Clinical trial NCT04486950
Conditions: Healthy Volunteer
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2020-07-07; Completion date: 2021-05-27
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
It is hoped that a medicine called TAK-951 will eventually be used to treat nausea and vomiting. Before then, the sponsor needs to understand how the body processes TAK-951 in healthy adults.

The main aims of this study are as follows:

* To check for side effects from TAK-951 when given at a slow and fast infusion rate.
* To learn how much TAK-951 participants can receive without getting side effects from it.

Participants will receive a single infusion of either TAK-951 or placebo. In this study, a placebo looks like TAK-951 but does not have any medicine in it. Participants will receive either a low dose or high dose of TAK-951. The infusion will take from 1-3 hours.

Participants will stay in the study clinic for about 4 days to receive the study medicine (TAK-951 or placebo) and check for side effects. They will have follow-up visits at the clinic about 2 weeks and 4 weeks after treatment.

Detailed description:
The drug being tested in this study is called TAK-951. The study will evaluate the safety, tolerability and PK of TAK-951 in healthy participants.

The study will enroll approximately 40 healthy participants. Each cohort will have 8 participants to be randomized and a minimum of 3 cohorts will be evaluated. Participants will be randomly assigned (by chance, like flipping a coin) to receive TAK-951 or placebo in a 6:2 ratio in one of the following 3 cohorts, which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Cohort 1 (Low Dose): TAK-951 20 mcg Infusion Over 60 Minutes
* Cohort 2 (High Dose): TAK-951 1 mg Infusion Over 60 Minutes
* Cohort 3: TAK-951 1 mg Infusion over 120 Minutes

Sentinel dosing will be done in first 2 participants in each cohort. The dosing in rest of the cohort will done if there are no significant safety or tolerability concerns. Additional 2 cohorts, each cohort with 8 participants may be added in study to evaluate additional intravenous dosing regimen after clinical data analysis of first 3 cohorts. Dosing of the subsequent cohort will be based on the analysis of the previous cohort's data.

This single-center trial will be conducted in the United States. The overall time to participate in this study is up to 57 days. All participants will return to clinic after 14 and 28 days after the last visit to the clinic for a follow-up assessment.

Arms: arm 1: TAK-951 20 microgram (mcg) or TAK-951 placebo-matching, infusion, intravenously, over a period of 60 minutes on Day 1. arm 2: TAK-951 1 milligram (mg) or TAK-951 placebo-matching, infusion, intravenously, over a period of 60 minutes on Day 1. Dose level will be determined based on safety, tolerability and PK data from previous cohorts. arm 3: TAK-951 1 mg or TAK-951 placebo-matching, infusion, intravenously, over a period of 120 minutes on Day 1. Dose level will be determined based on safety, tolerability and PK data from previous cohorts.
Interventions: intervention 1: TAK-951 intervention 2: TAK-951 Placebo
Intervention descriptions: intervention 1: TAK-951 intravenous infusion. intervention 2: TAK-951 placebo-matching intravenous infusion.

Protocol documents:
Prot_000.pdf: 



Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects Following Intravenous 
Administration
NCT Number: NCT04486950
Protocol Approve Date: 8 January 2021
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects Following Intravenous 
Administration
Study Identifier:
TAK-951-1004
Compound:
TAK-951
Date:
08 January 2021
Version/Amendment 
No.
2
Amendment History:
Date
Amendment Number
Type
Region
08 January 2021
1
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Study ID TAK-951-1004
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................12
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................13
3.1
Cohorts 1 and 2 and any Cohort with an Infusion less than or Equal to 60 Minutes..13
3.2
Cohort 3 and any Cohort with an Infusion greater than 60 Minutes ..........................17
4.0
INTRODUCTION.........................................................................................................22
4.1
Background .............................................................................................................22
4.2
Rationale for the Proposed Study.............................................................................22
4.3
Benefit/Risk Profile .................................................................................................23
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................24
5.1
Study Objectives......................................................................................................24
5.1.1
Study Primary Objective..................................................................................24
5.1.2
Study Secondary Objectives.............................................................................24
5.1.3
Study Exploratory Objective............................................................................24
5.2
Endpoints.................................................................................................................24
5.2.1
Primary Endpoint.............................................................................................24
5.2.2
Secondary Endpoints .......................................................................................24
5.2.3
Exploratory Endpoint.......................................................................................25
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................25
6.1
Study Design ...........................................................................................................25
6.2
Dose Escalation .......................................................................................................27
6.3
Stopping Rules.........................................................................................................27
6.4
Rationale for Study Design, Dose, and Endpoints ....................................................27
6.4.1
Rationale of Study Design ...............................................................................27
6.4.2
Rationale for Dose...........................................................................................28
6.4.3
Rationale for Endpoints ...................................................................................28
6.4.4
Future Biomedical Research ............................................................................29
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures ............29
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................29
6.6
Study Beginning and End/Completion .....................................................................30
6.6.1
Definition of Beginning of the Study ...............................................................30
6.6.2
Definition of End of the Study.........................................................................30
6.6.3
Definition of Study Completion.......................................................................30
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Study ID TAK-951-1004
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6.6.4
Definition of Study Discontinuation.................................................................30
6.6.5
Criteria for Premature Termination or Suspension of the Study........................30
6.6.6
Criteria for Premature Termination or Suspension of a Site..............................30
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............30
7.1
Inclusion Criteria .....................................................................................................30
7.2
Exclusion Criteria ....................................................................................................31
7.3
Excluded Medications, Supplements, Dietary Products............................................33
7.4
Diet, Fluid, Activity.................................................................................................33
7.4.1
Diet and Fluid..................................................................................................33
7.4.2
Activity ...........................................................................................................34
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................34
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................35
7.7
Subject Replacement................................................................................................35
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................35
8.1
Clinical Study Drug .................................................................................................35
8.1.1
Clinical Study Drug Labeling ..........................................................................35
8.1.2
Clinical Study Drug Inventory and Storage......................................................35
8.1.3
Clinical Study Drug Blinding...........................................................................36
8.1.4
Randomization Code Creation and Storage......................................................36
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure.................................36
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.............................36
9.0
STUDY PROCEDURES...............................................................................................37
9.1
Administrative Procedures.......................................................................................37
9.1.1
Informed Consent Procedure............................................................................37
9.1.2
Inclusion and Exclusion...................................................................................37
9.1.3
Medical History/Demography..........................................................................37
9.1.4
Concomitant Medications ................................................................................37
9.2
Clinical Procedures and Assessments.......................................................................37
9.2.1
Physical Examination ......................................................................................38
9.2.2
Height and Weight...........................................................................................38
9.2.3
Body Mass Index.............................................................................................38
9.2.4
Vital Signs.......................................................................................................38
9.2.5
12-Lead ECG...................................................................................................39
9.2.6
Cardiodynamic ECGs ......................................................................................40
9.2.7
Telemetry ........................................................................................................40
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Study ID TAK-951-1004
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9.2.8
Study Drug Administration..............................................................................40
9.2.9
AE Monitoring ................................................................................................41
9.2.10
Laboratory Procedures and Assessments..........................................................41
9.3
Pharmacokinetic Samples ........................................................................................42
9.3.1
PK Measurements............................................................................................43
9.3.2
Immunogenicity Measurements .......................................................................44
9.3.3
Biomarker Measurements ................................................................................44
9.3.4
PGx Measurements..........................................................................................44
9.3.5
Confinement....................................................................................................44
10.0
ADVERSE EVENTS ....................................................................................................45
10.1
Definitions and Elements of AEs .............................................................................45
10.1.1
SAEs ...............................................................................................................47
10.1.2
Special Interest AEs.........................................................................................48
10.2
AE Procedures.........................................................................................................48
10.2.1
Assigning Severity/Intensity of AEs ................................................................48
10.2.2
Assigning Causality of AEs .............................................................................49
10.2.3
Start Date.........................................................................................................49
10.2.4
End Date..........................................................................................................49
10.2.5
Pattern of Adverse Event (Frequency)..............................................................49
10.2.6
Action Taken With Study Treatment................................................................49
10.2.7
Outcome..........................................................................................................50
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, LFTs and ADA
........................................................................................................................50
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...53
11.0
STATISTICAL METHODS..........................................................................................53
11.1
Statistical and Analytical Plans ................................................................................53
11.1.1
Analysis Sets ...................................................................................................54
11.1.2
Analysis of Demography and Other Baseline Characteristics ...........................54
11.1.3
PK Analysis.....................................................................................................54
11.1.4
PK/PD Analysis...............................................................................................54
11.1.5
Immunogenicity Analysis ................................................................................54
11.1.6
Safety Analysis................................................................................................55
11.2
Interim Analysis and Criteria for Early Termination ................................................55
11.3
Determination of Sample Size..................................................................................56
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................56
12.1
Study-Site Monitoring Visits ...................................................................................56
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12.2
Protocol Deviations..................................................................................................56
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................56
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................57
13.1
IRB and/or IEC Approval ........................................................................................57
13.2
Subject Information, Informed Consent, and Subject Authorization .........................58
13.3
Subject Confidentiality ............................................................................................59
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................59
13.4.1
Publication and Disclosure...............................................................................59
13.4.2
Clinical Study Registration ..............................................................................60
13.4.3
Clinical Study Results Disclosure ....................................................................60
13.5
Insurance and Compensation for Injury....................................................................60
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................60
14.1
Administrative Information......................................................................................60
14.1.1
Study Contact Information...............................................................................60
14.1.2
INVESTIGATOR AGREEMENT ...................................................................61
14.1.3
Study-Related Responsibilities.........................................................................62
14.1.4
List of Abbreviations .......................................................................................62
15.0
DATA HANDLING AND RECORDKEEPING............................................................64
15.1
CRFs (Electronic and Paper)....................................................................................64
15.2
Record Retention .....................................................................................................64
16.0
REFERENCES..............................................................................................................65
17.0
APPENDICES...............................................................................................................66
LIST OF IN-TEXT TABLES
Table 6.a
Planned Dose Levels of TAK-951......................................................................26
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................33
Table 9.a
Primary Specimen Collections ...........................................................................43
Table 10.a
Takeda Medically Significant AE List................................................................48
Table 10.b
NCI CTCAE ......................................................................................................48
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................66
Appendix B
Elements of the Subject Informed Consent.........................................................68
Appendix C
Investigator Consent to the Use of Personal Information ....................................71
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Study ID TAK-951-1004
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Appendix D
Pregnancy and Contraception.............................................................................72
Appendix E
Detailed Description of Amendments to Text.....................................................73
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Study ID TAK-951-1004
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc, (TDC Americas)
95 Hayden Avenue
Lexington, Massachusetts USA 02421
Telephone: +
Compound:
TAK-951
Study Identifier: TAK-951-1004 
Phase: 1
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects Following Intravenous Administration
Study Design:
This is a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of TAK-951 administered intravenously in healthy adult subjects.
At least 3 cohorts of 8 subjects each will be dosed sequentially. Subjects from each cohort will be admitted into the 
clinical research unit (CRU) on Day -2. On Day -1 baseline heart rate and blood pressure assessments will be taken, 
time-matched to the Day 1 assessments. Subjects will receive a single dose with TAK-951 or matching placebo on 
Day 1, according to the randomization scheme, after a minimum of 8 hours of fasting. Subjects will be randomized to 
receive TAK-951 or matching placebo in a 6:2 ratio in a double-blind manner. Pharmacokinetic samples will be taken 
up to 30 hours after the start of infusion. Subjects will be discharged after the completion of the study assessments on 
Day 2. 
All subjects who received any amount of study drug (including subjects who terminate the study early) will return to 
the CRU 14 (±2) and 28 (±3) days after dosing for follow-up procedures, and to determine if any adverse event (AE) 
has occurred since the last study visit. 
Subjects may be admitted earlier than Day -2 for COVID-19 testing not related to study protocol as per clinical study 
unit requirements.
Dosing regimen for each cohort: 
Cohort 1: a low dose (20 μg) TAK-951 or placebo administered as a 60-minute intravenous (IV) infusion on 
Day 1,
Cohort 2: a high dose (1.0 mg) TAK-951 or placebo administered as a 60-minute IV infusion on Day 1,
Cohort 3: 1.0 mg TAK-951 or placebo administered as a 120-minutes IV infusion on Day 1.
Two (2) dose levels will allow assessment of the PK/pharmacodynamic (PD) relationship between exposure and heart 
rate and blood pressure (ie, semi-recumbent heart rate increase, blood pressure decrease, and orthostatic vital sign 
changes [orthostatic heart rate increase and orthostatic blood pressure decrease]) and will support development of an 
IV dosage form in the future if deemed necessary.
Two (2) additional cohorts may be enrolled (for a total of 5 cohorts), each cohort with 8 subjects, to explore additional 
IV dosing regimens. In total the enrollment will be up to approximately 40 subjects. Dosing regimen of the subsequent 
cohort will be based on the analysis of the previous cohort’s data.
For Cohort 4 and 5, as applicable, PK sampling and time-matched vital sign assessments scheduled relative to infusion 
timing will be based on emerging clinical data analysis. As such, this timing will be provided in a separate document 
and will not exceed 30 hours post start of infusion. The number of planned PK and vital sign assessments may be less 
than or equal to those in the protocol.
A staggered dosing approach will be used. The sentinel subjects will be dosed at least 24-hours before the remaining 
6 subjects in each cohort. In each cohort, after dosing the first 2 subjects (the sentinel group – 1 receiving TAK-951 
and 1 receiving placebo) the Investigator will review all available blinded safety and tolerability data up to 8 hour 
post-dose. If after dosing the sentinel group, the Investigator and the Sponsor agree that there are no significant 
safety/tolerability concerns, then the rest of the cohort will be dosed. There will be at least 1 hour between dosing of 
each subject in each cohort, except for the sentinel subjects. A dose-escalation/blinded safety review meeting will be 
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TAK-951
Study ID TAK-951-1004
Page 8 of 78
Protocol Incorporating Amendment No. 1
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held between the Investigator and Sponsor after each cohort is completed to review the safety and available PK data 
from samples taken up to 1-day post-dose, in order to confirm the dose level and/or infusion rate for the subsequent 
cohort. PK data from the first low dose cohort is required to allow dosing of the high dose for the second and third 
cohorts and the determination of the rate of infusion for the third cohort. The dose and the infusion rate for Cohorts 4 
and 5 will be selected based on emerging clinical data analysis and is not expected to exceed the highest exposures 
seen in the first in human (FIH) TAK-951-1001 study. 
Sponsor is to remain blinded during the review of available safety and PK data. Once a decision is made to proceed to 
the next cohort, the Sponsor may be unblinded following dose escalation/safety meetings to allow additional analysis.
Cohort 4 and 5 may run concurrently, sequentially or be omitted and will not exceed the highest exposure observed in 
the FIH study.
Safety will be assessed by monitoring for AEs, vital signs, safety 12-lead electrocardiograms (ECG)s/telemetry, safety 
laboratory assessments, and physical examinations throughout the study. 
Immunogenicity will be assessed prior to dosing and approximately 14 and 28 days after dosing.
Study Primary Objective:
To evaluate the overall safety and tolerability of a single IV infusion of TAK-951 administered with at least 2 different 
infusion rates (rapid and slow) at the same dose level in healthy subjects.
Secondary Objectives:
To assess the PK of TAK-951 following a single IV infusion of TAK-951 in healthy subjects.
To assess for anti-drug antibodies following a single IV infusion of TAK-951 in healthy subjects.
Study Subject Population: Healthy male and female (non-childbearing potential only) subjects aged 19 to 55 years 
inclusive, at screening. Body Mass Index (BMI) 18.0-32.0 kg/m2, inclusive, at screening.
Planned Number of Subjects:
Up to 40 subjects and up to 5 cohorts
Eight (8) subjects per cohort
At least 3 cohorts are planned for this study. Cohorts 4 
and 5 may be added based on emerging clinical data 
analysis from this study.
Planned Number of Sites:
1
Dose Levels:
Cohort 1: 20 μg infusion of TAK-951 or matching 
placebo, 60-minute IV on Day 1
Cohort 2: 1.0 mg infusion of TAK-951 or matching 
placebo, 60-minute IV on Day 1
Cohort 3: 1.0 mg infusion of TAK-951 or matching 
placebo, 120-minute IV on Day 1
If dosed, Cohorts 4 and 5 dose(s) of TAK-951 and 
infusion rate(s) of TAK-951 and placebo will be 
decided based on the emerging clinical data analysis of 
the previous cohorts. 
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Study ID TAK-951-1004
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Duration of Treatment:
Cohort 1: a single IV infusion over a 60-minute 
infusion
Cohort 2: a single IV infusion over a 60-minute 
infusion
Cohort 3: a single IV infusion over a 120-minute.
If dosed, the treatment duration(s) for Cohorts 4 and 5 
will be decided based on the emerging clinical data
analysis from the previous cohorts.
Planned Study Duration:
Approximately 57 days from screening until last follow-up 
visit.
Criteria for Inclusion:
In order to be eligible for study participation, subjects must: 
1.
Healthy, adult, male or female (of non-childbearing potential only), 19-55 years of age, inclusive, at screening.
2.
Continuous non-smoker who has not used nicotine- and tobacco-containing products and/or cannabis products for 
at least 3 months prior to dosing and throughout the study. 
3.
Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2 at screening. 
4.
Medically healthy based on no clinically significant medical history, physical examination, laboratory profiles, 
vital signs or ECGs, as deemed by the Investigator or designee.
5.
Female must be of non-childbearing potential as described in Appendix D.
6.
A non-vasectomized, male subject must agree to use a barrier contraception (eg, condom with spermicide) or 
abstain from sexual intercourse from dosing and until 90 days after dosing. No restrictions are required for a 
vasectomized male provided his vasectomy has been performed 4 months or more prior to dosing of study drug. A 
male who has been vasectomized less than 4 months prior to dosing must follow the same restrictions as a 
non-vasectomized male (see Appendix D).
7.
If male, must agree not to donate sperm from dosing until 90 days after dosing.
8.
Understands the study procedures in the informed consent form (ICF) and be willing and able to comply with the 
protocol.
Criteria for Exclusion:
Subjects must not be enrolled in the study if they meet any of the following criteria:
1.
Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
Has a documented history of any clinically significant disorders, including psychiatric, cardiovascular, 
nephrological, neurological, metabolic, or gastrointestinal disease. 
3.
History of any illness that, in the opinion of the Investigator or designee, might confound the results of the study 
or poses an additional risk to the subject by their participation in the study.
4.
History or presence of alcoholism or drug abuse within the past 2 years prior to dosing.
5.
Drink alcohol in excess of 21 glasses/units per week for males or 14 glasses/units per week for females, with one 
unit = 150 mL of wine or 360 mL of beer or 45 mL of 45% alcohol.
6.
History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds.
7.
Have any tattoos, scars or skin issue at planned IV infusion site which could interfere with dosing.
8.
History or presence of:

Three (3) or more incidences of vasovagal syncope within the last 5 years prior to screening.

Family history of unexplained sudden death or channelopathy.

Brugada syndrome (ie, right bundle branch block [RBBB] pattern with ST-elevation in leads V1-V3).

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 QTcF interval, hypokalemia, 
hypomagnesemia, or conduction abnormalities;

Risk factors for Torsade de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT 
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Study ID TAK-951-1004
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Syndrome);

Any clinically significant ECG findings or medical history including: long or short QT interval with 
Fridericia correction method (QTcF) (over 450 milliseconds [msec] or less than 360 msec), bifascicular 
block or QRS ≥120 msec or PR interval >200 msec at screening or Day -1 pre-Hour 0.

Documented history of sinoatrial block or sinus pause ≥3 seconds. 
9.
Semi-recumbent blood pressure (average of duplicate) is less than 90/60 mmHg or greater than 140/90 mmHg at 
screening.
10. Has an average semi-recumbent heart rate <60 or >100 bpm (at screening, at Day -1 pre-Hour 0, or at pre-dose 
Day 1); athletic subjects with an average semi-recumbent heart rate <60 bpm can be enrolled only with medical 
monitor approval. If subject has heart rate <60 bpm Investigator should obtain medical approval from Sponsor.
11. Has orthostatic hypotension defined as a decrease in systolic blood pressure ≥20 mmHg or a decrease in diastolic 
blood pressure ≥10 mmHg after 2 minutes of standing when compared with blood pressure from the 
semi-recumbent position at screening and at Day -1 pre-Hour 0. The semi-recumbent blood pressure will be an 
average of duplicate measurements. 
12. Has postural orthostatic tachycardia, defined as an increase of 30 bpm or heart rate >120 bpm after standing for 2 
minutes.
13. Female subjects of childbearing potential.
14. Female subjects with a positive pregnancy test or who is lactating.
15. Positive urine drug or alcohol results at screening or check-in.
16. Positive urine cotinine at screening or check-in.
17. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or 
hepatitis C virus (HCV).
18. Unable to refrain from or anticipates the use of any drug, including prescription and non-prescription medications, 
herbal remedies, or vitamin supplements beginning 14 days prior to dosing and throughout the study. Thyroid 
hormone replacement medication may be permitted if the subject has been on same stable dose for the last 
3 months prior to study drug administration. After dosing, acetaminophen (up to 2 g per 24 hours) may be 
administered at the discretion of the Investigator or designee. Hormone replacement therapy will also be allowed.
19. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 
30 days prior to dosing and throughout the study.
20. Donation of blood or significant blood loss within 56 days prior to dosing.
21. Plasma donation within 7 days prior to dosing.
22. Participation in another clinical study within 30 days prior to dosing. The 30-day window will be derived from the 
date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of the current study.
23. Positive results for Coronavirus disease 2019 (COVID-19) testing at screening or check-in.
Criteria for Evaluation and Analyses:
Primary Endpoint:
The primary endpoint of the study is safety and tolerability as assessed through AEs,vital signs, safety 
ECGs/telemetry, safety laboratory assessments, and physical examinations.
Secondary Endpoints:
The secondary endpoints will be assessed through evaluation of the following parameters: 
Pharmacokinetic parameters:

Area under the TAK-951 plasma concentration time curve from time 0 to infinity (AUC∞).

TAK-951 plasma concentration at end of infusion (Ceoi).

Area under the TAK-951 plasma concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast). 

Terminal disposition phase half-life (t½z).

Terminal disposition phase rate constant (λz).
Immunogenicity:
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TAK-951
Study ID TAK-951-1004
Page 11 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
!
Anti-drug antibodies titer.
Statistical Considerations:
The safety analysis set will consist of all subjects who are enrolled and receive full or partial dose of study drug or 
placebo. The PK analysis set will consist of all subjects who received the active study drug and have at least one 
measurable plasma concentration of TAK-951. 
Safety summaries will be based on the safety analysis set. All safety data including AEs, clinical laboratory tests, vital 
signs, and ECG will be summarized using descriptive statistics. No formal statistical tests or inference will be 
performed for safety analyses. All summaries will be performed by treatment (cohort) and pooled placebo (placebos 
pooled from all cohorts).
The plasma concentrations of TAK-951 will be summarized by TAK-951 dose and infusion rate over each scheduled 
sampling time, using descriptive statistics. The PK parameters of TAK-951 will be determined from the 
concentration-time profiles for all evaluable subjects using noncompartmental analysis approach. Actual sampling 
times, rather than scheduled sampling times, will be involved in the derivation of PK parameters. Additional PK 
parameters may be calculated as appropriate. Further details will be specified in the statistical analysis plan (SAP).
Plasma PK parameters of TAK-951 will be calculated and summarized as detailed in the Clinical Pharmacology 
Analysis Plan (CPAP).
The relationship of time-matched TAK-951 exposure and PD effects (ie, semi-recumbent heart rate and blood pressure 
changes and orthostatic vital sign changes) will be assessed.
Sample Size Justification: 
Up to approximately 40 adult subjects (8 per cohort) are planned to be randomized. A formal sample size calculation 
was not performed for this study. The current sample size is deemed appropriate to evaluate the safety, tolerability, 
PK, and PD of TAK-951 following IV administration. A minimum of 3 cohorts will be evaluated.
CCI
Property of Takeda: For Non-Comme
mercial Use 
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TAK-951
Study ID TAK-951-1004
Page 12 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
2.0
STUDY SCHEMATIC
Study schematic per cohort. Dosing of subsequent cohorts is based on dose escalation criteria as listed in Section 6.2. 
Within a cohort, sentinel subjects will be dosed at least 24 hours before the remaining subjects. There will be at least 1 
hour between dosing of each subject in each cohort, except for the sentinel.
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TAK-951
Study ID TAK-951-1004
Page 13 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES 
3.1
Cohorts 1 and 2 and any Cohort with an Infusion less than or Equal to 60 Minutes
Study Procedures a)
Scr b)
Study Days
Days →
-2
-1
Hours →
C-I e)
Pre
0
0.083
0.17
0.25
0.5
1
(EOI) 
f)
1.25
1.5
2
4
8
12
Hour:Minutes →
0
0:05
0:10
0:15
0:30
1:00
1:15
1:30
2:00
4:00
8:00
12:00
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Safety Evaluations 
Full Physical Examination g)
X
X
Height 
X
Weight and BMI
X
X
12-Lead Safety ECG (triplicate)
X
X h)
Vital Signs (HR) i)
X
X
Vital Signs (HR and BP) i)
X
X
X
X
X
X
Orthostatic Vital Signs (HR and BP) j)
X
X h)
X
X
X
X
Vital Signs (RR and T)
X
Hem and Serum Chem l)
X
X
Urinalysis
X
X
Serum Pregnancy Test (females only)
X
X
Serum FSH (PMP females only)
X
Urine Drug and Alcohol Screen
X
X
Urine Cotinine Screen
X
X
HIV/Hepatitis Screen m)
X
AE Monitoring
X
X
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TAK-951
Study ID TAK-951-1004
Page 14 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
CONFIDENTIAL
Study Procedures a)
Scr b)
Study Days
Days →
-2
-1
Hours →
C-I e)
Pre
0
0.083
0.17
0.25
0.5
1
(EOI) 
f)
1.25
1.5
2
4
8
12
ConMeds Monitoring
X
X
Other Procedures
Confinement in the CRU
X
Visit
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1004
Page 15 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
CONFIDENTIAL
Study Procedures a)
Study Days
FU d)
Days →
1
2
ET c)
Day 15 
(±2)
Day 29
(±3)
Hours →
Pre
0
0.083
0.17
0.25
0.5
1
(EOI) f)
1.25
1.5
2
4
8
12
24
30
Hour:Minutes →
0
0:05
0:10
0:15
0:30
1:00
1:15
1:30
2:00
4:00
8:00
12:00
24:00
30:00
Safety Evaluations 
Full Physical Examination g)
X
X
12-Lead Safety ECG 
(triplicate)
X h)
X
X
Vital Signs (HR) i)
X
X
Vital Signs (HR and BP) i)
X
X
X
X
X
X
X
X
Orthostatic Vital Signs (HR 
and BP) j)
X h)
X
X
X
X
X
Telemetry k)
X
Hem and Serum Chem l)
X
X
X
Urinalysis
X
X
Serum Pregnancy Test 
(females only)
X
X
AE Monitoring
X
X
X
ConMeds Monitoring
X
X
X
Study Drug Dosing / PK
TAK-951 IV or Matching 
Placebo Dosing n)
X
Blood for TAK-951 PK o)
X
X
X
X
X
X p)
X p)
X
X
X
X
X
X
X
X
Other Procedures
Holter Monitoring q)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA
X
X
X
X
Confinement in the CRU
X
Return Visits
X
X
a)
For details on Procedures, refer to Section 9.0.
b)
Within 28 days prior to dosing.
c)
To be performed prior to early termination from the study.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1004
Page 16 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
CONFIDENTIAL
Study Procedures a)
Study Days
FU d)
Days →
1
2
ET c)
Day 15 
(±2)
Day 29
(±3)
Hours →
Pre
0
0.083
0.17
0.25
0.5
1
(EOI) f)
1.25
1.5
2
4
8
12
24
30
d)
All subjects who received any amount of study drug (including subjects who terminate the study early) will return to the CRU 14 (±2) and 28 (±3) days after dosing for 
follow-up procedures, and to determine if any AE has occurred since the last study visit.
e)
Subjects will be admitted to the CRU on Day -2, at the time indicated by the CRU. In accordance with local regulatory guidance for the COVID-19 pandemic, the clinical study 
unit will implement standard COVID-19 procedures as per their internal guidance documents. Subjects may be admitted earlier than Day -2 for COVID-19 testing not related to 
study protocol as per CRU requirements.
f)
A sample will be obtained at the end of infusion for each cohort. For Cohorts 1 and 2, end of infusion time point will be 1 hour, events listed at the 1 hour timepoint and the EOI 
timepoint will only be performed once. The study events at the end of infusion will proceed in this order: blood samples, vital signs, safety ECGs, and Holter ECGs, meals and 
snacks.
g)
Symptom-driven physical examination may be performed at other times, at the Investigator’s or designee’s discretion.
h)
To be performed within 2 hour prior to Hour 0.
i)
All blood pressure and heart assessments should be made in duplicate, and the average of both assessments should be used to calculate the final result. The Investigator can take 
a third measurement if there is inconsistency between assessments. Day -1 time points will time-matched (± 5 minutes) to the Day 1 clock time (ie, time-matched baseline).
j)
For orthostatic vital signs, a blood pressure and heart rate assessment will be performed after the duplicate semi-recumbent assessment has been completed. Standing 
assessments must not be performed if semi-recumbent systolic blood pressure is <85 mmHg or if the subject presents with signs or symptoms suggestive of postural 
hypotension after standing. Day -1 time points will be time-matched (± 5 minutes) to the Day 1 clock time (ie, time-matched baseline).
k)
To be monitored from 2 hours prior to the start of infusion until 24 hours following the start of infusion.
l)
Samples for serum chemistry will be obtained after a fast of at least 8 hours, however, in case of dropouts or rechecks, subjects may not have fasted for 8 hours prior to the serum 
chemistry sample is taken.
m)
Hepatitis panel, including antibodies for HBsAg and HCV.
n)
The sentinel subjects will be dosed at least 24-hour before the remaining 6 subjects in each cohort. Dosing in the remaing subjects of the cohort will be staggered by at least 
1 hour.
o)
PK blood sample collection should be collected as close to exact time points as possible. Please refer to section 9.2.
p)
Performed immediately after the end of infusion.
q)
Three pre-dose samples will be taken at -0.75, -0.5 and -0.25 hours before the start of infusion. Each time point will be extracted in triplicate. During the extractions that are less 
than 1 hour post start of infusion subjects may not have been resting for 10 minutes due to the proximity of sample collection.
Abbreviations: ADA = Anti-drug antibodies, AE = Adverse event(s), BMI = Body mass index, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, ConMeds = Concomitant 
medications, CRU = Clinical research unit, ECG = Electrocardiogram, EOI = End of infusion, ET = Early termination, FSH = Follicle-stimulating hormone, FU = Follow-up, 
HBsAg = hepatitis B surface antigen, HCV = hepatatist C virus, Hem = Hematology, HIV = Human immunodeficiency virus, HR = Heart rate, IV = Intravenous, mmHg = 
millimeters of mercury, PK = Pharmacokinetics, PMP = Postmenopausal, Pre = Predose or prior to Hour 0, RR = Respiratory rate, Scr = Screening, T = Temperature. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1004
Page 17 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
CONFIDENTIAL
3.2
Cohort 3 and any Cohort with an Infusion greater than 60 Minutes
Study Procedures a)
Scr b)
Study Days
Days →
-2
-1
Hours →
C-I e)
Pre
0
0.25
0.5
1
1.5
2
(EOI) 
f)
2.083
2.25
2.5
3
5
8
12
Hour:Minutes →
0
0:15
0:30
1:00
1:30
2:00
2:05
2:15
2:30
3:00
5:00
8:00
12:00
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Safety Evaluations 
Full Physical Examination g)
X
X
Height 
X
Weight and BMI
X
X
12-Lead Safety ECG (triplicate)
X
X h)
Vital Signs (HR) i)
X
Vital Signs (HR and BP) i)
X
X
X
X
X
X
X
Orthostatic Vital Signs (HR and 
BP) j)
X
X h)
X
X
X
X
X
Vital Signs (RR and T)
X
Hem and Serum Chem l)
X
X
Urinalysis
X
X
Serum Pregnancy Test (females 
only)
X
X
Serum FSH (PMP females only)
X
COVID-19 test
X
X
Urine Drug and Alcohol Screen
X
X
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TAK-951
Study ID TAK-951-1004
Page 18 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
CONFIDENTIAL
Study Procedures a)
Scr b)
Study Days
Days →
-2
-1
Hours →
C-I e)
Pre
0
0.25
0.5
1
1.5
2
(EOI) 
f)
2.083
2.25
2.5
3
5
8
12
Urine Cotinine Screen
X
X
HIV/Hepatitis Screen m)
X
AE Monitoring
X
X
ConMeds Monitoring
X
X
Other Procedures
Confinement in the CRU
X
Visit
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1004
Page 19 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
CONFIDENTIAL
Study Procedures a)
Study Days
ET 
c)
FU d)
Days →
1
2
Day 15 
(±2)
Day 29
(±3)
Hours →Pre
0
0.25
0.5
1
1.5
2
(EOI) 
f)
2.083
2.25
2.5
3
5
8
12
24
30
Hour:Minutes →
0
0:15
0:30
1:00
1:30
2:00
2:05
2:15
2:30
3:00
5:00
8:00
12:00
24:00
30:00
Safety Evaluations 
Full Physical Examination 
g)
X
X
12-Lead Safety ECG 
(triplicate)
X h)
X
X
Vital Signs (HR) i)
X
Vital Signs (HR and BP) i)
X
X
X
X
X
X
X
X
X
Orthostatic Vital Signs (HR 
and BP) j)
X h)
X
X
X
X
X
X
Telemetry k)
X
Hem and Serum Chem l)
X
X
X
Urinalysis
X
X
Serum Pregnancy Test 
(females only)
X
X
AE Monitoring
X
X
X
ConMeds Monitoring
X
X
X
Study Drug Dosing / PK
TAK-951 IV or Matching 
Placebo Dosing n)
x
Blood for TAK-951 PK o)
X
X
X
X
X
X p)
X p)
X
X
X
X
X
X
X
X
X
Other Procedures
Holter Monitoring q)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA
X
X
X
X
Confinement in the CRU
X
Return Visits
X
X
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TAK-951
Study ID TAK-951-1004
Page 20 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
CONFIDENTIAL
Study Procedures a)
Study Days
ET 
c)
FU d)
Days →
1
2
Day 15 
(±2)
Day 29
(±3)
Hours →Pre
0
0.25
0.5
1
1.5
2
(EOI) 
f)
2.083
2.25
2.5
3
5
8
12
24
30
a)
For details on Procedures, refer to Section 9.0.
b)
Within 28 days prior to dosing.
c)
To be performed prior to early termination from the study.
d)
All subjects who received any amount of study drug (including subjects who terminate the study early) will return to the CRU 14 (±2) and 28 (±3) days after 
dosing for follow-up procedures, and to determine if any AE has occurred since the last study visit.
e)
Subjects will be admitted to the CRU on Day -2, at the time indicated by the CRU. In accordance with the local regulatory guidance for COVID-19 pandemic, 
the clinical study unit will implement standard COVID-19 procedures as per their internal guidance documents. Subjects may be admitted earlier than Day -2 
for COVID-19 testing not related to study protocol as per CRU requirements.
f)
A sample will be obtained at the end of infusion for each cohort. For Cohorts 4 and 5, infusion rate will be determined from emerging clinical data analysis and 
end of infusion sample will occur at one of the existing sampling time points. The study events at the end of infusion will proceed in this order: blood samples, 
vital signs, safety ECGs and Holter ECGs, meals and snacks.
g)
Symptom-driven physical examination may be performed at other times, at the Investigator’s or designee’s discretion.
h)
To be performed within 2 hour prior to Hour 0.
i)
All blood pressure and heart assessments should be made in duplicate, and the average of both assessments should be used to calculate the final result. The 
Investigator can take a third measurement if there is inconsistency between assessments. Day -1 time points will time-matched (± 5 minutes) to the Day 1 clock 
time (ie, time-matched baseline).
j)
For orthostatic vital signs, a blood pressure and heart rate assessment will be performed after the duplicate semi-recumbent assessment has been completed. 
Standing assessments must not be performed if semi-recumbent systolic blood pressure is <85 mmHg or if the subject presents with signs or symptoms 
suggestive of postural hypotension after standing. Day -1 time points will be time-matched (± 5 minutes) to the Day 1 clock time (ie, time-matched baseline).
k)
To be monitored from 2 hours prior to the start of infusion until 24 hours following the start of infusion.
l)
Samples for serum chemistry will be obtained after a fast of at least 8 hours, however, in case of dropouts or rechecks, subjects may not have fasted for 8 hours 
prior to the serum chemistry sample is taken.
m) Hepatitis panel, including antibodies for HBsAg and HCV.
n)
The sentinel subjects will be dosed at least 24-hour before the remaining 6 subjects in each cohort. Dosing in the remaing subjects of the cohort will be 
staggered by at least 1 hour.
o)
PK blood sample collection should be collected as close to exact time points as possible. Please refer to section 9.2.
p)
Performed immediately after the end of infusion.
q)
Three pre-dose samples will be taken at -0.75, -0.5 and -0.25 hours before the start of infusion. Each time point will be extracted in triplicate. During the 
extractions that are less than 1 hour post start of infusion subjects may not have been resting for 10 minutes due to the proximity of sample collection.
Abbreviations: ADA = Anti-drug antibodies, AE = Adverse event(s), BMI = Body mass index, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1004
Page 21 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
CONFIDENTIAL
Study Procedures a)
Study Days
ET 
c)
FU d)
Days →
1
2
Day 15 
(±2)
Day 29
(±3)
Hours →Pre
0
0.25
0.5
1
1.5
2
(EOI) 
f)
2.083
2.25
2.5
3
5
8
12
24
30
ConMeds = Concomitant medications, CRU = Clinical research unit, ECG = Electrocardiogram, EOI = End of infusion, ET = Early termination, 
FSH = Follicle-stimulating hormone, FU = Follow-up, HBsAg = hepatitis B surface antigen, HCV = hepatatist C virus, Hem = Hematology, HIV = Human 
immunodeficiency virus, HR = Heart rate, IV = Intravenous, mmHg = millimeters of mercury, PK = Pharmacokinetics, PMP = Postmenopausal, Pre = Predose or 
prior to Hour 0, RR = Respiratory rate, Scr = Screening, T = Temperature. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1004
Page 22 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
4.0
INTRODUCTION
4.1
Background
TAK-951 is a peptide agonist of the glucose insulinotropic peptide (GIP) receptor that is resistant 
to dipeptidyl peptidase-4 degradation. GIP is an incretin hormone that results in glucose dependent
insulin secretion via its action on the GIP receptor on pancreatic beta cells. The glucose 
dependence of GIP’s insulinotropic action suggests a low risk of hypoglycemia following 
administration of TAK-951 to humans when administered in normoglycemic conditions. In 
addition to pancreatic beta cells, nonclinical studies have revealed that the GIP receptor is also 
expressed on gamma aminobutyric acid (GABA)ergic neurons in the area postrema. The area 
postrema (the chemoreceptor trigger zone) not only has excitatory pathways to the brainstem to 
induce emesis, but also has GABAergic inhibitory inputs, directly activated by GIP receptor 
agonists. Studies conducted by Takeda have demonstrated expression of the GIP receptor in 
humans on these neurons. By specifically activating the inhibitory GABAergic neurons of the area 
postrema via GIP receptor agonism, TAK-951 has the potential to inhibit nausea and vomiting via 
neural pathways triggered by a variety of chemical agents and physiological signals, including the 
neurotransmitters dopamine, serotonin, and substance P. 
TAK-951 is currently proposed for the treatment of nausea and vomiting. From the human GIP IV 
infusion studies under hyperglycemic clamp in healthy subjects and in diabetic and glucose 
intolerant patients, reversible heart rate increases of about 8 to 10 beats per minute were observed. 
Although these findings indicate that TAK-951 has the potential for cardiovascular effects in 
humans, the changes are anticipated to be transient, reversible, and monitorable through 
noninvasive approaches. Preliminary data from the TAK-951-1001 FIH study indicate that 
subcutaneous administration of TAK-951 can increase heart rate, decrease diastolic blood pressure 
and lead to orthostatic changes in vital signs including orthostatic tachycardia and hypotension. 
In addition, refer to the IB for detailed background information on TAK-951.
4.2
Rationale for the Proposed Study
The ongoing FIH study (TAK-951-1001) is assessing the safety and tolerability of single and 
multiple ascending doses of TAK-951 administered subcutaneously to adult subjects. This IV 
infusion study will support development of an IV dosage form if deemed necessary.
To that end, this study is designed as a phase 1, randomized, double-blind, placebo-controlled 
study to evaluate the safety, tolerability, and PK of TAK-951 in at least 3 cohorts of healthy adult
subjects following a single IV infusion administration with at least two dose levels. Infusion 
duration for the first two cohorts will be 60 minutes. Infusion duration for subsequent cohorts may 
be longer or shorter than 60 minutes and will be determined based upon emerging clinical data 
analysis from previous cohorts.
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
resistant
esistan
depend
depen
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ose
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essio
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itory G
ential to
ential to
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s and
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 P. 
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in healt
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rea
reases o
se
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AK-951
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dur
b


TAK-951
Study ID TAK-951-1004
Page 23 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
4.3
Benefit/Risk Profile
The single dose of subcutaneous TAK-951 (Study TAK-951-1001) was safe and well tolerated up 
to 4000 μg (4000 μg preliminary geometric mean PK: Cmax 54.3 ng/mL, AUClast 339 h*ng/mL). 
Although the subcutaneous bioavailability of TAK-951 is assumed to be high (~90%) based on 
non-clinical data (minipig), starting with a low infusion dose of 20 μg (20 μg preliminary
geometric mean PK following subcutaneous dose: Cmax 0.201 ng/mL, AUClast 0.562 h*ng/mL) 
allows for a potentially greater exposure following IV administration if the subcutaneous 
bioavailability is actually very low (~1%). In this hypothetical case, a potential 100-fold greater 
bioavailability would result in AUC and Cmax exposures 100 fold greater than predicted at 20 ∀g. 
This would still be within the exposures seen at the 4000 μg subcutaneous dose level in 
TAK-951-1001. Thus, the exposure in this study is not anticipated to exceed the exposure 
observed following subcutaneous doses in study TAK-951-1001 and therefore should have a 
comparable AE profile. 
Risk mitigation measures have been incorporated into this study by adding a sentinel dosing of 
2 subjects in each cohort and dosing the sentinel group at least 24-hours prior to dosing of the 
remaining 6 subjects in each cohort. 
Safety monitoring procedures, such as frequent heart rate and blood pressure assessments, 
orthostatic blood pressure and heart rate measurements, telemetry, and 12-lead ECGs are being 
implemented in this study to assess subject safety and tolerability of study drug. The potential risks 
related to heart rate increase, decreased blood pressure, and injection site reactions will be 
monitored clinically and/or with laboratory tests and have been considered when determining the 
stopping rules for this clinical study. Subjects will be evaluated for the development of anti-drug 
antibodies (ADA) as part of the study. The use of a clinical study facility monitored by the 
Investigator increases subject safety since subjects are closely monitored and rapid institution of 
appropriate care can be given when needed in a timely manner.
There will be no direct health benefit for study subjects from receipt of study drugs. An indirect 
health benefit to the healthy subjects enrolled in this study is the free medical tests received at 
screening and during the study.
Overall, the potential risks associated with the study are considered reasonable and well managed.
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TAK-951
Study ID TAK-951-1004
Page 24 of 78
Protocol Incorporating Amendment No. 1
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Study Objectives
5.1.1
Study Primary Objective
To evaluate the overall safety and tolerability of a single IV infusion of TAK-951 administered 
with at least 2 different infusion rates (rapid and slow) at the same dose level in healthy subjects..
5.1.2
Study Secondary Objectives
To assess the PK of TAK-951 following a single IV infusion of TAK-951 in healthy subjects.
To assess for anti-drug antibodies following a single IV infusion of TAK-951 in healthy subjects.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint of the study is safety and tolerability as assessed through AEs, vital signs, 
safety ECGs/telemetry, safety laboratory assessments, and physical examinations.
5.2.2
Secondary Endpoints 
Secondary endpoints will be assessed through evaluation of the following:PK parameters:
!
Area under the TAK-951 plasma concentration time curve from time 0 to infinity (AUC∞).
!
TAK-951 plasma concentration at end of infusion (Ceoi).
!
Area under the TAK-951 plasma concentration-time curve from time 0 to the time of the last 
quantifiable concentration (AUClast).
!
Terminal disposition phase half-life (t½z).
!
Terminal disposition phase rate constant (λz).
Immunogenicity:
!
Anti-drug antibodies titer.
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TAK-951
Study ID TAK-951-1004
Page 25 of 78
Protocol Incorporating Amendment No. 1
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety,
tolerability, and PK of TAK-951 administered intravenously in healthy adult subjects.
At least 3 cohorts of 8 subjects each will be dosed sequentially. Subjects from each cohort will be 
admitted into the CRU on Day -2. On Day -1 baseline heart rate and blood pressure assessments 
will be taken, time-matched to the Day 1 assessments. Subjects will receive a single dose with 
TAK-951 or matching placebo on Day 1, according to the randomization scheme, after a minimum 
of 8 hours of fasting. Subjects will be randomized to receive TAK-951 or matching placebo in a 
6:2 ratio in a double-blind manner. Pharmacokinetic samples will be taken up to 30 hours after the 
start of infusion. Subjects will be discharged after the completion of the study assessments on Day 
2.
All subjects who received any amount of study drug (including subjects who terminate the study
early) will return to the CRU 14 (±2) and 28 (±3) days after dosing for follow-up procedures, and 
to determine if any AE has occurred since the last study visit.
Dosing regimen for each cohort: 
Cohort 1: a low dose (20 μg) TAK-951 or placebo administered as a 60-minute IV infusion 
on Day 1,
Cohort 2: a high dose (1.0 mg) TAK-951 or placebo administered as a 60-minute IV 
infusion on Day 1,
Cohort 3: 1.0 mg TAK-951 or placebo administered as a 120-minutes IV infusion on 
Day 1.
Two (2) additional cohorts may be enrolled (for a total of 5 cohorts), each cohort with 8 subjects, to 
explore additional IV dosing regimens. In total the enrollment will be approximately 40 subjects. 
Dosing of the subsequent cohort will be based on the analysis of the previous cohort’s data;
however, the cohorts will not exceed the highest exposure observed in the FIH study.
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TAK-951
Study ID TAK-951-1004
Page 26 of 78
Protocol Incorporating Amendment No. 1
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For Cohort 4 and 5, PK sampling and time-matched vital sign assessments scheduled relative to 
infusion timing will be based on emerging clinical data analysis. As such, this timing will be 
provided in a separate document and will not exceed 30 hours post start of infusion. The number of 
planned samples may be less than or equal to those in the protocol.
A staggered dosing approach will be used. The sentinel subjects will be dosed at least 24-hours 
before the remaining 6 subjects in each cohort. In each cohort, after dosing the first 2 subjects (the 
sentinel group - 1 receiving TAK-951 and 1 receiving placebo) the Investigator will review all 
available blinded safety and tolerability data up to 8 hour post-dose. If after dosing the sentinel 
group, the Investigator and the Sponsor agree that there are no significant safety/tolerability 
concerns, then the rest of the cohort will be dosed. There will be at least 1 hour between dosing of 
each subject in each cohort, except for the sentinel subjects. A dose-escalation/blinded safety 
review meeting will be held between the Investigator and Sponsor after each cohort is completed 
to review the safety and available PK data from samples taken up to 1-day post-dose, in order to 
confirm the dose level and/or infusion rate for the subsequent cohort. PK data from the first low 
dose cohort is required to allow dosing of the high dose for the second and third cohorts and the 
determination of the rate of infusion for the third cohort. The dose and the infusion rate for Cohort 
4 and 5 will be selected based on emerging clinical data analysis and is not expected to exceed the 
highest exposures seen in the FIH TAK-951-1001 study. 
Sponsor is to remain blinded during the review of available safety and PK data. Once a decision is 
made to proceed to the next cohort, the Sponsor may be unblinded following dose escalation/safety 
meetings to allow additional analysis.
The dose and rate for Cohorts 4 and 5 will be determined by clinical data analysis so as not to 
exceed the highest exposure seen in the currently ongoing FIH study (TAK-951-1001). Cohorts 4 
and 5 may run concurrently, sequentially or be omitted.
Safety will be assessed by monitoring for AEs, vital signs, safety 12-lead ECGs/telemetry, safety 
laboratory assessments, and physical examinations throughout the study.
Immunogenicity will be assessed prior to dosing and approximately 14 and 28 days after dosing.
In accordance with local regulatory guidance for the COVID-19 pandemic, the clinical study unit 
will implement standard COVID-19 procedures as per their internal guidance documents. Subjects 
may be admitted earlier than Day -2 for COVID-19 testing not related to study protocol as per 
CRU requirements.
The planned dose levels of TAK-951 to be evaluated are outlined in Table 6.a. 
Table 6.a
Planned Dose Levels of TAK-951
Cohort
Total Dose
Infusion Duration
Cohort 1
20 g and matching placebo
60-minute
Cohort 2
1.0 mg and matching placebo
60-minute
Cohort 3
1.0 mg and matching placebo
120-minute
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Study ID TAK-951-1004
Page 27 of 78
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6.2
Dose Escalation
The sentinel subjects will be dosed at least 24-hours before the remaining 6 subjects in each cohort. 
After dosing the first 2 subjects (the sentinel group - 1 receiving TAK-951 and 1 receiving placebo) 
the Investigator will review all available blinded safety and tolerability data up to 8 hour post-dose. 
If after dosing the sentinel group, there are no significant safety/tolerability concerns, then the rest 
of the cohort will be dosed. There will be at least 1 hour between dosing of each subject in each 
cohort, except for the sentinel subjects. A dose-escalation/blinded safety review meeting will be 
held between the Investigator and Sponsor after each cohort is completed to review the safety and 
available PK data from samples taken up to 1-day post dose, in order to confirm the dose level 
and/or infusion rate for the subsequent cohort.
Cohort 1 will be administered a 20 µg dose of TAK-951 or matching placebo as a single 60-minute 
IV infusion. 
Cohort 2 will receive a higher dose of TAK-951 or matching placebo as a 60-minute infusion. The 
dose will be determined based on the safety and the plasma concentrations from Cohort 1. The 
exposure from the selected dose is expected to not exceed the exposure seen at the highest dose 
deemed to be safe in the single ascending dose (SAD) portion of the FIH study (TAK-951-1001). 
The dose and the infusion rate for Cohort 4 and 5 will be determined by emerging clinical data 
analysis and will not to exceed the highest exposure seen in the FIH study (TAK-951-1001). 
6.3
Stopping Rules
The Investigator and/or the Sponsor may pause further dosing for safety review or discontinue the 
study if any of the stopping rules are met or safety concerns identified at one of the planned 
TAK-951 dose, as listed here:

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk is no 
longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.

Any notable Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher 
AE or a related SAE.

One subject experiences a clinically significant arrhythmia.
6.4
Rationale for Study Design, Dose, and Endpoints
6.4.1
Rationale of Study Design 
This study has been designed to examine the safety, tolerability, and PK of various doses of 
TAK-951 infused at least two different rates (slow and fast).
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TAK-951
Study ID TAK-951-1004
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Protocol Incorporating Amendment No. 1
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6.4.2
Rationale for Dose 
Cohort 1 will be administered 20 µg TAK-951 or matching placebo in a single 60-minute IV 
infusion. Simulations using a fit for purpose population PK model predict plasma concentrations 
above the 20 pg/mL lower limit of quantitation for up to approximately 10-12 hours following a 
60-minute infusion dose administration. The predicted concentration at end of infusion (Ceoi) with 
an assumed absolute bioavailability (F) of 90% was comparable to the Cmax observed in the 
ongoing FIH study following a 20 µg subcutaneous administration. The predicted Ceoi with an 
assumed F of 30% was comparable to the observed Cmax following a 60 µg subcutaneous 
administration. The current highest doses in the ongoing FIH are 4000 µg SAD and 450 µg twice 
daily, 8 hours apart for 5 days. Although the subcutaneous bioavailability of TAK-951 is assumed 
to be high (~90%) based on non-clinical data (minipig), starting with a low infusion dose of 20 µg 
allows for a potentially greater exposure following IV administration if the subcutaneous 
bioavailability is actually very low (~1%). In this hypothetical case, a potential 100-fold greater 
bioavailability would result in AUC and Cmax exposures 100-fold greater than predicted at 20 g. 
This would still be within the exposures seen at the 4000 µg subcutaneous dose level in 
TAK-951-1001. 
Cohort 2 will receive a 1.0 mg as a 60-minute infusion. 
Cohort 3 will receive a 1.0 mg dose as a 120-minute infusion.
Additional cohorts (Cohorts 4 and 5) may be added to explore additional IV dosing regimens 
ensuring the predicted exposure will not be exceeding the exposure seen at the highest dose 
deemed to be safe in SAD portion of the FIH study.
For Cohort 4 and 5, as applicable, PK sampling and time-matched vital sign assessments 
scheduled relative to infusion timing will be based on emerging clinical data analysis. As such, this 
timing will be provided in a separate document and will not exceed 30 hours post start of infusion. 
The number of planned samples may be less than or equal to those in the protocol.
Please refer to Section 6.2 for additional details on the dose and rate determination for Cohorts 2 
and up.
6.4.3
Rationale for Endpoints
6.4.3.1
Safety Endpoints 
The key safety endpoints are typical for phase 1 studies and also takes into consideration GIP 
pharmacology-related cardiovascular effects and will be assessed through monitoring of AEs, vital 
signs, safety ECGs/telemetry, safety laboratory assessments, and physical examinations.
6.4.3.2
Pharmacokinetic Endpoints
The PK endpoints are standard for this type of study.
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Study ID TAK-951-1004
Page 29 of 78
Protocol Incorporating Amendment No. 1
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6.4.3.3
Immunogenicity Endpoints
The anti-drug antibodies will be assessed with the baseline sample and the post baseline samples. 
The formation of anti-drug antibodies such as IgM can occur 7 to 14 days after study drug 
administration. In this study we will be evaluating anti-drug antibodies at 14 (±2) and 28 (±3) days 
post-dose administration to assess potential immunogenicity.
6.4.4
Future Biomedical Research
Any residual PK plasma samples will be stored by the Sponsor or Bioanalytical facility for the
maximal 5 years determined by the Sponsor following the dosing. Tubes or containers will be 
identified with a barcode using an appropriate label. Immunogenicity samples will not be stored.
The purpose for storing samples is not to identify pre-existing medical conditions using 
genetic/genomic analysis using deeoxyribonucleic acid (DNA), or ribonucleic acid (RNA) but 
rather to analyze GIP pharmacology-related or safety observation-related biomarkers. Samples 
will not be submitted to a public database. The Sponsor and contract research organizations 
involved in the clinical conduct, bioanalytical analyses, and PK and statistical analysis of the data 
will have access to the samples and/or the data that resulted from the analysis, if performed. 
By signing the ICF, subjects agree to the possible future analysis of these samples (for metabolites). 
At any time, the subjects can contact the CRU staff to request destruction of the residual samples 
once PK assessments required to meet the current study’s objectives of the study are completed. 
Any additional research on these samples unspecified by this protocol will require approval from
the subjects.
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the critical component is safety and tolerability. The assessment should be 
performed as described in Section 9.2.
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of TAK-951 to any subject may not be modified for Cohort 1. The 
doses for the subsequent cohorts (dose level and/or rate of infusion) will be determined as 
indicated in Section 9.2.8. If necessary, a subject may be discontinued for the reasons described in 
Section 7.5 and Section 7.6. If indicated, the plasma PK samples may also be assayed and/or 
pooled for assay in an exploratory manner for metabolites.
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TAK-951
Study ID TAK-951-1004
Page 30 of 78
Protocol Incorporating Amendment No. 1
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6.6
Study Beginning and End/Completion
6.6.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the ICF) 
of the first subject.
6.6.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled study procedure as outlined in the 
Schedule of Study Procedures (Section 3.0).
6.6.3
Definition of Study Completion
The end of the study is scheduled after completion of the evaluations in the last follow-up visit for 
the last subject in the study.
This time period may change in the event that the study is terminated early or the last subject is lost 
to follow-up. 
6.6.4
Definition of Study Discontinuation
Celerion reserves the right to terminate the study in the interest of subject welfare.
The Sponsor reserves the right to suspend or terminate the study at any time.
6.6.5
Criteria for Premature Termination or Suspension of the Study
Refer to the Stopping Rules (see Section 6.3).
6.6.6
Criteria for Premature Termination or Suspension of a Site
Not applicable.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study:
1. Healthy, adult, male or female (of non-childbearing potential only), 19-55 years of age, 
inclusive, at screening.
2. Continuous non-smoker who has not used nicotine- and tobacco-containing products and/or 
cannabis products for at least 3 months prior to dosing and throughout the study.
3. BMI ≥18.0 and ≤32.0 kg/m2 at screening. 
4. Medically healthy based on no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the Investigator or designee.
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Study ID TAK-951-1004
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Protocol Incorporating Amendment No. 1
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5. Female must be of non-childbearing potential as described in Appendix D.
6. A non-vasectomized, male subject must agree to use a barrier contraception (eg, condom with 
spermicide) or abstain from sexual intercourse from dosing and until 90 days after dosing. No 
restrictions are required for a vasectomized male provided his vasectomy has been performed 
4 months or more prior to dosing of study drug. A male who has been vasectomized less than 
4 months prior to dosing must follow the same restrictions as a non-vasectomized male (see 
Appendix D).
7. If male, must agree not to donate sperm from dosing until 90 days after dosing.
8. Understands the study procedures in the ICF and be willing and able to comply with the 
protocol.
7.2
Exclusion Criteria
Subjects must not be enrolled in the study if they meet any of the following criteria:
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. Has a documented history of any clinically significant disorders, including psychiatric, 
cardiovascular, nephrological, neurological, metabolic, or gastrointestinal disease.
3. History of any illness that, in the opinion of the Investigator or designee, might confound the 
results of the study or poses an additional risk to the subject by their participation in the study.
4. History or presence of alcoholism or drug abuse within the past 2 years prior to dosing.
5. Drink alcohol in excess of 21 glasses/units per week for males or 14 glasses/units per week for 
females, with one unit = 150 mL of wine or 360 mL of beer or 45 mL of 45% alcohol.
6. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related 
compounds.
7. Have any tattoos, scars or skin issue at planned IV infusion site which could interfere with 
dosing.
8. History or presence of:

Three (3) or more incidences of vasovagal syncope within the last 5 years prior to 
screening.

Family history of unexplained sudden death or channelopathy.

Brugada syndrome (ie, RBBB pattern with ST-elevation in leads V1-V3).

Cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial 
infarction, stroke, sick sinus syndrome, pulmonary congestion, symptomatic or significant 
cardiac arrhythmia, second-degree AV block type 2, third-degree AV block, prolonged 
QTcF interval, hypokalemia, hypomagnesemia, or conduction abnormalities;
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Study ID TAK-951-1004
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
Risk factors for Torsade de Pointes (eg, heart failure, cardiomyopathy, or family history of 
Long QT Syndrome);

Any clinically significant ECG findings or medical history including: long or short QT 
interval with QTcF (over 450 msec or less than 360 msec), bifascicular block or QRS 
≥120 msec or PR interval >200 msec at screening or Day -1 pre-Hour 0.

Documented history of sinoatrial block or sinus pause ≥3 seconds. 
9. Semi-recumbent blood pressure (average of duplicate) is less than 90/60 mmHg or greater than 
140/90 mmHg at screening.
10. Has an average semi-recumbent heart rate <60 or >100 bpm (at screening, at Day -1 pre-Hour 
0, or at pre-dose Day 1); athletic subjects with an average semi-recumbent heart rate <60 bpm 
can be enrolled only with medical monitor approval. If subject has heart rate <60 bpm 
Investigator should obtain medical approval from Sponsor.
11. Has orthostatic hypotension defined as a decrease in systolic blood pressure ≥20 mmHg or a 
decrease in diastolic blood pressure ≥10 mmHg after 2 minutes of standing when compared 
with blood pressure from the semi-recumbent position at screening and at Day -1 pre-Hour 0. 
The semi-recumbent blood pressure will be an average of duplicate measurements. 
12. Has postural orthostatic tachycardia, defined as an increase of 30 bpm or heart rate >120 bpm 
after standing for 2 minutes. 
13. Female subjects of childbearing potential.
14. Female subjects with a positive pregnancy test or who is lactating.
15. Positive urine drug or alcohol results at screening or check-in.
16. Positive urine cotinine at screening or check-in.
17. Positive results at screening for HIV, HBsAg, or HCV.
18. Unable to refrain from or anticipates the use of any drug, including prescription and 
non-prescription medications, herbal remedies, or vitamin supplements beginning 14 days 
prior to dosing and throughout the study. Thyroid hormone replacement medication may be 
permitted if the subject has been on same stable dose for the last 3 months prior to study drug 
administration. After dosing, acetaminophen (up to 2 g per 24 hours) may be administered at 
the discretion of the Investigator or designee. Hormone replacement therapy will also be 
allowed.
19. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or 
designee, within the 30 days prior to dosing and throughout the study.
20. Donation of blood or significant blood loss within 56 days prior to dosing.
21. Plasma donation within 7 days prior to dosing.
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Protocol Incorporating Amendment No. 1
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22. Participation in another clinical study within 30 days prior to dosing. The 30-day window will 
be derived from the date of the last blood collection or dosing, whichever is later, in the 
previous study to Day 1 of the current study.
23. Positive results for COVID-19 testing at screening or check-in.
7.3
Excluded Medications, Supplements, Dietary Products
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.2. After 
dosing, acetaminophen (up to 2 g per 24 hour) may be administered at the discretion of the 
Investigator or designee. Thyroid hormone replacement medication may be permitted if the 
subject has been on the same stable dose for the last 3 months prior to dosing. Hormone 
replacement therapy will also be allowed.
If deviations occur, the Investigator or designee in consultation with the Sponsor if needed will 
decide on a case by case basis whether the subject may continue participation in the study.
All medications taken by subjects during the course of the study will be recorded.
Use of excluded agents (prescription or nonprescription) or dietary products is outlined in 
Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Dosing (Days -28 to 
predose [Day 1])
After Dosing (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 7 days prior to dosing
Prohibited from dosing until the 
last PK collection.
Xanthine and/or caffeine
Prohibited from 24 hours prior to dosing a
Prohibited from dosing until the 
last PK collection.a
Medications 
See Sections 7.1 and 7.2
See Sections 7.1 and 7.2
Nicotine- and 
tobacco-containing and/or 
cannabis products
Prohibited from at least 3 months prior to dosing
Prohibited from dosing until last 
follow-up visit.
Food substance
Grapefruit/Seville orange
Prohibited from 28 days prior to dosing
Prohibited from dosing until the 
last PK collection.
a small amounts of caffeine derived from normal foodstuffs (eg, 250 mL/8 oz./1 cup decaffeinated coffee or other 
decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. chocolate bar, per day, would not be 
considered a deviation to this restriction).
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
On Day -1 of each cohort, subjects will be fasted overnight (at least 8 hours) and will continue to 
fast for 4 hours after Hour 0 for the collection of baseline time-matched heart rate and blood 
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Study ID TAK-951-1004
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pressure assessments. On Day 1 of each cohort, TAK-951 will be administered following an 
overnight fast (at least 8 hours) and subjects will continue to fast for 4 hours (after Hour 0) post 
start of infusion.
On Day 1 of each cohort, meals and snacks must be completed at least 1 hour before any Holter 
recording extractions and/or safety ECG.
When confined, standard meals and snacks will be provided at appropriate times and water will be 
provided ad libitum. Subjects will be required to fast from all food and drink except water between 
meals and snacks.
7.4.2
Activity
Subjects will remain semi-recumbent position for the duration of the infusion and for the first
4 hours following the end of infusion, except when they are standing or seated for study procedures 
or AEs.
However, should AEs occur at any time, subjects may be placed in an appropriate position or will 
be permitted to lie down on their right side. During the first 4 hours after the end of infusion, 
subjects may be allowed to rise for brief periods under supervision (eg, in order to use the toilet 
facilities). 
Subjects must be awakened at least 1 hour prior to the start of the cardiodynamic ECGs on Day 1 
and at least 1 hour prior to the start of the cardiodynamic ECG recording scheduled at the 24-hour
(Day 2) post-dose time point. On Day 1, subjects will remain awake for at least 12 hours post dose 
as the QT-RR relationship is different during sleep. However, subjects must lie down for at least 
10 minutes prior to ECG recordings to avoid tachycardia secondary to physical activity.
Subjects will be instructed to refrain from strenuous physical activity which could cause muscle 
aches or injury, including contact sports at any time from screening until completion of the study. 
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 CRF using the following categories.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE 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 PTE or AE.
2. Positive urine drug or alcohol or cotinine results.
3. Positive pregnancy test.
4. Difficulties in blood collection.
5. Liver function test (LFT) abnormalities:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper 
limit of normal (ULN) in conjunction with elevated total bilirubin >2 times the ULN with 
no alternate etiology, in the opinion of the Investigator.
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If during the study any of the study stopping criteria are met, further dosing will be paused, and the 
safety data will be reviewed by the Sponsor along with the Investigator. A recommendation will be 
made to continue, modify, temporarily suspend, or terminate the study as described in Section 6.3.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The Investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the Investigator. In addition, efforts should be made to perform all procedures scheduled for the 
end-of-study or early termination as described in Section 3.0.
7.7
Subject Replacement
Replacement of discontinued or withdrawn subjects due to any reason (does not include 
discontinuations due to drug related safety) will be assessed on a case by case basis by the Sponsor
and Investigator to ensure a minimum of 6 PK-evaluable subjects complete the cohort.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
TAK-951 is formulated for immediate-release and is available in dose strengths of 0.1mg/mL, 
1.0 mg/mL, and 10mg/mL in vials for injection. The matching placebo is normal saline. Refer to 
Section 9.2.8.
Details of the dosage form description and strengths, or composition for the extemporaneous 
preparation, can be found in the pharmacy manual.
8.1.1
Clinical Study Drug Labeling
TAK-951 will be provided to the site bearing a label in accordance with local regulatory 
requirements.
TAK-951 and placebo will be prepared by licensed pharmacy staff at the CRU according to the 
procedures outlined in the pharmacy manual.
See Section 9.2.8 for study drug administration details.
8.1.2
Clinical Study Drug Inventory and Storage
The same lot number will be used throughout the study. The lot numbers and expiration dates 
(where available) of the study drugs supplied will be recorded in the final report. Study drugs will 
be stored according to the product labels provided with the product.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied.
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8.1.3
Clinical Study Drug Blinding
This is a double-blind, placebo-controlled study.
8.1.4
Randomization Code Creation and Storage 
A computerized randomization scheme will be created by a Celerion statistician and it shall be 
considered blinded (as per the following). 
The randomization is available only to the CRU pharmacy staff that is preparing the drug who will 
not be involved in any other aspect of the study including administration of the drug. It will not be 
made available to the Sponsor, subjects, or members of the staff responsible for the monitoring and 
evaluation of safety assessments.
One set of sealed envelopes containing the randomization code will be supplied to the Investigator 
or designee at the start of the study.
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
Breaking of the blind is expressly forbidden except in the event of a medical emergency where the 
identity of the drug must be known in order to properly treat the subject.
In the event of a medical emergency, it is requested that the Investigator or designee make every 
effort to contact the Study Monitor or designee prior to breaking the blind. If breaking the blind is 
required because of a medical emergency, the treatment identity would be revealed by the 
Investigator or designee, for that subject only. In the event that the emergency is one, in which it 
appears that the other subjects may be at imminent risk, the blind may be broken for all subjects 
dosed at that dose level. The unblinding will be properly documented in the study file.
In all cases where the code is broken, the Investigator or designee should record the date and 
reason for code breaking.
At the end of the study, envelopes will be retained according to site procedures unless specified 
otherwise by the Sponsor.
In the absence of a medical emergency, the blinded randomization for this study will not be 
revealed until all data are entered in the database, edits checks are performed, queries closed, and 
the database is officially locked.
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
The Sponsor will supply sufficient quantities of the TAK-951 to allow completion of this study. 
Celerion will provide sufficient quantities of normal saline (placebo) for infusion to allow 
completion of the study. The lot numbers and expiration dates (where available) of the study drugs 
supplied will be recorded in the final report.
Records will be made of the receipt and dispensing of the study drugs supplied. At the conclusion 
of the study, any unused study drug will be retained by Celerion, returned to the Sponsor or 
designee, or destroyed, as per Sponsor instructions. Any remaining supplies that were purchased 
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by Celerion will be destroyed, if appropriate. If no supplies remain, this fact will be documented in 
the pharmacy product accountability records.
9.0
STUDY PROCEDURES
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign, and date an 
ICF summarizing the discussion prior to screening, and will be assured that they may withdraw 
from the study at any time without jeopardizing their medical care.
Subjects will be given a copy of their signed ICF.
9.1.1.1
Assignment of Screening and Randomization Numbers 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique identification number at the time of dosing, different from the screening number.
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (ie, Subject No. 101 will replace Subject No. 1).
9.1.1.2
Study Drug Assignment
All subjects will receive the treatments as detailed in Section 9.2.8. 
9.1.2
Inclusion and Exclusion 
Please refer to Sections 7.1 and 7.2.
9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of 
tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 7.3. All medications taken by 
subjects during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3.0) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the Investigator or designee and/or the Sponsor 
for reasons related to subject safety.
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For this study, safety and tolerability is the critical assessment. Procedures, as applicable, will be 
performed in the following the order below, with regard to the prescribed time (not applicable for 
the screening visit):
a.
Blood sample(s) collection (to be collected at exact time point).
b. Vital Signs (to be collected as close to the exact time point as possible).
c.
Safety ECG and Holter ECG recording extraction to be performed before or after items above, 
with priority for PK and then vital signs to be collected as close to exact time point as possible. 
d. Standardized meal or snack (meal/snack must be completed at least 1 hour before any Holter 
recording extractions and/or safety ECG).
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
9.2.1
Physical Examination
Qualified site personnel will conduct full physical examinations.
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the Investigator or designee.
9.2.2
Height and Weight
Height (cm) and body weight (kg) will be obtained with the subject’s shoes off, and jacket or coat 
removed. Height and weight will be reported as outlined in the Schedule of Study Procedures 
(Section 3.0).
9.2.3
Body Mass Index
The BMI equals a subject’s weight in kilograms divided by height in meters squared 
(BMI = kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4, round down, and 0.5 to 0.9, round up.
9.2.4
Vital Signs
Measurements of body temperature, respiratory rate, blood pressure, and heart rate, will be 
measured as outlined in the Schedule of Study Procedures (Section 3.0). Additional vital signs 
may be taken at any other times, if deemed necessary.
Body temperature will be measured with an oral (temperature taken at floor of the mouth) 
thermometer. The same method (ie, oral) must be used for all measurements for each individual 
subject and should be the same for all subjects.
Blood pressure and heart rate measurements will be performed with subjects in a semi-recumbent 
position, except when they are seated or standing because of study procedures and/or AEs 
(eg, nausea, dizziness) or if deemed necessary by the Investigator or designee. Subjects should rest 
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in a semi-recumbent position for at least 3 minutes before vital signs are measured. Blood pressure 
and heart rate should be made in duplicate with an interval of approximately 2 minutes between 
the 2 assessments. A third blood pressure assessment will be taken if results are inconsistent, at PI 
discretion. Final blood pressure read out should be the average of these assessments.
At the predose or prior to Hour 0 time points, blood pressure and heart rate will be measured within 
2 hour prior to dosing or Hour 0. When scheduled after the start of infusion, vital signs will be 
performed within approximately 15 minutes of the scheduled time point.
Subjects from each cohort will have baseline heart rate and blood pressure assessments performed 
on Day -1 which are time-matched (± 5 minutes) to the Day 1 assessments (ie, time-matched 
baseline).
Refer to Section 9.2.5 for when safety ECGs will trigger vital sign measurements.
For orthostatic vital signs, heart rate and blood pressure will be performed after the duplicate 
semi-recumbent assessment has been completed. The subject should stand still for approximately 
2 minutes before the standing heart rate and blood pressure assessment. Standing assessments 
must not be performed if semi-recumbent systolic blood pressure is <85 mmHg or if the subject 
presents with signs or symptoms suggestive of postural hypotension after standing. Subjects 
should continue to rest in a semi-recumbent position from the time of dosing until 4 hours 
post-dose except to stand for the measurement of standing vital signs or other study-related 
procedure. The semi-recumbant vital sign measurements will be taken in duplicate and the average 
will be used.
9.2.5
12-Lead ECG
Triplicate 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Ad hoc 12-lead ECGs will also be required, if a subject complains of palpitations, 
dizziness, breathlessness, chest tightness or any other symptoms suggestive of arrhythmia, 
between Day 1 (post-dose) and discharge. The ECG, blood pressure and heart rate measurements 
will be reviewed by the Investigator or medically qualified designee. If a clinically relevant 
abnormality is detected, the Investigator will follow the appropriate clinical protocols to stabilize 
the subject and will contact the Sponsor to discuss further management. 
The Investigator or designee 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.
The following parameters will be recorded on the CRF from the subject’s ECG trace: HR, RR 
interval, QRS interval, PR interval, QT interval, and QTcF.
The Investigator or designee 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 with the clinical study report.
ECGs will be performed with subjects in a semi-recumbent position. All ECG tracings will be 
reviewed by the Investigator or designee.
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At the predose or prior to Hour 0 time points ECG will be measured within 2 hours prior to dosing 
and prior to Hour 0. When scheduled after the start of infusion, ECGs will be performed within 
approximately 20 minutes of the scheduled time point.
9.2.6
Cardiodynamic ECGs
The 12-lead Holter ECG monitoring will be captured on Day 1 as indicated in in the Schedule of 
Study Procedures (Section 3.0). Continuous 12-lead Holter ECG monitoring will be performed 
from -0.75-hour until 24 hours after the start of infusion. For all pre- and post-dose ECG 
collections, three 10-second ECGs will be extracted at each extraction window time point.
ECG extraction time points will occur before or after PK blood draws. Accordingly, subjects will 
be supervised and quietly resting semi-recumbent beginning a minimum of 10 minutes before each 
actual ECG extraction window of 10 minutes, if possible. During the extractions that are less than 
1 hour post start of infusion, subjects may not have been resting for 10 minutes due to the 
proximity of sample collection. The rest period prior to the early PK draws (<1 hour post start of 
infusion) may need to be shortened to accommodate the events schedule. At all other timepoints, 
subjects will be supervised while remaining at rest, quiet, and awake and in a semi-recumbent 
position from at least 10 minutes if possible before the beginning of each ECG extraction time 
point and will remain quiet, awake, motionless, and semi-recumbent for at least 10 minutes after 
the beginning of each ECG extraction time point.
ECG data from Holter monitoring are not intended to be analyzed for real-time safety monitoring. 
9.2.7
Telemetry
Cardiac monitoring (heart rate and ECG) will be assessed via telemetry and will be performed as 
indicated in the Schedule of Study Procedures (Section 3.0).
Telemetry data will be used for real time safety monitoring to alert site staff and will not be stored 
or recorded in the CRFs.
9.2.8
Study Drug Administration
TAK-951 for IV infusion will be supplied as immediate release injection solution in 0.1 mg/mL, 
1.0 mg/mL, and 10 mg/mL vials.
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject as per the randomization scheme.
For IV dosing, the times of the beginning and the end of infusion will be recorded. Dosing 
interuptions will be recorded.
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Study ID TAK-951-1004
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Dosing regimen (frequency and food requirements). Single dose:
Cohort 1: a low dose (20 g) TAK-951 or placebo administered as a 60-minute IV infusion on 
Day 1
Cohort 2: a high dose (1.0 mg) TAK-951 or placebo administered as a 60-minute IV infusion 
on Day 1
Cohort 3: 1.0 mg TAK-951 or placebo administered as a 120-minutes IV infusion on Day 1.
If dosed, Cohorts 4 and 5 dose(s) of TAK-951 and infusion rate(s) of TAK-951 and placebo will be 
decided based on emerging clinical data analysis from the previous cohorts.
The ratio of active:placebo in each cohort will be 6:2 according to the randomization scheme and 
in a double-blinded fashion.
Subjects will fast for at least 8 hours before Hour 0 on Day -1 and Day 1 and will continue to fast 
for an additional 4 hours after Hour 0 on Day -1 and Day 1. Water is permitted. Standard meals 
will be administered at approximately 4 (lunch), 6 (snack), 10 (dinner), and 13 (snack) hours after 
start of dosing on Day 1. The same fasting requirements and meal/snack schedule will be followed 
on Day -1. 
9.2.9
AE Monitoring
AE monitoring begins after signing of the ICF. Subjects will be monitored throughout the study for 
adverse reactions to the study drugs and/or procedures as described in Section 10.0.
9.2.10
Laboratory Procedures and Assessments
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the Investigator or designee.
9.2.10.1
Clinical Laboratory Tests
9.2.10.1.1
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total and differential leukocyte count
9.2.10.1.2
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, subjects may not have fasted for 8 hours prior to when the serum chemistry sample 
being taken.
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Chemistry evaluations will consist of the following standard chemistry panel:
Blood Urea Nitrogen
Magnesium
Bilirubin (total and direct)
Sodium
Alkaline phosphatase (ALP)
Potassium
AST
Chloride
ALT
Glucose 
Albumin
Creatinine *
Gamma-glutamyl transferase (GGT)
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
9.2.10.1.3
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
9.2.10.1.4
Other 
HIV test
Urine drug screen:
Opiates (includes morphine, heroin (diacetylmorphine), 
codeine, 6-acetylmorphine, dihydrocodeine, hydrocodone, 
thebaine, and, hydromorphone)
Amphetamines
Barbiturates
Benzodiazepines
Cocaine
Cannabinoids
HBsAg
HCV (if antibody positive, confirm RNA negative)
Urine alcohol screen
Serum pregnancy test (for females only)
FSH (for postmenopausal females only)
Urine cotinine
COVID-19 testing (performed according to CRU 
standard procedures, provided in a separate 
document[s])
9.3
Pharmacokinetic Samples
Instructions for sample collection, processing, and shipping will be provided in separate 
documents.
To reflect plasma drug exposure more precisely, blood samples for determination of plasma 
TAK-951 will not be collected from the infusion line arm during study drug administration and the 
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physical set for drug administration will not be used to obtain PK samples. If the opposite arm is 
not available, blood samples should be collected at the site as distant to the infusion site as possible, 
and the site of the blood sampling should be documented.
Samples from all subjects who receive active drug will be assayed even if the subjects do not 
complete the study. Placebo samples will not be assayed. Samples for determination of plasma 
TAK-951 will be analyzed using validated bioanalytical methods.
Primary specimen collection parameters are provided in Table 9.a. If indicated, the plasma PK 
samples may also be assayed and/or pooled for assay in an exploratory manner for metabolites.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
TAK-951 sample for PK
Blood
Plasma
Plasma sample for PK analysis
Mandatory
ADA sample for 
immunogenicity
Blood
Serum
Serum sample forADA 
Mandatory
9.3.1
PK Measurements
Pharmacokinetic parameters of TAK-951 will be calculated using noncompartmental analysis 
methods from the individual concentration-time profiles from all evaluable subjects who received 
active drug. Actual sampling times, rather than scheduled sampling times, will be used in all 
computations involving sampling times. 
9.3.1.1
Plasma PK Measurements
PK parameters for plasma TAK-951 concentrations will be calculated as follows, as appropriate:
AUClast:
The area under the concentration-time curve, from time 0 to the last 
quantifiable concentration, as calculated by the linear-log trapezoidal 
method.
AUC:
The area under the concentration-time curve, from time 0 extrapolated to 
infinity. AUCis calculated as AUClast plus the ratio of the last measurable 
blood concentration to the elimination rate constant.
AUCextrap%:
Percent of AUCextrapolated, represented as (1 - AUClast/AUC)*100.
CL:
Total plasma clearance after IV administration, calculated as Dose/AUC.
Ceoi:
Concentration at the end of infusion.
tmax:
Time to reach Ceoi. If the maximum value occurs at more than one time 
point, tmax is defined as the first time point with this value.
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t½z:
Terminal disposition phase half-life will be calculated as 0.693/λz.
Where λz is the apparent first order terminal disposition phase rate constant 
calculated from a semilog plot of the plasma concentration versus time 
curve. The parameter will be calculated by linear least-squares regression 
analysis using the maximum number of points in the terminal log-linear 
phase (eg, three or more non-zero plasma concentrations).
Vz:
Volume of distribution during the terminal disposition phase after IV 
administration.
No value for λz, AUC#, AUCextrap%, CL, Vz, or t½z will be reported for cases that do not exhibit a 
terminal log-linear phase in the concentration versus time profile.
No PK parameters will be calculated for subjects with detectable concentrations at 2 or fewer 
consecutive time points. 
Individual and mean plasma concentration-curves (both linear and log-linear) will be included in 
the final report.
Additional PK parameters may be estimated as appropriate.
9.3.2
Immunogenicity Measurements
The status of anti-drug antibodies, titer, prior to and approximately14 and 28 days after dosing will 
be assessed.
9.3.4
PGx Measurements 
Not applicable
9.3.5
Confinement
Subjects will be housed on Day -2, at the time indicated by the CRU, until the Day 2 study 
procedures are completed. In accordance with the local local regulatory requirements for the
COVID-19 pandemic, the clinical study unit will implement standard COVID-19 procedures as 
per their internal guidance documents. Subjects may be admitted earlier than Day -2 for 
COVID-19 testing not related to study protocol as per CRU requirements. Subjects will return for 
CCI
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study procedures as indicated in Section 3.0. At all times, a subject may be required to remain at 
the CRU for longer at the discretion of the Investigator or designee.
10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (ie, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the Investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the Investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (ie, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
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Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray) should NOT be recorded as an AE unless related 
to a study procedure. However, if the subject experiences a worsening or complication of such 
a concurrent medical history condition, the worsening or complication should be recorded 
appropriately as an AE (worsening or complication occurs after informed consent is signed). 
Investigators should ensure that the event term recorded captures the change in the condition 
(eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, Investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (ie, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, Investigators should ensure that the AE term recorded 
captures the change in the condition (ie, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (ie, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (ie, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
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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 CRF, in order 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.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1
SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
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.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2
Special Interest AEs
The adverse events of special interest (AESI)s for TAK-951 include injection site reactions, 
hypotension, and tachycardia (refer to Section 10.2.8.5).
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
All AEs, including clinically significant treatment-emergent laboratory abnormalities, will be 
graded according to National Cancer Institute CTCAE: NCI CTCAE (NCI CTCAE v5.0). AEs not 
listed by the NCI CTCAE will be graded as displayed in Table 10.b.
Table 10.b
NCI CTCAE
Grade
Description
1 – Mild
asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
2 – Moderate
minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living.
3 - Severe or medically 
significant but not immediately 
life-threatening
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living.
4 - Life-threatening consequences
urgent intervention indicated.
5 - Fatal 
AE an event that results in the death of the subject.
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10.2.2
Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
Investigator.
10.2.4
End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5
Pattern of Adverse Event (Frequency) 
Episodic AEs (ie, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6
Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
(eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE).

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Drug interrupted – the dose was interrupted due to the particular AE.
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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 (ie, recovered from a cardiovascular accident but with some 
persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, LFTs and ADA
10.2.8.1
Collection Period
Collection of AEs (eg, AEs, SAEs, AESI, LFTs, and ADA) will commence at the time the subject 
signs the informed consent. Routine collection of AEs will continue until the follow-up visit on 
Day 15 (± 2 days) and on Day 29 (± 3 days). For subjects who discontinue prior to the 
administration of study medication, AEs will be followed until the subject discontinues study 
participation. 
10.2.8.2
Reporting AEs
At each study visit, the Investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
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changes observed. All AEs will be documented in the AE page of the CRF, whether or not the 
Investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with study drug.

Outcome of event.

Seriousness.
10.2.8.3
Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the Investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Appendix 14.1.1.
If reporting by fax, the site personnel need to confirm successful transmission of all pages and 
include an email address on the fax cover sheet so that an acknowledgment of receipt can be 
returned via E-mail within 1 business day.
If reporting by E-mail, site personnel need to confirm successful transmission by awaiting an 
acknowledgment of the receipt via E-mail within 1 business day. 
Any SAE spontaneously reported to the Investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation.
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Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
10.2.8.3.1
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
Investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. 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
Reporting Special Interest AEs 
AEs of special interest for TAK-951 include injection site reactions, hypotension, and tachycardia 
(refer to Section 10.2.8.5) and will be monitored by the Investigator and Sponsor.
10.2.8.5
Management of Specific AEs
Sinus Tachycardia
CTCAE Grade 
Management
CTCAE Grade 2 sinus tachycardia 
(ie, Symptomatic*; 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.
In MRD, the subject may be rechallenged with the agreement of the sponsor 
and investigator.
In MRD, if a subject develops a second episode of symptomatic tachycardia, 
discontinue treatment with study drug.
Any CTCAE 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; MRD: multiple rising dose. 
* Symptoms may include dizziness, light headedness, chest pain, chest heaviness, palpitations, and shortness of 
breath.
Low Blood Pressure
If a subject develops symptoms suggestive of hypotension or postural hypotension, blood pressure 
should be assessed for evidence of hypotension, which should be managed as per local guidelines, 
and the medical monitor should be contacted.
Injection Site Reaction
If a subject develops a CTCAE Grade 3 (ulceration or necrosis; severe tissue damage, operative 
intervention need) or 4 (life-threatening consequences; urgent intervention indicated) discontinue 
administration of TAK-951, provide immediate treatment and contact medical monitor.
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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).
10.2.8.6
Reporting of Abnormal LFTs
If subjects experience ALT or AST >3 times the ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, and GGT) should be performed 24 hours 
after the abnormality was noted, and the medical monitor should be contacted.
If ALT or AST remains elevated >3 times the ULN, the Investigator must contact the medical 
monitor for consideration of additional testing, close monitoring, possible discontinuation of study 
drug (if applicable), and discussion of the relevant subject details and possible alternative 
etiologies. The abnormality should be recorded as an AE and reported as per Section 10.2.8.2. 
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 13 must also be performed. In addition, an LFT 
Increases CRF must be completed and transmitted with the Takeda SAE form (as per 
Section 10.2.9). 
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, Investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
Sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in the SAP.
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11.1.1
Analysis Sets
11.1.1.1
Safety Set
The safety analysis set will consist of all subjects who are enrolled and received the full or partial 
dose of study drug or placebo.
11.1.1.2
PK Set
The PK analysis set will consist of all subjects who received the active study drug and have at least
one measurable plasma concentration of TAK-951.
11.1.1.3
Immunogenicity Set
The immunogenicity analysis set will include those subjects from the safety set who have a 
baseline and at least 1 post-baseline immunogenicity sample assessment.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Continuous demographic data (eg, age, weight, height, and BMI) will be listed and summarized 
using appropriate summary statistics for each treatment (cohort) and by pooled placebo. 
Categorical demographic data (eg, gender, race, ethnicity) will also be listed and tabulated.
11.1.3
PK Analysis
All PK data will be summarized using PK analysis set. 
The plasma concentration of TAK-951 will be summarized by TAK-951 dose and infusion rate 
over each scheduled sampling time, using descriptive statistics. The PK parameters of TAK-951 
will be determined from the concentration-time profiles for all evaluable subjects using 
noncompartmental analysis approach. Actual sampling times, rather than scheduled sampling 
times, will be involved in the derivation of PK parameters. 
Additional PK parameters may be calculated as appropriate. Further details will be specified in the 
SAP.
Values will be calculated for the plasma concentrations and the PK parameters for plasma as listed 
in Section 9.3.1.1 using appropriate summary statistics to be fully outlined in the CPAP.
11.1.5
Immunogenicity Analysis
All immunogenicity data will be summarized using immunogenicity analysis set. 
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Immunogenicity information will be summarized by treatment and point of time collection using 
descriptive statistics as applicable. Additional analysis may be performed on immunogenicity, if 
deemed necessary, such as the relationship between immunogenicity responses and PK/safety.
11.1.6
Safety Analysis
All safety data will be summarized using safety analysis set. The placebo subjects from all cohorts 
will be pooled into a single placebo group for all summaries and presentations.
11.1.6.1
AEs
TEAEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®) and summarized by treatment (cohort) and pooled placebo for the number 
of subjects reporting the TEAE and the number of TEAEs reported. A by-subject AE data listing 
including verbatim term, coded term, severity, and relationship to treatment will be provided.
11.1.6.2
Clinical Laboratory Evaluation
Baseline (check-in), postdose (after start of infusion), and change from baseline to postdose 
laboratory data will be summarized by treatment. Individual results of laboratory tests from 
hematology, chemistry, and urinalysis that meet Takeda’s markedly abnormal criteria will be 
summarized. All clinical laboratory data will be provided in the data listings. All summaries will 
be performed by treatment (cohort) and pooled placebo (placebos pooled from all cohorts).
11.1.6.3
Vital Signs
Baseline (time-match [Day -1]), post-dose (after start of infusion), and change from baseline to 
postdose vital signs data will be summarized by treatment. Individual vital signs results that meet 
Takeda’s markedly abnormal criteria (according to CTCAE) will be summarized. All vital signs 
data will be provided in the data listings. All summaries will be performed by treatment (cohort) 
and pooled placebo (placebos pooled from all cohorts).
11.1.6.4
Other Safety Parameters
Physical examination findings will be presented in the data listings.
Baseline (predose), postdose (after start of infusion), and change from baseline to postdose ECGs 
data will be summarized by treatment (cohort) and pooled placebo (placebos polled from all 
cohorts).
Medical history, and concurrent conditions will be coded using the MedDRA® and concomitant 
medications will be coded using the World Health Organization (WHO) drug dictionary and will 
be listed by subject.
11.2
Interim Analysis and Criteria for Early Termination
No formal interim analysis is planned. Section 6.0 describes the safety, tolerability and PK review 
that will take place after completion of each cohort and before starting of next cohort in the study.
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11.3
Determination of Sample Size
Up to approximately 40 adult subjects (8 per cohort) are planned to be randomized. A formal 
sample size calculation was not performed for this study. The current sample size is deemed 
appropriate to evaluate the safety, tolerability, PK, and PD of TAK-951 following IV
administration. A minimum of 3 cohorts will be evaluated.
12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the CRFs. 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 and by the IRB or IEC.
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 CRFs and associated source documents. It is important that the Investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the Investigator should consult with the Sponsor or 
designee (and IRB or IEC, 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. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the Sponsor should be notified 
immediately. The Investigator guarantees access for quality assurance auditors to all study 
documents as described in Section 12.1.
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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual subjects (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the International Conference on Harminsation (ICH) Harmonised Tripartite Guideline for 
GCP. Each Investigator will conduct the study according to applicable local or regional regulatory 
requirements and align his or her conduct in accordance with the “Responsibilities of the 
Investigator” that are listed in Appendix A. The principles of Helsinki are addressed through the 
protocol and through appendices containing requirements for informed consent and Investigator 
responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The Sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (ie, informed consent form) 
reviewed; and state the approval date. The Sponsor will ship drug/notify site once the Sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the Sponsor has 
received permission from competent authority to begin the study. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the Investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor.
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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
subject and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The Investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the Sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the Investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The Investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the Sponsor may allow a designee of the Investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the Investigator’s site file. The 
Investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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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 PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time prior to analysis. Notify Sponsor 
of consent withdrawal.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the Investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (eg, subject name, address, other identifier fields not 
collected on the subject’s CRF).
13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1
Publication and Disclosure
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the Investigator) without the consent of the Investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
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this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2
Clinical Study Registration 
In order to ensure that information on clinical studies reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical studies it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with Investigator’s city, state (for Americas Investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the Investigator name, address, and phone number to the callers requesting study 
information. Once subjects receive Investigator contact information, they may call the site 
requesting enrollment into the study. The investigative sites are encouraged to handle the study 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of study enrollment, they should be referred to the Sponsor.
Any Investigator who objects to the Sponsor providing this information to callers must provide the 
Sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3
Clinical Study Results Disclosure 
Takeda will post the results of clinical studies on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 
injury. If the Investigator has questions regarding this policy, he or she should contact the Sponsor 
or Sponsor’s designee.
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
Fax: 224-554-1052
Email: PVSafetyAmericas@tpna.com
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14.1.2
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the Sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3
Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.4
List of Abbreviations
g
Microgram
λz
Terminal disposition phase rate constant
AE
Adverse event
AESI
Adverse events of special interest
ADA
Anti-drug antibodies
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUClast
Area under the serum concentration-time curve, from time 0 to the time of the last 
quantifiable concentration, as calculated by the linear trapezoidal.
AUC
Area under the serum concentration versus time curve, from time 0 extrapolated to 
infinity. AUCis calculated as AUClast plus the ratio of the last measurable serum 
concentration to the elimination rate constant.
AV
Atrioventricular
BMI
Body mass index
Ceoi
End of infusion
CFR
Code of Federal Regulations
COVID-19
Coronavirus disease 2019
CTCAE
Common Terminology Criteria for Adverse Events
Cmax
Maximum observed concentration 
CPAP
Clinical Pharmacology Analysis Plan
CRF
Case report form
CRU
Clinical Research Unit
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
F
Absolute bioavailability 
FDA
Food and Drug Administration
FIH
First in human
FSH
Follicle-stimulating hormone
g
Gram
GABA
Gamma aminobutyric acid
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GIP
Glucose insulinotropic peptide
HBsAg
Hepatitis B surface antigen
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HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IU
International units
IV
Intravenous
kg
Kilogram
L
liters
LFT
Liver function test
ln
Natural log
m2
Meters squared
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
mL
Milliliter
mmHg
Millimeter of mercury
msec
Millisecond
NCI
National Cancer Institute
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PTE
Pretreatment event
QTcF
Corrected QT interval by Frederica
RBBB
Right bundle branch block
RNA
Ribonucleic acid
SAD
Single ascending dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SUSARs
Suspected unexpected serious adverse reactions
t½z
Terminal disposition phase half-life
TEAE
Treatment-emergent adverse event
Tmax
Time to first occurrence of Cmax
ULN
Upper limit of normal
US
United States
USA
United States of America
WHO
World Health Organization
X-minute
Duration of infusion
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA®. Drugs will be 
coded using the WHO Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the 
Investigator. The final signed CRFs are provided to the Sponsor in the format as decided upon 
between Celerion and the Sponsor (eg, CD, flashdrive, SFTP). This will be documented in the 
DMP (if applicable).
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The Principal Investigator must review the CRFs for completeness and accuracy and must sign and 
date the appropriate CRFs as indicated. Furthermore, the Investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the CRFs should be made by the Investigator or designee with use of change and modification 
records of the CRFs. The Principal Investigator must review the data change for completeness and 
accuracy, and must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed CRFs 
are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the Sponsor.
15.2
Record Retention
The Investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of CRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the Sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
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and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the Investigator to retain essential documents specified in ICH E6 
(Section 8.0) 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 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the Investigator and Sponsor.
16.0
REFERENCES
1.
National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), 
Revised: Nov-2017 (v5.0). Available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quic
k_Reference_8.5x11.pdf.
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on Investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the Investigator may participate in this study.
The Investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the Investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the Investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
Investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
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10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, 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 
contact and receive written approval from the Sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if so, 
what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(Investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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 PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Male subjects must use highly effective contraception (as defined in the informed consent) 
from dosing, throughout the duration of the study, and until 90 days after dosing. If the female 
partner of the subject is found to be pregnant during the study, the Investigator will offer the 
subject the choice to receive unblinded treatment information. 
26. A statement that clinical study information from this study will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of Investigator, including his or her name, 
address, and other personally identifiable information. In addition, Investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of Investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting Investigator site contact information, study details and results on publicly accessible 
clinical study registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in Investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects
From dosing, throughout the duration of the study, and until 90 days after dosing, nonsterilized** 
male subjects who are sexually active with a female partner of childbearing potential* must use 
barrier contraception (eg, condom with spermicide) or abstain from sexual intercourse. In addition, 
they must be advised not to donate sperm during this period.
Female Subjects and Their Male Partners
* A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral oophorectomy, hysteroscopic sterilization, and bilateral tubal 
ligation or bilateral salpingectomy performed at least 6 months prior to dosing. A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range (FSH >40 IU/L) may be used to 
confirm a post-menopausal state in younger women (eg, those <45 year old) or women who are 
not using hormonal contraception or hormonal replacement therapy. However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.
** No restrictions are required for a vasectomized male provided his vasectomy has been 
performed 4 months or more prior to dosing of study drug. A male who has been vasectomized less 
than 4 months prior to dosing must follow the same restrictions as a non-vasectomized male.
Pregnancy
Women of childbearing potential will not be included in this study.
If any subject is found to be pregnant during the study she should be withdrawn and any 
Sponsor-supplied drug should be immediately discontinued.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator.
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received (blinded or unblinded, as 
applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug 
(including comparator, if applicable) will be followed up to final outcome, using the pregnancy 
form. Pregnancies will remain blinded to the study team. The outcome, including any premature
termination, must be reported to the sponsor. An evaluation after the birth of the child will also be 
conducted.
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Appendix E
Detailed Description of Amendments to Text
Change 1. Flexible wording added to allow more or less cohorts than currently written in the 
protocol as clinical data emerges.
The change occurs in the protocol in Section 1.0 – Study Summary and Section 6.1 – Study Design
Initial 
wording: 
none
Amended or 
new wording:
Cohort 4 and 5 may run concurrently, sequentially or be omitted. Additional 
cohorts may be enrolled however the cohorts will not exceed the highest 
exposure observed in the FIH study.
Change 2.
Remove language restrictions for infusion duration as clinical data for cohort 2 
did not support a 1 mg over less than 60 minutes.
The change occurs in Section 1.0 – Study Summary, Section 6.1 – Study Design, Section 6.4.2 –
Rationale for the Dose, and Section 9.2.8 - Study Drug Administration.
Initial 
wording:
Cohort 3: a high dose (same as the Cohort 2) TAK-951 or placebo administered 
as an IV infusion over a period of less than 60 minutes (TBD) on Day 1.
Cohort 3 will be administered the same dose as Cohort 2, but as a single rapid IV 
infusion administration (rapid rate; duration of X minutes)
Amended or 
new wording
1.0 mg TAK-951 or placebo administered as 120 minutes IV infusion of on Day 
1.
Cohort 3 will receive a 1.0 mg dose as a 120-minute infusion.
Change 3.
Change of modeling and simulation wording to a more accurate description of 
emerging clinical data analysis to determine the next cohort’s dosing regimen
The change occurs in Section 1.0 – Study Summary, Section 3.0 – Schedule of Study Procedures, 
Section 6.1 – Study design, and Section 6.4.2 – Dose Rationale 
Initial 
wording:
…Modeling and simulation 
Amended or 
new wording
…emerging clinical data analysis
Change 4.
Allowance for flexibility in timepoints for Cohort 4 and 5
The change occurs in Section 1.0 – Study Summary and Section 6.1 – Study Design,
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Initial 
wording:
none
Amended or 
new wording:
For Cohort 4 and 5 as applicable, PK sampling and time-matched vital sign 
assessments scheduled relative to infusion timing will be based on emerging 
clinical data analaysis. As such, this timing will be provided in a separate 
document and will not exceed 30 hours post start of infusion. The number of 
planned samples may be less than or equal to those in the protocol.
Change 5.
A second Schedule of Study Procedures table was added for Cohort 3 and any 
infusion longer than 60 minutes with associated footnotes. The original Schedule 
of Study Procedures was retained as it was used for Cohort 1 and 2 and would be 
used if the dosing regimen is less than or equal to 60 minutes. Footnotes were 
added or updated.
The change occurs in Section 3.0 – Schedule of Study Procedures.
Initial 
wording:
None
Amended or 
new wording:
Table titled “Cohort 3 and any Cohort with an Infusion less than or Equal to 
60 minutes”
Change 6. 
The following change indicated in the protocol clarification letter (PCL) dated 30 
Jul 2020 was incorporated: The blood collection and the vital sign measurements 
are to be as close as possible to the exact time point.
The change occurs in Section 9.2 – Clinical Procedures and Assessments
Initial 
wording:
For this study, safety and tolerability is the critical assessment. Procedures, as 
applicable, will be performed in the following the order below, with regard to the 
prescribed time (not applicable for the screening visit).
a.
Holter ECG recording extraction 
b. Safety ECGs
c.
Vital Signs (to be collected as close to the exact time point as possible)
d. Blood sample(s) collection
e.
Standardized meal or snack (meal/snack must be completed at least 1 hour 
before any Holter recording extractions and/or safety ECG)
Amended or 
new wording:
For this study, PK, safety and tolerability is the critical assessment. Procedures, 
as applicable, will be performed with regard to the prescribed time (not 
applicable for the screening visit):
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Study ID TAK-951-1004
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Protocol Incorporating Amendment No. 1
08 January 2021
a. Blood sample collection (to be collected at exact time point)
b. Vital signs (to be collected as close to exact time point as possible)
c. Safety ECG and Holter ECG recording extraction to be performed before or 
after items above, with priority for PK and then vital signs to be collected as 
close to exact time point as possible. 
d. Standardized meal or snack (meal/snack must be completed at least 1 hour 
before any Holter recording extractions and/or safety ECG).
The change occurs in Section 3.0 – Schedule of Study Procedures
Initial 
wording:
The study events at the end of infusion will proceed in this order: Holter ECGs, 
safety ECGs, vital signs, blood samples, meals and snacks.
Admended or 
new wording:
The study events at the end of infusion will proceed in this order: blood samples, 
vital signs, safety ECGs and Holter ECGs, meals and snacks.
Change 7.
The following change indicated in the PCL dated 30 Jul 2020 was incorporated: 
For logistical reasons, the Holter monitoring resting and extraction periods after 
dosing up to the 1 hour time point may have a shorter resting period than the 10 
minutes stipulated in this section. 
The change occurs in Section 9.2.6 – Cardiodynamic ECGs
Initial 
wording:
ECG extraction time points will occur before PK blood draws.
Amended or 
new wording:
ECG extraction time points will occur before or after PK blood draws.
Initial 
wording:
none
Amended or 
new wording:
“During the extractions that are less than 1 hour post start of infusion subjects 
may not have been resting for 10 minutes due to the proximity of sample 
collection.”
Change 8.
The following change indicated in the protocol clarification letter (PCL) dated 30 
Jul 2020 was incorporated: Added language for COVID-19 related safety 
procedures.
The change occurs in Section 1.0 – Study Summary, Section 3.0 – Schedule of Study Procedures, 
Section 6.1 – Study Design, and Section 9.3.5 - Confinement
Initial 
wording:
none
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TAK-951
Study ID TAK-951-1004
Page 76 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
Amended or 
new wording:
In accordance with local regulatory guidance for the COVID-19 pandemic, the 
clinical study unit will implement standard COVID-19 procedures as per their 
internal guidance documents. Subjects may be admitted earlier than Day -2 for 
COVID-19 testing not related to study protocol as per CRU requirements.
The change occurs in Section 1.0 – Study Summary and Section 7.2 – Exclusion Criteria
Initial 
wording:
None
Amended or 
new wording:
23. Positive results for COVID-19 testing at screening or check-in.
The change occurs in Section 9.2.10 - Laboratory Procedures and Assessments
Initial 
wording:
none
Amended or 
new wording:
COVID-19 testing (performed according to CRU standard procedures, provided 
in a separate document[s])
Change 9.
The dose in Cohort 2 was specified based on the actual dose administered in this 
cohort was dosed prior to the writing of this amendment.
The change occurs in Section 1.0 – Study Summary, Section 6.4.2 – Rationale for the Proposed 
Study, Section 6.1 – Study Design and Section 9.2.8 – Study Drug Administration
Initial 
wording:
“TBD” or “To be determined”
Amended or 
new wording:
1.0 mg
Initial 
wording:
The dose level in Cohort 2 and 3 will be the same. The duration (X-minute) of 
Cohort 3 infusion will be less than 60 minutes. 
Amended or 
new wording:
none
Change 10. 
Clarifying infusion duration
In the protocol in Section 4.2 - Ratoinal for the proposed study.
Initial 
wording:
Infusion duration for subsequent cohorts may be faster or slower than 60 minutes 
and will be determined based upon data from previous cohorts
Amended or 
new wording:
Infusion duration for subsequent cohorts may be longer or shorter than 
60 minutes and will be determined based upon emerging clinical data analysis 
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TAK-951
Study ID TAK-951-1004
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Protocol Incorporating Amendment No. 1
08 January 2021
from previous cohorts
Change 12. 
The rationales for proposed study and dose were updated to match the known 
dose levels.
In the protocol Section 4.2 – Rationale for the Proposed Study
Initial 
wording:
To that end, this study is designed as a phase 1, randomized, double-blind, 
placebo-controlled study to evaluate the safety, tolerability, and PK of TAK-951 
in at least 3 cohorts of healthy adult subjects following a single IV infusion 
administration with at least two dose levels and different infusion rates, slow 
infusion, 60-minute, and a rapid rate(s).
Amended or
updated 
wording:
To that end, this study is designed as a phase 1, randomized, double-blind, 
placebo-controlled study to evaluate the safety, tolerability, and PK of TAK-951 
in at least 3 cohorts of healthy adult subjects following a single IV infusion 
administration with at least two dose levels. Infusion duration for the first two 
cohorts will be 60 minutes. Infusion duration for subsequent cohorts may be 
faster or slower than 60 minutes and will be determined based upon data from 
previous cohorts.
In the protocol Section 6.4.2 –Rationale for Dose
Intial 
wording:
Cohort 2 will receive a higher dose as a 60-minute infusion. 
Cohort 3 will be administered the same dose as Cohort 2, but as a single rapid IV 
infusion administration (rapid rate; duration of X-minute).
Additional cohorts (Cohorts 4 and 5) may be added to explore additional IV 
dosing regimens ensuring the predicted exposure (based on modeling and 
simulation with all previous PK data) will not be exceeding the exposure seen at 
the highest dose deemed to be safe in SAD portion of the FIH study.
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Study ID TAK-951-1004
Page 78 of 78
Protocol Incorporating Amendment No. 1
08 January 2021
Amended or 
updated 
wording:
Cohort 2 will receive a 1.0 mg as a 60-minute infusion. 
Cohort 3 will receive a 1.0 mg dose as a 120-minute infusion.
Additional cohorts (Cohorts 4 and 5) may be added to explore additional IV 
dosing regimens ensuring the predicted exposure will not be exceeding the 
exposure seen at the highest dose deemed to be safe in SAD portion of the FIH 
study.
For Cohort 4 and 5, as applicable, PK sampling and time-matched vital sign 
assessments scheduled relative to infusion timing will be based on emerging 
clinical data analysis. As such, this timing will be provided in a separate 
document and will not exceed 30 hours post start of infusion. The number of 
planned samples may be less than or equal to those in the protocol.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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(dd-MMM-yyyy HH:mm ‘UTC’) 
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects Following Intravenous 
Administration
NCT Number: NCT04486950
SAP Approve Date: 13 May 2021
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


STATISTICAL ANALYSIS PLAN
Study Number: TAK-951-1004
A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety,
Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects Following Intravenous 
Administration
Phase 1 
Version: Final
Date: 13 May 2021
Prepared by: 
Based on:
Original Protocol Dated: 07-May-2020
Protocol Amendment 1 Dated: 08-Jan-2021
PPD
Property of Takeda: Fo
inal
inal Pro
Pr
l
Use Only and Subject to the Applicable Terms of Use
luate th
uate t
l
ollowing
owing
rotocol
rotoco
For Non-Commercial Us


TAK-951-1004
Celerion Study Number CA29416
Page 2 of 27
Statistical Analysis Plan Final
13 May 2021
REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
Original version
13-MAY-2021
[Not Applicable]
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TAK-951-1004
Celerion Study Number CA29416
Page 3 of 27
Statistical Analysis Plan Final
13 May 2021
Approval Signatures
Electronic signature can be found on the last page of this document.
Study Title:
A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-951 in 
Healthy Subjects Following Intravenous Administration
Approvals:
Date
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
dy toto
y
AK-951 
95
Only and Subject 


TAK-951-1004
Celerion Study Number CA29416
Page 4 of 27
Statistical Analysis Plan Final
13 May 2021
TABLE OF CONTENTS
1.0
OBJECTIVES, ENDPOINTS, AND ESTIMANDS.........................................................8
1.1
Objectives..................................................................................................................8
1.1.1
Primary Objective..............................................................................................8
1.1.2
Secondary Objectives ........................................................................................8
1.1.3
Exploratory Objective........................................................................................8
1.2
Endpoints...................................................................................................................8
1.2.1
Primary Endpoint...............................................................................................8
1.2.2
Secondary Endpoints .........................................................................................8
1.2.3
Additional Endpoints.........................................................................................9
1.3
Estimand(s)................................................................................................................9
2.0
STUDY DESIGN............................................................................................................9
3.0
STATISTICAL HYPOTHESES AND DECISION RULES...........................................12
3.1
Statistical Hypotheses..............................................................................................12
3.2
Statistical Decision Rules.........................................................................................12
3.3
Multiplicity Adjustment...........................................................................................12
4.0
SAMPLE-SIZE DETERMINATION.............................................................................12
5.0
ANALYSIS SETS.........................................................................................................13
5.1
Safety Analysis Set..................................................................................................13
5.2
PK Analysis Set.......................................................................................................13
5.3
Immunogenicity Analysis Set ..................................................................................13
5.4
PD Analysis Set.......................................................................................................13
5.5
Immunogenicity/PK Analysis Set ............................................................................13
6.0
STATISTICAL ANALYSIS..........................................................................................13
6.1
General Considerations............................................................................................13
6.1.1
Handling of Treatment Misallocations .............................................................15
6.2
Study Information....................................................................................................15
6.3
Disposition of Subjects ............................................................................................15
6.4
Demographic and Other Baseline Characteristics.....................................................15
6.4.1
Demographics..................................................................................................15
6.4.2
Medical History and Concurrent Medical Conditions.......................................15
6.5
Medication History and Concomitant Medications...................................................16
6.6
Efficacy Analysis.....................................................................................................16
6.7
Safety Analysis........................................................................................................16
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Celerion Study Number CA29416
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Statistical Analysis Plan Final
13 May 2021
6.7.1
Adverse Events................................................................................................16
6.7.2
Adverse Events of Special Interest (if applicable) ............................................18
6.7.3
Clinical Laboratory Assessments .....................................................................18
6.7.4
Vital Signs.......................................................................................................19
6.7.5
Electrocardiograms..........................................................................................20
6.7.6
Physical Examination ......................................................................................20
6.7.7
Overdose .........................................................................................................21
6.7.8
Other Safety Analysis (if applicable) ...............................................................21
6.7.9
Extent of Exposure and Compliance ................................................................21
6.7.10
Immunogenicity Analysis ................................................................................21
6.8
Pharmacokinetic and Pharmacodynamic Analyses ...................................................22
6.8.1
Pharmacokinetic Analysis................................................................................22
6.8.2
Pharmacodynamic Analysis.............................................................................23
6.9
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis...................................................................................................................24
6.10
Preliminary Analysis................................................................................................24
6.11
Interim Analysis ......................................................................................................24
6.12
Data Monitoring Committee/Internal Review Committee.........................................24
6.13
Additional Analysis Related to COVID ...................................................................25
7.0
REFERENCES..............................................................................................................25
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES ................................................25
9.0
APPENDIX...................................................................................................................25
LIST OF IN-TEXT TABLES
Table 2.a
Planned Dose Levels of TAK-951......................................................................11
Table 2.b
Treatment Descriptions ......................................................................................11
Table 6.a
Vital Signs Collection (Cohorts 1 and 2) ............................................................19
Table 6.b
Vital Signs Collection (Cohort 3).......................................................................19
Table 6.c
Vital Signs Collection (Cohort 4).......................................................................19
Table 6.d
Reporting Thresholds for Orthostatic Vital Signs on Day 1 ................................20
Table 6.e
Collection of Blood Samples for Pharmacokinetic Analysis (Cohorts 1 and 2) ...22
Table 6.f
Collection of Blood Samples for Pharmacokinetic Analysis (Cohort 3)..............22
Table 6.g
Collection of Blood Samples for Pharmacokinetic Analysis (Cohort 4)..............22
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Celerion Study Number CA29416
Page 6 of 27
Statistical Analysis Plan Final
13 May 2021
LIST OF IN-TEXT FIGURES
Figure 2.a
Study Schematic ................................................................................................12
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TAK-951-1004
Celerion Study Number CA29416
Page 7 of 27
Statistical Analysis Plan Final
13 May 2021
ABBREVIATIONS
ADA
anti-drug antibodies
AE
adverse event
AUCextrap%
percent of AUC∞extrapolated
AUClast
area under the TAK-951 plasma concentration-time curve from time 0 to the time of the last 
quantifiable concentration
AUC∞
area under the TAK-951 plasma concentration-time curve from time 0 to infinity
BLQ
below the lower limit of quantitation 
BP
blood pressure 
Ceoi
TAK-951 plasma concentration at end of infusion
CFB
change from baseline
CL
total clearance after IV administration
COVID-19
coronavirus disease 2019
CPAP
Clinical Pharmacology Analysis Plan
CRF
case report form
CRU
clinical research unit
CV%
arithmetic percent coefficient of variation
DN
dose-normalized
ECG
electrocardiogram
FIH
first-in-human
Geom CV%
geometric percent coefficient of variation
Geom mean
geometric mean
HR
heart rate 
IV
Intravenous
mean
arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
n
number of observations
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PD
pharmacodynamic
PK
pharmacokinetic
SAE
serious adverse event
SD
standard deviation
SEM
standard error of the mean
TBD
to be determined
TFL
table, figure, and listing
tmax
time of first occurrence of Ceoi
t½z
terminal disposition phase half-life
Vz
volume of distribution during the terminal disposition phase after IV administration, calculated 
using the observed value of the last quantifiable concentration
λz
terminal disposition phase rate constant 
Note: The PK parameters presented in the clinical study report and in the in-text tables will be subscripted, whereas the PK 
parameters presented in the end-of-text tables will not be subscripted. In addition, AUC∞and z will be presented as AUCinf and 
Lambdaz in the end-of-text tables, respectively.
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TAK-951-1004
Celerion Study Number CA29416
Page 8 of 27
Statistical Analysis Plan Final
13 May 2021
1.0
OBJECTIVES, ENDPOINTS, AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objective
To evaluate the overall safety and tolerability of a single intravenous (IV) infusion of TAK-951 
administered with at least 2 different infusion rates (rapid and slow) at the same dose level in 
healthy subjects.
1.1.2
Secondary Objectives
∀
To assess the pharmacokinetics (PK) of TAK-951 following a single IV infusion of TAK-951 
in healthy subjects.
∀
To assess for anti-drug antibodies (ADA) following a single IV infusion of TAK-951 in 
healthy subjects.
1.2
Endpoints
1.2.1
Primary Endpoint
The primary endpoint of the study is safety and tolerability as assessed through adverse events 
(AEs), vital signs, safety electrocardiograms (ECGs)/telemetry, safety laboratory assessments, 
and physical examinations.
1.2.2
Secondary Endpoints
Secondary endpoints will be assessed through evaluation of the following PK parameters:
∀
Area under the TAK-951 plasma concentration-time curve from time 0 to infinity (AUC∞)
∀
TAK-951 plasma concentration at end of infusion (Ceoi)
∀
Area under the TAK-951 plasma concentration-time curve from time 0 to the time of the last 
quantifiable concentration (AUClast)
∀
Terminal disposition phase half-life (t½z)
∀
Terminal disposition phase rate constant (λz)
CCI
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TAK-951-1004
Celerion Study Number CA29416
Page 9 of 27
Statistical Analysis Plan Final
13 May 2021
Immunogenicity: 
∀
Anti-drug antibodies titer
1.3
Estimand(s)
Not applicable.
2.0
STUDY DESIGN
This is a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, and PK of TAK-951 administered intravenously in healthy adult subjects. 
At least 3 cohorts of 8 subjects each will be dosed sequentially. Subjects from each cohort will be 
admitted into the clinical research unit (CRU) on Day -2. On Day -1, baseline heart rate and 
blood pressure assessments will be taken, time-matched to the Day 1 assessments. Subjects will 
receive a single dose with TAK-951 or matching placebo on Day 1, according to the 
CCI
Property of Takeda:
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a: For Non-Commercial Use Only and Subject to the Applicable Terms o


TAK-951-1004
Celerion Study Number CA29416
Page 10 of 27
Statistical Analysis Plan Final
13 May 2021
randomization scheme, after a minimum of 8 hours of fasting. Subjects will be randomized to 
receive TAK-951 or matching placebo in a 6:2 ratio in a double-blind manner. PK samples will 
be taken up to 30 hours after the start of infusion. Subjects will be discharged after the 
completion of the study assessments on Day 2.
All subjects who received any amount of study drug (including subjects who terminate the study 
early) will return to the CRU 14 (±2) and 28 (±3) days after dosing for follow-up procedures, 
and to determine if any AE has occurred since the last study visit.
Two (2) additional cohorts may be enrolled (for a total of 5 cohorts), each cohort with 8 
subjects, to explore additional IV dosing regimens. In total, the enrollment will be approximately 
40 subjects. Dosing of the subsequent cohort will be based on the analysis of the previous 
cohort’s data; however, the cohorts will not exceed the highest exposure observed in the first-in-
human (FIH) study.
For Cohort 4 and 5, PK sampling and time-matched vital sign assessments scheduled relative to 
infusion timing will be based on emerging clinical data analysis. As such, this timing will be 
provided in a separate document and will not exceed 30 hours post start of infusion. The number 
of planned samples may be less than or equal to those in the protocol. 
A staggered dosing approach will be used. The sentinel subjects will be dosed at least 24-hours 
before the remaining 6 subjects in each cohort. In each cohort, after dosing the first 2 subjects 
(the sentinel group - 1 receiving TAK-951 and 1 receiving placebo) the Investigator will review
all available blinded safety and tolerability data up to 8 hours postdose. If after dosing the 
sentinel group, the Investigator and the Sponsor agree that there are no significant 
safety/tolerability concerns, then the rest of the cohort will be dosed. There will be at least 1 
hour between dosing of each subject in each cohort, except for the sentinel subjects. A dose-
escalation/blinded safety review meeting will be held between the Investigator and Sponsor after 
each cohort is completed to review the safety and available PK data from samples taken up to 1-
day postdose, in order to confirm the dose level and/or infusion rate for the subsequent cohort. 
PK data from the first low dose cohort is required to allow dosing of the high dose for the second 
and third cohorts and the determination of the rate of infusion for the third cohort. The dose and 
infusion rate for Cohort 4 and 5 will be selected based on emerging clinical data analysis and is 
not expected to exceed the highest exposures seen in the FIH TAK-951-1001 study.
Sponsor is to remain blinded during the review of available safety and PK data. Once a decision 
is made to proceed to the next cohort, the Sponsor may be unblinded following dose 
escalation/safety meetings to allow additional analysis.
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TAK-951-1004
Celerion Study Number CA29416
Page 11 of 27
Statistical Analysis Plan Final
13 May 2021
The dose and rate for Cohorts 4 and 5 will be determined by clinical data analysis so as not to 
exceed the highest exposure seen in the currently ongoing FIH study (TAK-951-1001). Cohorts 4 
and 5 may run concurrently, sequentially, or be omitted. 
Safety will be assessed by monitoring for AEs, vital signs, safety 12-lead ECGs/telemetry, safety 
laboratory assessments, and physical examinations throughout the study.
Immunogenicity will be assessed prior to dosing and approximately 14 and 28 days after dosing.
In accordance with local regulatory guidance for the coronavirus disease 2019 (COVID-19) 
pandemic, the clinical study unit will implement standard COVID-19 procedures as per their 
internal guidance documents. Subjects may be admitted earlier than Day -2 for COVID-19 
testing not related to study protocol as per CRU requirements.
Note: After review of the data by the Sponsor it was decided that only one additional cohort 
would be added to the study.
The planned dose levels of TAK-951 to be evaluated are outlined in the table below: 
Table 2.a
Planned Dose Levels of TAK-951
Cohort#
Total Dose
Infusion Duration
Cohort 1
20 µg and matching placebo
60-minute
Cohort 2
1.0 mg and matching placebo
60-minute 
Cohort 3
1.0 mg and matching placebo 
120-minute
Cohort 4
1.0 mg and matching placebo
180-minute 
Treatment descriptions to be evaluated are outlined in the table below: 
Table 2.b
Treatment Descriptions
Treatment A
A single 60-minute IV infusion of 20 µg TAK-951 administered to healthy subjects on Day 1 
(Cohort 1)
Treatment B
A single 60-minute IV infusion of 1.0 mg TAK-951 administered to healthy subjects on Day 1 
(Cohort 2)
Treatment C
A single 120-minute IV infusion of 1.0 mg TAK-951 administered to healthy subjects on Day 
1 (Cohort 3)
Treatment D
A single 180-minute IV infusion of 1.0 mg TAK-951 administered to healthy subjects on Day 
1 (Cohort 4)
Treatment P1
A single 60-minute IV infusion of placebo (normal saline) administered to healthy subjects on 
Day 1 (Pooled)
Treatment P2
A single 120-minute IV infusion of placebo (normal saline) administered to healthy subjects on 
Day 1 (Pooled)
Treatment P3
A single 180-minute IV infusion of placebo (normal saline) administered to healthy subjects on 
Day 1 (Pooled)
* : placebo subjects will be pooled according to the length of infusion (i.e, 60, 120, or 180 minutes). 
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The study schematic is presented in the figure below: 
Figure 2.a
Study Schematic
3.0
STATISTICAL HYPOTHESES AND DECISION RULES 
3.1
Statistical Hypotheses
Not applicable. 
3.2
Statistical Decision Rules
Not applicable.
3.3
Multiplicity Adjustment
Not applicable. 
4.0
SAMPLE-SIZE DETERMINATION
Up to approximately 40 adult subjects (8 per cohort) are planned to be randomized. A formal 
sample size calculation was not performed for this study. The current sample size is deemed 
Day -2: 
admit to 
clinical unit 
Day -1:  
time-
matched 
vital signs
Day 1:  
dose with 
TAK-951 IV 
or 
matching 
placebo
Day 2:
~30 hrs 
postdose 
discharge 
from 
clinical unit
Day 15 (±2):
follow up 
visit 
Day 29 
(±3): 
final follow 
up visit  
Study schematic per cohort. Dosing of subsequent cohorts is based on dose escalation criteria. Within a cohort, 
sentinel subjects will be dosed at least 24 hours before the remaining subjects. There will be at least 1 hour 
between dosing of each subject in each cohort, except for the sentinel.
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appropriate to evaluate the safety, tolerability, PK, and PD of TAK-951 following IV 
administration. A minimum of 3 cohorts will be evaluated.
5.0
ANALYSIS SETS
5.1
Safety Analysis Set
The safety analysis set will consist of all subjects who are enrolled and received the full or 
partial dose of study drug or placebo.
5.2
PK Analysis Set 
The PK analysis set will consist of all subjects who received the active study drug and have at 
least one measurable plasma concentration of TAK-951.
All subjects who comply sufficiently with the protocol and display an evaluable PK profile (eg, 
exposure to treatment, availability of measurements and absence of major protocol violations) 
will be included in the descriptive statistics.
5.3
Immunogenicity Analysis Set 
The immunogenicity analysis set will include those subjects from the safety analysis set who have 
a baseline and at least 1 postdose immunogenicity sample assessment.
5.4
PD Analysis Set
The PD analysis set will consist of all subjects who received the study drug or placebo and have 
at least one measurable time-matched Day -1 and Day 1 PD effect (semi-recumbent HR and 
semi-recumbent BP).
5.5
Immunogenicity/PK Analysis Set
The immunogenicity/PK analysis set will consist of all subjects in the PK set with a baseline and 
at least 1 postdose immunogenicity sample assessment.
6.0
STATISTICAL ANALYSIS
6.1
General Considerations
All PK analyses will be conducted using Phoenix® WinNonLin® Version 8.1, or higher. All 
statistical analyses will be conducted using SAS® Version 9.4. All data recorded on the case 
report form (CRF) will be listed by subject. All tables, figures, and listings (TFLs) shells and 
numbering list will be included and specified in the TFL Shells document.
The number of observations (n) will be presented as an integer (no decimal places), arithmetic 
mean (mean), median, and geometric mean (geom mean) values will be presented to 1 more 
level of precision than the individual values. Standard deviation (SD) and standard error of the 
mean (SEM) will be presented to 2 more levels of precision than the individual values. Minimum 
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and maximum values will be presented to the same precision as the individual values. Arithmetic
percent coefficient of variation (CV%) and geometric percent coefficient of variation (geom 
CV%) will be presented to 1 decimal place.
Concentration values below the lower limit of quantitation (BLQ) will be presented as ‘BLQ’ in 
the concentration table listings and footnoted accordingly. BLQ values will be treated as zero, 
and in the calculation of descriptive statistics, the generation of concentration plots, and the 
calculation of PK parameters, unless they are obvious outliers (e.g., BLQ value between 
measurable values), in which case they will be treated as missing.
A subject’s PK parameter data will be included in the listings but excluded from the descriptive 
statistics if one or more of the following criteria are met: 

A predose (0 hr) concentration is greater than 5% of that subject’s maximum concentration 
value in that period.

A subject did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist).

A subject deviates substantially from the protocol defined study procedures including but not 
limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist).
The details on PK parameter calculations and TFLs will be outlined in the Clinical 
Pharmacology Analysis Plan (CPAP) and TFL Shell document including specifics on the 
following:

Insufficient data to determine a reliable t1/2z value and other z-dependent parameters.

PK parameters presented by treatment, including the units, precision, and summary statistics 
that will be presented in in-text and end-of-text tables.

Concentration data presented by treatment, including the units, precision, and summary 
statistics that will be presented in end-of-text tables.

Concentration data file used for PK analysis.

PK parameter WinNonlin® output file used to generate the TFLs.

Arithmetic mean concentration-time figures presented as in-text and end-of-text figures.

Individual concentration-time figures presented in Appendix 16.2.6.
For safety analysis only, the semi-recumbent HR and BP baseline is defined as Day 1 predose. 
For orthostatic HR and BP, the time-matched changes at each time point will be derived. In 
addition, the time-matched changes on Day 1 versus Day -1 will also be derived for semi-
recumbent HR and BP as part of the PD analysis. 
Placebo subjects will be pooled for summaries according to the length of infusion.
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For demographic and safety data where appropriate, variables will be summarized descriptively. 
For the categorical variables, the count and percentage of each possible value will be tabulated, 
where applicable. The denominator for the proportion will be based on the number of subjects 
who provided non missing responses to the categorical variable. For continuous variables, the 
number of subjects with non-missing values, mean, SD, minimum, median, and maximum values 
will be tabulated. The level of precision will be presented as follows: minimum/maximum in the 
same precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be presented 
as an integer. Counts and percentages will be presented as integers.
6.1.1
Handling of Treatment Misallocations
Subjects who are misallocated treatments will be analyzed per the treatment received rather than 
the treatment they were randomized to. 
6.2
Study Information
A study information table will be generated including the following items: date of first subject’s 
signed informed consent form, date of first dose, date of last dose, date of last subject’s last 
visit/contact, date of last subject’s last procedure for collection of data for primary endpoint, the 
version of Medical Dictionary for Regulatory Activities (MedDRA®), the version of World 
Health Organization (WHO) Dictionary, and SAS version used for creating the datasets.
6.3
Disposition of Subjects
Disposition of subjects (number of subjects dosed, completed the study, discontinued from the 
study, and reason(s) for discontinuation) will be summarized by treatment and overall active 
treatment. Study completion status, including reason for discontinuation, will also be listed by 
subject. 
6.4
Demographic and Other Baseline Characteristics
6.4.1
Demographics
Demographic and baseline characteristics will be summarized descriptively by treatment and 
overall active treatment. Summary statistics (n, mean, SD, minimum, median, and maximum) 
will be generated for continuous variables (age [recorded in the CRF], weight, height and body 
mass index [BMI]) and the number and percentage of subjects within each category will be 
presented for categorical variables (sex, race, and ethnicity). Height, weight, and BMI recorded 
at screening will be used in the baseline summaries. Demographics data will also be listed as 
recorded on the CRF, including the date of informed consent.
6.4.2
Medical History and Concurrent Medical Conditions
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing the 
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informed consent form (ICF). Concurrent medical conditions are those significant ongoing 
conditions or diseases that are present at signing the ICF. Each subject’s medical history and 
concurrent medical conditions will be listed. Any medical condition started after taking the study 
drug(s) will be classified as an adverse event. All medical history will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA®) Version 23.0. If appropriate, the 
medical history listing will include whether the event was medical or surgical, the body system 
or organ class involved, coded term, start date (if known) and end date or whether the condition 
was ongoing, and a description of the condition or event. There will be no statistical analysis of 
medical history.
6.5
Medication History and Concomitant Medications 
Medication history to be obtained includes any medication relevant to eligibility criteria and 
safety evaluation stopped at or within 28 days prior to signing the ICF. Concomitant medication 
includes any medication other than study drug taken at any time between time of signing the ICF 
through the end of the study (including follow-up visit). All medication history and concomitant 
medications recorded during the study will be coded with the WHO Dictionary Version 01-Mar-
2020 b3 and listed. If appropriate, the listing will include the medication name, coded term, 
dosage, route of administration, start date and time (if known), end date and time, or whether it 
continued after study completion, and indication for use.
6.6
Efficacy Analysis
Not applicable. 
6.7
Safety Analysis
For each treatment group, safety and tolerability will be assessed through incidence, severity and 
type of adverse events. Safety will also be assessed through changes from baseline in subjects’ 
vital signs, safety ECGs and clinical laboratory assessments; along with symptom-driven 
physical examinations. All safety data will be listed by treatment, subject, and assessment time 
points, including rechecks, unscheduled assessments, and early termination, chronologically. 
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators.
6.7.1
Adverse Events
All AEs captured in the database will be listed, by treatment and subject, in data listings 
including; age/sex, weight, race, verbatim term, coded term, time from last dose, onset date/time, 
and resolution date/time. A separate listing, by treatment and subject will present frequency, 
severity, seriousness, outcome, action relative to study drug, relationship to study drug (related 
or not related), and whether AE was of special interest as recorded in the CRF. All AEs 
occurring during this study will be coded using MedDRA® Version 23.0. However, only 
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treatment-emergent adverse events (TEAEs) occurring after the start of infusion will be 
summarized. A TEAE is defined as any AEs newly occurring or worsening from the first dose 
and 14 days after last dose of study drug. A pre-treatment AE is defined as any AEs newly 
occurring or worsening before the first dose. 
All AEs, including TEAEs, will be severity graded according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0, with grading levels 1 to 
5 which correspond to mild, moderate, severe or medically significant but not immediately life-
threatening, life-threatening, and fatal. 
TEAEs will be tabulated by System Organ Class (SOC) and Preferred Term. Summaries will be 
presented by treatment including placebo. Only for the overview summary of TEAEs, will AEs 
be summarized with both number of events and number of subjects reporting events. Summary 
tables for AE frequency will be presented in two forms, one to include number of subjects 
reporting the AE (including percent of safety analysis set), and one for number of events. TEAEs 
and serious adverse events will be presented in this similar way. A summary table will be 
generated for most commonly reported non-serious TEAEs (i.e., those events reported by >5% of 
all subjects in each treatment, excluding serious adverse events [SAEs]). Additional TEAE 
summary tables will be presented by number of subjects for severity and relationship to study 
drug. A separate summary will be presented for TEAEs with a severity grade 3 or higher by 
relationship to study drug. TEAEs leading to discontinuation, pretreatment AEs, AEs of special 
interest (AESIs), and all-cause mortalities will be presented separately in the listings.
The following guidelines will be applied for the summary of AEs:

AEs with missing or unknown intensity will be considered as severe (or Grade 3). 

AEs with missing or unknown relationship to study drug will be counted as related. 

A subject with 2 or more AEs within the same level of the MedDRA term will be counted 
only once in that level.

SOCs will be sorted in alphabetical order. Within an SOC, adverse events will be sorted in 
descending order of total number of subjects with the preferred term among all the treatment 
groups.

For the summary of TEAEs by SOC and PT and intensity (toxicity grade), if a subject 
experiences more than 1 episode of a particular coded adverse event, the subject will be 
counted only once by the maximum toxicity grade of the episode (preferred term). Similarly, 
if a subject has more than 1 adverse event within an SOC, the subject will be counted only 
once by the maximum toxicity grade in that SOC.

For the summary of TEAEs by SOC and PT and relationship to study drug, if a subject 
experiences more than 1 episode of a particular coded adverse event, the subject will be 
counted only once by the closest relationship to the study drug of the episode (preferred 
term). Similarly, if a subject has more than 1 adverse event within an SOC, the subject will 
be counted only once by closest relationship to study drug in that SOC.
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6.7.2
Adverse Events of Special Interest (if applicable)
AESIs for TAK-951 include injection site reactions, hypotension, hypersensitivity, and sinus 
tachycardia of CTCAE grade 2 or higher. AESIs include those indicated by the PI on the CRF 
and those derived from the MedDRA terms below. AESIs will be listed.
AESIs
MedDRA Terms or definitions
Injection site reaction
Injection Site Reaction (HLT)
Hypotension
Hypotension (PT)
Hypersensitivity
Hypersensitivity reaction (SMQ)
Sinus Tachycardia 
Tachycardia (PT)
6.7.3
Clinical Laboratory Assessments
Hematology, serum chemistry, and urinalysis will be performed at screening, check-in (Day -2), 
Day 1 (after infusion), Day 2, and early termination (if applicable). Urine drug screening will be 
carried out at screening and check-in (Day-2) only. In addition, laboratory safety tests may be 
performed at various unscheduled time points, if deemed necessary by the Principal Investigator 
(PI). 
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by treatment (including placebo), and 
assessment time points. Data will be summarized from baseline (check-in) and presented along 
with the change from baseline. Baseline is defined as the last assessment including rechecks 
taken prior to the start of infusion (generally Day -2). All clinical laboratory listings and tables 
will be presented in conventional units, except for the markedly abnormal value analysis which 
will be presented in SI units.
For each laboratory test, a shift table will be developed comparing the frequency and percentage 
of the results at baseline (above normal (H), normal (N), or below normal (L)) with the postdose 
time points. For urinalysis tests, the categories are normal (N) and abnormal (A). Out-of-range 
values and corresponding recheck results will be listed. 
Additionally individual results of laboratory tests from serum chemistry and hematology that 
meet Takeda’s markedly abnormal criteria (see Appendix A) will be summarized.
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. If a value fails the reference range, it will 
automatically be compared to a laboratory clinically significant (CS) range. If the value falls 
within the CS range, it will be noted as “N” for not clinical significant. If the value fails the CS 
range, it will be flagged with a “Y” which prompts the PI to determine how the out-of-range 
value should be followed using 4 Investigator flags: "N", not clinically significant, "R", 
requesting a recheck, "^", checking at the next scheduled visit, or "Y", clinically significant. 
Additionally, the PI will provide a 4th flag when the 3rd flag indicates “R” or “^”. This 4th flag 
is intended to capture final CS (+)/NCS (-) when the 3rd flag does not document significance. 
All clinically significant laboratory tests, as indicated by the PI, and the corresponding values 
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will be listed by subject. All clinical laboratory data will be presented in by-subject data listings. 
CS results will also be presented as part of the listings.
6.7.4
Vital Signs
Vital sign measurements consist of body temperature, respiratory rate, BP, and HR. Temperature 
and respiratory rate will be collected at screening only. Orthostatic measurements for BP and HR 
will also be collected at screening and at the time points detailed below. HR and BP, for the 
different study cohorts, will be collected at the time points (and early termination if applicable) 
outlined in the table below: 
Table 6.a
Vital Signs Collection (Cohorts 1 and 2)
Assessment
Days
Scheduled Time (Hours)*
HR^
Day -1 and Day 1
0.083, 0.17 0.25, 1 (EOI), 1.25, 1.5, 12, 30$
BP^
Day -1 and Day 1
0.25, 1 (EOI), 1.25, 1.5, 12, and 30$
Orthostatic VS&
Day -1 and Day 1
predose and 0.5, 2, 4, 8, and 24$
Table 6.b
Vital Signs Collection (Cohort 3)
Assessment
Days
Scheduled Time (Hours)*
HR^
Day -1 and Day 1
0.25, 0.5, 1.5, 2 (EOI), 2.083, 2.25, 12, 30$
BP^
Day -1 and Day 1
0.25, 0.5, 1.5, 2 (EOI), 2.25, 12, 30$
Orthostatic VS&
Day -1 and Day 1
predose and 1, 2.5, 3, 5, 8, 24$
Table 6.c
Vital Signs Collection (Cohort 4)
Assessment
Days
Scheduled Time (Hours)*
HR^
Day -1 and Day 1
0.25, 0.5, 1.5, 2.5, 3 (EOI), 3.25, 12, 30$
BP^
Day -1 and Day 1
0.25, 0.5, 1.5, 2.5, 3 (EOI), 12, 30$
Orthostatic VS&
Day -1 and Day 1
predose and 1, 2, 3.5, 4, 7, 24$
*: The actual date and time of sample collection will be recorded on the source document in the case report form.
^: When scheduled after the start of infusion, vital signs will be performed within approximately 15 minutes of the 
scheduled time point.
$: Day 1 only.
&: Orthostatic VS include semi-recumbent and standing BP and HR measurements.
BP and HR measurements (excluding orthostatic VS) will be performed in duplicate and then an 
average taken which will be used for the final result of both.
The following safety vital sign parameters will be evaluated in this study: 

Absolute semi-recumbent HR.
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
Absolute semi-recumbent BP.

Change from baseline semi-recumbent HR.

Change from baseline semi-recumbent BP.
Absolute semi-recumbent HR and semi-recumbent BP will be listed and summarized 
descriptively by treatment and collection time using the following descriptive statistics: n, mean, 
SD, CV%, SEM, minimum, median, and maximum. Change from baseline for semi-recumbent 
HR and semi-recumbent BP will be also be summarized descriptively by treatment and 
collection time. Baseline will be defined as the Day 1 predose value. Excluded data will be 
presented and footnoted as such in the table listings, and those values will be excluded from the 
descriptive statistics. Any negative change from baseline values will be left as is.
The arithmetic mean absolute values and change from baseline profiles for semi-recumbent HR
and semi-recumbent BP will be presented by treatment on linear scale with and without SD. 
Additionally, counts and percentages of orthostatic vital signs will be summarized according to 
the following reporting thresholds for postdose Day 1 data only:
Table 6.d
Reporting Thresholds for Orthostatic Vital Signs on Day 1
Change in HR (bpm)
Change in Systolic BP (mmHg)
Change in Diastolic BP (mmHg)
≥30
≤-20
≤-10
Individual vital signs results that meet Takeda’s markedly abnormal criteria (see Appendix B) 
will be summarized. All vital sign collected as per the CRF will be presented in a by-subject 
listing.
6.7.5
Electrocardiograms
12-lead ECGs will be collected at screening, Day -1, Day 1 (predose) and Day 2 (also at early 
termination if applicable). ECGs will be measured in triplicate with an average taken as the final 
result. Additional unscheduled ECGs may be recorded at other times if deemed necessary by the 
PI. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results and change from baseline by treatment (including placebo) and time point of collection. 
Baseline is defined as the last assessment including rechecks taken prior to dosing. Baseline, 
postdose, and change from baseline will be summarized. ECG data will also be displayed in a 
data listing by subject.
6.7.6
Physical Examination
Physical examination will be performed at screening. Symptom-driven physical exams may be 
performed at other times at the discretion of the PI. Physical exam findings will be presented in 
the data listings by subject. Reproductive system findings will also be listed by subject.
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6.7.7
Overdose 
All cases of overdose will be presented in a data listing by subject. Any AEs associated with
overdose will be documented as AEs. 
6.7.8
Other Safety Analysis (if applicable)
Holter ECG and telemetry monitoring will be performed but the data will not be presented in the 
CSR.
Any additional safety analysis not addressed within this SAP will be considered out of scope and 
must be described in the CSR.
6.7.9
Extent of Exposure and Compliance
The date, time, treatment will be listed by subject. 
6.7.10
Immunogenicity Analysis
The ADA data will be assessed with the baseline sample and the post baseline samples. The 
formation of ADAs such as IgM can occur 7 to 14 days after study drug administration. In this 
study we will be evaluating anti-drug antibodies at 14 (±2) and 28 (±3) days postdose 
administration to assess potential immunogenicity.
All immunogenicity data will be listed and summarized by treatment and point of collection 
using the immunogenicity analysis set. 
Definitions of ADA negative and positive are as follows: 
∀
ADA Negative: defined as a sample that was evaluated as negative in the ADA screening 
assay. Samples that were determined to be positive in the ADA screening assay but the result 
was not confirmed in the ADA confirmatory assay were considered negative.
∀
ADA Positive: defined as a sample that was evaluated as positive in both the ADA screening 
and confirmatory assays. 
Subject ADA status will be grouped into 3 categories as follows: 
∀
Negative: defined as subjects who did not have confirmed ADA results. 
∀
Positive: defined as subjects who had at least 1 positive ADA result. 
–
Note: the cut off value for high/low positive ADA titer will be determined based on the 
ADA data, if applicable. 
CCI
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6.8
Pharmacokinetic and Pharmacodynamic Analyses
6.8.1
Pharmacokinetic Analysis
Blood samples for the assessment of plasma TAK-951 concentrations will be collected as 
outlined in the tables below for each cohort: 
Table 6.e
Collection of Blood Samples for Pharmacokinetic Analysis (Cohorts 1 and 2)
Analyte
Matrix
Scheduled Time (Hours)*
TAK-951
Plasma
Predose, and 0.083, 0.17, 0.25, 0.5, 1, 1.25, 1.5, 2, 4, 8, 12, 24, and 30 hours 
postdose.
*The actual date and time of sample collection will be recorded on the source document in the case report form. The 
collection time points listed in this table are collected after the start of infusion. 
Note: A sample will be obtained at the end of infusion for each cohort. For Cohorts 1 and 2, end of infusion time 
point will be at 1 hour (60 minutes). 
Table 6.f
Collection of Blood Samples for Pharmacokinetic Analysis (Cohort 3)
Analyte
Matrix
Scheduled Time (Hours)*
TAK-951
Plasma
Predose, and 0.25, 0.5, 1, 1.5, 2, 2.083, 2.25, 2.5, 3, 5, 8, 12, 24, and 30 hours 
postdose.
*The actual date and time of sample collection will be recorded on the source document in the case report form. The 
collection time points listed in this table are collected after the start of infusion. 
Note: A sample will be obtained at the end of infusion for each cohort. For Cohort 3, the end of infusion time point 
will be at 2 hours (120 minutes). 
Table 6.g
Collection of Blood Samples for Pharmacokinetic Analysis (Cohort 4)
Analyte
Matrix
Scheduled Time (Hours)*
TAK-951
Plasma
Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.25, 3.5, 4, 7, 12, 24, and 30 hours 
postdose. 
*The actual date and time of sample collection will be recorded on the source document in the case report form. The 
collection time points listed in this table are collected after the start of infusion. 
Note: A sample will be obtained at the end of infusion for each cohort. For Cohort 4, the end of infusion time point 
will be at 3 hours (180 minutes). 
Concentrations of TAK-951 will be listed and summarized descriptively by treatment (i.e., 
TAK-951 dose and infusion rate) and PK sampling time using the following descriptive 
statistics: n, mean, SD, CV%, SEM, minimum, median, and maximum. Excluded concentrations 
will be presented and footnoted as such in the concentration table listings, and those values will 
be excluded from the descriptive statistics. 
Individual subject concentration-time curves will be plotted by treatment on linear and semi-log 
scales. The arithmetic mean profiles of the concentration-time data will be plotted by treatment 
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on linear (with and without SD) and semi-log scales. For summary statistics and arithmetic mean 
plots by sampling time, the nominal PK sampling time will be used, for individual subject plots 
by time, the actual PK sampling time will be used. 
The PK parameters will be calculated from TAK-951 concentration-time profiles using 
non-compartmental analysis methods where all calculations will be based on actual sampling 
times after the start of infusion, wherever possible. The PK parameters will be summarized by
treatment (i.e., TAK-951 dose and infusion rate) using the following descriptive statistics: n, 
mean, SD, CV%, SEM, minimum, median, maximum, geom mean, and geom CV%. Excluded 
parameters will be presented and footnoted as such in the PK parameter table listings, and those 
values will be excluded from descriptive statistics. 
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TAK-951-1004
Celerion Study Number CA29416
Page 24 of 27
Statistical Analysis Plan Final
13 May 2021
6.9
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis
Not applicable
6.10
Preliminary Analysis
A preliminary PK analysis will be completed after database lock as described in the CPAP and 
Section 6.8.1 of the SAP, with the following changes: 1) unblinded QCed data will be used 
(unless the QAed data is available, in which case the QAed data will be used); 2) nominal times 
will be used for the calculation of PK parameters (not actual sampling times); 3) tables and 
figures will be created using Phoenix® WinNonlin® Version 8.1 or higher.
6.11
Interim Analysis
No formal interim analysis is planned for this study. 
6.12
Data Monitoring Committee/Internal Review Committee
A dose-escalation/blinded safety review meeting will be held between the Investigator and 
Sponsor after each cohort is completed to review the safety and available PK data from samples 
taken up to 1-day post dose, in order to confirm the dose level and/or infusion rate for the 
subsequent cohort.
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TAK-951-1004
Celerion Study Number CA29416
Page 25 of 27
Statistical Analysis Plan Final
13 May 2021
6.13
Additional Analysis Related to COVID
Depending on the prevalence of coronavirus disease (COVID) infections and illness in regions 
where the study is conducted, additional analysis may be performed to evaluate the impact of 
COVID on the safety of all participating subjects. This analysis will be agreed between the 
Sponsor and Celerion prior to database lock and may include but not limited to the following:
∀
COVID related discontinuation, including discontinuation due to adverse events in light of 
COVID infection and discontinuation due to COVID-related reasons other than COVID-
infection (eg, travel limitation, reduced site staff, etc.).
∀
COVID related AEs, including preferred term of “COVID-19 infection”.
∀
All SAEs in COVID infected subjects.
∀
All protocol deviations related to COVID.
∀
Data listing of all subjects affected by COVID-19 related study disruption, including subject 
ID, site ID, and description of how individual’s participation was altered.
7.0
REFERENCES
Not applicable.
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES
The following analyses are not outlined in the protocol but are described in this SAP: 
∀
Addition of absolute baseline definition for orthostatic vital signs
∀
Summary and change from baseline tables for orthostatic vital signs.
∀
Figure plots for summarization for orthostatic vital signs.
∀
COVID-19 related analysis.
9.0
APPENDIX 
CCI
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TAK-951-1004
Celerion Study Number CA29416
Page 26 of 27
Statistical Analysis Plan Final
13 May 2021
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
SI 
<0.8 × LLN
>1.2 × ULN
Hematocrit
SI
<0.8 × LLN
>1.2 × ULN
RBC count 
SI
<0.8 × LLN 
>1.2 × ULN
WBC count 
SI
<0.5 x LLN
>1.5 x ULN
Platelet Count
SI
<75 x 109/L
>600 x 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
SI
--
>3x ULN
AST
SI
--
>3x ULN
GGT
SI
--
>3*ULN, if baseline is normal;
>2*baseline, if baseline is high 
abnormal
Alkaline phosphatase
SI
--
>3*ULN, if baseline is normal;
>2*baseline, if baseline is high 
abnormal
Total Bilibrubin
SI
--
>1.5*ULN, if baseline is normal;
>1.5*baseline, if baseline is high 
abnormal
Albumin
SI
<25 g/L
--
Total protein
SI
<0.8x LLN
>1.2x ULN
Creatinine
SI
>177 mol/L
Blood urea nitrogen
SI
>10.7 mmol/L
Sodium
SI
<130 mmol/L
>150 mmol/L
Potassium
SI
<3.0 mmol/L
>5.5 mmol/L
Glucose
SI
<3 mmol/L
>10 mmol/L*
Chloride
SI
<75 mmol/L
>126 mmol/L
Calcium
SI
Corrected serum calcium of <LLN -
8.0 mg/dL; <LLN - 2.0 mmol/L; 
Ionized calcium <LLN - 1.0 mmol/L
Bicarbonate
SI
<8.0 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.
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TAK-951-1004
Celerion Study Number CA29416
Page 27 of 27
Statistical Analysis Plan Final
13 May 2021
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Systolic blood pressure
mm Hg
<85
>140
Diastolic blood pressure
mm Hg
<50
>90
Body temperature
oC
<35.6
>37.7
oF
<96.1
>99.9
Heart rate
(revised clinical guideline)
bpm
<50
>90
Heart rate
(traditional clinical consensus)
bpm
<60
>100
Respiratory Rate
breath per minute
<12
>16
BMI
<18.5
>25.0

Class 1: BMI of 30 to <35

Class 2: BMI of 35 to <40

Class 3: BMI of 40 or 
higher.
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