Clinical trial NCT04731922
Conditions: Healthy Participants
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2021-02-03; Completion date: 2022-07-24
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a study of TAK-510 for people with symptoms of feeling sick (nausea) or being sick (vomiting).

The main aims of the study are to check if healthy adults have side effects from TAK-510 and to check how much TAK-510 they can receive without getting side effects from it.

The study will be in 3 parts. Participants will take part in only 1 of the 3 parts of the study.

At the first visit, the study doctor will check if each person can take part. For those who can take part, they will be placed in 1 of many small groups. The 1st groups will join Part 1 of the study, the 2nd groups will join Part 2 and the 3rd groups will join Part 3. They will receive an injection under the skin of either TAK-510 or placebo. In this study, a placebo will look like the TAK-510 injection but will not have any medicine in it.

In Part 1, the 1st group of participants will receive 1 injection of either TAK-510 or placebo. Different participants within this group will receive lower to higher doses of TAK-510. The participants in this group will stay in the clinic for 4 days after their injection for some tests and check for any side effects from their treatment.

In Part 2, the 2nd group of participants will receive an injection of either TAK-510 or placebo, once a day for 5 days. Different participants within this group will receive lower to higher doses of TAK-510. The participants in this group will stay in the clinic for 9 days after their 1st injection for some tests and check for any side effects from their treatment.

In Part 3, the 3rd group of participants will visit the clinic 2 times. At the 1st visit, they will receive an injection either of TAK-510 or placebo, once a day for 7 days. Each participant in this group will receive lower to higher doses of TAK-510. They will stay in the clinic for 8 days after their 1st injection for some tests and check for any side effects from their treatment.

At the 2nd clinic visit, each participant will receive 1 single injection of TAK-510 or placebo. This will happen 7 days after their last injection from the previous clinic visit. They will receive the same dose as their previous dose. They will stay in the clinic for 3 days for some tests and check for any side effects from their treatment.

After treatment, all participants in the study will return to the clinic for a weekly check-up visit for up to 3 weeks.

Detailed description:
The drug being tested in this study is called TAK-510. The study will look at the safety, tolerability, and PK of TAK-510 in healthy participants.

The study will enroll up to approximately 224 healthy participants. Participants in each cohort will be randomized to receive treatment with TAK-510 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 3 parts and up to 28 cohorts as mentioned below.

* TAK-510, Part 1: Single rising dose (SRD) design to assess the safety, immunogenicity, tolerability, and PK of TAK-510
* TAK-510, Part 2: Multiple rising dose (MRD) design to assess the safety, immunogenicity, tolerability, and PK of TAK-510
* TAK-510, Part 3: Dose titration and redosing design to assess the safety, immunogenicity, tolerability, and PK of TAK-510

This multi-center trial will be conducted in the United States. The overall duration of the study is approximately 57 days. Participants will be followed up for 7 days after the last dose of study drug for a follow-up assessment.

Arms: arm 1: TAK-510 at starting dose of 5 microgram (mcg) or placebo-matching solution, subcutaneously, once on Day 1. Staggered dosing will be done in the first cohort of Part A (Cohort 1). Staggered dosing in subsequent Cohorts (Cohorts 2-12 and 21-25) will be used based on emerging safety, tolerability, and PK data from Cohort 1 as determined in the dose escalation meeting. arm 2: TAK-510 to be decided (TBD) or placebo-matching solution, subcutaneously, once daily from Day 1 through Day 5. Dose of MRD Cohorts (Cohorts 13-17 and 26-28) of Part 2 will be determined based on emerging safety, tolerability, and available PK data from Part 1 (SRD) and any available PK data from Part 2 as determined in the dose escalation meeting. arm 3: TAK-510 TBD or placebo-matching solution, subcutaneously, once daily from Days 1 to 7. Dose of dose titration and redosing Cohorts (Cohorts 18-20) of Part 3 will be based on emerging safety, tolerability, and available PK data from Part 1 (SRD) and Part 2 (MRD) as determined in the dose escalation meeting. Single redosing will be performed on Day 14 after 7 days of washout period following the 7 days treatment period.
Interventions: intervention 1: TAK-510 intervention 2: TAK-510 Placebo
Intervention descriptions: intervention 1: TAK-510 solution. intervention 2: TAK-510 placebo-matching solution.

Protocol documents:
Prot_000.pdf: 
NCT Number:  NCT04731922
Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of TAK-510 in Healthy Subjects
Study Number: TAK-510-1001
Document Version and Date: Amendment 3; 21 April 2022
Certain information within this document has been redacted (ie, specific content is masked irreversibly 
from view with a black bar) to protect either personally identifiable information or company 
confidential information. 
Clinical Study Protocol


TITLE PAGE
TAKEDA DEVELOPMENT CENTER AMERICAS, INC 
PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of TAK-510 in Healthy Subjects
Study Identifier:
TAK-510-1001
Compound:
TAK-510
Date:
21 April 2022
Version Number:
Amendment 3
Amendment History:
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
21 April 2022
Amendment 3
Substantial
Global
02 September 2021
Amendment 2
Substantial
Global
19 May 2021
Amendment 1
Substantial
Global
02 December 2020
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.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................9
1.1
Protocol Amendment 3 Summary of Changes..........................................................14
2.0
STUDY SCHEMATIC..................................................................................................21
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................22
3.1
Part 1 for SRD Cohorts 1 to 12 and 21 to 25 ............................................................22
3.2
Part 2 for MRD Cohorts 13 to 17 and 26 to 28: Screening Through Day 9, 
Follow-Up, and Early Termination...........................................................................25
3.2.1
Overall Schedule of Study Procedures for Part 2..............................................25
3.2.2
Part 2 for MRD Screening Through Day 1 Assessments ..................................29
3.2.3
Part 2 for MRD Days 2 to 4 Assessments.........................................................32
3.2.4
Part 2 for MRD Day 5 Through Day 9 Assessments, Follow-Up, and Early 
Termination.....................................................................................................34
3.3
Part 3 for Dose Titration and Redosing Cohorts 18 to 20: Screening Through Day 
15, Follow-Up, and Early Termination.....................................................................37
3.3.1
Overall Schedule of Study Procedures for Part 3..............................................37
3.3.2
Part 3 Screening Through Day 1 Assessments..................................................41
3.3.3
Part 3 Days 2 to 6 Assessments........................................................................44
3.3.4
Part 3 Day 7 and Day 8 Assessments ...............................................................46
3.3.5
Part 3 Day 9 Through Day 15 Assessments, Follow-Up, and Early 
Termination.....................................................................................................48
4.0
INTRODUCTION.........................................................................................................51
4.1
Background .............................................................................................................51
4.2
Rationale for the Proposed Study.............................................................................51
4.3
Benefit/Risk Profile .................................................................................................51
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................53
5.1
Study Objectives......................................................................................................53
5.1.1
Study Primary Objective..................................................................................53
5.1.2
Study Secondary Objectives.............................................................................54
5.1.3
Study Exploratory Objectives ..........................................................................54
5.2
Endpoints.................................................................................................................55
5.2.1
Primary Endpoint.............................................................................................55
5.2.2
Secondary Endpoints .......................................................................................55
5.2.3
Exploratory Endpoints .....................................................................................56
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................56
6.1
Study Design ...........................................................................................................56
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Study ID TAK-510-1001
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6.1.1
Overall Study Design.......................................................................................56
6.1.2
Part 1: SRD Cohorts 1 to 12 and 21 to 25.........................................................59
6.1.3
Part 2: MRD Cohorts 13 to 17 and 26 to 28 .....................................................60
6.1.4
Part 3: Dose Titration and Redosing Cohorts 18 to 20......................................62
6.2
Stopping Rules.........................................................................................................64
6.2.1
Stopping Criteria for Individual Subjects .........................................................64
6.2.2
Criteria for Premature Termination or Suspension of the Study........................64
6.3
Rationale for Study Design, Dose, and Endpoints ....................................................66
6.3.1
Rationale of Study Design ...............................................................................66
6.3.2
Rationale for Dose...........................................................................................66
6.3.2.1
FIH Starting Dose Consideration Based on Nonclinical Safety Study
Results,
Experience...............................................................................................66
6.3.2.2
FIH Maximum Dose Consideration .........................................................68
6.3.2.3
FIH Proposed Dose Regimen for the SRD Cohorts..................................68
6.3.2.4
Rationale for Dosing Interval...................................................................69
6.3.2.5
Rationale for Dose Titration and Redosing After Washout.......................69
6.3.3
Rationale for Endpoints ...................................................................................70
6.3.4
Critical Procedures Based on Study Objectives: Timing of Procedures ............70
6.4
Procedure Modifications Permitted Within Protocol Parameters ..............................70
6.5
Study Beginning and End/Completion .....................................................................70
6.5.1
Definition of Beginning of the Study ...............................................................70
6.5.2
Definition of End of the Study.........................................................................70
6.5.3
Definition of Study Discontinuation.................................................................71
6.5.4
Criteria for Premature Termination or Suspension of the Study........................71
6.5.4.1
Criteria for Premature Termination or Suspension of Study .....................71
6.5.4.2
Procedures for Premature Termination or Suspension of the Study ..........71
6.5.5
Criteria for Premature Termination or Suspension of a Site..............................71
6.5.5.1
Criteria for Premature Termination or Suspension of a Site......................71
6.5.5.2
Procedures for Premature Termination or Suspension of a Site ................71
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............72
7.1
Inclusion Criteria .....................................................................................................72
7.2
Exclusion Criteria ....................................................................................................73
7.3
Excluded and Allowed Concomitant Medications, Supplements, and Dietary
Products...................................................................................................................75
7.3.1
Concomitant Medications ................................................................................75
Property of Takeda: For N
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7.3.2
Fruit Juice........................................................................................................75
7.3.3
Alcohol............................................................................................................75
7.3.4
Caffeine...........................................................................................................75
7.3.5
Smoking ..........................................................................................................75
7.4
Diet, Fluid, Activity.................................................................................................76
7.4.1
Diet and Fluid..................................................................................................76
7.4.1.1
Part 1.......................................................................................................76
7.4.1.2
Part 2 and 3..............................................................................................76
7.4.2
Activity ...........................................................................................................76
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................76
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................77
7.7
Subject Replacement................................................................................................77
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................78
8.1
Clinical Study Drug .................................................................................................78
8.1.1
Clinical Study Drug Labeling ..........................................................................78
8.1.2
Clinical Study Drug Inventory and Storage......................................................78
8.1.3
Clinical Study Drug Blinding...........................................................................78
8.1.4
Randomization Code Creation and Storage......................................................79
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure.................................79
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.............................79
8.2
Ancillary Supplies ...................................................................................................80
9.0
STUDY PROCEDURES...............................................................................................80
9.1
Administrative Procedures.......................................................................................80
9.1.1
Informed Consent Procedure............................................................................80
9.1.1.1
Assignment of Screening and Randomization Numbers ...........................80
9.1.1.2
Study Drug Assignment...........................................................................81
9.1.2
Inclusion and Exclusion...................................................................................81
9.1.3
Medical History/Demography..........................................................................81
9.1.4
Concomitant Medications ................................................................................81
9.2
Clinical Procedures and Assessments.......................................................................81
9.2.1
Full Physical Examination ...............................................................................81
9.2.2
Height and Weight...........................................................................................81
9.2.3
BMI.................................................................................................................81
9.2.4
Vital Signs.......................................................................................................81
9.2.4.1
Follow-Up Safety Monitoring..................................................................83
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9.2.5
Glucose ...........................................................................................................84
9.2.6
ECG Procedure................................................................................................84
9.2.6.1
Screening and Safety ECGs .....................................................................84
9.2.6.2
Telemetry ................................................................................................84
9.2.7
Study Drug Administration..............................................................................85
9.2.8
AE Monitoring ................................................................................................85
9.2.9
Laboratory Procedures and Assessments..........................................................86
9.2.9.1
Hematology.............................................................................................86
9.2.9.2
Chemistry................................................................................................86
9.2.9.3
Urinalysis ................................................................................................87
9.2.9.4
Diagnostic Screening...............................................................................87
9.2.10
PK, Immunogenicity, Biomarker, and DNA Samples.......................................87
9.2.10.1
PK Measurements....................................................................................88
9.2.10.2
Immunogenicity (ADA) Measurements ...................................................90
9.2.10.3
Biomarker Measurements ........................................................................91
9.2.10.4
DNA Measurements ................................................................................91
9.3
Confinement ............................................................................................................92
9.3.1
Part 1 (SRD)....................................................................................................92
9.3.2
Part 2 (MRD)...................................................................................................92
9.3.3
Part 3 (Dose Titration and Redosing) ...............................................................92
9.4
Childbearing Status and Methods of Contraception..................................................93
9.4.1
Women of Childbearing Potential....................................................................93
9.4.1.1
Definition of Women of Childbearing Potential.......................................93
9.4.2
Women of Nonchildbearing Potential ..............................................................93
9.4.2.1
Contraception for Women of Nonchildbearing Potential..........................93
10.0
ADVERSE EVENTS ....................................................................................................93
10.1
Definitions and Elements of AEs .............................................................................93
10.1.1
SAEs ...............................................................................................................95
10.1.2
AEs of Special Interest.....................................................................................96
10.2
AE Procedures.........................................................................................................96
10.2.1
Assigning Severity/Intensity of AEs ................................................................96
10.2.2
Assigning Causality of AEs .............................................................................96
10.2.3
Start Date.........................................................................................................97
10.2.4
End Date..........................................................................................................97
10.2.5
Pattern of Adverse Event (Frequency)..............................................................97
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10.2.6
Action Taken With Study Treatment................................................................97
10.2.7
Outcome..........................................................................................................97
10.2.8
Collection and Reporting of AEs, SAEs, AESIs, and Abnormal LFTs .............98
10.2.8.1
Collection Period.....................................................................................98
10.2.8.2
Reporting AEs.........................................................................................98
10.2.8.3
Reporting SAEs.......................................................................................99
10.2.8.4
Management of Specific AEs.................................................................100
10.2.8.5
Reporting of Abnormal LFTs.................................................................101
10.2.9
Safety Reporting to Investigators, IRBs and/or IECs, and Regulatory 
Authorities.....................................................................................................101
11.0
STATISTICAL METHODS........................................................................................101
11.1
Statistical and Analytical Plans ..............................................................................101
11.1.1
Analysis Sets .................................................................................................102
11.1.1.1
Safety Analysis Set................................................................................102
11.1.1.2
PK Analysis Set.....................................................................................102
11.1.1.3
Immunogenicity Analysis Set ................................................................102
11.1.2
Analysis of Demography and Other Baseline Characteristics .........................102
11.1.3
PK Analysis...................................................................................................102
11.1.4
Safety Analysis..............................................................................................103
11.1.4.1
AEs .......................................................................................................103
11.1.4.2
Clinical Laboratory Evaluations.............................................................103
11.1.4.3
Vital Signs.............................................................................................103
11.1.4.4
ECG ......................................................................................................104
11.1.4.5
Other Safety Parameters ........................................................................104
11.1.5
Immunogenicity Analysis ..............................................................................104
11.1.6
Biomarker Analysis .......................................................................................105
11.2
Interim Analysis ....................................................................................................105
11.3
Determination of Sample Size................................................................................105
12.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................105
12.1
Study-Site Monitoring Visits .................................................................................105
12.2
Protocol Deviations................................................................................................106
12.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................106
13.0
ETHICAL ASPECTS OF THE STUDY......................................................................106
13.1
IRB and/or IEC Approval ......................................................................................107
13.2
Subject Information, Informed Consent, and Subject Authorization .......................107
13.3
Subject Confidentiality ..........................................................................................109
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13.4
Publication, Disclosure, and Clinical Study Registration Policy .............................109
13.4.1
Publication and Disclosure.............................................................................109
13.4.2
Clinical Study Registration ............................................................................109
13.4.3
Clinical Study Results Disclosure ..................................................................110
13.5
Insurance and Compensation for Injury..................................................................110
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.......................................110
14.1
Administrative Information....................................................................................110
14.1.1
Study Contact Information.............................................................................110
14.1.2
INVESTIGATOR AGREEMENT .................................................................111
14.1.3
Study-Related Responsibilities.......................................................................112
14.1.4
List of Abbreviations .....................................................................................112
15.0
DATA HANDLING AND RECORDKEEPING..........................................................114
15.1
Case Report Forms (Electronic and Paper).............................................................114
15.2
Record Retention ...................................................................................................114
16.0
REFERENCES............................................................................................................115
17.0
APPENDICES.............................................................................................................117
LIST OF IN-TEXT TABLES
Table 3.a
Part 1 for SRD Cohorts 1 to 12 and 21 to 25.......................................................22
Table 3.b
Part 2 for MRD Cohorts 13 to 17 and 26 to 28: Screening Through Day 9, 
Follow-Up, and ET ............................................................................................25
Table 3.c
Part 2 for MRD Screening Through Day 1 Assessments.....................................29
Table 3.d
Part 2 for MRD Days 2 to 4 Assessments...........................................................32
Table 3.e
Part 2 for MRD Day 5 Through Day 9 Assessments, Follow-Up, and ET...........34
Table 3.f
Part 3 for Dose Titration and Redosing Cohorts 18 to 20: Screening Through 
Day 15, Follow-Up, and ET ...............................................................................37
Table 3.g
Part 3 Screening Through Day 1 Assessments....................................................41
Table 3.h
Part 3 Days 2 to 6 Assessments ..........................................................................44
Table 3.i
Part 3 Day 7 and Day 8 Assessments..................................................................46
Table 3.j
Part 3 Day 9 Through Day 15 Assessments, Follow-Up, and ET........................48
Table 6.a
Overview of Treatment Cohorts.........................................................................58
Table 6.b
Human Dose-Related Concentrations and Exposures for Select Proposed Doses 
in Part 1 .............................................................................................................69
Table 9.a
Primary Specimen Collections ...........................................................................88
Table 10.a
NCI CTCAE ......................................................................................................96
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LIST OF IN-TEXT FIGURES
Figure 2.a
Study Schematic ................................................................................................21
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator...................................................................117
Appendix B
Elements of the Subject Informed Consent.......................................................119
Appendix C
Investigator Consent to the Use of Personal Information ..................................122
Appendix D
Pregnancy and Contraception...........................................................................123
Appendix E
Protocol History...............................................................................................126
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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-510
Study Identifier: TAK-510-1001
Phase: 1
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of TAK-510 in Healthy Subjects
Study Design:
This is a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of TAK-510 in healthy subjects. 
The study will consist of 3 parts:

Part 1 is a first-in-human, randomized, double-blind, placebo-controlled, single rising dose (SRD) design to
assess the safety, immunogenicity, tolerability, and PK of TAK-510 in healthy subjects. Up to 17 cohorts may be
enrolled.

Part 2 is a randomized, double-blind, placebo-controlled, multiple rising dose (MRD) design to assess the safety,
immunogenicity, tolerability, and PK of TAK-510 in healthy subjects. Up to 8 cohorts may be tested in
independent subject cohorts.

Part 3 is a randomized, double-blind, placebo-controlled, multiple-dose, dose titration and redosing design to
assess the safety, immunogenicity, tolerability, and PK of TAK-510 in healthy subjects. Up to 3 cohorts may be
tested in independent subject cohorts using a dose titration design, followed by redosing with a single dose of
study drug after a 7-day washout (168 hours after the previous dose).
TAK-510 and matching placebo will be administered subcutaneously (SC). Safety will be assessed by monitoring for 
adverse events (AEs), vital signs, electrocardiogram (ECG)/telemetry, safety laboratory assessments after each dose, 
and immunogenicity. PK sampling times and scheme may vary based on emerging safety, tolerability and PK data, but 
the maximal number of samples or the maximum time point will not change. Subjects may not participate in more than 
1 part or dosing cohort of the study.
Study Primary Objective:

Part 1:
–
To characterize the safety and tolerability of single SC doses of TAK-510 in healthy subjects.

Part 2:
–
To characterize the safety and tolerability of multiple SC doses of TAK-510 in healthy subjects.

Part 3:
–
To characterize the safety and tolerability of multiple SC dose regimens of TAK-510 that include titration
from lower doses in healthy subjects.
Secondary Objectives:

Part 1:
–
To characterize the PK of TAK-510 in plasma following single SC doses in healthy subjects.
–
To assess the immunogenicity of TAK-510 following single SC doses in healthy subjects.
–
To characterize the PK of TAK-510 in urine following single SC doses in healthy subjects.

Part 2:
–
To characterize the PK of TAK-510 in plasma following multiple SC doses in healthy subjects.
–
To assess the immunogenicity of TAK-510 following multiple SC doses in healthy subjects.
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–
To characterize the PK of TAK-510 in urine following multiple SC doses in healthy subjects.

Part 3:
–
To characterize the safety and tolerability of single SC rechallenge doses of TAK-510 after a washout from 
multiple SC dose regimens that include titration from lower doses in healthy subjects.
–
To assess the immunogenicity of TAK-510 following multiple SC dose regimens that include titration from 
lower doses, washout, and redosing in healthy subjects. 
Study Subject Population: Healthy male and female (nonchildbearing potential only) subjects aged 18 to 55 years, 
inclusive, at screening. Body mass index ≥18 and ≤30.0 (kg/m2) at the screening.
Planned Number of Subjects:
Part 1: Up to approximately 136 subjects.
Part 2: Up to approximately 64 subjects.
Part 3: Up to approximately 24 subjects.
Approximate values do not account for potential 
replacement of subjects who withdraw for nonsafety 
reasons.
Planned Number of Sites:
Up to 2 sites.
Dose Levels:
Part 1: TAK-510 SRD: starting dose 5 μg
Part 2: TAK-510 MRD: doses to be determined based 
on Part 1.
Part 3: TAK-510 Dose Titration and Redosing: doses 
to be determined based on Parts 1 and 2. 
Route of Administration:
Subcutaneous (SC)
Duration of Treatment:
Part 1: 1 day.
Part 2: 5 days.
Part 3: 15 days (7 days plus 1 day after 7 days of 
washout.)
Planned Study Duration:
Approximately 57 days from screening (Day -28) until last 
follow-up visit (Day 29).
Main Criteria for Inclusion:
In order to be eligible for study participation, the subject must: 
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 man or woman of nonchildbearing potential 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 
dosing and throughout the study.
5.
Have a body mass index ≥18 and ≤30.0 (kg/m2) at the screening visit.
6.
Be judged to be in good health (eg, no evidence of psychiatric, hepatic, renal, pulmonary, or cardiovascular 
disease) by the investigator, based on clinical evaluations including laboratory safety tests, medical history, 
physical examination, ECG, and vital sign measurements performed at the screening visit and before
administration of the initial dose of study drug or invasive procedure.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if:

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 study dose and/or 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.
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Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL

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 2 days after 
discharge.

The subject has a history or presence of: 
–
3 or more incidences of vasovagal syncope within the last 5 years prior to screening; or
–
A family history of unexplained sudden death or channelopathy; or
–
Brugada syndrome (ie, RBBB pattern with ST-elevation in leads V1-V3); or
–
Cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, stroke, sick 
sinus syndrome, pulmonary congestion, symptomatic or significant cardiac arrhythmia, 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; or
–
Risk factors for Torsade de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT 
Syndrome); or
–
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 >210 msec at screening or Day -1 
pre-Hour 0; or
–
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 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 time point values do not meet 
this criterion, must be discussed with the medical monitor for approval. 

The subject has an average HR <55 or >100 bpm from screening to predose, inclusive. Subjects with an average 
HR <55 bpm can be enrolled only with medical monitor approval. Any assessments after admission with an 
average HR <55 bpm, from Day -2 to predose (inclusive), 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 ≥20 mm Hg or a decrease in diastolic 
BP ≥10 mm Hg at approximately 3 minutes of standing when compared with BP from the semirecumbent position 
at screening to predose assessments, inclusive. In asymptomatic subjects, any assessments after screening that 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 3 minutes of standing, at screening to predose assessments, inclusive. Any assessments after 
screening that 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:

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: 

Part 1: plasma PK parameters for TAK-510
–
Maximum observed plasma concentration (Cmax).
–
Area under the plasma concentration-time curve from time 0 to infinity (AUC∞).
–
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration 
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Study ID TAK-510-1001
Page 12 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
(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 disposition phase after extravascular administration 
(Vz/F).

Part 2: plasma PK parameters for TAK-510 on Day 1
–
Cmax, tmax, and area under the plasma concentration-time curve during a dosing interval, where tau (τ) is the 
length of the dosing interval (AUCτ).

Part 2: plasma PK parameters for TAK-510 at steady state
–
AUCτ, Cmax, tmax, t1/2z, CL/F, Vz/F, observed plasma concentration at the end of a dosing interval (Ctrough), 
accumulation ratio based on AUCτ (Rac[AUC]), calculated as AUCτ at steady state/AUCτ after a single dose, 
and accumulation ratio based on Cmax (Rac[Cmax]), calculated as Cmax at steady state/Cmax after a single dose.

Parts 1 and 2: urine PK parameters for TAK-510
–
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) at steady state (Aeτ).
–
Fraction of administered dose of drug excreted from urine from time 0 to time t (fe,t). 
–
Renal clearance (CLR).

Part 3:
–
Safety and tolerability of single SC rechallenge doses after a washout from multiple SC dose regimens of
TAK-510 as assessed through vital signs, ECG, laboratory assessments, and AEs.

All parts of the study:
–
Status of subject’s antidrug antibody (ADA) assessment (ie, ADA-negative or ADA-positive, and low or 
high ADA titer). 
Statistical Considerations:
Safety analyses will be based on the safety analysis set (defined as all subjects who are randomized and receive at least 
1 dose of study treatment). No formal statistical tests or inference will be performed for safety analyses. All summary 
analyses will be performed by placebo, TAK-510 dose level (Parts 1 and 2 only)/dose regimen (Part 3 only), and 
TAK-510 overall within each part of the study separately. In particular, 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. Placebo data 
will be pooled across cohorts within each part of the study. The same dose level (Parts 1 and 2 only)/dose regimen 
(Part 3 only) will be pooled across cohorts within each part of the study where appropriate. For Part 3 only, similar 
safety summary analyses (excluding ADA assessments) will be performed for the single dose after washout from 
multiple dose regimens of TAK-510 by placebo, TAK-510 single dose level after washout, and TAK-510 single dose 
overall after washout.
The plasma (all parts of the study) and urine (Parts 1 and 2 only) concentrations of TAK-510 will be summarized by 
dose level (Parts 1 and 2 only)/dose regimen (Part 3 only) at each scheduled sampling day/time within each part of the 
study separately, using descriptive statistics based on the PK analysis set (defined as all subjects who receive at least 
1 dose of TAK-510 and have at least 1 measurable postdose plasma or urine concentration for TAK-510). The PK 
parameters of TAK-510 determined using a noncompartmental analysis approach will be summarized by dose level 
(Parts 1 and 2 only)/dose regimen (Part 3 only) of TAK-510, as appropriate, within each part of the study separately, 
using descriptive statistics based on the PK analysis set. 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. 
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TAK-510
Study ID TAK-510-1001
Page 13 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Sample Size Justification: 
The selected sample sizes in Parts 1, 2, and 3 of the study are considered sufficient for evaluation of safety and 
tolerability of TAK-510 in healthy subjects. No formal statistical hypothesis testing is planned in Parts 1, 2, or 3. 
Therefore, no formal power calculations were performed in the determination of sample size for the study.
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TAK-510
Study ID TAK-510-1001
Page 14 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
1.1
Protocol Amendment 3 Summary of Changes
Protocol Amendment 3 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 3. The 
primary reasons for this amendment are to: 
1. Clarify maximum exposure of TAK-510.
2. Revise study design to include additional single rising dose (SRD) and multiple rising dose
(MRD) cohorts.
3. Add safety measures at follow-up visits for coronavirus disease 2019 (COVID-19) monitoring.
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.
Title Page
For consistency
2.
Section 1.0 STUDY 
SUMMARY
Updated planned number of subjects.
To include subjects from 
additional single rising 
dose (SRD) and multiple 
rising dose (MRD) cohorts.
3.
Section 1.0 STUDY 
SUMMARY
Section 6.1.2 Part 1: SRD 
Cohorts 1 to 12 and 21 to 25
Section 6.1.3 Part 2: MRD 
Cohorts 13 to 17 and 26 to 28
Section 6.1.4 Part 3: Dose 
Titration and Redosing Cohorts 
18 to 20
Clarified that approximate sample sizes 
do not account for potential 
replacement of subjects and updated 
total sample size due to the increase in 
number of cohorts.
To clarify the approximate 
sample sizes and to update 
total sample size to account 
for the increase in number
of cohorts.
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Study ID TAK-510-1001
Page 15 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
4.
Section 1.0 STUDY 
SUMMARY
Section 2.0 STUDY 
SCHEMATIC
Section 3.1 Part 1 for SRD 
Cohorts 1 to 12 and 21 to 25
Section 3.2 Part 2 for MRD 
Cohorts 13 to 17 and 26 to 28: 
Screening Through Day 9, 
Follow-Up, and Early 
Termination
Section 6.1.1 Overall Study 
Design
Section 6.1.2 Part 1: SRD 
Cohorts 1 to 12 and 21 to 25
Section 6.1.3 Part 2: MRD 
Cohorts 13 to 17 and 26 to 28
Section 6.3.1 Rationale of Study
Design
Section 6.3.2.2 FIH Proposed 
Dose Regimen for the SRD 
Cohorts
Updated study design to add SRD and 
MRD cohorts. 
Figure 2.a, Table 3.a, Table 3.b, 
Table 3.f, Table 3.j, and Table 6.a were 
updated.
To clarify the maximum 
exposure cap for TAK-510 
and study doses that will 
produce concentrations in 
efficacious range.
6.
Section 3.1 Part 1 for SRD 
Cohorts 1 to 12 and 21 to 25
For Table 3.a, blood pressure (BP) and 
pulse assessments were added to the 
follow-up visits on Days 8, 14, and 29.
Correction of study 
procedures.
Section 3.2.1 Overall Schedule 
of Study Procedures for Part 2
For Table 3.b, BP and pulse 
assessments were added to the 
follow-up visit on Day 14.
Section 3.2.4 Part 2 for MRD 
Day 5 Through Day 9 
Assessments, Follow-Up, and 
Early Termination
For Table 3.e, BP and pulse 
assessments were added to the 
follow-up visits on Days 14, and 29. 
Section 3.2.2 Part 2 for MRD 
Screening Through Day 1 
Assessments
Section 3.3.2 Part 3 Screening 
Through Day 1 Assessments
Table 3.c and Table 3.g was updated to 
remove footnote h “Only serum 
chemistry to measure electrolytes 
(sodium, potassium, chloride, and 
carbon dioxide) should be performed at 
the 4-hour assessment.”
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TAK-510
Study ID TAK-510-1001
Page 16 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
Section 3.3.5 Part 3 Day 9 
Through Day 15 Assessments, 
Follow-Up, and Early 
Termination
For Table 3.j, BP and pulse assessments 
were added to the follow-up visit on 
Day 29 and the “inclusion/exclusion 
criteria” row was removed. In addition, 
a footnote for BMI was added for 
clarification.
7.
Section 3.1 Part 1 for SRD 
Cohorts 1 to 12 and 21 to 25
Section 3.2 Part 2 for MRD 
Cohorts 13 to 17 and 26 to 28: 
Screening Through Day 9, 
Follow-Up, and Early 
Termination
Section 3.3 Part 3 for Dose 
Titration and Redosing Cohorts 
18 to 20: Screening Through Day 
15, Follow-Up, and Early 
Termination
Section 9.2.4 Vital Signs
Section 11.1.4.3 Vital Signs
Table 3.a, Table 3.b, Table 3.c, 
Table 3.d, Table 3.e, Table 3.f, 
Table 3.g, Table 3.h, Table 3.i, and 
Table 3.j were updated.
Added language to define 
“inconsistent” BP measurements.
Text added for 
clarification.
8.
Section 3.1 Part 1 for SRD 
Cohorts 1 to 12 and 21 to 25
Section 3.2 Part 2 for MRD 
Cohorts 13 to 17 and 26 to 28: 
Screening Through Day 9, 
Follow-Up, and Early 
Termination
Section 3.3 Part 3 for Dose 
Titration and Redosing Cohorts 
18 to 20: Screening Through Day 
15, Follow-Up, and Early 
Termination
Section 9.2.10 PK, 
Immunogenicity, Biomarker, 
and DNA Samples
Section 9.2.10.4.1 Blood Sample 
for DNA
Section 9.2.10.4.2 Biological 
Sample Retention and 
Destruction
Table 3.a, Table 3.b, Table 3.e, 
Table 3.f, Table 3.i, Table 3.j, and 
Table 9.a were updated.
Removed collection of buccal epithelial 
cell sample from the study.
Buccal sampling removed 
due to technical issues with 
the sample for the assay.
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Study ID TAK-510-1001
Page 17 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
9.
Section 3.1 Part 1 for SRD 
Cohorts 1 to 12 and 21 to 25
Section 3.2 Part 2 for MRD 
Cohorts 13 to 17 and 26 to 28: 
Screening Through Day 9, 
Follow-Up, and Early 
Termination
Section 3.3 Part 3 for Dose 
Titration and Redosing Cohorts 
18 to 20: Screening Through Day 
15, Follow-Up, and Early 
Termination
Table 3.a, Table 3.b, Table 3.c, 
Table 3.f, and Table 3.g were updated.
Modified language in footnote for 
predose time-matched telemetry.
For clarification of time 
period for time-matched 
extractions.
10.
Section 1.0 STUDY 
SUMMARY
Section 6.1.1 Overall Study 
Design
Section 6.3.1 Rationale of Study
Design
Updated wording “dose/dose regimen” 
to “cohort.”
For consistency between 
Part 1 and Part 2/3.
11.
Section 3.3.5 Part 3 Day 9 
Through Day 15 Assessments, 
Follow-Up, and Early 
Termination
Table 3.j was updated to add adverse 
event (AE) monitoring on Days 9 to 13.
To clarify AE monitoring.
12.
Section 1.0 STUDY 
SUMMARY
Section 7.1 Inclusion Criteria
Section 7.2 Exclusion Criteria
Modified inclusion criterion #7 to 
clarify the birth control criteria for male 
subjects.
For clarification of birth 
control criteria #7 for male 
subjects.
Modified language in exclusion 
criterion #1 to “last dose.”
For correction of exclusion 
criterion #1 that criterion is 
after last dose of study 
drug.
Modified language in exclusion criteria 
#14 and #15.
For clarification of 
exclusion criteria #14 and 
#15. 
13.
Section 4.3 Benefit/Risk Profile
Myalgia was added to potential risks of 
TAK-510.
To include preliminary 
safety data from Study 
TAK-510-1001.
Updated with results from embryo-fetal 
development study.
To include audited draft 
results from a definitive rat 
embryo-fetal development.
“TAK-510 is a modified peptide with a 
lipidated conjugation” was removed.
Repetitive text was deleted
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TAK-510
Study ID TAK-510-1001
Page 18 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
“excluding women of childbearing 
potential” was added to the last 
paragraph.
For clarification.
14.
Section 6.1.2 Part 1: SRD 
Cohorts 1 to 12 and 21 to 25
Section 6.1.3 Part 2: MRD 
Cohorts 13 to 17 and 26 to 28
Section 6.1.4 Part 3: Dose 
Titration and Redosing Cohorts 
18 to 20
Section 6.3.2.2 FIH Maximum 
Dose Consideration
Section 6.3.2.2 FIH Proposed 
Dose Regimen for the SRD 
Cohorts
Section 6.3.2.4 Rationale for 
Dosing Interval
Exposure levels, details of highest 
planned doses, and preliminary 
pharmacokinetic (PK) data were added.
The maximum exposure of TAK-510 
was updated to 705,000 h*ng/mL. 
Table 6.b was updated.
To include observed 
preliminary human data.
To clarify the maximum 
exposure cap for TAK-510 
and study doses that will 
produce concentrations in 
efficacious range. This 
range was predicted by 
emerging information and 
will allow optimal onset of 
response of 30 minutes and 
highest dose exposures of 
at least 2-fold the 
anticipated efficacious 
exposure. The 
no-observed-adverse-effect 
level is unchanged.
15.
Section 6.1.2 Part 1: SRD 
Cohorts 1 to 12 and 21 to 25
Section 6.1.3 Part 2: MRD 
Cohorts 13 to 17 and 26 to 28
Section 6.1.4 Part 3: Dose 
Titration and Redosing Cohorts 
18 to 20
Language for injection volume added.
Text edited for clarification 
and consistency.
16.
Section 6.1.2 Part 1: SRD 
Cohorts 1 to 12 and 21 to 25
Section 6.1.3 Part 2: MRD 
Cohorts 13 to 17 and 26 to 28
Section 6.1.4 Part 3: Dose 
Titration and Redosing Cohorts 
18 to 20
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 to 
clarify that this is not an 
official committee. This is 
a dose escalation meeting 
and does not require a 
charter as would a Dose 
Escalation Committee.
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Study ID TAK-510-1001
Page 19 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
17.
Section 6.2.2 Criteria for 
Premature Termination or 
Suspension of the Study
a. Added language clarifying that
criteria apply when related to study
drug administration.
a. To clarify that criteria
apply when related to study
drug administration and for
better consistency.
b. Removed “vasovagal” from
“vasovagal syncope.”
Removed greater than or equal to sign 
in bullet for: “Two or more subjects 
experience a CTCAE v5.0 Grade ≥3 
event considered related to TAK-510 
administration”.
Added bullet for Grade ≥2 injection site 
reaction criterion.
b. For correction.
18.
Section 6.3.2.2 (previous 
numbering)
Previous Section 6.3.2.2, "Other 
Supporting Estimated 
Pharmacologically Active Exposures" 
was removed.
Removed because 
determination of doses 
 
efficacy
data and observed human 
PK data.
19.
Section 6.3.2.3 (previous 
numbering)
Previous Section 6.3.2.3 “Summary of 
FIH Starting Dose Consideration” was 
merged into Section 6.3.2.1.
To remove repetitive 
information.
20.
Section 6.4 Procedure 
Modifications Permitted Within 
Protocol Parameters
Removed details of Section 6.4 and 
provided general guidance.
For correction following 
the guidance of other 
studies in the program to 
document changes in the 
study file.
21.
Section 7.5 Criteria for 
Discontinuation or Withdrawal 
of a Subject
“AE” was updated to “TEAE.”
Text updated for 
clarification.
22.
Section 9.2.4.1 Follow-Up 
Safety Monitoring (new section)
Added to describe follow-up safety
monitoring procedures.
To continue safety 
monitoring of subjects who 
terminate early from the 
study.
23.
Section 9.2.6.1 Screening and 
Safety ECGs
Added “in semirecumbent position.”
For clarification.
24.
Section 9.2.9.3 Urinalysis
Changed “nitrate” to “nitrite.”
Correct an error.
25.
Section 9.2.10 PK, 
Immunogenicity, Biomarker, 
and DNA Samples
Footnotes added to Table 9.a.
Added language for sampling windows.
Footnotes added for 
clarification to provide 
time sampling windows for 
protocol-specified 
assessments.
f
of
o
criteria
criteria
lated to s
ated to
istration 
strati
nsisten
istenc
m
n
ts 
de ≥3 
≥3 
AK-510
51
e ≥2 inje
≥2 inj
For corr
For co
pli
he
n 6.3.2.2
6.3.2
Estimated
Estimat
ologically
ologicall
moved.
oved.
nd
Previous
Previou
FIH S
FIH
me
m
Us
rci
d Within
Withi
er
Criteria
Criter
nuation 
nuatio
Subject
ubject
No
ection
ction 9.9
Safety 
Safety
a:
Ta
3.
of
e
24
2
er
pe
p


TAK-510
Study ID TAK-510-1001
Page 20 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
26.
Section
For clarification.
27.
Section 10.2.8.3.1 SAE 
Follow-Up
Added “The site must use the eCRFs to 
report an SAE within 24 hours, and 
only if the eCRF is unavailable, should 
the site send a safety reporting form.”
To clarify serious adverse 
event reporting.
28.
Section 10.2.8.4.3 Injection Site 
Reaction
Language for Grade 2 injection site 
reactions added.
Text edited for 
clarification.
29.
Section 11.2 Interim Analysis
Language for interim analysis was 
revised.
Add flexibility to conduct 
an interim analysis when a 
data-dependent internal 
decision is needed to 
inform the subsequent 
development of TAK-510 
before database lock.
30.
Section 12.2 Protocol Deviations
Modified language to clarify protocol 
deviation.
For clarification of 
protocol deviation 
language.
31.
Section 15.1 Case Report Forms 
(Electronic and Paper)
Remove sentence regarding case report 
forms being required for each subject 
who signs an informed consent.
Correct an error. 
Property of Takeda: For Non-Commercial Use Only 
language
languag
on.
ly and Subject to the Applicable Terms of Use
f
of
o
m
fy seriou
serio
t reportin
report
ble
e
Tex
Te
c
e A
he
was 
as 
to 
ly
Rem
emove 
ove
forms 
form
wh
wh
Us
erci
r


TAK-510
Study ID TAK-510-1001
Page 21 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
2.0
STUDY SCHEMATIC
Figure 2.a
Study Schematic
D: day; MRD: multiple rising dose; QD: once daily. 
a The D8-13 washout period for Cohorts 19 and 20 is subject to change based on emerging safety, tolerability, and available pharmacokinetic data.
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Study ID TAK-510-1001
Page 22 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES 
3.1
Part 1 for SRD Cohorts 1 to 12 and 21 to 25
Table 3.a
Part 1 for SRD Cohorts 1 to 12 and 21 to 25
Day
Scheduled Time
Scheduled Time
Follow-u
p Visit 
Day 8
-1 day
Follow-u
p Visit 
Day 14
±2 days
Follow-u
p Visit 
Day 29
±3 days ET
-28 to -3 -2 a
Day -1 (Hours)
Day 1 (Hours)
Screening
0 0.5 1
2
3
4
5
7 10 12 16 24 b
Pre-
dose
0 0.5 1
2
3
4
5
7
10 12 16 24
30 48 72
96 c
(discharge)
Administrative Procedures
Informed consent
X
Inclusion/exclusion 
criteria
X
X
X
Medical 
history/demographics
X
Prior and concomitant 
medication review
X
X--------------------------------------------------------------------Continuous Review-----------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical 
examination
X
X
X d
X d
X
Height
X
Weight and BMI
X
X
TAK-510/placebo 
administration e
X
Temperature and 
respiratory rate 
X
X
X
X
X
X
BP and pulse f
X
X X X X X
X X X X X
X
X
X X
X
X
X X
X X
X X
X
X
X
X
X
X
X
X
X
Standing BP and 
pulse g
X
X
X
X
X X
X
X
X
X
X
X X
X
X
X
X
12-lead ECGs
X
X
X
X
X
X
ECG telemetry 
(12-lead)
X------------Continuous Monitoring h ------------X
X------------Continuous Monitoring------------X
Telemetry extraction i
X X X X X X
X X X X X
X
X
X X
X
X
X X
X X
X X
X
AE monitoring 
X j
X--------------------------------------------------------Continuous Monitoring-------------------------------------------------X
X
Laboratory Procedures/Assessments
Safety laboratory 
collection (hematology 
and serum chemistry) 
X
X
X
X k
X
X
X
X
X
X
Urinalysis
X
X
X
X
Serum sample for CK l
X
X
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 23 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.a
Part 1 for SRD Cohorts 1 to 12 and 21 to 25
Day
Scheduled Time
Scheduled Time
Follow-u
p Visit 
Day 8
-1 day
Follow-u
p Visit 
Day 14
±2 days
Follow-u
p Visit 
Day 29
±3 days ET
-28 to -3 -2 a
Day -1 (Hours)
Day 1 (Hours)
Screening
0 0.5 1
2
3
4
5
7 10 12 16 24 b
Pre-
dose
0 0.5 1
2
3
4
5
7
10 12 16 24
30 48 72
96 c
(discharge)
Glucose finger stick
X
X
X
Urine drug screen
X
X
Alcohol breath test
X
Cotinine test
X
X
Hepatitis screen m
X
HIV screen
X
βhCG (pregnancy) 
test n
X
X
X
X
Serum FSH test o
X
PK Evaluations
Plasma sample for 
TAK-510 PK 
X
X X
X
X
X X
X X
X X
X
X
X
X
X
X
Urine sample for 
TAK-510 PK p
X
X
X
X
X
Immunogenicity and Biomarker Evaluations
Serum sample for 
immunogenicity q
X
X
X
X
X
Blood sample for DNA 
(optional) r
X
X
Other
Confinement 
X-------------------------------------------------------------------------------------------------------X
ADA: antidrug antibodies; AE: adverse event; anti-HCV: antibodies to hepatitis C virus; AST: aspartate aminotransferase; βhCG: beta human chorionic gonadotropin; BMI: body 
mass index; BP: blood pressure; CK: creatine kinase; ECG: electrocardiogram; ET: early termination; FSH: follicle-stimulating hormone; 
 HBsAg: hepatitis B surface antigen; PK: pharmacokinetic; SRD: single rising dose.
a Subjects will be admitted to the site on Day -2. 
b The 24-hour sample on a given day is the same as the predose sample on the next day; only 1 assessment will be collected at this time point.
c Subjects will be confined for 96 hours after dosing (can be discharged after the 96-hour PK sample). 
d Physical examination at the indicated visit will be symptom-driven.
e Subjects will be administered a single dose of TAK-510 or matching placebo. 
Property of Takeda: For 
; anti
anti-HC
H
ne kinase
e kin
e antigen;
antige
e on Day
on Day
day is the
day is th
or No
X-------
-----
N
ercial Use Only and Subject to the Applicable Terms of Use
Te
lic
pp
6 24
30
24
3
Ap
Ap
he Ap
he
the
th
th
th
to th
to
to
to
t to
ctctct
ect
ec
bjec
bjejeje
Subje
Sub
ub
ub
d Sub
d
and
y an
an
X X
X
X
X
y a
Only a
X
On
On
On
s
Use
se
X
Us
i
s
ia
e ci
r 96 hours
96 hou
the indica
indi
nistered a
stere
or
Comme
Non-Co


TAK-510
Study ID TAK-510-1001
Page 24 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.a
Part 1 for SRD Cohorts 1 to 12 and 21 to 25
Day
Scheduled Time
Scheduled Time
Follow-u
p Visit 
Day 8
-1 day
Follow-u
p Visit 
Day 14
±2 days
Follow-u
p Visit 
Day 29
±3 days ET
-28 to -3 -2 a
Day -1 (Hours)
Day 1 (Hours)
Screening
0 0.5 1
2
3
4
5
7 10 12 16 24 b
Pre-
dose
0 0.5 1
2
3
4
5
7
10 12 16 24
30 48 72
96 c
(discharge)
f All BP and pulse assessments should be made in duplicate, 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 beats per minute in heart rate or a difference >10 mm Hg in systolic or diastolic BP) between assessments (see 
Section 9.2.4 for details). If 3 measurements are obtained, the final BP readout should be the average of the 2 more consistent assessments. 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.
g For standing BP and pulse assessment, a BP and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should stand still 
for approximately 3 minutes before this assessment. Standing assessments must not be performed if semirecumbent systolic BP 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). Day 1 time points will be time-matched (±5 minutes) to the 
Day -1 clock time (ie, time-matched baseline).
h At least 24 hours of continuous telemetry monitoring will be conducted between check-in on Day -2 and predose on Day 1.
i Predose time-matched telemetry extractions may take place between Day -2 and Day -1 in conjunction with the 24-hour predose continuous telemetry.
j Collection of AEs will commence at the time the subject signs the informed consent form.
k Only serum chemistry to measure electrolytes (sodium, potassium, chloride, and carbon dioxide) should be performed at the 4-hour assessment. 
l 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. 
m Hepatitis panel, including HBsAg and anti-HCV.
n Serum pregnancy test for female subjects only. 
o An FSH level will be obtained to assess postmenopausal status.
p Urine PK samples will be collected at the following time intervals: predose, 0-4, 4-7, 7-12, and 12-24 hours.
q Immunogenicity serum samples for ADA testing will be taken at predose on Day 1, at ET (if applicable), and at follow-up visits on Day 8, Day 14, and Day 29. 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.
r 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 discharge or at ET (if applicable).
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Te
lic
pp
6 24
30
24
3
Ap
Ap
he Ap
alculate th
culate
mm
mm Hg
H
re consist
e consi
ithin appr
ithin ap
mirecum
mirecum
mirecumb
mirecum
ea, blurr
a, blur
n Day 
Day -2
in conjun
n conju
form.
rm.
carbon di
arbon
es for CK
es for C
g.
ervals: pre
vals: p
aken at pre
en at p
llection. T
ection
NA collec
NA coll
he
da: For No


TAK-510
Study ID TAK-510-1001
Page 25 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
3.2
Part 2 for MRD Cohorts 13 to 17 and 26 to 28: Screening Through Day 9, Follow-Up, and Early Termination
3.2.1
Overall Schedule of Study Procedures for Part 2
Table 3.b
Part 2 for MRD Cohorts 13 to 17 and 26 to 28: Screening Through Day 9, Follow-Up, and ET
Days
ET
Screening
-2 a
-1
Dosing
6
7
8
9 
(Discharge)
Follow-up 
Visit 
Day 14 
±2 days
Follow-up 
Visit 
Day 29 
±3 days
-28 to -3
Pre
dose
1
2
3
4
5
Administrative Procedures
Informed consent
X
Inclusion/exclusion 
criteria
X
X
X
Medical 
history/demographics
X
Prior and concomitant 
medications
X-----------------------------------------------------------------Continuous review-----------------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
X
X
X b
X b
X
Height
X
Weight and BMI
X
X
Vital signs c
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing BP and pulse d
X
X
X
X
X
X
X
X
X
12-Lead ECGs
X
X
X
X
ECG telemetry (12-lead)
X e
X-------------- Continuous ---------------- X
Telemetry extraction f
X
X
X
X
X
X
X
X
TAK-510/placebo 
administration g
X
X
X
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 26 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.b
Part 2 for MRD Cohorts 13 to 17 and 26 to 28: Screening Through Day 9, Follow-Up, and ET
Days
ET
Screening
-2 a
-1
Dosing
6
7
8
9 
(Discharge)
Follow-up 
Visit 
Day 14 
±2 days
Follow-up 
Visit 
Day 29 
±3 days
-28 to -3
Pre
dose
1
2
3
4
5
AE monitoring
X
X
X-----------------------------------------------------------Continuous-------------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory 
collection h
X
X
X
X
X
X
X
X
X
X
X
LFTs
X
Serum sample for CK i
X
X
X
X
Glucose finger stick j
X
X
X
X
X
X
Urine drug screen
X
X
Alcohol breath test
X
Cotinine test
X
X
Hepatitis screen k
X
HIV test
X
βhCG (pregnancy) test l
X
X
X
X
Serum FSH test m
X
PK Evaluations
Plasma sample for 
TAK-510 PK 
X
X
X
X
X
X
X
X
X
X
X
Plasma sample for metID
X
X
X
X
X
X
Urine sample for 
TAK-510 PK 
X
X
X
X
Immunogenicity and Biomarkers
Serum sample for 
immunogenicity n
X
X
X
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 27 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.b
Part 2 for MRD Cohorts 13 to 17 and 26 to 28: Screening Through Day 9, Follow-Up, and ET
Days
ET
Screening
-2 a
-1
Dosing
6
7
8
9 
(Discharge)
Follow-up 
Visit 
Day 14 
±2 days
Follow-up 
Visit 
Day 29 
±3 days
-28 to -3
Pre
dose
1
2
3
4
5
Blood sample for DNA 
(optional) o
X
X
Other
Confinement r
X--------------------------------------------------------------------------------X
ADA: antidrug antibodies; AE: adverse event; ALT: alanine aminotransferase; ALP: alkaline phosphatase; anti-HCV: antibodies to hepatitis C virus; AST: aspartate 
aminotransferase; βhCG: beta human chorionic gonadotropin; BMI: body mass index; BP: blood pressure; CK: creatine kinase; ECG: electrocardiogram; ET: early termination; 
FSH: follicle-stimulating hormone; GGT: gamma-glutamyl transferase;
; HBsAg: hepatitis B surface antigen; LFT: liver function 
test; metID: metabolite identification; MRD: multiple rising dose; PK: pharmacokinetic; MRD: multiple rising dose.
a Subjects will be admitted to the site on Day -2. 
b Physical examination at the indicated visit will be symptom-driven.
c Vital signs will include body temperature, BP, respiratory rate, and pulse. On Day -1 and on dosing days, vital signs will be collected as described in Table 3.c (Part 2 for MRD 
Screening Through Day 1 Assessments), Table 3.d (Part 2 for MRD Days 2 to 4 Assessments), and Table 3.e (Part 2 for MRD Day 5 Through Day 9 Assessments, Follow-Up, and 
ET).
d All BP and pulse assessments should be made in duplicate, 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 beats per minute in heart rate or a difference >10 mm Hg in systolic or diastolic BP) between assessments (see 
Section 9.2.4 for details). If 3 measurements are obtained, the final BP readout should be the average of the 2 more consistent assessments. 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 the first dose. All BP and pulse 
assessments must be completed before PK blood sampling.
e At least 24 hours of continuous telemetry monitoring will be conducted between check-in on Day -2 and predose on Day 1.
f Predose time-matched telemetry extractions may take place between Day -2 and Day -1 in conjunction with the 24-hour predose continuous telemetry.
g Dosing regimen for TAK-510/placebo will be determined based on data from Part 1. 
h Safety laboratory will include hematology, serum chemistry, and urinalysis parameters. During Part 2 (MRD), if a LFT (includes ALP, ALT, AST, GGT, or total bilirubin) is 
Property o
Fo
e
;
merc
K: pharm
: phar
mm
Com
driven.
riven.
-Co
ry rate, an
ate, 
on-C
rt 2 for M
2 for
Non
or N
in duplica
dupli
or 
ifference
fferenc
a: F
ts are obta
are o
da: 
e, time
time-ma
keda
re PK blo
e PK bl
Take
telemetry
telemetr
f Ta
etry extra
try extr
of 
cial U
e; ALP
ALP:
al
mass ind
mass in
e On
e O
Use 
---------
------
e
Subject to the Applicable Terms of Use
Te
w-Up, 
Up
lic
7
App
t
e A p
to
ct t
S bje
S
510/pla
10/pl
rty o
l include h
nclud
Us
Only and S
ercia


TAK-510
Study ID TAK-510-1001
Page 28 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.b
Part 2 for MRD Cohorts 13 to 17 and 26 to 28: Screening Through Day 9, Follow-Up, and ET
Days
ET
Screening
-2 a
-1
Dosing
6
7
8
9 
(Discharge)
Follow-up 
Visit 
Day 14 
±2 days
Follow-up 
Visit 
Day 29 
±3 days
-28 to -3
Pre
dose
1
2
3
4
5
elevated, a repeat test should be performed before the next dose of study drug is administered. 
i 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. 
j Glucose finger stick will be performed at predose and ~1 hours postdose on each day.
k Hepatitis panel, including HBsAg and anti-HCV.
l Serum pregnancy tests for female subjects only.
m An FSH level will be obtained to assess postmenopausal status.
n Immunogenicity serum samples for ADA testing will be taken at predose on Day 1, on Day 8, at ET (if applicable), and at follow-up visits on Day 14 and Day 29. If ADAs are 
present, subjects may be asked to return for additional sample collections. The sampling time points will be the same for all subjects dosed with either placebo or study drug. 
o 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 discharge or at ET (if applicable).
Property of Takeda: For Non-Comm
mm
bje
ubje
Sub
ected at th
cted at
nd S
and
ly a
Only
e On
Use 
y 1, on D
y 1, on
l Us
sampling
amplin
l U
amples sh
amples
bject to the Applicable Terms of Use
Te
w-Up, 
Up
lic
7
App
t
e A p
to
ct t
bje
mmercia


TAK-510
Study ID TAK-510-1001
Page 29 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
3.2.2
Part 2 for MRD Screening Through Day 1 Assessments
Table 3.c
Part 2 for MRD Screening Through Day 1 Assessments
Day
-28 to -3
Day
-2 a
Scheduled Time
Day -1 (Hours)
Day 1 (Hours)
Screening
0
0.5
1
2
3
4
5
7
10
12
16
24 b
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24 b
Administrative Procedures
Informed consent
X
Inclusion/exclusion 
criteria
X
X
X
Medical history/
demographics
X
Prior and 
concomitant 
medications
X---------------------------------------------------------------Continuous review----------------------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical 
examination
X
X
Height
X
Weight and BMI
X
X
Temperature and 
respiratory rate
X
X
X
X
X
X
BP and pulse c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing BP and 
pulse d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGs 
X
X
X
X
ECG telemetry 
(12-lead)
X ---------------------- Continuous monitoring e ------------------------ X
X ---------------------- Continuous monitoring ------------------------ X
Telemetry 
extraction f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TAK-510/placebo 
administration
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 30 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.c
Part 2 for MRD Screening Through Day 1 Assessments
Day
-28 to -3
Day
-2 a
Scheduled Time
AE monitoring
X--------------------------------------------------------------Continuous review-----------------------------------------------------------------------------X
Day -1 (Hours)
Day 1 (Hours)
Screening
0
0.5
1
2
3
4
5
7
10
12
16
24 b
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24 b
Laboratory Procedures/Assessments
Safety laboratory 
collection g
X
X
X
X
Serum sample for CK 
h
X
X
Glucose finger stick 
X
X
Urine drug screen
X
X
Alcohol breath test
X
Cotinine test
X
X
Hepatitis screen i
X
HIV test
X
βhCG (pregnancy) 
test j
X
X
Serum FSH test k
X
PK Evaluations
Plasma sample for 
TAK-510 PK
X
X
X
X
X
X
X
X
X
X
X
X
Plasma sample for 
metID 
X
X
X
X
X
X
X
Urine sample for 
TAK-510 PK l
X
X
X
X
X
Immunogenicity and Biomarkers
Serum sample for 
immunogenicity
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Te
lic
----------
--
Ap
he
ose
os
0
th
to h
ject 
ct
X
je
bj
Su
nd
nd
nd
nd
and
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ly a
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O ly
O
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Us
Us
Us
Us
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rc
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mme
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Co
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N n C
No
F
N
Fo
Fo
eda: F
da: F
ed
ed
F
of Taked


TAK-510
Study ID TAK-510-1001
Page 31 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.c
Part 2 for MRD Screening Through Day 1 Assessments
Day
-28 to -3
Day
-2 a
Scheduled Time
Other
Confinement o
X--------------------------------------------------------------------------------------------------------------------------------------------------------------X
AE: adverse event; anti-HCV: antibodies to hepatitis C virus; βhCG: beta human chorionic gonadotropin; BMI: body mass index; BP: blood pressure; CK: creatine kinase; ECG: 
electrocardiogram; FSH: follicle-stimulating hormone; 
; HBsAg: hepatitis B surface antigen; LFT: liver function test; 
metID: metabolite identification; PK: pharmacokinetic.
a Subjects will be admitted to the site on Day -2. 
b The 24-hour sample on a given day is the same as the predose sample on the next day; only 1 assessment will be collected at this time point.
c All BP and pulse assessments should be made in duplicate, 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 beats per minute in heart rate or a difference >10 mm Hg in systolic or diastolicBP) between assessments (see 
Section 9.2.4 for details). If 3 measurements are obtained, the final BP readout should be the average of the 2 more consistent assessments. 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 the first dose. All BP and pulse 
assessments must be completed before PK blood sampling.
d For standing BP and pulse assessment, a BP and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should stand still 
for approximately 3 minutes before this assessment. Standing assessments must not be performed if semirecumbent systolic BP 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). Day 1 time points will be time-matched (±5 minutes) to the 
Day -1 clock time (ie, time-matched baseline).
e At least 24 hours of continuous telemetry monitoring will be conducted between check-in on Day -2 and predose on Day 1.
f Predose time-matched telemetry extractions may take place between Day -2 and Day -1 in conjunction with the 24-hour predose continuous telemetry.
g Safety laboratory will include hematology, serum chemistry, and urinalysis parameters. During Part 2 (MRD), if a LFT is elevated, a repeat test should be performed before the next 
dose of study drug is administered.
h 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. 
i Hepatitis panel, including HBsAg and anti-HCV.
j Serum pregnancy tests for female subjects only.
k An FSH level will be obtained for postmenopausal women.
l Urine PK samples will be collected at the following time intervals: predose, 0-4, 4-7, 7-12, and 12-24 hours.
o Subjects will be confined.
Property of
of
ty of
ed.
eda: For Non-Commercial Use Only and Subjec
ject 
MI: body 
MI: body
bjec
; HBsAg
; HBsA
Subj
d Su
and 
assessmen
sessm
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ments shou
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at the 
ct
Applicable Terms of Use
Te
lic
the Ap
of Take


TAK-510
Study ID TAK-510-1001
Page 32 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
3.2.3
Part 2 for MRD Days 2 to 4 Assessments
Table 3.d
Part 2 for MRD Days 2 to 4 Assessments
Scheduled Time
Days 2-4 (Hours)
Predose
0
0.5
1
2
3
4
5
7
10
12
16
24 a
Administrative Procedures
Prior and concomitant medications
X--------------------------------------------------------Continuous review----------------------------------------------------X
Clinic Procedures/Assessments
Temperature and respiratory rate 
X
X
X
X
BP and pulse b
X
X
X
X
X
X
X
X
X
X
X
X
Standing BP and pulse c
X
X
X
X
X
X
X
TAK-510/placebo administration d 
X
ECG telemetry (12-lead)
X------------------------------------------------------------Continuous monitoring-------------------------------------------X
Telemetry extraction
X
AE monitoring
X-----------------------------------------------------Continuous review--------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory collection e
X f
LFTs
X g
Glucose finger stick 
X
X
PK Evaluations
Plasma sample for TAK-510 PK
X h
Other
Confinement i
X----------------------------------------------------------------------------------------------------------------------------------X
AE: adverse event; BP: blood pressure; ECG: electrocardiogram; LFT: liver function test; PK: pharmacokinetic.
a The 24-hour sample on a given day is the same as the predose sample on the next day; only 1 assessment will be collected at this time point.
b All BP and pulse assessments should be made in duplicate, 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 beats per minute in heart rate or a difference >10 mm Hg in systolic or diastolic BP) between assessments 
(see Section 9.2.4 for details). If 3 measurements are obtained, the final BP readout should be the average of the 2 more consistent assessments. At predose, vital signs will 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 33 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.d
Part 2 for MRD Days 2 to 4 Assessments
Scheduled Time
Days 2-4 (Hours)
Predose
0
0.5
1
2
3
4
5
7
10
12
16
24 a
be measured within approximately 1 hour before the first dose. All BP and pulse assessments must be completed before PK blood sampling.
c For standing BP and pulse assessment, a BP and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should stand still 
for approximately 3 minutes before this assessment. Standing assessments must not be performed if semirecumbent systolic BP 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.). 
d Follow-up doses should be given at the same time as on Day 1.
e Safety laboratory will include hematology, serum chemistry, and urinalysis parameters. During Part 2 (MRD), if a LFT is elevated, a repeat test should be performed before the next 
dose of study drug is administered.
f Safety laboratory assessments (including hematology, serum chemistry, and urinalysis parameters) will be performed on Day 2 and Day 4.
g Sampling for LFTs will be performed on Day 3.
h Blood samples for PK may be drawn 10 minutes before dosing. 
i Subjects will be confined.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 34 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
3.2.4
Part 2 for MRD Day 5 Through Day 9 Assessments, Follow-Up, and Early Termination 
Table 3.e
Part 2 for MRD Day 5 Through Day 9 Assessments, Follow-Up, and ET
Scheduled Time
ET
Day 5 (Hours)
Day 6
Day 7
Day 8
Day 9
(Discharge)
Follow-
up Visit 
Day 14
±2 days
Follow-
up Visit 
Day 29
±3 days
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24
48
72
96
Prior and concomitant 
medications
X----------------------------------------------------------------Continuous review------------------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
X a
X a
X
Temperature and 
respiratory rate 
X
X
X
X
X
X
BP and pulse b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing BP and pulse c
X
X
X
X
X
X
X
X
TAK-510/placebo 
administration d
X
12-lead ECGs
X
ECG telemetry (12-lead)
X--------------------------------Continuous---------------------------------------X
Telemetry extraction
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X---------------------------------------------------------------------Continuous-------------------------------------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory 
collection e
X
X
X
X
X
Serum sample for CK f
X
X
Glucose finger stick 
X
X
βhCG (pregnancy) test g
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 35 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.e
Part 2 for MRD Day 5 Through Day 9 Assessments, Follow-Up, and ET
Scheduled Time
ET
Day 5 (Hours)
Day 6
Day 7
Day 8
Day 9
(Discharge)
Follow-
up Visit 
Day 14
±2 days
Follow-
up Visit 
Day 29
±3 days
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24
48
72
96
PK Evaluations
Plasma sample for 
TAK-510 PK
X h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma sample for metID
X h
X
X
X
X
X
X
X
Urine sample for 
TAK-510 PK i
X
X
X
X
Immunogenicity and Biomarkers
Serum sample for 
immunogenicity j
X
X
X
X
Blood sample for DNA 
(optional) k
X
X
Other
Confinement m
X------------------------------------------------------------------------------------------------------------------------------X
ADA: antidrug antibodies; AE: adverse event; βhCG: beta human chorionic gonadotropin; BP: blood pressure; CK: creatine kinase; ECG: electrocardiogram; ET: early termination; 
metID: metabolite identification; PK: pharmacokinetic.
a Physical examination at the indicated visit will be symptom-driven.
b All BP and pulse assessments should be made in duplicate, 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 beats per minute in heart rate or a difference >10 mm Hg in systolic or diastolic BP) between assessments (see 
Section 9.2.4 for details). If 3 measurements are obtained, the final BP readout should be the average of the 2 more consistent assessments. At predose, vital signs will be measured 
within approximately 1 hour before the first dose. All BP and pulse assessments must be completed before PK blood sampling.
c For standing BP and pulse assessment, a BP and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should stand still 
for approximately 3 minutes before this assessment. Standing assessments must not be performed if semirecumbent systolic BP 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.). 
d Follow-up doses should be given at the same time as those given on Day 1.
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TAK-510
Study ID TAK-510-1001
Page 36 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.e
Part 2 for MRD Day 5 Through Day 9 Assessments, Follow-Up, and ET
Scheduled Time
ET
Day 5 (Hours)
Day 6
Day 7
Day 8
Day 9
(Discharge)
Follow-
up Visit 
Day 14
±2 days
Follow-
up Visit 
Day 29
±3 days
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24
48
72
96
e Safety laboratory will include hematology, serum chemistry, and urinalysis parameters. Additional assessments may be collected at the investigator’s discretion.
f 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. 
g Serum pregnancy tests for female subjects only.
h Blood samples for PK and metID may be drawn 10 minutes before dosing.
i Urine PK samples will be collected at the following time intervals: predose, 0-4, 4-7, 7-12, and 12-24 hours.
j Immunogenicity serum samples for ADA testing will be taken at predose on Day 1, on Day 8, at ET (if applicable), and at follow-up visits on Day 14 and Day 29. If ADAs are 
present, subjects may be asked to return for additional sample collection. All subjects receiving either study drug or placebo will have the same collection time points.
k 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 discharge or at ET (if applicable).
m Subjects will be confined.
Property of Takeda: For Non-Commercial Us
Us
al U
t to the Applicable Terms of Use
Te
lic
7
Day 8
Day
App
pp
pp
he
pp
48
48
he
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Use 


TAK-510
Study ID TAK-510-1001
Page 37 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
3.3
Part 3 for Dose Titration and Redosing Cohorts 18 to 20: Screening Through Day 15, Follow-Up, and Early 
Termination
3.3.1
Overall Schedule of Study Procedures for Part 3
Table 3.f
Part 3 for Dose Titration and Redosing Cohorts 18 to 20: Screening Through Day 15, Follow-Up, and ET
Days
ET
Screen
-2 a
-1
Dosing
8
(Dis-
charge)
9 to 13 
Wash
out b
Day 13 
±1 day
(Confine 
again)
Day 14
±1 day
(Single 
Dose)
Day 15 
±1 day
(Dis-
charge)
Follow-
up Visit 
Day 29 
±3 days
-28 to
-3
Pre
dose
1
2
3
4
5
6
7
Administrative Procedures
Informed consent
X
Inclusion/exclusion 
criteria
X
X
X
Medical 
history/demographics
X
Prior and concomitant 
medications
X-----------------------------------------------------------------Continuous review-----------------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical 
examination
X
X
X c
X
X c
X
X
Height
X
Weight and BMI
X
X
X
Vital signs d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing BP and pulse 
e
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGs
X
X
X
X
X
X
ECG telemetry 
(12-lead)
X f
X --------------- Continuous ----------------- X
X
Telemetry extraction g
X
X
X
X
X
X
X
X
X
X
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 38 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.f
Part 3 for Dose Titration and Redosing Cohorts 18 to 20: Screening Through Day 15, Follow-Up, and ET
Days
ET
Screen
-2 a
-1
Dosing
8
(Dis-
charge)
9 to 13 
Wash
out b
Day 13 
±1 day
(Confine 
again)
Day 14
±1 day
(Single 
Dose)
Day 15 
±1 day
(Dis-
charge)
Follow-
up Visit 
Day 29 
±3 days
-28 to
-3
Pre
dose
1
2
3
4
5
6
7
TAK-510/placebo 
administration h
X
X
X
X
X
X
X
X
AE monitoring
X
X
X-----------------------------------------------------------Continuous-------------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory 
collection i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LFTs
X
X
Serum sample for 
CK j
X
X
X
X
Glucose finger stick k
X
X
X
X
X
X
X
X
X
Urine drug screen
X
X
X
Alcohol breath test
X
X
Cotinine test
X
X
X
Hepatitis screen l
X
HIV test
X
βhCG (pregnancy) 
test m
X
X
X
X
X
Serum FSH test n
X
PK Evaluations
Plasma sample for 
TAK-510 PK 
X
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity and Biomarkers
Serum sample for 
immunogenicity o
X
X
X
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 39 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.f
Part 3 for Dose Titration and Redosing Cohorts 18 to 20: Screening Through Day 15, Follow-Up, and ET
Days
ET
Screen
-2 a
-1
Dosing
8
(Dis-
charge)
9 to 13 
Wash
out b
Day 13 
±1 day
(Confine 
again)
Day 14
±1 day
(Single 
Dose)
Day 15 
±1 day
(Dis-
charge)
Follow-
up Visit 
Day 29 
±3 days
-28 to
-3
Pre
dose
1
2
3
4
5
6
7
Blood sample for 
DNA (optional) p
X
X
Other
Confinement s
X--------------------------------------------------------------------------------X
X--------------------------X
ADA: antidrug antibodies; AE: adverse event; anti-HCV: antibodies to hepatitis C virus; βhCG: beta human chorionic gonadotropin; BMI: body mass index; BP: blood pressure; CK: 
creatine kinase; ECG: electrocardiogram; ET: early termination; FSH: follicle-stimulating hormone; 
; HBsAg: hepatitis B surface 
antigen; LFT: liver function test; PK: pharmacokinetic.
a Subjects will be admitted to the site on Day -2. 
b Based on emerging safety, tolerability, and available PK data, subjects may be confined during washout at the discretion of the investigator in consultation with the sponsor and 
medical monitor. Duration of washout period may be shortened or lengthened in Cohorts 19 and 20 based on emerging data, refer to Section 6.1.4 for confinement and discharge 
during redosing interval.
c Physical examination at the indicated visit will be symptom-driven.
d Vital signs will include body temperature, BP, respiratory rate, and pulse. On Day -1 and on dosing days, vital signs will be collected as described in Table 3.g (Part 3 Screening 
Through Day 1 Assessments), Table 3.h (Part 3 Days 2 to 6 Assessments), Table 3.i (Part 3 Day 7 and Day 8 Assessments), and Table 3.j (Part 3 Day 9 Through Day 15 Assessments, 
Follow-Up, and ET).
e All BP and pulse assessments should be made in duplicate, 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 beats per minute in heart rate or a difference >10 mm Hg in systolic or diastolic BP) between assessments (see 
Section 9.2.4 for details). If 3 measurements are obtained, the final BP readout should be the average of the 2 more consistent assessments. 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 the first dose. All BP and pulse 
assessments must be completed before PK blood sampling.
f At least 24 hours of continuous telemetry monitoring will be conducted between check-in on Day -2 and predose on Day 1.
g Predose time-matched telemetry extractions may take place between Day -2 and Day -1 in conjunction with the 24-hour predose continuous telemetry.
Property of Takeda: For Non-Commercial U
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ty o
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elemetr
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Te
Day 15, F
Day 15,
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Wash
Wash
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Day
Day
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Only an


TAK-510
Study ID TAK-510-1001
Page 40 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.f
Part 3 for Dose Titration and Redosing Cohorts 18 to 20: Screening Through Day 15, Follow-Up, and ET
Days
ET
Screen
-2 a
-1
Dosing
8
(Dis-
charge)
9 to 13 
Wash
out b
Day 13 
±1 day
(Confine 
again)
Day 14
±1 day
(Single 
Dose)
Day 15 
±1 day
(Dis-
charge)
Follow-
up Visit 
Day 29 
±3 days
-28 to
-3
Pre
dose
1
2
3
4
5
6
7
h Dosing regimen for TAK-510/placebo will be determined based on data from Part 1. 
i Safety laboratory will include hematology, serum chemistry, and urinalysis parameters. During Part 3, if an LFT is elevated, a repeat test should be performed before the next dose 
of study drug is administered.
j 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. 
k Glucose finger stick will be performed at predose and ~1 hours postdose on each day.
l Hepatitis panel, including HBsAg and anti-HCV.
m Serum pregnancy tests for female subjects only.
n An FSH level will be obtained to assess postmenopausal status.
o Immunogenicity serum samples for ADA testing will be taken at predose on Day 1, on Day 8, at ET (if applicable), predose on Day 14, and at the follow-up visit on Day 29. If ADAs 
are present, subjects may be asked to return for additional sample collections. All subjects receiving either study drug or placebo will have the same collection time points. 
p 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 discharge or at ET (if applicable). 
Property of Takeda: For Non-Comm
mm
e Only and Subject to the Applicable Terms of Use
Te
Day 15, F
Day 15,
lic
13
Wash
Wash
out 
out b
Day
Day
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All subjec
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amples sh
amples
to
mercial


TAK-510
Study ID TAK-510-1001
Page 41 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
3.3.2
Part 3 Screening Through Day 1 Assessments
Table 3.g
Part 3 Screening Through Day 1 Assessments
Day
-28 to -3
Day
-2 a
Scheduled Time
Day -1 (Hours)
Day 1 (Hours)
Screening
0
0.5
1
2
3
4
5
7
10
12
16
24 b
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24 b
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/demographics
X
Previous and concomitant 
medications
X---------------------------------------------------------------Continuous review----------------------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
X
X
Height
X
Weight and BMI
X
X
Temperature and respiratory rate
X
X
X
X
X
X
BP and pulse c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing BP and pulse d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGs 
X
X
X
X
ECG telemetry (12-lead)
X -----------------------Continuous monitoring e -------------------- X
X ---------------------------Continuous monitoring ------------------------ X
Telemetry extraction f
X
X
X
X
X
X
X
X
TAK-510/placebo administration
X
AE monitoring
X--------------------------------------------------------------Continuous review-----------------------------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory collection g
X
X
X
X
Serum sample for CK h
X
X
Glucose finger stick 
X
X
Urine drug screen
X
X
Alcohol breath test
X
Cotinine test
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 42 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.g
Part 3 Screening Through Day 1 Assessments
Day
-28 to -3
Day
-2 a
Scheduled Time
Day -1 (Hours)
Day 1 (Hours)
Screening
0
0.5
1
2
3
4
5
7
10
12
16
24 b
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24 b
Hepatitis screen i
X
HIV test
X
βhCG (pregnancy) test j
X
X
Serum FSH test k
X
PK Evaluations
Plasma sample for TAK-510 PK
X
X
X
X
Immunogenicity and Biomarkers
Serum sample for immunogenicity
X
Other
Confinement n
X--------------------------------------------------------------------------------------------------------------------------------------------------------------X
AE: adverse event; anti-HCV: antibodies to hepatitis C virus; βhCG: beta human chorionic gonadotropin; BMI: body mass index; BP: blood pressure; CK: creatine kinase; ECG: 
electrocardiogram; FSH: follicle-stimulating hormone; 
; HBsAg: hepatitis B surface antigen; LFT: liver function test.
a Subjects will be admitted to the site on Day -2. 
b The 24-hour sample on a given day is the same as the predose sample on the next day; only 1 assessment will be collected at this time point.
c All BP and pulse assessments should be made in duplicate, 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 beats per minute in heart rate or a difference >10 mm Hg in systolic or diastolic BP) between assessments (see 
Section 9.2.4 for details). If 3 measurements are obtained, the final BP readout should be the average of the 2 more consistent assessments. 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 the first dose. All BP and pulse 
assessments must be completed before blood sampling.
d For standing BP and pulse assessment, a BP and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should stand still 
for approximately 3 minutes before this assessment. Standing assessments must not be performed if semirecumbent systolic BP 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). Day 1 time points will be time-matched (±5 minutes) to the 
Day -1 clock time (ie, time-matched baseline).
e At least 24 hours of continuous telemetry monitoring will be conducted between check-in on Day -2 and predose on Day 1.
f Predose time-matched telemetry extractions may take place between Day -2 and Day -1 in conjunction with the 24-hour predose continuous telemetry.
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TAK-510
Study ID TAK-510-1001
Page 43 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.g
Part 3 Screening Through Day 1 Assessments
Day
-28 to -3
Day
-2 a
Scheduled Time
Day -1 (Hours)
Day 1 (Hours)
Screening
0
0.5
1
2
3
4
5
7
10
12
16
24 b
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24 b
g Safety laboratory will include hematology, serum chemistry, and urinalysis parameters. During Part 3, if a LFT is elevated, a repeat test should be performed before the next dose of 
study drug is administered.
h 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. 
i Hepatitis panel, including HBsAg and anti-HCV.
j Serum pregnancy tests for female subjects only.
k An FSH level will be obtained for postmenopausal women.
Subjects will be confined.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-510
Study ID TAK-510-1001
Page 44 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
3.3.3
Part 3 Days 2 to 6 Assessments
Table 3.h
Part 3 Days 2 to 6 Assessments
Scheduled Time
Days 2-6 (Hours)
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24 a
Administrative Procedures
Previous and concomitant medications
X--------------------------------------------------------Continuous review----------------------------------------------------X
Clinic Procedures/Assessments
Temperature and respiratory rate 
X
X
X
X
BP and pulse b
X
X
X
X
X
X
X
X
X
X
X
X
Standing BP and pulse c
X
X
X
X
X
X
X
TAK-510/placebo administration d
X
ECG telemetry (12-lead)
X------------------------------------------------------------Continuous monitoring-------------------------------------------X
Telemetry extraction
X
X e
X e
X e
AE monitoring
X-----------------------------------------------------Continuous review--------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory collection f
X g
LFTs
X h
Glucose finger stick 
X
X
PK Evaluations
Plasma sample for TAK-510 PK
X i
X j
X j
X j
Other
Confinement k
X----------------------------------------------------------------------------------------------------------------------------------X
AE: adverse event; BP: blood pressure; ECG: electrocardiogram; LFT: liver function test; PK: pharmacokinetic.
a The 24-hour sample on a given day is the same as the predose sample on the next day; only 1 assessment will be collected at this time point.
b All BP and pulse assessments should be made in duplicate, 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 beats per minute in heart rate or a difference >10 mm Hg in systolic or diastolic BP) between assessments (see 
Section 9.2.4 for details). If 3 measurements are obtained, the final BP readout should be the average of the 2 more consistent assessments. At predose, vital signs will be measured 
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TAK-510
Study ID TAK-510-1001
Page 45 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.h
Part 3 Days 2 to 6 Assessments
Scheduled Time
Days 2-6 (Hours)
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24 a
within approximately 1 hour before the first dose. All BP and pulse assessments must be completed before PK blood sampling.
c For standing BP and pulse assessment, a BP and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should stand still 
for approximately 3 minutes before this assessment. Standing assessments must not be performed if semirecumbent systolic BP 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.). 
d Follow-up doses should be given at the same time as on Day 1.
e Telemetry extractions will be performed only on day(s) when the dose has changed from the previous day, and only if PK samples are collected at the given time point. 
f Safety laboratory will include hematology, serum chemistry, and urinalysis parameters. During Part 3, if a LFT is elevated, a repeat test should be performed before the next dose of 
study drug is administered.
g Safety laboratory assessments (including hematology, serum chemistry, and urinalysis parameters) will be performed on Day 2, Day 4, and Day 6.
h Samples for LFTs will be performed on Day 3 and Day 5.
i Blood samples for PK may be drawn 10 minutes before dosing. 
j Samples will be collected only on day(s) when the dose has changed from the previous day. Sampling times may change based on emerging data from Part 1.
k Subjects will be confined.
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TAK-510
Study ID TAK-510-1001
Page 46 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
3.3.4
Part 3 Day 7 and Day 8 Assessments
Table 3.i
Part 3 Day 7 and Day 8 Assessments
Scheduled Time
Day 7 (Hours)
Day 8
(Discharge)
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24
30
Previous and concomitant medications
X-----------------------------------------------------------Continuous review-----------------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
X a
Temperature and respiratory rate 
X
X
X
X
X
BP and pulse b
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing BP and pulse c
X
X
X
X
X
X
X
TAK-510/placebo administration d
X
12-lead ECG
X
ECG telemetry (12-lead)
X--------------------------------Continuous---------------------------------------X
Telemetry extraction
X
X
X
X
X
X
AE monitoring
X-------------------------------------------------------Continuous-------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory collection e
X
X
Serum sample for CK f
X
Glucose finger stick 
X
X
βhCG (pregnancy) test g
X
PK Evaluations
Plasma sample for TAK-510 PK
X h
X
X
X
X
X
Immunogenicity and Biomarkers
Serum sample for immunogenicity i
X
Blood sample for DNA (optional) j
X
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TAK-510
Study ID TAK-510-1001
Page 47 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.i
Part 3 Day 7 and Day 8 Assessments
Scheduled Time
Day 7 (Hours)
Day 8
(Discharge)
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24
30
Other
Confinement l
X------------------------------------------------------------------------------------------------------------------X
AE: adverse event; βhCG: beta human chorionic gonadotropin; BP: blood pressure; CK: creatine kinase; ECG: electrocardiogram; ET: early termination; PK: pharmacokinetic.
a Physical examination at the indicated visit will be symptom-driven.
b All BP and pulse assessments should be made in duplicate, 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 beats per minute in heart rate or a difference >10 mm Hg in systolic or diastolic BP) between assessments (see 
Section 9.2.4 for details). If 3 measurements are obtained, the final BP readout should be the average of the 2 more consistent assessments. At predose, vital signs will be measured 
within approximately 1 hour before the first dose. All BP and pulse assessments must be completed before PK blood sampling.
c For standing BP and pulse assessment, a BP and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should stand still 
for approximately 3 minutes before this assessment. Standing assessments must not be performed if semirecumbent systolic BP 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.). 
d Follow-up doses should be given at the same time as those given on Day 1.
e Safety laboratory will include hematology, serum chemistry, and urinalysis parameters. Additional assessments may be collected at the investigator’s discretion.
f 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. 
g Serum pregnancy tests for female subjects only.
h Plasma sample for TAK-510 PK may be drawn 10 minutes before dosing.
i Immunogenicity serum samples for ADA testing will be taken at predose on Day 1, on Day 8, at ET (if applicable), predose on Day 14, and at the follow-up visit on Day 29. If ADAs 
are present, subjects may be asked to return for additional sample collections. All subjects receiving either study drug or placebo will have the same collection time points. 
j If subjects have provided consent for the optional DNA collection, blood samples should be collected and can be collected at any time on Day 8 (discharge) or at ET (if applicable; 
see Table 3.j).
l Subjects will be confined.
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TAK-510
Study ID TAK-510-1001
Page 48 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
3.3.5
Part 3 Day 9 Through Day 15 Assessments, Follow-Up, and Early Termination
Table 3.j
Part 3 Day 9 Through Day 15 Assessments, Follow-Up, and ET
Days
9 to 13
Day
13
Scheduled Time
ET
Day 14 (Hours)
Follow-up 
Visit 
Day 29 
±3 days
Washout a
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24
30 
(Discharge)
(Day 15)
Administrative Procedures
Previous and concomitant 
medications
X
X----------------------------------------------------------Continuous review-----------------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
X
X b
X
X
Weight and BMI c
X
Temperature and respiratory rate
X
X
X
X
X
BP and pulse c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing BP and pulse d
X
X
X
X
X
X
X
X
X
12-lead ECGs 
X
X
X
ECG telemetry (12-lead)
X-----------------------------------------Continuous monitoring-----------------------------------------X
Telemetry extraction
X
X
X
X
X
X
X
X
TAK-510/placebo administration
X
AE monitoring
X
X----------------------------------------------------Continuous review-------------------------------------------------------------------X
X
Laboratory Procedures/Assessments
Safety laboratory collection e
X
X
X
X
X
X
Serum sample for CK f
X
Glucose finger stick 
X
X
Urine drug screen
X
Alcohol breath test
X
Cotinine test
X
βhCG (pregnancy) test g
X
X
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TAK-510
Study ID TAK-510-1001
Page 49 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.j
Part 3 Day 9 Through Day 15 Assessments, Follow-Up, and ET
Days
9 to 13
Day
13
Scheduled Time
ET
Day 14 (Hours)
Follow-up 
Visit 
Day 29 
±3 days
Washout a
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24
30 
(Discharge)
(Day 15)
PK Evaluations
Plasma sample for TAK-510 PK
X
X
X
X
X
X
X
X
X
Immunogenicity and Biomarkers
Serum sample for 
immunogenicity h
X
X
X
Other
Confinement k
X--------------------------------------------------------------------------------------------------------X
ADA: antidrug antibodies; AE: adverse event; anti-HCV: antibodies to hepatitis C virus; βhCG: beta human chorionic gonadotropin; BMI: body mass index; BP: blood pressure; CK: 
creatine kinase; ECG: electrocardiogram; ET: early termination; 
; HBsAg: hepatitis B surface antigen; PK: pharmacokinetic.
a Based on emerging safety, tolerability, and available PK data, subjects may be confined during washout at the discretion of the investigator in consultation with the sponsor and 
medical monitor. Duration of washout period may be shortened or lengthened in Cohorts 19 and 20 based on emerging data.
b Physical examination at the indicated visit will be symptom-driven.
c For BMI, any assessment on Days 13 through 15 will be acceptable as noted also in Table 3.f. All BP and pulse assessments should be made in duplicate, 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 beats per minute in heart rate
or a difference >10 mm Hg in systolic or diastolic BP) between assessments (see Section 9.2.4 for details). If 3 measurements are obtained, the final BP readout should be the 
average of the 2 more consistent assessments. At predose, vital signs will be measured within approximately 1 hour before the first dose. All BP and pulse assessments must be 
completed before PK blood sampling.
d For standing BP and pulse assessment, a BP and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should stand still 
for approximately 3 minutes before this assessment. Standing assessments must not be performed if semirecumbent systolic BP 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). Day 1 time points will be time-matched (±5 minutes) to the 
Day -1 clock time (ie, time-matched baseline).
e Safety laboratory will include hematology, serum chemistry, and urinalysis parameters.
f 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. 
g Serum pregnancy tests for female subjects only.
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TAK-510
Study ID TAK-510-1001
Page 50 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 3.j
Part 3 Day 9 Through Day 15 Assessments, Follow-Up, and ET
Days
9 to 13
Day
13
Scheduled Time
ET
Day 14 (Hours)
Follow-up 
Visit 
Day 29 
±3 days
Washout a
Pre
dose
0
0.5
1
2
3
4
5
7
10
12
16
24
30 
(Discharge)
(Day 15)
h Immunogenicity serum samples for ADA testing will be taken at predose on Day 1, on Day 8, at ET (if applicable), predose on Day 14, and at the follow-up visit on Day 29. If ADAs 
are present, subjects may be asked to return for additional sample collections. All subjects receiving either study drug or placebo will have the same collection time points. 
i If subjects have provided consent for the optional DNA collection, blood samples should be collected and can be collected on Day 8 (discharge; see Table 3.i) or at ET (if 
applicable).
k Subjects will be confined.
Property of Takeda: For Non-Commercial Use Only and
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TAK-510
Study ID TAK-510-1001
Page 51 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
4.0
INTRODUCTION
4.1
Background
Nausea and vomiting are among the most common and debilitating symptoms encountered in 
medicine as either symptoms of disease or side effects of treatments. Because of the complex 
multifactorial nature of nausea and vomiting, targeted therapies against the serotonin 3 (5-HT3) 
and neurokinin-1 receptors do not work effectively as monotherapies, making it a significant 
unmet medical need. 
4.2
Rationale for the Proposed Study
The purpose of this first-in-human (FIH) study is to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of TAK-510 in healthy subjects to support further development of 
TAK-510. The study will be conducted in 3 parts: SRD via SC administration will be assessed in 
Part 1, and repeat-dose SC administration will be assessed in Part 2 (MRD) and Part 3 (dose 
titration and redosing after washout).
4.3
Benefit/Risk Profile
This study represents the first study in humans with TAK-510.
The main objective of this study is to assess the safety and tolerability of TAK-510 in healthy 
subjects; as such, no clinical benefit is expected for study participants. 
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TAK-510
Study ID TAK-510-1001
Page 52 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
The potential risks of TAK-510 include HR increase, decreased BP, body weight loss, renal effects 
(proximal tubule vacuolation), elevated liver enzymes, injection site reaction, hypersensitivity,
immunogenicity, postural hypotension, and myalgia. These potential risks are based on safety 
observations from the Good Laboratory Practice (GLP)-compliant nonclinical safety 
pharmacology and repeat-dose toxicity studies conducted with TAK-510, and clinical experience 
with TAK-510 
(refer to the TAK-510 
Investigator’s Brochure for additional details). 
In nonclinical safety studies, the magnitude and duration of HR and BP changes in dogs were 
equivalent 
 at predicted therapeutic doses (sponsor data on file). 
Safety results from the 
FIH study demonstrated a transient increase in HR within the 
first hour of 
dosing as well as decreases in systolic BP and diastolic BP that were more 
prominent with postural changes (orthostatic) in some individuals within the first 2 hours 
postdosing (
; refer to the TAK-510 Investigator’s Brochure for additional 
details). Postural hypotension is an identified risk 
 Given the findings 
of decreased BP and increased HR
, it is hypothesized that TAK-510 causes vasodilation which leads to decreased BP 
and increased HR. 
Audited draft results from a definitive rat embryo-fetal development study indicate fetal 
malformations were observed in a single fetus at each of the mid and high dose 
; the no-observed-adverse-effect level (NOAEL) for embryo-fetal
development 
 (refer to investigator’s brochure, Section 4.3.6 for additional
details).
All of these factors could contribute to 
the risk of immunogenicity and thus an assessment of antidrug antibodies (ADA) in all parts of the 
study will be included as part of the risk mitigation strategy.
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TAK-510
Study ID TAK-510-1001
Page 53 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Subjects with a history of serious hypersensitivity to any medication or any component of 
TAK-510 formulation or with a history of significant multiple and/or severe allergies are excluded 
from this study. Subjects will be evaluated for the development of ADA as part of the study. The 
potential risks related to HR increase, decreased BP, body weight loss, renal effects (proximal 
tubule vacuolation), elevated liver enzymes, and injection site reactions will be monitored 
clinically and/or with laboratory tests and have been considered when determining the stopping 
rules for this clinical study.
In addition to the potential risks associated with study drug administration, there is minimal risk 
associated with study procedures, including scheduled periodic phlebotomy (limited to <575 mL). 
Total blood sampling volumes will not exceed approximately 319 mL (over 7 days of confinement) 
in Part 1, approximately 505 mL (over 11 days of confinement) in Part 2, and approximately 573 
mL (over 10 days of confinement followed by 3 days of confinement after washout) in Part 3. The 
maximum volume of blood sampling on any single day is approximately 117 mL in Part 1, 
approximately 147 mL in Part 2, and approximately 82 mL in Part 3.
To minimize the risks to the subjects in this study, the sponsor considers the following measures to 
be appropriate: selecting TAK-510 doses with appropriate safety margins based on nonclinical 
study data; managing study eligibility criteria; excluding women of childbearing potential; 
prespecifying safety monitoring procedures, such as frequent BP assessments that include 
orthostatic BP measurements, telemetry, and 12-lead electrocardiogram (ECG); developing 
guidance for investigators; and using a clinical study facility where close monitoring can be 
performed and urgent medical care can be initiated rapidly as appropriate. Overall, the proposed 
risk mitigation plan is adequate to monitor subjects enrolled in the study. 
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Study Objectives
5.1.1
Study Primary Objective
The primary objective of the study is:

Part 1:
–
To characterize the safety and tolerability of single SC doses of TAK-510 in healthy 
subjects.

Part 2:
–
To characterize the safety and tolerability of multiple SC doses of TAK-510 in healthy 
subjects.

Part 3:
–
To characterize the safety and tolerability of multiple SC dose regimens of TAK-510 that 
include titration from lower doses in healthy subjects.
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TAK-510
Study ID TAK-510-1001
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Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
5.1.2
Study Secondary Objectives
The secondary objectives of the study are:
!
Part 1:
–
To characterize the PK of TAK-510 in plasma following single SC doses in healthy 
subjects.
–
To assess the immunogenicity of TAK-510 following single SC doses in healthy subjects.
–
To characterize the PK of TAK-510 in urine following single SC doses in healthy subjects.
!
Part 2:
–
To characterize the PK of TAK-510 in plasma following multiple SC doses in healthy 
subjects.
–
To assess the immunogenicity of TAK-510 following multiple SC doses in healthy 
subjects. 
–
To characterize the PK of TAK-510 in urine following multiple SC doses in healthy 
subjects.
!
Part 3:
–
To characterize the safety and tolerability of single SC rechallenge doses of TAK-510 after 
a washout from multiple SC dose regimens that include titration from lower doses in 
healthy subjects.
–
To assess the immunogenicity of TAK-510 following multiple SC dose regimens that 
include titration from lower doses, washout, and redosing in healthy subjects.
5.1.3
Study Exploratory Objectives
Exploratory endpoints of this study include: 
–
To characterize the PK of TAK-510 in plasma following multiple SC doses and dosing 
schedules in healthy subjects.
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Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-510
Study ID TAK-510-1001
Page 55 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
5.2
Endpoints
5.2.1
Primary Endpoint

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). 
5.2.2
Secondary Endpoints 
Secondary endpoints include: 

Part 1: plasma PK parameters for TAK-510 
–
Maximum observed plasma concentration (Cmax).
–
Area under the plasma concentration-time curve from time 0 to infinity (AUC∞).
–
Area under the plasma 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 disposition phase after extravascular
administration (Vz/F).

Part 2: plasma PK parameters for TAK-510 on Day 1 
–
Cmax, tmax, and area under the plasma concentration-time curve during a dosing interval, 
where tau (τ) is the length of the dosing interval (AUCτ).

Part 2: plasma PK parameters for TAK-510 at steady state 
–
AUCτ, Cmax, tmax, t1/2z, CL/F, Vz/F, observed plasma concentration at the end of a dosing 
interval (Ctrough), accumulation ratio based on AUCτ (Rac[AUC]), calculated as AUCτ at 
steady state/AUCτ after a single dose, and accumulation ratio based on Cmax (Rac[Cmax]), 
calculated as Cmax at steady state/Cmax after a single dose.

Parts 1 and 2: urine PK parameters for TAK-510
–
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) at steady state (Aeτ).
–
Fraction of administered dose of drug excreted from urine from time 0 to time t (fe,t). 
–
Renal clearance (CLR).
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 56 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
!
Part 3:
–
Safety and tolerability of single SC rechallenge doses after a washout from multiple SC 
dose regimens of TAK-510 as assessed through vital signs, ECG, laboratory assessments, 
and AEs.
!
All parts of the study:
–
Status of subject’s ADA assessment (ie, ADA-negative or ADA-positive, and low or high 
ADA titer).
5.2.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters: 
!
Part 3 includes the following plasma PK parameters:
–
AUCτ, AUClast, Cmax.
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,
tolerability, and PK of TAK-510 in healthy subjects. 
The study will consist of 3 parts: 
!
Part 1 is a FIH, randomized, double-blind, placebo-controlled, SRD design to assess the safety,
immunogenicity, tolerability, and PK of TAK-510 in healthy subjects. Up to 17 cohorts may 
be enrolled. 
!
Part 2 is a randomized, double-blind, placebo-controlled, MRD design to assess the safety,
immunogenicity, tolerability, and PK of TAK-510 in healthy subjects. Up to 8 cohorts may be 
tested in independent subject cohorts. 
!
Part 3 is a randomized, double-blind, placebo-controlled, multiple-dose, dose titration and 
redosing design to assess the safety, immunogenicity, tolerability, and PK of TAK-510 in 
healthy subjects. Up to 3 cohorts may be tested in independent subject cohorts using a dose 
titration design, followed by redosing with a single dose of study drug after a 7-day washout 
(168 hours after the previous dose).
TAK-510 and matching placebo will be administered SC. Safety will be assessed by monitoring 
for AEs, vital signs, ECG/telemetry, safety laboratory assessments after each dose, and 
Property of Takeda: For Non-Commercial Use Only and S
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TAK-510
Study ID TAK-510-1001
Page 57 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
immunogenicity. PK sampling times and scheme may vary based on emerging safety, tolerability 
and PK data, but the maximal number of samples or the maximum time point will not change. 
Subjects may not participate in more than 1 part or dosing cohort of the study.
An overview of treatment cohorts is outlined in Table 6.a. A schematic of the study design is 
presented in Section 2.0. The schedule of study procedures is presented in Section 3.0.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-510
Study ID TAK-510-1001
Page 58 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Table 6.a
Overview of Treatment Cohorts
Cohort
Regimen
Treatment
Part 1
TAK-510
Placebo
1
SRD 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
21
6
2
22
6
2
23
6
2
24
6
2
25
6
2
Part 2 
TAK-510
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13
MRD
6
2
14
6
2
15
6
2
16
6
2
17
6
2
26
6
2
27
6
2
28
6
2
Part 3 
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Placebo
18
Dose Titration, Washout, 
Redosing
6
2
19
6
2
20
6
2
MRD: multiple rising dose; SRD: single rising dose.
a Up to 17 doses may be explored with a maximum escalation factor between cohorts of 5-fold at lower exposures and 
2-fold at high exposures.
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TAK-510
Study ID TAK-510-1001
Page 59 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
6.1.2
Part 1: SRD Cohorts 1 to 12 and 21 to 25
Part 1 will consist of up to 17 sequential cohorts with 8 healthy subjects per cohort. Subjects in 
each cohort will be randomly assigned to receive a single dose of TAK-510 or matching placebo 
via SC administration in a 3:1 ratio in a double-blind manner. Up to approximately 136 healthy
subjects will be randomized in Part 1 (approximate value do 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. Baseline HR and BP 
assessments, including postural measurements, will be taken on Day -1, and Day -1 HR and BP 
assessments will be time-matched to the Day 1 assessments. Subjects will be dosed with TAK-510 
or matching placebo on Day 1 after a minimum of 8 hours of fasting. Subjects will be confined for 
96 hours after dosing (ie, they can be discharged after the 96-hour PK sample). Assessments of 
postural hypotension will be measured predose and at 0.5, 2, 4, 7, 10, 24, 48, 72, and 96 hours after 
the dose on Day 1, as well as at time-matched time points on Day -1. Blood samples for 
assessment of TAK-510 plasma concentrations will be collected up to 96 hours postdose. Urine 
will be collected up to 24 hours postdose. 
Optional DNA 
samples will also be collected from subjects that provide consent for collection through a separate 
procedure. DNA samples can be collected at any time on the day of discharge or at early 
termination (if applicable). Samples for immunogenicity will be collected at discharge and at 
follow-up visits on Days 14 and 29.
Cohort 1 will use a staggered dosing scheme. After dosing the first 2 subjects (1 receiving 
TAK-510 and 1 receiving placebo), the investigator will review all available safety and tolerability 
data up to 24 hours postdose before dosing the remaining subjects in the cohort. A staggered 
dosing approach may be used for subsequent cohorts in Part 1 (if decided in the dose escalation 
meeting). Except the starting dose, doses may be modified based on emerging safety and available 
PK data during the study, but will have a corresponding dose that does not exceed the maximal 
defined exposure. 
The exposure levels (AUC∞) of TAK-510 range
 with a planned maximum dose escalation factor of 5-fold between lower 
exposures and 2-fold at high exposures.
 Doses may change 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 who drop out of the study may be 
replaced at the discretion of the sponsor after discussion with the investigator.
After completion of each dosing cohort, and before selecting the next dose, a blinded assessment 
of the safety and tolerability, laboratory results of at least 24 hours, and available PK data will be 
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TAK-510
Study ID TAK-510-1001
Page 60 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
analyzed in the dose escalation meeting (composed of representatives from the sponsor and site 
study teams).
The blind may be broken for select sponsor representatives before each blinded cohort review 
and/or dose escalation meeting, if necessary, due to safety considerations based on the 
prospectively prepared unblinding plan. Following each blinded dose cohort review and after dose 
escalation decisions have been made, the sponsor may be unblinded using the prospectively 
prepared unblinding plan, to enable further data review to inform later parts of the study.
Study Drug Administration
 The single SC 
dose of TAK-510 should be administered in the abdomen (at least 2 cm away from the umbilicus) 
followed by upper arms, then thigh, as alternative sites. In all cases, care should be taken to avoid 
areas of scars, moles, tattoos, or other irritated skin (eg, vitiligo, eczema, etc). TAK-510 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 pulse measurements. 
For additional information on study drug administration, please refer to the study pharmacy 
manual.
6.1.3
Part 2: MRD Cohorts 13 to 17 and 26 to 28
Part 2 may start before the completion of Part 1. If Part 2 is started before the completion of Part 1, 
the starting dose in Part 2 will be based on predicted exposure to be below that observed at the 
highest completed cohort in Part 1. The daily maximum exposure anticipated at steady state 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 
8 ascending cohorts of healthy subjects. In each cohort, 8 healthy subjects will be randomly 
assigned to receive TAK-510 or matching placebo in a 3:1 ratio in a double-blind manner. Up to 
approximately 64 healthy subjects may be randomized in Part 2 (approximate value do not account 
for potential replacement of subjects who withdraw for nonsafety reasons). 
Subjects will be admitted to the study unit on Day -2. Baseline HR and BP assessments will be 
taken on Day -1, and Day -1 HR and BP assessments will be time-matched to the Day 1 
assessments. Subjects will be dosed on Day 1 in each cohort/period after a minimum of 8 hours of 
fasting. Subjects will be confined until Day 9, 96 hours after the Day 5 dose, to assess safety,
tolerability, immunogenicity, and PK. Assessments of postural hypotension will be measured 
predose and at 0.5, 2, 4, 7, 10, and 24 hours after each dose, as well as at time-matched time points 
on Day -1. Blood samples for assessment of TAK-510 plasma concentrations will be collected up 
to 96 hours after the last dose. 
 Optional DNA samples will also be collected from subjects that provide consent for 
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TAK-510
Study ID TAK-510-1001
Page 61 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
collection through a separate procedure. DNA samples can be collected at any time on the day of 
discharge or at early termination (if applicable). Subjects will return after discharge for additional 
immunogenicity and other assessments at follow-up visits on Days 14 and 29.
In Part 2, up to 8 tolerated doses from Part 1 up to the current planned maximum exposure (AUC∞) 
of 705,000 h*ng/mL will be studied in an ascending manner. The daily 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 once daily. Based on safety, tolerability, and emerging PK data from Part 1 
and any available PK data from Part 2, reductions in dose and in repeat dosing duration may be 
implemented. 
After completion of each dosing cohort, and before selecting the next dose, a blinded assessment 
of the safety and tolerability, laboratory results of at least 24 hours after the last dose in the cohort, 
and available PK data will be analyzed in the dose escalation meeting (composed of 
representatives from the sponsor and site study teams). At the dose escalation meeting, the starting 
dose in Part 2 will be decided based on emerging safety, tolerability, and available PK data from 
Part 1.
The blind may be broken for select sponsor representatives before each blinded cohort review 
and/or dose escalation meeting, if necessary, due to safety concerns based on the prospectively 
prepared unblinding plan. Following each blinded dose cohort review and after dose escalation 
decisions have been made, the sponsor may be unblinded using the prospectively prepared 
unblinding plan, to enable further data review to inform later parts of the study. 
Subjects who drop out may be replaced at the discretion of the sponsor after discussion with the 
investigator.
Study Drug Administration
In Part 2, when administering TAK-510, injection sites must be rotated. 
The single SC dose of TAK-510 
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 TAK-510 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 TAK-510 
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 pulse measurements. For additional information on study 
drug administration, please refer to the study pharmacy manual.
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TAK-510
Study ID TAK-510-1001
Page 62 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
6.1.4
Part 3: Dose Titration and Redosing Cohorts 18 to 20
The overall purpose of Part 3 is to characterize the safety and tolerability of multiple SC dose 
regimens of TAK-510 involving dose titration over 7 days of treatment. The intent of this study 
part is to enable a descriptive comparison (ie, without hypothesis testing) of tolerability findings 
between Part 3 cohorts and cohorts in Parts 1 and 2 with comparable exposures, to determine 
whether dose titration results in different tolerability. The redosing component of Part 3 is 
intended to provide an evaluation to assess the effects of a single rechallenge dose (after 7 days 
[168 hours] of washout following the 7-day treatment period) on the safety and tolerability profile 
(vital signs, adverse events, and other safety parameters). 
Part 3 may start before the completion of Parts 1 and 2. If Part 3 is started before the completion of 
Part 2, the maximum daily exposure in Part 3 will be at a total daily exposure level below or at the 
highest completed cohort in Part 2 that has been determined to be well tolerated. Similar to Part 1 
and Part 2, a staggered dosing approach may be used for cohorts in Part 3. Part 3 consists of up to 
3 sequential cohorts of healthy subjects. In each cohort, 8 healthy subjects will be randomly 
assigned to receive TAK-510 or matching placebo in a 3:1 ratio in a double-blind manner. Up to 
approximately 24 healthy subjects may be randomized in Part 3 (approximate value do not account 
for potential replacement of subjects who withdraw for nonsafety reasons). 
Subjects will be admitted to the study unit on Day -2. Baseline HR and BP assessments will be 
taken on Day -1, and Day -1 HR and BP assessments will be time-matched to the Day 1 
assessments. Subjects will be dosed on Day 1 in each cohort/period after a minimum of 8 hours of 
fasting. Subjects will be confined until Day 8, 30 hours after the Day 7 dose, to assess safety,
tolerability, immunogenicity, and PK. Assessments of postural hypotension will be measured 
predose and at 0.5, 2, 4, 7, 10, and 24 hours after each dose, as well as at time-matched time points 
on Day -1. Blood samples for assessment of TAK-510 plasma concentrations will be collected on 
Days 1 to 7 and on Day 14, at predose and at select postdose time points to capture the predicted 
Cmax, as well as at 30 hours after the Day 7 and Day 14 doses. 
 Optional DNA samples will also be collected 
from subjects that provide consent for collection through a separate procedure. DNA samples can 
be collected at any time on the day of discharge (Day 8) or at early termination (if applicable). 
Subjects will be discharged on Day 8 and will be readmitted the evening prior to redosing. After a 
7-day washout (168 hours after the last dose of the 7-day treatment period), subjects will be dosed 
with a single dose of study drug (ie, at the same dose and double-blind treatment assignment as 
their highest daily dose during the 7-day treatment period). The duration of washout may be 
subject to change based on emerging safety, tolerability, and available PK data. Subjects will be 
confined the evening prior to redosing and for at least 30 hours after their redosing, while not being 
confined for the entire washout period. Subjects will return after discharge for additional 
immunogenicity and other assessments at follow-up visits on Day 29. Based on emerging safety,
tolerability, and available PK data, subjects may be confined during washout at the discretion of 
the investigator in consultation with the sponsor and medical monitor.
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TAK-510
Study ID TAK-510-1001
Page 63 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
In Part 3, up to 3 cohorts may be dosed sequentially for 7 days using a dose titration design of 1 to 
5 days at lower doses followed by 2 to 6 days at the highest dose for that cohort, which will not 
exceed the dose studied in the highest completed dose cohort in Part 2. Cohorts 18 and 19 may be 
started in parallel. The proposed dose titration designs for the 3 cohorts are as follows:
Cohort 18: Single doses that escalate on a daily basis will be given on the first 2 to 5 days of 
the 7-day dosing period, followed by a maximum daily dose on the remaining days of the 
7-day dosing period. 
Cohort 19: A lower starting dose will be given on the first 2 to 3 days of the 7-day dosing 
period, followed by a maximum daily dose for the remaining days of the 7-day dosing 
period. The lower starting dose is to be determined based on Cohort 18. 
Cohort 20: The initial daily dose(s) are to be determined by Cohorts 18 and 19 and will be 
given on the first 1 to 3 days, followed by the maximum daily dose for the remaining days 
of the 7-day dosing period. The maximum daily dose will be the same as that Cohorts 18 
and 19, or higher as supported by safety, tolerability, and PK data from at least the same 
daily dose (or higher) in Part 2 MRD cohorts.
Dose regimens up to the current planned maximum exposure level (AUC∞) of 705,000 h*ng/mL 
will be studied as determined by the prior dosing regimen in Part 2. The daily exposure will not 
exceed an exposure established as well tolerated in Part 2. Doses in Part 3 are planned to be 
administered SC once daily. Based on emerging PK data from Parts 1 and 2, and PK data from
prior cohorts in Part 3, adjustments to dose and to repeat dosing duration may be implemented. 
The dose escalation meeting will determine the doses and dose schedule of Cohort 18 and 19 based 
on safety, tolerability and available PK data from Parts 1 and 2. After completion of Cohort 18 and 
19, and before selecting the next dose schedule, a blinded assessment of the safety and tolerability,
laboratory results of at least 24 hours after the last dose in the cohort, and available PK data will be 
analyzed in the dose escalation meeting (composed of representatives from the sponsor and site 
study teams).
The blind may be broken for select sponsor representatives before each blinded cohort review 
and/or dose escalation meeting, if necessary, due to safety concerns based on the prospectively 
prepared unblinding plan. Following each blinded dose cohort review and after dose escalation 
decisions have been made, the sponsor may be unblinded using the prospectively prepared 
unblinding plan. 
Subjects who drop out may be replaced at the discretion of the sponsor after discussion with the 
investigator.
Study Drug Administration
In Part 3, when administering TAK-510, injection sites must be rotated.
. The single SC dose of TAK-510 
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 TAK-510 are given in the same spot, this 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-510
Study ID TAK-510-1001
Page 64 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
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 TAK-510 
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 pulse measurements. For additional information on study 
drug administration, please refer to the study pharmacy manual.
6.2
Stopping Rules
6.2.1
Stopping Criteria for Individual Subjects
Subjects will permanently discontinue study drug for any study drug-related adverse events that 
are rated Grade ≥3 in severity on the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) scale (v5.0).
6.2.2
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

Any subject experiences a Hy’s Law reaction (defined as alanine aminotransferase [ALT] or
aspartate aminotransferase [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-510, such that the risk is no longer
acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve
the primary study objectives or compromises subject safety.

The sponsor elects to terminate or suspend the study for administrative reasons including plans
to modify, suspend, or discontinue development of the study drug.
In addition, the study may be interrupted for review of the safety data during Parts 1, 2, or 3 if one 
of the below criteria is met:

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-510, or

Two or more subjects experience a CTCAE v5.0 Grade ≥3 hypotension (ie, requiring medical
intervention) and considered related to TAK-510, or

One subject experiences a CTCAE v5.0 Grade ≥3 syncope (fainting or orthostatic collapse)
and considered related to TAK-510, or
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TAK-510
Study ID TAK-510-1001
Page 65 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL

Two or more subjects experience a CTCAE v5.0 Grade 3 event considered related to TAK-510 
administration, or 

One subject experience a CTCAE v5.0 Grade 4 event considered related to TAK-510 
administration, or

One subject with ALT or AST >5 × ULN after TAK-510 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 increases in creatinine >1.5 × ULN after TAK-510 administration, or 

One subject with a serious adverse event (SAE) considered related to TAK-510 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).
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 the event is considered unlikely to be related to treatment with 
study drug by the investigator and sponsor.
During Study Drug Dosing in Part 2 (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 may continue provided it is at a lower daily dose than in Part 1 than that at which 
the event was observed, and the sponsor and investigator agree after careful review of the totality 
of the available blinded data.
During Study Drug Dosing in Part 3 (Titration and Redosing After Washout)
If the criteria for pausing occurs in MRD Part 2 or SRD Part 1 at a higher level than is being dosed 
in Part 3 (ie, higher level than the maximal dose during titration or Day 14), dosing in Part 3 may 
continue provided it is at a lower daily dose than in Parts 1 or 2 than that at which the event was 
observed, and the sponsor and investigator agree after careful review of the totality of the available 
blinded data.
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6.3
Rationale for Study Design, Dose, and Endpoints
6.3.1
Rationale of Study Design 
A randomized, double-blind, placebo-controlled design for Part 1 is considered adequate to 
characterize the safety, tolerability, and PK of single doses of TAK-510.
Part 2 of the study is a randomized, double-blind, placebo-controlled, sequential panel MRD study 
where up to 8 cohorts may be studied under repeat-dose conditions.
The intention with the dose titration part of Part 3 is to provide an exploratory evaluation to assess 
the safety and tolerability profile of dose titration at the start of the 7-day treatment period. This 
comparison will be descriptive (ie, without hypothesis testing) versus tolerability findings in Parts 
1 and 2 with comparable exposures to determine whether dose titration results in different 
tolerability. The redosing part of Part 3 is intended to provide an exploratory evaluation to assess 
the effects of a single dose (after 7 days [168 hours] of washout following the 7-day treatment 
period) on vital signs, adverse events, and other safety parameters.
6.3.2
Rationale for Dose 
The starting dose for this FIH study is 5 μg. The 4 considerations for the selection of the starting 
dose for the FIH study are summarized here and described in more detail below:
1. Nonclinical safety data and Food and Drug Administration (FDA) maximum safe starting dose 
guidance [10].
2. Nonclinical cardiovascular safety pharmacology data for TAK-510.
3. Benchmarking to 
 cardiovascular findings.
4. Lowest projected antiemetic effect and insulin secretion effect as demonstrated in nonclinical 
species.
6.3.2.1
FIH Starting Dose Consideration Based on Nonclinical Safety Study Results, 
Published 
 Results, 
 Experience
The principle of the FDA Guidance “Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers” [10] is to use a 10-fold safety factor 
on the no-observed-adverse-effect level (NOAEL) from nonclinical data to identify a starting 
clinical dose.
For TAK-510, NOAELs were identified in the 2-week GLP-compliant, repeat-dose toxicity 
studies, and no-observed-effect levels (NOELs) were identified in the respiratory and central
nervous system safety pharmacology studies. 
The NOAEL in the rat was 60 mg/kg (highest dose investigated); minimal body weight loss and 
dose-dependent minimal to moderate vacuolation of the proximal convoluted tubule of the kidney 
(without degeneration/necrosis or changes in clinical pathology) were considered nonadverse. The 
NOAEL in the dog was 15 mg/kg; body weight loss and associated clinical observations were 
considered adverse at 50 mg/kg. 
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However, cardiovascular effects in dogs were the principal finding in the safety pharmacology
studies. In this study, the lowest dose of 
 TAK-510 produced a transient increase in 
HR and a transient decrease in BP, and a NOEL was not identified.
Given the reversible nature of the cardiovascular changes, and the lack of other significant safety 
findings at this dose level, the
 TAK-510 dose is not anticipated to result in any 
clinically significant effects or significant safety risk.
 Incretin effects 
were as expected with transient, glucose-dependent increases in both insulin and glucagon 
reported. Cardiovascular effects were consistent across studies with an increase in HR and 
decrease in BP reported during the 2 to 4 hours of infusion. 
Additionally, the lowest dose tested 
 in the first-in-human 
clinical study of
 resulted in changes in BP 
(diastolic BP changes at 30 minutes) that were not considered clinically significant.
 
 Refer to the current edition of the 
TAK-510 Investigator’s Brochure for additional details of FIH study findings 
.
The selected FIH dose 
 and derived from a combination of 
nonclinical and clinical cardiovascular profiles in which submaximal or minimal cardiovascular 
changes, respectively, were reported. 
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In summary, given the totality of these findings from nonclinical safety, published literature, and 
nonclinical pharmacology, the proposed starting dose is 5 μg.
6.3.2.2
FIH Maximum Dose Consideration
No adverse toxicological findings were observed in 2-week repeat dose GLP-compliant 
toxicology study in rats at doses up to 60 mg/kg; however; body weight loss and associated clinical 
observations were considered adverse in dogs at 50 mg/kg. The NOAEL was determined to be the 
mid-dose of 15 mg/kg/day in dogs, which produced an AUC (705,000 h*ng/mL) that was less than 
half the rat NOAEL AUC (2,470,000 h*ng/mL); the dog was considered to be the most sensitive 
species. As per the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) “Guidance on Nonclinical Safety Studies for the Conduct 
of Human Clinical Trials and Marketing Authorization for Pharmaceuticals M3(R2)” [13], for 
situations where only one species demonstrates adverse toxicities, the maximum clinical dose will 
be limited to AUC exposure at the NOAEL in the species showing toxicity or half the AUC at the 
NOAEL in the species without toxicity. Thus, the AUC of TAK-510 in the clinic will not exceed 
705,000 h*ng/mL, which is the dog NOAEL AUC.
Preliminary data from other studies recently analyzed have helped refine 
 
 The doses that are 
predicted to maintain concentration in the efficacious range and allow for optimal onset of 
response within 30 minutes are planned to be evaluated.
Given the available formulation 
 and feasibility limitation of maximum administered 
volume of 1 mL per SC injection, 
 is the highest planned dose predicted to be evaluated in 
Part 1. The predicted exposure 
 will be
below the dog NOAEL (most sensitive species; AUC∞= 705,000 h*ng/mL).
6.3.2.3
FIH Proposed Dose Regimen for the SRD Cohorts
The proposed dose regimen with target PK and safety margins for select proposed doses is 
presented in Table 6.b.
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Table 6.b
Human Dose-Related Concentrations and Exposures for Select Proposed 
Doses in Part 1
Dose a (μg)
Cmax (ng/mL)
AUC∞(h*ng/mL)
Safety Margin NOAEL 
Exposure
5
AUC: area under the plasma concentration-time curve; AUC∞: area under the plasma concentration-time curve from 
time 0 to infinity; Cmax: maximum observed plasma concentration; NOAEL: no-observed-adverse-effect level; PK: 
pharmacokinetic.
Exposure at NOAEL in dog 705,000 h*ng/mL (AUC). 
Values represent geometric mean.
a Single dose administered. 
b Preliminary observed PK parameters.
c Predicted assuming linear PK from observed 
 preliminary human PK data from this ongoing study. 
It is planned that up to 17 doses may be explored with a maximum escalation factor between 
cohorts 
 at lower exposures and 
 at high exposures. 
Dose levels may be adjusted based on emerging safety and available PK data from previous 
cohorts, and after discussion between the sponsor and investigator. Doses may be repeated if 
safety and tolerability are acceptable, or lower doses may be studied to increase data within the 
dose range. Any decision to resume dosing at the current dose level or to escalate the dose will be 
made jointly by the investigator and the sponsor after careful evaluation of all available blinded 
data.
6.3.2.4
Rationale for Dosing Interval
Multiple dose cohorts (Part 2) will be administered TAK-510 once daily.
The dosing regimens selected for Parts 2 and 3 will have a projected AUC∞that will not exceed an 
AUC∞of 705,000 h*ng/mL or the highest AUC∞determined to be tolerated in Part 1.
6.3.2.5
Rationale for Dose Titration and Redosing After Washout
Part 3 of the study is intended to evaluate whether dose titration can result in a different tolerability, 
particularly with regard to cardiovascular effects, and whether redosing after a 7-day washout 
results in cardiovascular effects (ie, loss of potential attenuation of cardiovascular effects with 
dose titration and multiple dosing). GLP-compliant and non–GLP-compliant cardiovascular safety 
studies in telemetered dogs with TAK-510 have demonstrated: (1) a dose-response of 
cardiovascular effects, where the lowest dose tested 
 results in an ~ED50 (median 
effective dose) of maximal heart rate and blood pressure effects observed in dogs; (2) 
repeat-dosing at therapeutic doses results in a significant attenuation of cardiovascular effects 
following administration of the second daily dose. These data demonstrate that sub-therapeutic 
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doses can elicit minimal cardiovascular effects and that repeat dosing may elicit tachyphylaxis. 
Thus, Part 3 of this study is designed to test these concepts clinically to identify the appropriate 
tolerizing doses, escalation, and length of time of exposure that can potentially minimize 
cardiovascular effects at therapeutic doses. 
6.3.3
Rationale for Endpoints
The PK and safety endpoints are standard for this type of study and are used widely and are 
recognized as reliable, accurate, and relevant. Additional PK parameters may be calculated if 
deemed necessary for the interpretation of the data.
6.3.4
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the following procedures are critical: 
Parts 1, 2, and 3:

Timing of PK, BP, and telemetry assessments.

All other procedures should be performed as close as possible (either before or after) the 
scheduled times.

The order of priority can be changed during the study with joint agreement of the investigator 
and the sponsor.
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures. 
6.4
Procedure Modifications Permitted Within Protocol Parameters
This is a phase 1 study of TAK-510 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, for 
example, 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 informed consent form update if
the changes do not impact the burden of subjects or safety monitoring.
6.5
Study Beginning and End/Completion
6.5.1
Definition of Beginning of the Study
The overall study begins when the first subject signs the study informed consent form.
6.5.2
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, or is lost to follow-up (ie, the investigator is unable to contact the subject).
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6.5.3
Definition of Study Discontinuation
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. 
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.
6.5.4
Criteria for Premature Termination or Suspension of the Study
6.5.4.1
Criteria for Premature Termination or Suspension of Study 
See Section 6.2 for study-specific stopping rules and additional criteria for premature termination 
or suspension of the study.
6.5.4.2
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 early termination 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.
6.5.5
Criteria for Premature Termination or Suspension of a Site
6.5.5.1
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 Good Clinical Practices (GCP), protocol, or contractual 
agreement, is unable to ensure adequate performance of the study, or as otherwise permitted by the 
contractual agreement.
6.5.5.2
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 
early termination 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.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria 
To be eligible for participation in this study, the subject must:
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 man or woman of nonchildbearing potential 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 dosing and throughout the study.
5. Have a body mass index (BMI) ≥18 and ≤30.0 (kg/m2) at the screening visit.
6. Be judged to be in good health (eg, no evidence of psychiatric, hepatic, renal, pulmonary, or 
cardiovascular disease) by the investigator, based on clinical evaluations including laboratory 
safety tests, medical history, physical examination, ECG, and vital sign measurements 
performed at the screening visit and before administration of the initial dose of study drug or 
invasive procedure.
7. 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 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.
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c) Had a bilateral tubal ligation with appropriate documentation of surgical procedure.
d) Has a congenital condition resulting in no uterus.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has 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.
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-510.
5. The subject has a positive pregnancy test or is lactating or breastfeeding.
6. 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. 
7. The subject had major surgery or donated or lost 1 unit of blood (approximately 500 mL) 
within 4 weeks before the screening visit.
8. 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 2 days after discharge. 
9. The subject is unable to refrain from or anticipates using marijuana or cannabis-containing 
products beginning approximately 7 days before administration of the first dose of study drug, 
throughout the study until after the last PK dose. 
10. The subject has a history or presence of alcoholism or drug abuse within the past 2 years prior 
to dosing, or frequent or heavy use (ie, near-daily) of medical or recreational cannabis in the 
past 3 months before screening.
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 has had a previous major psychotic disorder.
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14. The subject has a history or presence of: 
–
3 or more incidences of vasovagal syncope within the last 5 years prior to screening; or
–
A family history of unexplained sudden death or channelopathy; or
–
Brugada syndrome (ie, RBBB pattern with ST-elevation in leads V1-V3); or
–
Cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial 
infarction, stroke, sick sinus syndrome, pulmonary congestion, symptomatic or significant 
cardiac arrhythmia, 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; or
–
Risk factors for Torsade de Pointes (eg, heart failure, cardiomyopathy, or family history of 
Long QT Syndrome); or
–
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 >210 msec at screening or Day -1 pre-Hour 0; or
–
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 time point values do not meet this criterion, must be discussed with the medical 
monitor for approval. 
16. The subject has an average HR <55 or >100 bpm from screening to predose, inclusive. 
Subjects with an average HR <55 bpm can be enrolled only with medical monitor approval.
Any assessments after admission with an average HR <55 bpm, from Day -2 to predose 
(inclusive), 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 systolic BP ≥20 mm Hg or a 
decrease in diastolic BP ≥10 mm Hg at approximately 3 minutes of standing when compared 
with BP from the semirecumbent position at screening to predose assessments, inclusive. In 
asymptomatic subjects, any assessments after screening that 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 3 minutes of standing, at screening to predose assessments, 
inclusive. Any assessments after screening that 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 
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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.
19. The subject has a known or suspected current COVID-19 infection or is at risk of COVID-19 
infection as assessed by the investigator.
7.3
Excluded and Allowed Concomitant Medications, Supplements, and 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 2 days after discharge 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.
The occasional use of acetaminophen (approximately <1 g/day) is allowed.
7.3.2
Fruit Juice
Subjects will refrain from consuming grapefruit juice, grapefruits, and products containing 
grapefruit beginning approximately 2 weeks before administration of the first dose of study drug, 
throughout the study, and until the last PK sample has been collected.
7.3.3
Alcohol
Subjects will refrain from consuming alcohol, 24 hours before admission until the final PK sample 
has been collected. 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 the PK blood sample at 30 hours 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 screening until 
discharge after the last scheduled dose.
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7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
7.4.1.1
Part 1
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 telemetry 
recording extractions and/or safety ECG.
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
Part 2 and 3
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 Days 
1 and 5 in Part 2, and Days 1, 7, and 14 in Part 3, 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 (including the washout interval in 
Part 3), and 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 TEAE. The subject has experienced a pretreatment event or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the pretreatment event or 
AE.
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
Liver function test (LFT) 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.
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, 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 
early termination 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.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
TAK-510 will be supplied to the study site by the sponsor 
for injection. The matching placebo is normal saline.
TAK-510 and placebo will be prepared for injection by licensed pharmacy staff at the clinical 
research unit according to the procedures outlined in the pharmacy manual.
Details regarding the dosage form description and strengths, or composition for the 
extemporaneous 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.
TAK-510 will be provided in a labeled glass vial and packaged in an appropriately labeled carton 
with a single-panel label that 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.
8.1.2
Clinical Study Drug Inventory and Storage
The same lot number will be used throughout the study. 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-510 must be stored at -25°C to -15°C (-13°F to 5°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 study; the investigator and subjects are blinded to treatment assignment. 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. Randomization code/disclosure 
envelopes or lists will be provided per the standard operating procedures of the study site. 
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After completion of each dosing cohort, and before selecting the next dose, a blinded assessment 
of the safety and tolerability, laboratory results of at least 24 hours after the last dose in the cohort, 
and available PK data will be performed in the dose escalation meeting (composed of 
representatives from the sponsor and site study teams).
The blind may be broken for select sponsor representatives before each blinded cohort review 
and/or dose escalation meeting, if necessary, due to safety concerns based on the prospectively 
prepared unblinding plan. Following each blinded dose cohort review and after dose escalation 
decisions have been made, the sponsor may be unblinded using the prospectively prepared 
unblinding plan, to enable further data review to inform later parts of the study.
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.
8.1.5
Clinical Study 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. 
Unblinding will be performed per the standard operating procedures of the study site.
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator and investigator’s designated site pharmacy must ensure that the sponsor- or 
contract research organization (CRO)-supplied drug is used in accordance with the protocol and 
pharmacy manual and is dispensed only to subjects enrolled in the study. To document appropriate 
use of the sponsor-supplied drug, the investigator pharmacy/site must maintain records of drug 
delivery to the site, site inventory, dispensation and use by each subject, and return to the sponsor 
or designee.
Upon receipt of sponsor-supplied drug, the designated blinded pharmacist must verify the contents 
of the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, designated site 
pharmacist should acknowledge the receipt of the shipment by signing bottom half of the packing 
list. If there are any discrepancies between the packing list versus the actual product received, 
Takeda must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file.
The investigator’s designated blinded pharmacist must maintain 100% accountability for all 
sponsor-supplied drugs received and dispensed during his or her entire participation in the study. 
Proper drug accountability includes, but is not limited to:

Monitoring expiration dates.
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
Frequently verifying that actual inventory matches documented inventory.

Verifying that the drug accountability log is completed for each prepared dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
8.2
Ancillary Supplies
All ancillary supplies will be provided by either the study site or the sponsor or designee, 
depending upon availability. The list of ancillary supplies and source information can be found in 
the pharmacy manual or in the referenced compounding manual when applicable. If provided by 
the sponsor, unused ancillary supplies will be accounted for and disposed of as directed by the 
sponsor or designee.
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 one 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 one randomization number.
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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-510 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.
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
9.2.1
Full Physical Examination
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.
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At screening, and from admission to the clinical research unit through predose (inclusive of 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, and first dose in Part 3) 
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 any dose after the first 
dose in Parts 2 and 3, the investigator may exercise discretion related to appropriateness of the 
subject’s ongoing study participation on the basis of 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 
(Part 2 and Part 3) or vital sign criteria defined in Section 7.2. Should dosing be delayed in Parts 2 
or 3 of the study, adjustment should be made on subsequent days to administer the dose as close as 
possible to the originally planned TAK-510 dosing time based on Day 1 dosing. 
Subjects should rest in a semirecumbent position for at least 3 minutes before vital signs are 
measured. Vital signs will include pulse rate (bpm), respiratory rate, and systolic and diastolic BP 
in all parts of the study. BP and pulse 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 
pulse assessment if results are inconsistent (ie, a difference >10 bpm in HR or a difference >10 mm
Hg in SBP or DBP between assessments). If 3 measurements are obtained, the final BP and pulse 
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 prior to 
dosing or Hour 0. When scheduled after the dose, vital signs will be performed within 
approximately 15 minutes of the scheduled time point. 
Orthostatic BP and pulse assessment will be performed with the subject standing after the 
semirecumbent assessment has been completed. The subject should stand still for approximately 3 
minutes before this assessment. 

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.

If there is a decrease in systolic BP ≥20 mm Hg or a decrease in diastolic BP ≥10 mm Hg after 
approximately 3 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. 
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
Standing assessments must not be performed if semirecumbent systolic BP 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 after 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.
When vital signs are scheduled at the same time as blood draws, they will be obtained before the 
scheduled blood draw.
9.2.4.1
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 
study site.
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 the study site
per policy, or if a subject should leave the study site due to unforeseen circumstances, the sponsor 
will be consulted immediately to discuss the following:

If the subject is asymptomatic in relation to cardiovascular symptoms but without telemetry 
observations during the postdose period, the subject could be discharged home after discussion 
with the sponsor, but with adequate 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 cardiovascular 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 cardiovascular 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, and 3 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 (in semirecumbent position), or experiences hypotension 
with systolic BP <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, 
pulse, 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
In Parts 1, 2, and 3, cardiac monitoring (pulse and ECG) will be assessed via telemetry and will be 
performed for at least 24 hours before dosing and at least 24 hours postdose. 
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 9.2.4.1 for details).
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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 in Parts 1, 2, and 3 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 thorough QT (TQT) 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 concentration-QT 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.
Collected ECG data from 12-lead telemetry may also be used to explore the relationship with 
TAK-510 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-510 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.
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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)
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 the upper limit of normal, total 
bilirubin will be fractionated
Protein (total)
Creatine kinase
ALT: alanine aminotransferase; AST: aspartate aminotransferase.
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 and 3, 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.
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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.
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.
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 and/or serum 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.
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Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary Specimen 
Derivative
Description of 
Intended Use
Sample 
Collection
Plasma sample for TAK-510 PK
Blood
Plasma
PK analysis
Mandatory
Plasma sample for metID
Blood
Plasma
metID analysis
Mandatory
Urine sample for TAK-510 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-510 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 samples to determine the metabolites 
of TAK-510. If conducted, these data will be reported separately and not be reported in the CSR.
PK parameters that will be determined after single dose and at steady state include, but are not 
limited to, the following:
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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/blood/serum 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-510 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) at steady state.
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.
9.2.10.1.1
Plasma for PK Measurements and Metabolite Identification
Plasma samples for PK analysis of TAK-510 will be collected into chilled blood collection tubes 
(vacutainer) containing the anticoagulant K2EDTA. The collected blood or resultant plasma 
samples may be archived for exploratory characterization of potential circulating metabolites. If 
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conducted, these data will be reported separately and not be reported in the CSR. A full description 
of PK sample collection, handling, storage, and shipping can be found in the laboratory manual.
The actual time of sample collection will be recorded on the source document and eCRF. Sampling 
time points may be adjusted based on the preliminary emerging concentration data collected from 
prior subject(s), but the total number of samples collected per subject should not exceed the 
planned number.
 An evaluation of the coverage and relative abundance of human catabolites 
will be conducted for cross-comparison to nonclinical species. Therefore, subject plasma samples 
will be collected for catabolite profiling analysis to provide an assessment of catabolite coverage 
in nonclinical safety testing [14]. Samples will be collected as specified in the Schedule of Study
Procedures (Section 3.0). These data will be reported separately and will not be reported in the 
CSR.
9.2.10.1.2
Urine for PK Measurements
Urine concentrations of TAK-510 will be measured by a validated high-performance liquid 
chromatography with tandem mass spectrometry assay. A full description of urine sample
collection, handling, storage, and shipping can be found in the laboratory manual. The collected 
urine samples may be archived following bioanalysis of TAK-510 levels for exploratory
characterization of potential urinary metabolites.
9.2.10.2
Immunogenicity (ADA) Measurements
Protein products have the potential to induce antidrug immune response that may affect the safety 
and efficacy of the compound under study. Detection and analysis of ADA formation is a helpful 
tool in understanding drug immunogenicity, efficacy, and safety. To understand drug 
immunogenicity, blood samples will be collected in all study parts according to the Schedule of 
Study Procedures (Section 3.0), on Day 1, predose, at Day 8, and at the follow-up visits. Other 
have reported the formation of ADAs; however, an ADA assay may be 
influenced by several factors including assay methodology, sample handling, timing of sample 
collection, concomitant medications, and underlying disease. Therefore, the incidences of ADA 
formation cannot be directly compared with the other products. ADA samples will be taken in all 
parts of the study across all cohorts.
A 3-tiered ADA testing strategy will be applied to this study. A sample will initially be screened 
for ADA by the ADA screening assay. Any positive sample in the screening assay is considered a 
potential positive, which will be confirmed for true positivity by the confirmatory assay. If a 
sample is confirmed as an ADA true positive, ADA titer will be assessed. 
The extra immunogenicity samples will be stored for future potential further ADA 
characterization which will be dependent on the initial assessment of the effect of ADA status on 
the observed PK, pharmacodynamic, safety, and efficacy profile of TAK-510 in this study as well 
as the regulatory request if it is applied.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applica
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9.2.10.4
DNA Measurements 
9.2.10.4.1
Blood Sample for DNA 
Sampling of blood for DNA analysis is optional in this study and both will be obtained for all 
subjects who consent to providing a sample for DNA. Collection of DNA will be performed for 
each consented subject as indicated in the Schedule of Study Procedures (Section 3.0). 
As DNA research is an evolving science, further assessments may be performed based on newly 
available data. DNA sequencing analysis will not be reported in the CSR.
Detailed instructions for collection, storing, handling, and shipping samples will be provided in the 
laboratory manual. 
9.2.10.4.2
Biological Sample Retention and Destruction
In this study, sample of blood for DNA analysis will be collected as described in Section 9.2.10.4.1.
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 
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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
Part 1 (SRD)
Subjects will report to the clinical site on Day -2. Subjects will remain in the clinic for 96 hours 
postdose (Day 5). At the discretion of the investigator, subjects may be requested to remain in the 
clinical site longer.
9.3.2
Part 2 (MRD)
Subjects will report to the clinical site on Day -2. Subjects will remain in the clinic until discharge 
on Day 9 (96 hours after last dose of study drug). At the discretion of the investigator, subjects may 
be requested to remain in the study site longer.
9.3.3
Part 3 (Dose Titration and Redosing)
Subjects will report to the clinical site on Day -2. Subjects will remain in the clinic until discharge
on Day 8, 30 hours after last dose of study drug. Based on emerging safety, tolerability, and 
available PK data, subjects may be confined during washout at the discretion of the investigator in 
consultation with the sponsor and medical monitor. Subjects will report to the clinical site for 
readmission on the evening before the scheduled day of study drug redosing (Day 13). Subjects 
will remain in the clinic until discharge on Day 15, 30 hours after the single dose of study drug on 
Day 14. At the discretion of the investigator, subjects may be requested to remain in the study site 
longer.
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9.4
Childbearing Status and Methods of Contraception
9.4.1
Women of Childbearing Potential
Women of childbearing potential will be excluded from this study.
9.4.1.1
Definition of Women of Childbearing Potential
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
A female subject of nonchildbearing potential is 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, bilateral salpingectomy, 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 Women of Nonchildbearing Potential
No contraception is required for women of nonchildbearing potential.
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.
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.
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
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 may be 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 
retest 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 
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…”).
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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 in the Dosing 
section 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 eCRF(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.
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.
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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-510 include injection site reactions, hypotension, and 
tachycardia. In addition, orthostatic hypotension is considered as a potential risk based on clinical 
experience 
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 NCI CTCAE v5.0. AEs not listed by the NCI CTCAE will be graded as 
displayed in Table 10.a.
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.
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 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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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 Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
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 one 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.”
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
Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – 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, AESIs, and Abnormal LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, AESIs, and abnormal LFTs) will commence at the time the 
subject signs the informed consent. Routine collection of AEs will continue until approximately 30 
days after the last dose of investigational product. For subjects who discontinue prior to the 
administration of study medication, AEs will be followed until the subject discontinues study 
participation. 
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).

Action taken with study drug.
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
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 form 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).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 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.
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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.
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 subject should be advised to lie flat, and pulse 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, pulse, and ECG measurements will be reviewed by the 
investigator, who will use their clinical judgment regarding further monitoring and management.
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-510 administration will be discontinued on occurrence 
of an event of CTCAE v5.0 Grade ≥3 hypotension (ie, requiring medical intervention).
If systolic BP 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 BP and HR should be 
rechecked in that position. If systolic BP 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-510, provide immediate treatment, and contact the 
medical monitor. Any injection site reaction assessed as a CTCAE v5.0 Grade 2 (ie, pain, 
lipodystrophy, edema, phlebitis) should be managed according to standard of care. Symptomatic 
treatment should be administered, and the investigator should contact the medical monitor.
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10.2.8.4.4
Hypersensitivity
If anaphylaxis or other serious allergic reactions occur, TAK-510 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. 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 and/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 and/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 study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB and/or IEC in accordance with national regulations.
11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan 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.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, or appropriateness of the 
planned statistical methods.
The impact due to COVID-19 will be summarized and listed based on all randomized subjects, 
where appropriate.
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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-510 and have at 
least 1 measurable postdose plasma or urine concentration for TAK-510.
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) for placebo, each TAK-510 dose level (Parts 1 and 2)/dose regimen 
(Part 3), and TAK-510 overall in Parts 1, 2, and 3 separately. The number and percentage of 
subjects in each class of the categorical demographic variables and baseline characteristics 
variables (eg, gender, ethnicity, race) will be tabulated for placebo, each TAK-510 dose level 
(Parts 1 and 2)/dose regimen (Part 3), and TAK-510 overall in Parts 1, 2, and 3 separately. Placebo 
data will be pooled across cohorts within each part of the study. The same dose level (Parts 1 
and 2)/dose regimen (Part 3) will be pooled across cohorts within each part of the study where 
appropriate. The safety analysis set will be used to summarize the demographics and baseline 
characteristics. All data will be provided in by-subject listings.
11.1.3
PK Analysis
The plasma (all parts of the study) and urine (Parts 1 and 2 only) concentrations of TAK-510 will 
be summarized by dose level (Parts 1 and 2 only)/dose regimen (Part 3 only) at each scheduled 
sampling day/time within each part of the study separately, using descriptive statistics (n, mean, 
standard deviation, geometric mean, percent coefficient of variation [%CV], median, minimum, 
and maximum) based on the PK analysis set. The PK parameters of TAK-510 determined using a 
noncompartmental analysis approach will be summarized by dose level (Parts 1 and 2 only)/dose 
regimen (Part 3 only) of TAK-510, as appropriate, within each part of the study separately, using 
descriptive statistics (n, mean, standard deviation, geometric mean, %CV, median, minimum, and 
maximum) based on the PK analysis set. 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. 
The same dose level (Parts 1 and 2 only)/dose regimen (Part 3 only) may be pooled across cohorts 
within each part of the study where appropriate. All data will be provided in by subject listings.
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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 may 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 placebo, 
TAK-510 dose level (Parts 1 and 2 only)/dose regimen (Part 3 only), and TAK-510 overall within 
each part of the study separately. In particular, 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. Placebo data will be pooled across cohorts within each part of the study. The same dose 
level (Parts 1 and 2 only)/dose regimen (Part 3 only) will be pooled across cohorts within each part
of the study where appropriate. For Part 3 only, similar safety summary analyses (excluding ADA 
assessments) will be performed for the single dose after washout from multiple dose regimens of 
TAK-510 by placebo, TAK-510 single dose level after washout, and TAK-510 single dose overall 
after washout. 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 MedDRA System Organ Class and Preferred Term 
and by placebo, each TAK-510 dose level (Parts 1 and 2)/dose regimen (Part 3), and TAK-510 
overall within each part of the study separately. Similar summary analyses will be provided for 
treatment-related TEAEs, SAEs, AESIs, and AEs leading to permanent treatment discontinuation 
as well. will be For Part 3 only, similar summary analyses of TEAEs will be performed for the 
single dose after 7 days of washout from multiple dose regimens of TAK-510 by placebo, 
TAK-510 single dose level after washout, and TAK-510 single dose overall after washout.
11.1.4.2
Clinical Laboratory Evaluations
Clinical laboratory parameters will be summarized using descriptive statistics for baseline, 
postdose, and change from baseline to postdose by placebo, each TAK-510 dose level (Parts 1 
and 2 only)/dose regimen (Part 3 only), and TAK-510 overall 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 
placebo, each TAK-510 dose level (Parts 1 and 2 only)/dose regimen (Part 3 only), and TAK-510 
overall within each part of the study separately. For Part 3 only, similar summary analyses of 
clinical laboratory data will be performed for the single dose after 7 days of washout from multiple 
dose regimens of TAK-510 by placebo, TAK-510 single dose level after washout, and TAK-510 
single dose overall after washout.
11.1.4.3
Vital Signs
Typically, BP and pulse assessments are made in duplicate with an interval of approximately 
2 minutes between the 2 assessments. The investigator can take a third BP and pulse assessment if 
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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 pulse assessment when results are inconsistent, the average value of the 2 
more consistent corresponding assessments (details will be provided in the statistical analysis plan) 
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 placebo, each TAK-510 dose level 
(Parts 1 and 2 only)/dose regimen (Part 3 only), and TAK-510 overall 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 placebo, each TAK-510 dose level (Parts 1 and 2 only)/dose regimen (Part 3 only), 
and TAK-510 overall within each part of the study separately. For Part 3 only, similar summary 
analyses of vital signs data will be performed for the single dose after 7 days of washout from 
multiple dose regimens of TAK-510 by placebo, TAK-510 single dose level after washout, and 
TAK-510 single dose overall after washout.
All vital sign data will be listed by subject and treatment group for each part of the study.
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 placebo, each 
TAK-510 dose level (Parts 1 and 2 only)/dose regimen (Part 3 only), and TAK-510 overall 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 placebo, each 
TAK-510 dose level (Parts 1 and 2 only)/dose regimen (Part 3 only), and TAK-510 overall within 
each part of the study separately. For Part 3 only, similar summary analyses of ECG data will be 
performed for the single dose after 7 days of washout from multiple dose regimens of TAK-510 by 
placebo, TAK-510 single dose level after washout, and TAK-510 single dose overall after 
washout.
ECG data will be listed by subject and treatment group for each part of the study.
11.1.4.5
Other Safety Parameters
Physical examination findings will only 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 
ADA-positive, and low or high ADA titer) will be tabulated by placebo, TAK-510 dose level 
(Parts 1 and 2 only)/dose regimen (Part 3 only), and TAK-510 overall at scheduled time points 
within each part of the study separately. The relationship between immunogenicity status 
(ADA-negative or ADA-positive, and low or high ADA titer) and PK, and safety will be analyzed 
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if they are applicable. Placebo data will be pooled across cohorts within each part of the study. The 
same dose level (Parts 1 and 2 only)/dose regimen (Part 3 only) will be pooled across cohorts 
within each part of the study where appropriate. All data will be provided in by subject listings.
11.1.6
Biomarker Analysis 
Biomarker measurements will be summarized using the safety analysis set. The concentrations 
 
 at each time point (ie, Day -1 and baseline [predose, Day 1]) will be summarized 
using descriptive statistics (n, mean, standard deviation, geometric mean, %CV, median, 
minimum, and maximum) by placebo, TAK-510 dose level (Parts 1 and 2 only)/dose regimen 
(Part 3 only) 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 placebo, 
TAK-510 dose level (Parts 1 and 2 only)/dose regimen (Part 3 only) within each part of the study
separately. The change from baseline 
 will be summarized 
using descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) by 
placebo, TAK-510 dose level (Parts 1 and 2 only)/dose regimen (Part 3 only), and TAK-510 
overall at scheduled time points within each part of the study separately. Placebo data will be 
pooled across cohorts within each part of the study. The same dose level will be pooled across 
cohorts within each part of the study where appropriate. All data will be provided in by subject 
listings.
11.2
Interim Analysis
Safety, tolerability, and available PK data will be reviewed in a blinded manner after completion of 
each cohort in the dose escalation meeting and before next dose escalation stage in the study (see 
Section 6.0).
If a data-dependent internal decision is needed to inform the subsequent development of TAK-510 
before 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 statistical analysis 
plan.
11.3
Determination of Sample Size
The selected sample sizes in Parts 1, 2, and 3 of the study are considered sufficient for evaluation 
of safety and tolerability of TAK-510 in healthy subjects. No formal statistical hypothesis testing 
is planned in Parts 1, 2, or 3. 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. 
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The investigator and study site guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB and/or IEC. In the event a monitor cannot visit the site in a timely 
manner, alternative monitoring approaches, such as remote source verification or telephone 
contact, may be used to ensure data quality and integrity and maintain patient 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), including but not limited to the 
Investigator’s Binder, study 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 study 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 and/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 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.
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13.1
IRB and/or IEC Approval
IRBs and/or IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB and/or IEC. If any 
member of the IRB and/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 
and/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 and/or IEC for approval. The IRB’s and/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 and/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 study. Until the site receives drug/notification no protocol activities, 
including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB and/or IEC. This may 
include notification to the IRB and/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 and/or IEC, and submission of the investigator’s final status report 
to IRB and/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 and/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 
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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.
The investigator is responsible for the preparation, content, and IRB and/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 and/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 and/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.
Informed consent for optional DNA sample collection and analysis will be collected in a separate 
section of the study informed consent form. Subjects who consented and provided a DNA sample 
can withdraw their consent for DNA sample analysis and request disposal of a stored sample at any 
time prior to analysis. Notify sponsor of consent withdrawal.
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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 
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, 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 Study 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 Study Registration 
In order to ensure that information on clinical studies 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 studies 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 
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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 study 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the study. The investigative sites are encouraged to handle the study 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of study 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 Study Results Disclosure 
Takeda will post the results of clinical studies 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 of Technical Requirements for Pharmaceuticals for
Human Use, E6(R2) Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 of this
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
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
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
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
CRO
contract research organization
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
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
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GLP
Good Laboratory Practice
HED
human equivalent dose
HR
heart rate
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
independent ethics committee
IRB
institutional review board
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
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
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
t1/2z
terminal disposition phase half-life
tmax
time of first occurrence of Cmax
TQT
thorough QT
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration
WBC
white blood cell
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Pharmac
harm
rrection 
rectio
n AUC
AUC
ed on C
d on 
event
vent
us(ly)
(ly)
sing dos
ing do
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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 the Medical Dictionary for 
Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization Drug 
Dictionary.
15.1
Case Report Forms (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 
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documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
ICH E6(R2) Section 5.5.11 requires the investigator to retain essential documents specified in ICH 
E6(R2) (Section 8) until at least 2 years after the last approval of a marketing application for a 
specified drug indication being investigated or, if an application is not approved, until at least 
2 years after the investigation is discontinued and regulatory authorities are notified. In addition, 
ICH E6(R2) Section 5.5.11 states that the study records should be retained until an amount of time 
specified by applicable regulatory requirements or for a time specified in the Clinical Study Site 
Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
16.0
REFERENCES
2. Wang S, Oestricker LZ, Wallendorf MJ, Sterl K, Dunai J, Kilpatrick CR, et al. Cholinergic 
signaling mediates the effects of xenin-25 on secretion of pancreatic polypeptide but not 
insulin or glucagon in humans with impaired glucose tolerance. PLoS One 
2018;13(2):e0192441.
Property of Takeda: For Non-Commercial Use Only an
 K, Dun
K, Du
on secre
on secre
aired gl
ired g
ject to the Applicable Terms of Use
H 
a
east 
ast 
addit
additioi
mount o
mount o
ical Stu
cal St
on recor
n reco
written ap
tten
and Subje
perty of Takeda: For Non-Commercial U


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10. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials
for Therapeutics in Adult Healthy Volunteers. US Dept of Health and Human Services, Food
and Drug Administration, Center for Drug Evaluation and Research. 06 July 2005. Publication
No. 5541.
13. ICH Harmonised Tripartite Guideline: Guidance on Nonclinical Safety Studies for the
Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals M3(R2).
International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use. 11 June 2009. Publication No. M3(R2).
14. Guidance for Industry: Safety Testing of Drug Metabolites. U.S. Department of Health and
Human Services, Food and Drug Administration, Center for Drug Evaluation and Research
(CDER). March 2020 Revision 2.
15. Abdullah N, Beg M, Soares D, Dittman JS, McGraw TE. Downregulation of a GPCR by
beta-Arrestin2-mediated switch from an endosomal to a TGN recycling pathway. Cell Rep
2016;17(11):2966-78.
Property of Takeda: For Non-Commercial Use Only and Subje
nclinica
clinic
uthoriza
uthoriz
chnical 
hnica
 Public
Publ
Drug Me
rug Me
nistratio
strati
Dittman 
ttma
ch from 
h from
rty of Takeda: For Non-Comm
ble Terms o
rials
als
es, Food
es, Foo
Publica
ublic
Use
of Us
ject to the Applicab


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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 
study-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-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 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 patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. 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 of the subject is found to be pregnant during the 
study, the investigator will offer the subject the choice to receive unblinded treatment 
information. 
26. A statement that clinical study information from this study 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, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
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 audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical study 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
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 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.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming postmenopausal 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 high FSH level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a 
postmenopausal state in younger women (eg, those aged <45 years) 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.
** No restrictions are required for a vasectomized male subject provided the subject is at least 
1 year after bilateral vasectomy. 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.
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: 
–
IUD (Intrauterine device).
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success).

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.
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–
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).

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, postovulation 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.
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5. During the course of the study, regular serum hCG (human chorionic gonadotropin) pregnancy 
tests will be performed for female subjects, 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 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. 
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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TAK-510
Study ID TAK-510-1001
Page 126 of 137
Protocol Incorporating Amendment No. 3
21 April 2022
CONFIDENTIAL
Appendix E
Protocol History
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
21 April 2022
Amendment 3
Substantial
Global
02 September 2021
Amendment 2
Substantial
Global
19 May 2021
Amendment 1
Substantial
Global
02 December 2020
Initial protocol
Not applicable
Global
Protocol Amendment 2 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 2. The 
primary reasons for this amendment are to: 
1. Add serum sampling for measurement of creatine kinase levels.
2. Add at least 24 hours of continuous telemetry monitoring before the first dose.
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 study 
parts. 
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.
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TAK-510
Study ID TAK-510-1001
Page 127 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
1.
Section 3.1 Part 1 for SRD Cohorts 
1 to 
Section 3.2.1 Overall Schedule of 
Study Procedures for Part 2
Section 3.2.2 Part 2 Screening 
Through Day 1 Assessments
Section 3.3.1 Overall Schedule of 
Study Procedures for Part 3 Section 
3.3.2 Part 3 Screening Through 
Day 1 Assessments
Section 9.2.6.2 Telemetry
Table 3.a, Table 3.b, Table 3.c, 
Table 3.f, Table 3.g
Added at least 24 hours of 
continuous telemetry monitoring 
before the first dose of TAK-510 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 to 
approximately 24 hours postdose” 
to “at least 24 hours before dosing 
and at least 24 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. 
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TAK-510
Study ID TAK-510-1001
Page 128 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
2.
Section 3.1 Part 1 for SRD Cohorts 
1 to 
Section 3.2.1 Overall Schedule of 
Study Procedures for Part 2
Section 3.2.2 Part 2 Screening 
Through Day 1 Assessments 
Section 3.2.3 Part 2 Days 2 to 4 
Assessments
Section 3.2.4 Part 2 Day 5 Through 
Day 9 Assessments, Follow-Up, 
and Early Termination
Section 3.3.1 Overall Schedule of 
Study Procedures for Part 3
Section 3.3.2 Part 3 Screening
Through Day 1 Assessments
Section 3.3.3 Part 3 Days 2 to 6 
Assessments
Section 3.3.4 Part 3 Day 7 and Day 
8 Assessments
Section 3.3.5 Part 3 Day 9 Through 
Day 15 Assessments, Follow-Up, 
and Early Termination 
Section 9.2.6.2 Telemetry
Table 3.a, Table 3.b, Table 3.c, 
Table 3.d, Table 3.e, Table 3.f, 
Table 3.g, Table 3.h, Table 3.i, 
Table 3.j
Clarified that telemetry is 
electrocardiogram 12-lead 
telemetry.
Clarification
3.
Section 3.1 Part 1 for SRD Cohorts 
1 to 
Table 3.a
Removed X indicating telemetry 
extraction from the Day 1 Hour 0 
time point in Part 1. 
To remove an extraction time 
point that is redundant with 
the predose extraction on 
Day 1.
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TAK-510
Study ID TAK-510-1001
Page 129 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
4.
Section 3.1 Part 1 for SRD Cohorts 
1 to 
Section 3.2.1 Overall Schedule of 
Study Procedures for Part 2
Section 3.2.2 Part 2 Screening 
Through Day 1 Assessments
Section 3.2.4 Part 2 Day 5 Through 
Day 9 Assessments, Follow-Up, 
and Early Termination
Section 3.3.1 Overall Schedule of 
Study Procedures for Part 3
Section 3.3.2 Part 3 Screening 
Through Day 1 Assessments
Section 3.3.4 Part 3 Day 7 and Day 
8 Assessments
Section 3.3.5 Part 3 Day 9 Through 
Day 15 Assessments, Follow-Up, 
and Early Termination
Section 9.2.9.2 Chemistry
Table 3.a, Table 3.b, Table 3.c, 
Table 3.e, Table 3.f, Table 3.g, 
Table 3.i, Table 3.j
Added serum sample collection of 
creatine kinase (CK) at pre- and 
postdose time points on Day 1, at 
discharge, and at early termination.
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 after TAK-510 dosing 
and to evaluate any 
association with events of 
myalgia.
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TAK-510
Study ID TAK-510-1001
Page 130 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
5.
Section 3.1 Part 1 for SRD Cohorts 
1 to 12
Section 3.2.1 Overall Schedule of 
Study Procedures for Part 2
Section 3.2.4 Part 2 Day 5 Through 
Day 9 Assessments, Follow-Up, 
and Early Termination
Section 3.3.1 Overall Schedule of 
Study Procedures for Part 3
Section 3.3.4 Part 3 Day 7 and Day 
8 Assessments
Section 3.3.5 Part 3 Day 9 Through 
Day 15 Assessments, Follow-Up, 
and Early Termination
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 
and Redosing Cohorts 18 to 20
Table 9.a Primary Specimen 
Collections
Section 9.2.10.4 DNA 
Measurements
Table 3.a, Table 3.b, Table 3.e, 
Table 3.f, Table 3.i, Table 3.j
Added collection of optional blood 
samples for DNA at discharge or at 
early termination in all study parts.
Revised text to indicate that if 
subjects have provided consent for 
the optional DNA collection, both 
buccal swabs and blood samples 
should be collected.
Table 3.f
Removed statement that only 
1 DNA sample will be collected 
per subject from the footnote.
Inclusion of optional blood 
samples for DNA 
sequencing.
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TAK-510
Study ID TAK-510-1001
Page 131 of 137
Protocol Incorporating Amendment No. 3
21 April 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 Part 1 for SRD Cohorts 
1 to 12
Section 3.2.1 Overall Schedule of 
Study Procedures for Part 2
Section 3.2.2 Part 2 Screening 
Through Day 1 Assessments
Section 3.3.1 Overall Schedule of 
Study Procedures for Part 3
Section 3.3.2 Part 3 Screening 
Through Day 1 Assessments
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 
and Redosing Cohorts 18 to 20
Section 9.3.1 Part 1 (SRD)
Section 9.3.2 Part 2 (MRD)
Section 9.3.3 Part 3 (Dose Titration 
and Redosing)
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.
7.
Section 3.1 Part 1 for SRD Cohorts 
1 to 12
Section 3.2.2 Part 2 Screening 
Through Day 1 Assessments
Section 3.3.2 Part 3 Screening 
Through Day 1 Assessments
Table 3.a, Table 3.c, Table 3.g
Revised footnote for safety 
laboratory assessments at the 
4-hour time points 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 the 4-hour 
time points and removing the 
list of excluded 
measurements. 
8.
Section 3.2.2 Part 2 Screening 
Through Day 1 Assessments
Section 3.2.3 Part 2 Days 2 to 4 
Assessments
Table 3.c, Table 3.d
Removed footnote for samples for 
pharmacokinetics and metabolite 
identification stating that the 
24-hour sample on Day 1 is the 
same as the predose sample on Day 
2.
To remove redundancy with 
the footnote for the 24-hour 
columns.
9.
Section 4.3 Benefit/Risk Profile
Updated blood sampling volume 
totals for each study part.
To reflect the increase in 
blood sampling volume with 
the addition of sampling for 
DNA and CK.
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TAK-510
Study ID TAK-510-1001
Page 132 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
10.
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 
and Redosing Cohorts 18 to 20
Section 1.0 STUDY SUMMARY
Removed the phrase “due to 
reasons unrelated to safety” in 
statement that the approximate 
subject number accounts for 
potential replacement of subjects 
who withdraw.
Removed “for reasons unrelated to 
safety” from the statement 
describing replacement of subjects 
at the discretion of the sponsor 
after discussion with investigator. 
To align with language with 
Section 7.7, Subject 
Replacement, allowing 
replacement of subjects as 
appropriate following 
discussion between the 
investigator and sponsor.
11.
Section 6.2.2 Criteria for 
Premature Termination or 
Suspension of the Study
Added language “at rest while 
semirecumbent.”
To clarify the stopping 
criterion related to sinus 
tachycardia.
12.
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.
13.
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 dosing on subsequent 
dosing days and to provide a 
window for discussion on a 
case-by-case basis between 
the investigator and the 
medical monitor.
14.
Section 9.2.10.4.1 Buccal 
Epithelial Cells Sample and Blood 
Sample for DNA
Added statement that DNA 
sequencing analysis will not be 
reported in the clinical study 
report. 
To clarify the planned 
reporting approach for DNA 
analysis. 
15.
Section 12.1 Study-Site 
Monitoring Visits
Added a statement that alternative 
monitoring approaches may be 
used in the event a monitor cannot 
visit the site in a timely manner.
To allow remote source data 
verification in extenuating 
circumstances.
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TAK-510
Study ID TAK-510-1001
Page 133 of 137
Protocol Incorporating Amendment No. 3
21 April 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. Modify exclusion criteria for vital signs (including orthostatic assessments of heart rate [HR] 
and blood pressure [BP]). In particular, more specific criteria are implemented to account for 
intrasubject variability with multiple Day -1 assessments that impact subject eligibility for 
randomization.
2. Revise vital sign assessment and monitoring procedures (including orthostatic assessments of 
HR and BP).
3. Update the schedule of assessment tables to correct discrepancies.
4. Provide clarification for some of the protocol language.
5. Provide language in case the study is affected by the coronavirus disease 2019 (COVID-19) 
pandemic.
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 2.0 STUDY SCHEMATIC
Section 3.3.1 Overall Schedule of 
Study Procedures for Part 3
Figure 2.a 
Updated schematic to add a 
footnote for washout period.
Table 3.f, Table 3.j
Added text to footnote b (Table 3.f) 
and footnote a (Table 3.j) 
indicating that the duration of 
washout period may be shortened 
or lengthened in Cohorts 19 and 20.
Added a footnote to reflect 
the flexibility of the washout 
period in Part 3 as previously 
detailed in the body of the 
protocol.
2
Section 3.1 Part 1 for SRD Cohorts 
1 to 12
Section 3.2.2 Part 2 Screening 
Through Day 1 Assessments 
Section 3.3.2 Part 3 Screening 
Through Day 1 Assessments 
Tables 3.a, 3.c, 3.g 
Added a footnote to indicate that 
the 24-hour sample on a given day 
is the same as the predose sample 
on the next day.
To clarify that the 24-hour 
measurements are the same 
as the next day predose 
measurements for vital signs. 
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TAK-510
Study ID TAK-510-1001
Page 134 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
3
Section 3.1 Part 1 for SRD Cohorts 
1 to 12
Section 3.2.1 Overall Schedule of 
Study Procedures for Part 2 
Section 3.2.2 Part 2 Screening 
Through Day 1 Assessments 
Section 3.3.1 Overall Schedule of 
Study Procedures for Part 3 
Section 3.3.2 Part 3 Screening 
Through Day 1 Assessments
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 
and Redosing Cohorts 18 to 20
Section 11.1.6 Biomarker Analysis
Table 3.a, 3.b, 3.c, 3.f, 3.g
For plasma sample for 
glucose-dependent insulinotropic 
polypeptide moved from collection 
at screening to collection at Day -1 
Time 0 and updated the 
corresponding footnote and text 
accordingly.
Modify timing of sample 
from screening to Day -1 for 
administrative and feasibility 
purposes.
4
Section 3.2 Part 2 for MRD 
Cohorts 13 to 17: Screening 
Through Day 9, Follow-Up, and 
Early Termination
Section 3.3 Part 3 for Dose 
Titration and Redosing Cohorts 18 
to 20: Screening Through Day 15, 
Follow-Up, and Early Termination
Added a level 3 heading (Section 
3.2.1 and 3.3.1) to denote that 
Table 3.b is the overall schedule of 
events for Part 2 cohorts and Table 
3.f is the overall schedule of events 
for Part 3.
To clarify that day-by-day
schedules of events is 
preceded by an overall 
assessment table for Parts 2 
and 3.
5
Section 3.2.1 Overall Schedule of 
Study Procedures for Part 2
Section 3.2.2 Part 2 Screening 
Through Day 1 Assessments
Section 3.3.1 Overall Schedule of 
Study Procedures for Part 3
Section 3.3.2 Part 3 Screening 
Through Day 1 Assessments
Table 3.b, Table 3.c, Table 3.f, 
Table 3.g
Removed X at Day -2 for BP and 
pulse (vital signs) and for standing 
BP and pulse.
For consistency with tables 
in Part 1 SRD.
6
Section 3.2.1 Overall Schedule of 
Study Procedures for Part 2
Section 3.3.1 Overall Schedule of 
Study Procedures for Part 3 
Table 3.b, 3.f, 
Changed individual “X”s to 
“X---continuous---X” as 
electrocardiogram (ECG) 
telemetry is a continuous reading.
For consistency with ECG 
telemetry measurements with 
other tables.
f
of
o
ample
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Day -1
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and 
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pe


TAK-510
Study ID TAK-510-1001
Page 135 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
7
Section 3.2.1 Overall Schedule of 
Study Procedures for Part 2
Table 3.b Shifted urine sample for 
pharmacokinetic (PK) from Day 7 
to Days 5 and 6.
For consistency between 
overall schedule of 
assessments (SOA) for Part 2 
and the SOA detailing the 
individual day.
8
Section 3.2.2 Part 2 Screening 
Through Day 1 Assessments 
Section 3.3.2 Part 3 Screening 
Through Day 1 Assessments 
Table 3.c, 3.g
Changed ECG telemetry spanning 
from Day -1 through Day 1, to only 
Day 1.
For consistency with other 
tables and telemetry 
procedure outlined in 
protocol.
9
Section 3.3.1 Overall Schedule of 
Study Procedures for Part 3
Section 6.1.4 Part 3: Dose Titration 
and Redosing Cohorts 18 to 20
Table 3.f
Shifted Day 15 DNA sample to 
Day 8 (discharge) and modified 
footnote ‘m’ indicating that only 1 
DNA sample will be collected per 
subject.
For consistency with other 
tables.
10
Section 3.3.2 Part 3 Screening 
Through Day 1 Assessments
Section 3.3.5 Part 3 Day 9 Through 
Day 15 Assessments, Follow-Up, 
and Early Termination 
Table 3.c, 3.g, 3.j
Removed glucose finger stick at 
Day -2 and Day -1 Hour 3; and Day 
13.
Corrected errors on glucose 
finger sticks on Day -2 and 
Day -1 in this SOA. Now is 
consistent with other tables 
in the study.
11
Section 3.3.4 Part 3 Day 7 and Day 
8 Assessments
Table 3.i
Added row for 12-lead ECG at Day 
8 (discharge).
Corrected error.
12
Section 7.1 Inclusion Criteria
Section 9.4.2 Women of 
Nonchildbearing Potential
Appendix D Pregnancy and 
Contraception
Added bilateral tubal ligation and 
bilateral salpingectomy to 
Inclusion Criteria 7.
To include history of 
bilateral tubal ligation and 
bilateral salpingectomy as 
meeting criterion for surgical 
sterility for eligibility of 
female subjects.
13
Section 7.2 Exclusion Criteria
Section 1.0 STUDY SUMMARY
Modified exclusion criteria 
(#15-18) for semirecumbent blood 
pressure, heart rate, orthostatic 
hypotension, and orthostatic 
tachycardia.
To control for intrasubject 
variability observed in vital 
signs in healthy subjects, in 
particular with multiple 
Day -1 time-matched 
assessments. Repeat 
measurements and flexibility 
for borderline values now 
detailed for orthostatic vital 
signs to account for 
variability while maintaining 
vital sign criteria for 
eligibility and dosing.
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TAK-510
Study ID TAK-510-1001
Page 136 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
14
Section 7.2 Exclusion Criteria
Section 7.5 Criteria for 
Discontinuation or Withdrawal of a 
Subject
Section 11.1 Statistical and 
Analytical Plans
Added Exclusion Criteria 19 for 
subjects who are excluded due to 
current coronavirus disease 2019 
(COVID-19) infection.
Added language for subject 
withdrawal for reasons related to 
COVID-19 pandemic.
Added language in case of impact 
in analysis due to COVID-19.
Due to the COVID-19 
pandemic, language was 
added to exclusion criteria, 
subject withdrawal, and 
analysis sections.
15
Section 9.2.4 Vital Signs
Section 3.0 SCHEDULE OF 
STUDY PROCEDURES
Modified vital signs procedures 
and updated relevant footnotes in 
SOAs for consistency.
Modified to include 
procedures for repeat vital 
sign measurements detailed 
in exclusion criteria and how 
to report the repeat 
measurements.
16
Section 9.2.6 ECG Procedure
Modified semirecumbent time 
from 10 minutes to 5 minutes.
Required rest period before 
ECG extractions shortened 
for feasibility while 
maintaining quality of 
extractions.
17
Section 11.1.3 PK Analysis
Added language for population PK 
analysis.
To better clarify possible 
additional PK analyses.
18
Section 10.2.8.4.1 Sinus 
Tachycardia
Modified language in sinus 
tachycardia management 
procedures. 
To clarify the language for 
management of a subject 
with symptoms suggestive of 
arrhythmia. Removed 
language referring to 
management of grade 2 sinus 
tachycardia from this 
paragraph because the 
management of grade 2 sinus 
tachycardia is detailed in the 
existing table in Section 
10.2.8.4.1.
19
Appendix D Pregnancy and 
Contraception
Remove bullet for “true sexual 
abstinence” as a method of 
contraception.
Removed language to fix 
discrepancy as sexual 
abstinence is not an 
acceptable method of 
contraception in this study.
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TAK-510
Study ID TAK-510-1001
Page 137 of 137
Protocol Incorporating Amendment No. 3
21 April 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 
20
Appendix D Pregnancy and 
Contraception
Remove urine hCG test.
Serum samples will be 
collected for hCG to align 
with the schedule of 
assessments.
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SAP_001.pdf: 
NCT Number:  NCT04731922
Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of TAK-510 in Healthy Subjects
Study Number: TAK-510-1001
Document Version and Date: Amendment 1; 31 October 2022
Certain information within this document has been redacted (ie, specific content is masked irreversibly 
from view with a black bar) to protect either personally identifiable information or company 
confidential information. 
Statistical Analysis Plan


STATISTICAL ANALYSIS PLAN
Study Number: TAK-510-1001
1.0
TITLE PAGE
A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of TAK-510 in Healthy Subjects
PHASE 1
Version: 2.0 (Amendment 1)
Date: 31 October 2022
Prepared by:
Manager, Statistical and Quantitative Sciences,
Takeda Development Center Americas, Inc.
Based on:
Protocol Amendment 03, Protocol Date: 21 April 2022
Statistical Analysis Plan, Original Version, Date: 09 March 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.
Property of Takeda: For Non-Comm
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1.1
APPROVAL SIGNATURES
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonization E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
Electronic signatures can be found on the last page of this document.
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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
APPROVAL SIGNATURES.....................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
INTRODUCTION...........................................................................................................7
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................8
4.4
Study Design .............................................................................................................8
5.0
STUDY ENDPOINTS...................................................................................................11
5.1
Primary Endpoints ...................................................................................................11
5.2
Secondary Endpoints ...............................................................................................11
5.3
Exploratory Endpoints .............................................................................................12
6.0
INTERIM ANALYSIS..................................................................................................12
7.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
8.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
8.1
General Principles....................................................................................................12
8.1.1
Definition of Study Day and Study Visit Windows......................................14
8.1.2
Conventions for Missing Data.....................................................................14
8.1.3
Conventions for Missing/Partial Dates for Adverse Event/Concomitant 
Medication/Procedures................................................................................14
8.2
Analysis Sets ...........................................................................................................15
8.3
Disposition of Subjects ............................................................................................16
8.4
Protocol Deviations..................................................................................................16
8.5
Demographic and Other Baseline Characteristics.....................................................16
8.6
Medical History and Concurrent Medical Conditions...............................................17
8.7
Medication History and Concomitant Medications...................................................17
8.8
Study Drug Exposure and Compliance.....................................................................17
8.9
Summary of the Impact due to COVID-19...............................................................17
8.10
Efficacy Analysis.....................................................................................................18
8.11
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses................................18
8.11.1
Pharmacokinetic Analysis ...........................................................................18
8.11.2
Pharmacodynamic Analysis ........................................................................19
8.11.3
Biomarker Analysis.....................................................................................19
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8.12
Safety Analysis........................................................................................................19
8.12.1
Adverse Events ...........................................................................................20
8.12.2
Clinical Laboratory Evaluations ..................................................................21
8.12.3
Vital Signs ..................................................................................................22
8.12.4
12-Lead ECGs.............................................................................................24
8.12.5
Analysis of Other Safety Parameters ...........................................................24
8.13
Immunogenicity Analysis ........................................................................................24
8.14
Interim Analysis ......................................................................................................25
9.0
REFERENCES..............................................................................................................25
10.0
CHANGES IN THE STATISTICAL ANALYSIS PLAN..............................................25
10.1
Changes to Protocol Planned Analyses.....................................................................25
10.2
Revision History......................................................................................................26
11.0
APPENDIX...................................................................................................................27
LIST OF IN-TEXT TABLES
Table 4.a
Overview of Treatment Cohorts.........................................................................10
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ..................................................................................9
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory.............................28
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs......................................29
Appendix C
Criteria for Identification of Markedly Abnormal Orthostatic Changes...............30
Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters..........31
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LIST OF ABBREVIATIONS
λz
terminal disposition phase rate constant
ADA 
anti-drugs 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
MedDRA
Medical Dictionary for Regulatory Activities
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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
TBILI
total bilirubin
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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3.0
INTRODUCTION
This document describes the statistical analyses to be performed and data presentations to be 
produced for this randomized, double-blind, placebo-controlled, phase 1 study to evaluate the 
safety, tolerability, and pharmacokinetics of TAK-510 in healthy subjects.
The purpose of this statistical analysis plan (SAP) is to ensure the credibility of the study 
findings by specifying the statistical approaches to the analyses of the double-blinded data prior 
to database lock. This SAP was developed based on the International Conference on 
Harmonization (ICH) E3 and E9 Guidelines and in reference to the following document:

Protocol TAK-510-1001 Amendment 03 dated 21 April 2022.
Any deviations during the analysis and reporting process from the current statistical analysis plan 
will be described and justified in the final report. Analysis issues that suggest changes to the 
principal features stated in the protocol will be documented in a protocol amendment. Otherwise, 
the statistical analysis plan will be updated through an amendment in which the changes in the 
analysis will be documented.
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objectives of this study are:

Part 1:
–
To characterize the safety and tolerability of single SC doses of TAK-510 in healthy 
subjects.

Parts 2:
–
To characterize the safety and tolerability of multiple SC doses of TAK-510 in healthy 
subjects.

Part 3:
–
To characterize the safety and tolerability of multiple SC dose regimens of TAK-510 that 
include titration from lower doses in healthy subjects.
4.2
Secondary Objectives
The secondary objectives of this study are:

Part 1:
–
To characterize the PK of TAK-510 in plasma following single SC doses in healthy 
subjects.
–
To assess the immunogenicity of TAK-510 following single SC doses in healthy subjects.
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–
To characterize the PK of TAK-510 in urine following single SC doses in healthy 
subjects.
!
Part 2:
–
To characterize the PK of TAK-510 in plasma following multiple SC doses in healthy 
subjects.
–
To assess the immunogenicity of TAK-510 following multiple SC doses in healthy 
subjects.
–
To characterize the PK of TAK-510 in urine following multiple SC doses in healthy 
subjects.
!
Part 3:
–
To characterize the safety and tolerability of single SC rechallenge doses of TAK-510 
after a washout from multiple SC dose regimens that include titration from lower doses in 
healthy subjects.
–
To assess the immunogenicity of TAK-510 following multiple SC dose regimens that 
include titration from lower doses, washout, and redosing in healthy subjects.
!
Part 3:
–
To characterize the PK of TAK-510 in plasma following multiple SC doses and dosing 
schedules in healthy subjects.
4.4
Study Design
This is a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety,
tolerability, and pharmacokinetics (PK) of TAK-510 in healthy subjects.
The study will consist of 3 parts (Figure 4.a):
!
Part 1 is a first-in-human, randomized, double-blind, placebo-controlled, single rising dose 
(SRD) design to assess the safety, immunogenicity, tolerability, and PK of TAK-510 in 
healthy volunteers. Up to 17 cohorts may be enrolled.
!
Part 2 is a randomized, double-blind, placebo-controlled, multiple rising dose (MRD) design 
to assess the safety, immunogenicity, tolerability, and PK of TAK-510 in healthy volunteers. 
Up to 8 doses/dose regimens may be tested in independent subject cohorts.
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
Part 3 is a randomized, double-blind, placebo-controlled, multiple-dose, dose titration and 
redosing design to assess the safety, immunogenicity, tolerability, and PK of TAK-510 in 
healthy volunteers. Up to 3 dose regimens may be tested in independent subject cohorts using 
a dose titration design, followed by redosing with a single dose of study drug after a 7-day 
washout (168 hours after the previous dose).
TAK-510 and matching placebo will be administered subcutaneously (SC). Safety will be 
assessed by monitoring for adverse events (AEs), vital signs, electrocardiogram 
(ECG)/telemetry, safety laboratory assessments after each dose, and immunogenicity. PK 
sampling times and scheme may vary based on emerging safety, tolerability and PK data, but the 
maximal number of samples or the maximum time point will not change. Subjects may not 
participate in more than 1 part or dosing cohort of the study. An overview of treatment cohorts is 
presented in Table 4.a.
Figure 4.a
Schematic of Study Design
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Table 4.a
Overview of Treatment Cohorts
Cohort
Regimen
Treatment
Part 1
TAK-510
Placebo
1
SRD 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
21
6
2
22
6
2
23
6
2
24
6
2
25
6
2
Part 2 
TAK-510
Placebo
13
MRD
6
2
14
6
2
15
6
2
16
6
2
17
6
2
26
6
2
27
6
2
28
6
2
Part 3 
TAK-510
Placebo
18
Dose Titration, Washout, 
Redosing
6
2
19
6
2
20
6
2
MRD: multiple rising dose; SRD: single rising dose.
a Up to 17 doses may be explored with a maximum escalation factor between cohorts of 5-fold at lower exposures 
and 2-fold at high exposures.
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5.0
STUDY ENDPOINTS
5.1
Primary Endpoints

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 AEs.
5.2
Secondary Endpoints

Part 1: plasma PK parameters for TAK-510
–
Maximum observed plasma concentration (Cmax).
–
Area under the plasma concentration-time curve from time 0 to infinity (AUC
).
–
Area under the plasma 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 (t/).
–
Apparent clearance after extravascular administration (CL/F).
–
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration (Vz/F).

Part 2 : plasma PK parameters for TAK-510 on Day 1
–
Cmax, tmax, and area under the plasma concentration-time curve during a dosing interval, 
where tau (τ) is the length of the dosing interval (AUCτ).

Part 2: plasma PK parameters for TAK-510 at steady state
–
AUC, Cmax, tmax, t/, CL/F, Vz/F, observed plasma concentration at the end of a dosing 
interval (Ctrough), accumulation ratio based on AUCτ (Rac[AUC]), calculated as AUCτ at 
steady state/AUCτ after a single dose and accumulation ratio based on Cmax(Rac[Cmax]), 
calculated as Cmax at steady state/Cmax after a single dose.

Parts 1 and 2: urine PK parameters for TAK-510
–
Amount of drug excreted in urine from time 0 to time t (A).
–
Amount of drug excreted in urine from time 1 to time 2 (A).
–
Amount of drug excreted in urine during a dosing interval (τ) at steady state (A).
–
Fraction of administered dose of drug excreted from urine from time 0 to time t (f,).
–
Renal clearance (CLR).
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!
Part 3:
–
Safety and tolerability of single SC rechallenge doses after a washout from multiple SC 
dose regimens of TAK-510 as assessed through vital signs, ECG, laboratory assessments, 
and AEs.
!
All parts of the study:
–
Status of subject’s ADA assessment (i.e., ADA-negative or ADA-positive, and low or 
high ADA titer).
!
Part 3 includes the following plasma PK parameters:
–
AUC, AUClast, Cmax.
6.0
INTERIM ANALYSIS
An interim analysis may be performed for all available data from completed subjects in Parts 1 
and 2 if a data-dependent internal decision is needed to inform the subsequent development of 
TAK-510 before database lock. A final analysis will be performed after the end of the study to 
report all data from all study parts. Safety, tolerability, and available PK data will be reviewed in 
a blinded manner after completion of each cohort and before next dose escalation stage in the 
study.
7.0
DETERMINATION OF SAMPLE SIZE
The selected sample sizes in Parts 1, 2, and 3 of the study are considered sufficient for the 
evaluation of safety and tolerability of TAK-510 in healthy volunteers. No formal statistical
hypothesis testing is planned in Parts 1, 2, and 3. Therefore, no formal power calculations were 
performed in the determination of sample size for the study.
8.0
METHODS OF ANALYSIS AND PRESENTATION
8.1
General Principles
All study-related raw and derived data for randomized subjects will be presented in by-subjects 
listings. All available data from Study Parts (e.g., 1, 2, and/or 3) will be analyzed and presented 
separately. 
Data listings and summary statistics and statistical analyses will be performed for subjects 
included in the relevant analysis populations (Safety/PK/Immunogenicity).
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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.
The following conventions will be applied to present the analyses results in this SAP, 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 Pharmacokinetics 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 Pharmacokinetics: 

by dose level (Parts 1 and 2 only)/dose regimen (Part 3 only if applicable) of TAK-
510, as appropriate, within each part of the study separately.
–
For disposition, demographics and baseline characteristics, concomitant medication, AEs, 
and Impact due to COVID-19:

by placebo, each TAK-510 dose level (Parts 1 and 2 only)/dose regimen (Part 3 only 
if applicable), TAK-510 overall (i.e., combining all TAK-510 arms, not applicable to 
summary of disposition, demographics and baseline characteristics, concomitant 
medication), and total (i.e., combining placebo and TAK-510 arms), as appropriate, 
within each part of the study separately.
–
For the rest:

by placebo, dose level (Parts 1 and 2 only)/dose regimen (Part 3 only if applicable) of 
TAK-510, as appropriate, within each part of the study separately.
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
Treatment arm pooling: 
–
Placebo data will be pooled across cohorts within each part of the study where 
appropriate.
–
The same dose level (Parts 1 and 2 only)/dose regimen (Part 3 only if applicable) will be 
pooled across cohorts within each part of the study 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 3.1.0 or higher will be utilized to ensure 
compliance with CDISC standards.
8.1.1
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.
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. 
8.1.2
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. These values will be flagged in the data listings and 
deviations from this convention may be considered on a case-by-case basis as deemed 
appropriate.
8.1.3
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. 
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–
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. 

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.
8.2
Analysis Sets

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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
PK Analysis Set
–
The PK analysis set consists of all subjects who receive at least 1 dose of TAK-510 and 
have at least 1 measurable postdose plasma or urine concentration for TAK-510.

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.
A summary of analysis sets based on all randomized subjects will be provided. Details of subject 
assignment to the analysis sets will be provided in a by-subject listing for all randomized 
subjects.
8.3
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 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.
8.4
Protocol Deviations
All significant protocol deviations that occur during the study will be reviewed and finalized 
prior to database lock. Listing of all significant protocol deviations will be provided for all 
randomized subjects.
8.5
Demographic 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 (e.g., age, 
height, weight, and BMI) by treatment arm using safety analysis set. The number and percentage 
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of subjects in each class of the categorical demographic variables and baseline characteristics 
variables (e.g., sex, ethnicity, race) will be tabulated by treatment arm using safety analysis set. 
All data will be provided in by-subject listings using safety analysis set.
8.6
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.
8.7
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 started on and 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. 
8.8
Study Drug Exposure and Compliance
Treatment exposure (e.g., duration of treatment = last dose date – first dose date +1, number of 
dose 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.
8.9
Summary of the 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. 
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
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.
8.10
Efficacy Analysis
Not applicable
8.11
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses
8.11.1
Pharmacokinetic Analysis
The plasma (all parts of the study) and urine (Parts 1 and 2 only) concentrations of TAK-510 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. 
The major, but not limited to, PK parameters of TAK-510 (i.e., Cmax, tmax, t/, AUC
, 
AUClast, AUC, CL/F, Vz/F, A , A, A, f,, CLR,   details are described in CPAP) 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 and 2 only) concentrations of 
TAK-510, and PK parameters will be presented in by-subject listings based on PK analysis set.
PK analysis and relevant details will be described in the Clinical pharmacology analysis plan 
(CPAP).
Dose proportionality will be assessed graphically (log-transformed dose-normalized Cmax and 
AUC versus dose) and by using a power model within each part of the study (Parts 1 and 2 only) 
separately using the method below, where appropriate:
For each part of the study (Parts 1 and 2 only), the dose proportionality of AUCs and Cmax will 
be evaluated using a power model [1] with the form: 
 = exp() ∗(dose)! ∗exp(error)
where Y is the PK parameter of interest, exp() and $ 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
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. 
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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 may 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.
In addition, exploratory metabolite profiling may be conducted on plasma or urine samples to 
determine the metabolites of TAK-510. If conducted, the analysis plan will be documented 
separately, data will be reported separately and not be reported in the CSR.
8.11.2
Pharmacodynamic Analysis 
Not applicable.
8.11.3
Biomarker Analysis
The concentrations of 
 at each time point (i.e., Day -1 0 hour and baseline 
[predose, Day 1]) and Overall (i.e., all available data within each part of the study) 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 (i.e., 0 to <Q1, Q1 to < median, median to <Q3, ≥Q3, where quartile is determined by all 
available data within each part of the study) of
 concentrations will be presented
for each time point and Overall (i.e., all available data within each part of the study) by treatment 
arm based on safety analysis set. The baseline, postbaseline values, and change from baseline 
 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 (i.e., 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.
8.12
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.
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8.12.1
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-510 include injection site reactions, hypotension, and tachycardia.
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.

Treatment-related TEAEs by SOC and PT - number and percentage of subjects.

TEAEs by PT - number and percentage of subjects.

Most frequent TEAEs (≥ 5% in total subjects within each part of the study) by PT - number 
and percentage of subjects.

Treatment-related TEAEs by PT - number and percentage of subjects.

Toxicity grade of TEAEs by SOC and PT - number and percentage of subjects.

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.

TEAE with toxicity grade 3 or higher by PT – number and percentage of subjects.

Treatment-related TEAEs with toxicity grade 3 or higher by PT – number and percentage of 
subjects.

Most frequent non-serious TEAEs (>5% in any treatment arm within each part of the study) 
by PT - number and percentage of subjects.
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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-510 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 3 only, similarly, the TEAEs that started or worsened after the single SC rechallenge 
dose (after 7 days of washout from multiple dose regimens of the study treatment) will be 
summarized by placebo and level of the single SC rechallenge dose of TAK-510, TAK-510 
single SC rechallenge dose overall, and total based on safety analysis set.
8.12.2
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 
Appendix A). All postbaseline clinical lab results including scheduled and unscheduled 
measurements will be included in the MAV evaluation. For the clinical laboratory parameter of 
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 × ULN; 
–
>3 –≤5 × ULN; 
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–
>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 (TBILI): 
–
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 3 only if applicable, similarly, the clinical laboratory data after the single SC 
rechallenge dose (after 7 days of washout from multiple dose regimens of the study treatment) 
will be summarized by placebo and level of the single SC rechallenge dose of TAK-510, and 
TAK-510 single SC rechallenge dose overall based on safety analysis set.
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.
8.12.3
Vital Signs
Typically, blood pressure (BP) and pulse assessments are made in duplicate with an interval of 
approximately 2 minutes between the 2 assessments. The investigator can take a third BP and 
pulse 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 pulse assessment when 
results are inconsistent, the average value of the 2 more consistent corresponding assessments 
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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 summarized using descriptive statistics by 
treatment arm at each nominal timepoint where appropriate based on safety analysis set.
For each orthostatic vital sign parameter (i.e., BP and Pulse), the difference between standing 
and semi-recumbent (i.e., 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 (i.e., semi-recumbent BP and pulse, standing BP and pulse, orthostatic BP 
and pulse) 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 signs (i.e., semi-recumbent BP and pulse, standing BP and pulse, 
orthostatic BP and pulse). 
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 (Appendix B). The orthostatic hypotension will be identified by criteria for 
identification of markedly abnormal orthostatic changes (Appendix C). 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, the number and percentage 
of subjects with at least 1 postbaseline value meeting the Takeda’s MAV criteria will be 
presented by treatment arm based on safety analysis set. 
For Part 3 only if applicable, similar summary analyses of vital signs after the single SC 
rechallenge dose (after 7 days of washout from multiple dose regimens of the study treatment) 
will be summarized by placebo and level of the single SC rechallenge dose of TAK-510, and 
TAK-510 single SC rechallenge dose overall based on safety analysis set.
All vital sign data will be presented in the by-subject listings.
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8.12.4
12-Lead ECGs
ECG parameters (i.e., 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 (heart rate, PR interval, QRS interval, and QTc 
interval) will be evaluated against the Takeda’s predefined markedly abnormal value (MAV) 
criteria (Appendix D). 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 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 3 only, similar summary analyses of ECG data after the single SC rechallenge dose 
(after 7 days of washout from multiple dose regimens of the study treatment) will be summarized 
by placebo and level of the single SC rechallenge dose of TAK-510, and TAK-510 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.
8.12.5
Analysis of Other Safety Parameters 
Physical examination findings will only be presented in by-subject listings based on safety 
analysis set.
8.13
Immunogenicity Analysis
ADA positive is defined as subjects who have confirmed positive ADA status in at least 1 
postbaseline assessments. ADA negative is defined as subjects who do not have a confirmed 
positive ADA status in any postbaseline assessment.
For 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.
Immunogenicity will be summarized using the number and percentage of subjects in the 
following categories: ADA status (ADA negative, ADA positive), ADA titer (low or high) at 
baseline and postbaseline visits by treatment arm based on immunogenicity analysis set. 
The summary of TEAE by PT and immunogenicity categories (ADA status (ADA negative, 
ADA positive), ADA titer (low or high)) and treatment arm based on immunogenicity analysis 
set may be provided to explore the relationship between immunogenicity status and safety, if 
deemed necessary.
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The summary of plasma concentration and PK parameters (including but not limited to Cmax , 
AUCs and CL/F where appropriate) by immunogenicity categories (ADA status (ADA negative, 
ADA positive), ADA titer (low or high)) 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.
8.14
Interim Analysis
Safety, tolerability, and available PK data will be reviewed in a blinded manner after completion 
of each cohort and before next dose escalation stage in the study.
Two scenarios where the data-dependent internal decision will activate an interim analysis and 
associated analyses are detailed below:
1. A decision about whether to complete Part 3 has not been made.
2. Study will end after completion of Parts 1 and 2 (IA will become final analysis).
In the event of scenario 1, the interim analyses of PK (per method in Section 8.11.1), Safety (per 
method in Section 8.12), and immunogenicity (per method in Section 8.13) endpoints, based on 
the data cut prespecified by the study team, will be performed.
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.
9.0
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.
10.0
CHANGES IN THE STATISTICAL ANALYSIS PLAN
10.1
Changes to Protocol Planned Analyses
Not applicable.
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10.2
Revision History
Version 
Approval Date
Primary Rationale for Revision
1.0
09 March 2021
Not Applicable
2.0
31 October 2022
Updated the texts in Section 4.4 Study Design, Section 6.0 Interim 
Analysis, Section 8.14 Interim Analysis, Figure 4.a, and Table 4.a to 
reflect the updates in Protocol Amendment 03.
Added summary for TEAE with toxicity grade 3 or higher in Section 
8.12.1.
Added the statistical algorithm in Section 8.12.3 (previous Section 
8.13.3) to calculate the average value if a second or a third 
measurement has been made per protocol specified procedure for 
vital signs assessment.
Clarified the MAV evaluation for values at scheduled and 
unscheduled visits in Section 8.12.3 and updated the tables in 
Appendix B and Appendix C.
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11.0
APPENDIX
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Appendix A
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. 
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.
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Appendix B
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
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
Pulse rate
bpm
<50
>120
Respiratory Rate
breath per minute
<12
>16
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Appendix C
Criteria for Identification of Markedly Abnormal Orthostatic Changes
Parameter
Criteria 
Orthostatic Hypotension
Decrease in SBP ≥ 20 mmHg OR a decrease in DBP ≥ 10 mmHg on 
standing
Orthostatic Tachycardia
Defined as an increase of >30 bpm or HR >120 bpm on standing
Note: Orthostatic measurement = standing vital measurement – semi-recumbent vital measurement.
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TAK-510-1001
Page 31 of 31
Statistical Analysis Plan Amendment 1.0
31 October 2022
CONFIDENTIAL
Appendix D
Criteria for 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
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