A Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, 3-Part Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Takeda

For non-commercial use only

 
 
 
TAKEDA DEVELOPMENT CENTER AMERICAS INC 
PROTOCOL 
A Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, 3-Part Phase 1 Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects 
Sponsor: 
Takeda Development Center Americas, Inc. 
95 Hayden Avenue 
Lexington, MA 02421 USA 
Study Number: 
TAK-951-1008 
IND Number: 
141732 
EudraCT Number: 
Not Applicable 
Compound: 
TAK-951 
Date: 
16 March 2023 
Version/Amendment 
Number: 
2 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
16 March 2023 
Amendment 2 
Substantial 
United States 
24 January 2023 
Amendment 1 
Substantial 
United States 
23 November 2021 
Initial protocol 
Not applicable 
United States 
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 (e)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. 
For non-commercial use only

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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................8 
1.1 
Contacts..........................................................................................................................8 
1.2 
Approval ........................................................................................................................9 
1.3 
Protocol Amendment 2 Summary of Changes.............................................................11 
2.0 
STUDY SUMMARY.........................................................................................................14 
3.0 
STUDY REFERENCE INFORMATION .........................................................................19 
3.1 
Study-Related Responsibilities ....................................................................................19 
3.2 
List of Abbreviations ...................................................................................................20 
4.0 
INTRODUCTION .............................................................................................................22 
4.1 
Background ..................................................................................................................22 
4.1.1 
Clinical Studies ....................................................................................................22 
4.1.1.1 
Adverse Events in TAK-951-1001 FIH Study ............................................23 
4.1.1.2 
Injection Site Reactions in TAK-951-1001 FIH Study ...............................23 
4.1.1.3 
Vital Sign Changes in TAK-951-1001 FIH Study ......................................24 
4.1.2 
 ..............................................................................................24 
4.2 
Rationale for the Proposed Study ................................................................................25 
4.3 
Benefit/Risk Profile .....................................................................................................26 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................27 
5.1 
Objectives ....................................................................................................................27 
5.1.1 
Primary Objective ................................................................................................27 
5.1.2 
Secondary Objectives ..........................................................................................27 
5.1.3 
Exploratory Objectives ........................................................................................28 
5.2 
Endpoints .....................................................................................................................28 
5.2.1 
Primary Endpoints ...............................................................................................28 
5.2.2 
Secondary Endpoints ...........................................................................................28 
5.2.3 
Additional/Exploratory Endpoints .......................................................................29 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................30 
6.1 
Study Design ................................................................................................................30 
6.1.1 
Part 1: SRD Cohorts 1 to 6 ..................................................................................32 
6.1.2 
Part 2: MRD Cohorts 7 to 10 ...............................................................................33 
6.1.3 
Part 3: Dose Titration and Redosing Cohorts 11 to 15 ........................................34 
6.2 
Dose Escalation ............................................................................................................36 
6.3 
Study Drug Administration ..........................................................................................37 
6.4 
Justification for Study Design, Dose, and Endpoints ..................................................38 
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6.4.1 
Justification for Study Design .............................................................................38 
6.4.2 
Justification for Dose for SRD, MRD, and Titration ..........................................38 
6.4.3 
Justification for Dosing Interval ..........................................................................40 
6.4.4 
Justification for Dose Titration and Redosing After Washout ............................41 
6.5 
Premature Termination or Suspension of Study or Study Site ....................................41 
6.5.1 
Criteria for Premature Termination of the Study ................................................41 
6.6 
Criteria for Premature Suspension of the Study ..........................................................41 
6.6.1 
Criteria for Premature Termination or Suspension of Study Sites ......................43 
6.6.2 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) ...............................................................................43 
6.6.3 
Definition of End-of-Study ..................................................................................43 
6.6.4 
Total Study Duration ...........................................................................................43 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............44 
7.1 
Inclusion Criteria .........................................................................................................44 
7.2 
Exclusion Criteria ........................................................................................................45 
7.3 
Excluded and Allowed Concomitant Medications, Supplements, and Dietary 
Products........................................................................................................................47 
7.3.1 
Concomitant Medications ....................................................................................47 
7.3.2 
Fruit Juice ............................................................................................................47 
7.3.3 
Alcohol ................................................................................................................47 
7.3.4 
Caffeine ...............................................................................................................48 
7.3.5 
Smoking ...............................................................................................................48 
7.4 
Diet, Fluid, and Activity ..............................................................................................48 
7.4.1 
Diet and Fluid ......................................................................................................48 
7.4.1.1 
Part 1 ...........................................................................................................48 
7.4.1.2 
Part 2 and 3 .................................................................................................48 
7.4.2 
Activity ................................................................................................................49 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject .............................................49 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject .......................................50 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT .......................................................50 
8.1 
Clinical Study Drug .....................................................................................................50 
8.1.1 
Study Drugs .........................................................................................................50 
8.1.1.1 
TAK-951 .....................................................................................................50 
8.1.1.2 
Comparator ..................................................................................................50 
8.1.2 
Clinical Study Drug Labeling ..............................................................................51 
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8.1.3 
Clinical Study Drug Inventory and Storage ........................................................51 
8.1.4 
Accountability and Destruction of Sponsor-Supplied Drugs ..............................51 
8.2 
Ancillary Supplies ........................................................................................................52 
8.3 
Randomization Code Creation and Storage .................................................................52 
8.4 
Blinding........................................................................................................................52 
9.0 
STUDY PLAN ...................................................................................................................53 
9.1 
Administrative Procedures ...........................................................................................53 
9.1.1 
Informed Consent Procedure ...............................................................................53 
9.1.1.1 
Assignment of Screening and Randomization Numbers ............................53 
9.1.1.2 
Study Drug Assignment ..............................................................................53 
9.1.2 
Demographics and Medical History ....................................................................53 
9.1.3 
Concomitant Medications ....................................................................................54 
9.2 
Clinical Procedures and Assessments ..........................................................................54 
9.2.1 
Full Physical Examination ...................................................................................54 
9.2.2 
Weight and Height ...............................................................................................54 
9.2.3 
BMI ......................................................................................................................54 
9.2.4 
Vital Sign Procedure ............................................................................................54 
9.2.4.1 
Orthostatic Measurements ...........................................................................55 
9.2.4.2 
Wearable Device .........................................................................................56 
9.2.4.3 
Follow-up Safety Monitoring ......................................................................56 
9.2.5 
Glucose ................................................................................................................57 
9.2.6 
ECG Procedure ....................................................................................................57 
9.2.6.1 
Screening and Safety ECGs ........................................................................57 
9.2.6.2 
Telemetry ....................................................................................................58 
9.2.7 
Study Drug Administration .................................................................................59 
9.2.8 
AE Monitoring .....................................................................................................59 
9.3 
Laboratory Procedures and Assessments .....................................................................59 
9.3.1 
Hematology .........................................................................................................59 
9.3.2 
Chemistry ............................................................................................................60 
9.3.3 
Urinalysis .............................................................................................................60 
9.3.4 
Diagnostic Screening ...........................................................................................61 
9.4 
PK, Immunogenicity, Biomarker, and DNA Samples .................................................61 
9.4.1 
PK Measurements ................................................................................................62 
9.4.1.1 
Plasma for PK Measurements and Metabolite Identification .....................63 
9.4.2 
Biomarker Measurements ....................................................................................64 
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9.4.2.1 
 ...............................................................................64 
9.4.2.2 
 .............................65 
9.4.3 
DNA Measurements ............................................................................................65 
9.4.3.1 
Blood Sample for DNA Analysis ................................................................65 
9.4.3.2 
Biological Sample Retention and Destruction ............................................65 
9.5 
Confinement .................................................................................................................66 
9.5.1 
Part 1 SRD ...........................................................................................................66 
9.5.2 
Part 2 MRD ..........................................................................................................66 
9.5.3 
Part 3 Dose Titration and Redosing .....................................................................66 
9.6 
Contraception and Pregnancy Avoidance Procedure ...................................................66 
9.6.1 
Male Subjects and Their Female Partners ...........................................................66 
9.6.2 
Female Subjects and Their Male Partners ...........................................................67 
9.6.3 
Definitions and Procedures for Contraception and Pregnancy Avoidance .........67 
9.6.4 
Pregnancy ............................................................................................................69 
9.6.5 
Documentation of Screen Failure ........................................................................70 
10.0 
ADVERSE EVENTS .........................................................................................................70 
10.1 
Definitions....................................................................................................................70 
10.1.1 
Pretreatment Events .............................................................................................70 
10.1.2 
Definition and Elements of AEs ..........................................................................70 
10.1.3 
SAEs ....................................................................................................................72 
10.1.4 
AEs of Special Interest ........................................................................................73 
10.2 
Procedures ....................................................................................................................73 
10.2.1 
Assigning Severity/Intensity of AEs ...................................................................73 
10.2.2 
Assigning Causality of AEs .................................................................................74 
10.2.3 
Start Date .............................................................................................................74 
10.2.4 
End Date ..............................................................................................................74 
10.2.5 
Pattern of AE (Frequency) ...................................................................................74 
10.2.6 
Action Taken With Study Treatment ..................................................................75 
10.2.7 
Outcome ..............................................................................................................75 
10.2.8 
Collection and Reporting of AEs ........................................................................75 
10.2.8.1 AE Collection Period ..................................................................................75 
10.2.8.2 AE Reporting ..............................................................................................76 
10.2.8.3 Reporting SAEs ...........................................................................................76 
10.2.8.4 Management of Specific AEs......................................................................77 
10.2.8.5 Reporting of Abnormal LFTs .....................................................................78 
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10.2.9 
Collection and Reporting of SAEs ......................................................................78 
10.2.10 Reporting of Abnormal Liver-Associated Test Results ......................................79 
10.3 
Follow-up of SAEs ......................................................................................................79 
10.3.1 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities ................80 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................80 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................80 
12.1 
CRFs ............................................................................................................................80 
12.2 
Record Retention .........................................................................................................81 
13.0 
STATISTICAL METHODS ..............................................................................................82 
13.1 
Statistical and Analytical Plans ....................................................................................82 
13.1.1 
Analysis Sets .......................................................................................................82 
13.1.1.1 Safety Analysis Set .....................................................................................82 
13.1.1.2 PK Analysis Set ..........................................................................................82 
13.1.1.3 Immunogenicity Analysis Set .....................................................................82 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ..........................82 
13.1.3 
PK Analysis .........................................................................................................83 
13.1.4 
Safety Analysis ....................................................................................................83 
13.1.4.1 AEs ..............................................................................................................84 
13.1.4.2 Clinical Laboratory Evaluations .................................................................84 
13.1.4.3 Vital Signs ...................................................................................................84 
13.1.4.4 ECG .............................................................................................................84 
13.1.4.5 Other Safety Parameters ..............................................................................85 
13.1.5 
Immunogenicity Analysis ....................................................................................85 
13.1.6 
Biomarker Analysis .............................................................................................85 
13.2 
Interim Analysis ...........................................................................................................85 
13.3 
Determination of Sample Size .....................................................................................86 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................86 
14.1 
Study-Site Monitoring Visits .......................................................................................86 
14.2 
Protocol Deviations ......................................................................................................86 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................87 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................87 
15.1 
IRB ...............................................................................................................................87 
15.2 
Subject Information, Informed (e)Consent, and Subject Authorization ......................88 
15.3 
Subject Confidentiality ................................................................................................89 
15.4 
Clinical Trial Disclosures and Publication ..................................................................90 
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CONFIDENTIAL 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
prescribing information and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, life, dignity, integrity, confidentiality of personal information, safety, privacy, and well-
being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Council for Harmonisation, E6(R2) Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events (SAEs) defined in 
Section 10.3.1 of this protocol. 
• Terms outlined in the clinical study site agreement. 
• Responsibilities of the Investigator (Appendix B). 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State) 
Location of Facility (Country) 
 
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1.3 
Protocol Amendment 2 Summary of Changes 
Protocol Amendment 2 Summary and Rationale: 
This section describes the changes in reference to the protocol incorporating Amendment 2. The 
primary reason for this amendment is:  
• To provide information about the previously completed cohorts and doses and to specify the 
starting cohort, starting dose, and proposed dose escalation (single rising dose [SRD]) in 
Part 1 of the study. 
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. 
See Appendix E for protocol history, including all previous amendments. 
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 2.0 STUDY 
SUMMARY 
Table 6.a Overview of 
Treatment Cohorts 
Section 6.1.1 Part 1: SRD 
Cohorts 1 to 6 
Section 6.2 Dose Escalation 
Table 6.b Injection Volumes, 
Number of Injections, and 
Predicted Exposures for Select 
Doses in Part 1 (SRD)  
Section 6.4.2 Justification for 
Dose for SRD, MRD, and 
Titration 
Defined the starting cohort 
under Protocol Amendment 2 
(ie, per the modified study 
procedures defined by 
Protocol Amendments 1 and 
2) as Cohort 5, which will be 
dosed at 
 single dose. 
Specified the dose for 
Cohort 6 at either 
 
(repeat of Cohort 5) or 
escalation of 
 
.  
Specified that dosing of 
additional cohorts in Part 1 
(ie, beyond Cohort 6) 
requires an assessment of 
complete safety and 
pharmacokinetic (PK) data 
before dosing and is limited 
to doses of 
 single 
doses without an updated 
safety rationale (including 
safety, tolerability, and PK 
data from Cohorts 5 and 6). 
To specify the starting cohort, 
starting dose, and proposed dose 
escalation (single rising dose 
[SRD]) in Part 1 of the study. 
2.  
Table 6.a Overview of 
Treatment Cohorts 
Section 6.1.1 Part 1: SRD 
Cohorts 1 to 6 
Table 6.b Injection Volumes, 
Revised planned maximum 
dose in Part 1 (SRD) from 
. Dosing of 
cohorts in Part 1 with doses 
greater than 
 will 
To update the planned maximum 
TAK-951 single dose based on 
current safety, tolerability, and 
PK data. 
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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  
Number of Injections, and 
Predicted Exposures for Select 
Doses in Part 1 (SRD)  
Section 6.4.2 Justification for 
Dose for SRD, MRD, and 
Titration 
require additional supporting 
clinical safety, tolerability, 
and PK data from Cohorts 5 
and 6 from Part 1 (SRD). 
3.  
Section 4.3 Benefit/Risk Profile 
Section 6.4.2 Justification for 
Dose for SRD, MRD, and 
Titration 
Added description of doses 
and safety results from 
Cohorts 1 through 4 in Part 1 
(SRD). 
To provide information about 
the previously completed 
cohorts dosed in Part 1 (SRD) of 
this study under the original 
protocol (ie, safety data from 
Cohorts 1, 2, 3, and 4, which 
were dosed with single doses of 
 
respectively). 
4.  
Section 6.1 Study Design 
Section 6.1.2 Part 2: MRD 
Cohorts 7 to 10 
Section 6.1.3 Part 3: Dose 
Titration and Redosing Cohorts 
11 to 15 
Revised text to state that 
dosing of Parts 2 and 3 will 
not be initiated before dosing 
of Cohorts 5 and 6 in Part 1. 
To ensure that Parts 2 and 3 are 
not initiated before additional 
information is available for 
single TAK-951 doses in Part 1. 
5.  
Section 6.3 Study Drug 
Administration  
Added statement to clarify 
that the maximal doses in 
Parts 1 and 2 will be limited 
by the dose cap specified in 
Protocol Amendment 2 (ie, 
exposure level with 
 
dosing) in addition to the 
maximal dose based on 
nonclinical data in the 
original protocol and 
maximum injection volumes 
in the original protocol. 
To adjust the planned maximal 
dose for single dose and repeat-
dose (BID and TID) 
administration of TAK-951 
based on current understanding 
of safety, tolerability, and PK of 
TAK-951. 
6.   
Section 6.6 Criteria for 
Premature Suspension of the 
Study 
Specified a planned pause in 
Part 1 to review safety, 
tolerability, and PK from the 
first 2 dose cohorts (ie, 
Cohorts 5 and 6) in Part 1.  
Specified that dose levels not 
previously studied in Part 1  
(ie, 
 single dose) will 
require additional supporting 
clinical safety, tolerability, 
To define procedures for 
re-evaluation of safety, 
tolerability, and PK data 
required to exceed a single dose 
of 
 in Part 1. 
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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  
and PK data for doses from 
Cohorts 5 and 6 in Part 1. 
7.  
Section 4.3 Benefit/Risk Profile 
Added reasoning for the 
removal of the 0.5-hour 
postdose time point for 
orthostatic vital signs 
assessments in Protocol 
Amendment 1 (ie, occurrence 
of orthostatic events in the 
current study). 
To provide rationale for this 
change previously made in 
Protocol Amendment 1 to 
mitigate risk and support 
benefit-risk assessments. 
8.  
Section 14.1 Study-Site 
Monitoring Visits 
Revised to remove “to the 
study site” when referring to 
monitoring visits. 
Clarification. 
 
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2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Development Center Americas, Inc. 
Compound: 
TAK-951 
Title of Protocol: A Randomized, Double-Blind, 
Sponsor-Open, Placebo-Controlled, 3-Part Phase 1 Study 
to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of TAK-951 in Healthy Subjects 
IND No.: 141732 
EudraCT No.: 
Not Applicable 
Study Number: TAK-951-1008 
Phase: 1 
Study Design: 
This is a phase 1, randomized, double-blind, sponsor-open, placebo-controlled study to evaluate the safety, 
tolerability, and pharmacokinetics (PK) of TAK-951 in healthy subjects. Subjects will be randomized to receive 
TAK-951 or matching placebo. 
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. The study will be 
conducted sponsor-open. Sponsor discussions with investigators and within the study team will be conducted in a 
blinded manner (ie, no unblinded information will be communicated to blinded investigators, site staff or blinded 
study monitoring personnel). 
The study will consist of 3 parts:  
• 
Part 1 is a randomized, double-blind, sponsor-open, placebo-controlled, single-rising dose (SRD) design to 
assess the safety, tolerability, PK, and immunogenicity of TAK-951 in healthy subjects. Up to 6 cohorts may 
be enrolled.  
• 
Part 2 is a randomized, double-blind, sponsor-open, placebo-controlled, multiple-rising dose (MRD) design 
to assess the safety, tolerability, PK, and immunogenicity of TAK-951 in healthy subjects. Up to 4 cohorts 
may be enrolled.  
• 
Part 3 is a randomized, double-blind, sponsor-open, placebo-controlled, multiple-dose, dose titration and 
redosing design to assess the safety, tolerability, PK, and immunogenicity of TAK-951 in healthy subjects. 
Up to 5 dose regimens will be tested in independent subject cohorts using a dose titration design, followed 
by redosing with a single dose of study drug after a 2- to 7 day variable washout period. 
Primary Objectives: 
• 
Part 1: To characterize the safety and tolerability of single subcutaneous (SC) doses of TAK-951 in healthy 
subjects. 
• 
Part 2: To characterize the safety and tolerability of multiple SC doses of TAK-951 in healthy subjects. 
• 
Part 3: To characterize the safety and tolerability of multiple SC dose regimens of TAK-951 that include 
titration from lower doses in healthy subjects. 
Secondary Objectives: 
• 
Part 1: 
– 
To characterize the PK of TAK-951 in plasma following single SC doses in healthy subjects. 
– 
To assess the immunogenicity of TAK-951 following single SC doses in healthy subjects. 
• 
Part 2: 
– 
To characterize the PK of TAK-951 in plasma following multiple SC doses in healthy subjects. 
– 
To assess the immunogenicity of TAK-951 following multiple SC doses in healthy subjects.  
• 
Part 3: 
– 
To characterize the safety and tolerability of single SC rechallenge doses of TAK-951 after a washout 
from multiple SC dose regimens that include titration from lower doses in healthy subjects. 
– 
To assess the immunogenicity of TAK-951 following multiple SC dose regimens that include titration 
from lower doses, washout, and redosing in healthy subjects. 
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Subject Population: Healthy male and female subjects aged 18 to 55 years, inclusive, at screening. Body mass 
index (BMI) ≥18 and ≤32.0 (kg/m2) at screening. 
Number of Subjects: 
Part 1: Up to approximately 48 subjects.  
Part 2: Up to approximately 32 subjects. 
Part 3: Up to approximately 40 subjects. 
Approximate values do not account for potential 
replacement of subjects who withdraw for nonsafety 
reasons. 
Number of Sites:  
Up to 3 sites in the United States (US). 
Dose Level(s): 
Part 1: TAK-951 SRD: starting dose 
 (starting dose 
 [Cohort 5] under Protocol Amendment 2). 
Part 2: TAK-951 MRD: doses to be determined based on 
Part 1. 
Part 3: TAK-951 Dose Titration and Redosing: doses to 
be determined based on Parts 1 and 2. 
Route of Administration: 
SC 
Duration of Treatment: 
Part 1: 1 day. 
Part 2: 5 days. 
Part 3: 8 to 13 days (5 days plus 1 day after variable 2 to 
7 days of washout). 
Period of Evaluation: 
Each part of the study will be approximately 60 days 
from screening until last follow-up visit. 
Main Criteria for Inclusion: 
In order to be eligible for study participation, the subject must:  
• 
Understand the study procedures and agree to participate by providing written informed consent. 
• 
Be willing and able to comply with all study procedures and restrictions. 
• 
Be a healthy man or woman aged 18 to 55 years, inclusive, at the screening visit. 
• 
Continuous nonsmoker who has not used nicotine- and tobacco-containing products for at least 3 months 
prior to dosing and throughout the study. 
• 
Have a BMI ≥18 and ≤32.0 (kg/m2) at the screening visit. 
• 
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, electrocardiogram (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, whichever is longest, 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 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, as 
determined by the investigator. 
• 
The subject has a positive pregnancy test or is lactating or breastfeeding. 
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• 
The subject is unable to refrain from or anticipates using any 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]), sinoatrial 
block or sinus pause ≥3 seconds. 
• 
The subject has an average semirecumbent blood pressure (BP) <90/60 mm Hg or >140/90 mm Hg from 
screening to predose, inclusive. Any assessments on Day -1 that do not meet this criterion must be discussed 
with the medical monitor for approval.  
• 
The subject has an average semirecumbent HR (pulse) <55 or >100 bpm at any time point from screening to 
predose, inclusive. Subjects with an average pulse <55 bpm can be enrolled only with medical monitor 
approval. Any assessments after admission with an average pulse <55 bpm at any time point, from Day -2 to 
predose (inclusive), will be left to the judgment of the investigator, unless the pulse rate 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 a pulse rate >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 before determination that the subject is eligible to 
proceed. 
Main Criteria for Evaluation and Analyses: 
The primary endpoint for this study is: 
• 
All parts of the study: 
– 
The primary safety endpoints of the study are safety and tolerability as assessed through physical 
examinations, vital signs, ECG, laboratory assessments, and adverse events (AEs). 
The secondary endpoints will be assessed through evaluation of the following parameters:  
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• 
Part 1: plasma PK parameters for TAK-951 
– 
Maximum observed plasma concentration (Cmax). 
– 
Area under the plasma concentration-time curve from time 0 to 24 hours (AUC24). 
– 
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-951 on Day 1 
– 
Cmax, tmax, AUC24, 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-951 at steady state 
– 
AUCτ, AUC24, Cmax,ss, 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. 
• 
Part 3: 
– 
Safety and tolerability of single SC rechallenge doses after a washout from multiple SC dose regimens 
of TAK-951 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 (all subjects who are randomized and receive at least 1 
dose of study treatment). Subjects will be analyzed according to the study treatment actually received. No formal 
statistical tests or inference will be performed for safety analyses. All safety data will be summarized 
descriptively by placebo, TAK-951 dose level (Parts 1 and 2)/dose regimen (Part 3), and TAK-951 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 clinical laboratory evaluations, vital signs, and ECG 
will be provided. 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. 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-951 by placebo, TAK-951 single dose 
level after washout, and TAK-951 single dose overall after washout.  
The plasma (all parts of the study) concentrations of TAK-951 will be summarized descriptively by dose level 
(Parts 1 and 2)/dose regimen (Part 3) at each scheduled sampling day/time within each part of the study 
separately based on the PK analysis set (all subjects who receive at least 1 dose of TAK-951 and have at least 
1 measurable postdose plasma concentration for TAK-951). Subjects will be analyzed according to the study 
treatment actually received. The PK parameters of TAK-951 determined using a noncompartmental analysis 
approach will be summarized descriptively by dose level (Parts 1 and 2)/dose regimen (Part 3) of TAK-951, as 
appropriate, within each part of the study separately, 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 allows. No formal statistical comparisons will be conducted. The 
same dose level (Parts 1 and 2)/dose regimen (Part 3) may be pooled across cohorts within each part of the study 
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where appropriate.  
To support internal decision making regarding further development of 
 
 TAK-951, an interim analysis of safety, 
tolerability, and PK at a time point dependent on emerging clinical data from TAK-951-1008 may be conducted. 
If the interim analysis is conducted, the interim analysis will include all available data (including, but not limited 
to treatment-emergent adverse events [TEAEs], vital signs, ECG, laboratory assessments, physical examinations, 
and PK). Additional interim analyses may be conducted for sponsor internal decision-making and would be 
defined in the statistical analysis plan. The details of interim analysis (timing, datasets, and methods), data access 
management plan, and distribution of results will be described in a separate documents (ie, the statistical analysis 
plan and data access management plan). A final analysis will be performed at the end of the study after final 
database lock.  
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-951 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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3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities  
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform these activities 
either in full or in partnership with the sponsor. 
The study is being funded by Takeda. Payments for the conduct of the study that will be made to 
study sites (and, if applicable, investigators and/or other study staff) will be specified in the 
Clinical Study Site Agreement(s). All investigators and sub-investigators must declare potential 
conflicts of interests to the sponsor. The sponsor will provide a financial disclosure form that 
must be signed by each investigator and sub-investigator before the study starts at their study 
site; in addition, any potential conflicts of interests that are not covered by this financial 
disclosure form should be disclosed separately to the sponsor before the start of the study at their 
site. 
All institutional affiliations of the investigator(s) and sub-investigator(s) should be declared on 
their curriculum vitae, which must be provided to the sponsor before the start of the study. 
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3.2 
List of Abbreviations 
%CV 
percent coefficient of variation 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC24 
area under the plasma concentration-time curve from time 0 to 24 hours 
AUC∞ 
area under the plasma concentration-time curve from time 0 to infinity, calculated 
using the observed value of the last quantifiable concentration 
AUCτ 
area under the plasma concentration-time curve during a dosing interval 
AUClast 
area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration 
AV 
atrioventricular 
BMI 
body mass index 
bpm 
beats per minute 
BID 
twice daily 
BP 
blood pressure 
CL/F 
apparent clearance after extravascular administration 
Cmax 
maximum observed concentration 
Cmax,ss 
maximum observed concentration at steady state 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CRU 
clinical research unit 
CSR 
clinical study report 
CV 
cardiovascular 
DBP 
diastolic blood pressure 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDA 
electrodermal activity  
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
 
 
 
 
 
 
hCG 
human chorionic gonadotropin 
HR 
heart rate 
HRV 
heart rate variability 
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ICH 
International Conference on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
INR 
international normalized ratio 
IRB 
institutional review board 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
UK Medicines and Healthcare products Regulatory Agency 
MRD 
multiple rising dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
 
 
PK 
pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency 
QD 
once daily 
QTc 
corrected QT interval 
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 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SRD 
single rising dose 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
t1/2z 
terminal disposition phase half-life 
TID 
3 times daily 
tmax 
time of first occurrence of Cmax 
ULN 
upper limit of normal 
UK 
United Kingdom 
US 
United States 
Vss 
volume of distribution at steady state after intravenous administration 
Vz/F 
apparent volume of distribution during the terminal disposition phase after 
subcutaneous administration 
WBC 
white blood cell 
 
 
 
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4.3 
Benefit/Risk Profile  
The current study represents an extension study of the FIH study, TAK-951-1001. The main 
purpose of this study in healthy subjects is to assess the safety and tolerability of TAK-951 at 
higher doses; as such, no clinical benefit is expected for study participants. 
The antiemetic properties of TAK-951 have been demonstrated in different preclinical models of 
emesis in rodents, ferrets, and dogs. Based on the safety findings from nonclinical studies 
conducted with TAK-951 
, the potential risks of TAK-951 
include increased HR and decreased BP. For peptide-based therapeutics administered SC, 
immunogenicity, and injection site reactions and more serious hypersensitivity reactions are 
potential risks. 
Based on the safety findings from nonclinical studies conducted with TAK-951, increase in HR, 
decrease in BP, and synergistic effect when combined with beta blockers are potential risks. 
Safety results from the FIH study demonstrated a transient increase in HR within the first hour of 
TAK-951 dosing as well as decreases in SBP and DBP that were more prominent with postural 
changes (orthostatic) in some individuals within the first 2 hours post dosing. These changes 
were not clearly dose dependent or related to increased exposure. Postural hypotension 
(<20 mm Hg in SBP or <10 mm Hg DBP within 3 minutes of standing) is considered an 
identified risk. After receiving a single-dose of TAK-951, 4 subjects (5%) experienced 
orthostatic hypotension, including 2 subjects with a Grade 3 event and 5 subjects (7%) reporting 
postural dizziness. Current preliminary PK and vital sign data reveal that the magnitude of 
change from baseline in HR and DBP may be saturated at higher doses. Section 6.4.2 
summarizes preliminary blinded safety data from Cohorts 1 to 4 
  
To minimize the risks to the subjects in this study, the sponsor considers the following measures 
to be appropriate: selecting TAK-951 doses with appropriate safety margins based on nonclinical 
study data; managing study eligibility criteria; prespecifying safety monitoring procedures, such 
as frequent BP assessments that included orthostatic BP measurements, telemetry, and Holter 
electrocardiogram (ECG); developing guidance for investigators; and using a clinical study 
facility where close monitoring could have been performed and rapid institution of appropriate 
care could have been given when needed in a timely manner. 
In addition, by Protocol Amendments 1 and 2, subjects will be required to remain in a supine or 
semirecumbent position during the 2 hours after dosing without the 0.5 hour postdose orthostatic 
vital sign assessment. As an additional safety step, a modified orthostatic assessment and 
physical counterpressure maneuvers will be implemented. In Study TAK-951-1008, reported 
AEs related to orthostatic vital sign changes (presyncope, syncope, and orthostatic hypotension) 
had onset by the 2-hour time point. Thus, having subjects remain semirecumbent for up to 2 
hours will further mitigate the risks to subjects (ie, with the observed vital sign changes in the 
first 2 hours of Cohorts 1-4 dosed with 
), while providing additional 
safety data with respect to orthostatic vital signs at later time points. 
Subjects with a history of serious hypersensitivity to any medication or any component of 
TAK-951 formulation or with a history of significant multiple and/or severe allergies are 
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excluded from this study. Subjects are evaluated for the development of antidrug antibodies 
(ADA) as part of the study. The potential risks related to increased HR, decreased BP, and 
injection site reactions are monitored clinically and/or with laboratory tests and were 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 
approximately 600 mL). Overall, the mitigation measures are adequate to monitor safety of the 
subjects participating in the study.  
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
The primary objective for each part of the study is as follows: 
• Part 1: To characterize the safety and tolerability of single SC doses of TAK-951 in healthy 
subjects. 
• Part 2: To characterize the safety and tolerability of multiple SC doses of TAK-951 in 
healthy subjects. 
• Part 3: To characterize the safety and tolerability of multiple SC dose regimens of TAK-951 
that include titration from lower doses in healthy subjects. 
5.1.2 
Secondary Objectives 
The secondary objectives for each part of the study are as follows: 
• Part 1: 
– To characterize the PK of TAK-951 in plasma following single SC doses in healthy 
subjects. 
– To assess the immunogenicity of TAK-951 following single SC doses in healthy subjects. 
• Part 2: 
– To characterize the PK of TAK-951 in plasma following multiple SC doses in healthy 
subjects. 
– To assess the immunogenicity of TAK-951 following multiple SC doses in healthy 
subjects.  
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• Part 3: 
– To characterize the safety and tolerability of single SC rechallenge doses of TAK-951 
after a washout from multiple SC dose regimens that include titration from lower doses in 
healthy subjects. 
– To assess the immunogenicity of TAK-951 following multiple SC dose regimens that 
include titration from lower doses, washout, and redosing in healthy subjects. 
5.1.3 
Exploratory Objectives 
Exploratory endpoints of this study include the following:  
 
 
  
 
• Part 2: To assess the effects of TAK-951 on wearable/digital device biomarkers in healthy 
subjects. 
• Part 3: To characterize the PK of TAK-951 in plasma following multiple SC doses and 
dosing schedules in healthy subjects. 
5.2 
Endpoints 
5.2.1 
Primary Endpoints 
• All parts of the study: 
– The primary safety endpoints of the study are safety and tolerability as assessed through 
physical examinations, vital signs, ECG, laboratory assessments, and AEs.  
5.2.2 
Secondary Endpoints  
Secondary endpoints include:  
• Part 1: plasma PK parameters for TAK-951  
– Maximum observed plasma concentration (Cmax). 
– Area under the plasma concentration-time curve from time 0 to 24 hours (AUC24). 
– 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). 
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– 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-951 on Day 1.  
– Cmax, tmax, AUC24, 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-951 at steady state. 
AUCτ, AUC24, maximum observed concentration at steady state (Cmax,ss), 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. PK parameters will be calculated as permitted by the data. Additional PK parameters may 
be computed, as needed. 
• Part 3: 
– Safety and tolerability of single SC rechallenge doses after a washout from multiple SC 
dose regimens of TAK-951 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 
Additional/Exploratory Endpoints  
Exploratory endpoints will be assessed through the following parameters:  
 
 
 
  
• Part 2: Change from baseline (Day -2 before first dose) in wearable/digital device parameters 
including: electrodermal activity (EDA), HR, heart rate variability (HRV), actigraphy, and 
temperature through 48 hours post last dose. 
• PK parameters in Part 3 may be computed as permitted by data collected. 
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design  
This is a phase 1, randomized, double-blind, sponsor-open, placebo-controlled study to evaluate 
the safety, tolerability, and PK of TAK-951 in healthy subjects. Subjects will be randomized to 
receive TAK-951 or matching placebo. 
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. 
The study will be conducted sponsor-open. Sponsor discussions with investigators and within the 
study team will be conducted in a blinded manner (ie, no unblinded information will be 
communicated to blinded investigators, site staff, or blinded study monitoring personnel). 
The study will consist of 3 parts:  
• Part 1 is a randomized, double-blind, sponsor-open, placebo-controlled, SRD design to assess 
the safety, tolerability, PK, and immunogenicity of TAK-951 in healthy subjects. Up to 6 
cohorts may be enrolled.  
• Part 2 is a randomized, double-blind, sponsor-open, placebo-controlled, MRD design to 
assess the safety, tolerability, PK, and immunogenicity of TAK-951 in healthy subjects. Up 
to 4 cohorts may be enrolled.  
• Part 3 is a randomized, double-blind, sponsor-open, placebo-controlled, multiple-dose, dose 
titration and redosing design to assess the safety, tolerability, PK, and immunogenicity of 
TAK-951 in healthy subjects. Up to 5 dose regimens will be tested in independent subject 
cohorts using a dose titration design, followed by redosing with a single dose of study drug 
after a 2- to 7-day variable washout period. 
TAK-951 and matching placebo will be administered SC. Any part of the study may not be 
conducted based on the sponsor’s decision. The daily maximum exposure anticipated at steady 
state will not exceed an exposure established as tolerated in previous parts of the study. Part 3 
will be conducted at the discretion of the sponsor based on a review of the available safety and 
PK data from Parts 1 and 2. At the discretion of the sponsor, Parts 2 and 3 may be initiated 
before completion of all cohorts in Parts 1 and 2, respectively, as otherwise permissible in the 
protocol. Dosing of Parts 2 and 3 will not be initiated before dosing of Cohorts 5 and 6 in Part 1 
(see Section 6.1.2 and 6.1.3). 
Safety will be assessed by monitoring for AEs, vital signs including orthostatic assessments, 
12-lead ECGs, telemetry, safety laboratory assessments after each dose, and immunogenicity. 
PK sampling times may vary based on emerging safety, tolerability and PK data, but the 
maximal number of samples will not change.  
An overview of treatment cohorts is presented in Table 6.a. A schematic of the study design is 
included as Figure 6.a. Schedules of assessments for Part 1, Part 2, and Part 3 of the study are 
presented in Appendix A.  
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Figure 6.a 
Schematic of Study Design  
 
BID: twice daily; D: day; MRD: multiple rising dose; QD: once daily; TID: 3 times daily. 
Additional cohorts may be included in Part 1 (see Cohorts 6a and 6b in Table 6.a), as determined at the dose escalation meeting based on emerging safety, 
tolerability, and available PK data during the study.  
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Table 6.a 
Overview of Treatment Cohorts 
Cohort 
Regimen 
Treatment 
Part 1 
 
TAK-951 
Placebo 
1 (staggered) 
SRD 
6 
2 
2 (staggered) 
6 
2 
3 (staggered) 
6 
2 
4 (staggered) 
6 
2 
5 (staggered) 
6 
2 
6 (staggered) 
6 
2 
6a (staggered) 
6 
2 
6b (staggered) 
6 
2 
Part 2  
 
TAK-951 
Placebo 
7 
MRD 
6 
2 
8 
6 
2 
9 
6 
2 
10 
6 
2 
Part 3  
 
TAK-951 
Placebo 
11 
Dose Titration, 
Washout, 
Redosing 
6 
2 
12 
6 
2 
13 
6 
2 
14 
6 
2 
15 
6 
2 
MRD: multiple rising dose; SRD: single rising dose. 
The starting dose in Part 1 (SRD) will be 
 (Cohort 1); starting doses of subsequent Parts 1, 2, and 3 cohorts 
will be determined at the dose escalation meeting based on emerging safety, tolerability, and available PK data as 
otherwise permitted in the protocol. Dosing will resume with modified procedures as described in Protocol 
Amendment 1 and 2 at 
 (ie, Cohort 5). Cohort 6 may be dosed at 
 (repeat of Cohort 5) or at 
 as 
determined at the dose escalation meeting (see Section 6.2). The planned maximum dose in Part 1 (SRD) will be 
 (until additional supporting clinical safety, tolerability, and PK data are available from Cohorts 5 and 6 and 
provided for Food and Drug Administration review before dosing). Additional cohorts may be included in Part 1 
(Cohorts 6a and 6b as shown above), as determined at the dose escalation meeting based on emerging safety, 
tolerability, and available PK data during the study. However, dosing of an additional Part 1 cohort (single dose 
) will not occur until after a pause to review safety and PK data from Cohorts 5 and 6. 
 
6.1.1 
Part 1: SRD Cohorts 1 to 6 
Part 1 will consist of up to 6 sequential cohorts with 8 healthy subjects per cohort. Subjects in 
each cohort will be randomly assigned to receive a single dose of TAK-951 or matching placebo 
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approach may be used for cohorts in Part 2. Part 2 will consist of sequential dosing in up to 
4 ascending cohorts of healthy subjects. In each cohort, 8 healthy subjects will be randomly 
assigned to receive TAK-951 or matching placebo in a 3:1 ratio in a double-blind, sponsor-open 
manner. Up to approximately 32 healthy subjects may be randomized in Part 2 (approximate 
value does not account for potential replacement of subjects who withdraw due to non-safety 
reasons).  
The schedule of study assessments for Part 2 (MRD) are presented in the following tables: 
Table A-2 
Part 2 for MRD: Screening Through Day 1; BID 
Table A-3 
Part 2 for MRD: Days 2 Through 4; BID 
Table A-4 
Part 2 for MRD: Day 5 Through Discharge, Follow-Up, and ET; BID 
Table A-5 
Part 2 for MRD: Screening Through Day 1; TID 
Table A-6 
Part 2 for MRD: Days 2 Through 4; TID 
Table A-7 
Part 2 for MRD: Day 5 Through Discharge, Follow-Up, and ET; TID. 
Subjects will be admitted to the study unit on Day -2. Baseline pulse and BP assessments will be 
taken on Day -1, and will be time-matched to the Day 1 assessments, include postural 
measurements. At least 24 hours of baseline continuous telemetry will be collected within 
48 hours before first dose administration. Subjects in each cohort will be dosed with TAK-951 or 
matching placebo on Day 1 after a minimum of 8 hours of fasting for a total of 5 days of dosing. 
Subjects will be confined up to 48 hours after the Day 5 dose to assess safety, tolerability, and 
PK (ie, they can be discharged after the completion of the 48-hour assessments). Blood samples 
for assessment of TAK-951 concentrations will be collected predose and at the specified time 
points postdose as described in schedule of study procedures. Blood samples 
 
 metabolite profiling/metabolite identification will 
also be collected. Optional DNA samples will also be collected from subjects that provide 
consent for collection through a separate procedure. Immunogenicity will be assessed predose 
and during the specified follow-up visits. 
In Part 2, up to 4 doses will be studied in an ascending manner. The daily maximum exposure in 
Part 2 will not exceed highest exposure determined to be tolerated in Part 1. Doses in Part 2 are 
planned to be administered SC either BID or TID. Doses and frequency will be determined in the 
dose escalation meeting (See Section 6.2) based on emerging safety, tolerability, and available 
PK data. The sponsor may decide to administer lower doses, repeat doses, and add or cancel 
cohort(s) if deemed appropriate. 
Subjects who withdraw from the study for nonsafety reasons may be replaced at the discretion of 
the sponsor after discussion with the investigator. 
6.1.3 
Part 3: Dose Titration and Redosing Cohorts 11 to 15 
Dosing of Part 3 will not be initiated before dosing of Cohorts 5 and 6 in Part 1. The overall 
purpose of Part 3 is to characterize the safety and tolerability of multiple SC dose regimens of 
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TAK-951 involving dose titration over 5 days of treatment. The intent of this study part is to 
enable a descriptive analysis (ie, without hypothesis testing) of safety and tolerability findings 
with dose titration. The redosing component of Part 3 is intended to provide an evaluation to 
assess the effects of a single rechallenge dose (after 2 to 7 days [48 to 168 hours] of washout 
following the 5-day treatment period) on the safety and tolerability profile (vital signs, AEs, and 
other safety parameters) of TAK-951.  
The schedule of study assessments for Part 3 (dose titration and redosing) are presented in the 
following tables: 
Table A-8 
Part 3: Screening Through Day 1 Assessments; QD 
Table A-9 
Part 3: Days 2 Through 4 Assessments; QD 
Table A-10 
Part 3: Day 5 Through Washout Assessments; QD 
Table A-11 
Part 3: Redosing Through Discharge, Follow-Up, and ET;  
Table A-12 
Part 3: Screening Through Day 1; BID 
Table A-13 
Part 3: Days 2 Through 4 Assessments; BID 
Table A-14 
Part 3: Day 5 Through Washout Assessments; BID 
Table A-15 
Part 3: Screening Through Day 1; TID 
Table A-16 
Part 3: Days 2 Through 4; TID 
Table A-17 
Part 3: Day 5 Through Washout Assessments; TID 
Part 3 may start before the completion of Parts 1 and 2. If Part 3 is started before the completion 
of Part 2, the starting dose will be decided in the dose escalation meeting (see Section 6.2); the 
doses for each cohort and dose frequencies will also be determined. The maximum daily 
exposure in Part 3 will be at a total daily exposure level at or below the highest completed cohort 
in Part 1 or Part 2 that has been determined to be tolerated. A staggered dosing approach may be 
used for cohorts in Part 3. Part 3 consists of up to 5 cohorts of healthy subjects, which may be 
dosed in parallel. In each cohort, 8 healthy subjects will be randomly assigned to receive 
TAK-951 or matching placebo in a 3:1 ratio in a double-blind, sponsor-open manner. Up to 
approximately 40 healthy subjects may be randomized in Part 3 (approximate value does not 
account for potential replacement of subjects who withdraw due to non-safety reasons).  
Subjects will be admitted to the study unit on Day -2. Baseline pulse and BP assessments will be 
taken on Day -1, and will be time-matched to the Day 1 assessments. At least 24 hours of 
baseline continuous telemetry will be collected within 48 hours before the first dose. Subjects 
will be dosed with TAK-951 or matching placebo on Day 1 in each cohort/period after a 
minimum of 8 hours of fasting. Subjects will be confined up to 24 hours after the Day 5 dose to 
assess safety, tolerability, and PK. Blood samples for assessment of TAK-951 concentrations 
will be collected predose and at the specified time points postdose as described in the 
corresponding schedule of study procedures. 
 
. Subjects will be discharged on Day 6 and after a 2- 
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to 7-day washout (48 to 168 hours after the last dose of the 5-day treatment period), they will be 
readmitted the evening before redosing. Subjects will be dosed with a single dose of study drug 
(ie, at the same dose and double-blind, sponsor-open treatment assignment as their highest daily 
dose during the 5-day treatment period). The duration of washout before redosing may be subject 
to change based on emerging safety, tolerability, and available PK data. Subjects will be 
confined the evening before redosing and for at least 24 hours after their redosing, while not 
being confined for the entire washout period. Subjects will return for additional immunogenicity 
and other assessments at the follow-up visit 14 ± 3 days after the redose. 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. 
Doses in Part 3 are planned to be administered SC once daily (QD), BID, or TID depending upon 
emerging safety, tolerability, and available PK data. The daily exposure will not exceed an 
exposure established as tolerated in Part 2. Based on emerging PK data from Parts 1 and 2, or PK 
data from prior cohorts in Part 3, adjustments to dose and to repeat dosing duration may be 
implemented. The PK data from the TAK-951-1001 FIH study will also be utilized to evaluate 
various titration schemes. 
The members of the dose escalation meeting will determine the doses and dose schedule of 
Part 3 cohorts based on safety, tolerability and available PK data. After completion of each 
cohort, 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 (Day 5 dose) in the cohort, 
and available PK data will be analyzed at the dose escalation meeting. The dose will not exceed 
the dose studied in the highest completed dose cohort in Parts 1 and 2.  
Subjects who completed the entire Part 1 or 2, including the follow-up visits, may enroll in Part 3 
provided it is at least 4 weeks after the last follow-up visit in the previously enrolled part. 
Subjects who withdraw may be replaced at the discretion of the sponsor after discussion with the 
investigator. 
6.2 
Dose Escalation  
The dose escalation meeting will occur with representatives from the sponsor (Clinical Science, 
Clinical Pharmacology, Global Patient Safety Evaluations, and Clinical Operations) and site 
investigators, who are responsible for assessing the safety and tolerability, laboratory results of at 
least 24 hours after the last dose in the cohort, and available PK data for each dosing cohort after 
completion and before selecting the next dose. See Section 6.1 for specified doses in Cohorts 5 
and 6 of Part 1, and requirement for review of safety, tolerability, and PK data from Cohorts 5 
and 6 before dosing an additional cohort
. 
The sponsor will be open and the investigator and site study team will remain blinded. 
Discussions within the dose escalation meeting will be conducted in a blinded manner (ie, no 
unblinded information will be communicated at the dose escalation meeting). 
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other irritated skin (eg, vitiligo, eczema, etc). If repeat injections of study drug are given in the 
same spot, this may cause scarring and hardening of fatty tissue, which may interfere with the 
absorption of the drug, and therefore injections should not be given at the same location 
repeatedly. Each study drug injection must be administered approximately 2 inches 
(5 centimeters) apart and must not be administered into an area where the skin appears to be 
tender to touch, signs of bruising/bleeding are noted, or the area seems indurated or 
erythematous. If locating injection sites on the abdomen, avoid giving the injection in the 
umbilicus, ribs, or hip bone. If injecting in the thighs, use the outer areas, below the groin and 
above the knee. Subjects will be semirecumbent during dosing with subsequent observation and 
monitoring in that position following administration to mitigate the risk of orthostatic 
hypotension and other cardiovascular AEs for 2 hours. Subjects will be requested to stand for 
orthostatic BP and pulse measurements 2 hours post dose. 
For additional information on study drug administration, please refer to the study pharmacy 
manual.  
6.4 
Justification for Study Design, Dose, and Endpoints 
6.4.1 
Justification for Study Design  
A randomized, double-blind, sponsor-open, placebo-controlled design for Part 1 is considered 
adequate to characterize the safety, tolerability, and PK of single doses of TAK-951.  
Part 2 of the study is a randomized, double-blind, sponsor-open, placebo-controlled, sequential 
panel MRD study where up to 6 doses/dose regimens will 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 5-day treatment period. 
Tolerability findings will be reviewed 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 2 to 7 days of 
washout following the 5-day treatment period) on vital signs, AEs, and other safety parameters. 
6.4.2 
Justification for Dose for SRD, MRD, and Titration  
The starting dose for Part 1 of this study will be
 (Cohort 1) and the maximum dose will not 
exceed exposures as defined below. The starting dose with implementation of Protocol 
Amendment 2 will be
 (Cohort 5). Cohort 6 may be dosed at
 (repeat of Cohort 5) or at 
 as determined at the dose escalation meeting (see Section 6.2). 
The safety, tolerability, and PK of TAK-951 in healthy subjects has been evaluated in the FIH 
TAK-951-1001 study. However, the maximum tolerated dose was not identified in this FIH 
study. The highest evaluated dose was
 in the SRD and
 BID for 5 days in the MRD. 
Based on the overall safety data of Study TAK-951-1001, TAK-951 was well tolerated at the 
highest doses evaluated in SRD and MRD. Postural hypotension was confirmed as an identified 
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• Two or more subjects experience a CTCAE v5.0 Grade ≥3 hypotension (ie, requiring 
medical intervention) and considered related to TAK-951/placebo, or 
• One subject experiences a CTCAE v5.0 Grade ≥3 vasovagal syncope (fainting or orthostatic 
collapse), considered related to TAK-951/placebo, or 
• Two or more subjects experience a CTCAE v5.0 Grade ≥3 event considered related to 
TAK- 951/placebo, or  
• One subject experiences a CTCAE v5.0 Grade 4 event considered related to 
TAK-951/placebo, or 
• One subject with ALT or AST >5 × ULN after TAK-951 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-951 administration, or 
• One subject with an SAE considered related to TAK-951/placebo, or  
• Two or more subjects experience a CTCAE v5.0 Grade ≥2 injection site reaction (defined as 
pain combined with lipodystrophy and/or edema). 
The totality of the safety data from the study will be reviewed by representatives of the sponsor 
and site investigators at the dose escalation meeting once the dosing is paused. If notable AEs or 
safety concerns are identified after review of the data, the investigator and/or the sponsor may 
consider potential changes in the next planned dose level. Possible changes in dose 
administration include, but are not limited to: 
• Administration of an intermediate dose between the current and next planned dose. 
• Repeated administration of the current dose. 
• Administration of a lower dose than the existing dose levels. 
• Study termination.  
Study drug dosing may resume if no safety concern is identified by the investigator and sponsor. 
In addition, there is planned suspension of the study to review safety, tolerability, and PK data 
from Cohort 5 (
) and Cohort 6 (
) single doses before dosing additional cohorts in 
Part 1. Dosing of cohorts in Part 1 with doses greater than 
 will require additional 
supporting clinical safety, tolerability, and PK data from Cohorts 5 and 6 from Part 1 (SRD). 
During Study Drug Dosing in Part 2 (MRD) 
If the criteria for pausing occur 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 data. 
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During Study Drug Dosing in Part 3 (Titration and Redosing) 
If the criteria for pausing occur 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 12), 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 after careful review of the totality of the available data at the dose 
escalation meeting. 
6.6.1 
Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
6.6.2 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed 
by applicable study sites during the course of termination or study suspension. 
6.6.3 
Definition of End-of-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, withdraws consent from overall study participation, is lost to follow-up (ie, the 
investigator is unable to contact the subject), or the sponsor ends the study, whichever occurs 
first. 
6.6.4 
Total Study Duration  
• Part 1 will consist of a 28-day screening period, a 1-day treatment period, and a follow-up 
period of 28 days.  
• Part 2 will consist of a 28-day screening period, a 5-day treatment period, and a follow-up 
period of 28 days. 
• Part 3 will consist of a 28-day screening period, a 5-day treatment period, a 2- to 7-day 
washout period, a 1-day retreatment period, and a follow-up period of 14 days. 
The duration of follow up in any part of the study may be altered by the sponsor based on 
evolving data. The investigator may extend the duration of follow up for individual subjects as 
needed to evaluate subject safety. 
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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including laboratory test results, need to be confirmed before the first dose of 
study drug as outlined in the Schedule of Study Procedures (Appendix A).  
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 aged 18 to 55 years, inclusive, at the screening visit.  
4. Be a 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 ≤32 (kg/m2) at the screening visit. 
6. Be judged to be in good health (eg, no evidence of psychiatric, hepatic, renal, pulmonary, or 
CV disease) by the investigator, based on clinical evaluations including laboratory safety 
tests, medical history, physical examination, ECG, and vital sign measurements performed at 
the screening visit and before administration of the initial dose of study drug or invasive 
procedure. 
7. Meet the following birth control requirements (see Section 9.6):  
– Is a male subject who is sterile or agrees to use an appropriate method of contraception, 
including a condom with or without spermicidal cream or jelly, from the first dose of 
study drug until 30 days 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. 
– Is a male subject who agrees not to donate sperm from the first dose of study drug until 
30 days after the last dose of study drug. 
– Women of childbearing potential are eligible for the study provided they have a negative 
pregnancy test, are not lactating or breastfeeding, and are willing and agreeable to use 
highly effective contraception during the study and up to 30 days after the last dose of 
study drug. 
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– Is a female subject of nonchildbearing potential, defined by at least 1 of the following 
criteria: 
a) Postmenopausal (defined as 12 months of spontaneous amenorrhea in females 
aged >45 years or 6 months of spontaneous amenorrhea in females aged >45 years 
with serum follicle-stimulating hormone (FSH) levels >40 mIU/mL). Appropriate 
documentation of FSH levels is required. 
b) Surgically sterile by hysterectomy, bilateral salpingectomy, and/or bilateral 
oophorectomy with appropriate documentation of surgical procedure. 
c) Had a bilateral tubal ligation with appropriate documentation of surgical procedure. 
d) Has a congenital condition resulting in no uterus. 
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, whichever is longest, 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, as determined by the investigator. 
4. The subject has a known hypersensitivity or contraindication to any component of TAK-951. 
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 any 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.  
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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, as determined by the investigator. 
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 test or urine drug screen results at screening or check-in. 
13. The subject has had a previous major psychiatric disorder. 
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), sinoatrial block or 
sinus pause ≥3 seconds. 
15. The subject has an average semirecumbent BP <90/60 mm Hg or >140/90 mm Hg from 
screening to predose, inclusive. Any assessments on Day -1 that do not meet this criterion 
must be discussed with the medical monitor for approval.  
16. The subject has an average semirecumbent HR (pulse) <55 or >100 bpm at any time point 
from screening to predose, inclusive. Subjects with an average HR (pulse) <55 bpm can be 
enrolled only with medical monitor approval. Any assessments after admission with an 
average HR (pulse) <55 bpm at any time point, from Day -2 to predose (inclusive), will be 
left to the judgment of the investigator, unless HR (pulse) is <50 bpm, which must be 
discussed with the medical monitor for approval. 
17. The subject has orthostatic hypotension defined as a decrease in SBP ≥20 mm Hg or a 
decrease in DBP ≥10 mm Hg at approximately 3 minutes of standing when compared with 
BP from the semirecumbent position at screening to predose assessments, inclusive. In 
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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 
pulse >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 before determination 
that the subject is eligible to proceed. 
19. The subject has a known or suspected current coronavirus disease 2019 (COVID-19) 
infection or is at risk of COVID-19 infection as assessed by the investigator. 
7.3 
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 test at the discretion of the 
investigator.  
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7.3.4 
Caffeine 
In Part 1, subjects will refrain from consuming caffeinated beverages from the evening of Day -3 
until the PK blood sample at 48 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. 
7.4 
Diet, Fluid, and 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 pulse 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 pulse and BP assessments. 
On Days 1 and 5 in Part 2, and Days 1, 5, and the day before redosing 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. 
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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. For 
screen failure subjects, refer to Section 9.6.5. 
1. Pretreatment event or AE. 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.  
2. 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. See Appendix D. 
3. Significant protocol deviation. The discovery that the participant did not meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health. 
4. Lost to follow-up. The subject did not attend visits and attempts to contact the subject were 
unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.  
5. 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.  
6. Study termination. The sponsor, IRB, or regulatory agency terminates the study. 
7. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.6.4.  
8. AE of potential injection site reaction. An AE of potential injection site reaction may require 
discontinuation of study drug if in the judgment of the investigator continued participation 
imposes risk or discomfort to the subject’s continuing on study drug (eg, in receiving 
multiple injections/day in Part 2 of the study).  
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8.1.2 
Clinical Study Drug Labeling 
A clinical label will be affixed to study drug containers in accordance with local regulatory 
requirements. 
8.1.3 
Clinical Study Drug Inventory and Storage 
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-951 must be stored at -25°C to -15°C with protection from light. 
The temperature excursion information can be found in the pharmacy manual or in the 
referenced compounding manual when applicable. Receipt and dispensing of study drug must be 
recorded by authorized personnel at the study site. 
8.1.4 
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 drugs (TAK-951 vials), 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 unblinded 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, the 
designated site pharmacist should acknowledge the receipt of the shipment by signing the 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. 
• 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. 
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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. 
8.3 
Randomization Code Creation and Storage  
Randomization personnel of the sponsor or designee will generate the randomization schedule. 
All randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
Subjects in each cohort will be randomly assigned to receive TAK-951 or matching placebo in a 
3:1 ratio in a double-blind, sponsor-open manner. Subject randomization will not be stratified. 
In Part 1, all cohorts will use a staggered dosing scheme. After dosing the first 2 subjects 
(1 receiving TAK-951 and 1 receiving placebo), the investigator will review all available safety 
and CV tolerability profile data up to at least 48 hours postdose and discuss with the sponsor 
before dosing the remaining subjects in the cohort. A staggered dosing approach may be used for 
subsequent cohorts in Parts 2 or 3 (if decided during the dose escalation meeting). Except for 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. 
Subjects who drop out of the study may be replaced at the discretion of the sponsor after 
discussion with the investigator. 
8.4 
Blinding 
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. 
The study will be conducted sponsor-open. 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.  
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 
reviewed during the dose escalation meeting. 
Discussions with the dose escalation meeting members will be conducted in a blinded manner 
(ie, such that no unblinded information is communicated to other members of the meeting).  
The operational plan for blinding will describe study procedures for maintaining the blind of 
investigators and site personnel including procedures related to investigator participation in the 
dose escalation meetings, medical monitoring, site monitoring, and querying of data before the 
database lock. 
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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. Where appropriate, the medical 
monitor should be contacted before the blind is broken. Unblinding will be performed per the 
standard operating procedures of the study site. 
9.0 
STUDY PLAN 
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 C. 
9.1.1.1 
Assignment of Screening and Randomization Numbers  
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before randomization or allocation. Each subject will be 
assigned only 1 screening number. Screening numbers must not be reused for different subjects. 
Any subject who is screened multiple times will be assigned a new screening number for each 
screening event. Rescreening of subjects will be considered on a case-by-case basis by the 
sponsor. This case-by-case consideration by the sponsor includes screening of subjects in Part 3 
who have completed the entire Part 1 or 2 and are potentially eligible for Part 3, as described in 
Section 6.1. 
All eligible subjects will be randomly allocated and will receive a randomization number. The 
randomization number identifies the subject for all procedures occurring after randomization. 
Once a randomization number is assigned to a subject, it can never be reassigned to another 
subject. A single subject cannot be assigned more than 1 randomization number. 
9.1.1.2 
Study Drug Assignment 
On Day 1, subjects will be assigned a randomization number in ascending numerical order at the 
clinical site. The randomization number encodes the subject assignment to either TAK-951 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 
Demographics and Medical History 
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. 
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9.1.3 
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 (Appendix A). 
9.2.2 
Weight and Height 
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 Sign Procedure 
Body temperature will be measured with either an oral (temperature taken at floor of the mouth) 
or tympanic thermometer. The same method (ie, oral or tympanic) must be used for all 
measurements for each individual subject and should be the same for all subjects. The same size 
cuff must be used for all BP measurements for each individual subject. 
At screening, and from admission to the clinical research unit through predose (inclusive of 
Day -1 and predose on Day 1) vital signs including orthostatic BP and pulse 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, pulse, orthostatic BP, and orthostatic pulse assessments 
immediately before 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 
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the dose as close as possible to the originally planned TAK-951 dosing time based on Day 1 
dosing.  
Subjects should rest in a semirecumbent position for at least 5 minutes before vital signs are 
measured. Vital signs will include pulse (bpm), respiratory rate, and SBP and DBP 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 rate assessment if results are inconsistent (ie, a difference >10 bpm in pulse or a 
difference >10 mmHg 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. 
Subjects in each study part will have baseline pulse 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 before Hour 0 time points, BP and pulse will be measured within 1 hour 
± 10 minutes before dosing at Hour 0. When scheduled after the dose, vital signs will be 
performed within approximately 15 minutes of the scheduled time point.  
When vital signs are scheduled at the same time as blood draws, they will be obtained before the 
scheduled blood draw. 
Subjects will remain semirecumbent for the first 4 hours with vital signs obtained at the 
timepoints indicated in Appendix A, 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. 
Prior to discharge, vital signs will be assessed and must meet the following criteria: 
semirecumbent pulse <100 bpm and BP >90/60 mmHg and no symptoms or signs of postural 
hypotension and tachycardia. The investigator may repeat these assessments before determining 
whether a subject can be discharged. If 3 measurements are obtained, the final BP and pulse 
readout should be the average of the 2 more consistent assessments. 
9.2.4.1 
Orthostatic Measurements 
Orthostatic BP and pulse rate assessments will be performed in the outlined sequence as follows: 
1. After resting for 5 minutes in a semirecumbent position, BP and pulse will be measured. 
2. Subjects will then sit at bedside with crossed legs for 3 minutes.  
3. Subjects will then stand for 2 minutes before collecting vital signs. 
• If the pulse 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 pulse values and the 
average should be reported. 
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• If there is a decrease in SBP ≥20 mm Hg or a decrease in DBP ≥10 mm Hg at approximately 
2 minutes of standing when compared with BP from the semirecumbent position and the 
subject is asymptomatic, semirecumbent and standing measurements may be repeated after 
the subject has remained in the semirecumbent or supine position for 15 minutes. Individual 
BP values and the average should be reported. 
• Standing assessments must not be performed if semirecumbent SBP is <85 mm Hg or if the 
subject presents with signs or symptoms suggestive of postural hypotension after standing 
(eg, lightheadedness or dizziness, nausea, blurry vision, etc). See Section 10.2.8.4.2 for 
management of symptomatic hypotension.  
9.2.4.2 
Wearable Device  
For Part 2 (MRD), subjects will be provided with a wearable device (embracePlus) at check-in 
and will be asked to wear the device on their dominant wrist daily until discharge, except when 
the device is being charged.  
The device will measure:  
1. EDA, also known as the electrodermal response (and in older terminology as “galvanic skin 
response”) is the phenomenon during which skin momentarily becomes a better conductor of 
electricity when either external or internal stimuli occur that are physiologically arousing. 
2. HR is the speed of the heartbeat measured by the number of contractions of the heart per 
minute. The HR can vary according to the body’s physical needs, including the need to 
absorb oxygen and excrete carbon dioxide, and is also modulated by other factors including 
genetics, physical fitness, stress and psychological status, diet, drugs, hormonal status, 
environment and disease/illness as well as the interaction between and among these factors.  
3. HRV is a measure of the variation in time between each heartbeat. This variation is 
controlled by the autonomic nervous system, which subconsciously regulates, among other 
things, HR, BP, breathing, and digestion. 
Raw data will be collected on embracePlus and transferred to a cell phone and will consequently 
be uploaded to a cloud storage location for further analysis. Details on the analysis of data from 
the wearable device will be provided in a separate document (Biomarker Analysis Plan).  
9.2.4.3 
Follow-up Safety Monitoring 
All subjects who terminate Part 2 or 3 of the study early 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 (AMA) form will be 
provided to the subject prior to discharge from the CRU. 
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Any subject who terminates the study early for any reason, eg, if a subject tests positive for 
COVID-19 (Point of Care or Polymerase Chain) and is required to discharge from CRU per 
policy or if a subject should leave the CRU due to unforeseen circumstances, the sponsor will be 
consulted immediately to discuss the following: 
• If the subject is asymptomatic in relation to CV symptoms but without telemetry 
observations during the postdose period, the subject could be discharged home after 
discussion with the sponsor, and with potential real-time monitoring (eg, Holter monitor, 
remote continuous telemetry monitoring and ambulatory blood pressure) for the protocol-
specified telemetry observation period. 
• If the subject is asymptomatic in relation to CV symptoms but with telemetry observations 
during the postdose period, the subject could be discharged to home after discussion with the 
sponsor. Adequate real-time monitoring (eg, Holter monitor, remote continuous telemetry 
monitoring and ambulatory blood pressure) for the protocol-specified telemetry observation 
period will be implemented and potential transfer to emergency department will be 
considered in consultation with the sponsor.  
• If the subject has CV symptoms with or without telemetry observations during the postdose 
period, the recommendation is to discuss disposition with the sponsor and potentially 
discharge to the emergency department.  
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 Appendix A). 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 at rest for at least 5 minutes with no 
physical exertion, or experiences hypotension with SBP <85 mm Hg between Day 1 (postdose) 
and discharge. If the subject experiences symptoms suggestive of hypotension, the subject should 
be instructed to lie flat, BP and HR should be re-assessed, and a 12-lead ECG should be 
performed to assess arrhythmia. The BP, HR, and ECG, measurements will be reviewed by the 
investigator, who will use clinical judgment regarding further monitoring and management. See 
Section 10.2.8.4 for management of symptomatic tachycardia or hypotension.  
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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 duration, 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 (HR and ECG) will be assessed via telemetry and will be 
performed for at least 24 hours before dosing and at least 24 hours postdose.  
Subjects should remain sitting or supine for at least 5 minutes before each telemetry reading. At 
the Hour 0 time point, telemetry may be assessed in the semirecumbent position to allow for the 
most efficient capture of the other multiple assessments. 
Telemetry data (12-lead) will be used for real-time safety monitoring to alert site staff and will 
not be recorded in the eCRF. Data will be stored for review. If an AE occurs, a 12-lead ECG 
should be collected and interpreted by the investigator as specified in Section 9.2.6.1. Real-time 
actively monitored telemetry may be limited to less than 12 leads (ie, 2 leads for real time alerts).  
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 Appendix A). 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 before 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 
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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. 
If further review of data is requested by the sponsor for safety assessment, the site investigator 
should review results and interpretation of results and determine clinical significance. Results, 
including interpretation and associated documentation should be filed in the source documents. 
The sponsor should be informed of the investigator’s review of the content filed in the source 
documents. 
Collected ECG data from 12-lead telemetry may also be used to explore the relationship with 
TAK-951 exposure. If conducted, the results from these analyses will not be included in the CSR 
but will be reported separately. 
9.2.7 
Study Drug Administration 
Study drug (TAK-951 or matching placebo) will be administered as shown in the Schedule of 
Study Procedures in Appendix A. 
9.2.8 
AE Monitoring 
AE monitoring begins after signing of the informed consent form. Changes in subject health 
status from the baseline assessment until study drug administration should be captured in the 
subject’s medical history. A complete description of AE collections and procedures is provided 
in Section 10.0. 
9.3 
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 (Appendix A). 
9.3.1 
Hematology 
Hematology will consist of the following tests: 
Erythrocytes (red blood cells [RBCs]) 
Hemoglobin 
Hematocrit 
Platelets 
Leukocytes (white blood cells [WBCs] with absolute 
differential) 
 
 
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9.3.2 
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. 
9.3.3 
Urinalysis 
Urinalysis will consist of the following tests: 
Protein 
Glucose 
Blood 
Nitrite 
Specific gravity 
 
 
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of 
RBC/high-power field, WBC/high-power field, and casts. 
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9.3.4 
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 test. A breath or 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 
Methamphetamines 
 
9.4 
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 (Appendix A). Please refer to the laboratory manual for 
information on the collection 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. If indicated, these samples may also be assayed and/or 
pooled for assay in an exploratory manner for metabolites and/or additional biomarkers. 
Primary specimen collection parameters are provided in Table 9.a. 
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Table 9.a 
Primary Specimen Collections 
Specimen Name 
Primary 
Specimen 
Primary Specimen 
Derivative 
Description of 
Intended Use 
Sample 
Collection 
Plasma sample for TAK-951 PK 
Blood 
Plasma 
PK analysis 
Mandatory 
Plasma sample for metID 
Blood 
Plasma 
metID 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; 
PK: pharmacokinetic. 
 
9.4.1 
PK Measurements  
The PK parameters of TAK-951 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-951. If conducted, these data will be reported separately and not be reported 
in the CSR. 
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PK parameters that will be determined after single dose and at steady state include, but are not 
limited to, the following: 
Symbol/Term 
Definition 
Plasma/Blood/Serum 
AUC24 
Area under the plasma concentration-time curve from the time 0 to time 24 hours.  
AUCτ 
Area under the plasma concentration-time curve during a dosing interval, where tau (τ) is 
the length of the dosing interval. 
AUClast 
Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration. 
AUC∞ 
Area under the plasma concentration-time curve from time 0 to infinity, calculated as 
AUC∞ = AUCt + Clast/λz 
Rac(AUC) 
Accumulation ratio (based on AUC), calculated as AUCτ at steady state/AUCτ after a 
single dose. 
Rac(Cmax) 
Accumulation ratio (based on Cmax), calculated as Cmax at steady state/Cmax after a single 
dose. 
Cmax 
Maximum observed plasma/blood/serum concentration. 
Cmax,ss 
Maximum observed steady-state plasma/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. 
 
Additional PK parameters may be calculated as appropriate. Additional details will be provided 
in the clinical pharmacology analysis plan. 
9.4.1.1 
Plasma for PK Measurements and Metabolite Identification 
Plasma samples for PK analysis of TAK-951 will be measured by a validated liquid 
chromatography with tandem mass spectrometry (LC/MS/MS) assay and samples 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 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. 
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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. 
9.5 
Confinement 
9.5.1 Part 1 SRD 
Subjects will report to the clinical site on Day -2. Subjects will remain in the clinic for 48 hours 
postdose (Day 3). At the discretion of the investigator, subjects may be requested to remain in 
the clinical site longer.  
9.5.2 Part 2 MRD 
Subjects will report to the clinical site on Day -2. Subjects will remain in the clinic until 
discharge on Day 7 (48 hours after last dose of study drug). At the discretion of the investigator, 
subjects may be requested to remain in the study site longer. 
9.5.3 Part 3 Dose Titration and Redosing 
Subjects will report to the clinical site on Day -2. Subjects will remain in the clinic until first 
discharge on Day 6, 24 hours after the fifth dose of study drug. Subjects will report to the clinical 
site for readmission on the evening before the scheduled day of study drug redosing. Subjects 
will remain in the clinic until final discharge, 24 hours after the single redose of study drug. 
Based on emerging safety, tolerability, and available PK data, subjects may be confined during 
the variable washout period at the discretion of the investigator in consultation with the sponsor 
and medical monitor. At the discretion of the investigator, subjects may be requested to remain 
in the study site longer. 
9.6 
Contraception and Pregnancy Avoidance Procedure 
9.6.1 
Male Subjects and Their Female Partners 
From signing of informed consent, throughout the duration of the study, and for 30 days after last 
dose of study drug, nonsterilized** male subjects who are sexually active with a female partner 
of childbearing potential* must use barrier contraception (eg, condom with or without 
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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. 
9.6.2 
Female Subjects and Their Male Partners 
From signing of informed consent, throughout the duration of the study, and for 30 days after last 
dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use a highly effective/effective method of contraception (from 
the list below).  
For studies in which teratogenicity/genotoxicity/embryotoxicity has been demonstrated (IP or 
comparator or background medication), or there is a lack of adequate reproductive toxicity data, 
female subjects should be instructed to use 2 highly effective methods of contraception/one 
highly effective and 1 effective method (from the list below).  
In addition they must be advised not to donate ova during this period. 
9.6.3 
Definitions and Procedures for Contraception and Pregnancy Avoidance 
The following definitions apply for contraception and pregnancy avoidance procedures. 
* A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high FSH level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a 
post-menopausal state in younger women (eg, those <45 years old) or women who are not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. 
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy. 
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, the only acceptable methods of contraception are:  
• Non-Hormonal Methods:  
– Intrauterine device (IUD).  
– Bilateral tubal occlusion.  
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– Vasectomized partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment of the 
surgical success.  
– Same-sex partners not utilizing assisted reproductive technology. 
• Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method (Evaluate on compound-by-compound and 
protocol-by-protocol basis and obtain clinical pharmacology justification). 
– Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months; 
• Oral. 
• Intravaginal (eg, ring). 
• Transdermal. 
– Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter until she has 
been on contraceptive for 3 months; 
• Oral. 
• Injectable. 
• Implantable. 
2. Unacceptable methods of contraception are: 
• Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods). 
• Spermicides only. 
• Withdrawal. 
• No method at all. 
• Use of female and male condoms together. 
• Cap/diaphragm/sponge without spermicide and without condom. 
• Sexual abstinence is NOT an acceptable method of contraception. 
3. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign an 
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consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study. 
4. During the course of the study, regular urine human chorionic gonadotropin (hCG) 
pregnancy tests will be performed only for women of childbearing potential and all subjects 
(male and female) will receive continued guidance with respect to the avoidance of 
pregnancy and sperm donation as part of the study procedures. Such guidance should include 
a reminder of the following: 
• Contraceptive requirements of the study. 
• Reasons for use of barrier methods (ie, condom) in males with pregnant partners. 
• Assessment of subject compliance through questions such as: 
– Have you used the contraception consistently and correctly since the last visit? 
– Have you forgotten to use contraception since the last visit?  
– Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”) 
– Is there a chance you could be pregnant? 
5. In addition to a negative serum hCG pregnancy test at screening, female subjects of 
childbearing potential must also have a negative urine hCG pregnancy test before receiving 
any dose of study medication (as close as possible and prior to first dose of study medication, 
preferably on the same day).  
9.6.4 
Pregnancy 
If any subject is found to be pregnant during the study, she must be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 30 days after the last dose, should also be 
recorded following authorization from the subject’s partner. 
If the pregnancy occurs during administration of active study drug, eg, after admission or within 
30 days after the last dose of active study drug, the pregnancy must be reported immediately, 
using a pregnancy notification form, to the contact listed in Section 1.0. 
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. Subjects randomized to placebo need not be followed. 
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). 
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All pregnancies, including female partners of male subjects, in subjects on active study drug will 
be followed up to final outcome, using the pregnancy form. Pregnancies will remain blinded to 
the study team. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted.  
9.6.5 
Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent and receive study 
treatment. Screen failures will be captured outside of the clinical database as part of the study 
source documentation.  
10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
Pretreatment Events 
A pretreatment event is defined as any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study but before administration of 
any study drug; it does not necessarily have to have a causal relationship with study 
participation. 
10.1.2 
Definition and Elements of AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. This includes any newly occurring event or a 
previous condition that has increased in severity or frequency since the administration of study 
drug. 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.) 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study drug or a concomitant medication. 
• Be considered unfavorable by the investigator for any reason. 
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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 findings are only considered to be AEs if they are 
judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory or ECG re-test and/or continued monitoring of an abnormal value or finding are 
not considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation or monitoring of an abnormality is not considered an intervention. 
• If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE. 
Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as AEs. Baseline evaluations 
(eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as AEs unless related to 
study procedures. However, if the subject experiences a worsening or complication of such a 
concurrent medical condition, the worsening or complication should be recorded 
appropriately as an AE. Investigators should ensure that the event term recorded captures the 
change in the condition (eg, “worsening of…”). 
• If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) 
any occurrence of an episode should only be captured as an AE if the condition becomes 
more frequent, serious or severe in nature. Investigators should ensure that the AE term 
recorded captures the change in the condition from baseline (eg “worsening of…”). 
• If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as an AE if occurring to a 
greater extent to that which would be expected. Investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”). 
Worsening of AEs: 
• If the subject experiences a worsening or complication of an AE after any change in study 
drug, the worsening or complication should be recorded as a new AE. Investigators should 
ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”). 
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Changes in intensity of AEs: 
• If the subject experiences changes in intensity of an AE, the event should be captured once 
with the maximum intensity recorded. 
Preplanned procedures (surgeries or interventions): 
• Preplanned procedures (surgeries or therapies) that were scheduled before signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening 
of the condition should be recorded as an AE. Complications resulting from any planned 
surgery should be reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy. 
Overdose: 
• An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to 
decide whether a dose is to be considered an overdose, in consultation with the sponsor. 
• All cases of overdose (with or without associated AEs) will be documented on an overdose 
page of the eCRF, to capture this important safety information consistently in the database. 
AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0. 
• SAEs of overdose should be reported according to the procedure outlined in Section 10.2.9. 
• In the event of drug overdose, the subject should be treated symptomatically. 
• Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be documented on an eCRF. Any manifested side effects will be 
considered AEs and will be recorded on the AE page of the eCRF. 
10.1.3 
SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
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2. Is LIFE THREATENING. 
• The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
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 10.1.2 and 10.1.3). 
10.1.4 
AEs of Special Interest  
AEs of special interest for TAK-951 include injection site reactions, hypotension, orthostatic 
tachycardia, and tachycardia. In addition, orthostatic hypotension is considered an identified risk 
based on previous clinical experience. 
10.2 
Procedures 
10.2.1 
Assigning Severity/Intensity of AEs  
All AEs, including clinically significant treatment-emergent laboratory abnormalities, will be 
graded according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 5.0 
(ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50, NIH Cancer 
Therapy Evaluation Program, Accessed 20 November 2021). AEs not listed by the NCI CTCAE 
will be graded as displayed in Table 10.a. 
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Table 10.a 
NCI CTCAE Grading Guidelines Version 5.0 
Grade 
Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal AE; an event that results in the death of the subject. 
AE: adverse event; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events. 
 
10.2.2 
Assigning Causality of AEs 
The relationship of each AE to study medication will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a 
causal relationship is at least a reasonable possibility, ie, the relationship 
cannot be ruled out, although factors other than the drug, such as underlying 
diseases, complications, concomitant drugs, and concurrent treatments, may 
also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained by other 
factors, such as underlying diseases, complications, concomitant 
medications, and concurrent treatments. 
10.2.3 
Start Date  
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator. 
10.2.4 
End Date  
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
10.2.5 
Pattern of AE (Frequency)  
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous. 
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10.2.6 
Action Taken With Study Treatment 
• Drug withdrawn – a study medication is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study medication. 
• Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
• Not applicable – a study medication was stopped for a reason other than the particular AE 
(eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE). 
• Drug interrupted – the dose was interrupted due to the particular AE. 
10.2.7 
Outcome  
• Recovered/resolved – subject returned to first assessment status with respect to the AE. 
• Recovering/resolving – the intensity is lowered by 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.” 
• Recovered/resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a CV accident but with some 
persisting paresis). 
• Fatal – an AE that is considered as the cause of death. 
Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study. 
10.2.8 
Collection and Reporting of AEs 
10.2.8.1 
AE Collection Period  
Collection of AEs (ie, AEs, SAEs, special interest AEs, 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 before the administration of study medication, AEs will be followed until the subject 
discontinues study participation.  
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10.2.8.2 
AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
SAE 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 before 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 drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event: 
1. Event term. 
2. Start and stop date and time. 
3. Pattern of AE (frequency). 
4. Severity/intensity. 
5. Causality (investigator’s opinion of the causal relationship between the event and 
administration of study drugs) (related or not related).  
6. Action concerning study drug. 
7. Outcome of event. 
8. 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. 
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The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 3.0. 
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. 
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. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
10.2.8.4 
Management of Specific AEs 
10.2.8.4.1 
Sinus Tachycardia 
CTCAE Grade  
Management 
CTCAE v5.0 Grade 2 sinus 
tachycardia (ie, Symptomatic a; 
nonurgent medical intervention 
indicated) with HR 120 and above at 
rest for at least 5 minutes with no 
physical exertion.  
Evaluate ECG for abnormalities, manage as per local guidelines and call 
the medical monitor immediately.  
 
Any CTCAE v5.0 Grade 3 sinus 
tachycardia (ie, urgent medical 
intervention indicated) or Grade 4 
(life-threatening) 
Evaluate ECG for abnormalities, manage as per local guidelines and call 
the medical monitor immediately.  
In all subjects, discontinue further treatment with study drug. 
CTCAE: Common Terminology Criteria for Adverse Events; ECG: electrocardiogram; HR: heart rate; MRD: 
multiple rising dose. 
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. 
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10.2.8.4.2 
Low BP 
If a subject develops symptoms suggestive of hypotension or postural hypotension, BP should be 
assessed for evidence of hypotension, which should be managed as per local guidelines, and the 
medical monitor should be contacted. TAK-951 administration will be discontinued on 
occurrence of an event of CTCAE v5.0 Grade ≥3 hypotension (ie, requiring medical 
intervention). 
If SBP is <85 mm Hg or if the subject is experiencing symptoms suggestive of postural 
hypotension after standing, the subject should be advised to lie flat, and BP and pulse should be 
rechecked in that position. If SBP remains <85 mm Hg, a 12-lead ECG should be performed and 
the investigator will use their clinical judgment regarding further monitoring and management. 
10.2.8.4.3 
Injection Site Reaction 
If a subject develops a CTCAE v5.0 Grade ≥2 injection site reaction (defined as pain combined 
with lipodystrophy and/or edema) discontinue administration of TAK-951, provide immediate 
treatment and contact medical monitor. 
10.2.8.4.4 
Hypersensitivity 
If anaphylaxis or other serious allergic reactions occur, TAK-951 administration will be 
discontinued immediately and appropriate management initiated (eg, epinephrine, and 
antihistamines, and further immediate care as necessary).  
AEs of special interest must be recorded as AEs in the eCRF. An evaluation form along with all 
other required documentation must be submitted to the sponsor. 
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 9.3 must also be performed. 
10.2.9 
Collection and Reporting of SAEs 
All AEs spontaneously reported by the subject or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the appropriate page of the eCRF (see Section 10.2.8 for the period of 
observation). Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as a single comprehensive event. 
Regardless of causality, SAEs must be reported (see Section 10.2.8 for the period of observation) 
by the investigator to the Takeda Global Patient Safety Evaluation department or designee within 
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24 hours of becoming aware of the event. A sample of the paper-based SAE form and processing 
directions are in the Study Manual.  
SAE Reporting Contact Information 
Fax numbers: 
United States and Canada 
+1-224-554-1052 
Email address: 
PVSafetyAmericas@tpna.com 
 
In case of fax, site personnel need to confirm successful transmission of all pages and include an 
email address on the cover sheet so that an acknowledgment of receipt can be returned via email 
within 1 business day. 
Email submission of SAE forms with a PDF attachment should only be used in the case where 
fax is not possible and EDC is not feasible within 24 hours of receiving the event. In case of 
email, site personnel need to confirm successful transmission by awaiting an acknowledgment of 
the receipt via email within 1 business day.  
If SAEs are reported via fax or by email, EDC must be updated as soon as possible with the 
appropriate information. Information in the SAE report or form must be consistent with the data 
provided on the eCRF. 
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 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. 
10.2.10 
Reporting of Abnormal Liver-Associated Test Results 
For any subject with ALT >3 × ULN AND total bilirubin >2 × ULN OR international 
normalized ratio (INR) >1.5 × ULN for which an alternative etiology has not been found, report 
the event as an SAE, contact the Medical Monitor and Takeda Trial Clinician within 24 hours, 
and follow the additional monitoring, evaluation, and follow-up recommendations in 
Appendix D. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form in an EDC 
SAE report is not feasible) or provide other written documentation and transmit it immediately 
within 24 hours of receipt. 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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10.3.1 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all SUSARs and any other applicable SAEs to 
regulatory authorities, investigators and IRBs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as expedited report within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of a study drug/sponsor supplied drug or that would be 
sufficient to consider changes in the study drug/sponsor supplied drug administration or in the 
overall conduct of the trial. The study site also will forward a copy of all expedited reports to his 
or her IRB in accordance with local regulations. 
11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 
A dose escalation meeting will be held to review the emerging data as described in Section 6.2. 
An external safety adjudication committee (ESAC) will perform a blinded review of ongoing 
cardiovascular AEs of interest throughout the conduct of the study. Details will be provided in 
the adjudication committee charter.  
12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent medical conditions will be coded using the latest 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization (WHO) Drug Dictionary. 
12.1 
CRFs 
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs. 
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.  
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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 the sponsor or its designee. The sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. 
The completed eCRFs are the sole property of the sponsor and should not be made available in 
any form to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor.  
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms (including consent to use 
digital tools and applications, if applicable), subject authorization forms regarding the use of 
personal health information (if separate from the informed (e)consent forms), electronic copy of 
eCRFs, including the audit trail, and detailed records of drug disposition to enable evaluations or 
audits from regulatory authorities, the sponsor or its designees. Any source documentation 
printed on degradable thermal sensitive paper should be photocopied by the site 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 study site agreement between 
the investigator and sponsor. 
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans  
A statistical analysis plan (SAP) will be prepared and finalized before interim analysis and 
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. 
Depending on the prevalence of COVID-19 infections in regions where the study is conducted, 
analysis may be performed to evaluate the impact of COVID-19 on the safety of all randomized 
subjects, where appropriate.  
13.1.1 
Analysis Sets 
13.1.1.1 
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. 
The safety analysis set will be used for the analyses of demographics and baseline 
characteristics, all safety endpoints, and biomarkers. 
13.1.1.2 
PK Analysis Set 
The PK analysis set consists of all subjects who receive at least 1 dose of TAK-951 and have at 
least 1 measurable postdose plasma concentration for TAK-951. Subjects will be analyzed 
according to the study treatment actually received. The PK analysis set will be used for the 
analyses of plasma concentrations and PK parameters of TAK-951. 
13.1.1.3 
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. 
Subjects will be analyzed according to the study treatment actually received. The 
immunogenicity analysis set will be used for the analyses of immunogenicity (status of subject’s 
ADA assessments). 
13.1.2 
Analysis of Demographics 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-951 dose level (Parts 1 and 2)/dose regimen 
(Part 3), and TAK-951 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 
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variables (eg, gender, ethnicity, race) will be tabulated for placebo, each TAK-951 dose level 
(Parts 1 and 2)/dose regimen (Part 3), and TAK-951 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. 
13.1.3 
PK Analysis 
The plasma concentrations of TAK-951 will be summarized by dose level (Parts 1 and 2 (BID 
and TID, separately))/dose regimen (Part 3) 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-951 determined using a noncompartmental analysis 
approach will be summarized by dose level (Parts 1 and 2 (BID and TID, separately))/dose 
regimen (Part 3) of TAK-951, 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)/dose regimen (Part 3) may be pooled across 
cohorts within each part of the study where appropriate. All data will be provided in by-subject 
listings. 
A population PK analysis may be conducted and a more detailed description of these analyses 
will be given in a separate analysis plan. The results from these analyses will not be included in 
the CSR and may be a standalone report. 
13.1.4 
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 data will be summarized descriptively by 
placebo, TAK-951 dose level (Parts 1 and 2)/dose regimen (Part 3), and TAK-951 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 clinical laboratory 
evaluations, vital signs, and ECG will be provided. 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. 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-951 by placebo, TAK-951 single dose level 
after washout, and TAK-951 single dose overall after washout. All data will be provided in by 
subject listings.  
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13.1.4.1 
AEs 
The summary of 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-951 
dose level (Parts 1 and 2)/dose regimen (Part 3), and TAK-951 overall within each part of the 
study separately. Similar summary analyses will be provided for treatment-related TEAEs, 
SAEs, AEs of special interest, and AEs leading to permanent treatment discontinuation as well. 
For Part 3 only, similar summary analyses of TEAEs will be performed for the single dose after 
washout from multiple dose regimens of TAK-951 by placebo, TAK-951 single dose level after 
washout, and TAK-951 single dose overall after washout. 
13.1.4.2 
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-951 dose level (Parts 1 
and 2)/dose regimen (Part 3), and TAK-951 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-951 
dose level (Parts 1 and 2)/dose regimen (Part 3), and TAK-951 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 washout from multiple dose regimens of TAK-951 by 
placebo, TAK-951 single dose level after washout, and TAK-951 single dose overall after 
washout. 
13.1.4.3 
Vital Signs 
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-951 dose 
level (Parts 1 and 2)/dose regimen (Part 3), and TAK-951 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 but not limited to BP) will be 
presented by placebo, each TAK-951 dose level (Parts 1 and 2)/dose regimen (Part 3), and 
TAK-951 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 washout from multiple 
dose regimens of TAK-951 by placebo, TAK-951 single dose level after washout, and TAK-951 
single dose overall after washout. 
13.1.4.4 
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-951 dose level (Parts 1 and 2)/dose regimen (Part 3), and TAK-951 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, 
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on emerging clinical data from TAK-951-1008 may be conducted. If the interim analysis is 
conducted, the interim analysis will include all available data (including, but not limited to 
TEAEs, vital signs, ECG, laboratory assessments, physical examinations, and PK). Additional 
interim analyses may be conducted for sponsor internal decision-making and would be defined in 
the SAP. The details of interim analysis (timing, datasets, and methods), data access 
management plan, and distribution of results will be described in a separate documents (ie, SAP 
and data access management plan). 
13.3 
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-951 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.  
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits will be made periodically during the study to ensure that all aspects of the 
protocol are followed. Source documents will be reviewed for verification of data recorded on 
the eCRFs. Source documents are defined as original documents, data, and records. The 
investigator and study site guarantee access to source documents by the sponsor or its designee 
(CRO) and by the IRB. 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. 
14.2 
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 will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB, as required) to determine the appropriate course of action. There 
will be no exemptions (a prospectively approved deviation) from the inclusion or exclusion 
criteria. 
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. 
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14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the United States [US] FDA, the United Kingdom 
(UK) Medicines and Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and 
Medical Devices Agency [PMDA of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator guarantees access 
for quality assurance auditors to all study documents as described in Section 14.1. 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed (e)consent and investigator responsibilities. 
15.1 
IRB  
IRBs 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 IRB. If any member of the IRB has direct participation in this 
study, written notification regarding his or her abstinence from voting must also be obtained. 
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 IRB for the 
protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB for approval. The IRB’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (eg, informed consent form) reviewed; and 
state the approval date. The sponsor will ship drug/notify site once the sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the sponsor has received 
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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. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the IRB, 
and submission of the investigator’s final status report to IRB. All IRB approvals and relevant 
documentation for these items must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor. 
15.2 
Subject Information, Informed (e)Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study, including the use of electronic devices and associated 
technologies (if applicable). The informed consent form and the subject information sheet (if 
applicable) further explain the nature of the study, its objectives, and potential risks and benefits, 
and the date informed consent is given. The informed consent form will detail the requirements 
of the participant and the fact that he or she is free to withdraw at any time without giving a 
reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form and if applicable, the subject authorization form. The informed consent form, 
subject authorization form (if applicable), and subject information sheet (if applicable) must be 
approved by both the IRB or IEC and the sponsor before use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB. 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 
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applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and before the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using a ballpoint pen with either blue or black ink in the case of written 
informed consent. The investigator must also sign and date the informed consent form and 
subject authorization (if applicable) at the time of consent or after receipt of subject signature (in 
the case of eConsent) and before the subject enters 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, or certified copy (if applicable), subject 
authorization form (if applicable), and subject information sheet (if applicable) will be 
maintained by the study site. The investigator must document the date the subject signs the 
informed consent in the subject’s medical record. Copies of the signed informed consent form, 
the signed subject authorization form (if applicable), and subject information sheet (if applicable) 
shall be provided to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form. 
Subjects who consented and provided a pharmacogenomic sample for DNA analysis can 
withdraw their consent and request disposal of a stored sample at any time before analysis. 
Notify sponsor of consent withdrawal. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject 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. 
In the event that a serious data breach is detected, the sponsor or its designee and the investigator 
(as applicable) will take appropriate corrective and preventative actions in response. These 
actions will be documented and the relevant regulatory agency(ies) will be notified as 
appropriate. Where appropriate, the relevant individuals materially affected by the breach would 
also be notified; in the case of study subjects, this would be done through the investigator. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit the monitor or the sponsor’s designee, representatives 
from any regulatory authority (eg, FDA, UK MHRA, PMDA), the sponsor’s designated auditors, 
and the appropriate IRBs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
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participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Clinical Trial Disclosures and Publication 
15.4.1 
Clinical Trial Registration and Results Disclosure 
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum, register all 
interventional clinical trials before study start and disclose the results of those trials in a manner 
and timeframe compliant with Takeda policy and all applicable laws and regulations. Clinical 
trial registration and results disclosures will occur on ClinicalTrials.gov, other clinical trial 
registries/databases as required by law, and on Takeda’s corporate website(s). 
15.4.2 
Publication  
During and after the study, only the sponsor may make study information available to other study 
investigators or to regulatory agencies, except as required by law or regulation.  
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication venue (eg, congress, journal) will appropriately 
reflect contributions to the production, review, and approval of the document.  
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
subjects. Refer to the study site agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 
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Part 3 Redosing Through Discharge, Follow-Up, and ET Assessments 
 
Refer to Table A-11 Part 3: Redosing Through Discharge, Follow-Up, and ET; QD/BID/TID for schedule of study procedures for 
redosing day through discharge. 
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Part 3 Redosing Through Discharge, Follow-Up, and ET Assessments 
 
Refer to Table A-11 Part 3: Redosing Through Discharge, Follow-Up, and ET; QD/BID/TID for schedule of study procedures for 
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Appendix B 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 who will assist in the protocol. 
3. If the investigator/institution retains the services of any individual or party to perform trial-
related duties and functions, the investigator/institution should ensure that this individual or 
party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated. 
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before 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 will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB 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, and 
issue a final report within 3 months of study completion. 
8. Ensure that requirements for informed (e)consent, as outlined in 21 CFR Part 50, ICH and 
local regulations, are met. 
9. Obtain valid informed (e)consent from each subject who participates in the study, and 
document the date of (e)consent in the subject’s medical chart. Valid informed (e)consent is 
the most current version approved by the IRB. Each informed (e)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 (e)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 
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 
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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 C 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, and 
the monitor may inspect the records. By signing an informed (e)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 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 
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subject’s 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 pharmacogenomic 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 subject authorization (either contained within the informed (e)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; 
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 drug(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. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from Screening throughout the duration of the study, and for 30 days after the last 
dose of study drug. Regular pregnancy tests will be performed throughout the study for all 
female subjects of childbearing potential. If a subject is found to be pregnant during study, 
study drug will be discontinued and the investigator will offer the subject the choice to 
receive unblinded treatment information. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed (e)consent throughout the duration of the study, and for 30 days 
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. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov. 
 
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Appendix D  Guidance on Abnormal Liver-associated Test Result Monitoring, Evaluation, 
and Follow-up 
Investigators must be vigilant for abnormal liver test results in subjects during the clinical trial. 
Transient fluctuations in serum aminotransferases occur commonly in clinical trial subjects, but 
it is crucial that the investigator identifies and evaluates subjects with possible hepatic injury. 
This guidance is intended to aid investigations of abnormal liver test results in clinical trial 
subjects who had no known liver disease and had either normal or near normal baseline liver test 
results (ie, ALT <2 × ULN, total bilirubin <1.5 × ULN, and alkaline phosphatase <1.5 × ULN) at 
the time of enrollment. 
In evaluating trial subjects with abnormal liver test results, the investigator should perform 
follow-up laboratory tests to confirm the abnormal test results and monitor the subject. If the 
abnormal liver test results are confirmed, then the subject should be monitored and, if necessary, 
additional diagnostic tests should be performed as shown in Figure 1. Suggested hepatic 
investigations are listed in Table 1. Criteria for considering discontinuation of study drug are 
shown in Figure 2.  
Subjects with Combined Elevations in Aminotransferase and Bilirubin 
If a subject has elevated ALT >3 × ULN with concurrent elevated total bilirubin >2 × ULN or 
elevated INR >1.5, the investigator must contact the Medical Monitor and Takeda Trial Clinician 
within 24 hours. Hepatic investigations as suggested in Table 1 should be initiated. Any event of 
elevated ALT ≥3 × ULN with concurrent elevated total bilirubin >2 × ULN or elevated INR >1.5 
for which an alternative etiology has not been identified must be reported as an SAE. 
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Figure 1: Abnormal Liver-associated Test Results: Monitoring and Follow-up 
§ Repeat in 3-5 days.
§ Perform follow-up laboratory tests: Complete 
blood count with differential, ALT, AST, ALP, 
GGT, total (TBIli) and direct bilirubin. 
§ If TBili ≥2x ULN, then perform INR. 
ALT ≥5x ULN 
Tbili <2x ULN
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma 
glutamyl transferase; INR, international normalized ratio; Tbili, total  bilirubin; ULN, upper limit of normal.
Treatment-emergent ALT ≥3x ULN
Abnormal Liver-Associated Test Results 
Monitoring and Follow-up 
ALT  <5x ULN 
Tbili <2x ULN
ALT ≥3x ULN 
Tbili ≥2x ULN
ALT <3x ULN 
Tbili ≥2x ULN
(ALP not elevated.)
§ Conduct hepatic 
investigation.   
(See Table 1.)
§ Consider a 
gastroenterologist 
consultation.
Continue 
monitoring.
ALT <5x ULN
ALT >5x ULN, 
rising ALT
§ Consider 
interrupting  study 
drug. 
    (See Figure 2.)  
§ Conduct hepatic 
investigation.
    (See Table 1.)
§ Consider a 
gastroenterologist 
consultation.
Continue 
monitoring.
§ Follow-up is 
essential. 
§ Contact Medical 
Monitor and 
Takeda Trial 
Clinician within 24 
hours.
§ Conduct hepatic 
investigation .
     (See Table 1.) 
§ Consider a 
gastroenterologist 
consultation.
§ Consider stopping 
study drug.  
    (See Figure 2.)  
§ Consider a 
hematologist 
consultation. 
§ Continue study 
drug.
§ Continue 
monitoring. 
 
 
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Table 1: Hepatic Investigation  
Medical History  
• 
Concomitant medications (including over-the-counter medications, such as 
acetaminophen, and herbal supplements). 
• 
Medical conditions (eg, ischemia, hypotension, severe hypoxemia, congestive 
heart failure, sepsis).  
• 
Alcohol intake.  
• 
Hepatobiliary disorder. 
• 
Previous liver disease or metabolic syndrome (eg, obesity, insulin resistance, 
diabetes, or dyslipidemia). 
• 
Travel history. 
Physical Examination 
(symptoms, signs, and 
laboratory results) 
• 
General malaise, fatigue, nausea, or vomiting. 
• 
Right upper quadrant pain or tenderness, fever, jaundice, rash. 
• 
Eosinophilia >5%. 
Hepatic/Hepatobiliary 
imaging 
Perform as appropriate (eg, abdominal ultrasound, computed tomography, 
magnetic resonance imaging, or other hepatobiliary imaging). 
Viral hepatitis serology  
 
• 
Hepatitis A antibody (total and IgM). 
• 
Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (anti-
HBs), Hepatitis B core antibody (IgM anti-HBc), Hepatitis C antibodies (anti-
HCV). 
• 
Hepatitis E (IgG and IgM). 
• 
Consider PCR for Hepatitis B, C, and E. 
• 
Consider Epstein-Barr virus serology (viral capsid antigen [VCA] nuclear 
antigen [EBNA], early antigen [EA]). 
• 
Consider cytomegalovirus serology (IgG and IgM). 
Autoimmune hepatitis 
serology 
• 
Anti-nuclear antibody (ANA). 
• 
Anti-smooth muscle antibody (ASMA). 
• 
Anti-liver-kidney microsomal antibody (anti-LKM).  
 
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Figure 2: Abnormal Liver-associated Test Results: Considerations for Study Drug 
Discontinuation  
Any of the following:
§ ALT >8x ULN at any time
§ ALT >5x ULN for >2 weeks with repeated measurements.
§ ALT ≥3x ULN AND symptoms of hepatitis and/or eosinophilia (>5%).
§ ALT ≥3x ULN AND Tbili >2x ULN OR INR >1.5 in specimens obtained on the same day.
§ Consider study drug discontinuation. 
§ Contact the Medical Monitor and Takeda Trial Clinician within 24 hours.
§ Collect additional information on symptoms, clinical signs, concomitant 
medications, recent history (including travel history), and risk factors.
§ Perform follow-up laboratory tests:  ALT, AST, ALP, GGT, total and direct bilirubin, 
CPK, and INR.
§ Perform hepatic investigation. (See Table 1.)
§ Perform additional diagnostic follow-up tests including hepatobiliary imaging as 
appropriate. 
§ Consider consultation with a gastroenterologist or hepatologist. 
§ Any event of ALT ≥3x ULN AND Tbili >2x ULN OR INR >1.5  for which an alternative 
etiology has not been found should be reported  as an SAE and additional information 
on hepatic investigation provided.  
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, 
creatine phosphokinase; GGT, gamma glutamyl transferase; INR, international normalized ratio; Tbili, 
total bilirubin; ULN, upper limit of normal.
Abnormal Liver-Associated Test Results  
Considerations for  Study Drug Discontinuation
Follow abnormal liver-associated test results until resolution or return to baseline. 
 
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Appendix E  Protocol History 
Date 
Amendment Number 
Amendment Type 
Region 
16 March 2023 
Amendment 2 
Substantial 
United States 
24 January 2023 
Amendment 1 
Substantial 
United States 
23 November 2021 
Initial protocol 
Not applicable 
United States 
 
Protocol Amendment 1 Summary and Rationale: 
The primary reasons for this amendment are:  
• Study design modified to be sponsor-open; the study remains blinded to investigators, study 
site staff, and subjects. 
• Removal of the 0.5 hour timepoint for assessing orthostatic vital signs (standing blood 
pressure and pulse) on Day 1 of Parts 1, 2 and 3. 
• Addition of early termination remote monitoring safety measures. 
• Addition of a safety step to reduce the risk of syncope while comprehensively assessing 
semirecumbent and standing vital signs.  
• Addition of steps to reduce the risks of orthostatic vital signs as follows: 
– Require subjects to be supine/semirecumbent for the first 2 hours after dosing. 
– Implementation of an external safety adjudication committee before reinitiating dosing. 
– Use of a modified orthostatic challenge whereby subjects will be semirecumbent for 
5 minutes; then, after semirecumbent vital signs are recorded, they will sit for 3 minutes 
with legs crossed, then stand for 2 minutes before collecting vital signs in this position. 
• Clarification of timing of the proposed interim analysis. 
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. 
Title page 
Section 2.0 STUDY 
SUMMARY 
Wording “sponsor-open” was 
added to the protocol title. 
The protocol title was updated 
because the study has been 
modified to sponsor-open. 
2. 
Section 2.0 STUDY 
SUMMARY 
Section 6.1 Study Design 
Section 6.2 Dose Escalation 
Section 6.4.1 Justification for 
Added language to modify 
the study to sponsor open. 
The study design is modified to 
sponsor-open for oversight of 
the study for efficient evaluation 
of study data in an unblinded 
manner. The study remains 
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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  
Study Design 
Section 8.3 Randomization Code 
Creation and Storage 
Section 8.4 Blinding 
blinded to investigators, study 
site staff, and subjects. 
3. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion Criteria 
Added “semirecumbent” to 
exclusion criteria #16. 
To clarify that this criteria is for 
semirecumbent, and not standing 
measurements. 
4. 
Section 6.3 Study Drug 
Administration 
Appendix A Schedules of Study 
Procedures 
Parts 1, 2, and 3 – removal of 
standing blood pressure and 
pulse measurement at the 0.5 
hour timepoint on Day -1 and 
Day 1.  
Additional risk mitigation for 
prevention of syncope. 
Removal of the 0.5 hour post-
dose orthostatic challenge 
addresses the observation that 
symptomatic orthostatic adverse 
events mainly take place before 
the 2 hour assessment timepoint.  
5. 
Section 9.2.4 Vital Sign 
Procedure 
Section 9.2.4.1 Orthostatic 
Measurements 
Appendix A Schedules of Study 
Procedures 
Use of a modified orthostatic 
challenge: Subjects will be 
semirecumbent for 5 
minutes; then, after 
semirecumbent vital signs are 
recorded, they will sit for 3 
minutes with legs crossed, 
then stand for 2 minutes 
before collecting vital signs. 
Takeda proposes an additional 
safety step to reduce the risk of 
syncope while comprehensively 
assessing semirecumbent and 
standing vital signs. 
6. 
Section 9.2.4.3 Follow-up Safety 
Monitoring 
Addition of early termination 
remote monitoring safety 
measures. 
To ensure that telemetry 
monitoring is provided for the 
confinement period outlined in 
the protocol even if the subject 
early terminates. 
7. 
Section 9.2.6 ECG Procedure 
QRS interval changed to 
QRS duration. 
Wording change  
8. 
Section 9.3.3 Urinalysis 
Urinalysis nitrite rather than 
nitrate will be determined. 
Correction of typographical 
error. 
9. 
Section 9.6.5 Documentation of 
Screen Failure 
Clarification that screen 
failures will be captured 
outside of the clinical 
database as part of the study 
source documentation. 
Clarification of where screen 
failures will be reported. 
10. 
Section 10.2.9 Collection and 
Reporting of SAEs 
Updated SAE form language. 
Updated language for accuracy. 
11. 
Section 11.0 STUDY-SPECIFIC 
COMMITTEES 
Inclusion of an external 
safety adjudication 
Takeda determined that an 
external safety event 
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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  
committee that will review 
ongoing CV adverse events 
during the conduct of study. 
adjudication committee is an 
appropriate additional risk 
mitigation and assessment step, 
which is therefore added in this 
protocol to be specified in the 
charter for the external safety 
adjudication committee. 
12. 
Section 13.2 Interim Analysis 
Clarification of timing of 
proposed interim analysis. 
Updates to the plan for 
interim analysis and 
clarification of the potential 
timing of the interim 
analysis. 
To update the plan of the interim 
analysis and clarify its potential 
timing. 
 
 
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