohort 24
Cohort 24 will receive a dose of TAK-105-a or matching placebo on Day 1 and 8, which will be 
determined by the available safety, tolerability, CV, and PK data from Parts 1 and 2. Subjects will 
be discharged 48 hours after Day 8 dose. Subjects will not be treated on Day 15, as the third dose 
will be withheld until Day 22. Subjects will return to the clinic on Day 21 for fasting and 
confinement before Day 22 dosing and assessments. Subjects will be monitored for 48 hours post 
third dose for CV effects and safety, tolerability, and PK. If CV effects are found, the redosing 
interval may be shortened for the subsequent cohorts (ie, days between second and third dose will 
be less days). If no CV effects are found, the redosing interval may be lengthened for the 
subsequent cohorts (ie, days between second and third dose will be more days). The modified 
redosing interval will be changed based on emerging PK and CV data.
A potential CV effect will be monitored using the following criteria based on cohort level data: 
–
Maximal increase in mean change from baseline HR ≥10 bpm when compared to baseline 
predosing value on same day of dosing in semirecumbent vital signs, or 
–
Maximal decrease in mean change from baseline SPB or DBP ≥5 mmHg when compared 
to baseline predosing value in semirecumbent vital signs.
These monitoring criteria are empirically derived from 
 human data 
 
. Nonclinical data in dogs demonstrates that molecules within this class 
impart a similar magnitude of maximal HR and BP effects. These monitoring criteria may be 
modified based on evolving hemodynamic data from this study. Orthostatic data will also be 
reviewed by cohort to determine the maximal change from baseline in orthostatic vital sign 
measurements upon redosing. 
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6.1.5.2
Cohorts 25, 26, and 27
The dosing scheme for subsequent optional cohorts will follow that of Cohort 24. However, the 
redosing interval (ie, third dose) for Cohorts 25, 26 (optional), and 27 (optional) may be shortened 
to Day 16 to 21 or lengthened up to Day 29 based on the available PK and CV data.
The schedule of study procedures for Part 4 are presented in Table 3.p (Week 1), Table 3.q
(Week 2), and Table 3.r (variable third dose week, follow-up, and ET).
6.1.6
Part 5a/b: SRD and MRD in Japanese Subjects Cohorts 28 to 32
Parts 5a (SRD) and 5b (MRD) may be performed in parallel with Parts 1 and 2 based on the review 
of safety and PK data at least at the matching dose from the previous parts. Part 5a/b will consist of 
up to 5 cohorts (up to 3 cohorts in SRD and 2 cohort in MRD [optional]) with 8 healthy subjects of 
Japanese descent per cohort. Subjects in each cohort will be randomly assigned to receive a single 
dose of TAK-105-a or matching placebo via SC administration in a 3:1 ratio in a double-blind, 
sponsor-open manner. Up to approximately 40 healthy Japanese subjects will be randomized in 
Part 5 (the number of subjects is approximate and does not account for potential replacement of 
subjects who withdraw for nonsafety reasons). The MRD cohorts in Part 5b will be optional, 
depending on the PK/safety data observed in Part 2 MRD.
The schedule of study assessments for Part 5a SRD cohorts (Cohorts 28 to 30) are presented in 
Table 3.s (Days 1 through 8) and Table 3.t (follow-up or early termination [ET]) and Part 5b MRD 
cohorts (Cohorts 31 and 32; [optional]) are presented in Table 3.u (Screening through Day 7; 
Week 1), Table 3.v (Days 8 through 14; Week 2), Table 3.w (Days 15 through 21; Week 3), and 
Table 3.x (Days 22 to 82; Week 4, follow-up and ET).
The overall study designs will follow that of Part 1 for SRD (see Section 6.1.2 ) and Part 2 for 
MRD (see Section 6.1.3).
The cohorts in Part 5 will be dosed with doses of TAK-105-a that are determined during the dose 
escalation meeting and based on emerging safety, tolerability, and available PK data during the 
study, but will have a corresponding top dose that does not exceed the maximal defined exposure 
based on nonclinical safety studies. The dose planned for the optional Japanese MRD cohorts will 
be based on emerging PK, tolerability, and safety data. 
6.1.7
Part 6: TAK-105-b New Formulation
A new formulation of TAK-105 (Process B), called TAK-105-b, was generated for improved 
stability of TAK-105 and will be evaluated in Part 6. This part will consist of up to 2 cohorts with 
8 healthy subjects per cohort. Subjects in each cohort will be randomly assigned to receive a single 
dose of new formulation TAK-105-b or matching placebo via SC administration in a 3:1 ratio in a 
double-blind, sponsor-open manner. Up to approximately 16 healthy subjects will be randomized 
in Part 6 (the number of subjects is approximate and does not account for potential replacement of 
subjects who withdraw for nonsafety reasons). 
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The cohorts in Part 6 (Cohorts 33 and 34 [optional]) will follow the SRD study design (Figure 2.c) 
and schedule of assessments presented in Table 3.y (Days 1 through 8) and Table 3.z, and 
Table 3.b (follow-up or early termination [ET]).
If formulation differences between TAK-105-a and TAK-105-b are observed in Part 5, additional 
Japanese cohort(s) may be added to assess PK and safety of the new formulation in Japanese 
subjects. 
6.1.8
Study Drug Administration
The study drug used in Parts 1 to 5 is TAK-105-a (Process A formulation) or matching placebo and 
in Part 6 is TAK-105-b (Process B formulation) or matching placebo.
In Parts 1, 5a, and 6, the single SC dose of study drug (TAK-105-a/b or matching placebo) should 
be administered in the abdomen at least 2 cm away from the umbilicus. In all cases, care should be 
taken to avoid areas of scars, moles, tattoos, or other irritated skin (eg, vitiligo, eczema, etc). Study 
drug must not be administered into an area where the skin appears to be tender to touch, signs of 
bruising/bleeding are noted, or the area seems indurated or erythematous. When locating injection 
sites on the abdomen, avoid giving the injection in the umbilicus, ribs, or hip bone. Subjects will be 
semirecumbent during dosing until requested to stand for orthostatic BP and HR measurements.
In Parts 2, 3, 4, and 5b when administering study drug, injection sites must be rotated. The first 
dose of study drug should be administered in the abdomen first (at least 2 cm away from the 
umbilicus), followed by upper arms, then thigh as alternative sites, avoiding areas of scars, moles, 
tattoos, or other irritated skin (eg, vitiligo, eczema, etc). If repeat injections of study drug are given 
in the same spot, this may cause scarring and hardening of fatty tissue, which may interfere with 
the absorption of the drug, and therefore injections should not be given at the same location 
repeatedly. Each study drug injection must be administered approximately 2 inches 
(5 centimeters) apart and must not be administered into an area where the skin appears to be tender 
to touch, signs of bruising/bleeding are noted, or the area seems indurated or erythematous. If 
locating injection sites on the abdomen, avoid giving the injection in the umbilicus, ribs, or hip 
bone. If injecting in the thighs, use the outer areas, below the groin and above the knee. Subjects 
will be semirecumbent during dosing until requested to stand for orthostatic BP and HR
measurements.
In Part 6, the new formulation of TAK-105 (Process B), TAK-105-b, will be administered the 
same as the single SC dose of TAK-105-a, using the same administration instructions above (see 
Parts 1, 5a, and 6). 
For additional information on study drug administration, please refer to the study pharmacy 
manual.
6.2
Dose Escalation
A dose escalation meeting will occur with representatives from the sponsor, including Clinical 
Sciences, Clinical Pharmacologist, Global Patient Safety Evaluation, the investigator, and possibly 
other members of the site study team. The representatives will review the safety, tolerability, and 
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laboratory data of at least 7 days after the last dose, and available PK data will be evaluated to 
decide on the dose and regimen to be administered in the subsequent cohorts. Available PK data 
will also be assessed to ensure no dose exceeds the maximal defined exposure.
As outlined in the operational plan for blinding, the sponsor will be open and the investigator and 
site study team will remain blinded. Discussions within the dose escalation meeting will be 
conducted in a blinded manner (ie, no unblinded information will be communicated at the dose 
escalation meeting). 
Additional cohorts may be enrolled if it is deemed appropriate by the investigator and the sponsor. 
Dose levels may also be repeated or lowered based on emerging data. Optional cohorts may not be 
enrolled as deemed appropriate by the investigator and the sponsor.
All decisions will be documented in the study file.
6.3
External Safety Adjudication Committee
An external safety adjudication committee (ESAC) will perform a blinded review of ongoing 
cardiovascular AEs of interest throughout the conduct of the study. Details will be provided in the 
adjudication committee charter.
6.4
Stopping Rules 
6.4.1
Stopping Criteria for Individual Subjects
Subjects will permanently discontinue study drug for any study drug-related AEs that are rated 
Grade ≥3 in severity on the Common Terminology Criteria for Adverse Events (CTCAE) scale.
6.4.2
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 premature termination of the study (across all parts):

Any subject experiences a Hy’s Law reaction (defined as ALT or AST >3 × the upper limit of 
normal [ULN] in conjunction with elevated total bilirubin >2 × ULN without findings of 
cholestasis or other alternate etiology).

New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk profile for TAK-105, such that the risk is no longer 
acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises subject safety or 
compromises the ability to achieve the primary study objectives.
The sponsor may elect to terminate or suspend the study for administrative reasons including plans 
to modify, suspend, or discontinue development of the study drug. 
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In addition, dosing in the study (across all parts) will be paused to review safety data if any one of 
the stopping criteria is met within an individual dose cohort: 

Two or more subjects experience a sinus tachycardia with HR >120 bpm at rest while 
semirecumbent with symptoms of palpitation or lightheadedness requiring medical 
intervention and considered related to TAK-105/placebo, or

Two or more subjects experience a CTCAE v5.0 Grade ≥3 hypotension (ie, requiring medical 
intervention) and considered related to TAK-105/placebo, or

One subject experiences a CTCAE v5.0 Grade ≥3 syncope (fainting or orthostatic collapse) 
and considered related to TAK-105/placebo, or

Two or more subjects experience a CTCAE v5.0 Grade 3 event considered related to TAK-105 
administration, or 

One subject experience a CTCAE Grade 4 event considered related to TAK-105 
administration, or

One subject with ALT or AST >5 × ULN after TAK-105 administration, or

One subject with ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%), or

One subject with a serious adverse event (SAE) considered related to TAK-105 administration, 
or

Two or more subjects experience a CTCAE v5.0 Grade ≥2 injection site reaction (defined as 
pain combined with lipodystrophy and/or edema).
The totality of the safety data from the study will be reviewed by the sponsor once the dosing is 
paused. If a safety concern is identified after review of the data, the investigator and/or the sponsor 
may consider potential changes in the next planned dose level. Possible changes in dose 
administration include, but are not limited to:

Administration of an intermediate dose between the current and next planned dose.

Repeated administration of the current dose.

Administration of a lower dose than the existing dose levels.

Study termination. 
Study drug dosing may resume if no safety concern is identified by the investigator and sponsor.
During Study Drug Dosing in MRD
If the criteria for pausing occurs in SRD Part 1 at a higher level than is being dosed in MRD Part 2, 
dosing in Part 2 or Part 5b may continue provided it is at a lower weekly dose than in Part 1 at 
which the event was observed, and the sponsor and investigator agree after careful review of the 
totality of the available data.
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Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
6.6
Procedure Modifications Permitted Within Protocol Parameters
This is a phase 1 study of TAK-105 in humans, and the PK and safety profiles of the compound are 
still being elucidated. This protocol is written to accommodate the dependence on evolving data 
and the inherent dynamic nature of phase 1 clinical studies. Minor changes in procedures, eg, 
changes to the specific dose regimen in any cohort or the specific timing of assessments, will be 
documented and may not require a protocol amendment or ICF update if the changes do not impact 
the burden of subjects or safety monitoring.
6.7
Study Beginning and End/Completion
6.7.1
Definition of Beginning of the Study
The overall study begins when the first subject signs the study informed consent form.
6.7.2
Definition of End of the Study
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from the 
study, is lost to follow-up (ie, the investigator is unable to contact the subject), or the sponsor ends 
the study, whichever occurs first.
6.7.3
Definition of Study Discontinuation
Study discontinuation because of safety reasons: 

Early study termination because of concerns of safety to the study subjects arising from 
clinical or nonclinical studies with the study treatment(s), comparator(s), drug(s) of the same 
class, or methodology(ies) used in this study.
Study discontinuation because of nonsafety reasons, such as the following: 

A finding (eg, PK, efficacy) from another nonclinical or clinical study using the study 
treatment results in the study being stopped for a nonsafety-related reason. 

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this study 
become available and results in the study being stopped for a nonsafety-related reason. 

The study is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
6.7.4
Criteria for Premature Termination or Suspension of the Study
6.7.4.1
Criteria for Premature Termination or Suspension of Study 
See Section 6.4 for study-specific stopping rules and additional criteria for premature termination 
or suspension of the study.
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6.7.4.2
Procedures for Premature Termination or Suspension of the Study
In the event that the sponsor, an Institutional Review Board (IRB) and/or Independent Ethics 
Committee (IEC), or regulatory authority elects to terminate or suspend the study or the 
participation of an investigational site, a study-specific procedure for ET or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.
6.7.5
Criteria for Premature Termination or Suspension of a Site
6.7.5.1
Criteria for Premature Termination or Suspension of a Site 
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.7.5.2
Procedures for Premature Termination or Suspension of a Site
In the event that the sponsor, an IRB and/or IEC, or regulatory authority elects to terminate or 
suspend the study or the participation of an investigational site, a study-specific procedure for ET 
or suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or study suspension.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
To be eligible for participation in this study, the subject must:
For All Cohorts
1. Understand the study procedures and agree to participate by providing written informed 
consent.
2. Be willing and able to comply with all study procedures and restrictions.
3. Be a healthy male or WONCBP (woman of nonchildbearing potential) female subject aged 18 
to 55 years, inclusive, at the screening visit.
4. Continuous nonsmoker who has not used nicotine- and tobacco-containing products for at least 
3 months prior to screening and through discharge.
5. Subject has not had frequent or heavy use (ie, near-daily) of medical or recreational cannabis 
for at least 3 months prior to screening and through discharge.
6. Have a body mass index (BMI) ≥18 and ≤30.0 (kg/m2) at the screening visit.
7. Be judged to be in good health (eg, no evidence of psychiatric, hepatic, renal, pulmonary, or 
CV disease) by the investigator, based on clinical evaluations including laboratory safety tests, 
medical history, physical examination, ECG, and vital sign measurements performed at the 
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screening visit and before administration of the initial dose of study drug or invasive 
procedure.
8. Meet the following birth control requirements (see Appendix D):
–
Is a male subject who is sterile or agrees to use an appropriate method of contraception, 
including a condom with spermicidal cream or jelly, from the first dose of study drug until 
5 half-lives (approximately 46 days for TAK-105) after the last dose of study drug. No 
restrictions are required for a vasectomized male subject provided the subject is at least 1 
year after bilateral vasectomy procedure before the first dose of study drug. A male subject 
whose vasectomy procedure was performed less than 1 year before the first dose of study 
drug must follow the same restrictions as a nonvasectomized man. Appropriate 
documentation of surgical procedure should be provided. Male subjects should agree to use 
condom with spermicide from screening time point if they cannot bring documentation for 
bilateral vasectomy.
–
Is a male subject who agrees not to donate sperm from the first dose of study drug until 
5 half-lives after the last dose of study drug.
–
Is a female subject of nonchildbearing potential, defined by at least 1 of the following 
criteria:
a) Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged 
>45 years or 6 months of spontaneous amenorrhea in females aged >45 years with 
serum follicle-stimulating hormone (FSH) levels >40 mIU/mL). Appropriate 
documentation of FSH levels is required.
b) Surgically sterile by hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy with appropriate documentation of surgical procedure.
c) Had a bilateral tubal ligation with appropriate documentation of surgical procedure.
d) Has a congenital condition resulting in no uterus.
Additional inclusion criteria for Japanese subjects in Part 5 (Cohorts 28 to 32 only):
9. The subject has 2 Japanese parents and 4 Japanese grandparents, as confirmed by interview.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
For All Cohorts
1. The subject has participated in another investigational study within 4 weeks (or based on local 
regulations) or within 5 half-lives of the investigational product before the screening visit. The 
4-week or 5 half-lives window will be derived from the date of the last dose and/or AE related 
to the study procedure in the previous study to the screening visit of the current study.
2. The subject is an employee of the sponsor or study site or immediate family member 
(eg, spouse, parent, child, sibling) of the sponsor or study site.
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3. The subject has a history of significant multiple and/or severe allergies (eg, food, drug, latex 
allergy) or has had an anaphylactic reaction or significant intolerance to prescription or 
nonprescription drugs or food.
4. The subject has a known hypersensitivity or contraindication to any component of TAK-105.
5. The subject has a positive pregnancy test or is lactating or breastfeeding.
6. The subject has a known or suspected current coronavirus disease 2019 (COVID-19) infection 
or is at risk of COVID-19 infection as assessed by the investigator.
7. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, 
or human immunodeficiency antibody/antigen, at the screening visit. 
8. The subject had major surgery or donated or lost 1 unit of blood (approximately 500 mL) 
within 4 weeks before the screening visit.
9. The subject is unable to refrain from or anticipates using all medications including herbal 
medicines beginning approximately 7 days before administration of the first dose of study 
drug, throughout the study until the last follow-up visit. 
10. The subject has a history or presence of alcoholism or drug abuse within the past 2 years prior 
to dosing.
11. The subject drinks alcohol in excess of 7 drinks/week for women or 14 drinks/week for men 
(where 1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces 
[45 mL] of hard liquor [45% alcohol]) within 3 months before screening.
12. The subject has a positive alcohol breath test or urine drug screen results at screening or 
check-in.
13. The subject with previous major psychotic disorder.
14. The subject has a history or presence of: 
–
3 or more incidences of syncope (eg, vasovagal) within the last 5 years prior to screening;
–
A family history of unexplained sudden death or channelopathy;
–
Brugada syndrome (ie, RBBB [right bundle branch block] pattern with ST-elevation in 
leads V1-V3);
–
CV or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, 
stroke, sick sinus syndrome, pulmonary congestion, symptomatic or significant cardiac 
arrhythmia, supraventricular or ventricular tachycardia, second-degree atrioventricular 
(AV) block type 2, third-degree AV block, prolonged QT interval with Fridericia 
correction method (QTcF) interval, hypokalemia, hypomagnesemia, or conduction 
abnormalities;
–
Risk factors for Torsade de Pointes (eg, heart failure, cardiomyopathy, or family history of 
Long QT Syndrome);
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–
Any clinically significant ECG findings or medical history including: long or short QTcF 
(over 450 msec or less than 360 msec), bifascicular block or QRS ≥120 msec or PR interval 
>200 msec at screening or Day 1 pre-Hour 0;
–
The subject has a documented history of sinus bradycardia (<45 bpm) based upon vital 
signs assessments, sinoatrial block as evidenced on ECG or sinus pause ≥3 seconds on 
ECG or predose telemetry.
15. The subject has an average semirecumbent BP less than 90/60 mm Hg or greater than 
140/90 mm Hg from screening to predose, inclusive. Any assessments on Day -1, where 2 
consecutive timepoint values do not meet this criterion, must be discussed with the medical 
monitor for approval. 
16. From screening to Day -2, subjects with an average semirecumbent HR <55 or >100 bpm 
should be excluded. From Day -2 to predose, enrollment of subjects with an average HR 
<55 or >100 bpm will be left to the judgment of the investigator, unless HR is <50 bpm, which 
must be discussed with the medical monitor for approval.
17. The subject has orthostatic hypotension defined as a decrease in SBP ≥20 mm Hg or a decrease 
in DBP ≥10 mm Hg at approximately 2 minutes of standing when compared with BP from the 
semirecumbent position at screening to predose assessments, inclusive. In asymptomatic 
subjects, any assessments after screening which do not meet this criterion may be repeated 
after the subject has remained in the semirecumbent or supine position for 15 minutes. If the 
repeat assessment is exclusionary based on the above criterion, the subject will not be eligible. 
If the repeat assessment is not exclusionary, the subject will be eligible.
18. The subject has postural orthostatic tachycardia, defined as an increase of >30 bpm or 
HR >120 bpm at approximately 2 minutes of standing, at screening to predose assessments, 
inclusive. Any assessments after screening which do not meet this criterion may be repeated 
with the subject remaining standing for up to a total of 5 minutes, provided that the subject 
remains asymptomatic. If the repeat assessment occurring within 5 minutes is exclusionary 
based on the above criterion, the subject will not be eligible. A confirmed orthostatic increase 
of >30 bpm, but <40 bpm, on 1 or more Day -1 assessments may not be considered 
exclusionary if not considered clinically significant by the investigator and the medical 
monitor. Such assessments must be discussed with the medical monitor prior to determination 
that the subject is eligible to proceed.
7.3
Excluded Medications, Supplements, Dietary Products
7.3.1
Concomitant Medications
The use of concomitant medications approximately 7 days before administration of the first dose 
of study drug, throughout the study until the last follow-up visit is not permitted. Subjects must be 
instructed not to take any medications without first consulting with the investigator. Any 
concomitant medication use must first be discussed with the sponsor, unless the investigator or 
designee considers immediate administration is necessitated. 
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The occasional use of acetaminophen (approximately <1 g/day) is allowed. 
7.3.2
Fruit Juice
Subjects will refrain from consuming Seville oranges, pomelos, grapefruit juice, grapefruits, and 
products containing grapefruit beginning approximately 2 weeks before administration of the first 
dose of study drug, throughout the study until discharge.
7.3.3
Alcohol
Subjects will refrain from consuming alcohol, 24 hours before admission until discharge. Subjects 
may undergo an alcohol breath test at the discretion of the investigator. 
7.3.4
Caffeine
In Part 1, subjects will refrain from consuming caffeinated beverages from the evening of Day -2 
until discharge after dosing in each cohort. At all other times in Part 1 and in Parts 2 and 3, 
caffeinated beverages or xanthine-containing products will be limited to amounts of no more than 
6 units per day (1 unit = 120 mg of caffeine).
7.3.5
Smoking
Subjects will abstain from the use of tobacco- or nicotine-containing products from 3 months prior 
to screening to discharge after last scheduled dose.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
7.4.1.1
Parts 1, 5a and 6 
On Day -1 of each cohort, subjects will fast overnight (at least 8 hours) and will continue to fast for 
4 hours after Hour 0 for the collection of baseline time-matched HR and BP assessments. On 
Day 1 of each cohort, subjects will fast overnight (at least 8 hours) before study drug dosing and 
will continue to fast for an additional 4 hours (after Hour 0) postdose. 
On Day 1 of each cohort, meals and snacks must be completed at least 1 hour before any safety
ECGs.
Normal fluid intake of water is permitted and encouraged, and decaffeinated coffee or tea with 
nothing added are also permitted. Standard meals will be administered at approximately 4 (lunch), 
7 (snack), 10 (dinner), and 13 (snack) hours postdose on Day 1. Standardized meals will be served 
on all other confinement days.
7.4.1.2
Parts 2, 3, 4, and 5b
On Day -1 of each cohort, subjects will fast overnight (at least 8 hours) and will continue to fast for 
4 hours after Hour 0 for the collection of baseline time-matched HR and BP assessments. In all 
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parts of the study, subjects will fast overnight (at least 8 hours) before the dose and will continue to 
fast for an additional 4 hours (after Hour 0) postdose. 
Normal fluid intake of water is permitted and encouraged, and decaffeinated coffee or tea with 
nothing added are also permitted. Standard meals will be administered at approximately 4 (lunch), 
7 (snack), 10 (dinner), and 13 (snack) hours postdose on dosing days. All meals should be served 
at approximately the same time each day.
7.4.2
Activity 
Subjects will avoid strenuous physical activity (eg, weight lifting, running, bicycling) from 
72 hours before admission to the study site, throughout the study until after discharge after the last 
scheduled dose.
7.5
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 electronic case report form (eCRF) using the following categories.

Pretreatment event or AE. The subject has experienced a pretreatment event or AE that 
requires ET because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the pretreatment event or AE. 

Liver testing abnormalities.
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN without 
findings of cholestasis or other alternate etiology.

Significant protocol deviation. The discovery that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health. 

Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.

Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (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. 

Study termination. The sponsor, IRB and/or IEC, or regulatory agency terminates the study. 

Pregnancy. The subject is found to be pregnant. Note: If the subject is found to be pregnant, the 
subject must be withdrawn immediately. 
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Note: The specific reasons should be recorded in the “specify” field of the eCRF.
If a subject chooses to withdraw from study participation due to personal concerns related to the 
COVID-19 pandemic (other than a COVID-19-related AE), this should be specified as the reason 
for subject withdrawal in the eCRF. The reason for discontinuation should be entered on the eCRF 
including unavoidable circumstances such as the COVID-19 pandemic.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the ET 
visit. 
7.7
Subject Replacement
If a subject discontinues from the study, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and sponsor. The study site should contact the sponsor for the 
replacement subject’s treatment assignment and allocation number.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT 
8.1
Clinical Study Drug
Study drug in Parts 1 to 5a/b is TAK-105-a (Process A formulation) or matching placebo and in 
Part 6 is TAK-105-b (Process B formulation) or matching placebo, which will be administered SC. 
The study drug will be supplied to the study site by the sponsor in dose strengths of 
 and 
its matching placebo in the single-use vials for injection with open label manner. The matching 
placebo will be also used as the diluent for active vials to dilute 
 active vials to target 
concentration for dose strength at each study cohort. 
Details regarding the dosage form description, composition, compounding process, or dosing 
syringe preparation can be found in the pharmacy manual. Study drug will be packaged to support 
enrollment and replacement of subjects as required. 
8.1.1
Clinical Study Drug Labeling
A clinical label will be affixed to study drug containers in accordance with local regulatory 
requirements.
The label description will contain, but will not be limited to, the following: sponsor’s name and 
address, protocol number, packaging job/lot number, name and strength of the product, caution 
statement, and storage conditions.
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8.1.2
Clinical Study Drug Inventory and Storage
The lot numbers and expiration dates (where available) of the study drugs supplied will be 
recorded in the final report. 
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied.
Study drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label and must remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained.
TAK-105-a and matching placebo must be stored at -25°C to -15°C (-13°F to 5°F) with protection 
from light. TAK-105-b and matching placebo must be stored at 2°C to 8°C (36°F to 46°F) with 
protection from light.
The temperature excursion information can be found in the pharmacy manual. Receipt and 
dispensing of study drug must be recorded by authorized personnel at the study site.
8.1.3
Clinical Study Drug Blinding
This is a double-blind, sponsor-open study; the investigator and subjects are blinded to treatment 
assignment. The sponsor may be open to treatment assignment in the evaluation of data including 
safety and PK for efficient oversight of the study, however will remain blinded in study drug 
preparation and drug dispensing during dosing of each cohort. An unblinded study drug supply 
will be provided to an unblinded pharmacist or other qualified personnel at the study site who will 
blind the study supplies. Treatment identity (name and strength or potency) will be included on the 
study drug container label. 
All members of the sponsor team will be blinded during randomization and dosing of each cohort 
(ie, in preparation for dosing of subjects while members of the sponsor team may be unblinded in 
review of data). Discussions within the dose escalation meetings will be conducted in a blinded 
manner (ie, such that no unblinded information is communicated to other members of the 
meeting). The subjects and investigators (including the site staff) will remain blinded. 
The operational plan for blinding will describe study procedures for maintaining the blind of 
investigators and site personnel including procedures related to investigator participation in the 
dose escalation meetings, medical monitoring, site monitoring and querying of data prior to the 
database lock.
8.1.4
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
Subjects in each cohort will be randomly assigned to receive TAK-105 or matching placebo in a 
3:1 ratio in a double-blind, sponsor-open manner. Subject randomization will not be stratified.
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8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure
The study drug blind will be maintained through a randomization schedule held by the unblinded 
pharmacist at the study site or by the sponsor. The study drug blind shall not be broken by the 
investigator unless information concerning the study drug is necessary for the medical treatment of 
the subject. If possible, the medical monitor should be contacted before the blind is broken by the 
investigator. Unblinding of blinded site personnel will be performed per the standard operating 
procedures of the study site. 
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator or designee must ensure that the study drug is used in accordance with the 
protocol and is dispensed only to subjects enrolled in the study. To document appropriate use of 
study drug (TAK-105 or matching placebo), the investigator or designee must maintain records of 
all study drug deliveries to the site, site inventory, dispensation and use by each subject, 
destruction of drug supply at the site, and/or study drug returned to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must promptly verify the 
contents of the shipments against the packing list. The verifier should ensure that the quantity is 
correct and that the study drug is in good condition. If there are any discrepancies between the 
packing list versus the actual product received, the sponsor (or representative) must be contacted to 
resolve the issue as outlined in the pharmacy manual. The packing list should be filed in the 
investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all study drugs during his or 
her entire participation in the study. Proper drug accountability includes, but is not limited to, the 
following:

Frequent verification that actual inventory matches documented inventory.

Verification that the log is completed for the drug lot (or medication ID number) used to 
prepare each dose.

Verification that all containers used are documented accurately on the log.

Verification that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator or designee must record the current inventory of all study drugs (TAK-105 or 
matching placebo) on a sponsor-approved drug accountability log. The following information will 
be recorded at a minimum: protocol number and title; name of investigator; site identifier and 
number; description of sponsor-supplied drugs; expiry date; date and amount dispensed including 
initials, seal, or signature of the person dispensing the drug; and the date and amount returned to 
the site by the subject, including the initials, seal, or signature of the person receiving the 
sponsor-supplied drug. The log should include all required information as a separate entry for each 
subject to whom sponsor-supplied drug is dispensed.
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The site destruction SOP will be approved by the sponsor. If the site will return the drug to the 
depot, instructions will be provided by Clinical Supplies.
9.0
STUDY PROCEDURES
The following sections describe the study procedures to be performed and data to be collected as 
indicated in the Schedule of Study Procedures (Section 3.0). For each procedure, subjects are to be 
assessed by the same investigator or site personnel whenever possible. Please note that it may 
become necessary to perform the following procedures at unscheduled time periods, per the 
discretion of the investigator.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Appendix B.
9.1.1.1
Assignment of Screening and Randomization Numbers
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before randomization or allocation. Each subject will be 
assigned only 1 screening number. Screening numbers must not be reused for different subjects. 
Any subject who is screened multiple times will be assigned a new screening number for each 
screening event. Rescreening of subjects will be considered on a case-by-case basis by the 
sponsor.
All eligible subjects will be randomly allocated and will receive a randomization number. The 
randomization number identifies the subject for all procedures occurring after randomization. 
Once a randomization number is assigned to a subject, it can never be reassigned to another 
subject. A single subject cannot be assigned more than 1 randomization number.
9.1.1.2
Study Drug Assignment
On Day 1, subjects will be assigned a randomization number in ascending numerical order at the 
clinical site. The randomization number encodes the subject assignment to either TAK-105 or 
placebo, according to the randomization schedule generated before the study. Each subject will be 
dispensed blinded study drug, labeled with his/her unique randomization number, throughout the 
study.
9.1.2
Inclusion and Exclusion 
Each subject will be assessed through randomization, according to the eligibility criteria provided 
in Section 7.0.
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9.1.3
Medical History/Demography 
Qualified site personnel will collect subject significant medical history (past and concurrent 
medical conditions), per the clinical site’s standard of care and appropriate clinical judgment, and 
subject demographics.
9.1.4
Concomitant Medications 
Qualified site personnel will review subject prior and concomitant medication use. Medications 
are defined as prescription and over-the-counter drugs, vaccines, supplements, nutraceuticals, and 
oral herbal preparations.
9.2
Clinical Procedures and Assessments
The time window for all measurements is ±10 minutes. If a 10 minute deviation occurs in any
measurement, subsequent measurements may deviate by up to 10 minutes and the ±10 minutes 
window will apply.
9.2.1
Full Physical Exam
Qualified site personnel will conduct full or symptom-driven physical examinations as indicated in 
the Schedule of Study Procedures (Section 3.0).
9.2.2
Height and Weight
Body weight and height will be obtained with the subject’s shoes off, and jacket or coat removed.
9.2.3
BMI
BMI equals a subject’s weight in kilograms divided by height in meters squared (BMI = kg/m2). 
BMI will be rounded to the nearest whole number according to the standard convention of 
0.1 to 0.4, round down, and 0.5 to 0.9, round up.
9.2.4
Vital Signs
Body temperature will be measured with either an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (ie, oral or tympanic) must be used for all measurements 
for each individual subject and should be the same for all subjects. The same size cuff must be used 
for all BP measurements for each individual subject.
At screening, and from admission to the clinical research unit through predose (inclusive of 
Day -2, Day -1, and predose on Day 1) vital signs including orthostatic BP and HR will be used to 
assess for eligibility for randomization and dosing (see exclusion Criteria #15 to #18 in 
Section 7.2). 
After randomization, results of BP, HR, orthostatic BP, and orthostatic HR assessments 
immediately prior to dosing (the single dose in Part 1, first dose in Part 2, first dose in Part 3, and 
first dose in Part 4) should be consistent with the vital sign criteria as defined in Section 7.2
(exclusion criteria). If vital sign criteria are outside of the specified range defined in Section 7.2 for 
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any dose after the first dose in Parts 2, 3, and 4, the investigator may exercise discretion related to 
appropriateness of the subject’s ongoing study participation based on assessment of clinical 
significance of vital signs and any ongoing AEs. The investigator will regularly update the Takeda 
medical monitor of vital sign findings outside of the ranges described in Section 7.2 and ongoing 
AEs. No protocol deviation will be issued for dosing that may be delayed for up to 1 hour due to an 
ongoing AE (Parts 2, 3, and 4) or vital sign criteria defined in Section 7.2. Should dosing be 
delayed in Parts 2, 3, or 4 of the study, adjustment should be made on subsequent days to 
administer the dose as close as possible to the originally planned TAK-105 dosing time based on 
Day 1 dosing.
Subjects should rest in a semirecumbent position for at least 5 minutes before vital signs are 
measured. Vital signs will include HR rate (bpm), respiratory rate, SDP, and DBP in all parts of the 
study. BP and HR assessments should be made in duplicate with an interval of approximately 2 
minutes between the 2 assessments. The investigator can take a third BP and HR assessment if 
results are inconsistent (ie, a difference >10 bpm in HR or a difference >10 mmHg in SBP or DBP 
between assessments). If 3 measurements are obtained, the final BP and HR readout should be the 
average of the 2 more consistent assessments. All original values (all 3) should be entered into the 
database and the average will be derived in the datasets.
Subjects in each study part will have baseline HR and BP assessments performed on Day -1 which 
are time-matched (±5 minutes) to the Day 1 assessments (ie, time-matched baseline). 
At the predose or prior to Hour 0 time points, BP and HR will be measured within 1 hour 
±10 minutes prior to dosing or at Hour 0. When scheduled after the dose, vital signs will be 
performed within approximately 15 minutes of the scheduled time point. 
When vital signs are scheduled at the same time as blood draws, they will be obtained before the 
scheduled blood draw.
Prior to discharge, vital signs will be assessed and must meet the following criteria: 
semirecumbent HR <100 bpm and BP >90/60 mmHg and no symptoms or signs of postural 
hypotension and tachycardia. The investigator may repeat these assessments before determining 
whether a subject can be discharged. If 3 measurements are obtained, the final BP and HR readout 
should be the average of the 2 more consistent assessments.
9.2.4.1
Orthostatic Measurements
Orthostatic BP and HR assessment will be performed in the outlined sequence as follows:
1. After resting for 5 minutes in a semirecumbent position, BP and HR will be measured.
2. Subjects will then sit at bedside with crossed legs for 3 minutes.
3. Subjects will then stand for 2 minutes before collecting vital signs.

If the HR increases by more than 30 bpm on standing and the subject is asymptomatic, the 
subject may remain standing for up to a total of 5 minutes and the investigator may repeat 
standing measurements within 5 minutes as appropriate. Individual HR values and the average 
should be reported.
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
If there is a decrease in SBP ≥20 mm Hg or a decrease in DBP ≥10 mm Hg at approximately 2 
minutes of standing when compared with BP from the semirecumbent position and the subject 
is asymptomatic, semirecumbent and standing measurements may be repeated after the subject 
has remained in the semirecumbent or supine position for 15 minutes. Individual BP values 
and the average should be reported.

Standing assessments must not be performed if semirecumbent SBP is <85 mm Hg or if the 
subject presents with signs or symptoms suggestive of postural hypotension after standing (eg, 
lightheadedness or dizziness, nausea, blurry vision, etc). See Section 10.2.8.4.2 for 
management of symptomatic hypotension.
Subjects will remain semirecumbent for the first 4 hours with vital signs obtained at 0.5, 1, 2, 3, 
and 4 hours post dosing, except at the time that orthostatic vital signs are obtained or for other 
study-related procedures if needed. Subjects will then be permitted to ambulate provided that their 
vital signs remain stable and there are no significant orthostatic changes observed.
9.2.4.2
Follow-Up Safety Monitoring 
All subjects who early terminate the study will be provided with the telemetry patch and BP cuff 
for safety monitoring for the duration of the protocol-specified observation period. Any additional 
AE data will be collected in the database. Follow-up telemetry and BP cuff data will not be entered 
into the database, but the telemetry patch and BP report will be stored in the site source documents. 
If the subject does not agree to allow the use of monitoring and would like to withdraw from the 
study, an Against Medical Advice form will be provided to the subject prior to discharge from the 
CRU.
Any subject who early terminates the study for any reason, eg, if a subject tests positive for 
COVID-19 (Point of Care or Polymerase Chain) and is required to discharge from CRU per policy 
or if a subject should leave the CRU due to unforeseen circumstances, the sponsor will be 
consulted immediately to discuss the following:

If the subject is asymptomatic in relation to CV symptoms but without telemetry observations 
during the postdose period, the subject could be discharged home after discussion with the 
sponsor, and with potential real-time monitoring (eg, Holter monitor, remote continuous 
telemetry monitoring and ambulatory blood pressure) for the protocol-specified telemetry 
observation period.

If the subject is asymptomatic in relation to CV symptoms but with telemetry observations 
during the postdose period, the subject could be discharged to home after discussion with the 
sponsor. Adequate real-time monitoring (eg, Holter monitor, remote continuous telemetry 
monitoring and ambulatory blood pressure) for the protocol-specified telemetry observation 
period will be implemented and potential transfer to emergency department will be considered 
in consultation with the sponsor. 

If the subject has CV symptoms with or without telemetry observations during the postdose 
period, the recommendation is to discuss disposition with the sponsor and potentially 
discharge to the emergency department. 
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Based on assessment, a decision will be made to either remove the monitor because of sufficient 
data/safety assessment, continue remote monitoring under the supervision of an external 
physician, or refer the subject to the emergency department or outpatient cardiology.
9.2.5
Glucose
Blood glucose will be monitored using finger-stick blood samples in Parts 1, 2, 3, and 4 and will 
also be monitored using safety laboratory testing.
9.2.6
ECG Procedure
9.2.6.1
Screening and Safety ECGs
A 12-lead ECG will be collected at the time points specified in the Schedule of Study Procedures 
(see Section 3.0). Ad hoc 12-lead ECGs will also be required if a subject complains of palpitations, 
dizziness, breathlessness, chest tightness, or any other symptoms suggestive of arrhythmia, 
develops tachycardia with HR >120 bpm, or experiences hypotension with SBP <85 mm Hg 
between Day 1 (postdose) and discharge. If the subject experiences symptoms suggestive of 
hypotension, the subject should be instructed to lie flat, BP and HR should be re-assessed, and a 
12-lead ECG should be performed to assess arrhythmia. The BP, HR, and ECG, measurements 
will be reviewed by the investigator, who will use clinical judgment regarding further monitoring 
and management. See Section 10.2.8.4 for management of symptomatic tachycardia or 
hypotension.
The investigator will interpret the safety ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The time that 
the ECG was performed will be recorded. If the 12-lead ECG tracing is incomplete, or has motion 
or other artefact, the ECG will be repeated.
The following parameters will be recorded on the eCRF from the subject’s ECG trace: HR, RR 
interval, QRS interval, PR interval, QT interval, and QTcF (using the formula QTcF = QT/RR1/3). 
The investigator will be responsible for providing the interpretation of all safety ECGs 
(normal/abnormal). These results will be reviewed by the investigator for subject safety and will 
be provided in an appropriate format with the clinical study report (CSR).
ECGs will be performed with subjects in a semirecumbent position. All ECG tracings will be 
reviewed by the investigator or designee.
9.2.6.2
Telemetry
For all parts of the study, cardiac monitoring (HR and ECG) will be assessed via telemetry and will 
be performed for at least 24 hours before dosing and from dosing through the hours postdose as 
described below:

Part 1, 5a, and 6 (SRD)- Continuous ECG telemetry (monitoring) will continue through to Day 
8.
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
Part 2 and Part 5b (MRD)- Continuous ECG telemetry (monitoring) will continue through at 
least Day 10, and at least 48 hours postdose on Days 15 and 22. 

Part 3 Continuous ECG telemetry (monitoring) will continue through at least Day 10, and for 
some cohorts at least 48 hours postdose on Days 15 and 22. 

Part 4 Continuous ECG telemetry (monitoring) will continue through at least Day 10, and at 
least 48 hours post the third dose. 
Real-time actively monitored telemetry may be limited to less than 12 leads (ie, 2 leads for real 
time alerts).
All subjects who terminate early from the study will have remote blood pressure monitoring and 
real-time continuous single lead telemetry (monitoring) for the duration of the protocol-specified 
observation period included in the protocol (see Section 9.2.4.2 for details).
Subjects should remain sitting or supine for at least 5 minutes before each telemetry reading. At 
the Hour 0 time point, telemetry may be assessed in the semirecumbent position to allow for the 
most efficient capture of the other multiple assessments.
Telemetry data (12-lead) will be used for real-time safety monitoring to alert site staff and will not 
be recorded in the eCRF. Data will be stored for review. If an AE occurs, a 12-lead ECG should be 
collected and interpreted by the investigator as specified in Section 9.2.6.1.
Extractions of the 12-lead telemetry will be captured with a minimum of 48 hours of cardiac 
monitoring (24 hours predose and 24 hours postdose) (see Section 3.0). The purpose of the 
telemetry extraction data is to support future detailed concentration-QT (c-QT) analysis as 
described below. For all postdose ECG collections, three 10-second ECGs will be extracted at 
each extraction window time point. 
ECG extraction time points will occur before PK blood draws. Accordingly, subjects will be 
supervised and quietly resting semirecumbent beginning a minimum of 5 minutes before each 
actual ECG extraction window of 5 minutes if possible. The rest period prior to the early PK draws 
(<1 hour postdose) may need to be shortened to accommodate the events schedule. At all other 
time points, subjects will be supervised while remaining at rest, quiet, and awake and in a 
semirecumbent position from at least 5 minutes before the beginning of each ECG extraction time 
point and will remain quiet, awake, motionless, and semirecumbent for at least 5 minutes after the 
beginning of each ECG extraction time point.
ECG extraction data from 12-lead telemetry will be archived. The continuous telemetry data are 
not intended to be analyzed as a predefined safety endpoint for all subjects for this study. However, 
these data will be available for real-time safety monitoring and to further evaluate individual 
subjects who present with symptoms or signs that could be suggestive of an arrhythmia. Data will 
be archived for potential future through QT (TQT) analysis unless a safety signal is detected and 
additional information is required for proper interpretation of the findings. eCRF data for 
telemetry extractions will only include date and start and stop time and whether assessment was 
performed.
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If further review of data is requested by the sponsor for safety assessment, the site investigator 
should review results and interpretation of results and determine clinical significance. Results,
including interpretation and associated documentation should be filed in the source documents. 
The sponsor should be informed of the investigator’s review of the content filed in the source 
documents.
Collected ECG data from 12-lead telemetry may also be used to explore the relationship with 
TAK-105 exposure. If conducted, the results from these analyses will not be included in the CSR 
but will be reported in a standalone report. 
9.2.7
Study Drug Administration
Study drug (TAK-105 or matching placebo) will be administered as shown in the Schedule of 
Study Procedures in Section 3.0.
9.2.8
AE Monitoring
AE monitoring begins after signing of the informed consent form. Changes in subject health status 
from the baseline assessment until study drug administration should be captured in the subject’s 
medical history. A complete description of AE collections and procedures is provided in 
Section 10.0.
9.2.9
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be collected following a minimum 8-hour overnight fast at the time points stipulated 
in the Schedule of Study Procedures (Section 3.0).
9.2.9.1
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells [RBCs])
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs] with absolute 
differential)
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9.2.9.2
Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride and lipase
Creatinine
Glucose 
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total); if above ULN, total bilirubin will be 
fractionated
Protein (total)
Creatine kinase
Other Assessments
Cortisol (6:00 – 9:00 AM collection)
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal.
Samples for laboratory evaluations are collected at specified timepoints or as deemed necessary by site investigator.
If subjects experience ALT or AST >3 × ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase, and international 
normalized ratio) should be performed 24 hours after the abnormality was noted, and the medical 
monitor should be contacted. In Parts 2, 3, and 4, if subjects experience ALT or AST >3 × ULN or 
total bilirubin >2 × ULN, laboratory tests for ALT and AST should be repeated before the next 
scheduled dose. 
If ALT or AST remains elevated >3 × ULN, the investigator must contact the medical monitor for 
consideration of additional testing, close monitoring, possible discontinuation of study drug, and 
discussion of the relevant subject details and possible alternative etiologies. The abnormality 
should be recorded as an AE.
Please see Section 7.5 for subject discontinuation criteria regarding abnormal liver test results and 
Section 10.2.8.5 for guidance on reporting abnormal liver test results.
9.2.9.3
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrite
Specific gravity
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of 
RBC/high-power field, WBC/high-power field, and casts.
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9.2.9.4
Diagnostic Screening
Other
Hepatitis B surface antigen
Hepatitis C virus antibody
HIV
FSH (for females only)
Serum pregnancy test (βhCG) (for females only)
Urine cotinine
βhCG: beta human chorionic gonadotropin; FSH: follicle-stimulating hormone; HIV: human immunodeficiency virus.
Alcohol Screen
Subjects will undergo an alcohol breath test. A urine alcohol test may be performed at the 
discretion of the investigator.
Urine
The urine drug screening assessment will include the following tests:
Amphetamines
3,4-methylenedioxy-methamphetamine
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
9.2.10
PK, Immunogenicity, Biomarker, and DNA Samples
Samples for PK, ADA, and other biomarker analysis will be collected as specified in the Schedule 
of Study Procedures (Section 3.0). Please refer to the laboratory manual for information on the 
collection, processing, and shipment of samples to the central laboratory.
The decision as to which plasma samples collected will be assayed for evaluation of PK will be 
determined by the sponsor (eg, samples at lower doses may not be assayed if samples at higher 
doses reveal undetectable drug concentrations). If indicated, these samples may also be assayed 
and/or pooled for assay in an exploratory manner for metabolites and/or additional biomarkers.
Primary specimen collection parameters are provided in Table 9.a.
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Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary Specimen 
Derivative
Description of 
Intended Use
Sample 
Collection
Plasma sample for TAK-105 PK
Blood
Plasma
PK analysis
Mandatory
Plasma sample for metID
Blood
Plasma
metID analysis
Mandatory
Urine sample for TAK-105 PK
Urine
N/A
PK analysis
Mandatory
Serum sample for immunogenicity
Blood
Serum
ADA analysis
Mandatory
Blood sample for DNA
Blood
DNA
DNA analysis
Optional
ADA: antidrug antibody; 
; metID: metabolite identification; N/A: 
not applicable; PK: pharmacokinetic.
During the confinement period, the sponsor's expectation is that the investigators will ensure that every effort is made 
to collect all blood samples at the precise protocol-scheduled time (as shown in the schedule of study procedures,
Section 3.0). PK blood collection must not deviate from the nominal collection time set forth in the protocol by more 
than ±5 minutes. In case of repeat vital sign measurements, PK samples may be collected within ±10 minutes of 
nominal time. 
During the confinement period, the collection time of samples collected for the assessment of 
 
, hematology, and chemistry, must not deviate from the nominal collection time set in the protocol 
(Section 3.0) by more than ±10 minutes.
Follow up laboratory assessments can be taken at any time during the follow-up visit.
Samples drawn outside these parameters will be considered a protocol deviation but may be considered on case by 
case basis.
9.2.10.1
PK Measurements 
The PK parameters of TAK-105 will be determined from the concentration-time profiles for all 
evaluable subjects. Actual sampling times, rather than scheduled sampling times, will be involved 
in all computations involving sampling times.
Exploratory metabolite profiling may be conducted on blood and urine samples to determine the 
metabolites of TAK-105. If conducted, these data will be reported separately and not be reported in 
the CSR.
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Plasma PK parameters that will be determined after single dose and at steady state in different 
parts of the study include, but are not limited to, the following:
Symbol/Term
Definition
Plasma/Blood/Serum
AUC24
Area under the plasma concentration-time curve from the time 0 to time 24 hours. 
AUCτ
Area under the plasma concentration-time curve during a dosing interval, where tau (τ) is the 
length of the dosing interval.
AUClast
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration.
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity, calculated as 
AUC∞= AUCt + Clast/λz
Rac(AUC)
Accumulation ratio (based on AUC), calculated as AUCτ at steady state/AUCτ after a single 
dose.
Rac(Cmax)
Accumulation ratio (based on Cmax), calculated as Cmax at steady state/Cmax after a single dose.
Cmax
Maximum observed plasma/blood/serum concentration.
Cmax,ss
Maximum observed steady-state plasma concentration during a dosing interval.
CL/F
Apparent clearance after extravascular administration, calculated as = Dose/AUC∞after a 
single dose and as Dose/AUCτ after multiple dosing (at steady state).
Ctrough
Observed plasma concentration at the end of a dosing interval.
λz
Terminal elimination rate constant calculated as the negative of the slope of the log-linear 
regression of the natural logarithm concentration-time curve during the terminal phase.
t1/2z
Terminal disposition phase half-life calculated as ln(2)/λz.
tlag
Lag time to first quantifiable concentration.
tmax
Time of first occurrence of Cmax.
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated as (CL/F)/λz.
The following urine PK parameters of TAK-105 will be determined after SC administration in 
Parts 1 and 2:
Urine
Aet1-t2
Amount of drug excreted in urine from time 1 to time 2, calculated as Cur × Vur, where Cur is the 
concentration of drug excreted in urine and Vur is the volume of urine excreted.
Aet
Total amount of drug excreted in urine from time 0 to time t.
Aeτ
Amount of drug excreted in urine during a dosing interval (τ) after last dose.
fe
Fraction of drug excreted in urine, calculated as (Aet/dose) . 
CLR
Renal clearance, calculated as Ae0-24/AUC24.
Additional PK parameters may be calculated as appropriate. Additional details will be provided in 
the clinical pharmacology analysis plan.
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Detailed instructions for collection, storing, handling, and shipping samples will be provided in the 
laboratory manual. 
9.2.10.5.2
Biological Sample Retention and Destruction
In this study, samples of blood for DNA analysis will be collected as described in 
Section 9.2.10.5.1. Any leftover samples, if not used, will be preserved and retained at the 
sponsor-selected long-term storage facility for up to 5 years from the end of the study. Genetic 
material will be initially stored at a vendor or comparable laboratory, under contract to the sponsor, 
with validated procedures in place, and then preserved and retained at a long-term storage vendor, 
or a comparable laboratory, with validated procedures in place, for up to but not longer than 
15 years from the end of the study when the CSR is signed, or if less, the maximum period 
permitted under applicable law or until consent is withdrawn. 
The sponsor and vendors working with the sponsor will have access to the samples collected and 
any test results. All samples collected during the study will be stored securely with limited access, 
and the sponsor will require anyone who works with the samples to agree to hold the research 
information and any results in confidence.
The sample will be labeled with a unique sample identifier as in the main study but using a code 
that is different from the code attached to the health information and other clinical test results 
collected in the study. The sample and data are linked to personal health information with code 
numbers; the samples are stripped of all personal identifying information but a key linking the 
samples to clinical analysis data exists. This link means that the subject may be identified but only 
indirectly. The sample identifier will be kept secure by or on behalf of the sponsor. 
Subjects who consented and provided a sample for DNA analysis can withdraw their consent at 
any time and request disposal of a stored sample. Any remaining sample that can be identified as 
coming from the subject will be destroyed. The investigator and sponsor may continue to use and 
distribute any information and test results gathered before the request to withdraw.
9.3
Confinement
9.3.1
SRD (Parts 1, 5a, and 6)
Subjects will report to the clinical site on Day -2. Subjects will remain in the clinic until discharge 
on Day 8 (7 days after last dose of study drug). At the discretion of the investigator, subjects may 
be requested to remain in the clinical site longer. 
9.3.2
MRD (Parts 2 and 5b)
Subjects will report to the clinical site on Day -2. Subjects will remain in the clinic until discharge 
on Day 24 (48 hours after last dose of study drug). At the discretion of the investigator, subjects 
may be requested to remain in the study site longer.
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9.3.3
Part 3 (Dose Titration)
Subjects will report to the clinical site on Day -2. Subjects will remain in the clinic until discharge 
either on Day 10, 17, or 24 depending on the cohort (ie, 48 hours after last dose of study drug). At 
the discretion of the investigator, subjects may be requested to remain in the study site longer.
9.3.4
Part 4 (Redosing)
Subjects will report to the clinical site on Day -2. Subjects will remain in the clinic until discharge 
on Day 10 (48 hours after second dose of study drug) and will return to the clinic the day prior to 
the third dose and will be confined until 48 hours post third (last) dose. At the discretion of the 
investigator, subjects may be requested to remain in the study site longer.
9.4
Childbearing Status and Methods of Contraception
9.4.1
Women of Childbearing Potential
Women of childbearing potential (WOCBP) will be excluded from this study.
9.4.1.1
Definition of WOCBP
A woman is considered of childbearing potential (ie, fertile) following menarche and until 
becoming postmenopausal, unless permanently sterile.
9.4.2
Women of Nonchildbearing Potential
WONCBP are defined as satisfying at least 1 of the following criteria: 

Postmenopausal: At least 12 months of spontaneous amenorrhea and an FSH concentration 
>40 mIU/mL.

Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
documentation of surgical procedure. 

Has no uterus as a result of a congenital condition.

Has had a bilateral tubal ligation with appropriate documentation of surgical procedure. 
9.4.2.1
Contraception for WONCBP
No contraception is required for WONCBP.
10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
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An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting 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 medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus 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 parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

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:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or complication 
of such a concurrent medical history condition, the worsening or complication should be 
recorded appropriately as an AE (worsening or complication occurs after informed consent is 
signed). Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
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severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

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 captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.

All cases of overdose (with or without associated AEs) will be documented on an overdose 
page of the eCRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE case report form(s)
(CRF[s]) according to Section 10.0.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
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10.1.1
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. Is 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.
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2
AEs of Special Interest
AEs of special interest (AESIs) for TAK-105 include injection site reactions, hypotension 
including postural hypotension, and tachycardia. 
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
All AEs, including clinically significant treatment-emergent laboratory abnormalities, will be 
graded according to National Cancer Institute (NCI) CTCAE v5.0. AEs not listed by the NCI 
CTCAE will be graded as displayed in Table 10.a.
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Table 10.a
NCI-CTCAE
Grade
Description
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated.
2
Moderate; minimal, local, or noninvasive intervention indicated; limiting
age-appropriate instrumental activities of daily living (ADL).
3
Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.
4
Life-threatening consequences; urgent intervention indicated.
5
Fatal AE; an event that results in the death of the subject.
AE: adverse event; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events.
10.2.2
Assigning Causality of AEs
The relationship of each AE to study medication(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 a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4
End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5
Pattern of AE (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
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10.2.6
Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE.

Drug interrupted – the dose was interrupted due to the particular AE.
10.2.7
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 has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; 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 become 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.”

Recovered/resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a CV accident but with some persisting 
paresis).

Fatal – an AE that is 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.
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal Liver 
Function Tests 
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, special interest AEs, and abnormal liver function tests [LFTs]) 
will commence at the time the subject signs the informed consent and continue until the last follow 
up visit (see Schedule of Study Procedures s Section 3.0). For subjects who discontinue prior to the 
administration of study medication, AEs will be followed until the subject discontinues study 
participation. 
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10.2.8.2
Reporting AEs
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 an
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with trial drug.

Outcome of event.

Seriousness.
10.2.8.3
Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE eCRF entry must be completed, in English and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).
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
Causality assessment.
The SAE information should be transmitted within 24 hours to the attention of the contact listed in 
Appendix 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
10.2.8.3.1
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. The site must use the eCRF to report an SAE within 
24 hours, and, only if the eCRF is unavailable, should the site send a safety reporting form. 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.
10.2.8.4
Management of Specific AEs
10.2.8.4.1
Sinus Tachycardia
CTCAE Grade 
Management
CTCAE v5.0 Grade 2 sinus tachycardia 
(ie, Symptomatic a; nonurgent medical 
intervention indicated) with HR 120 and 
above at rest for at least 5 minutes with 
no physical exertion. 
Evaluate ECG for abnormalities, manage as per local guidelines and call 
the medical monitor immediately. 
Any CTCAE v5.0 Grade 3 sinus 
tachycardia (ie, urgent medical 
intervention indicated) or Grade 4 
(life-threatening)
Evaluate ECG for abnormalities, manage as per local guidelines and call 
the medical monitor immediately. 
In all subjects, discontinue further treatment with study drug.
CTCAE: Common Terminology Criteria for Adverse Events; ECG: electrocardiogram; HR: heart rate.
a Symptoms may include dizziness, light headedness, chest pain, chest heaviness, palpitations, and shortness of breath.
If a subject complains of palpitations, dizziness, breathlessness, chest tightness, or any other 
symptoms suggestive of arrhythmia, the subjects should be advised to lie flat, and HR and BP 
should be measured and recorded, followed by a 12-lead ECG (urgently if hypotension is detected; 
otherwise as soon as is feasible). The BP, HR, and ECG measurements will be reviewed by the
investigator, who will use their clinical judgment regarding further monitoring and management.
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10.2.8.4.2
Low BP
If a subject develops symptoms suggestive of hypotension or postural hypotension, BP should be 
assessed for evidence of hypotension, which should be managed as per local guidelines, and the 
medical monitor should be contacted. TAK-105 administration will be discontinued on occurrence 
of an event of CTCAE v5.0 Grade ≥3 hypotension (ie, requiring medical intervention).
If SBP is <85 mm Hg or if the subject is experiencing symptoms suggestive of postural 
hypotension after standing, the subject should be advised to lie flat, and HR and BP should be 
rechecked in that position. If SBP remains <85 mm Hg, a 12-lead ECG should be performed, and 
the investigator will use their clinical judgment regarding further monitoring and management. 
10.2.8.4.3
Injection Site Reaction
If a subject develops a CTCAE v5.0 Grade 3 (ulceration or necrosis; severe tissue damage; need 
for operative intervention) or Grade 4 (life-threatening consequences; urgent intervention 
indicated), discontinue administration of TAK-105, provide immediate treatment, and contact the 
medical monitor.
10.2.8.4.4
Hypersensitivity
If anaphylaxis or other serious allergic reactions occur, TAK-105 administration will be 
discontinued immediately and appropriate management initiated (eg, epinephrine, antihistamines, 
and further immediate care as necessary). 
10.2.8.5
Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN the event should 
be recorded as an SAE and reported as per Section 10.2.8.3. Treatment with TAK-105 should be 
discontinued. The investigator must contact the medical monitor for discussion of the relevant 
subject details and possible alternative etiologies, such as acute viral hepatitis A or B or other acute 
liver disease. Follow-up laboratory tests as described in Section 9.2.9 must also be performed. 
10.2.9
Safety Reporting to Investigators, IRBs or IECs, 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 and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted 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 an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
The impact due to COVID-19 will be summarized and listed based on all randomized subjects, 
where appropriate.
If an optional dose level/dose regimen/study part in Table 6.a is not actually investigated in this 
study, no statistical analysis specified in Section 11.0 will be applied to that dose level/dose 
regimen/study part. In addition, the following conventions will be applied to present the analyses 
results, unless otherwise specified.

Descriptive statistics: 
–
For continuous data (study drug exposure and compliance, clinical laboratory data, vital 
signs, ECGs, etc.):

n, mean, standard deviation, median, minimum, and maximum. 
–
For PK and biomarkers:

n, arithmetic mean, standard deviation, percent coefficient of variation [%CV], 
geometric mean, geometric %CV, median, minimum, and maximum. 
–
For categorical data:

frequency counts and percentages. 
–
Percentages will be reported to 1 decimal place. For the calculation of summary statistics 
and statistical analysis, unrounded data will be used.

By treatment arm (TAK-105 or placebo): 
–
For PK: 

by dose level (Parts 1, 2, 5 and 6 only)/dose regimen (Parts 3 and 4 only) of TAK-105, 
as appropriate, within each part of the study separately. The dose levels in Parts 5a 
(SRD) and 5b (MRD) will be grouped separately.
–
For AEs and impact due to COVID-19:

by placebo, each TAK-105 dose level (Parts 1, 2, 5 and 6 only)/dose regimen (Parts 3 
and 4 only), TAK-105 overall (ie, combining all TAK-105 arms), and total (ie, 
combining placebo and TAK-105 arms), as appropriate, within each part of the study 
separately. The dose levels in Parts 5a (SRD) and 5b (MRD) will be grouped 
separately.
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
For all other analyses:

by placebo, dose level (Parts 1, 2, 5 and 6 only)/dose regimen (Parts 3 and 4 only) of 
TAK-105, as appropriate, within each part of the study separately. The dose levels in 
Parts 5a (SRD) and 5b (MRD) will be grouped separately.

Treatment arm pooling: 
–
For Parts 1, 2, 3, 4, and 6, placebo will be pooled across cohorts within each part of the 
study where appropriate. The placebo will be pooled across cohorts in Parts 5a (SRD) and 
5b (MRD) separately.
–
The same dose level (Parts 1, 2, and 6 only)/dose regimen (Parts 3 and 4 only) of TAK-105 
will be pooled across cohorts within each part of the study separately where appropriate. 
The same dose levels of TAK-105 will be pooled across cohorts in Parts 5a (SRD) and 5b 
(MRD) separately.
11.1.1
Analysis Sets
11.1.1.1
Safety Analysis Set
The safety analysis set consists of all subjects who are randomized and receive at least 1 dose of 
study treatment. Subjects will be analyzed according to the study treatment actually received.
11.1.1.2
PK Analysis Set
The PK analysis set consists of all subjects who receive at least 1 dose of TAK-105 and have at 
least 1 measurable postdose plasma or urine concentration for TAK-105.
11.1.1.3
Immunogenicity Analysis Set
The immunogenicity analysis set consists of all subjects who receive at least 1 dose of study 
treatment and have the baseline sample and at least 1 postbaseline sample ADA assessment.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) will be 
provided for continuous demographic variables and baseline characteristics variables (eg, age, 
height, weight, and BMI) by treatment arm in Parts 1, 2, 3, 4, 5 and 6 separately. In particular, 
these descriptive statistics for Part 5a (SRD) and 5b (MRD) will be provided separately. The count 
and percentage of subjects in each class of the categorical demographic variables and baseline 
characteristics variables (eg, gender, ethnicity, race) will be tabulated by treatment arm in Parts 1, 
2, 3, 4, 5, and 6 separately. In particular, these frequency summaries for Part 5a (SRD) and 5b 
(MRD) will be provided separately. The safety analysis set will be used to summarize the 
demographics and baseline characteristics. All data will be provided in by-subject listings.
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11.1.3
PK Analysis
The plasma (all parts of the study) and urine (Parts 1, 2, and 5 a/b only) concentrations of TAK-105 
will be summarized by treatment arm at each scheduled sampling day/time within each part of the 
study separately, using descriptive statistics based on the PK analysis set. In particular, the 
summary of plasma concentration of TAK-105 for Parts 5a (SRD) and 5b (MRD) will be provided 
separately, as data allows. The plasma PK (all parts of the study) and urine PK (Parts 1, 2, and 5 a/b 
only) parameters of TAK-105 determined using a noncompartmental analysis approach will be 
summarized by treatment arm, at each scheduled day where appropriate, within each part of the 
study separately, using descriptive statistics based on the PK analysis set. In particular, the 
summary of PK parameters of TAK-105 for Parts 5a (SRD) and 5b (MRD) will be provided 
separately. Dose proportionality may be assessed graphically (log-transformed dose-normalized 
Cmax and AUC versus dose) and by using a power model within each part of the study separately as 
data allow; no formal statistical comparisons will be conducted. All data will be provided in 
by-subject listings.
A population PK analysis may be conducted and a more detailed description of these analyses will 
be given in a separate analysis plan. The results from these analyses will not be included in the 
CSR and will be a standalone report. 
11.1.4
Safety Analysis
Safety analyses will be based on the safety analysis set. No formal statistical tests or inference will 
be performed for safety analyses. All safety summary analyses will be performed by treatment arm 
within each part of the study separately. In particular, the safety summaries for Part 5a (SRD) and 
5b (MRD) will be provided separately. The number and percentage of subjects with at least 1 
postdose value meeting the sponsor’s markedly abnormal criteria for BP and HR will be provided. 
All data will be provided in by-subject listings.
11.1.4.1
AEs
The summary of treatment-emergent adverse events (TEAEs) will include the number and 
percentage of subjects with at least 1 TEAE by Medical Dictionary for Regulatory Activities
(MedDRA) System Organ Class and Preferred Term and by treatment arm within each part of the 
study separately. Similar summary analyses will be provided for treatment-related TEAEs, SAEs, 
AESIs, and TEAEs leading to permanent treatment discontinuation as well. 
11.1.4.2
Clinical Laboratory Evaluation
Clinical laboratory parameters will be summarized using descriptive statistics for baseline, 
postdose, and change from baseline to postdose by treatment arm at each study scheduled visit 
within each part of the study separately. The number and percentage of subjects with at least 
1 postdose value meeting the sponsor’s markedly abnormal criteria for clinical laboratory 
parameters will be presented by treatment arm within each part of the study separately.
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11.1.4.3
Vital Signs
Typically, BP and HR assessments are made in duplicate with an interval of approximately 
2 minutes between the 2 assessments. The investigator can take a third BP and HR assessment if 
results are inconsistent (as defined in Section 9.2.4). If the assessments are made in duplicate, the 
average value of the duplicate assessments will be used in the summary analysis. If the investigator 
takes a third BP and HR assessment when results are inconsistent, the average value of the 2 more 
consistent corresponding assessments (details will be provided in the SAP) will be used in the 
summary analysis. 
Vital signs (including, but not limited to BP) data will be summarized using descriptive statistics 
for baseline, postdose, and change from baseline to postdose by treatment arm at each study 
scheduled visit within each part of the study separately. The number and percentage of subjects 
with at least 1 postdose value meeting the sponsor’s markedly abnormal criteria for vital signs 
(including by not limited to BP) will be presented by treatment arm within each part of the study 
separately. Meanwhile, the time-matched difference between Day 1 and Day -1 values of vital 
signs will summarized using descriptive statistics by treatment arm at each nominal time point 
within each part of the study separately where appropriate. For each orthostatic vital sign 
parameter, the difference between standing and semirecumbent (ie, standing vital sign 
measurement –semirecumbent vital sign measurement) will be summarized by treatment arm at 
each study scheduled visit within each part of the study separately.
11.1.4.4
ECG 
ECG parameters (including but not limited to HR, QT/QTc, PR) will be summarized using 
descriptive statistics for baseline, postdose, and change from baseline to postdose by treatment arm 
at each study scheduled visit within each part of the study separately. The number and percentage 
of subjects with at least 1 postdose value meeting the sponsor’s markedly abnormal criteria for 
ECG parameters (including but not limited to HR, QT/QTc, and increase from baseline in 
QT/QTc) will be presented by treatment arm within each part of the study separately.
11.1.4.5
Other Safety Parameters
Physical examination findings will be presented in the data listings.
11.1.5
Immunogenicity Analysis 
Immunogenicity will be summarized using the immunogenicity analysis set. The number and 
percentage of subjects in each category of the immunogenicity status (ADA-negative or 
transiently and persistently ADA-positive, and low or high ADA titer) will be tabulated by 
treatment arm at scheduled time points within each part of the study separately. In particular, the 
summary of immunogenicity for Parts 5a (SRD) and 5b (MRD) will be provided separately. ADA 
negative is defined as subjects who do not have a confirmed positive ADA status in any 
postbaseline assessment. Transiently ADA positive will be defined as subjects who have 
confirmed positive ADA status in 1 or 2 postbaseline assessments. Persistently ADA positive will 
be defined as subjects who have confirmed positive ADA status in more than 2 postbaseline 
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assessments. For ADA positive (transiently ADA positive or persistently ADA positive) only, 
high ADA titer is defined as subject who has at least 1 postbaseline ADA titer >16; low ADA titer 
is defined as subject whose postbaseline ADA titers are all ≤16. 
The relationship between immunogenicity status (ADA-negative or transiently and persistently 
ADA-positive, and low or high ADA titer) and plasma drug concentration and PK parameters, and 
safety will be explored. All data will be provided by subject listings.
11.1.6
Biomarker Analysis 
Biomarker measurements will be summarized using the safety analysis set. The baseline 
concentrations of 
 will be summarized using descriptive statistics by treatment 
arm within each part of the study separately. In addition, the number and percentage of subjects 
within each of the 4 categories defined by quartile (ie, 0 to <Q1, Q1 to <median, median to <Q3, 
≥Q3) of 
 concentrations will be presented for each time point by treatment arm 
within each part of the study separately. The change from baseline in the 
 
 will be summarized using descriptive statistics by treatment arm at scheduled time 
points within each part of the study separately. In particular, the summary of biomarker 
measurements for Parts 5a (SRD) and 5b (MRD) will be provided separately. All data will be 
provided in by-subject listings.
11.2
Interim Analysis 
Safety, tolerability, and available PK data will be reviewed after completion of each cohort in the 
dose escalation meetings and before next dose escalation stage in the study (see Section 6.0).
In case a data-dependent decision is needed to inform the subsequent development of TAK-105 
prior to database lock an interim analysis may be deemed necessary. The details about situations 
when such a case occurs and associated interim analyses will be provided in the SAP.
11.3
Determination of Sample Size
The selected sample sizes in all parts of the study are considered sufficient for evaluation of safety 
and tolerability of TAK-105 in healthy subjects. No formal statistical hypothesis testing is 
planned; therefore, no formal power calculations were performed in the determination of the 
sample size for this study.
12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
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 study site guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC. In the event a monitor cannot 
visit the site in a timely manner, alternative monitoring approaches, such as remote source 
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verification or telephone contact, may be used to ensure data quality and integrity and maintain 
subject safety.
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 in this sponsor-open, double-blind 
study), including but not limited to the Investigator’s Binder, trial drug, subject medical records, 
informed consent documentation, and review of eCRFs and associated source documents. It is 
important that the investigator and other study personnel are available during the monitoring visits 
and that sufficient time is devoted to the process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that have a 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) for medical and safety assessments. 
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
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 FDA, the European Medicines Agency [EMA], the United 
Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and 
Medical Devices Agency of Japan). If the study site is contacted for an inspection by a regulatory 
body, the sponsor should be notified immediately. The investigator guarantees access for quality 
assurance auditors to all study documents as described in Section 12.1.
13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix A. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
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and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
13.2
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. 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, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
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The investigator is responsible for the preparation, content, and IRB or IEC 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 or IEC and the sponsor prior to 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 or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent 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 given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a sample for DNA analysis can withdraw their consent and 
request disposal of a stored sample at any time prior to analysis. Notify sponsor of consent 
withdrawal.
13.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
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of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, the EMA, the United Kingdom Medicines and Healthcare products 
Regulatory Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated 
auditors, and the appropriate IRBs and IECs to review the subject’s original medical records 
(source data or documents), including, but not limited to, laboratory test result reports, 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 13.2).
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).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2
Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
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requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
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.
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information 
Study contact numbers can be found in the study manual, the communication plan, or other similar 
documents provided to the site. 
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14.1.2
Investigator Agreement
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6(R2) Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.9 of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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14.1.3
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
14.1.4
List of Abbreviations
%CV
percent coefficient of variation
ADA
antidrug antibody
AE
adverse event
AESI
adverse event of special interest
Aet
amount of drug excreted in urine from time 0 to time t
Aet1-t2
amount of drug excreted in urine from time 1 to time 2
Aeτ
amount of drug excreted in urine during a dosing interval (τ) at steady state
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUClast
area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration
AUCτ
area under the plasma concentration-time curve during a dosing interval, where tau (τ) is 
the length of the dosing interval
AV
atrioventricular
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CFR
Code of Federal Regulations
CL/F
apparent clearance after extravascular administration, calculated using the observed value 
of the last quantifiable concentration
CLR
renal clearance
Cmax
maximum observed plasma concentration
COVID-19
coronavirus disease 2019
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
observed plasma concentration at the end of a dosing interval
CV
cardiovascular
DBP
diastolic blood pressure
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
ET
early termination
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FDA
Food and Drug Administration
fe,t
fraction of administered dose of drug excreted from urine from time 0 to time t
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HED
human equivalent dose
HR
heart rate
ICH
International Council for Harmonisation
IEC
independent ethics committee
IRB
institutional review board
LC/MS/MS
liquid chromatography with tandem mass spectrometry
LFT
liver function test (LFT includes AST, ALT, alkaline phosphatase, and bilirubin)
MedDRA
Medical Dictionary for Regulatory Activities
metID
metabolite identification
MRD
multiple-rising dose
NCI
National Cancer Institute
NOAEL
no-observed-adverse-effect level
NOEL
no-observed-effect level
PPB
plasma protein binding
PK
pharmacokinetic(s)
QTcF
QT interval with Fridericia correction method
QW
once weekly
Rac(AUC)
accumulation ratio based on AUCτ
Rac(Cmax)
accumulation ratio based on Cmax
RBBB
right bundle branch block
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SC
subcutaneous(ly)
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reactions
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
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Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration
WBC
white blood cell
WOCBP
women of childbearing potential
WONCBP
woman of nonchildbearing potential
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15.0
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 conditions will be coded using MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
The sponsor or its designee will supply investigative 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.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
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2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of DNA analysis will not be disclosed to an individual, unless 
prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for subjects, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for 5 
half-lives after the last dose of study drug. Regular pregnancy tests will be performed 
throughout the study for all female subjects of childbearing potential. If a subject is found to be 
pregnant during study, study drug will be discontinued and the investigator will offer the 
subject the choice to receive unblinded treatment information. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 5 half-lives 
after the last dose of study drug. If the partner or wife of the subject is found to be pregnant 
during the study, the investigator will offer the subject the choice to receive unblinded 
treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, the European Union, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and auditing of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
[For Americas- and Europe-conducted studies include text below as applicable.]
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 5 half-lives after 
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.
In studies with no risk of fetotoxicity/teratogenicity/genotoxicity: Male subjects are not required to 
use barrier contraception.
Female Subjects and Their Male Partners
From signing of informed consent, throughout the duration of the study, and for 5 half-lives 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 below).
For studies in which teratogenicity/genotoxicity/embryotoxicity has been demonstrated 
(investigational medicinal product or comparator or background medication), or there is a lack of 
adequate reproductive toxicity data, female subjects should be instructed to use 2 highly effective 
methods of contraception/1 highly effective and 1 effective method (from the list below). 
In addition, they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a WOCBP, ie, fertile, following menarche and until becoming 
post-menopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral tubal ligation, bilateral salpingectomy, and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 
A FSH level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a 
post-menopausal state in younger women (eg, those <45 year old) or women who are not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy. They should agree to use condom with spermicide from first dose if they cannot 
bring documentation for bilateral vasectomy.
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The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are 
included/excluded, the only acceptable methods of contraception are: 

Non-Hormonal Methods: 
–
Intrauterine device (IUD).
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success).

Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method (Evaluate on compound-by-compound and protocol –
by-protocol basis and obtain clinical pharmacology justification).
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months 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;

Oral.

Intravaginal (eg, ring).

Transdermal.
–
Progestogen-only hormonal contraception associated with 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 shorter till she has been 
on contraceptive for 3 months;

Oral.

Injectable.

Implantable.
2. If genotoxicity/teratogenicity/embryotoxicity is unlikely to be caused by the investigational 
drug, comparator, background therapy or standard of care medications effective methods of 
contraception (there may be a higher than 1% failure rate) are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom).
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
Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action PLUS condom with or without spermicide.
3. 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.
4. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
5. During the course of the study, regular serum/urine human chorionic gonadotropin (hCG) 
pregnancy tests will be performed only for WOCBP and all subjects (male and female) will 
receive continued guidance with respect to the avoidance of pregnancy and sperm donation as 
part of the study procedures. 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?
Pregnancy
Women of childbearing potential will not be included in this study.
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug [list all that apply] should be immediately discontinued. In addition, any 
pregnancies in the partner of a male subject during the study or for 5 half-lives after the last dose, 
should also be recorded following authorization from the subject’s partner. 
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Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator. 
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 (blinded or unblinded, as 
applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug 
(including comparator, if applicable) 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.
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Appendix E
Protocol History
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
19 December 2022
Amendment 4
Substantial
Global
23 March 2022
Amendment 3
Substantial
Global
09 September 2021
Amendment 2
Substantial
Global
29 July 2021
Amendment 1
Nonsubstantial
Global
27 May 2021
Initial protocol
Not applicable
Global
Protocol Amendment 3 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 3. The 
primary reasons for this amendment are to: 
1. Add follow-up monitoring for subjects who early terminate from the study.
2. Add safety measures at follow-up visits for COVID monitoring.
3. Add collection windows for PK sampling.
4. Remove buccal epithelial cell sampling from the study.
5. Address inconsistencies in the schedule of study procedures.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 3
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
1.
Section 1.0 Study Summary
Section 6.1.2 Part 1: SRD Cohorts 
1 to 12
Section 6.1.3 Part 2: MRD 
Cohorts 13 to 17
Section 6.1.4 Part 3: Dose 
Titration Cohorts 18 to 23
Section 6.1.5 Part 4: Redosing 
Study Cohorts 24, 25, 26, and 27
Section 6.4.2.6 Rationale for 
MRD Dose Selection
Updated description of 
planned number of subjects 
and of interim analysis.
To correct inaccuracies in 
approximation of subjects and to 
correct interim analysis language 
in summary to match main body.
2.
Section 2.0 Study Schematic
Modified language in box for 
Cohort 24.
For clarification that the third 
dose is on Day 22 for Cohort 24.
3.
Section 3.2.4 Part 2 for MRD 
Cohorts 13 to 17 (Week 4, 
Follow-Up, and ET)
Table 3.b, 3.f, 3.j, 3.m, 3.o, 3.r
Added temperature and 
respiratory rate and vital sign 
Additional safety measures added 
at follow-up visits due to 
COVID-19 pandemic. 
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Protocol Amendment 3
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
Section 3.3.4 Part 3 Dose Titration 
Cohorts (Week 4, Follow-Up, and 
ET)
Section 3.4.3 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 3, 
Follow-Up, and ET)
Section 3.5.2 Part 3 Dose Titration 
Cohorts 22 and 23 (Week 2, 
Follow-Up, and ET)
Section 3.6.3 Part 4 Redosing 
Cohorts 24 Through 27 (Third 
Dose Week, Follow-Up, and ET)
measurements to each 
follow-up visit.
4.
Section 3.1.2 Part 1 for SRD 
Cohort 1 to 12 (Follow-Up 
Through ET)Section 3.2.4
Section 3.3.4 Part 3 Dose Titration 
Cohorts (Week 4, Follow-Up, and 
ET)
Section 3.4.3 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 3, 
Follow-Up, and ET)
Section 3.5.2 Part 3 Dose Titration 
Cohorts 22 and 23 (Week 2, 
Follow-Up, and ET)
Section 3.6.3 Part 4 Redosing 
Cohorts 24 Through 27 (Third 
Dose Week, Follow-Up, and ET)
Table 3.b, 3.f, 3.j, 3.m, 3.o, 3.r
Removed glucose finger stick 
assessments at ET visit.
To remove procedures that are not 
considered necessary at the early 
termination visit and for 
consistency.
5.
Section 3.0 Schedule of Study 
Procedures
Section 9.2.10 PK, 
Immunogenicity, Biomarker, and 
DNA Samples
Section 9.2.10.5 DNA 
Measurements
Table 3.a, 3.b, 3.f, 3.j, 3.r, 9.a, 
Removed collection of buccal 
epithelial cell sample from the 
study.
Buccal sampling removed due to 
technical issues with the sample 
for the assay.
6.
Section 3.0 Schedule of Study 
Procedures
Section 9.2.4 Vital Signs
Section 11.1.4.3 Vital Signs
All tables in Section 3.0. 
Updated language for repeat 
BP and HR assessments.
Modified footnote for repeat BP 
and HR assessments to be in 
agreement with Standard 
Operating Procedures for entry of 
data into the electronic database.
7.
Section 3.1.1 Part 1 for SRD 
Cohort 1 to 12 (Days 1 Through 8)
Section 3.2.1 Part 2 for MRD 
Table 3.a, 3.c, 3.g, 3.k, 3.n, 3.p
Modified language in footnote 
for predose time-matched 
For clarification of time period for 
time-matched extractions.
For non-commercial use only


TAK-105
Study ID TAK-105-1001
Page 182 of 190
Protocol Incorporating Amendment No. 4
19 December 2022
CONFIDENTIAL
Protocol Amendment 3
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
Cohorts 13 to 17 (Week 1)
Section 3.3.1 Part 3 Dose Titration 
Cohorts 18 and 19 (Week 1)
Section 3.4.1 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 1)
Section 3.5.1 Part 3 Dose Titration 
Cohorts 22 and 23 (Week 1)
Section 3.6.1 Part 4 Redosing 
Cohorts 24 Through 27 (Week 1)
telemetry.
8.
Section 6.1.1 Overall Study 
Design
Table 6.a
Added note stating the planned 
starting dose.
For flexibility in the protocol.
9.
Section 6.1.2 Part 1: SRD Cohorts 
1 to 12
Section 6.1.3 Part 2: MRD 
Cohorts 13 to 17
Section 6.1.4 Part 3: Dose 
Titration Cohorts 18 to 23
Section 6.1.5 Part 4: Redosing 
Study Cohorts 24, 25, 26, and 27
Section 6.2 Dose Escalation
Section 6.3.2 Criteria for 
Premature Termination or 
Suspension of the Study
Section 8.1.3 Clinical Study Drug 
Blinding
Section 11.2 Interim Analysis
Changed terminology of 
“Dose Escalation Committee” 
to “dose escalation meeting”.
Modified terminology for 
clarification.
10.
Section 6.3.2 Criteria for 
Premature Termination or 
Suspension of the Study
a. Added language clarifying 
that criteria apply when related 
to study drug administration.
b. Removed “vasovagal” from 
“vasovagal syncope”.
Removed greater than equal 
sign in bullet for: “Two or 
more subjects experience a 
CTCAE v5.0 Grade ≥ 3 event 
considered related to 
TAK-105 administration”.
Added bullet for Grade ≥2 
injection site reaction 
a. To clarify criteria apply when 
related to study drug 
administration and for better 
consistency. 
b. For correction.
For non-commercial use only


TAK-105
Study ID TAK-105-1001
Page 183 of 190
Protocol Incorporating Amendment No. 4
19 December 2022
CONFIDENTIAL
Protocol Amendment 3
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
criterion.
11.
Section 6.5 Procedure 
Modifications Permitted Within 
Protocol Parameters
Removed details of 
Section 6.5 and provided 
general guidance.
For correction following the 
guidance of other studies in the 
program to document changes in 
the study file.
12.
Section 1.0 Study Summary
Section 7.1 Inclusion Criteria
Section 7.2 Exclusion Criteria
Appendix D Pregnancy and 
Contraception
Modified inclusion criteria #8 
to clarify male subjects birth 
control criteria.
Modified language in 
exclusion criteria #1 “last 
dose”.
Modified language in 
exclusion criteria #14 and #15.
For clarification of male birth 
control criteria #8.
For correction of exclusion 
criteria #1 that criteria is after last 
dose of study drug.
For clarification of exclusion 
criteria #14 and #15. 
13.
Section 9.2.4.1 Follow-Up Safety 
Monitoring (new section)
Section 9.2.6.2 Telemetry
Added language to define 
“inconsistent” BP 
measurements and to describe 
follow-up safety monitoring 
procedures.
For clarification and to continue 
safety monitoring of subjects who 
terminate early from the study.
14.
Section 9.2.9.3 Urinalysis
Changed “nitrate” to “nitrite”.
To correct an error.
15.
Section 9.2.10 PK, 
Immunogenicity, Biomarker, and 
DNA Samples
Table 9.a
Added note including 
language for sampling 
windows.
Notes added for clarification to 
provide time sampling windows 
for protocol-specified 
assessments.
16.
Section 10.2.8.3.1 SAE 
Follow-Up
Added: “The site must use the 
eCRFs to report SAE within 
24 hours, and only if the eCRF 
is unavailable, should the site 
send a safety reporting form.”
To clarify SAE reporting.
17.
Section 12.2 Protocol Deviations
Modified language to clarify 
protocol deviation.
For clarification of protocol 
deviation language.
18.
Section 15.1 CRFs (Electronic 
and Paper)
Remove sentence regarding 
CRFs are required for each 
subject who signs an informed 
consent.
To correct an error. 
19.
Appendix D Pregnancy and 
Contraception
Removed true abstinence as a 
form of birth control.
To correct discrepancies.
Protocol Amendment 2 Summary and Rationale:
For non-commercial use only


TAK-105
Study ID TAK-105-1001
Page 184 of 190
Protocol Incorporating Amendment No. 4
19 December 2022
CONFIDENTIAL
This section describes the changes in reference to the protocol incorporating Amendment 2. The 
primary reasons for this amendment are to: 
1. Add at least 24 hours of continuous telemetry monitoring before the first dose.
2. Add serum sampling for measurement of creatine kinase levels.
3. Include additional guidance for the investigator regarding vital sign assessments collected 
before dosing.
4. Specify that only serum electrolytes (sodium, potassium, chloride, and carbon dioxide) are 
measured at the 4-hour postdose time point on Day 1.
5. Add collection of a blood sample for DNA at discharge or at early termination in all applicable 
study parts. 
6. Add footnotes for cortisol sample, blood sample for pharmacokinetics (PK), and metabolite 
identification.
7. Address inconsistencies in the early termination visits in the schedule of study procedures.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
1.
Section 3.1.1 Part 1 for SRD 
Cohort 1 to 12 (Days 1 Through 8)
Section 3.2.1 Part 2 for MRD 
Cohorts 13 to 17 (Week 1)
Section 3.3.1 Part 3 Dose Titration 
Cohorts 18 and 19 (Week 1)
Section 3.4.1 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 1)
Section 3.5.1 Part 3 Dose Titration 
Cohorts 22 and 23 (Week 1)
Section 3.6.1 Part 4 Redosing 
Cohorts 24 Through 27 (Week 1)
Section 9.2.6.2 Telemetry
Table 3.a, Table 3.c, Table 3.g, 
Table 3.k, Table 3.n, Table 3.p:
Added at least 24 hours of continuous 
telemetry monitoring before the first 
dose of TAK-105 or placebo.
Added predose telemetry extractions 
time-matched to extractions on Day 
1.
Section 9.2.6.2 Telemetry:
Changed “approximately 2 hours 
before dosing through the hours 
postdose” to “at least 24 hours before 
dosing and from dosing through the 
hours postdose” of cardiac 
monitoring.
Revised “23.5 hours of continuous 
cardiac monitoring” to “48 hours of 
cardiac monitoring (24 hours predose 
and 24 hours postdose).”
To extend baseline 
telemetry measurements to 
a period of at least 24 hours 
before dosing to aid in 
evaluation of any rhythm 
findings following dosing.
To add predose telemetry 
extraction time points to 
support future 
concentration-QT analysis.
2.
Section 3.1.1 Part 1 for SRD 
Cohort 1 to 12 (Days 1 Through 8)
Section 3.2 Part 2 for MRD 
Table 3.a, Table 3.c, Table 3.d, Table 
3.e, Table 3.f, Table 3.g, Table 3.h, 
Table 3.i, Table 3.j, Table 3.k, Table 
Clarification
For non-commercial use only


TAK-105
Study ID TAK-105-1001
Page 185 of 190
Protocol Incorporating Amendment No. 4
19 December 2022
CONFIDENTIAL
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
Cohorts 13 to 17
Section 3.3 Part 3 Dose Titration 
Cohorts 18 and 19
Section 3.4 Part 3 Dose Titration 
Cohorts 20 and 21
Section 3.5 Part 3 Dose Titration 
Cohorts 22 and 23
Section 3.6 Part 4 Redosing 
Cohorts 24 Through 27
Section 9.2.6.2 Telemetry
3.l, Table 3.m, Table 3.n, Table 3.o, 
Table 3.p, Table 3.q, Table 3.r:
Clarified that telemetry is ECG 
12-lead telemetry.
3.
Section 3.1.1 Part 1 for SRD 
Cohort 1 to 12 (Days 1 Through 8)
Section 3.1.2 Part 1 for SRD 
Cohort 1 to 12 (Follow-Up 
Through ET)
Section 3.2.1 Part 2 for MRD 
Cohorts 13 to 17 (Week 1)
Section 3.2.4 Part 2 for MRD 
Cohorts 13 to 17 (Week 4, 
Follow-Up, and ET)
Section 3.3.1 Part 3 Dose Titration 
Cohorts 18 and 19 (Week 1)
Section 3.3.4 Part 3 Dose Titration 
Cohorts (Week 4, Follow-Up, and 
ET)
Section 3.4.1 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 1)
Section 3.4.3 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 3, 
Follow-Up, and ET)
Section 3.5.1 Part 3 Dose Titration 
Cohorts 22 and 23 (Week 1)
Section 3.5.2 Part 3 Dose Titration 
Cohorts 22 and 23 (Week 2, 
Follow-Up, and ET)
Section 3.6.1 Part 4 Redosing 
Cohorts 24 Through 27 (Week 1)
Section 3.6.2 Part 4 Redosing 
Cohorts 24 Through 27 (Week 2)
Section 3.6.3 Part 4 Redosing 
Cohorts 24 Through 27 (Third 
Table 3.a, Table 3.b, Table 3.c, Table 
3.f, Table 3.g, Table 3.j, Table 3.k, 
Table 3.m, Table 3.n, Table 3.o, 
Table 3.p, Table 3.q, and Table 3.r:
Added serum sample collection of 
creatine kinase (CK) at predose and 
24 hours postdose on Day 1, at 
discharge, and at early termination 
for all parts of the study; also at 48 
hours after the first dose for Part 1 
(SRD).
Added footnote to allow for 
additional serum samples for CK at 
the investigator’s discretion if CK is 
elevated in an individual subject after 
dosing, and to note that the medical 
monitor will be updated regularly on 
any findings of elevated CK and 
plans for continued monitoring.
To enable assessment of 
potential changes in CK 
levels following TAK-105 
dosing and to evaluate any 
association with events of 
myalgia.
For non-commercial use only


TAK-105
Study ID TAK-105-1001
Page 186 of 190
Protocol Incorporating Amendment No. 4
19 December 2022
CONFIDENTIAL
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
Dose Week, Follow-Up, and ET)
Section 9.2.9.2 Chemistry
4.
Section 3.1.2 Part 1 for SRD 
Cohort 1 to 12 (Follow-Up 
Through ET)
Section 3.2.4 Part 2 for MRD 
Cohorts 13 to 17 (Week 4, 
Follow-Up, and ET)
Section 3.3.4 Part 3 Dose Titration 
Cohorts (Week 4, Follow-Up, and 
ET)
Section 3.4.3 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 3, 
Follow-Up, and ET)
Section 3.5.2 Part 3 Dose Titration 
Cohorts 22 and 23 (Week 2, 
Follow-Up, and ET)
Section 3.6.3 Part 4 Redosing 
Cohorts 24 Through 27 (Third 
Dose Week, Follow-Up, and ET)
Table 3.b, Table 3.f, Table 3.j, Table 
3.m, Table 3.o, Table 3.r:
Added safety laboratory sample 
collection; temperature and 
respiratory rate; and standing blood 
pressure and HR assessments at the 
early termination visit.
To collect safety and 
pharmacokinetic (PK) 
information for subjects 
with early termination and 
to be consistent with the 
rest of the protocol.
5.
Section 6.1.2 Part 1: SRD Cohorts 
1 to 12
Section 6.1.3 Part 2: MRD Cohorts 
13 to 17
Section 3.1.1 Part 1 for SRD 
Cohort 1 to 12 (Days 1 Through 8)
Section 3.1.2 Part 1 for SRD 
Cohort 1 to 12 (Follow-Up 
Through ET)
Section 3.2.4 Part 2 for MRD 
Cohorts 13 to 17 (Week 4, 
Follow-Up, and ET)
Section 3.3.4 Part 3 Dose Titration 
Cohorts (Week 4, Follow-Up, and 
ET)
Section 3.6.3 Part 4 Redosing 
Cohorts 24 Through 27 (Third 
Dose Week, Follow-Up, and ET)
Table 9.a Primary Specimen 
Collections
Section 9.2.10.5 DNA 
Measurements
Table 3.a, Table 3.b, Table 3.f, Table 
3.j, Table 3.r:
Added collection of optional blood 
samples for DNA at discharge or at 
early termination in all applicable 
study parts.
Revised text to indicate if subjects 
have provided consent for the 
optional DNA collection, both buccal 
swabs and blood samples should be 
collected.
Inclusion of optional blood 
samples for DNA 
sequencing.
For non-commercial use only


TAK-105
Study ID TAK-105-1001
Page 187 of 190
Protocol Incorporating Amendment No. 4
19 December 2022
CONFIDENTIAL
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
6.
Section 3.1.1 Part 1 for SRD 
Cohort 1 to 12 (Days 1 Through 8)
Section 3.2 Part 2 for MRD 
Cohorts 13 to 17
Section 3.3 Part 3 Dose Titration 
Cohorts 18 and 19
Section 3.4 Part 3 Dose Titration 
Cohorts 20 and 21
Section 3.5 Part 3 Dose Titration 
Cohorts 22 and 23
Section 3.6 Part 4 Redosing 
Cohorts 24 Through 27
Table 3.a, Table 3.c, Table 3.d, Table 
3.e, Table 3.f, Table 3.g, Table 3.h, 
Table 3.i, Table 3.j, Table 3.k, Table 
3.l, Table 3.m, Table 3.n, Table 3.o, 
Table 3.p, Table 3.q, and Table 3.r:
Revised footnote for safety 
laboratory assessments at the 4-hour 
postdose time point to specify that 
only serum chemistry to measure 
electrolytes (sodium, potassium, 
chloride, and carbon dioxide) should 
be performed.
To clarify the footnote by 
stating the measurements 
to be performed at 4 hours 
postdose and removing the 
list of excluded 
measurements.
7.
Section 3.1.1 Part 1 for SRD 
Cohort 1 to 12 (Days 1 Through 8)
Section 3.2.1 Part 2 for MRD 
Cohorts 13 to 17 (Week 1)
Section 3.3.1 Part 3 Dose Titration 
Cohorts 18 and 19 (Week 1)
Section 3.4.1 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 1)
Section 3.5.1 Part 3 Dose Titration 
Cohorts 22 and 23 (Week 1)
Section 3.6.1 Part 4 Redosing 
Cohorts 24 Through 27 (Week 1)
Section 6.1.2 Part 1: SRD Cohorts 
1 to 12
Section 6.1.3 Part 2: MRD Cohorts 
13 to 17
Section 6.1.4 Part 3: Dose Titration 
Cohorts 18 to 23
Section 6.1.5 Part 4: Redosing 
Study Cohorts 24, 25, 26, and 27
Section 9.3 Confinement
Removed the option to admit subjects 
to the site on Day -1 if the Day -2 
assessments can be performed on 
Day -1.
To specify that subjects 
must be admitted to the site 
on Day -2 to allow for at 
least 24 hours of 
continuous telemetry 
monitoring before the first 
dose of study drug.
8.
Section 3.3 Part 3 Dose Titration 
Cohorts 18 and 19
Section 3.4 Part 3 Dose Titration 
Cohorts 20 and 21
Section 3.5 Part 3 Dose Titration 
Cohorts 22 and 23
Section 3.6 Part 4 Redosing 
Cohorts 24 Through 27
Table 3.g, Table 3.h, Table 3.i, Table 
3.j, Table 3.k, Table 3.l, Table 3.m, 
Table 3.n, Table 3.o, Table 3.p, Table 
3.q, Table 3.r:
Added footnote to cortisol test 
indicating the collection period.
To be consistent with the 
rest of the protocol.
For non-commercial use only


TAK-105
Study ID TAK-105-1001
Page 188 of 190
Protocol Incorporating Amendment No. 4
19 December 2022
CONFIDENTIAL
Protocol Amendment 2
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
9.
Section 3.2.2 Part 2 for MRD 
Cohorts 13 to 17 (Week 2)
Section 3.2.3 Part 2 for MRD 
Cohorts 13 to 17 (Week 3)
Section 3.2.4 Part 2 for MRD 
Cohorts 13 to 17 (Week 4, 
Follow-Up, and ET)
Section 3.3.2 Part 3 Dose Titration 
Cohorts 18 and 19 (Week 2)
Section 3.3.3 Part 3 Dose Titration 
Cohorts 18 and 19 (Week 3)
Section 3.3.4 Part 3 Dose Titration 
Cohorts (Week 4, Follow-Up, and 
ET)
Section 3.4.2 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 2)
Section 3.4.3 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 3, 
Follow-Up, and ET)
Section 3.5.2 Part 3 Dose Titration 
Cohorts 22 and 23 (Week 2, 
Follow-Up, and ET)
Section 3.6.2 Part 4 Redosing 
Cohorts 24 Through 27 (Week 2)
Table 3.d, Table 3.e, Table 3.f, Table 
3.h, Table 3.i, Table 3.j, Table 3.l, 
Table 3.m, Table 3.o, Table 3.q:
Added footnote to plasma sampling 
for PK and/or metabolite 
identification to indicate that blood 
draw may occur 10 minutes before 
dosing.
To give flexibility in blood 
collection period during 
predosing period to be 
consistent with studies 
within the same program. 
Applies to non–first dose 
predose sampling and non–
redosing dose (Part 4). 
10.
Section 9.1.1.1 Assignment of 
Screening and Randomization 
Numbers
Added statement that rescreening of 
subjects will be considered on a 
case-by-case basis by the sponsor.
To ensure that a discussion 
with the sponsor occurs 
before a subject is 
rescreened.
11.
Section 9.2.4 Vital Signs
Added additional guidance for the 
investigator regarding vital sign 
assessments collected before each 
dose.
To allow for the 
investigator’s clinical 
assessment of vital signs 
before subsequent days of 
dosing and to provide a 
window for discussion on a 
case-by-case basis between 
the investigator and the 
sponsor.
12.
Section 12.1 Study-Site 
Monitoring Visits
Added a statement that allows for 
alternative monitoring approaches in 
the event a monitor cannot visit the 
site in a timely manner.
To allow remote source 
data verification in 
extenuating circumstances.
For non-commercial use only


TAK-105
Study ID TAK-105-1001
Page 189 of 190
Protocol Incorporating Amendment No. 4
19 December 2022
CONFIDENTIAL
Protocol Amendment 1 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 1. The 
primary reasons for this amendment are to: 
1. Revise the number of planned investigational sites.
2. Update the Schedule of Study Procedures tables to correct discrepancies.
3. Correct discrepancy in exclusion criterion #9.
4. Clarify continuous telemetry time periods.
5. Clarify timing of adverse event (AE) collection period.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
1
Section 1.0 Study Summary
Updated the planned number of 
sites from 2 to 3.
Increased the maximal 
number of sites for flexibility 
in study operations.
2
Section 3.1.1 Part 1 for SRD 
Cohort 1 to 12 (Days 1 Through 8)
Section 3.2.1 Part 2 for MRD 
Cohorts 13 to 17 (Week 1)
Section 3.3.1 Part 3 Dose Titration 
Cohorts 18 and 19 (Week 1)
Section 3.4.1 Part 3 Dose Titration 
Cohorts 20 and 21 (Week 1)
Section 3.5.1 Part 3 Dose Titration 
Cohorts 22 and 23 (Week 1)
Section 3.6.1 Part 4 Redosing 
Cohorts 24 Through 27 (Week 1)
Table 3.a, 3.c, 3.g, 3.k, 3.n, and 3.p:
Removed the column for 96-hour 
timepoint and shifted 96-hour 
assessments to Day 5. Relabeled 
the Day 5 heading to include 
96 hours.
Updated footnote ‘m’ and ‘p’ in 
Table 3.a; ‘m’ and ‘o’ in Table 3.c; 
‘m’ in Table 3.g, 3.k, 3.n, and 3.p 
for urine pharmacokinetic (PK) 
samples and biomarker samples to 
align with updated tables.
To correct error since 
96 hours is the same as Day 5 
timepoint.
3
Section 3.1.1 Part 1 for SRD 
Cohort 1 to 12 (Days 1 Through 8)
Table 3.a: Added collection of 
standing blood pressure (BP) and 
HR at Day 5 and removed BP and 
HR collection at Time 0.
To be consistent with the 
other parts of the study.
4
Section 3.6.3 Part 4 Redosing 
Cohorts 24 Through 27 (Third 
Dose Week, Follow-Up, and ET)
Revised footnote ‘f’ for 
immunogenicity serum samples.
Corrected error to clarify that 
collections are at follow-up 
visits at 28 days after third 
dose in addition to Day 82.
5
Section 6.3.2 Criteria for 
Premature Termination or 
Suspension of the Study
Added language “at rest while 
semirecumbent.”
To clarify the stopping 
criteria related to sinus 
tachycardia.
For non-commercial use only


TAK-105
Study ID TAK-105-1001
Page 190 of 190
Protocol Incorporating Amendment No. 4
19 December 2022
CONFIDENTIAL
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description 
Rationale 
6
Section 7.2 Exclusion Criteria
Section 1.0 Study Summary
Updated language in exclusion 
criterion #9 regarding concomitant 
medications.
Updated language for 
consistency with language in 
Section 7.3.1 as 
recommended by the United 
States Food and Drug 
Administration (US FDA).
7
Section 9.2.6.2 Telemetry
Added language for each part of 
the study extending telemetry 
monitoring beyond 24 hours 
postdose.
To clarify that telemetry is 
collected beyond 24 hours 
postdose in each part of the 
study.
8
10.2.8.1 Collection Period
Modified language for adverse 
event (AE) collection period.
To correct that AE collection 
period should follow the 
Schedule of Study 
Procedures not 30 days after 
last dose.
9
Section 11.1.5 Immunogenicity 
Analysis
Section 1.0 Study Summary
Modified the language to read 
“plasma drug concentration.” 
Revised language for 
accuracy.
For non-commercial use only


For non-commercial use only

SAP_001.pdf: 
For non-commercial use only


STATISTICAL ANALYSIS PLAN 
Study Number: TAK-105-1001 
Study Title: A Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, Phase 1 
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-105 in Healthy 
Subjects 
Phase: 1 
Version: 2.0 (Amendment 1) 
Date: 05/15/2023 
Prepared by: 
, PhD 
, Statistical and Quantitative Sciences, 
Takeda Development Center Americas, Inc. 
Based on: 
Protocol Amendment 04, Protocol Date: 19 December 2022 
Statistical Analysis Plan, Original Version, Date: 19 July 2021 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda. 
For non-commercial use only


TAK-105-1001 
Page 2 of 34
Statistical Analysis Plan 
15 May 2023
CONFIDENTIAL 
REVISION HISTORY 
Version 
Approval Date 
Primary Rationale for Revision 
1.0 
19 July 2021 
Not Applicable 
2.0 
15 May 2023 
To remain consistent with Protocol Amendment 04. 
For non-commercial use only


TAK-105-1001 
Page 3 of 34
Statistical Analysis Plan  
15 May 2023
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................7 
1.1 
Objectives ......................................................................................................................7 
1.1.1 
Primary Objective ..................................................................................................7 
1.1.2 
Secondary Objective(s) .........................................................................................7 
1.1.3 
Exploratory Objective(s) .......................................................................................8 
1.2 
Endpoints .......................................................................................................................9 
1.2.1 
Primary Endpoint(s) ..............................................................................................9 
1.2.2 
Secondary Endpoint(s) ..........................................................................................9 
1.2.3 
Exploratory Endpoint(s) ......................................................................................10 
2.0 
STUDY DESIGN...............................................................................................................10 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................15 
3.1 
Statistical Hypotheses ..................................................................................................15 
3.2 
Statistical Decision Rules ............................................................................................15 
3.3 
Multiplicity Adjustment ...............................................................................................15 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................15 
5.0 
ANALYSIS SETS .............................................................................................................15 
5.1 
Safety Analysis Set ......................................................................................................15 
5.2 
Pharmacokinetic Analysis Set......................................................................................16 
5.3 
Immunogenicity Analysis Set ......................................................................................16 
6.0 
STATISTICAL ANALYSIS .............................................................................................16 
6.1 
General Considerations ................................................................................................16 
6.1.1 
Definition of Study Day and Study Visit Windows ............................................17 
6.1.2 
Handling of Treatment Misallocations ................................................................18 
6.1.3 
Conventions for Missing Data .............................................................................18 
6.1.4 
Conventions for Missing/Partial Dates for Adverse Event/Concomitant 
Medication/Procedures ........................................................................................18 
6.2 
Disposition of Subjects ................................................................................................19 
6.3 
Demographic and Other Baseline Characteristics .......................................................20 
6.3.1 
Demographics and Baseline Characteristics .......................................................20 
6.3.2 
Medical History and Concurrent Medical Conditions .........................................20 
6.4 
Medication History and Concomitant Medications .....................................................20 
6.5 
Efficacy Analysis .........................................................................................................20 
6.6 
Safety Analysis ............................................................................................................21 
6.6.1 
Adverse Events ....................................................................................................21 
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Page 4 of 34
Statistical Analysis Plan  
15 May 2023
 
CONFIDENTIAL 
6.6.2 
Clinical Laboratory Evaluations ..........................................................................22 
6.6.3 
Vital Signs ...........................................................................................................24 
6.6.4 
12-Lead ECGs .....................................................................................................25 
6.6.5 
Physical Examinations .........................................................................................25 
6.6.6 
Extent of Exposure and Compliance ...................................................................25 
6.7 
Immunogenicity Analysis ............................................................................................26 
6.8 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses .................................27 
6.8.1 
Pharmacokinetic Analysis ...................................................................................27 
6.8.2 
Pharmacodynamic Analysis ................................................................................28 
6.8.3 
Biomarker Analysis .............................................................................................28 
6.9 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis........................................................................................................................28 
6.10 
Summary of Impact due to COVID-19 ........................................................................29 
6.11 
Interim Analyses ..........................................................................................................29 
7.0 
REFERENCES ..................................................................................................................30 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................30 
9.0 
APPENDIX ........................................................................................................................30 
9.1 
Changes From the Previous Version of the SAP .........................................................30 
9.2 
Data Handling Conventions .........................................................................................31 
9.2.1 
General Data Reporting Conventions ..................................................................31 
9.2.2 
Definition of Baseline ..........................................................................................31 
9.2.3 
Definition of Study Day and Study Visit Windows ............................................32 
9.3 
Analysis Software ........................................................................................................32 
9.4 
Criteria for Identification of Markedly Abnormal Laboratory ....................................32 
9.5 
Criteria for Identification of Markedly Abnormal Values for Vital Signs ..................33 
9.6 
Criteria for Identification of Markedly Abnormal Orthostatic Changes .....................34 
9.7 
Criteria for Identification of Markedly Abnormal Values for the 12-Lead ECG 
Parameters ....................................................................................................................34 
 
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ABBREVIATIONS 
λz  
terminal elimination rate constant 
ADA 
antidrug antibodies 
AE  
adverse event 
AESI  
adverse event of special interest 
Aet  
amount of drug excreted in urine from time 0 to time t 
Aet1-t2  
amount of drug excreted in urine from time 1 to time 2 
Aeτ  
amount of drug excreted in urine during a dosing interval (τ) at steady state 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase 
AUC  
area under the plasma concentration-time curve 
AUC∞  
area under the plasma concentration-time curve from time 0 to infinity 
AUClast  
area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration 
AUCτ  
area under the plasma concentration-time curve during a dosing interval, where tau (τ) 
is the length of the dosing level 
BMI  
body mass index 
BP  
blood pressure 
BLQ  
below limit quantification 
CL/F  
apparent clearance after extravascular administration, calculated using the observed 
value of the last quantifiable concentration 
CLR  
renal clearance 
Cmax  
maximum observed plasma concentration 
CSR  
clinical study report 
CTCAE  
Common Terminology Criteria for Adverse Events 
Ctrough  
observed plasma concentration at the end of a dosing interval 
CV  
coefficient of variation 
ECG  
electrocardiogram 
eCRF  
electronic case report form 
fe,t  
fraction of administered dose of drug excreted from urine from time 0 to time t 
FIH  
first-in-human 
HR  
heart rate 
  
 
  
 
  
 
GLP  
Good Laboratory Practice 
ICH  
International Conference on Harmonization 
IRB  
Institutional Review Board 
LLN  
lower limit of normal 
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MedDRA  
Medical Dictionary for Regulatory Activities 
MRD  
Multiple rising dose 
PD  
Pharmacodynamic 
PK  
Pharmacokinetic(s) 
CPAP  
clinical pharmacology analysis plan 
PT  
Preferred Term 
Q1  
25th percentile 
Q3  
75th percentile 
QTcF  
QT interval with Fridericia correction 
Rac(AUC)  
accumulation ratio based on AUCτ 
Rac(Cmax)  
accumulation ratio based on Cmax 
RBC  
red blood cell 
SAE  
serious adverse event 
SC  
subcutaneous(ly) 
SRD  
single rising dose 
SOC  
system organ class 
ULN  
upper limit of normal 
TEAE  
treatment-emergent adverse event 
t1/2z  
terminal disposition phase half-life 
tmax  
time of first occurrence of Cmax 
TQT  
thorough QT 
Vz/F  
apparent volume of distribution during the terminal disposition phase after extravascular 
 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
The primary objectives of the study are to characterize the safety and tolerability of: 
• Part 1: 
– Single SC doses of TAK-105-a in healthy subjects. 
• Part 2: 
– Multiple SC doses of TAK-105-a in healthy subjects. 
• Part 3: 
– Multiple SC dose regimens of TAK-105-a that include titration from lower doses in 
healthy subjects. 
• Part 4: 
– Multiple SC dose regimens of TAK-105-a that include weekly dosing, withholding, then 
redosing in healthy subjects. 
• Part 5: 
– Single SC doses and multiple SC doses of TAK-105-a in healthy Japanese subjects. 
• Part 6: 
– Single SC doses of new formulation TAK-105-b in healthy subjects. 
1.1.2 
Secondary Objective(s) 
The secondary objectives of the study are: 
• Part 1: 
– To characterize the PK of TAK-105 in plasma following single SC dose of TAK-105-a in 
healthy subjects. 
– To assess the immunogenicity of TAK-105 following single SC dose in healthy subjects. 
– To characterize the PK of TAK-105 in urine following single SC dose of TAK-105-a in 
healthy subjects. 
• Part 2: 
– To characterize the PK of TAK-105 in plasma following multiple SC doses of TAK-105-a 
in healthy subjects. 
– To assess the immunogenicity of TAK-105 following multiple SC doses in healthy 
subjects.  
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–
To characterize the PK of TAK-105 in urine following multiple SC doses of TAK-105-a in
healthy subjects.
•
Parts 3 and 4: To assess the immunogenicity of TAK-105 following multiple SC dose
regimens that include titration from lower doses for Part 3 and weekly dosing, withholding,
then redosing for Part 4 in healthy subjects.
•
Part 5:
–
To characterize the plasma PK of TAK-105 following a single SC dose and multiple SC
doses of TAK-105-a in healthy Japanese subjects.
–
To assess the immunogenicity of TAK-105 following single SC doses and multiple SC
doses in healthy Japanese subjects.
–
To characterize the urinary PK of TAK-105 following a single SC dose and multiple SC
doses of TAK-105-a in healthy Japanese subjects.
•
Part 6:
–
To characterize the plasma PK of TAK-105 following single SC doses of TAK-105-b in
healthy subjects.
–
To assess the immunogenicity of TAK-105 following a single SC dose of TAK-105-b in
healthy subjects.
1.1.3 
Exploratory Objective(s) 
•
Parts 3 and 4:
–
To characterize the PK of TAK-105 in plasma following multiple SC dose regimens that
include titration from lower doses for Part 3 and weekly dosing, withholding, then
redosing for Part 4 in healthy subjects.
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1.2 
Endpoints 
1.2.1 
Primary Endpoint(s) 
The primary endpoint of the study is: 
• All parts of the study: 
– The primary safety endpoint of the study is safety and tolerability as assessed through 
vital signs, ECG, laboratory assessments, and adverse events (AEs). 
1.2.2 
Secondary Endpoint(s) 
Secondary endpoints include:  
• Parts 1, 5a, and 6: plasma PK parameters for TAK-105 
– Maximum observed plasma concentration (Cmax). 
– Area under the concentration-time curve from time 0 to infinity (AUC∞). 
– Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast). 
– Time of first occurrence of Cmax (tmax). 
– Terminal disposition phase half-life (t1/2z). 
– Apparent clearance after extravascular administration (CL/F). 
– Apparent volume of distribution during the terminal elimination phase after 
extravascular administration(Vz/F). 
• Parts 2 and 5b: plasma PK parameters for TAK-105 on Day 1 (the first dose): 
– Cmax, tmax, and area under the concentration-time curve during a dosing interval, where 
tau (τ) is the length of the dosing interval (AUCτ).  
• Parts 2 and 5b: plasma PK parameters for TAK-105 on Day 22 (the fourth dose): 
AUCτ, Cmax, tmax, t1/2z, CL/F, Vz/F, observed plasma concentration at the end of a dosing 
interval (Ctrough). 
• Parts 1, 2, and 5a/b include the following urine PK parameters: 
– Amount of drug excreted in urine from time 0 to time t (Aet).  
– Amount of drug excreted in urine from time 1 to time 2 (Aet1-t2).  
– Amount of drug excreted in urine during a dosing interval (τ) after last dose (Aeτ). 
– Fraction of administered dose of drug excreted from urine from time 0 to time t (fe,t).  
– Renal clearance (CLR).  
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• All parts of the study: 
– Status of subject’s ADA assessment (ie, ADA-negative or transiently and persistently 
ADA-positive, and low or high ADA titer). 
1.2.3 
Exploratory Endpoint(s) 
Exploratory endpoints will be assessed through the following parameters:  
 
 
 
 
 
 
• Parts 3 and 4 include the following plasma PK parameters: 
– AUCτ.  
– AUClast.  
– Cmax.  
2.0 
STUDY DESIGN 
This is a phase 1, randomized, double-blind, sponsor-open, placebo-controlled study to evaluate 
the safety, immunogenicity, tolerability, and PK of TAK-105 in healthy subjects.  
The study will consist of 6 parts:  
• Part 1 is a first in human (FIH), randomized, double-blind, sponsor-open, placebo-
controlled single rising doese (SRD) design to assess the safety, immunogenicity, tolerability, 
and PK of TAK-105-a in healthy volunteers. Up to 12 cohorts may be enrolled.  
• Part 2 is a randomized, double-blind, sponsor-open, placebo-controlled, multiple rising dose 
(MRD) design to assess the safety, immunogenicity, tolerability, and PK of TAK-105-a in 
healthy volunteers. Up to 5 cohorts may be enrolled.  
• Part 3 is a randomized, double-blind, sponsor-open, placebo-controlled, multiple-dose, dose 
titration design to assess the safety, immunogenicity, tolerability, and PK of TAK-105-a in 
healthy volunteers. Up to 6 cohorts may be enrolled.  
• Part 4 is a randomized, double-blind, sponsor-open, placebo-controlled, redosing after a 
period of withholding study drug design to assess the safety, immunogenicity, tolerability, 
and PK of TAK-105-a in healthy volunteers. Up to 4 cohorts may be enrolled.  
• Part 5 is a randomized, double-blind, sponsor-open, placebo-controlled SRD (Part 5a) and 
MRD (Part 5b) design to assess the safety, immunogenicity, tolerability, and PK of 
TAK-105-a in healthy Japanese subjects. Up to 5 cohorts may be enrolled. 
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• Part 6 randomized, double-blind, sponsor-open, placebo-controlled SRD design to assess the 
safety, immunogenicity, tolerability, and PK of a new formulation of TAK-105-b in healthy 
subjects. Up to 2 cohorts may be enrolled. 
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. 
The study will be conducted sponsor-open. Sponsor discussions with investigators and within the 
study team will be conducted in a blinded manner (ie, no unblinded information will be 
communicated to blinded investigators, site staff or blinded study monitoring personnel). 
Study drug in Parts 1 to 5 is TAK-105-a (Process A formulation) or matching placebo and in 
Part 6 is TAK-105-b (Process B formulation) or matching placebo, which will be administered 
SC.  
While Parts 1 (SRD) and 2 (MRD) of TAK-105-1001 are intended to be completed as planned, 
subsequent parts of the study (ie, Parts 3 or 4) may not be conducted at the discretion of the 
sponsor. Parts 1 and 2 will be initiated in advance of Parts 3 and 4. Parts 3 and 4 will be 
conducted at the discretion of the sponsor based on a review of the available safety and PK data 
from Parts 1 and 2. At the discretion of the sponsor, Parts 3 and 4 may be initiated before 
completion of all cohorts in Parts 1 and 2 as otherwise permissible in the protocol. Parts 5 may 
be performed in parallel with Parts 1 and 2 based on the review of safety and PK data at the 
matching dose from the previous parts. Part 6 with the new drug formulation of TAK-105 
(TAK-105-b) may be performed in parallel with Part 1 provided that the new formulation is 
available and after Part 1 SRD data are available. 
Safety will be assessed by monitoring for adverse events (AEs), vital signs including orthostatic 
assessments, 12-lead electrocardiograms (ECGs), telemetry, safety laboratory assessments after 
each dose, and immunogenicity. PK sampling times may vary based on emerging safety, 
tolerability and PK data, but the maximal number of samples will not change. Subjects may not 
participate in more than 1 part or more than 1 dosing cohort of the study.  
A scheme of the overall study design is presented in Figure 2.a (Parts 1 to 4) and Figure 2.b 
(Parts 5a/b and 6). An overview of treatment cohorts is presented in Table 2.a. 
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Figure 2.a 
Schematic of Study Design: Parts 1 to 4 
 
MRD: multiple-rising dose; QW: once weekly. 
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Figure 2.b 
Schematic of Study Design: Parts 5 and 6 
 
JP: Japanese; MRD: multiple-rising dose; QW: once weekly; SRD: single-rising dose; TBD: to be determined.  
Part 5 will consist of subjects of Japanese origin (see Protocol Section 7.1 for details). 
 
Table 2.a 
Overview of Treatment Cohorts 
Cohort 
Regimen 
TAK-105 formulation 
Treatment 
TAK-105 
Placebo 
Part 1 
1 
SRD 
TAK-105-a 
6 
2 
2 
6 
2 
3 
6 
2 
4 
6 
2 
5 
6 
2 
6 
6 
2 
7 
6 
2 
8 
6 
2 
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Table 2.a 
Overview of Treatment Cohorts 
Cohort 
Regimen 
TAK-105 formulation 
Treatment 
TAK-105 
Placebo 
9 
6 
2 
10  
6 
2 
11 
6 
2 
12 
6 
2 
Part 2  
13 
MRD 
TAK-105-a 
6 
2 
14 
6 
2 
15 
6 
2 
16 
6 
2 
17 
6 
2 
Part 3  
18 
Dose Titration 
TAK-105-a 
6 
2 
19 
6 
2 
20 (optional) 
6 
2 
21 (optional) 
6 
2 
22 (optional) 
6 
2 
23 (optional) 
6 
2 
Part 4 
24 
Redosing 
TAK-105-a 
6 
2 
25 
6 
2 
26 (optional) 
6 
2 
27 (optional) 
6 
2 
Part 5a (Japanese subjects) 
28 
SRD 
TAK-105-a 
6 
2 
29 
6 
2 
30 
6 
2 
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Table 2.a 
Overview of Treatment Cohorts 
Cohort 
Regimen 
TAK-105 formulation 
Treatment 
TAK-105 
Placebo 
Part 5b (Japanese subjects) a 
31 (optional) 
MRD 
TAK-105-a 
6 
2 
32 (optional) 
6 
2 
Part 6 
33 
SRD 
TAK-105-b 
6 
2 
34 (optional) 
6 
2 
MRD: multiple-rising dose; PK: pharmacokinetic; SRD: single-rising dose. 
The starting dose in Part 1 (SRD) will be
. The starting doses of subsequent cohorts in Parts 1, 2, 3, and 4, 
will be determined at the dose escalation meeting based on emerging safety, tolerability, and available PK data. 
Additional cohorts may be included in any part of the study, as determined at the dose escalation meeting based 
on emerging safety, tolerability, and available PK data during the study. 
a The MRD cohorts in Part 5b will be optional, depending on the PK/safety data observed in Part 2 MRD. 
 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES  
3.1 
Statistical Hypotheses 
No formal statistical hypothesis testing is planned in this study.  
3.2 
Statistical Decision Rules 
No formal statistical decisions are planned in this study.  
3.3 
Multiplicity Adjustment 
Not Applicable  
4.0 
SAMPLE-SIZE DETERMINATION 
The selected sample sizes in all parts of the study are considered sufficient for the evaluation of 
safety and tolerability of TAK-105 in healthy subjects. No formal statistical hypothesis testing is 
planned; therefore, no formal power calculations were performed in the determination of sample 
size for the study. 
5.0 
ANALYSIS SETS 
5.1 
Safety Analysis Set 
The safety analysis set consists of all subjects who are randomized and receive at least 1 dose of 
study treatment. Subjects will be analyzed according to the study treatment actually received. 
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5.2 
Pharmacokinetic Analysis Set  
The Pharmacokinetic (PK) analysis set consists of all subjects who receive at least 1 dose of 
TAK-105 and have at least 1 measurable postdose plasma or urine concentration for TAK-105. 
5.3 
Immunogenicity Analysis Set 
The immunogenicity analysis set consists of all subjects who receive at least 1 dose of study 
treatment and have the baseline sample and at least 1 postbaseline sample antidrug antibodies 
(ADA) assessment. 
6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
All data for randomized subjects will be presented in by-subjects listings. All available data from 
Study Parts (eg, 1, 2, 3, 4, 5, and/or 6) will be analyzed separately. In particular, data from 
Parts 5a (SRD) and 5b (MRD) will be analyzed separately, as data allows. 
Data listings and summary statistics and statistical analyses will be performed for subjects 
included in the relevant analysis populations (Safety/PK/Immunogenicity). 
The following conventions will be applied to present the analyses results, unless otherwise 
specified. 
• Descriptive statistics:  
– For continuous data (study drug exposure and compliance, clinical laboratory data, vital 
signs, ECGs, etc.):  
• n, mean, standard deviation, median, minimum, and maximum.  
– For PK and biomarkers: 
• n, arithmetic mean, standard deviation, percent coefficient of variation [%CV], 
geometric mean, geometric %CV, median, minimum, and maximum.  
– For categorical data: 
• frequency counts and percentages.  
– Percentages will be reported to 1 decimal place. For the calculation of summary statistics 
and statistical analysis, unrounded data will be used. 
• By treatment arm:  
– For PK:  
• by dose level (Parts 1, 2, 5, and 6 only)/dose regimen (Parts 3 and 4 only) of 
TAK-105, as appropriate, within each part of the study separately. 
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– For disposition, demographics and baseline characteristics, and concomitant medication: 
• by placebo, each TAK-105 dose level (Parts 1, 2, 5, and 6)/dose regimen (Parts 3 and 
4 only), and total (ie, combining placebo and TAK-105 arms), as appropriate, within 
each part of the study separately. 
– For AEs and impact due to COVID-19: 
• by placebo, each TAK-105 dose level (Parts 1, 2, 5, and 6)/dose regimen (Parts 3 and 
4 only), TAK-105 overall (ie, combining all TAK-105 arms), and total (ie, combining 
placebo and TAK-105 arms), as appropriate, within each part of the study separately. 
– For immunogenicity and biomarker: 
• by placebo, each TAK-105 dose level (Parts 1, 2, 5, and 6)/dose regimen (Parts 3 and 
4 only), and TAK-105 overall (ie, combining all TAK-105 arms, as appropriate, 
within each part of the study separately. 
– For all other analyses: 
• by placebo, dose level (Parts 1, 2, 5, and 6)/dose regimen (Parts 3 and 4 only) of 
TAK-105, as appropriate, within each part of the study separately. 
• Treatment arm pooling:  
– Placebo will be pooled across cohorts within each part of the study where appropriate. 
– The same dose level (Parts 1, 2, 5, and 6)/dose regimen (Parts 3 and 4 only) of TAK-105 
will be pooled across cohorts within each part of the study separately where appropriate. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) Analysis Data Model Version 2.1, and CDISC ADaM 
Implementation Guide Version 1.1. Pinnacle 21 Version 2.1.0 or higher will be utilized to ensure 
compliance with CDISC standards. 
6.1.1 
Definition of Study Day and Study Visit Windows 
Study day will be calculated relative to the date of the first dose of the study drug in each study 
part. Study days prior to the first dose of study drug in each study part will be calculated as: (date 
of assessment/event - date of first dose of study drug in that study part). Study days on or after 
the first dose of study drug in each study part will be calculated as: (date of assessment/event - 
date of first dose of study drug in that study part +1). 
All data will be categorized on the basis of the visit at which they are collected. Visit designators 
are predefined values that appear as part of the visit tab in the electronic case report form 
(eCRF). More than 1 result for a parameter may be obtained in a visit window. In such an event, 
the result with the date closest to the scheduled visit day will be used. In the event of 
2 observations equidistant to the scheduled visit day, the later of the observations will be used. 
Summaries will be provided for scheduled visits only. 
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The study window convention will not be applied to the eCRF data listings. The data listings for 
eCRF data will display the raw data as collected and entered in the eCRF.  
6.1.2 
Handling of Treatment Misallocations 
Subjects will be analyzed as treated.  
6.1.3 
Conventions for Missing Data  
There will be no imputation of incomplete or missing data. 
Plasma or urine concentrations that are below the limit of quantification (BLQ) will be treated as 
zero in the summary of concentration values. Deviations from this convention may be considered 
on a case-by-case basis as deemed appropriate. 
6.1.4 
Conventions for Missing/Partial Dates for Adverse Event/Concomitant 
Medication/Procedures 
The start date that is completely or partially missing will be imputed as follows: 
• If month and year are known but day is missing:  
– If month and year are the same as month and year of the 1st dose date, the day of the 1st 
dose date will be used to impute the missing day.  
– If month and year are prior to the month and year of the 1st dose date, the last day of the 
month will be used to impute the missing day.  
– If month and year are after the month and year of the 1st dose date, the 1st day of the 
month will be used to impute the missing day.  
• If year is known, but both day and month are missing:  
– If the year is same as year of the 1st dose date, the month and day of the 1st dose date will 
be used to impute the missing month and day, respectively.  
– If the year is prior to the year of the 1st dose date, December 31st of the year will be used 
to impute the missing month and day, respectively.  
– If the year is after the year of the 1st dose date, January 1st of the year will be used to 
impute the missing month and day, respectively. 
• If all (day, month, year) are missing, the 1st dose date will be used to impute the missing year, 
month, and day, respectively.  
Imputing missing start date is mandatory. After imputation, all imputed dates are checked against 
the stop dates to ensure that start dates do not occur after stop dates. If an imputed start date 
occurs after the stop date, then change the imputed start date to be the same as the stop date.  
The stop dates that are completely or partially missing will be imputed as follows:  
• If the AE is “ongoing”, no imputation is necessary.  
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• If month and year are known but day is missing, the last day of the month will be used to 
impute the missing day. 
• If year is known, but both day and month are missing:  
– December 31st of the year will be used to impute the missing month and day, 
respectively.  
• If all (day, month, year) are missing, the event will be considered as ongoing.  
Imputing missing stop date is not mandatory if event is considered as ongoing. However, if it is 
to be done, the rules are outlined above. If subject dies, then use death date for the stop date. 
After imputation, all imputed dates are checked against start dates to ensure that stop dates do 
not occur before start dates. If an imputed stop date occurs prior to the start date, then change the 
imputed stop date to be the same as the start date. 
6.2 
Disposition of Subjects 
Disposition of all randomized subjects (denominator) will be tabulated (count and percent). The 
summaries of disposition will be presented by treatment arm. 
Disposition of all randomized subjects will be tabulated for each part of the study: 
• 
Subjects who were randomized but not treated, if applicable; 
• 
Subjects who completed the study investigational products; 
• 
Subjects who prematurely discontinued study investigational products; 
• 
Subjects who completed all planned study visits; 
• 
Subjects who prematurely discontinued study visits. 
Primary reasons for discontinuation of study drug/visits, as entered on the electronic case report 
form (eCRF), will be tabulated. Reasons for discontinuation include adverse event, failure to 
meet continuation criteria, lost to follow-up, pregnancy, protocol deviation, study terminated by 
sponsor, withdrawal by subject, liver function test (LFT) abnormalities, and Other. The date of 
first dose, date of last dose, duration of treatment (last dose date – first dose date +1), number of 
dose received, and the reason for premature discontinuation of study drug/study visit will be 
presented for each subject in listings. 
All significant protocol deviations that occur during the study will be reviewed and finalized 
prior to database lock. Significant protocol deviations will be summarized by treatment arm 
within each part of the study separately. Listing of all significant protocol deviations will be 
provided for all randomized subjects. 
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6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics and Baseline Characteristics 
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) will be 
provided for continuous demographic variables and baseline characteristics variables (eg, age, 
height, weight, and BMI) by treatment arm in Parts1, 2, 3, 4, 5 and 6 separately. In particular, 
data from Part 5a (SRD) and 5b (MRD) will be analyzed separately, as data allows. The count 
and percentage of subjects in each class of the categorical demographic variables and baseline 
characteristics variables (eg, sex, ethnicity, race) will be tabulated by treatment arm in Parts 1, 2, 
3, 4, 5 and 6 separately. In particular, data from Part 5a (SRD) and 5b (MRD) will be analyzed 
separately, as data allows. The safety analysis set will be used to summarize the demographics 
and baseline characteristics. 
All data will be provided in by-subject listings using safety analysis set. 
6.3.2 
Medical History and Concurrent Medical Conditions 
Medical history includes any significant conditions or diseases relevant to the disease under 
study that stopped at or prior to signing of informed consent. Concurrent medical conditions 
include significant ongoing conditions or diseases present at signing of informed consent. 
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA, version 23 or higher) and will be presented in listings based 
on safety analysis set. 
6.4 
Medication History and Concomitant Medications  
Medication history includes all medications, other than study treatment, which was stopped at or 
prior to the first dose of study treatment. Concomitant medication includes all medication, other 
than study treatment, which was continued taking or started after the first dose of study 
treatment, through the end of the safety follow-up period.  
Medication history and concomitant medication will be coded using the World Health 
Organization Drug Dictionary (WHODrug, March, 2020 or higher) coding system. 
The summary of concomitant medication will include the number and percentage of subjects by 
preferred term within each Anatomical Therapeutic Chemical (ATC) class level 2 by treatment 
arm using safety analysis set. The summary table will be presented with ATC class sorted in 
alphabetical order and preferred term sorted in decreasing frequency based on the total number 
of subjects. A subject will be counted only once within a given ATC class and within a given 
preferred term, even if he/she received the same concomitant medication at different times. 
All medication history and concomitant medication data will be provided in by-subject listings 
using safety analysis set.  
6.5 
Efficacy Analysis 
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6.6 
Safety Analysis 
Safety analyses will be based on the safety analysis set. No formal statistical tests or inference 
will be performed for safety analyses.  
All safety data will be provided by-subject listings based on safety analysis set. 
6.6.1 
Adverse Events 
All adverse events will be coded using MedDRA latest version. In this dictionary, each verbatim 
term is coded to a lower level term and then mapped to a preferred MedDRA term, which is then 
mapped to an SOC. All adverse events will be included in the data listings but only treatment-
emergent adverse events will be included in the summary tables. 
A treatment-emergent adverse event (TEAE) is defined as an AE that started or worsened after 
first dose of the study treatment and within 30 days of last dose of study treatment (AE onset 
date - date of last dose ≤30). AEs with missing onset dates will be summarized with TEAEs 
regardless of toxicity grade and relationship to study medication. AEs of special interest (AESIs) 
for TAK-105 include injection site reactions, hypotension, tachycardia and postural hypotension 
The summary of treatment-emergent adverse events (TEAEs) will include the number and 
percentage of subjects with at least 1 TEAE by MedDRA System Organ Class and Preferred 
Term and treatment arm based on safety analysis set.  
The following summaries will be presented: 
• Overview of TEAEs during the study - number and percentage of subjects, number of events. 
• TEAEs by SOC and PT - number and percentage of subjects, number of events. 
• Treatment-related TEAEs by SOC and PT - number and percentage of subjects, number of 
events. 
• TEAEs by PT - number and percentage of subjects, number of events. 
• Most frequent non-serious TEAEs (>5% in any treatment arm within each part of the study) 
by PT - number and percentage of subjects, number of events. 
• Treatment-related TEAEs by PT - number and percentage of subjects, number of events. 
• Toxicity grade of TEAEs by SOC and PT - number and percentage of subjects, number of 
events. 
• Serious TEAEs by SOC and PT - number and percentage of subjects, number of events. 
• AESIs by SOC and PT - number and percentage of subjects, number of events. 
• Treatment-related Serious TEAEs by SOC and PT - number and percentage of subjects, 
number of events. 
• TEAEs leading to permanent treatment discontinuation by SOC and PT - number and 
percentage of subjects, number of events. 
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• TEAEs with Toxicity Grade >=3 by PT - number and percentage of subjects, number of 
events. 
• Treatment-related TEAEs with Toxicity Grade >=3 by PT - number and percentage of 
subjects, number of events. 
• Serious TEAEs leading to permanent treatment discontinuation by SOC and PT - number and 
percentage of subjects, number of events. 
• Most frequent TEAEs (≥ 5% in total subjects within each part of the study) by PT - number 
and percentage of subjects, number of events. 
In the summary of TEAE, a subject with multiple occurrences of the same PT within a SOC is 
counted only once in that PT within that SOC, SOCs will be sorted in alphabetical order, and 
within an SOC, PT will be sorted in descending order of total number of subjects with the PT for 
TAK-105 overall in each part of the study, respectively.  
For the summary of TEAEs by SOC, preferred term and maximum toxicity grade, if a subject 
experiences more than 1 episode of a particular coded adverse event, the subject will be counted 
only once by the maximum toxicity grade of the episode (preferred term). Similarly, if a subject 
has more than 1 adverse event within an SOC, the subject will be counted only once by the 
maximum toxicity grade in that SOC. 
TEAEs classified in the eCRF as related to the study treatment will also be summarized by 
preferred term and SOC. Adverse events with missing relationship will be classified as related to 
study treatment. 
For Part 4 only, as data allows, similarly, the TEAEs that started or worsened after the single SC 
rechallenge dose (after a modified period of withholding study treatment after second dose) will 
be summarized by placebo and level of the single SC rechallenge dose of TAK-105-a, 
TAK-105-a single SC rechallenge dose overall, and total based on safety analysis set. 
6.6.2 
Clinical Laboratory Evaluations 
Clinical laboratory tests will be evaluated and presented using International System of Units (SI) 
units unless otherwise stated. If duplicate data for a laboratory test at a given time point are 
received and deemed valid per data review, the results will be averaged and the average value 
will be used. 
The clinical laboratory parameters (serum chemistry tests, urinalysis, hematology laboratory 
tests) will be summarized using descriptive statistics for baseline, postbaseline values, and 
change from baseline by treatment arm based on safety analysis set. The clinical laboratory 
parameters will be only summarized at the scheduled visits. 
In addition, individual result for serum chemistry tests and hematology laboratory tests will be 
evaluated against the Takeda’s predefined laboratory markedly abnormal value (MAV) criteria 
Section 9.4). All postbaseline clinical lab results including scheduled and unscheduled 
measurements will be included in the MAV evaluation. For the clinical laboratory parameter of 
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interest, the number and percentage of subjects with at least 1 postdose value meeting the 
Takeda’s MAV criteria will be presented by treatment arm based on safety analysis set.  
In addition, the number and percentage of subjects within each of the following categories of 
liver function tests during the on-treatment period will be summarized by treatment arm based on 
safety analysis set. 
• ALT:  
– >3 × upper limit of normal (ULN);  
– >3 –≤5 × ULN;  
– >5 –≤8 × ULN;  
– >8 –≤20 × ULN;  
– >20 × ULN.  
• AST:  
– >3 × ULN;  
– >3 –≤5 × ULN; 
– >5 –≤8 × ULN;  
– >8 –≤20 × ULN; 
– >20 × ULN.  
• ALT or AST:  
– ALT >3 × ULN or AST >3 × ULN;  
– (ALT >3 × ULN and ALT ≤5 × ULN) or (AST >3 × ULN and AST ≤5 × ULN);  
– (ALT >5 × ULN and ALT ≤8 × ULN) or (AST >5 × ULN and AST ≤8 × ULN);  
– (ALT >8 × ULN and ALT ≤20 × ULN) or (AST >8 × ULN and AST ≤20 × ULN);  
– ALT >20 × ULN or AST >20 ×ULN.  
• ALT/AST and Total Bilirubin:  
– ALT >3 × ULN AND TBILI >2 × ULN;  
– AST >3 × ULN AND TBILI >2 × ULN;  
– (ALT >3 × ULN or AST >3 × ULN) AND TBILI >2 × ULN. 
For Part 4 only, as data allows, similarly, the clinical laboratory data after the single SC 
rechallenge dose (after a modified period of withholding study treatment after second dose) will 
be summarized by placebo and level of the single SC rechallenge dose of TAK-105-a, and 
TAK-105-a single SC rechallenge dose overall based on safety analysis set. 
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All clinical laboratory data will be presented in the by-subject listings. Clinical laboratory data 
outside of the normal reference range will be flagged in the listing along with values meeting 
MAV criteria. 
6.6.3 
Vital Signs 
Typically, blood pressure (BP) and heart rate (HR) assessments are made in duplicate with an 
interval of approximately 2 minutes between the 2 assessments. The investigator can take a third 
BP and HR assessment if results are inconsistent (see Protocol Section 9.2.4). If the assessments 
are made in duplicate, the average value of the duplicate assessments will be used in the 
summary analysis for each scheduled visit. If the investigator takes a third BP and HR 
assessment when results are inconsistent, the average value of the 2 more consistent 
corresponding assessments will be used in the summary analysis for each scheduled visit. The 2 
more consistent assessments and final average can then be obtained by the following steps: 
a) Calculate the absolute difference between two different measurements. 
b) Pick the pair with smallest difference to calculate the average if no ties in the absolute 
difference occurs. 
c) If the smallest difference is tied, pick the pair with later assessment times for calculating 
the average. 
The baseline, postbaseline values, and change from baseline of vital signs (including but not 
limited to BP) data will be summarized using descriptive statistics by treatment arm at each 
study scheduled visit based on safety analysis set. Meanwhile, the time-matched difference 
between Day 1 and Day -1 values of vital signs will be summarized using descriptive statistics 
by treatment arm at each nominal timepoint where appropriate based on safety analysis set. 
For each orthostatic vital sign parameter (ie, BP and HR), the difference between standing and 
semi-recumbent (ie, standing vital sign measurement – semi-recumbent vital sign measurement) 
at each study scheduled visit will be summarized by treatment arm based on safety analysis set.  
For visualization purpose, the line plot with error bars, with study scheduled visits as x-axis and 
vital sign parameter (ie, semi-recumbent BP and HR, standing BP and HR, orthostatic BP and 
HR) as y-axis, will be used to plot group means (± SD) of vital sign measurements that will be 
color coded for each treatment arm based on safety analysis set. Similar line plot with error bars 
will be used to plot group means (± SD) of time-matched difference between Day 1 and Day -1 
values of vital sign parameter (ie, semi-recumbent BP and HR, standing BP and HR, orthostatic 
BP and HR). 
In addition, average result at each scheduled visit and individual result at each unscheduled visit 
for vital signs will be evaluated against the Takeda’s predefined markedly abnormal value 
(MAV) criteria (Section 9.5). Orthostatic hypotension and orthostatic tachycardia will be 
identified by criteria for identification of markedly abnormal orthostatic changes (Section 9.6). 
All postbaseline vital signs including both scheduled and unscheduled measurements will be 
included in the MAV evaluation. For each vital sign parameter or orthostatic hypotension or 
orthostatic tachycardia, the number and percentage of subjects with at least 1 postbaseline value 
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meeting the Takeda’s MAV criteria will be presented by treatment arm based on safety analysis 
set.  
For Part 4 only, as data allows, similarly, the vital signs parameters after the single SC 
rechallenge dose (after a modified period of withholding study treatment after second dose) will 
be summarized by placebo and level of the single SC rechallenge dose of TAK-105-a, and 
TAK-105-a single SC rechallenge dose overall based on safety analysis set. 
All vital sign data will be presented in the by-subject listings.  
6.6.4 
12-Lead ECGs 
ECG parameters (ie, heart rate, PR interval, RR interval, QRS interval, QT interval, and QTc 
interval (Fridericia’s)) will be summarized using descriptive statistics for baseline, postbaseline 
value, and change from baseline by treatment arm based on safety analysis set. The ECG 
parameters will be only summarized at the scheduled visits. 
In addition, individual result for ECG parameters (ie, heart rate, PR interval, QRS interval, and 
QTc interval) will be evaluated against the Takeda’s predefined MAV criteria (Section 9.7). All 
postbaseline ECG data including scheduled and unscheduled measurements will be included in 
the MAV evaluation. For the ECG parameter of interest, the number and percentage of subjects 
with at least 1 postdose value meeting Takeda’s MAV criteria for ECG parameters will be 
presented by treatment arm based on safety analysis set.  
The investigator’s ECG interpretation (Normal, Abnormal but not clinically significant, or 
Abnormal and clinically significant, Not evaluable) will be summarized using a shift table as 
cross-tabulations (baseline versus each scheduled postbaseline visit) of numbers and percentage 
of subjects in each of appropriate categories by treatment arm based on safety analysis set. 
For Part 4 only, as data allows, similarly, the ECG data after the single SC rechallenge dose 
(after a modified period of withholding study treatment after second dose) will be summarized 
by placebo and level of the single SC rechallenge dose of TAK-105-a, and TAK-105-a single SC 
rechallenge dose overall based on safety analysis set. 
All ECG data along with values meeting MAV criteria will be presented in the by-subject 
listings based on safety analysis set. 
6.6.5 
Physical Examinations 
Physical examination findings may be presented in by-subject listings based on safety analysis 
set, as data allows. 
6.6.6 
Extent of Exposure and Compliance 
Treatment exposure (eg, duration of treatment = last dose date – first dose date +1, number of 
doses received) will be summarized using descriptive statistics by treatment arm based on safety 
analysis set. All study drug exposure and compliance data will be provided in by-subject listings 
using safety analysis set 
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6.7 
Immunogenicity Analysis 
The number and percentage of subjects within each of the following categories for ADA status 
and ADA titer of immunogenicity at scheduled visits will be summarized by treatment arm based 
on immunogenicity analysis set within each part of the study separately. In particular, the 
summary of immunogenicity for Parts 5a (SRD) and 5b (MRD) will be provided separately, as 
data allows.  
ADA status will be summarized in the following categories: 
• ADA negative, defined as subject who does not have a confirmed positive ADA status in any 
Baseline and postbaseline assessments. 
• Pre-existing ADA positive, defined as subjects who has a confirmed positive ADA status in 
the Baseline assessment, and 
– Does not have a confirmed positive ADA status in any postbaseline assessment, or  
– Has confirmed positive ADA status in at least 1 postbaseline assessments, and the 
maximum titer value among the postbaseline assessments is <4 times the Baseline titer 
value.  
• Treatment-boosted ADA positive, defined as subject who has a confirmed positive ADA 
status in the Baseline assessment and in at least 1 postbaseline assessments, and the 
maximum titer value among the postbaseline assessments is ≥4 times the Baseline titer value. 
• Treatment-induced ADA positive, defined as subject who does not have a confirmed positive 
ADA status in the Baseline assessment, and has confirmed positive ADA status in at least 1 
postbaseline assessments. 
• In addition, treatment-induced and treatment-boosted ADA positive will further be 
summarized in the following categories: 
– Transiently ADA positive, defined as subject who has 1 or 2 confirmed positive ADA 
status in postbaseline assessments. 
– Persistently ADA positive, defined as subject who has >2 confirmed positive ADA status 
in postbaseline assessments. 
For ADA positive (if any pre-existing, treatment-boosted, and treatment-induced ADA positive) 
only, ADA titer will be summarized in the following categories:  
• High ADA titer, defined as subject who has at least 1 Baseline and/or postbaseline ADA 
titer >16. 
• Low ADA titer, defined as subject whose Baseline and postbaseline ADA titers are all ≤16. 
The summary of TEAE by PT and immunogenicity categories (ie, ADA negative and ADA 
positive, if any pre-existing, treatment-boosted, and treatment-induced ADA positive; for ADA 
positive only, ADA high titer and ADA low titer) and treatment arm based on immunogenicity 
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analysis set may be provided to explore the relationship between immunogenicity status and 
safety, if deemed necessary. 
The summary of plasma study drug concentration and PK parameters (including but not limited 
to Cmax , AUCs and CL/F where appropriate) by immunogenicity categories (ie, ADA negative 
and ADA positive, if any pre-existing, treatment-boosted, and treatment-induced ADA positive; 
for ADA positive only, ADA high titer and ADA low titer) and treatment arm based on 
immunogenicity analysis set may be provided to explore the relationship between 
immunogenicity status and PK, if deemed necessary. 
All immunogenicity data will be provided in by-subject listings based on immunogenicity 
analysis set. 
6.8 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
6.8.1 
Pharmacokinetic Analysis 
The plasma (all parts of the study) and urine (Parts 1, 2, and 5a/b only) concentrations of 
TAK-105 will be summarized by treatment arm using descriptive statistics, at scheduled 
sampling day/time within each part of the study separately, based on the PK analysis set. In 
particular, the summary of plasma and urine concentration of TAK-105 for Parts 5a (SRD) and 
5b (MRD) will be provided separately, as data allows. 
PK parameters of TAK-105, but not limited to (ie, Cmax, tmax, t1/2𝑧, AUC∞, AUClast, AUC𝜏, CL/F, 
Vz/F, A𝑒𝑡 , A𝑒𝑡1−𝑡2, A𝑒𝜏, f𝑒,𝑡, CLR, ) that were determined using a non-compartmental analysis will 
be summarized by treatment arm using descriptive statistics based on the PK analysis set. If a PK 
parameter cannot be estimated from a subject’s concentration data, the PK parameter will be 
considered as missing in the summary tables.  
Individual plasma (all parts of the study) and urine (Parts 1, 2, and 5a/b only) concentrations of 
TAK-105, and PK parameters will be presented in by-subject listings based on PK analysis set. 
Details of the pharmacokinetics analysis will be described in clinical pharmacology analysis plan 
(CPAP). 
Dose proportionality will be assessed graphically and by using a power model within each part 
of the study (Parts 1, 2, and 5a/b only) and days (Parts 2 and 5b only) separately using the 
method below, where appropriate: 
For each part of the study (Parts 1, 2, and 5a/b only), as data allows, the dose proportionality of 
AUCs and Cmax will be evaluated using a power model [1] with the form:  
𝑌= exp(𝛼) ∗(dose)𝛽∗exp(error) 
where Y is the PK parameter of interest, exp(𝛼) and 𝛽 are the coefficient and exponent of the 
power equation, respectively. Equivalently, by taking the natural logarithm (ln), the power model 
can be analyzed using linear regression model with the form:  
ln(Y) =α + β*ln(dose) + error 
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where α is the intercept, and β is the slope, and ln(dose) is the dose for each subject. Estimates of 
slope and intercept along with their 90% confidence intervals (CIs) will be reported.  
A minimum of 3 values per dose must be available for a given parameter to assess the dose 
proportionality using the power model. In particular, dose proportionality is indicated if the 90% 
CI of the slope β of power model falling within the limits [1]: 
(1 + ln(. 8)
ln(r) , 1 + ln(1.25)
ln(r) ) 
where r is the ratio of the highest and the lowest dose in a given part of the study. 
Dose proportionality will also be assessed graphically using scatter plots with regression lines 
presented and ln(dose) as the x-axis versus the ln(PK parameter) as the y-axis. 
The assessment of linearity may also be determined visually from plots by the 
Pharmacokineticist. This assessment may override the statistical assessment; where this occurs; it 
will be detailed in the CSR. 
A population PK and exposure response (ER) analysis may be conducted and a more detailed 
description of these analyses will be given in a separate analysis plan. The results from these 
analyses will not be included in the CSR and will be a standalone report. 
6.8.2 
Pharmacodynamic Analysis 
Not Applicable.  
6.8.3 
Biomarker Analysis 
The concentrations of 
 at each time point (ie, Day-1 0 hour and baseline 
[predose, Day 1]) will be summarized by treatment arm using descriptive statistics based on 
safety analysis set. In addition, the number and percentage of subjects within each of the 
4 categories defined by quartile (ie, 0 to <Q1, Q1 to < median, median to <Q3, ≥Q3, where 
quartile is determined by all available data at specified time point within each part of the study) 
of 
 concentrations will be presented for each time point by treatment arm based 
on safety analysis set. The baseline, postbaseline values, and change from baseline in the 
 at scheduled time points within each part of the study will be 
summarized by treatment arm using descriptive statistics based on safety analysis set. All data 
will be provided by-subject listings. 
Duplicate biomarker (ie, more than one set of data for a particular visit) for a given time point is 
not expected. For continuous data, if duplicate data are received and deemed valid per data 
review, the results will be averaged and the average value will be used. The average value will 
be added to the analysis dataset. 
6.9 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis 
Not Applicable 
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6.10 
Summary of Impact due to COVID-19 
The impact due to COVID-19 will be summarized using the number and percentage of subjects 
in each category of impact by treatment arm based on all randomized subjects: 
• Subjects with at least one study visit impacted due to COVID-19.  
• Subject with adjusted methods of contact used due to COVID-19 by study visit 
– Subjects with assessments done per the adjusted method of contact by study visit. 
All COVID-19 impact data will be provided in by-subject listings for all randomized subjects. 
6.11 
Interim Analyses 
Safety, tolerability, and available PK data will be reviewed after completion of each cohort in the 
dose escalation meetings and before next dose escalation stage in the study. 
In case a data-dependent internal decision is needed to inform the subsequent development of 
TAK-105 prior to database lock, an interim analysis may be deemed necessary.  
Three scenarios where the data-dependent internal decision may activate an interim analysis and 
associated analyses are detailed below:  
1. A decision about whether to complete Parts 3 and 4 has not been made.  
2. Dose selection for the development of phase 2 studies. 
3. Study may end after completion of Parts 1 and 2 (IA will become final analysis).  
In the event of scenarios 1 and 2, the interim analyses of the endpoints below, based on the data 
cut prespecified by the study team, will be presented to the study team for review for internal 
decision making. 
• PK Analysis  
– PK concentration per method in Section 6.8.1. 
– PK parameters per method in Section 6.8.1. 
– Dose proportionality assessment per method in Section 6.8.1. 
• Treatment-emergent adverse event (TEAE) per method in Section 6.6.1. 
– Overview of TEAEs. 
– Treatment-related TEAEs. 
– TEAEs by maximum severity. 
– TEAEs Grade 3 or Higher. 
– Treatment-related TEAEs Grade 3 or Higher. 
– SAE. 
– SAE leading to study drug discontinuation. 
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– AESI. 
• Vital Signs per method in Section 6.6.3. 
• Lab data per method in Section 6.6.2. 
• ECG Data per method in Section 6.6.4. 
• Immunogenicity per method in Section 6.7. 
In the event of scenario 2 where the study ends after completion of Parts 1 and 2, all relevant 
analysis described in this SAP for Parts 1 and 2 will be completed.  
The interim analysis will be performed by a separate set of unblinded statisticians and 
programmers at the contract research organization (CRO) who are not involved in the daily 
activities of the study. To maintain the blind of TAK-105-1001 and to ensure the unbiased study 
conduct, results of the interim analyses may only be distributed within a limited team from 
Takeda. The subjects and investigators (including site staff) will remain blinded. 
7.0 
REFERENCES 
1. Jurgen Hummel, Sue McKendrick, Charlie Brindley and Raymond French. Exploratory 
assessment of dose proportionality: review of current approaches and proposal for a practical 
criterion. Pharmaceut. Statist. 2009; 8: 38–49. 
2. Immunogenicity testing of therapeutic protein products–developing and validating assays for 
anti-drug antibody detection. US FDA, 2019. 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
Additional analysis on pre-existing ADA positive, treatment-boosted ADA positive, and 
treatment-induced ADA positive for immunogenicity data were added to follow the FDA 
Guidance on Immunogenicity Testing of Therapeutic Protein Products [2]. 
9.0 
APPENDIX  
9.1 
Changes From the Previous Version of the SAP 
SAP Section  
Change  
Rationale for Change 
Study Title 
1.0 OBJECTIVES, 
ENDPOINTS AND 
ESTIMANDS 
2.0 STUDY DESIGN 
Added the language of sponsor-open.  
To be consistent with Protocol 
Amendment 04. 
1.0 OBJECTIVES, 
ENDPOINTS AND 
ESTIMANDS 
2.0 STUDY DESIGN 
4.0 SAMPLE-SIZE 
Added additional parts and cohorts for 
Japanese subjects and new formulation 
of TAK-105, TAK-105-b. 
To be consistent with Protocol 
Amendment 04. 
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SAP Section  
Change  
Rationale for Change 
DETERMINATION 
6.1 General Considerations 
6.3.1 Demographics and 
Baseline Characteristics 
6.8.1 Pharmacokinetic 
Analysis 
6.2 Disposition of Subjects 
Added language for protocol deviation 
analysis.  
To be consistent with standard analysis 
plan for protocol deviation. 
6.6 Safety Analysis 
Specified analysis plan for Part 4 
redosing cohorts on each safety 
parameter.  
To support safety and tolerability 
assessment for redosing cohorts.  
6.6.1 Adverse Events 
Added additional summary for TEAEs.  
To support safety and tolerability 
assessment for TAK-105. 
6.6.3 Vital Signs 
Added statistical algorithm to calculate 
the average value if a second or a third 
measurement on vital signs has been 
made per protocol specified procedure.  
Updated MAV evaluation plan for 
orthostatic hypotension and orthostatic 
tachycardia based on the scheduled 
standing measurement only. 
To be consistent with Protocol 
amendment 04. 
 
 
To support safety and tolerability 
assessment for TAK-105 on the 
orthostatic vital signs. 
6.7 Immunogenicity 
Analysis 
Added the definition of pre-existing 
ADA positive, treatment-boosted ADA 
positive, treatment-induced ADA 
positive, transiently ADA positive, and 
persistently ADA positive. 
To be consistent with Protocol 
amendment 04 and FDA Guidance on 
Immunogenicity Testing of Therapeutic 
Protein Products.  
6.11 Interim Analyses 
Revised the interim analyses 
parameters. 
To be consistent with the proposed IA 
output for the study. 
9.5 Criteria for 
Identification of Markedly 
Abnormal Values for Vital 
Signs 
Added MAV for Body Temperature in 
oF and MAV for Respiratory Rate. 
To be consistent with Takeda 
 
MAV plan.  
 
9.2 
Data Handling Conventions  
9.2.1 
General Data Reporting Conventions  
9.2.2 
Definition of Baseline  
Baseline is defined as the most recent non-missing value of each assessment prior to the 
subject’s first dose of study treatment, unless otherwise stated. Mean change from baseline is the 
mean of all individual subjects’ change from baseline values. Each individual change from 
baseline will be calculated by subtracting the individual subject’s baseline value from the value 
at the timepoint. The individual subject’s change from baseline values will be used to calculate 
the mean change from baseline using appropriate SAS® procedures such as Proc Univariate. 
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9.2.3 
Definition of Study Day and Study Visit Windows 
Study day will be calculated relative to the date of the first dose of the study drug in each study 
part. Study days prior to the first dose of study drug in each study part will be calculated as: (date 
of assessment/event - date of first dose of study drug in that study part). Study days on or after 
the first dose of study drug in each study part will be calculated as: (date of assessment/event - 
date of first dose of study drug in that study part +1). 
All data will be categorized based on the visit at which they are collected. Visit designators are 
predefined values that appear as part of the visit tab in the electronic case report form (eCRF). 
More than 1 result for a parameter may be obtained in a visit window. In such an event, the result 
with the date closest to the scheduled visit day will be used. In the event of 2 observations 
equidistant to the scheduled visit day, the later of the observations will be used. Summaries will 
be provided for scheduled visits only. 
The study window convention will not be applied to the eCRF data listings. The data listings for 
eCRF data will display the raw data as collected and entered in the eCRF.  
9.3 
Analysis Software  
SAS® version 9.4 or higher will be used for all statistical analyses provided in the CSR.  
9.4 
Criteria for Identification of Markedly Abnormal Laboratory  
Hematology—Criteria for Markedly Abnormal Values 
Parameter 
Unit 
Low Abnormal 
High Abnormal 
Hemoglobin 
SI  
<0.8 × LLN 
>1.2 × ULN 
Hematocrit 
SI 
<0.8 × LLN 
>1.2 × ULN  
RBC count  
SI 
<0.8 × LLN  
>1.2 × ULN 
WBC count  
SI 
<0.5 x LLN 
>1.5 × ULN 
Platelet Count 
SI 
<75 x 109/L 
>600 × 109/L 
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell.  
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Serum Chemistry—Criteria for Markedly Abnormal Values 
Parameter 
Unit  
Low Abnormal 
High Abnormal 
ALT 
SI 
-- 
>3 × ULN 
AST 
SI 
-- 
>3 × ULN 
GGT 
SI 
-- 
>3 × ULN, if baseline is normal; 
>2 × baseline, if baseline is high 
abnormal 
Alkaline phosphatase 
SI 
-- 
>3 × ULN, if baseline is normal; 
>2 × baseline, if baseline is high 
abnormal 
Total Bilirubin 
SI 
-- 
>1.5 × ULN, if baseline is normal; 
>1.5 × baseline, if baseline is high 
abnormal 
Albumin 
SI  
<25 g/L 
-- 
Total protein 
SI 
<0.8x LLN 
>1.2 × ULN 
Creatinine 
SI 
 
>177 mol/L 
Blood urea nitrogen 
SI 
 
>10.7 mmol/L 
Sodium 
SI 
<130 mmol/L 
>150 mmol/L 
Potassium 
SI 
<3.0 mmol/L 
>5.5 mmol/L 
Glucose 
SI 
<3 mmol/L 
>10 mmol/L* 
Chloride 
SI 
<75 mmol/L 
>126 mmol/L 
Calcium 
SI 
Corrected serum calcium of <LLN - 
8.0 mg/dL; <LLN - 2.0 mmol/L; 
Ionized calcium <LLN - 1.0 mmol/L 
 
Bicarbonate 
SI  
<8.0 mmol/L 
 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal. 
 
9.5 
Criteria for Identification of Markedly Abnormal Values for Vital Signs 
Parameter 
Unit 
Lower Criteria  
Upper Criteria 
Pulse Rate 
bpm 
<50  
>120 
Systolic blood pressure 
mm Hg 
<85  
>180  
Diastolic blood pressure 
mm Hg 
<50  
>110 
Body temperature 
oC 
<35.6 
>37.7 
 
oF 
<96.1 
>99.9 
Respiratory Rate 
Breath per minute 
<12 
>16 
 
For non-commercial use only


TAK-105-1001 
Page 34 of 34
Statistical Analysis Plan  
15 May 2023
 
CONFIDENTIAL 
9.6 
Criteria for Identification of Markedly Abnormal Orthostatic Changes 
Parameter 
 
Criteria  
Orthostatic Hypotension 
 
Orthostatic Tachycardia 
 
Decrease in SBP ≥20 mm Hg or a decrease in DBP ≥10 mm Hg on 
standing  
Defined as an increase of >30 bpm or HR >120 bpm on standing 
Note: Orthostatic measurement = standing vital measurement – semi-recumbent vital measurement. 
 
9.7 
Criteria for Identification of Markedly Abnormal Values for the 12-Lead ECG 
Parameters  
Parameter 
Lower Criteria 
Upper Criteria 
Heart rate 
<50 beats per minute 
>120 beats per minute 
PR 
≤80 milliseconds 
≥200 milliseconds 
QTcF Interval 
 
≥500 milliseconds OR  
≥30 milliseconds change from baseline and 
≥450 milliseconds 
QRS 
≤80 milliseconds 
≥120 milliseconds 
 
For non-commercial use only


Signature Page for 16-1-9-1 Statistical Analysis Plan Amend 1.0_2023-05-15
Title: 16-1-9-1 Statistical Analysis Plan Amend 1.0_2023-05-15
Document Number: TDN-000179931 v1.0
Approval
Statistics
17-May-2023 14:59:17 GMT+0000
For non-commercial use only