Clinical trial NCT05567393
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2019-03-07; Completion date: 2020-11-02
Enrollment: 128 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of TAK-951 for people with symptoms of nausea and vomiting. The main aims of this study in healthy adults 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.
* To check how much TAK-951 stays in the blood over time to work out the best dose.

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 evaluated the safety, tolerability and pharmacokinetics (PK) of TAK-951 in healthy participants.

The study enrolled 128 healthy participants and consisted of 2 parts: Single-rising Dose (SRD) part (13 cohorts) of sequential panel design, and Multiple-rising Dose (MRD) part (5 cohorts) of sequential panel design. Participants in each cohort were randomized to receive treatment with TAK-951 or matching placebo using SC injection, once daily on Day 1 (for SRD part) and twice daily (BID) on Days 1 through 5 (for MRD part) following a minimum fast of 8 hours.

This single center trial was conducted in the United States. The overall time to participate in this study was approximately 155 days.

Arms: arm 1: TAK-951 placebo-matching, single dose, subcutaneous (SC) injection, on Day 1 in fasted healthy participants in the single-rising dose (SRD) period. arm 2: TAK-951 Dose 1, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 3: TAK-951 Dose 2, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 4: TAK-951 Dose 2, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 5: TAK-951 Dose 3, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 6: TAK-951 Dose 4, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 7: TAK-951 Dose 5, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 8: TAK-951 Dose 6, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 9: TAK-951 Dose 7, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 10: TAK-951 Dose 8, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 11: TAK-951 Dose 9, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 12: TAK-951 Dose 10, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 13: TAK-951 Dose 11, single dose, SC injection, on Day 1 in fasted healthy participants in the SRD period. arm 14: TAK-951 placebo-matching, SC injection, for 5 days from Days 1 to 5 in fasted healthy participants in the multiple-rising dose (MRD) period. arm 15: TAK-951 Dose 1A, SC injection, for 5 days from Days 1 to 5 in fasted healthy participants in the MRD period. arm 16: TAK-951 Dose 2A, SC injection, for 5 days from Days 1 to 5 in fasted healthy participants in the MRD period. arm 17: TAK-951 Dose 3A, SC injection, for 5 days from Days 1 to 5 in fasted healthy participants in the MRD period. arm 18: TAK-951 Dose 4A, SC injection, for 5 days from Days 1 to 5 in fasted healthy participants in the MRD period.
Interventions: intervention 1: TAK-951 Placebo intervention 2: TAK-951
Intervention descriptions: intervention 1: TAK-951 placebo-matching SC injection intervention 2: TAK-951 SC injection

Protocol documents:
Prot_000.pdf: 



Title:  Randomized, Double-Blind, Placebo-Controlled, Three-Part Phase 1 Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects
NCT Number: NCT05567393
Protocol Approve Date: 23 September 2020
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.


TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Three-Part Phase 1 Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects
Study Identifier:
TAK-951-1001
Compound:
TAK-951
Date:
23 September 2020
Amendment 
Number:
4.0
Amendment History:
Date
Amendment Number
Amendment Type
All Sites
03 January 2019
Initial protocol
Not applicable
United States
11 April 2019
01
Substantial
United States
15 May 2019
02
Substantial
United States
28 June 2019
03
Substantial
United States
23 September 2020
04
Substantial
United States
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1001
Page 2 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
1.1
Protocol Amendment 04 Summary of Changes ........................................................10
2.0
STUDY SCHEMATIC..................................................................................................11
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................12
3.1
Part 1 for SRD Cohorts 1 to 6 and 13 to 19 ..............................................................12
3.2
Part 2 has been removed from the study in Protocol Amendment 04 ........................14
3.3
Part 3 for MRD Cohorts 10 to 12 and 20: Days 1 Through 5 and Early Termination
15
3.3.1
Part 3 Day 1 Assessments ................................................................................18
3.3.2
Part 3 Days 2 to 4 Assessments........................................................................22
3.3.3
Part 3 Day 5 Assessments and Early Termination ............................................24
4.0
INTRODUCTION.........................................................................................................26
4.1
Background .............................................................................................................26
4.2
Rationale for the Proposed Study.............................................................................26
4.3
Benefit-Risk Profile .................................................................................................26
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................27
5.1
Study Objectives......................................................................................................27
5.1.1
Study Primary Objective..................................................................................27
5.1.2
Study Secondary Objective..............................................................................27
5.1.3
Study Exploratory Objectives ..........................................................................27
5.2
Endpoints.................................................................................................................28
5.2.1
Primary Endpoint.............................................................................................28
5.2.2
Secondary Endpoints .......................................................................................28
5.2.3
Exploratory Endpoints .....................................................................................28
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................29
6.1
Study Design ...........................................................................................................29
6.1.1
Part 1: SRD Cohorts 1 to 6 and 13 to 19...........................................................30
6.1.2
Part 2...............................................................................................................31
6.1.3
Part 3: MRD Cohorts 10 to 12 and 20 ..............................................................31
6.2
Rationale for Study Design, Dose, and Endpoints ....................................................32
6.2.1
Rationale of Study Design ...............................................................................32
6.2.2
Rationale for Dose...........................................................................................33
6.2.3
Starting Dose for This Study............................................................................35
6.2.4
Rationale for Endpoints ...................................................................................35
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Study ID TAK-951-1001
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6.2.5
Critical Procedures Based on Study Objectives: Timing of Procedures ............36
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................36
6.4
Study Beginning and End/Completion .....................................................................37
6.4.1
Definition of Beginning of the Study ...............................................................37
6.4.2
Definition of End of the Study.........................................................................37
6.4.3
Definition of Study Discontinuation.................................................................37
6.4.4
Criteria for Premature Termination or Suspension of a Site..............................38
6.4.5
Stopping Rules ................................................................................................38
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............39
7.1
Inclusion Criteria .....................................................................................................39
7.2
Exclusion Criteria ....................................................................................................40
7.3
Excluded/Allowed Concomitant Medications, Supplements, Dietary Products.........41
7.3.1
Concomitant Medications ................................................................................41
7.3.2
Fruit Juice........................................................................................................42
7.3.3
Alcohol............................................................................................................42
7.3.4
Caffeine...........................................................................................................42
7.3.5
Smoking ..........................................................................................................42
7.4
Diet, Fluid, Activity.................................................................................................42
7.4.1
Diet and Fluid..................................................................................................42
7.4.2
Activity ...........................................................................................................43
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................43
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................44
7.7
Subject Replacement................................................................................................44
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................44
8.1
Clinical Study Drug .................................................................................................44
8.1.1
Study Drugs.....................................................................................................44
8.1.2
Clinical Study Drug Labeling ..........................................................................44
8.1.3
Clinical Study Drug Inventory and Storage......................................................45
8.1.4
Clinical Study Drug Blinding...........................................................................45
8.1.5
Randomization Code Creation and Storage......................................................45
8.1.6
Clinical Study Blind Maintenance/Unblinding Procedure.................................45
8.1.7
Accountability and Destruction of Sponsor-Supplied Drugs.............................45
8.2
Ancillary Supplies ...................................................................................................46
9.0
STUDY PROCEDURES...............................................................................................46
9.1
Administrative Procedures.......................................................................................47
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Study ID TAK-951-1001
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9.1.1
Informed Consent Procedure............................................................................47
9.1.2
Inclusion and Exclusion...................................................................................47
9.1.3
Medical History/Demography..........................................................................47
9.2
Clinical Procedures and Assessments.......................................................................47
9.2.1
Full Physical Examination ...............................................................................47
9.2.2
Height and Weight...........................................................................................48
9.2.3
Body Mass Index.............................................................................................48
9.2.4
Vital Signs.......................................................................................................48
9.2.5
Glucose ...........................................................................................................48
9.2.6
ECG Procedure................................................................................................49
9.2.7
Study Drug Administration..............................................................................50
9.2.8
........................................................................50
9.2.9
AE Monitoring ................................................................................................50
9.3
Laboratory Procedures and Assessments..................................................................50
9.3.1
Hematology.....................................................................................................50
9.3.2
Chemistry........................................................................................................51
9.3.3
Urinalysis ........................................................................................................51
9.3.4
Diagnostic Screening .......................................................................................51
9.4
PK, 
 and Immunogenicity Samples ..........................52
9.4.1
PK Measurements............................................................................................53
9.4.2
Immunogenicity (ADA) Measurements ...........................................................55
9.4.3
................................................................................55
9.4.4
...................................................................56
9.5
Confinement ............................................................................................................57
9.5.1
Part 1 (SRD)....................................................................................................57
9.5.2
Part 2 (SD Apo Challenge) ..............................................................................57
9.5.3
Part 3 (MRD)...................................................................................................58
9.6
Childbearing Status and Methods of Contraception..................................................58
9.6.1
Women of Childbearing Potential....................................................................58
9.6.2
Women of Nonchildbearing Potential ..............................................................58
10.0
ADVERSE EVENTS ....................................................................................................58
10.1
Definitions and Elements of AEs .............................................................................58
10.1.1
SAEs ...............................................................................................................60
10.1.2
Special Interest AEs.........................................................................................61
10.2
AE Procedures.........................................................................................................62
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10.2.1
Assigning Severity of AEs...............................................................................62
10.2.2
Assigning Causality of AEs .............................................................................62
10.2.3
Start Date.........................................................................................................62
10.2.4
End Date..........................................................................................................62
10.2.5
Pattern of AE (Frequency) ...............................................................................63
10.2.6
Action Taken With Study Treatment................................................................63
10.2.7
Outcome..........................................................................................................63
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs................................................................................................................63
10.2.9
Safety Reporting to Investigators, IRBs, and Regulatory Authorities................66
11.0
STATISTICAL METHODS..........................................................................................66
11.1
Statistical and Analytical Plans ................................................................................66
11.1.1
Analysis Sets ...................................................................................................67
11.1.2
Analysis of Demography and Other Baseline Characteristics ...........................67
11.1.3
.......................................................67
11.1.4
PK Analysis.....................................................................................................67
11.1.5
Safety Analysis................................................................................................68
11.1.6
....................................................................................68
11.1.7
Immunogenicity Analysis ................................................................................68
11.2
Interim Analysis and Criteria for Early Termination ................................................69
11.3
Determination of Sample Size..................................................................................69
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................69
12.1
Study-Site Monitoring Visits ...................................................................................69
12.2
Protocol Deviations..................................................................................................69
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................69
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................70
13.1
IRB Approval ..........................................................................................................70
13.2
Subject Information, Informed Consent, and Subject Authorization .........................71
13.3
Subject Confidentiality ............................................................................................72
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................72
13.4.1
Publication and Disclosure...............................................................................72
13.4.2
Clinical Trial Registration................................................................................73
13.4.3
Clinical Study Results Disclosure ....................................................................73
13.5
Insurance and Compensation for Injury....................................................................73
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................74
14.1
Administrative Information......................................................................................74
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Study ID TAK-951-1001
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14.1.1
Study Contact Information...............................................................................74
14.1.2
INVESTIGATOR AGREEMENT ...................................................................75
14.1.3
Study-Related Responsibilities.........................................................................76
14.1.4
List of Abbreviations .......................................................................................77
15.0
DATA HANDLING AND RECORDKEEPING............................................................79
15.1
CRFs (Electronic and Paper)....................................................................................79
15.2
Record Retention .....................................................................................................79
16.0
REFERENCES..............................................................................................................80
17.0
APPENDICES...............................................................................................................81
LIST OF IN-TEXT TABLES
Table 6.a
Overview of Treatment Cohorts.........................................................................30
Table 6.b
Predicted Human Dose-Related Concentrations and Exposures for Planned 
Doses in Part 1...................................................................................................35
Table 9.a
Primary Specimen Collections ...........................................................................53
Table 10.a
Takeda Medically Significant AE List................................................................61
Table 10.b
NCI CTCAE ......................................................................................................62
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................81
Appendix B
Elements of the Subject Informed Consent.........................................................83
Appendix C
Investigator Consent to the Use of Personal Information ....................................86
Appendix D
Pregnancy and Contraception.............................................................................87
Appendix E
Detailed Description of Amendments to Text.....................................................90
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TAK-951
Study ID TAK-951-1001
Page 7 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
1.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc. (Takeda Global Research and 
Development–United States)
Compound:
TAK-951
Study Identifier: TAK-951-1001
Phase: 1
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Three-Part Phase 1 Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects.
Study Design:
This is a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of TAK-951 in healthy subjects. 
The study will consist of 2 parts: 
!
Part 1 is a first-in-human (FIH), randomized, double-blind, placebo-controlled, single-rising dose (SRD) study to
assess the safety, tolerability, and PK of TAK-951 in healthy volunteers. Up to 13 cohorts may be enrolled.
Subjects will be randomized to receive TAK-951 or matching placebo.
!
Part 2 of the study has been removed in Protocol Amendment 04 dated 23 September 2020
!
Part 3 is a randomized, double-blind, placebo-controlled, multiple-rising dose (MRD) study. 
Safety and tolerability will be assessed during all parts of the study through physical examination, including vital sign 
assessment, electrocardiogram (ECG)/telemetry, clinical laboratory assessments, collection of adverse events (AEs) 
and immunogenicity.
TAK-951 and matching placebo will be administered subcutaneously. 
Study Primary Objective:
!
Part 1
–
To characterize the safety (including immunogenicity) and tolerability of single subcutaneous (SC) doses of
TAK-951 in healthy subjects.
! Part 3
–
To characterize the safety (including immunogenicity) and tolerability of multiple SC doses of TAK-951 in
healthy subjects.
Study Secondary Objective
!
Part 1
–
To characterize the PK of TAK-951 following single SC doses in healthy subjects.
!
Part 3
–
To characterize the PK of TAK-951 following multiple SC doses in healthy subjects.
Study Exploratory Objectives
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TAK-951
Study ID TAK-951-1001
Page 8 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
Study Subject Population: Healthy volunteers aged 18 to 55 years, inclusive.
Planned Number of Subjects:
Part 1: up to 104
Part 2: Has been removed from the study in Protocol 
Amendment 04.
Part 3: up to 32
Planned Number of Sites:
This study is planned on being conducted at one or more 
sites within the United States. 
Dose Levels:
Part 1: TAK-951 SRD: starting dose 20 μg.
Part 2: has been removed from the study in Protocol 
Amendment 04.
Part 3: TAK-951 MRD: dose to be confirmed based on 
SRD results.
Route of Administration:
TAK-951
Duration of Treatment:
Part 1: 1 day.
Part 2: Has been removed from the study in Protocol 
Amendment 04.
Part 3: 5 days.
Planned Study Duration:
Total approximately up to 155 days.
Part 1: screening, 28 days; treatment period, 1 day; 
follow-up, 14-32 days. 
Part 2: Has been removed from the study in Protocol 
Amendment 04.
Part 3: screening, 28 days; treatment period, 5 days; 
follow-up, 14-32 days.
Main Criteria for Inclusion:
To be eligible for study participation, subjects must: 
1.
Understand the study procedures and agree to participate by providing written informed consent.
2.
Be willing and able to comply with all study procedures and restrictions.
3.
Be a healthy male or WONCBP (woman of nonchildbearing potential) female subject aged 18 to 55 years, 
inclusive, at the screening visit.
4.
Have a BMI ≥18 and ≤30.0 (kg/m2) at the screening visit.
5.
Be judged to be in good health by the investigator, based on clinical evaluations including laboratory safety tests, 
medical history, physical examination, ECG, and vital sign measurements performed at the screening visit and 
before administration of the initial dose of study drug or invasive procedure.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if: 
1.
The subject has participated in another investigational study within 4 weeks (or based on local regulations) before 
the screening visit. The 4-week window will be derived from the date of the last study procedure and/or AE 
related to the study procedure in the previous study to the screening visit of the current study.
2.
The subject is an employee of the sponsor or study site or immediate family member (eg, spouse, parent, child, 
sibling) of the sponsor or study site.
3.
The subject has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or has had an 
anaphylactic reaction or significant intolerance to prescription or nonprescription drugs or food.
4.
The subject has a known hypersensitivity or contraindication to any component of TAK-951. 
5.
The subject has a positive pregnancy test. Women of childbearing potential are not eligible for the study.
6.
The subject is a lactating/nursing woman.
7.
The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, 
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TAK-951
Study ID TAK-951-1001
Page 9 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
or HIV antibody/antigen, at the screening visit. Note: Subjects with positive hepatitis B virus or hepatitis C 
virus serology may be enrolled if quantitative reverse transcriptase-polymerase chain reaction for hepatitis B 
virus or hepatitis C virus RNA is negative.
8.
The subject had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks before 
the screening visit.
9.
The subject is unable to refrain from or anticipates using all medications, including herbal medicines, beginning 
approximately 7 days before administration of the first dose of study drug throughout the study until 2 days after 
discharge. 
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study is safety and tolerability as assessed through physical examinations, vital signs, 
ECG/telemetry, laboratory assessments, AEs, and immunogenicity.
The secondary endpoints will be assessed through evaluation of the following PK parameters on Day 1 in Parts 1 and 
3, at steady state: 

Part 1: plasma PK parameters for TAK-951
–
Maximum observed plasma concentration (Cmax)
–
Area under the plasma concentration time curve from time 0 to infinity (AUC∞)

Part 3: plasma PK parameters for TAK-951
–
Cmax on Day 1.
–
Area under the plasma concentration-time curve during a dosing interval where tau (τ) is the length of the 
dosing interval (AUCτ) on Day 1.
Statistical Considerations:
The primary, secondary, and exploratory endpoints will be analyzed in randomized subjects in Parts 1 and 3 who 
received at least 1 dose of study drug.
Safety analyses will be based on the safety analysis set. All safety data including AEs, 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 pooled placebo within each part and by TAK-951 dose level.
The PK parameters of TAK-951 will be summarized by dose, cohort, day, and dosing regimen (as appropriate), using 
descriptive statistics. Dose proportionality will be assessed graphically (dose-normalized Cmax and AUC versus dose); 
no formal statistical comparisons will be conducted.
Sample Size Justification:
For Parts 1 and 3, the chosen sample sizes are considered sufficient for evaluation of safety, tolerability, and PK. The 
study is not statistically powered to perform hypothesis testing in Parts 1 and 3.
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Study ID TAK-951-1001
Page 10 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
1.1
Protocol Amendment 04 Summary of Changes
This document describes the changes in reference to the protocol incorporating amendment 04. 
The primary reason for this amendment is to remove all references to Part 2 of the study to
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix E.
Changes in Amendment 04
1. Removed all references to Part 2 from the study.
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e condu
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App
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TAK-951
Study ID TAK-951-1001
Page 11 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
2.0
STUDY SCHEMATIC
 intravenous; MRD: multiple-rising dose; SC: subcutaneous; SD: single dose; SRD: single-rising 
Refer to Table 6.a for a full overview of treatment cohorts, including planned treatments.
Part 2 of Study TAK-951-1001 has been removed from the study in Protocol Amendment 04.
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TAK-951
Study ID TAK-951-1001
Page 12 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES
3.1
Part 1 for SRD Cohorts 1 to 6 and 13 to 19
Day
Scheduled Time
Early 
Termination
-28 to -2
-1
Day 1 (Hours)
Follow-up Visit 
Day 14±2 days
Follow-up Visit 
Day 29 ±3 days
Screening
Pre-
dose
0
0.5
1
2
3
4
6
8
10
12
14
16 24
30
(discharge) 48 a
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/demographics
X
Prior and concomitant medication 
review
X
X--------------------------------------------------------------------Continuous Review-----------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
X
X
X
X
Height
X
Weight and BMI
X
X
TAK-951/placebo administration b
X
Temperature and respiratory rate 
X
X
X
X
X
X
Blood pressure and pulse c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing blood pressure and pulse d
X
X
X
X
X
X
X
12-lead ECGs
X
X
X
X
Telemetry 
X-------------------------Continuous Monitoring-------------------------X
Holter monitoring 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring 
X e
X--------------------------------------------------------Continuous Monitoring-------------------------------------------------X
X
Laboratory Procedures/Assessments
Safety laboratory collection 
(hematology and serum chemistry)
X
X
X
X
X
X
Urinalysis
X
X
X
X
Glucose finger stick
X
X
X
Urine drug screen
X
X
Alcohol breath test
X
Cotinine test
X
X
Hepatitis screen f
X
HIV screen
X
βhCG (pregnancy) test g
X
X
X
X
Serum FSH test h
X
PK Evaluations
Blood sample for PK 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sample for PK i
X
X
X
X
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1001
Page 13 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
Day
Scheduled Time
Early 
Termination
-28 to -2
-1
Day 1 (Hours)
Follow-up Visit 
Day 14±2 days
Follow-up Visit 
Day 29 ±3 days
Screening
Pre-
dose
0
0.5
1
2
3
4
6
8
10
12
14
16 24
30
(discharge) 48 a
Biomarker Evaluations
Blood sample for ADA
X
X
X
X
Other
Confinement 
X-------------------------------------------------------------------------------------------------------X
ADA: antidrug antibodies; AE: adverse event; anti-HC
n chorionic gonadotropins; BMI: body mass index; ECG: 
electrocardiogram; FSH: follicle-stimulating hormone;
HBsAg: hepatitis B surface antigen; 
; PK: 
pharmacokinetic.
a Additional procedures may be performed at the investigator’s discretion. 
b Subjects will be administered a single dose of TAK-951 or matching placebo. Refer to Section 7.4.1 for further details.
c All blood pressure and pulse assessments should be made in duplicate, and the average of both assessments should be used to calculate the final result. The investigator can take a 
third measurement if there is inconsistency between assessments. On Day -1, vital signs will be assessed at check-in and blood pressure will be assessed again postprandially 
(approximately ±60 min after lunch, 24 hours before the Day 1 scheduled lunch, based on postdose protocol requirements). At predose, vital signs will be measured within 
approximately 1 hour before dosing.
d Standing blood pressure and pulse will be performed on Day -1 (postprandial), Day 1 predose (approximately 1 hour before), and at 0.5, 2, 4, 8, and 24 hours after dosing to assess 
orthostatic blood pressure and pulse. For standing blood pressure and pulse assessment, a third blood pressure and pulse assessment will be performed after the duplicate 
semirecumbent assessment has been completed. The subject should stand still for approximately 2 minutes before this assessment. Standing assessments must not be performed if 
semirecumbent systolic blood pressure is <85 mm Hg or if the subject presents with signs or symptoms suggestive of postural hypotension after standing (eg, lightheadedness or 
dizziness, nausea, blurry vision) (Section 9.2.4). 
e Collection of AEs will commence at the time the subject signs the informed consent form.
f Hepatitis panel, including HBsAg and anti-HCV.
g Serum pregnancy test for female subjects only. 
h An FSH level will be obtained to assess postmenopausal status.
i Urine PK samples will be collected at the following time intervals: predose, 0-4, 4-8, 8-12, 12-16, and 16-24 hours.
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TAK-951
Study ID TAK-951-1001
Page 14 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
3.2
Part 2 has been removed from the study in Protocol Amendment 04
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1001
Page 15 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
3.3
Part 3 for MRD Cohorts 10 to 12 and 20: Days 1 Through 5 and Early Termination
Day-28 to 
-2
Day
-1
Days
Early 
Termination
Dosing
Follow-up 
Visit Day 
14±2 days
Follow-up 
Visit Day 
29±3 days
Screening
Predose
1
2
3
4
5
6 (Discharge)
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/demographics
X
Prior and concomitant 
medications
X-----------------------------------------------------------------Continuous review-----------------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
X
X
X
X
Height
X
Weight and BMI
X
X
Vital signs a
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGs
X
X
ECG telemetry/continuous blood 
pressure monitoring
X
X
X
X
X
X
TAK-951/placebo administration b
X
X
X
X
X
AE monitoring
X
X
X-----------------------------------------------------------Continuous-------------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory collection c
X
X
X
X
X
X
X
X
X
X
Glucose finger stick d
X
X
X
X
X
X
Urine drug screen
X
X
Alcohol breath test
X
Cotinine test
X
X
Hepatitis screen e
X
HIV test
X
βhCG (pregnancy) test f
X
X
X
X
Serum FSH test g
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1001
Page 16 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
Day-28 to 
-2
Day
-1
Days
Early 
Termination
Dosing
Follow-up 
Visit Day 
14±2 days
Follow-up 
Visit Day 
29±3 days
Screening
Predose
1
2
3
4
5
6 (Discharge)
PK Evaluations
Blood sample for PK 
X
X
X
X
X
X
X
X
Urine sample for PK 
X
X
X
Biomarkers
Blood sample for ADA 
X
X
X
X
Other
Confinement k
X--------------------------------------------------------------------------------X
ADA: antidrug antibodies; AE: adverse event; anti-HCV: antibodies to hepatitis C virus; βhCG: beta human chorionic gonadotropin; BMI: body mass index; ECG: 
electrocardiogram; FSH: follicle-stimulating hormone
BsAg: hepatitis B surface antigen; 
; PK: 
pharmacokinetic.
a Vital signs will include body temperature, blood pressure, respiratory rate, and pulse. On dosing days, vital signs will be collected as described in Section 3.3.1 (Part 3 Day 1 
Assessments), Section 3.3.2 (Part 3 Days 2 to 4 Assessments), and Section 3.3.3 (Part 3 Day 5 Assessments).
b Dosing regimen for TAK-951/placebo will be determined based on data from Part 1. Refer to Section 7.4.1 for further details.
c Safety laboratory will include hematology, serum chemistry, and urinalysis parameters.
d Glucose finger stick at ~3 hours postdose on each day.
e Hepatitis panel, including HBsAg and anti-HCV.
f Serum pregnancy tests for female subjects only.
g An FSH level will be obtained to assess postmenopausal status.
h
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TAK-951
Study ID TAK-951-1001
Page 17 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
Day-28 to 
-2
Day
-1
Days
Early 
Termination
Dosing
Follow-up 
Visit Day 
14±2 days
Follow-up 
Visit Day 
29±3 days
Screening
Predose
1
2
3
4
5
6 (Discharge)
j
k Subjects will be confined (Section 9.5.3).
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TAK-951
Study ID TAK-951-1001
Page 18 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
3.3.1
Part 3 Day 1 Assessments
Scheduled Time
Day
-28 to -2
Day
-1
Day 1 (Hours)
Screening
Pre
dose
0
0.5
1
2
3
4
6
Pre
dose
8
8
8.5
9
10
11
12
13
14
16
24
Administrative Procedures
Informed consent
X
Inclusion/exclusion 
criteria
X
X
X
Medical 
history/demographics
X
Previous and 
concomitant 
medications
X---------------------------------------------------------------Continuous review----------------------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical 
examination
X
X
Height
X
Weight and BMI
X
X
Temperature and 
respiratory rate
X
X
X
X
X
X
Blood pressure and 
pulse a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing blood 
pressure and pulse b
X
X
X
X
X
X
X
X
X
X
12-lead ECGs 
X
X
X
X
ECG telemetry/ 
continuous blood 
pressure monitoring
X-------------------------------------------------------------Continuous monitoring-------------------------------------------------------X
TAK-951/placebo 
administration
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1001
Page 19 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
Scheduled Time
Day
-28 to -2
Day
-1
Day 1 (Hours)
Screening
Pre
dose
0
0.5
1
2
3
4
6
Pre
dose
8
8
8.5
9
10
11
12
13
14
16
24
AE monitoring
X--------------------------------------------------------------Continuous review-----------------------------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory 
collection c
X
X
X
X
Glucose finger stick 
X
X
Urine drug screen
X
X
Alcohol breath test
X
Cotinine test
X
X
Hepatitis screen d
X
HIV test
X
βhCG (pregnancy) 
test e
X
X
Serum FSH test f
X
PK Evaluations
Blood sample for PK 
g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sample for PK
X
X
X
X
X
X
Biomarkers
Blood sample for 
ADA 
X
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Takeda: For Non


TAK-951
Study ID TAK-951-1001
Page 20 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
Scheduled Time
Day
-28 to -2
Day
-1
Day 1 (Hours)
Screening
Pre
dose
0
0.5
1
2
3
4
6
Pre
dose
8
8
8.5
9
10
11
12
13
14
16
24
Other
Confinement j
X--------------------------------------------------------------------------------------------------------------------------------------------------------------X
ADA: antidrug antibodies; AE: adverse event; anti-HCV: antibodies to hepatitis C virus; βhCG: beta human chorionic gonadotropin; BMI: body mass index; ECG: 
electrocardiogram; FSH: follicle-stimulating hormone
HBsAg: hepatitis B surface antigen; 
; PK: 
pharmacokinetic.
a All blood pressure and pulse assessments should be made in duplicate, and the average of both assessments should be used to calculate the final result. The investigator can take a 
third measurement if there is inconsistency between assessments. On Day -1, vital signs will be assessed at check-in and blood pressure will be assessed again postprandially 
(approximately ±60 min after lunch, 24 hours before the Day 1 scheduled lunch, based on postdose protocol requirements). At predose, vital signs will be measured within 
approximately 1 hour before the first dose and 30 minutes before the second dose (ie, 8-hour TAK-951/placebo administration). All blood pressure and pulse assessments must be 
completed before PK blood sampling.
b Standing blood pressure and pulse will be performed on Day -1 (postprandial), Day 1 predose (approximately 1 hour before), and at 0.5, 2, 4, 8 (predose), 8.5, 10, 12, and 24 hours 
after dosing to assess orthostatic blood pressure and pulse. For standing blood pressure and pulse assessment, a third blood pressure and pulse assessment will be performed after the 
duplicate semirecumbent assessment has been completed. The subject should stand still for approximately 2 minutes before this assessment. Standing assessments must not be 
performed if semirecumbent systolic blood pressure is <85 mm Hg or if the subject presents with signs or symptoms suggestive of postural hypotension after standing (eg, 
lightheadedness or dizziness, nausea, blurry vision) (Section 9.2.4).
c Safety laboratory will include hematology, serum chemistry, and urinalysis parameters.
d Hepatitis panel, including HBsAg and anti-HCV.
e Serum pregnancy tests for female subjects only.
f An FSH level will be obtained for postmenopausal women.
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TAK-951
Study ID TAK-951-1001
Page 21 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
Scheduled Time
Day
-28 to -2
Day
-1
Day 1 (Hours)
Screening
Pre
dose
0
0.5
1
2
3
4
6
Pre
dose
8
8
8.5
9
10
11
12
13
14
16
24
g Blood sample for PK may be drawn 10 minutes before the second dose at 8 hours. The 24-hour sample on Day 1 is the same as the predose sample on Day 2. Only one sample will 
be collected.
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TAK-951
Study ID TAK-951-1001
Page 22 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
3.3.2
Part 3 Days 2 to 4 Assessments
Scheduled Time
Days 2-4 (Hours)
Pre
dose
0
0.5
1
2
3
4
6
Pre
dose
8
8
8.5
9
10
11
12
13
14
16
24
Administrative Procedures
Previous and concomitant 
medications
X--------------------------------------------------------Continuous review----------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
Temperature and respiratory rate 
X
X
X
X
Blood pressure and pulse a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing blood pressure and pulse b
X
X
X
X
X
X
X
X
X
TAK-951/placebo administration c 
X
X
ECG telemetry/continuous blood 
pressure monitoring
X----------------------------------------------------------------Continuous monitoring-----------------------------------------------X
AE monitoring
X---------------------------------------------------------Continuous review------------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory collection d
X
X
Glucose finger stick 
X
X
Pharmacokinetics Evaluations
Blood sample for PK e
X
X
Biomarkers
Blood sample for ADA
Other
Confinement f
X---------------------------------------------------------------------------------------------------------------------------------------X
AE: adverse event; ECG: electrocardiogram; PK: pharmacokinetic.
a All blood pressure and pulse assessments should be made in duplicate, and the average of both assessments should be used to calculate the final result. The investigator can take a 
third measurement if there is inconsistency between assessments. At predose, vital signs will be measured within approximately 1 hour before the first dose and 30 minutes before the 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1001
Page 23 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
Scheduled Time
Days 2-4 (Hours)
Pre
dose
0
0.5
1
2
3
4
6
Pre
dose
8
8
8.5
9
10
11
12
13
14
16
24
second dose (ie, 8-hour TAK-951/placebo administration). All blood pressure and pulse assessments must be completed before PK blood sampling.
b Standing blood pressure and pulse will be performed at 0.5, 2, 4, 8 (predose), 8.5, 10, 12, and 24 hours after dosing to assess orthostatic blood pressure and pulse. For standing blood 
pressure and pulse assessment, a third blood pressure and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should 
stand still for approximately 2 minutes before this assessment. Standing assessments must not be performed if semirecumbent systolic blood pressure is <85 mm Hg or if the subject 
presents with signs or symptoms suggestive of postural hypotension after standing (eg, lightheadedness or dizziness, nausea, blurry vision, etc.) (Section 9.2.4). 
c Follow-up doses should be given at the same time as on Day 1.
d Safety laboratory will include hematology, serum chemistry, and urinalysis parameters.
e Trough sample will be collected before the first dose that day. Blood sample for PK may be drawn 10 minutes before dosing. The 24-hour sample on Day 1 is the same as the predose 
sample on Day 2. Only one sample will be collected.
f Subjects will be confined (Section 9.5.3).
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1001
Page 24 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
3.3.3
Part 3 Day 5 Assessments and Early Termination
Scheduled Time
Day 5 (Hours)
Predose 0
0.5
1
2
3
4
6
Pre
dose
8
8
8.5
9
10
11
12
13
14
16
24
Day 6
(Dis
charge)
Follow-
up Visit 
Day 14±2 
days
Follow-
up Visit 
Day 29 ±3 
days
Early 
Termination
Previous and concomitant 
medications
X---------------------------------------------------------------------Continuous 
review-----------------------------------------------------------------------------X
Clinic Procedures/Assessments
Full physical examination
X
X
Temperature and 
respiratory rate 
X
X
X
X
X
X
Blood pressure and pulse a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Standing blood pressure 
and pulse b
X
X
X
X
X
X
X
X
X
X
TAK-951/placebo 
administration c
X
X
ECG telemetry/ continuous 
blood pressure monitoring
X-----------------------------------------------Continuous--------------------------------------------------------
X
AE monitoring
X--------------------------------------------------------------------------Continuous------------------------------------------------------------------------------------------X
Laboratory Procedures/Assessments
Safety laboratory 
collection d
X
X
X
X
Glucose finger stick 
X
X
βhCG (pregnancy) test e
X
X
PK Evaluations
Blood sample for PK f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sample for PK
X
X
X
X
X
Biomarkers
Blood sample for ADA g
X
X
X
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Co
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No
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X
X
X
X
N
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X
For
or
F
a: F
of Takeda:


TAK-951
Study ID TAK-951-1001
Page 25 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
CONFIDENTIAL
Scheduled Time
Day 5 (Hours)
Predose 0
0.5
1
2
3
4
6
Pre
dose
8
8
8.5
9
10
11
12
13
14
16
24
Day 6
(Dis
charge)
Follow-
up Visit 
Day 14±2 
days
Follow-
up Visit 
Day 29 ±3 
days
Early 
Termination
Other
Confinement j
X------------------------------------------------------------------------------------------------------------------------------X
ADA: antidrug antibodies; AE: adverse event; βhCG: beta human chorionic gonadotropin; ECG: electrocardiogram;
 PK: pharmacokinetic.
a All blood pressure and pulse assessments should be made in duplicate, and the average of both assessments should be used to calculate the final result. The investigator can take a 
third measurement if there is inconsistency between assessments. At predose, vital signs will be measured within approximately 1 hour before the first dose and 30 minutes before the 
second dose (ie, 8-hour TAK-951/placebo administration). All blood pressure and pulse assessments must be completed before PK blood sampling.
b Standing blood pressure and pulse will be performed at 0.5, 2, 4, 8 (predose), 8.5, 10, 12, and 24 hours after dosing to assess orthostatic blood pressure and pulse. For standing blood 
pressure and pulse assessment, a third blood pressure and pulse assessment will be performed after the duplicate semirecumbent assessment has been completed. The subject should 
stand still for approximately 2 minutes before this assessment. Standing assessments must not be performed if semirecumbent systolic blood pressure is <85 mm Hg or if the subject 
presents with signs or symptoms suggestive of postural hypotension after standing (eg, lightheadedness or dizziness, nausea, blurry vision, etc.) (Section 9.2.4). 
c Follow-up doses should be given at the same time as those given on Day 1.
d Safety laboratory will include hematology, serum chemistry, and urinalysis parameters.
e Serum pregnancy tests for female subjects only.
f Blood sample for PK may be drawn 10 minutes before dosing.
g Biomarker samples for ADA testing will be taken at predose on Day 1, before discharge on Day 6, Day 14, and at follow-up visit Day 29 ±3 days. If ADAs are present, subjects may 
be asked to return for additional sample collections.
h 
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TAK-951
Study ID TAK-951-1001
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Protocol Incorporating Amendment No. 04
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4.0
INTRODUCTION
4.1
Background
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.
4.2
Rationale for the Proposed Study
The purpose of this first-in-human (FIH) study is to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of TAK-951 in healthy subjects to support further development of 
TAK-951. The study will be conducted in 2 parts: single-rising doses (SRD) will be assessed in 
Part 1 and repeat dose administration will be assessed in Part 3. Part 2 has been removed from the 
study in Protocol Amendment 04, dated 23 September 2020.
4.3
Benefit-Risk Profile
This study represents the first study in humans with TAK-951. 
The main purpose of this study in healthy subjects is to assess the safety and tolerability of
TAK-951; as such, no clinical benefit is expected for study participants. 
The antiemetic properties of TAK-951 have been demonstrated in different preclinical models of 
emesis in rodents, ferrets, and dogs. Based on the safety findings from nonclinical studies 
conducted with TAK-951 and human GIP infusion studies, the potential risks of TAK-951 include 
HR increase and decreased blood pressure. 
, immunogenicity, and injection site reactions and more serious hypersensitivity 
reactions are always possible.
To minimize the risks to the subjects in this study, the sponsor considers the following measures to 
be appropriate: selecting TAK-951 doses with appropriate safety margins based on nonclinical 
study data; managing study eligibility criteria; prespecifying safety monitoring procedures, such 
as frequent blood pressure assessments that include orthostatic blood pressure measurements in 
Parts 1 and 3, telemetry, and Holter electrocardiogram (ECG); developing guidance for 
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TAK-951
Study ID TAK-951-1001
Page 27 of 91
Protocol Incorporating Amendment No. 04
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investigators; and using a clinical study facility where close monitoring can be performed and 
rapid institution of appropriate care can be given when needed in a timely manner. 
Subjects with a history of serious hypersensitivity to any medication or any component of 
TAK-951 formulation or with a history of significant multiple and/or severe allergies are excluded 
from this study. Subjects will be evaluated for the development of anti-drug antibodies (ADA) as 
part of the study. The potential risks related to heart rate (HR) 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.
In addition to the potential risks associated with study drug administration, there is minimal risk 
associated with study procedures, including scheduled periodic phlebotomy (limited to <500 mL).
Overall, the potential risks associated with the study are considered reasonable and acceptable.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Study Objectives
5.1.1
Study Primary Objective
!
Part 1
–
To characterize the safety (including immunogenicity) and tolerability of single 
subcutaneous (SC) doses of TAK-951 in healthy subjects.
! Part 3
–
To characterize the safety (including immunogenicity) and tolerability of multiple SC 
doses of TAK-951 in healthy subjects.
5.1.2
Study Secondary Objective
!
Part 1
–
To characterize the PK of TAK-951 following single SC doses in healthy subjects.
!
Part 3
–
To characterize the PK of TAK-951 following multiple SC doses in healthy subjects.
5.1.3
Study Exploratory Objectives
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TAK-951
Study ID TAK-951-1001
Page 28 of 91
Protocol Incorporating Amendment No. 04
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5.2
Endpoints
5.2.1
Primary Endpoint
!
Parts 1 and 3
–
The primary safety endpoint of the study is safety and tolerability as assessed through 
physical examinations, vital signs, ECG/telemetry, laboratory assessments, AEs, and 
immunogenicity.
5.2.2
Secondary Endpoints 
!
Part 1: plasma PK parameters for TAK-951
–
Maximum observed plasma concentration (Cmax).
–
Area under the plasma concentration time curve from time 0 to infinity (AUC∞).
!
Part 3: plasma PK parameters for TAK-951
–
Cmax on Day 1.
–
Area under the plasma concentration-time curve during a dosing interval, where tau (τ) is 
the length of the dosing interval (AUCτ) on Day 1.
5.2.3
Exploratory Endpoints
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TAK-951
Study ID TAK-951-1001
Page 29 of 91
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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 in healthy subjects. 
The study will consist of 2 parts (see Table 6.a): 
!
Part 1 is a FIH, randomized, double-blind, placebo-controlled, SRD study to assess the safety,
tolerability, and PK of TAK-951 in healthy volunteers. Up to 13 cohorts may be enrolled. 
Subjects will be randomized to receive TAK-951 or matching placebo.
!
Part 2 of Study TAK-951-1001 has been removed from the study in Protocol Amendment 04. 
!
Part 3 is a randomized, double-blind, placebo-controlled, multiple-rising dose (MRD) study. 
TAK-951 and matching placebo will be administered subcutaneously. Any part of the study may 
not be conducted at the discretion of the sponsor. Safety will be assessed by monitoring for AEs, 
vital signs, ECG/telemetry, safety laboratory assessments after each dose and immunogenicity.
Sampling times may vary based on emerging PK data, but the maximal number of samples or the 
maximum time point will not change.
An overview of treatment cohorts is presented in Table 6.a.
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TAK-951
Study ID TAK-951-1001
Page 30 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
Table 6.a
Overview of Treatment Cohorts
Cohort
Regimen
Treatment
Part 1
TAK-951
Placebo
1
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6
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4
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MRD: multiple-rising dose; SRD: single-rising dose.
Part 2 of Study TAK-951-1001 has been removed from the study in Protocol Amendment 04.
6.1.1
Part 1: SRD Cohorts 1 to 6 and 13 to 19
Part 1 will consist of up to 13 cohorts of 8 healthy subjects. Subjects in each cohort will be 
randomly assigned to receive a single dose of TAK-951 or placebo in a 3:1 ratio in a double-blind 
manner. Up to 104 healthy subjects will be randomized in Part 1.
Subjects from each cohort will be admitted into the study unit on Day -1 and will be dosed with 
TAK-951 or matching placebo on Day 1 after a minimum of 8 hours of fasting. Subjects will be 
confined for a minimum of 30 hours after dosing (can be discharged after the 30-hour PK sample) 
and may be confined for up to 48 hours postdose at the discretion of the investigator, if needed to 
ensure subject safety. After discharge, subjects will return to the study unit for additional 
assessments as indicated in the schedule of assessments (see Section 3.1). Blood samples for 
assessment of TAK-951 plasma concentrations will be collected up to 48 hours postdose. Urine 
will be collected up to 24 hours post TAK-951 dose. 
Based on agreement between the investigator and sponsor, a staggered dosing approach may be 
used for cohorts in Part 1. After dosing the first 2 subjects of each cohort (1 receiving TAK-951 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951
Study ID TAK-951-1001
Page 31 of 91
Protocol Incorporating Amendment No. 04
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and 1 receiving placebo) the investigator will review all available safety and tolerability data 
before dosing the remaining subjects in the cohort. The investigator will also consult Takeda as 
needed at any time.
Doses may be subject to change based on emerging PK and safety data. The sponsor may 
decide to administer lower doses, repeat doses, and cancel or add cohort(s) if deemed necessary. 
Subjects who drop out of the study for nonsafety reasons may be replaced at the discretion of the 
sponsor after discussion with the investigator.
After completion of each dosing cohort, and before selecting the next evaluable dose, a fully 
blinded assessment of the safety and tolerability, laboratory results of at least 24 hours, and 
available PK data will be performed by the site and select sponsor safety team.
Following each fully blinded dose cohort review, while the site personnel and study subjects will 
remain blinded to study drug assignment, the sponsor and select sponsor representatives may be 
unblinded to the completed cohort treatments. Precautions will be taken not to unblind the study
staff, including the investigator and the subject, until the study is completed. The blind may be 
broken before each blinded cohort review and/or dose escalation meeting, if necessary, due to 
safety concerns.
Study Drug Administration
In Part 1, all attempts should be made to administer the single SC dose of TAK-951 in the 
abdomen. In all cases, care should be taken to avoid areas of scars or moles. TAK-951 must not be 
administered into an area where the skin appears to be tender to touch, signs of bruising/bleeding 
are noted, or the area seems indurated or erythematous. When locating injection sites on the 
abdomen, avoid giving the injection in the umbilicus, ribs, hip bone. For additional information on 
study drug administration, please refer to the study pharmacy manual.
6.1.2
Part 2
Part 2 of Study TAK-951-1001 has been removed from the study in Protocol Amendment 04.
6.1.3
Part 3: MRD Cohorts 10 to 12 and 20
Part 3 may start before the completion of Part 1. If Part 3 is started before the completion of Part 1, 
the starting dose in Part 3 will be at a dose level below that currently being studied in Part 1. 
Similar to Part 1, a staggered dosing approach may be used for cohorts in Part 3. Site personnel and 
study subjects will be blinded to study drug assignment, but selected sponsor vendors (third-party 
open) may be unblinded (Section 6.1.1). Part 3 consists of up to 4 sequential ascending cohorts of 
healthy subjects. In each cohort, 8 healthy subjects will be randomly assigned to receive TAK-951 
or matching placebo in a 3:1 ratio in a double-blind manner. Up to 32 healthy subjects may be 
randomized in Part 3. 
Subjects will be admitted to the study unit on Day -1 and will be dosed on Day 1 in each 
cohort/period after a minimum of 8 hours of fasting. Subjects will be confined until Day 6, 
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Study ID TAK-951-1001
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Protocol Incorporating Amendment No. 04
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30 hours after last dose on Day 5 to assess safety, tolerability, and PK. Subjects will return after 
discharge for additional assessments as indicated in the study flow chart.
In Part 3,
 safe and tolerable doses from Part 1 
 will be 
studied in an ascending manner. Based on emerging PK data from Part 1, adjustments to dose and 
to repeat dosing duration may be implemented. 
The schedule of assessments for Part 3 can be found in Section 3.3.
After completion of each dosing cohort, and before selecting the next evaluable dose, a fully 
blinded assessment of the safety and tolerability, laboratory results of at least 24 hours, and 
available PK data will be performed by the site and select sponsor safety team.
Following each fully blinded dose cohort review, while the site personnel and study subjects will 
remain blinded to study drug assignment, the sponsor and select sponsor vendors (third-party open) 
may be unblinded to the completed cohort treatments. Precautions will be taken not to unblind the 
study staff, including the investigator and the subject, until the study is completed. The blind may 
be broken before each blinded cohort review and/or dose escalation meeting, if necessary, due to 
safety concerns.
Subjects who drop out may be replaced at the discretion of the sponsor after discussion with the 
investigator.
Study Drug Administration
In Part 3, when administering TAK-951, injection sites must be rotated. All attempts should be 
made to administer the single SC dose of TAK-951 in the abdomen first, followed by upper arms, 
then thigh as alternative sites, avoiding areas of scars or moles. If repeat injections of TAK-951 are 
given in the same spot, this may cause scarring and hardening of fatty tissue, which may interfere 
with the absorption of the drug; if feasible, injections should not be given at the same location 
repeatedly. Each TAK-951 injection must be administered approximately 2 inches (5 centimeters) 
apart and must not be administered into an area where the skin appears to be tender to touch, signs 
of bruising/bleeding are noted, or the area seems indurated or erythematous. If locating injection 
sites on the abdomen, avoid giving the injection in the umbilicus, ribs, hip bone. If injecting in the 
thighs, use the outer areas, below the groin and above the knee. For additional information on 
study drug administration, please refer to the study pharmacy manual.
6.2
Rationale for Study Design, Dose, and Endpoints
6.2.1
Rationale of Study Design 
A randomized, double-blind, placebo-controlled design for Part 1 is considered adequate to 
characterize the safety, tolerability, and PK of single doses of TAK-951. 
Part 2 of Study TAK-951-1001 has been removed from the study in Protocol Amendment 04.
Part 3 of the study is a randomized, double-blind, placebo-controlled, sequential panel MRD study 
 studied under repeat dose conditions.
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Study ID TAK-951-1001
Page 33 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
6.2.2
Rationale for Dose 
6.2.2.1
TAK-951
The starting dose for this FIH study is 20 μg and is based on the rationale detailed below.
FIH Starting Dose Consideration Based on Nonclinical Safety Study Results
The principle of the Food and Drug Administration (FDA) Guidance “Estimating the Maximum 
Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers” is to use 
a 10-fold safety factor on the no-observed-adverse-effect-level (NOAEL) from nonclinical data to 
identify a starting clinical dose.
For TAK-951, NOAELs were identified in the 2-week Good Laboratory Practice (GLP)-compliant, 
repeat-dose toxicity studies, and no-observed-effect-levels (NOELs) were identified in the 
respiratory and central nervous system safety pharmacology studies. 
However, cardiovascular effects in dogs were the principal finding in the safety pharmacology
studies. In this study, the lowest dose 
 TAK-951 produced a transient increase in 
HR and a transient decrease in blood pressure, and a NOEL was not identified. By comparison, 
there were no effects on cardiovascular parameters in cynomolgus monkeys 
 
Given the reversible nature of the cardiovascular changes, variable effects between species, and 
the lack of other significant safety findings, the 
 TAK-951 dose is not anticipated to 
result in adverse effects.
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Study ID TAK-951-1001
Page 34 of 91
Protocol Incorporating Amendment No. 04
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Summary of FIH Starting Dose Consideration
In summary, given the totality of these findings from nonclinical safety, published literature and 
preclinical pharmacology, the proposed starting dose is 
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TAK-951
Study ID TAK-951-1001
Page 35 of 91
Protocol Incorporating Amendment No. 04
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Rationale for Dosing Interval
The dosing regimens selected for Part 3 will have a projected AUC 
above for Part 1.
6.2.3
Starting Dose for This Study
Refer to Section 6.2.2.
6.2.4
Rationale for Endpoints
The PK and safety endpoints are standard for this type of study and are used widely and are 
recognized as reliable, accurate, and relevant. Additional PK parameters may be calculated if 
deemed necessary for the interpretation of the data.
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Study ID TAK-951-1001
Page 36 of 91
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6.2.5
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the following procedures are critical:
Parts 1 and 3:
!
Timing of PK, blood pressure, and Holter assessments (Holter assessments in Part 1 only).
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a phase 1 study of TAK-951 in humans, and the PK and safety profiles of the compound are 
still being elucidated. This protocol is written with some flexibility to accommodate the inherent 
dynamic nature of phase 1 clinical studies. Modifications to the dose, dosing regimen, and/or 
clinical or laboratory procedures, as outlined below, may be required to achieve the scientific goals 
of the study objectives and/or to ensure appropriate safety monitoring of the study subjects.
As such, the following alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily exposure, may not exceed that 
currently outlined in Section 6.2.2:
!
The duration of study drug administration (eg, number of days) in the study may be decreased.
!
In Parts 1 and 3, the dose of study drug administered may be repeated or decreased in 
subsequent cohorts.
!
In Part 3, the dosing interval may be adjusted in subsequent cohorts 
 based on available PK data. The total exposure, however, will not exceed 
2590 h*ng/mL (Table 6.a).
!
Instructions to take study drug with or without food or drink may be modified based on newly 
available data.
!
The PK sampling scheme may be modified during the study based on newly available PK data 
(eg, to obtain data closer to the time of first occurrence of Cmax). If indicated, these collected 
samples may also be assayed in an exploratory manner for metabolites and/or additional 
markers.
!
Up to an additional 49 mL (never more than 50 mL) of blood may be drawn for PK analyses. 
This blood volume may include repeat samples or modified PK time points based on emerging 
data. The total blood volume withdrawn from any single subject will not exceed the maximum 
allowable volume during his/her participation in the entire study.
!
The timing of planned procedures for assessment of safety procedures (eg, vital signs, ECGs, 
safety laboratory tests) may be modified during the study based on newly available safety,
tolerability, and PK (eg, to obtain data closer to the time of first occurrence of Cmax). These 
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Study ID TAK-951-1001
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changes will not increase the number of study procedures for a given subject during his/her 
participation in the entire study.

Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information.
It is understood that the current study may employ some or none of the alterations described above. 
Any alteration made to this protocol to meet the study objectives must be detailed by the sponsor in 
a letter to the study file and forwarded to the investigator for retention. 
6.4
Study Beginning and End/Completion
6.4.1
Definition of Beginning of the Study
The overall study begins when the first subject signs the study informed consent form.
6.4.2
Definition of End of the Study
The overall study ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from the 
study, or is lost to follow-up (ie, the investigator is unable to contact the subject).
6.4.3
Definition of Study Discontinuation
Study discontinuation because of nonsafety reasons, such as the following: 

A finding (eg, PK, efficacy) from another nonclinical or clinical study using the study 
treatment(s) results in the study being stopped for a nonsafety-related reason. 

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this study 
become available and results in the study being stopped for a nonsafety-related reason. 

The study is stopped because of nonscientific and nonsafety reasons, such as slow enrollment. 
Study discontinuation because of safety reasons: 

Early study termination because of unanticipated concerns of safety to the study subjects 
arising from clinical or nonclinical studies with the study treatment(s), comparator(s), drug(s) 
of the same class, or methodology(ies) used in this study.
6.4.3.1
Criteria for Premature Termination or Suspension of Study 
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practice, protocol, or contractual agreement, or is 
unable to ensure adequate performance of the study, or as otherwise permitted by the contractual 
agreement.
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Study ID TAK-951-1001
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6.4.3.2
Procedures for Premature Termination or Suspension of the Study
In the event that the sponsor, an Institutional Review Board (IRB), or regulatory authority elects to 
terminate or suspend the study or the participation of an investigational site, a study-specific 
procedure for early termination or suspension will be provided by the sponsor; the procedure will 
be followed by applicable investigational sites during the course of termination or study 
suspension.
6.4.4
Criteria for Premature Termination or Suspension of a Site
6.4.4.1
Criteria for Premature Termination or Suspension of a Site 
The study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of Good Clinical Practices (GCP), protocol, or contractual 
agreement, is unable to ensure adequate performance of the study, or as otherwise permitted by the 
contractual agreement.
6.4.4.2
Procedures for Premature Termination or Suspension of a Site
In the event that the sponsor, an IRB, or regulatory authority elects to terminate or suspend the 
study or the participation of an investigational site, a study-specific procedure for early 
termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable investigational sites during the course of termination or study suspension.
6.4.5
Stopping Rules
The safety assessments will provide measures of safety and tolerability of TAK-951 following 
each single and/or multiple dose regimen. 
If notable AEs or safety concerns are found at one of the planned TAK-951 dose levels, the 
principal investigator and/or the sponsor may pause the dosing for safety review and consider 
potential changes in the next planned dose level. Possible changes in dose administration include, 
but are not limited to:

Administration of an intermediate dose between the current and next planned dose.

Repeated administration of the current dose.

Administration of a lower dose than the existing dose levels.

Study termination.
Notable AEs include:

Any SAE.

Any TAK-951 related Grade 3 or higher AE (CTCAE version 5.0).
Furthermore, the principal investigator and the sponsor may also consider the number and/or 
severity of AEs as consideration to pause dosing or to discontinue the study.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including laboratory test results, need to be confirmed before the first dose of 
study drug as outlined in the Schedule of Study Procedures in Section 3.0.
7.1
Inclusion Criteria 
The subject must understand the study procedures and agree to participate by providing written 
informed consent. The subject must be willing and able to comply with all study procedures and 
restrictions.
To be eligible for participation in this study, the subject must:
1. Understand the study procedures and agree to participate by providing written informed 
consent.
2. Be willing and able to comply with all study procedures and restrictions.
3. Be a healthy male or WONCBP (woman of nonchildbearing potential) female subject aged 18 
to 55 years, inclusive, at the screening visit.
4. Have a BMI ≥18 and ≤30.0 (kg/m2) at the screening visit.
5. Be judged to be in good health (eg, no evidence of psychiatric, hepatic, renal, pulmonary, or 
cardiovascular disease) by the investigator, based on clinical evaluations including laboratory 
safety tests, medical history, physical examination, ECG, and vital sign measurements 
performed at the screening visit and before administration of the initial dose of study drug or 
invasive procedure.
6. Meet the following birth control requirements:
–
Is a male subject who is sterile or agrees to use an appropriate method of contraception, 
including a condom with or without spermicidal cream or jelly, from the first dose of study 
drug until 5 half-lives after the last dose of study drug. No restrictions are required for a 
vasectomized male subject provided the subject is at least 1 year after bilateral vasectomy 
procedure before the first dose of study drug. A male subject whose vasectomy procedure 
was performed less than 1 year before the first dose of study drug must follow the same 
restrictions as a nonvasectomized man. Appropriate documentation of surgical procedure 
should be provided.
–
Is a male subject who agrees to not donate sperm from the first dose of study drug until 
5 half-lives after the last dose of study drug.
–
Is a female subject of nonchildbearing potential, defined by at least 1 of the following 
criteria:
–
Postmenopausal (defined as 12 -months of spontaneous amenorrhea in females 
aged >45 years or 6 months of spontaneous amenorrhea in females aged >45 years with 
serum follicle-stimulating hormone (FSH) levels >40 mIU/mL). Appropriate 
documentation of FSH levels is required.
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–
Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
documentation of surgical procedure.
–
Had a tubal ligation with appropriate documentation of surgical procedure.
–
Has a congenital condition resulting in no uterus.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has participated in another investigational study within 4 weeks (or based on local 
regulations) before the screening visit. The 4-week window will be derived from the date of 
the last study procedure and/or AE related to the study procedure in the previous study to the 
screening visit of the current study.
2. The subject is an employee of the sponsor or study site or immediate family member (eg, 
spouse, parent, child, sibling) of the sponsor or study site.
3. The subject has a history of significant multiple and/or severe allergies (eg, food, drug, latex 
allergy) or has had an anaphylactic reaction or significant intolerance to prescription 
or nonprescription drugs or food.
4. The subject has a known hypersensitivity or contraindication to any component of TAK-951.
5. The subject has a positive pregnancy test. Women of childbearing potential are not eligible for 
the study.
6. The subject is a lactating/nursing female.
7. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, 
or human immunodeficiency antibody/antigen, at the screening visit. Note: Subjects with 
positive hepatitis B virus or hepatitis C virus serology may be enrolled if 
quantitative polymerase chain reaction for hepatitis B virus or hepatitis C virus ribonucleic 
acid is negative.
8. The subject had major surgery or donated or lost 1 unit of blood (approximately 500 mL) 
within 4 weeks before the screening visit.
9. The subject is unable to refrain from or anticipates using all medications including herbal 
medicines beginning approximately 7 days before administration of the first dose of study drug, 
throughout the study until 2 days after discharge. 
10. Heavy consumption of alcohol within 3 months before screening (7 drinks/week for women, 
14 drinks/week for men, where 1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] 
of beer or 1.5 ounces [45 mL] of hard liquor) or use of soft drugs (such as marijuana) within 3 
months before screening, or hard drugs (such as cocaine and phencyclidine) within 1 year 
before screening. 
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11. The subject has used nicotine-containing products (including, but not limited to, cigarettes, 
pipes, cigars, chewing tobacco, nicotine patch, or nicotine gum) within 28 days before 
check-in (Day -1) or cotinine test is positive at screening or Day -1.
12. The subject has a substance abuse disorder or has a positive urine drug results for drugs of 
abuse at screening or Day -1.
13. The subject has had 3 incidences of vasovagal syncope within the last 5 years.
14. Subject with previous major psychotic disorder.
15. The subject has had family history of unexplained sudden death or channelopathy.
16. The subject has any clinically significant ECG findings including: long or short QT interval 
with Fridericia correction method (QTcF) (over 450 msec or less than 360 msec), 
second-degree atrioventricular (AV) block type 2, third-degree AV block, bifascicular block or 
QRS ≥0.12 at screening or admission.
17. The subject has Brugada syndrome (RBBB pattern with ST-elevation in leads V1-V3).
18. The subject has a documented history of sinus bradycardia (<45 bpm), sinoatrial block or sinus 
pause ≥3 seconds.
19. The subject has a documented history of any clinically significant disorders, including 
psychiatric, cardiovascular, nephrological, neurological, metabolic, and gastrointestinal 
disease including prior cholecystectomy.
20. The subject has an average semirecumbent systolic blood pressure <90 mm Hg or diastolic 
blood pressure <60 mm Hg at screening or admission.
21. The subject has an average HR <60 or >100 bpm (at screening, at Day -1, or at predose); 
athletic subjects with an average HR <60 bpm can be enrolled only with medical monitor 
approval.
22. The subject has orthostatic hypotension defined as a decrease in systolic blood pressure 
≥20 mm Hg or a decrease in diastolic blood pressure ≥10 mm Hg after 2 minutes of standing 
when compared with blood pressure from the sitting position at screening, and at Day -1. 
Subjects with postural orthostatic tachycardia, defined as HR >120 bpm standing, will also be 
excluded.
7.3
Excluded/Allowed Concomitant Medications, Supplements, Dietary Products
7.3.1
Concomitant Medications
The use of concomitant medications approximately 7 days before administration of the first dose 
of study drug, throughout the study until 2 days after discharge is not permitted. Subjects must be 
instructed not to take any medications without first consulting with the investigator. Any 
concomitant medication use must first be discussed with the sponsor, unless the investigator or 
designee considers immediate administration is necessitated.
The occasional use of acetaminophen (approximately <1 g/day) is allowed.
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7.3.2
Fruit Juice
Subjects will refrain from consuming grapefruit juice, grapefruits, and products containing 
grapefruit beginning approximately 2 weeks before administration of the first dose of study drug, 
throughout the study, and until the last PK sample has been collected.
7.3.3
Alcohol
Subjects will refrain from consuming alcohol, 24 hours before admission until the final PK sample 
has been collected. Subjects may undergo an alcohol breath test at the discretion of the 
investigator. 
7.3.4
Caffeine
In Part 1, subjects will refrain from consuming caffeinated beverages, 24 hours before the 
screening visit and follow-up visit and from 24 hours before admission and until the last PK blood 
sample has been collected in each cohort. At all other times, caffeinated beverages or 
xanthine-containing products will be limited to amounts of no more than 6 units per day 
(1 unit = 120 mg of caffeine).
7.3.5
Smoking
Subjects will abstain from the use of tobacco- or nicotine-containing products before dosing and 
during confinement in the clinic.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
7.4.1.1
Part 1
In Part 1 of the study, subjects will fast for at least 8 hours before study drug dosing and will 
continue to fast for an additional 4 hours postdose. Water is permitted. Standard meals will be 
administered at approximately 4 (lunch), 7 (snack), 10 (dinner), and 13 (snack) hours postdose on 
Day 1. Standardized meals will be served on all other confinement days.
7.4.1.2
Part 2
Part 2 of Study TAK-951-1001 has been removed from the study in Protocol Amendment 04.
7.4.1.3
Part 3
In Part 3 of the study on Days 1 and 5, subjects will fast for at least 8 hours before the first dose and 
will continue to fast for an additional 4 hours postdose. Water is permitted. Standard meals will be 
administered at approximately 4 (lunch), 7 (snack), 10 (dinner) and 13 (snack) hours postdose on 
dosing days. All meals should be served at approximately the same time each day.
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7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (eg, weight lifting, running, 
bicycling) from the screening visit until administration of the initial dose of study drug, throughout 
the study (including washout intervals between treatment periods), and until the follow-up visit.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories.

The primary reason for discontinuation or withdrawal of the subject from the study or study 
drug should be recorded in the electronic case report form using the following categories.

Pretreatment event or AE. The subject has experienced a pretreatment event or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the pretreatment event or 
AE.

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.

Significant protocol deviation. The discovery that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.

Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents.

Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an AE 
should not be recorded in the “voluntary withdrawal” category. Similarly, lack of efficacy should 
not be recorded in the “voluntary withdrawal” category.

Study termination. The sponsor, IRB, or regulatory agency terminates the study.

Pregnancy. The subject is found to be pregnant. Note: If the subject is found to be pregnant, the 
subject must be withdrawn immediately.
Note: The specific reasons should be recorded in the “specify” field of the electronic case report 
form.
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7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
early termination visit. 
7.7
Subject Replacement
If a subject discontinues from the study, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and sponsor. The study site should contact the sponsor for the 
replacement subject’s treatment assignment and allocation number.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
8.1.1
Study Drugs
In this protocol, the term study medication refers to all or any of the drugs defined below. 
TAK-951 SC injection and matching placebo injection will be provided to the investigator by the 
sponsor.
Details regarding the dosage form description and strengths, or composition for the 
extemporaneous preparation, of the active drug and placebo can be found in the pharmacy manual 
or in the referenced compounding manual when applicable. Study drug will be packaged to 
support enrollment and replacement of subjects as required.
8.1.1.1
TAK-951
The study site will be supplied by the sponsor with the following medication in an open-label 
manner:
 The study medication 
will be provided in a labeled glass vial and packaged in an appropriately labeled carton with a 
single-panel label that will contain, but will not be limited to, the following: sponsor’s name and 
address, protocol number, packaging job/lot number, name and strength of the product, caution 
statement and storage conditions.
Additional reference information and administration instructions can be found in the pharmacy 
manual. 
8.1.2
Clinical Study Drug Labeling
A clinical label will be affixed to study drug containers in accordance with local regulatory
requirements.
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8.1.3
Clinical Study Drug Inventory and Storage
Study drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label and must remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained.
The temperature excursion information can be found in the pharmacy manual or in the referenced 
compounding manual when applicable. Receipt and dispensing of study drug must be recorded by
authorized personnel at the study site.
8.1.4
Clinical Study Drug Blinding
This is a double-blind study; the investigator and subjects are blinded to treatment assignment. An 
unblinded study drug supply will be provided to an unblinded pharmacist or other qualified 
personnel at the study site who will blind the study supplies. Treatment identity (name and strength 
or potency) will be included on the study drug container label. Randomization code/disclosure 
envelopes or lists will be provided per the standard operating procedures of the study site.
After completion of each dosing cohort, and before selecting the next evaluable dose, a fully 
blinded assessment of the safety and tolerability, laboratory results of at least 24 hours, and 
available PK data will be performed by the site and select sponsor safety team.
Following each fully blinded dose cohort review, while the site personnel and study subjects will 
remain blinded to study drug assignment, the sponsor and select sponsor vendors (third-party open) 
may be unblinded to the completed cohort treatments. Precautions will be taken not to unblind the 
study staff, including the investigator and the subject, until the study is completed. The blind may 
be broken before each blinded cohort review and/or dose escalation meeting, if necessary, due to 
safety concerns.
8.1.5
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.1.6
Clinical Study Blind Maintenance/Unblinding Procedure
The study drug blind will be maintained through a randomization schedule held by the unblinded 
pharmacist at the study site or by the sponsor. The study drug blind shall not be broken by the 
investigator unless information concerning the study drug is necessary for the medical treatment of 
the subject. If possible, the medical monitor should be contacted before the blind is broken. 
Unblinding will be performed per the standard operating procedures of the study site.
8.1.7
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator and investigator’s designated site pharmacy must ensure that the sponsor or 
contract research organization (CRO) supplied drug is used in accordance with the protocol and 
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pharmacy manual and is dispensed only to subjects enrolled in the study. To document appropriate 
use of the sponsor supplied drugs (TAK-951 vials), the investigator pharmacy/site must maintain 
records of drug delivery to the site, site inventory, dispensation and use by each subject, and return 
to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the designated blinded pharmacist must verify the contents 
of the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, designated site 
pharmacist should acknowledge the receipt of the shipment by signing bottom half of the packing 
list. If there are any discrepancies between the packing list versus the actual product received, 
Takeda must be contacted to resolve the issue. The packing list should be filed in the investigator’s 
essential document file.
The investigator’s designated blinded pharmacist must maintain 100% accountability for all 
sponsor-supplied drugs received and dispensed during his or her entire participation in the study. 
Proper drug accountability includes, but is not limited to:

Monitoring expiration dates.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the drug accountability log is completed for each prepared dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
8.2
Ancillary Supplies
All ancillary supplies will be provided by either the study site or the sponsor or designee, 
depending upon availability. The list of ancillary supplies and source information can be found in 
the pharmacy manual or in the referenced compounding manual when applicable. If provided by 
the sponsor, unused ancillary supplies will be accounted for and disposed of as directed by the 
sponsor or designee.
9.0
STUDY PROCEDURES
The following sections describe the study procedures to be performed and data to be collected as 
indicated in the schedule of study procedures (Section 3.0). For each procedure, subjects are to be 
assessed by the same investigator or site personnel whenever possible. Please note that it may 
become necessary to perform the following procedures at unscheduled time periods, per the 
discretion of the investigator.
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9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters into the study and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Appendix B.
9.1.1.1
Assignment of Screening and Randomization Numbers 
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before randomization or allocation. Each subject will be 
assigned only one screening number. Screening numbers must not be reused for different subjects. 
Any subject who is screened multiple times will be assigned a new screening number for each 
screening event.
All eligible subjects will be randomly allocated and will receive a randomization number. The 
randomization number identifies the subject for all procedures occurring after randomization. 
Once a randomization number is assigned to a subject, it can never be reassigned to another subject. 
A single subject cannot be assigned more than one randomization number.
9.1.1.2
Study Drug Assignment
On Day 1, subjects will be assigned a randomization number in ascending numerical order at the 
clinical site. The randomization number encodes the subject assignment to either TAK-951 or 
placebo, according to the randomization schedule generated before the study. Each subject will be 
dispensed blinded study drug, labeled with his/her unique randomization number, throughout the 
study.
9.1.2
Inclusion and Exclusion 
Each subject will be assessed through randomization, according to the eligibility criteria provided 
in Section 7.0.
9.1.3
Medical History/Demography
Qualified site personnel will collect subject significant medical history (past and concurrent 
medical conditions), per the clinical site’s standard of care and appropriate clinical judgment, and 
subject demographics.
Qualified site personnel will review subject prior and concomitant medication use. Medications 
are defined as prescription and over-the-counter drugs, vaccines, supplements, nutraceuticals, and 
oral herbal preparations.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Examination
Qualified site personnel will conduct full physical examinations.
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9.2.2
Height and Weight
Body weight and height will be obtained with the subject’s shoes off, and jacket or coat removed.
9.2.3
Body Mass Index
Body mass index (BMI) equals a subject’s weight in kilograms divided by height in meters 
squared (BMI = kg/m2). BMI will be rounded to the nearest whole number according to the 
standard convention of 0.1 to 0.4, round down, and 0.5 to 0.9, round up.
9.2.4
Vital Signs
Body temperature will be measured with either an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (ie, oral or tympanic) must be used for all measurements 
for each individual subject and should be the same for all subjects. At predose, vital signs will be 
measured within approximately 1 hour predose.
Subjects should rest in a semirecumbent position for at least 3 minutes before vital signs are 
measured. Vital signs will include pulse rate (beats per minute [bpm]), respiratory rate, and 
systolic and diastolic blood pressure in all parts of the study. Blood pressure and pulse assessments 
should be made in duplicate with an interval of approximately 2 minutes between the 2 
assessments. The PI can take a third BP assessment if results are inconsistent. The final BP read 
out should be the average of these assessments. 
For orthostatic blood pressure and pulse assessment, a third blood pressure and pulse assessment 
with the subject standing will be performed after the duplicate semirecumbent assessment has been 
completed. The subject should stand still for approximately 2 minutes before this assessment.
Standing assessments must not be performed if semirecumbent systolic blood pressure is <85 mm 
Hg or if the subject presents with signs or symptoms suggestive of postural hypotension after 
standing (eg, lightheadedness or dizziness, nausea, blurry vision, etc).
The same method (eg, same size cuff, manual or automated) must be used for all measurements for 
each individual subject and should be the same for all subjects.
Subjects should continue to rest in a semirecumbent position from the time of dosing until 4 hours 
postdose except to stand for the measurement of standing vital signs (if needed) or other 
study-related procedure.
When vital signs are scheduled at the same time as blood draws, they will be obtained before the 
scheduled blood draw.
9.2.5
Glucose 
Blood glucose will be monitored using finger-stick blood samples in Parts 1 and 3 and will also be 
monitored using safety laboratory testing.
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9.2.6
ECG Procedure
9.2.6.1
Screening and Safety ECGs
A 12-lead ECG will be collected at the time points specified in the Schedule of Study Procedures 
(see Section 3.0). 
The investigator will interpret the safety ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The time that 
the ECG was performed will be recorded.
The following parameters will be recorded on the eCRF from the subject’s ECG trace: HR, RR 
interval, QRS interval, PR interval, QT interval, and QTcF.
The investigator will be responsible for providing the interpretation of all safety ECGs 
(normal/abnormal). These results will be reviewed by the investigator for subject safety and will 
be provided in an appropriate format with the clinical study report.
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 
(postdose) and discharge. Pulse will be checked immediately, and if it is greater than 120 bpm, a 
12-lead ECG, blood pressure and pulse will be measured and recorded. The ECG, blood pressure 
and pulse measurements will be reviewed by the Investigator, who will use clinical judgment 
regarding further monitoring and management.
9.2.6.2
Telemetry
In Parts 1 (SRD) and 3 (MRD), cardiac monitoring (pulse and ECG) will be assessed via telemetry 
and will be performed for approximately 2 hours before dosing through to approximately 24 hours 
postdose.
Subjects should remain sitting or supine for at least 5 minutes before each telemetry reading. At 
the 0-hr timepoint, telemetry may be assessed in the semirecumbent position to allow for the most 
efficient capture of the other multiple assessments. 
9.2.6.3
Holter
The 12-lead Holter ECG monitoring will be captured on Day 1 of Part 1 (SRD) with a minimum of 
23.5 hours of continuous cardiac monitoring. Continuous 12-lead Holter ECG monitoring will be 
performed from 1 hour predose until 24 hours postdose. For all postdose ECG collections, three 
10-second ECGs will be extracted at each extraction window time point. 
ECG extraction time points will occur before PK blood draws. Accordingly, subjects will be 
supervised and quietly resting supine beginning a minimum of 10 minutes before each actual ECG 
extraction window of 10 minutes. Subjects will be supervised while remaining at rest, quiet, and 
awake and in a supine position from at least 10 minutes before the beginning of each ECG 
extraction time point and will remain quiet, awake, motionless, and supine for at least 10 minutes 
after the beginning of each ECG extraction time point.
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9.2.7
Study Drug Administration
Study Drug (TAK-951) will be administered as shown in the Schedule of Study Procedures in 
Section 3.0.
9.2.9
AE Monitoring
AE monitoring begins after signing of the informed consent form. Changes in subject health status 
from the baseline assessment until study drug administration should be captured in the subject’s 
medical history. A complete description of AE collections and procedures is provided in Section 
10.0.
9.3
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be collected following a minimum 8-hour overnight fast at the time points stipulated 
in the schedule of study procedures (Section 3.0).
9.3.1
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells [RBCs])
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs] with absolute
differential
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9.3.2
Chemistry 
Chemistry evaluations will consist of the following chemistry panel:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride and lipase
Creatinine
Glucose 
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total) if above the upper limit of normal, total 
bilirubin will be fractionated
Protein (total)
ALT: alanine aminotransferase; AST: aspartate aminotransferase
If subjects experience ALT or AST >3 times the ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, gamma-glutamyl transferase, and 
international normalized ratio) should be performed 24 hours after the abnormality was noted, and 
the medical monitor should be contacted.
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, and discussion of the relevant subject details and possible alternative etiologies. The 
abnormality should be recorded as an AE.
Please refer to Section 7.5 for subject discontinuation criteria regarding abnormal liver test results 
and Section 10.2.8.5 for guidance on reporting abnormal liver test results.
9.3.3
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrate
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of 
RBC/high-power field, WBC/high-power field, and casts.
9.3.4
Diagnostic Screening
Other 
HIV
Hepatitis screen (hepatitis B surface antigen, hepatitis C 
virus antibody)
FSH
βhCG (pregnancy) test
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Alcohol Screen
Subjects will undergo an alcohol breath test. A urine alcohol test may be performed at the 
discretion of the investigator.
Urine
The urine drug screening assessment will include the following tests:
Amphetamines
3,4-methylenedioxy-methamphetamine
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
9.4
PK, 
, and Immunogenicity Samples
Samples for PK, ADA 
 analysis will be collected as specified in the Schedule 
of Study Procedures (Section 3.0). Please refer to the laboratory manual for information on the 
collection, processing, and shipment of samples to the central laboratory.
The decision as to which plasma and/or serum samples collected will be assayed for evaluation of 
PK will be determined by the sponsor (eg, samples at lower doses may not be assayed if samples at 
higher doses reveal undetectable drug concentrations). 
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Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for PK
Plasma
Plasma
PK measurement
Mandatory
Urine sample for PK
Urine
Urine
PK measurement
Mandatory
Blood sample for ADA
Blood
Blood
ADA analysis
Mandatory
ADA: anti-drug antibody;
a A single follow-up optional sample will be collected.
9.4.1
PK Measurements 
The PK parameters of TAK-951 will be determined from the concentration-time profiles for all 
evaluable subjects. Actual sampling times, rather than scheduled sampling times, will be involved 
in all computations involving sampling times.
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The following plasma PK parameters will be determined after single dose and at steady state: 
Symbol/Term
Definition
Plasma/Blood/Serum
AUC24
Area under the plasma/blood/serum concentration-time curve from the time 0 to time 24 
hours. 
AUCτ
Area under the plasma/blood/serum concentration-time curve during a dosing interval, where 
tau (τ) is the length of the dosing interval.
AUClast
Area under the plasma/blood/serum concentration-time curve from time 0 to time of the last 
quantifiable concentration.
AUC∞
Area under the plasma/blood/serum concentration-time curve from time 0 to infinity, 
calculated as AUC∞= AUCt+Clast/λz
R
Accumulation ratio (index) calculated as AUCτ at steady state/AUC∞after a single dose.
Rac(AUC)
Accumulation ratio (based on AUC), calculated as AUCτ at steady state/AUCτ after a single 
dose.
Cmax
Maximum observed plasma/blood/serum concentration.
Cmax,ss
Maximum observed steady-state plasma/blood/serum concentration during a dosing interval.
CL/F
Apparent clearance after extravascular administration, calculated as = Dose/AUC∞after a 
single dose and as Dose/AUCτ after multiple dosing (at steady state).
λz
Terminal elimination rate constant calculated as the negative of the slope of the log-linear 
regression of the natural logarithm concentration-time curve during the terminal phase.
t1/2z
Terminal disposition phase half-life calculated as ln(2)/λz.
tlag
Lag time to first quantifiable concentration.
tmax
Time of first occurrence of Cmax.
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated as (CL/F)/λz.
The following urine PK parameters of TAK-951 will be determined after SD administration in Part 
1:
Urine
Aet1-t2
Amount of drug excreted in urine from time 1 to time 2, calculated as Cur× Vur, where Cur is 
the concentration of drug excreted in urine and Vur is the volume of urine excreted.
Aet
Total amount of drug excreted in urine from time 0 to time t.
Aeτ
Amount of drug excreted in urine during a dosing interval (τ) at steady state.
fe
Fraction of drug excreted in urine, calculated as (Aet/dose) × 100. Molecular weight 
adjustment needed for metabolites.
CLR
Renal clearance calculated as Ae0-24/AUC24.
Additional PK parameters may be calculated as appropriate. Further details will be provided in the 
clinical pharmacology analysis plan.
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9.4.1.1
Plasma or Serum for PK Measurements
Blood samples for PK analysis of TAK-951 will be collected into chilled blood collection tubes 
(vacutainer) containing the anticoagulant K2EDTA. The collected blood samples may be archived 
for additional analysis of potential metabolites.
The actual time of sample collection will be recorded on the source document and eCRF. Sampling 
time points may be adjusted based on the preliminary emerging concentration data collected from 
prior subject(s), but the total number of samples collected per subject should not exceed the 
planned number.
9.4.1.2
PK Sample Analysis
Plasma and urine concentrations of TAK-951 will be measured by a validated high-performance 
liquid chromatography with tandem mass spectrometry assay.
9.4.2
Immunogenicity (ADA) Measurements 
Protein products have the potential to induce anti-drug immune response which may affect the 
safety and efficacy of the compound under study. Detection and analysis of ADA formation is a 
helpful tool in understanding drug immunogenicity, efficacy, and safety. To understand drug 
immu
mples will be collected on Day 1, predose, and at the follow-up visit. 
Othe
have reported the formation of ADAs, however, an ADA assay may be 
influenced by several factors including assay methodology, sample handling, timing of sample 
collection, concomitant medications, and underlying disease. Therefore, the incidences of ADA 
formation cannot be directly compared with the other products. ADA samples will be taken in all 
parts of the study across all cohorts.
9.4.3
Biomarker Measurements
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9.5
Confinement
9.5.1
Part 1 (SRD)
Subjects will report to the clinical site the evening before the scheduled day of study drug 
administration (Day -1). Subjects will remain in the clinic for 30 hours postdose (Day 2) or until 48 
hours postdose if requested by the investigator and deemed necessary to ensure subject safety. At 
the discretion of the investigator, subjects may be requested to remain in the clinical site longer.
9.5.2
Part 2 (SD Apo Challenge)
Part 2 of Study TAK-951-1001 has been removed from the study in Protocol Amendment 04.
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9.5.3
Part 3 (MRD)
Subjects will report to the clinical site the evening before the scheduled day of study drug 
administration (Day -1). Subjects will remain in the clinic from Day-1 until discharge on Day 6. 
Subjects will be discharged 30 hours after last dose of TAK-951/placebo. At the discretion of the 
investigator, subjects may be requested to remain in the study site longer.
9.6
Childbearing Status and Methods of Contraception
9.6.1
Women of Childbearing Potential
Women of childbearing potential will be excluded from this study.
9.6.1.1
Definition of Women of Childbearing Potential
A woman is considered of childbearing potential (ie, fertile) following menarche and until 
becoming postmenopausal, unless permanently sterile.
9.6.2
Women of Nonchildbearing Potential
A female subject of nonchildbearing potential is defined as satisfying at least 1 of the following 
criteria:

Postmenopausal: At least 12 months of spontaneous amenorrhea and a FSH 
concentration >40 mIU/mL.

Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
documentation of surgical procedure.

Has no uterus as a result of a congenital condition.
9.6.2.1
Contraception for WONCBP
No contraception is required for WONCBP.
10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs).
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
Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, x-ray) should NOT be recorded as an AE unless related to 
a study procedure. However, if the subject experiences a worsening or complication of such a 
concurrent medical history condition, the worsening or complication should be recorded 
appropriately as an AE (worsening or complication occurs after informed consent is signed). 
Investigators should ensure that the event term recorded captures the change in the condition 
(eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent 
than that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
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Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) due to a worsening of the pre-existing condition, the worsening of the condition 
should be captured appropriately as an AE. Complications resulting from any planned surgery 
should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.

All cases of overdose (with or without associated AEs) will be documented on an overdose 
page of the eCRF, 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.
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2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT assessed by the investigator or sponsor, 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).
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
AEs of special interest for TAK-951 include injection site reactions, hypotension, and tachycardia. 
These AEs will be monitored by the investigator and sponsor.
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10.2
AE Procedures
10.2.1
Assigning Severity of AEs
All AEs, including clinically significant treatment-emergent laboratory abnormalities, will be 
graded according to NCI CTCAE v5.0. AEs not listed by the NCI CTCAE will be graded as 
displayed in Table 10.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 (ADL).
3
Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.
4
Life-threatening consequences; urgent intervention indicated.
5
Fatal AE; an event that results in the death of the subject.
NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events.
10.2.2
Assigning Causality of AEs
The relationship of each AE to study medication 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.
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10.2.5
Pattern of AE (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6
Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE
(eg, the study has been terminated, the subject died, dosing with study medication had not yet
started or dosing with study medication was already stopped before the onset of the AE).

Drug interrupted – the dose was interrupted due to the particular AE.
10.2.7
Outcome 

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or
signs/symptoms have almost disappeared; the abnormal laboratory value improved but has not
returned to the normal range or to the baseline value; the subject died from a cause other than
the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs, or symptoms; the
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed
study period has become worse than when it started; is an irreversible congenital anomaly; the
subject died from another cause with the particular AE state remaining “Not recovered/not
resolved.”

Recovered/resolved with sequelae – the subject recovered from an acute AE but was left with
permanent/significant impairment (eg, recovered from a 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, and Abnormal LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, AEs, SAEs, special interest AEs, and abnormal LFTs) will commence at the 
time the subject signs the informed consent. Routine collection of AEs will continue until 
approximately 30 days after the last dose of investigational product. For subjects who discontinue 
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before 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 before 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 before the first exposure to 
investigational product, related or unrelated to the study procedure, need not be followed up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (investigator’s opinion of the causal relationship between the event and 
administration of study drugs).

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.
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
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.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4
Management of Specific AEs
Sinus Tachycardia
CTCAE Grade 
Management
CTCAE Grade 2 sinus tachycardia (ie, 
Symptomatic a; nonurgent medical 
intervention indicated) with HR 120 and 
above at rest for at least 5 minutes with 
no physical exertion. 
Evaluate ECG for abnormalities, manage as per local guidelines and call 
the medical monitor immediately. 
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.
a 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.
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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.
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). 
10.2.8.5
Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST >3 times the ULN and total bilirubin >2 times the ULN, 
the event should be recorded as an SAE and reported as per Section 10.2.8.3. The investigator must 
contact the medical monitor for discussion of the relevant subject details and possible alternative 
etiologies, such as acute viral hepatitis A or B or other acute liver disease. Follow-up laboratory 
tests as described in Section 9.3 must also be performed. 
10.2.9
Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs, as 
applicable, in accordance with national regulations in the countries where the study is conducted. 
Relative to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, SUSARs will be submitted 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 in accordance with national regulations.
11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the study database, subject evaluability, or appropriateness of the 
planned statistical methods.
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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 receive study drug. 
Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries. 
11.1.1.2
PK Set
The PK analysis set will consist of all subjects who receive study drug and have at least 1 
measurable plasma concentration of TAK-951.
11.1.1.4
Immunogenicity Set
The immunogenicity set consists of patients who receive at least 1 dose of TAK-951 and have an 
ADA status assessment at baseline, and at least 1 postbaseline sample.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Descriptive statistics (N, mean, standard deviation, median, minimum, and maximum) will be 
generated for continuous demographic variables and baseline characteristics variables (eg, age, 
height, weight, and BMI) for pooled placebo group, each TAK-951 dose level, TAK-951 overall in 
Part 1 and Part 3. The number and percentage of subjects in each class of the categorical 
demographic variables and baseline characteristics variables (eg, gender, ethnicity, race) will be 
tabulated for pooled placebo group, each TAK-951 dose level, and overall. Placebo data will be 
pooled across cohorts within each part of the study. Individual subject demographic and baseline 
characteristics data will be listed.
11.1.4
PK Analysis
The plasma and urine concentrations of TAK-951 will be summarized by dose, cohort, day, and 
dosing condition (as appropriate) 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. Dose 
CCI
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11.1
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proportionality will be assessed graphically (dose-normalized Cmax and AUC versus dose) as data 
allows; no formal statistical comparisons will be conducted.
Additional PK parameters may be calculated as appropriate. Further details will be specified in the 
SAP.
11.1.5
Safety Analysis
Safety analyses will be based on the safety analysis set. No formal statistical tests or inference will 
be performed for safety analyses. All summaries will be performed by pooled placebo within each 
part, and TAK-951 dose level.
11.1.5.1
AEs
Treatment-emergent adverse events (TEAEs) will be summarized by placebo, each TAK-951 dose 
level and TAK-951 overall for each part of the study.
11.1.5.2
Clinical Laboratory Evaluations
Baseline, postdose, 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.
11.1.5.3
Vital Signs
Vital signs data will be summarized using descriptive statistics for each cohort. Individual vital 
sign results meeting the sponsor’s markedly abnormal criteria will also be summarized.
11.1.5.4
ECG
ECG data captured through telemetry and Holter will be listed by subject and treatment group for 
each part.
11.1.5.5
Other Safety Parameters
Physical examination findings will be presented in the data listings.
11.1.7
Immunogenicity Analysis
Immunogenicity will be summarized using the Immunogenicity set. Descriptive statistics will be 
used to summarize subjects in the following categories: ADA negative, ADA positive, low or high 
ADA titer.
CCI
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The relationship between immunogenicity status (ADA and ADA titer) and PK, 
and 
safety may be explored. Further details will be provided in the SAP.
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 next dose escalation stage in the 
study.
11.3
Determination of Sample Size
For Parts 1 and 3, the selected sample sizes are considered sufficient for evaluation of safety,
tolerability, PK, and PD. The study is not statistically powered to perform hypothesis testing in 
Parts 1 and 3.
12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
investigator’s binder, study drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB, as required) to determine the appropriate course of action. There will be no 
exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
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, 
CCI
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where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
Products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator guarantees access for quality assurance auditors to all study 
documents as described in Section 12.1.
13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix A. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
13.1
IRB Approval
IRBs must be constituted according to the applicable state and federal/local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the IRB. If any member of the IRB has direct participation in this 
study, written notification regarding his or her abstinence from voting must also be obtained. 
Those Americas sites unwilling to provide names and titles of all members due to privacy and 
conflict of interest concerns should instead provide a Federal Wide Assurance Number or 
comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the IRB for the 
protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the informed 
consent form, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB for approval. The IRB’s written approval of the protocol and subject informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study specific screening activity). The IRB 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, informed consent form) reviewed; and state the approval date. The 
sponsor will ship drug/notify site once the sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor has received permission from competent 
authority to begin the study. Until the site receives drug/notification no protocol activities, 
including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the IRB, 
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and submission of the investigator’s final status report to IRB. All IRB approvals and relevant 
documentation for these items must be provided to the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor.
13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form and, if applicable, the subject authorization form. The informed consent form, 
subject authorization form (if applicable), and subject information sheet (if applicable) must be 
approved by the IRB and the sponsor before use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB. 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 before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using 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 before the subject enters 
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 
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investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time before 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 to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
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The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2
Clinical Trial Registration 
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.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1
Study Contact Information 
Study contact numbers can be found in the study manual, the communication plan, or other similar 
documents provided to the site.
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14.1.2
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.9 of this protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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14.1.3
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
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14.1.4
List of Abbreviations
ADA
anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC∞
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
AUCτ
area under the concentration-time curve during a dosing interval
AV
atrioventricular
BMI
body mass index
BPM
beats per minute
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed concentration
CRO
contract research organization
CTX
carboxy-terminal collagen crosslinks
EC50
half-maximal effective concentration
eCRF
electronic case report form
ECG
electrocardiogram
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GLP-1
glucagon like peptide-1
hCG
human chorionic gonadotropin
HED
human equivalent dose
HR
heart rate
ICH
International Conference on Harmonisation
IRB
institutional review board
IV
intravenous
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MRD
multiple-rising dose
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NRS
Numeric Rating System
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PK
pharmacokinetic
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
single dose
SRD
single-rising dose
SUSAR
suspected unexpected serious adverse reactions
TAG
triacylglyceride
TEAE
treatment-emergent adverse event
T1/2z
terminal disposition phase half-life
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal phase after extravascular 
administration
WBC
white blood cell
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization Drug 
Dictionary.
15.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
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enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
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.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
16.0
REFERENCES
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
H 
cified 
ified 
years aft
ears a
ICH
CH E6
E
me spec
me spe
y Si
Site Ag
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i
ts on rec
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roperty of Takeda: For Non-Commercial Use Only and Subje


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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 that conform to 21
CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB will be responsible for initial review, continuing review, and approval of
the protocol. Promptly report to the IRB all changes in research activity and all anticipated
risks to subjects. Make at least yearly reports on the progress of the study to the IRB, and issue
a final report within 3 months of study completion.
8. Ensure that requirements for informed 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. Each informed consent form should contain a subject
authorization section that describes the uses and disclosures of a subject’s personal
information (including personal health information) that will take place in connection with the
study. If an informed consent form does not include such a subject authorization, then the
investigator must obtain a separate subject authorization form from each subject or the
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of
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2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB, 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 and whom to contact in the event of a research-related 
injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
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legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of 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;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 5 half-lives 
after the last dose of study drug. If the partner or wife of the subject is found to be pregnant 
during the study, the investigator will offer the subject the choice to receive unblinded 
treatment information. 
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.
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 trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the study, and for 5 half-lives after 
last dose of study drug, nonsterilized** male subjects who are sexually active with a female 
partner of childbearing potential* must use barrier contraception (eg, condom with or without 
spermicidal cream or jelly). In addition, they must be advised not to donate sperm during this 
period. Females of childbearing potential who are partners of male subjects are also advised to use 
additional contraception as shown in the list containing highly effective/effective contraception 
below.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high FSH level in the 
postmenopausal range (FSH >40 IU/L) may be used to confirm a postmenopausal state in younger 
women (eg, those <45 years old) or women who are not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are 
included/excluded, the only acceptable methods of contraception are: 

Non-Hormonal Methods: 
–
IUD (Intrauterine device).
–
Bilateral tubal occlusion.
–
Vasectomised partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomised partner has received medical assessment of the 
surgical success.
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the 
subject. True abstinence is defined as refraining from heterosexual intercourse during the 
entire period of the study, from 1 month prior to the first dose until 5 half-lives.
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
Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the efficacy 
of the contraception method (evaluate on compound-by-compound and protocol-by-protocol 
basis and obtain clinical pharmacology justification).
–
Combined (estrogen and progestogen) hormonal contraception associated with inhibition 
of ovulation initiated at least 3 months prior to the first dose of study drug OR combined 
with a barrier method (male condom, female condom or diaphragm) if for shorter duration 
until she has been on contraceptive for 3 months;

Oral †.

Intravaginal † (eg, ring).

transdermal †.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation1 
initiated at least 3 months prior to the first dose of study drug OR combined with a barrier 
method (male condom, female condom or diaphragm) if for shorter duration until she has 
been on contraceptive for 3 months;

oral †.

Injectable.

Implantable.
2. If genotoxicity/teratogenicity/embryotoxicity is unlikely to be caused by the investigational 
drug, comparator, background therapy or standard of care medications effective methods of 
contraception (there may be a higher than 1% failure rate) are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom).

Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action PLUS condom with or without spermicide.
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
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Study ID TAK-951-1001
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4. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
5. During the study, regular serum/urine human chorionic gonadotropin (hCG) pregnancy tests 
will be performed for female subjects and all subjects (male and female) will receive continued 
guidance with respect to the avoidance of pregnancy and sperm donation as part of the study 
procedures. Such guidance should include a reminder of the following:

contraceptive requirements of the study

reasons for use of barrier methods (ie, condom) in males with pregnant partners

assessment of subject compliance through questions such as
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit?
–
Are your menses late? (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
–
Is there a chance you could be pregnant?
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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Page 90 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
Appendix E
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 04.
Rationale for Change: All references to Part 2 of the study have been removed 
The following sections contain these changes:
!
Section 1.0 STUDY SUMMARY
!
Section 2.0 STUDY SCHEMATIC
!
Section 3.2 Part 2 for SD Apo Cohorts 7 to 9 (section content has been deleted)
!
Section 4.2 Rationale for the Proposed Study
!
Section 4.3 Benefit-Risk Profile
!
Section 5.1 Study Objectives
!
Section 5.2 Endpoints
!
Section 6.1 Study Design, including references to Part 2 in Table 6.a
!
Section 6.1.2
!
Section 6.2.1 Rationale of Study Design
!
Section 6.2.2.
!
Section 6.2.2.3
!
Section 6.2.4 Rationale for Endpoints
CCI
CCI
CCI
CCI
CCI
Property of Takeda: For Non-Commercial U
change
chang
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TAK-951
Study ID TAK-951-1001
Page 91 of 91
Protocol Incorporating Amendment No. 04
23 September 2020
!
Section 6.2.5 Critical Procedures Based on Study Objectives: Timing of Procedures
!
Section 6.3 Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
!
Section 6.4.5 Stopping Rules
!
Section 7.2 Exclusion Criteria and Section 1.0 STUDY SUMMARY Main Criteria for 
Exclusion
!
Section 7.4.1.2 Part 2 (under Diet and Fluid)
!
Section 8.1.1.2
!
Section 8.1.1.3 
!
Section 8.1.2 Use of Rescue Medication (section has been deleted)
!
Section 8.1.3 Clinical Study Drug Inventory and Storage
!
Section 8.1.7 Accountability and Destruction of Sponsor-Supplied Drugs
!
Section 8.3 Companion Medication (section has been deleted)
!
Section 8.4 Rescue Medication (section has been deleted)
!
Section 9.2.4 Vital Signs
!
Section 9.2.5 Glucose
!
Section 9.2.6.2 Telemetry
!
Section 9.2.7 Study Drug Administration
!
!
!
Section 9.5.2 Part 2 (SD Apo Challenge)
!
Section 11.1.1.3 PD Set
!
Section 11.1.2 Analysis of Demography and Other Baseline Characteristics
!
!
!
Section 11.3 Determination of Sample Size
CCI
CCI
CCI
CCI
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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:  Randomized, Double-Blind, Placebo-Controlled, Three-Part Phase 1 Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects
NCT Number: NCT05567393
SAP Approve Date: 12 October 2020
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.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-951-1001
A Randomized, Double-Blind, Placebo-Controlled, Three-Part Phase 1 Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of TAK-951 in Healthy Subjects
PHASE 1
Version: 3.0
Date: 12 October 2020
Prepared by:
Based on:
Protocol Version: Amendment 4.0
Protocol Date:  23 September 2020
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Phase 1
Phase
951 in 
951 in
sion
on: 3.3
12 Oct
12 O
Protoc
Proto
Pr
P
or Non-Co
op


TAK-951-1001
Page 2 of 26
Statistical Analysis Plan Version 3.0
12 October 2020
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951-1001
Page 3 of 26
Statistical Analysis Plan Version 3.0
12 October 2020
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objective......................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................7
4.4
Study Design .............................................................................................................7
4.4.1
Part 1: SRD Cohorts 1 to 6 and 13 to 19.............................................................9
4.4.2
Part 3: MRD Cohorts 10 to 12 and 20 ..............................................................10
5.0
ANALYSIS ENDPOINTS.............................................................................................11
5.1
Primary Endpoint.....................................................................................................11
5.2
Secondary Endpoints ...............................................................................................11
5.3
Exploratory Endpoints .............................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Definition of Study Day, Baseline and Study Visit Windows...........................12
7.1.2
Conventions for Missing Data..........................................................................13
7.2
Analysis Sets ...........................................................................................................13
7.3
Disposition of Subjects ............................................................................................13
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................14
7.6
Medication History and Concomitant Medications...................................................14
7.7
Study Drug Exposure and Compliance.....................................................................15
7.8
Efficacy Analysis.....................................................................................................15
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................15
7.9.1
Pharmacokinetic Analysis................................................................................15
7.9.2
Pharmacodynamic Analysis.............................................................................17
7.10
Other Outcomes.......................................................................................................17
7.11
Safety Analysis........................................................................................................17
7.11.1
Adverse Events................................................................................................18
7.11.2
Clinical Laboratory Evaluations.......................................................................19
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Statistical Analysis Plan Version 3.0
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7.11.3
Vital Signs and Weight ....................................................................................19
7.11.4
12-Lead ECGs.................................................................................................20
7.11.5
Other Observations Related to Safety...............................................................20
7.12
Interim Analysis ......................................................................................................21
7.13
Changes in the Statistical Analysis Plan...................................................................21
7.13.1
Revision History..............................................................................................21
8.0
REFERENCES..............................................................................................................22
LIST OF TABLES
Table 4.a
Overview of Treatment Cohorts...........................................................................8
Table 4.b
Part 1: Schematic Representation and Planned Doses – Cohorts 1-6.....................9
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................23
Appendix B
Criteria for Abnormal Vital Signs ......................................................................24
Appendix C
Criteria for Identification of Markedly Abnormal Orthostatic Changes...............25
Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters..........26
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951-1001
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Statistical Analysis Plan Version 3.0
12 October 2020
3.0
LIST OF ABBREVIATIONS
%CV 
coefficient of variation 
λz
terminal disposition phase rate constant 
AE 
adverse event 
Aet
amount of drug excreted in urine from time 0 to time t 
Aeτ
amount of drug excreted in urine during a dosing interval 
ANCOVA 
analysis of covariance 
ANOVA
analysis of variance
AUC∞
area under the concentration-time curve from time 0 to infinity 
AUCτ
area under the concentration-time curve during a dosing interval 
AUClast
area under the CSF concentration-time curve from time 0 to time of the last 
quantifiable concentration
AUC24 
area under the concentration-time curve from time 0 to time 24 hours 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CL/F 
apparent clearance after extravascular administration 
CLR
renal clearance 
Cmax
maximum observed concentration 
Cmax, ss
maximum observed concentration during a dosing interval, at steady state 
CSF 
cerebrospinal fluid 
CV 
conventional units 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
fe, t 
fraction of administered dose of drug excreted in urine from time 0 to time t 
IA
interim analysis
MAV 
markedly abnormal value 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
multiple-rising dose 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PT 
preferred term 
PTE 
pretreatment event
QD 
once daily 
R
Accumulation ratio (index)
Rac(AUC)
accumulation ratio based on AUC
Rac(Cmax)
accumulation ratio based on Cmax
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951-1001
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Statistical Analysis Plan Version 3.0
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SI 
International System of Units 
SOC 
system organ class 
SRD 
single-rising dose 
TEAE 
treatment emergent adverse event 
t1/2z
terminal disposition phase half-life 
tlag
Lag time to first quantifiable concentration
tmax
time of first occurrence of Cmax
Vz/F 
apparent volume of distribution during the terminal disposition phase after 
extravascular administration 
WHODrug 
World Health Organization Drug Dictionary
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TAK-951-1001
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Statistical Analysis Plan Version 3.0
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4.0
OBJECTIVES
4.1
Primary Objective
!
Parts 1 
–
To characterize the safety (including immunogenicity) and tolerability of single SC doses 
of TAK-951 in healthy subjects.
!
Part 3
–
To characterize the safety (including immunogenicity) and tolerability of multiple SC 
doses of TAK-951 in healthy subjects.
4.2
Secondary Objectives
The secondary objectives of this study are:
!
Parts 1 
–
To characterize the plasma PK of TAK-951 following single SC doses in healthy subjects.
!
Part 3
–
To characterize the plasma PK of TAK-951 following multiple SC doses in healthy 
subjects.
4.3
Exploratory Objectives
4.4
Study Design
This is a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety,
tolerability, and PK of TAK-951 in healthy subjects. 
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Statistical Analysis Plan Version 3.0
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The study will consist of 2 parts: 
!
Part 1 is a FIH, randomized, double-blind, placebo-controlled, SRD study to assess the safety, 
tolerability and PK of TAK-951 in healthy volunteers. Up to 13 cohorts will be enrolled. 
Subjects will be randomized to receive TAK-951 or matching placebo.
!
Part 2 of the study has been removed in Protocol Amendment 04.
!
Part 3 is a randomized, double-blind, placebo-controlled, multiple rising dose (MRD) study. 
TAK-951 and matching placebo will be administered subcutaneously. Any part of the study may 
not be conducted at the discretion of the sponsor. Safety will be assessed by monitoring for AEs,
vital signs, ECG/telemetry, safety laboratory assessments after each dose and immunogenicity.
Sampling times may vary based on emerging PK data, but the maximal number of samples or the 
maximum time point will not change.
An overview of treatment cohorts is presented in Table 4.a.
Table 4.a
Overview of Treatment Cohorts
Cohort
Regimen
Treatment
Part 1
TAK-951
Placebo
1
SRD
6
2
2
6
2
3
6
2
4
6
2
5
6
2
6
6
2
13
6
2
14
6
2
15
6
2
16
6
2
17
6
2
18
6
2
19
6
2
Part 3
TAK-951
Placebo
10
MRD
6
2
11
6
2
12
6
2
20
6
2
IV: intravenous; MRD: multiple rising dose; SC: subcutaneous; SD: single dose; SRD: single rising dose
Part 2 of Study TAK-951-1001 has been removed from the study in Protocol Amendment 04.
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Statistical Analysis Plan Version 3.0
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4.4.1
Part 1: SRD Cohorts 1 to 6 and 13 to 19
Part 1 will consist of up to 13 cohorts of 8 healthy subjects. Subjects in each cohort will be 
randomly assigned to receive a single dose of TAK-951 or placebo in a 3:1 ratio in a 
double-blind manner. Up to approximately 104 healthy subjects will be randomized in Part 1 
(see Table 4.b). 
Table 4.b
Part 1: Schematic Representation and Planned Doses – Cohorts 1-6
TAK-951
Dose 1 
TAK-951
Dose 2a
TAK-951
Dose 3a
TAK-951
Dose 4a
TAK-951
Dose 5a
TAK-951
Dose 6a
Cohort 1
Cohort 2
Cohort 3
Cohort 4
Cohort 5
Cohort 6
6 active
6 active
6 active
6 active
6 active
6 active
2 placebo
2 placebo
2 placebo
2 placebo
2 placebo
2 placebo
a Dose may be subject to change based on emerging data.
Subjects from each cohort will be admitted into the study unit on Day -1 and will be dosed with 
TAK-951 or matching placebo on Day 1 after a minimum of 8 hours of fasting. Subjects will be 
confined for a minimum of 30 hours after dosing (can be discharged after the 30-hour PK sample) 
and may be confined for up to 48 hours postdose at the discretion of the investigator, if needed to 
ensure subject safety. After discharge, subjects will return to the study unit for additional 
assessments as indicated in the schedule of assessments. Blood samples for assessment of 
TAK-951 plasma concentrations will be collected up to 48 hours postdose. Urine will be 
collected up to 24 hours post TAK-951 dose. 
A staggered dosing approach may be used for cohorts in Part 1. After dosing the first 2 subjects 
of each cohort (1 receiving TAK-951 and 1 receiving placebo) the investigator will review all
available safety and tolerability data prior to dosing the remaining subjects in the cohort. The 
investigator will also consult Takeda as needed at any time.
Doses may be subject to change based on emerging PK and safety data. The sponsor 
may decide to administer lower doses, repeat doses, and cancel or add cohort(s) if deemed 
necessary. Subjects who drop out of the study for nonsafety reasons may be replaced at the 
discretion of the sponsor after discussion with the investigator.
After completion of each dosing cohort, and before selecting the next evaluable dose, a fully 
blinded assessment of the safety and tolerability, laboratory results of at least 24 hours, and 
available PK data will be performed by the site and select sponsor safety team.
Following each full blinded dose cohort review, while the site personnel and study subjects will 
be blinded to study drug assignment, the sponsor and select sponsor representatives may be 
unblinded to the completed cohort treatments. However, precautions will be taken not to unblind 
the study staff, including the investigator and subject, until the study is completed. The blind 
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TAK-951-1001
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Statistical Analysis Plan Version 3.0
12 October 2020
may be broken before each blinded cohort review and/or dose escalation meeting, if necessary, 
due to safety concerns. 
Study Drug Administration
In Part 1, all attempts should be made to administer the single SC dose of TAK-951 in the 
abdomen. In all cases, care should be taken to avoid areas of scars or moles. TAK-951 must not 
be administered into an area where the skin appears to be tender to touch, signs of 
bruising/bleeding are noted, or the area seems indurated or erythematous. When locating 
injection sites on the abdomen, avoid giving the injection in the umbilicus, ribs, hip bone. For 
additional information on study drug administration, please refer to the Study Pharmacy Manual.
Part 2 of study TAK-951-1001 has been removed from the study in Protocol Amendment 04.
4.4.2
Part 3: MRD Cohorts 10 to 12 and 20
Part 3 may start before completion of Part 1. If Part 3 is started before the completion of Part 1, 
the starting dose in Part 3 will be at a dose level below that currently being studied in Part 1. 
Similarly to Part 1, a staggered dosing approach may be used for cohorts in Part 3. Site personnel 
and study subjects will be blinded to study drug assignment, but selected sponsor vendors (third-
party open) may be unblinded. Part 3 consists of up to 4 sequential ascending cohorts of healthy 
subjects. In each cohort, 8 healthy subjects will be randomly assigned to receive TAK-951 or 
matching placebo in a 3:1 ratio in a double-blind manner. Up to approximately 32 healthy 
subjects will be randomized in Part 3. 
Subjects will be admitted to the study unit on Day -1 and will be dosed on Day 1 in each 
cohort/period after a minimum of 8 hours of fasting. Subjects will be confined until Day 6, 
30 hours after last dose on Day 5 to assess safety, tolerability and PK. Subjects will return after 
discharge for additional assessments including PK sampling as indicated in the study flow chart. 
Four safe and tolerable doses from Part 1 
will be studied in 
Part 3 in an ascending manner. Based on emerging PK data from Part 1, adjustment to dose, 
dosing frequency, and repeat dosing duration may be implemented. 
After completion of each cohort and before selecting the next evaluable dose, a blinded 
assessment of the safety and tolerability, laboratory at least 24 hours, and available PK data will 
be performed by the site and select sponsor safety team. 
Following each fully blinded dose cohort review, while the site personnel and study subjects will 
remain blinded to study drug assignment, the sponsor and select sponsor vendor (third-party
open) may be unblinded to the completed cohort treatments. Precautions will be taken not to 
unblind the study staff, including the investigator and subject, until the study is completed. The 
blind may be broken before each blinded cohort review and/or dose escalation meeting, if 
necessary, due to safety concerns.
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TAK-951-1001
Page 11 of 26
Statistical Analysis Plan Version 3.0
12 October 2020
Subjects who drop out may be replaced at the discretion of the sponsor after discussion with the 
investigator.
Study Drug Administration
In Part 3, when administering TAK-951, injection sites must be rotated. All attempts should be 
made to administer the single SC dose of TAK-951 in the abdomen first, followed by upper arms, 
then thigh as alternative sites, avoiding areas of scars or moles. If repeat injections of TAK-951 
are given in the same spot, this may cause scarring and hardening of fatty tissue, which may 
interfere with the absorption of the drug; if feasible, injections should not be given at the same 
location repeatedly. Each TAK-951 injection must be administered approximately 2 inches 
(5 centimeters) apart and must not be administered into an area where the skin appears to be 
tender to touch, signs of bruising/bleeding are noted, or the area seems indurated or erythematous. 
If locating injection sites on the abdomen, avoid giving the injection in the umbilicus, ribs, hip 
bone. If injecting in the thighs, use the outer areas, below the groin and above the knee. For 
additional information on study drug administration, please refer to the Study Pharmacy Manual.
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint 
!
Parts 1and 3
∀
The primary safety endpoint of the study is safety and tolerability as assessed through
physical examinations, vital signs, ECG/telemetry, laboratory assessments, AEs and 
immunogenicity. 
5.2
Secondary Endpoints
!
Part 1: plasma PK parameters for TAK-951
–
Maximum observed plasma concentration (Cmax).
–
Area under the plasma concentration time curve from time 0 to infinity (AUC∞).
!
Part 3: plasma PK parameters for TAK-951
–
Cmax on Day 1.
–
Area under the plasma concentration-time curve during a dosing interval (AUCτ), where 
tau (τ) is the length of the dosing interval on Day 1. 
5.3
Exploratory Endpoints
!
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TAK-951-1001
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Statistical Analysis Plan Version 3.0
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6.0
DETERMINATION OF SAMPLE SIZE
For Parts 1 and 3, the selected sample sizes are considered sufficient for evaluation of safety,
tolerability, PK, and PD. The study is not statistically powered to perform hypothesis testing in 
Parts 1 and 3.
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All study-related raw and derived data for randomized subjects will be presented in listings by 
cohort. All summaries will be presented for each study part separately. 
Continuous data will be summarized using the following descriptive statistics: number of 
subjects (N), mean, standard deviation (SD), median, minimum, and maximum, where 
appropriate. Where indicated, the coefficient of variation (%CV) and geometric mean will also 
be included in the summary of continuous data. Categorical data will be summarized using the 
number and percent of subjects for each category, where appropriate. Percentages will be 
reported to 1 decimal place.
Data from Study Parts 1 and 3 will analyzed separately. Summaries for Study Parts 1 and 3 will 
be presented by pooled placebo, each TAK-951 dose level, TAK-951 overall and overall. 
All statistical analyses will be performed using the SAS System Version 9.4 or higher.
7.1.1
Definition of Study Day, Baseline and Study Visit Windows
Study day will be calculated relative to the date of the first dose of the study drug in each study
part. Study days prior to the first dose of study drug in each study part will be calculated as: 
{date of assessment/event – date of first dose of study drug in that study part}. Study days on or 
after the first dose of study drug in each study part will be calculated as: {date of 
assessment/event – date of first dose of study drug in that study part + 1}.
There will be no visit windowing.
In Study Parts 1 and 3, Baseline values is defined as the last observed value before the first dose 
of study medication, unless otherwise stated. 
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Statistical Analysis Plan Version 3.0
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7.1.2
Conventions for Missing Data
There will be no imputation of incomplete or missing data. 
Plasma or urine concentrations that are below the limit of quantification (BLQ) will be treated as 
zero in the summarization of concentration values and derivation of PK parameters. These values 
will be flagged in the data listings and deviations from this convention may be considered on a 
case-by-case basis as deemed appropriate.
7.2
Analysis Sets
Safety Set 
The Safety Set will include all randomized subjects who receive at least 1 dose of investigational 
products in a given part of the study. Subjects in this set will be used for demographic, baseline 
characteristics, and safety summaries. 
Pharmacokinetic Set 
The PK analysis set will consist of all subjects who receive TAK-951 and have at least 1 
measurable plasma concentration of TAK-951. All subjects with valid PK parameter estimates 
will be included in the summaries and analyses for that parameter. 
Pharmacodynamic Set
The PD analysis set for Parts 1 and 3 will include all subjects who are randomized and received
study drug and have at least 1 non-missing PD measurement. Part 2 of Study TAK-951-1001 has 
been removed from the study in Protocol Amendment 04.
7.3
Disposition of Subjects
Disposition of all screened subjects (denominator) will be tabulated (count and percent); there 
will be no inferential analysis of subject disposition data. 
For Study Parts 1 and 3, summaries will be presented by pooled placebo, each TAK-951 dose 
level, TAK-951 overall and overall. 
Disposition of all randomized subjects will be tabulated for each part of the study: 
–
All treated subjects (denominator) 
–
Subjects who were randomized but not treated, if applicable 
–
Subjects who completed the study investigational products
–
Subjects who prematurely discontinued study investigational products
–
Subjects who completed all study visits 
–
Subjects who prematurely discontinued study visits.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951-1001
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Statistical Analysis Plan Version 3.0
12 October 2020
Primary reasons for discontinuation of study drug/visits, as entered on the electronic case report 
form (eCRF), will be tabulated. Reasons for discontinuation include adverse event, significant 
protocol deviation, lost to follow-up, voluntary withdrawal, sponsor study termination, IRB 
study termination, regulatory agency study termination, pregnancy, and other. The date of first 
dose, date of last dose, duration of treatment and the reason for premature discontinuation of 
study drug/study visit will be presented for each subject in listings.
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by study part for subjects in the 
Safety Set. 
For Study Parts 1 and 3, summaries will be presented by pooled placebo, each TAK-951 dose 
level, TAK-951 overall and overall. 
Summary statistics will be presented for continuous variables (age, height, weight, and body 
mass index [BMI]). The number and percentage subjects within each category will be presented 
for categorical variables (gender, race, etc). Individual subject demographic and baseline 
characteristic data will be listed.
7.5
Medical History and Concurrent Medical Conditions
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA, version 18 or higher) coding system. 
Medical history includes any significant conditions or diseases relevant to the disease under 
study that stopped at or prior to signing of informed consent. Ongoing conditions are considered 
concurrent medical conditions. 
All medical history and concurrent medical condition data will be listed by site (study center) 
and subject number. The listing will contain subject identifier, treatment, system organ class 
(SOC), preferred term (PT), whether there was any medical history or concurrent condition, and, 
if yes, a detail of the medical history or concurrent condition. No inferential statistics will be 
presented.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 28 days prior to signing of informed consent. Concomitant medications are recorded on 
the eCRF and include any medications, other than study drug, taken at any time between 
informed consent and the end of the study.
All medication history and concomitant medications will be listed by site (study center) and 
subject number. The listings will contain subject identifier, treatment, preferred medication name, 
dose, unit, frequency, route, start date, stop date, whether the medication was ongoing, and 
reason for use. No inferential statistics will be presented. 
Medication history and concomitant medications will be coded using the WHODrug Version 
01March 2015 or higher. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-951-1001
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Statistical Analysis Plan Version 3.0
12 October 2020
7.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in the data listing for all subjects. 
Summaries of PK data will be provided by dose in Study Parts 1 and 3. No other summary
statistics for the extent of exposure to study investigational products or compliance calculations 
will be performed for this study. 
7.8
Efficacy Analysis
Not applicable
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
All PK summaries and analyses will be based on the PK set. PK parameters of TAK-951 will be 
derived using non-compartmental analysis methods. The PK parameters of TAK-951 will be 
determined from the concentration-time data for all evaluable subjects. Actual sampling times, 
rather than scheduled sampling times, will be used in all computations involving sampling times. 
Blood samples for determination of TAK-951 will be collected according to the following 
schedule: 
Study Part
Analyte
Matrix
Day
Scheduled Times (Hours)
1
TAK-951
Plasma
1
Predose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 30, 48 
hours postdose
3
TAK-951
Plasma
1
Predose and at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 hours postdose
2, 3, 4
Predose
5
Predose and at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours postdose
6
Discharge
Concentrations of TAK-951 in plasma will be summarized by study part, dose, and day over 
each scheduled sampling time using descriptive statistics. Individual plasma TAK-951 
concentration data will be presented in a data listing. 
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TAK-951-1001
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Statistical Analysis Plan Version 3.0
12 October 2020
The following plasma PK parameters will be determined after SD and at steady state:
Symbol/Term
Definition
Plasma/Blood/Serum
AUC24
Area under the plasma/blood/serum concentration-time curve from the time 0 to time 24 hours. 
AUCτ
Area under the plasma/blood/serum concentration-time curve during a dosing interval, where tau 
(τ) is the length of the dosing interval.
AUClast
Area under the plasma/blood/serum concentration-time curve from time 0 to time of the last 
quantifiable concentration.
AUC∞
Area under the plasma/blood/serum concentration-time curve from time 0 to infinity, calculated as 
AUC∞=AUCt+Clast/λz
R
Accumulation ratio (index) calculated as AUCτ at steady state/AUC∞after a single dose.
Rac(AUC)
Accumulation ratio (based on AUC), calculated as AUCτ at steady state/AUCτ after a single dose.
Cmax
Maximum observed plasma/blood/serum concentration.
Cmax,ss
Maximum observed steady-state plasma/blood/serum concentration during a dosing interval.
CL/F
Apparent clearance after extravascular administration, calculated as =Dose/AUC∞after a single 
dose and as Dose/AUCτ after multiple dosing (at steady state).
λz
Terminal elimination rate constant, calculated as the negative of the slope of the log-linear 
regression of the natural logarithm concentration-time curve during the terminal phase.
t1/2z
Terminal disposition phase half-life, calculated as ln(2)/λz.
tlag
Lag time to first quantifiable concentration.
tmax
Time of first occurrence of Cmax.
Vz/F
Apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated as (CL/F)/λz.
Descriptive statistics (N, arithmetic mean, geometric mean, SD, %CV, median, minimum, and 
maximum) will be used to summarize the plasma PK parameters for TAK-951 by dose for Study 
Parts 1 and 3. In addition, geometric mean will be computed for Cmaxand AUCs. Individual 
plasma PK parameters will be presented in a data listing. 
Serial urine samples for determination of TAK-951 will be collected according to the following 
schedule: 
Study Part
Analyte
Matrix
Day
Scheduled Times (Hours)
1
TAK-951
Urine
1
Predose and at 0-4, 4-8, 8-12, 12-16, and 16-24 hours postdose
3
TAK-951
Urine 
1, 5
Predose and at 0-4, 4-8, 8-12, 12-16, and 16-24 hours postdose
The urine volume and the urine concentrations of TAK-9511 will be summarized by dose over 
each scheduled sampling interval using descriptive statistics. Individual urine TAK-951 
excretion data will be presented in a data listing.
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TAK-951-1001
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Statistical Analysis Plan Version 3.0
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The following urine PK parameters of TAK-951 will be determined in Part 1 and part 3:
Symbol/Term
Definition
Aet1-t2
Amount of drug excreted in urine from time 1 to time 2, calculated as Cur×Vur, where Cur is the 
concentration of drug excreted in urine and Vur is the volume of urine excreted.
Aet
Total amount of drug excreted in urine from time 0 to time t.
Aeτ
Amount of drug excreted in urine during a dosing interval (τ) at steady state
fe
Fraction of drug excreted in urine, calculated as (Aet/dose)×100. Molecular weight adjustment 
needed for metabolites.
CLR
Renal clearance, calculated as Ae0-24/AUC24.
Descriptive statistics (N, arithmetic mean, geometric mean, SD, %CV, median, minimum, and 
maximum) will be used to summarize the urine PK parameters for TAK-951. Individual urine 
PK parameters will be presented in a data listing.
In Study Parts 1 and 3, the relationship between dose and key PK parameters (Cmax and AUCs) 
will be assessed using the power model. The power model can be described by the following 
equation: 
ln( 	
	)= + 1 ln(	) + 
where  is the intercept and 1 is the slope with random error ε. Dose proportionality will be 
declared if the 90% confidence interval (CI) for 1 lies entirely within the critical region, 
(1 + 
 (.)
 () , 1 + 
 (.)
 () )
where  is the ratio of the highest and the lowest dose in a given part of the study. Dose 
proportionality for subjects who are administered all of the study drug will be tested for 
TAK-951 Cmax and AUCs on Day 1 for Study Part 1 and on Days 1 and 5 separately for Study
Part 3. 
7.9.2
Pharmacodynamic Analysis
Part 2 of Study TAK-951-1001 has been removed from the study in Protocol Amendment 04.
7.10
Other Outcomes
7.11
Safety Analysis
The Safety Set will be used for all summaries of safety and tolerability assessment including AEs, 
clinical laboratory parameters, vital sign parameters, 12-lead ECG results, and other safety 
parameters. 
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-951-1001
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Statistical Analysis Plan Version 3.0
12 October 2020
The safety summaries for Study Parts 1 and 3 will be presented separately by pooled placebo, 
each TAK-951 dose level, TAK-951 overall, and overall. 
7.11.1
Adverse Events
All adverse events will be coded using MedDRA latest version. In this dictionary, each verbatim 
term is coded to a lower level term, and then mapped to a preferred MedDRA term, which is then 
mapped to an SOC. All adverse events will be included in the data listings but only treatment 
emergent adverse events will be included in the summary tables.
A treatment-emergent adverse event (TEAE) is defined as an AE that started or worsened after 
first study drug administration and within 30 days of last dose of study drug (AE onset date –
date of last dose ≤30). AEs with missing onset dates will be summarized with TEAEs regardless 
of toxicity grade and relationship to study medication.
The following summaries will be presented:

Overview of TEAEs during the study - number and percentage of subjects, number of events.

TEAEs by SOC and PT - number and percentage of subjects.

TEAEs by PT - number and percentage of subjects.

Toxicity grade of TEAEs by SOC and PT - number and percentage of subjects.

Relationship of TEAEs by SOC and PT - number and percentage of subjects.

Drug-related TEAEs by SOC and PT - number and percentage of subjects.

TEAEs Related to Study Procedure by SOC and PT - number and percentage of subjects.

TEAEs leading to study discontinuation by SOC and PT - number and percentage of subjects.

Serious TEAEs by SOC and PT - number and percentage of subjects, number of events.
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.
In the high-level adverse event summary tables, TEAEs will be summarized regardless of 
severity and relationship to study drug. Within each subject, multiple reports of events that map 
to a common MedDRA term will be counted only once.
At the adverse event level, the summary tables will present the number of subjects reporting each 
of these MedDRA events, ie, the number of subjects reporting 1 or more events that map to the 
given MedDRA term.
At the SOC level, the summary tables will present the number of subjects reporting 1 or more 
events that map to the given SOC. That is, the number of subjects reported at the SOC level will 
be less than or equal to the sum of the subject counts across all adverse events within that SOC.
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Statistical Analysis Plan Version 3.0
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In selected summaries (see above), adverse events will be summarized by the number of events 
reported in addition to the number and percentage of subjects with events.
For the summary of TEAEs by SOC, preferred term and maximum toxicity grade, if a subject 
experiences more than 1 episode of a particular coded adverse event, the subject will be counted 
only once by the maximum toxicity grade of the episode (preferred term). Similarly, if a subject 
has more than 1 adverse event within an SOC, the subject will be counted only once by the 
maximum toxicity grade in that SOC.
TEAEs classified in the eCRF as related to the study medication will also be summarized by 
preferred term and SOC. If a subject experiences more than 1 episode of a particular coded 
adverse event, the subject will be counted only once for the preferred term. Similarly, if a subject 
has more than 1 adverse event within an SOC, the subject will be counted only once in that SOC. 
Adverse events with missing relationship will be classified as related to study drug.
Listings for TEAEs, TEAEs leading to study discontinuation, SAEs, deaths, and AE of special 
interest will be presented.
7.11.2
Clinical Laboratory Evaluations
Clinical laboratory tests will be evaluated and presented using International System of Units (SI) 
units unless otherwise stated. Only observations within 7 days of the last dose of study drug will 
be included in the tables. No inferential statistics will be presented unless otherwise stated.
Descriptive statistics (N, mean, median, SD, minimum and maximum) of clinical laboratory 
variables will be summarized for baseline, postbaseline values, and change from baseline by 
treatment group and overall at each measurement. Only the scheduled measurements will be 
included in the summary.
Individual results for hematology laboratory tests and serum chemistry tests will be evaluated 
against the Takeda predefined laboratory markedly abnormal value (MAV) criteria 
(Appendix A). All subjects that meet the MAV criteria will be presented in a data listing. If a 
subject has a MAV for a particular laboratory test, all values for that subject and for that 
parameter will be listed. The number and percentage of subjects with at least 1 postbaseline 
markedly abnormal laboratory test result will be presented by treatment group and overall. All 
postbaseline clinical lab results within 7 days of the last dose, including scheduled and 
unscheduled measurements will be included in the MAV summaries. The mapping of the 
subjects with postbaseline results which meet the MAV criteria will be listed as a table.
Listings of all clinical laboratory data will be provided. Laboratory data outside of the normal 
reference range will be flagged on the listing along with values meeting MAV criteria
7.11.3
Vital Signs and Weight
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters at baseline, each post-baseline visit, and change from baseline 
to each post-baseline visit. Only observations within 7 days of the study drug will be included in 
the tables.
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Statistical Analysis Plan Version 3.0
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All individual vital signs that meet Takeda’s predefined criteria for markedly abnormal values 
(Appendix B) will be listed. The number and percentage of subjects with at least 1 postbaseline 
markedly abnormal vital sign measurement will be summarized. All postbaseline vital signs 
within 7 days of the last dose, including both scheduled and unscheduled measurements, will be 
included in the MAV summaries. The mapping of the subjects with postbaseline results which 
meet the MAV criteria will be listed as a table.
Orthostatic hypotension, identified by the criteria defined in Appendix C, will be calculated at 
every time point where sitting/standing and semi-recumbent measurements are available using 
the formula: sitting/standing vital measurement – semi-recumbent vital measurement at 1 minute 
and 3 minutes. The mapping of the subjects who meet the criteria for orthostatic hypotension will 
be listed by study visit as a table. All orthostatic hypotension observations, including ones at 
unscheduled visits, will be included in the subject mappings.
All vital sign data will be presented in the listings. Vital sign MAVs will be flagged in the 
listings.
7.11.4
12-Lead ECGs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize the ECG parameters including heart rate, PR interval, RR interval, QRS interval, QT 
interval, and QTc interval (Fridericia’s) for baseline, each post-baseline visit, and change from 
baseline to each post-baseline visit. Only the scheduled measurements will be included in the 
summary. Only observations within 7 days of the study drug will be included in the tables. No 
inferential statistics will be presented. 
A shift table for the investigator’s ECG interpretation will provide the number of subjects in each 
of the appropriate categories (Normal, Abnormal but not clinically significant, or Abnormal and 
clinically significant) at the scheduled visit relative to the Baseline status. 
All individual ECGs that meet Takeda’s predefined criteria for markedly abnormal values 
(Appendix D) will be listed. The number and percentage of subjects with at least one markedly 
abnormal ECG measurement will be summarized. All post dose ECGs within 7 days of the last
dose, including both scheduled and unscheduled measurements, will be included in the MAV 
summaries. The mapping of the subjects who meet the MAV criteria will be listed as a table.
All ECG data will be presented in the listings. ECG MAVs will be flagged in the listings.
7.11.5
Other Observations Related to Safety
Immunogenicity will be summarized using the safety set. Descriptive statistics will be used to 
summarize subjects in the following categories: ADA negative, ADA positive, low or high ADA 
titer.
The injection site assessment for local tolerability will be summarized by the severity level for 
each assessment (Erythema, Ecchymosis, Induration, Tenderness, Warmth, Swelling, and 
Lipoatrophy) by the assessment timepoints. 
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Statistical Analysis Plan Version 3.0
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7.12
Interim Analysis
An interim analysis (IA) will be conducted after the completion of Part 1 SRD portion of study 
to support the safety review and regulatory interactions. Takeda personnel will be unblinded to 
the treatment assignments of individual subjects of Part 1 SRD portion of data, while the site 
personnel and study subjects will remain blinded to study treatment assignment. The details of 
IA data access and distribution will be described in a separate document (i.e., data access 
management plan).
The statistical methodologies to be used in the interim analysis are as described in this SAP. In 
particular, 

Only the data/cohort(s) from Part 1 SRD portion of study will be included in the IA.

The IA will focus on key safety data including subject disposition, demographic and 
baseline characteristics, TEAEs, lab, vital signs, and ECG.
7.13
Changes in the Statistical Analysis Plan 
The following changes from the protocol have been made in this SAP:

An IA after the completion of Part 1 SRD portion of study is added in the SAP version 
2.0. Refer to Section 7.12 for details.

All references to Part 2 of the study were removed in this version of SAP per Protocol 
Amendment 4 dated 23Sept2020.
7.13.1
Revision History
Version
Date 
Description of Changes
1.0
April 12, 2019
N/A
2.0
April 3, 2020
Updated the texts for study design in Section 4.4 based on Protocol 
Amendment 3 dated 28Jun2019.
Clarified the data from Part 1 and Part 3 will analyzed separately in Section 
7.1.
Added an IA after the completion of SRD portion of study in Section 7.12.
3.0
October 12, 2020
Removed all references to Part 2 of the study throughout the SAP per Protocol 
Amendment 4 dated 23Sept2020.
Added urine PK sample timepoints for Part 3 in Section 7.9.1. 
Updated high abnormal criteria for markedly abnormal laboratory values for 
GGT, Alkaline phosphatase, Total Bilirubin in Appendix A.
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Statistical Analysis Plan Version 3.0
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8.0
REFERENCES
1. Bruce G. Wolff, MD, et al. Alvimopan, a Novel, Peripherally Acting µ Opioid Antagonist. 
Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of 
Major Abdominal Surgery and Postoperative Ileus.
2. Irinel Popescu, et al. The Ghrelin Agonist TZP-101 for Management of Postoperative Ileus 
After Partial Colectomy: A Randomized, Dose-Ranging, Placebo-Controlled Clinical Trial.
3. Grant Bochicchio, et al. Ghrelin Agonist TZP-101/Ulimorelin Accelerates Gastrointestinal 
Recovery Independently of Opioid Use and Surgery Type: Covariate Analysis of Phase 2 
Data.
4. Justin T Brady, et al. The use of alvimopan for postoperative ileus in small and large bowel 
resections.
5. Conor P. Delaney, et al. Postoperative upper and lower gastrointestinal recovery and 
gastrointestinal morbidity in patients undergoing bowel resection: pooled analysis of placebo 
data from 3 randomized controlled trials.
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Statistical Analysis Plan Version 3.0
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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 × ULN
Platelet Count
SI
<75 x 109/L
>600 × 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
SI
--
>3 × ULN
AST
SI
--
>3 × ULN
GGT
SI
--
>3 × ULN, if baseline is normal;
>2 × baseline, if baseline is high 
abnormal
Alkaline phosphatase
SI
--
>3 × ULN, if baseline is normal;
>2 × baseline, if baseline is high 
abnormal
Total Bilirubin
SI
--
>1.5 × ULN, if baseline is normal;
>1.5 × baseline, if baseline is high 
abnormal
Albumin
SI 
<25 g/L
--
Total protein
SI
<0.8x LLN
>1.2 × ULN
Creatinine
SI
>177 mol/L
Blood urea nitrogen
SI
>10.7 mmol/L
Sodium
SI
<130 mmol/L
>150 mmol/L
Potassium
SI
<3.0 mmol/L
>5.5 mmol/L
Glucose
SI
<3 mmol/L
>10 mmol/L*
Chloride
SI
<75 mmol/L
>126 mmol/L
Calcium
SI
Corrected serum calcium of <LLN -
8.0 mg/dL; <LLN - 2.0 mmol/L; 
Ionized calcium <LLN - 1.0 mmol/L
Bicarbonate
SI 
<8.0 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.
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Statistical Analysis Plan Version 3.0
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Appendix B
Criteria for Abnormal Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse Rate
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85
>180 
Diastolic blood pressure
mm Hg
<50 
>110
Body temperature
oC
<35.6
>37.7
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Statistical Analysis Plan Version 3.0
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Appendix C
Criteria for Identification of Markedly Abnormal Orthostatic Changes 
Parameter
Criteria 
Orthostatic Hypotension
(Orthostatic Systolic Blood Pressure < -20 mm Hg OR 
Orthostatic Diastolic Blood Pressure < -10 mm Hg) AND Heart Rate 
Increase > 20 beats/min 
Note: Orthostatic measurement = standing vital measurement – supine vital measurement.
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Statistical Analysis Plan Version 3.0
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Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters
Parameter
Lower Criteria
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
PR
≤80 milliseconds
≥200 milliseconds
QTcF Interval
≥500 milliseconds OR
≥30 milliseconds change from baseline and
≥450 milliseconds
QRS
≤80 milliseconds
≥120 milliseconds
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