Clinical trial NCT03870555
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2019-03-08; Completion date: 2019-05-16
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, and PK of single ascending intravenous doses of TAK-954.

Detailed description:
The drug being tested in this study is called TAK-954. This study will assess the safety, tolerability, PK and PD of single ascending TAK-954 higher intravenous doses than those previously studied.

The study will enroll approximately 6 participants. Participants will be randomly assigned (By chance, like flipping a coin) to one of the three treatment sequences-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need).

In each treatment sequence, each participant will receive 2 doses of active drug out of 3 dose levels (TAK-954 0.5 mg, TAK-954 1 mg, or TAK-954 2 mg) and 1 dose of Placebo. Dose escalation will be based on the available safety/tolerability data from the previous period.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 73 days. Participants will make a final visit on Day 16 after receiving their last dose of study drug for a follow-up assessment.

Arms: arm 1: Period 1: TAK-954 placebo-matching infusion, administered intravenously over 60-minutes, once on Day 1 and Day 2.

Period 2: TAK-954 0.1 milligram (mg), infusion, administered intravenously over 60-minutes, once on Day 1, TAK-954 1 mg infusion, administered intravenously over 60-minutes, once on Day 2.

Period 3: TAK-954 0.1 mg, infusion, administered intravenously over 60-minutes, once on Day 1, TAK-954 2 mg infusion, administered intravenously over 60-minutes, once on Day 2.

A washout period of at least 16 days will be maintained between each Treatment Period. arm 2: Period 1: TAK-954 0.1 mg, infusion, administered intravenously over 60-minutes, once on Day 1, TAK-954 0.5 mg infusion, administered intravenously over 60-minutes once on Day 2.

Period 2: TAK-954 placebo-matching infusion, administered intravenously over 60-minutes, once on Day 1 and Day 2.

Period 3: TAK-954 0.1 mg, infusion, administered intravenously over 60-minutes, once on Day 1, TAK-954 2 mg, infusion, administered intravenously over 60-minutes, once on Day 2.

A washout period of at least 16 days will be maintained between each Treatment Period. arm 3: Period 1: TAK-954 0.1 mg, infusion, administered intravenously over 60-minutes, once on Day 1, TAK-954 0.5 mg, infusion, administered intravenously over 60-minutes once on Day 2.

Period 2: TAK-954 0.1 mg, infusion, administered intravenously over 60-minutes, once on Day 1, TAK-954 1 mg, infusion, administered intravenously over 60-minutes, once on Day 2.

Period 3: TAK-954 placebo-matching infusion, administered intravenously over 60-minutes, once on Day 1 and Day 2. A washout period of at least 16 days will be maintained between each Treatment Period.
Interventions: intervention 1: TAK-954 intervention 2: TAK-954 Placebo
Intervention descriptions: intervention 1: TAK-954 infusion administered intravenously. intervention 2: TAK-954 placebo-matching infusion intravenous.

Protocol documents:
Prot_000.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, 
3-Period, Incomplete Block Design Study to Investigate the Safety, Tolerability,
Pharmacokinetics and Pharmacodynamics of TAK-954 in Healthy Adult Participants.
NCT Number: NCT03870555
Protocol Approve Date: 11 March 2019
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.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, 
3-Period, Incomplete Block Design Study to Investigate the Safety, Tolerability,
Pharmacokinetics and Pharmacodynamics of TAK-954 in Healthy Adult Participants.
Study Identifier:
TAK-954-1009
Compound:
TAK-954
Date:
11 March 2019
Version/Amendment 
Number:
Amendment 01
Amendment History: 
Date
Amendment Number
Amendment Type
Region
07 February 2019
Initial Version
11 March 2019
01
Not Applicable
United States
Propert
non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study ID TAK-954-1009
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Protocol Incorporating Amendment No. 01
11 March 2019
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................13
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................15
3.1
Screening and Period 1 ............................................................................................15
3.2
Periods 2 and 3 ........................................................................................................18
4.0
INTRODUCTION.........................................................................................................21
4.1
Background .............................................................................................................21
4.2
Rationale for the Proposed Study.............................................................................22
4.3
Benefit/Risk Profile .................................................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................23
5.1
Hypothesis...............................................................................................................23
5.2
Study Objectives......................................................................................................23
5.2.1
Study Primary Objectives............................................................................23
5.2.2
Study Secondary Objective .........................................................................23
5.2.3
Study Exploratory Objectives......................................................................23
5.3
Endpoints.................................................................................................................23
5.3.1
Primary Endpoints.......................................................................................23
5.3.2
Secondary Endpoints...................................................................................24
5.3.3
Exploratory Endpoints.................................................................................24
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................26
6.1
Study Design ...........................................................................................................26
6.2
Dose Escalation .......................................................................................................27
6.3
Rationale for Study Design, Dose, and Endpoints ....................................................27
6.3.1
Rationale of Study Design...........................................................................27
6.3.2
Rationale for Dose ......................................................................................28
6.3.2.1
Starting Dose for This Study...................................................................28
6.3.2.2
Maximum Dose/Exposure for This Study...............................................28
6.3.3
Rationale for Endpoints...............................................................................29
6.3.3.1
Safety Endpoints ....................................................................................29
6.3.3.2
Pharmacokinetic Endpoints ....................................................................29
6.3.3.3
Pharmacodynamic Endpoints..................................................................29
6.3.4
Future Biomedical Research........................................................................29
6.3.5
Critical Procedures Based on Study Objectives: Timing of Procedures........30
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................30
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Study ID TAK-954-1009
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6.5
Study Beginning and End/Completion .....................................................................30
6.5.1
Definition of Beginning of the Study...........................................................30
6.5.2
Definition of End of the Study.....................................................................30
6.5.3
Definition of Study Completion ..................................................................30
6.5.4
Definition of Study Discontinuation............................................................30
6.5.5
Criteria for Premature Termination or Suspension of the Study...................31
6.5.6
Criteria for Premature Termination or Suspension of a Site.........................31
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS .....32
7.1
Inclusion Criteria .....................................................................................................32
7.2
Exclusion Criteria ....................................................................................................32
7.3
Excluded Medications, Supplements, Dietary Products............................................34
7.4
Diet, Fluid, Activity.................................................................................................35
7.4.1
Diet and Fluid .............................................................................................35
7.4.2
Activity.......................................................................................................35
7.5
Criteria for Discontinuation or Withdrawal of a Participant......................................35
7.6
Procedures for Discontinuation or Withdrawal of a Participant ................................36
7.7
Participant Replacement ..........................................................................................36
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................37
8.1
Clinical Study Drug .................................................................................................37
8.1.1
Clinical Study Drug Labeling......................................................................37
8.1.2
Clinical Study Drug Inventory and Storage .................................................37
8.1.3
Clinical Study Drug Blinding ......................................................................37
8.1.4
Randomization Code Creation and Storage .................................................37
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure............................38
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs ........................38
9.0
STUDY PROCEDURES...............................................................................................39
9.1
Administrative Procedures.......................................................................................39
9.1.1
Informed Consent Procedure.......................................................................39
9.1.1.1
Assignment of Screening and Randomization Numbers..........................39
9.1.1.2
Study Drug Assignment..........................................................................39
9.1.2
Inclusion and Exclusion ..............................................................................39
9.1.3
Medical History/Demography .....................................................................40
9.1.4
Concomitant Medications............................................................................40
9.2
Clinical Procedures and Assessments.......................................................................40
9.2.1
Physical Examination..................................................................................40
9.2.2
Height and Weight ......................................................................................40
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Study ID TAK-954-1009
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9.2.3
BMI ............................................................................................................40
9.2.4
Vital Signs ..................................................................................................40
9.2.5
12-Lead ECG..............................................................................................41
9.2.6
Study Drug Administration .........................................................................41
9.2.7
AE Monitoring............................................................................................41
9.2.8
Laboratory Procedures and Assessments .....................................................42
9.2.8.1
Clinical Laboratory Tests........................................................................42
9.3
PK, PD, and Biomarkers Samples............................................................................43
9.3.1
PK Measurements .......................................................................................43
9.3.1.1
Plasma for PK Measurements.................................................................44
9.3.1.2
Urine for PK Measurements ...................................................................45
9.3.2
PD Measurements .......................................................................................45
9.3.3
Biomarkers Measurements ..........................................................................45
9.3.4
Confinement ...............................................................................................46
10.0
ADVERSE EVENTS ....................................................................................................47
10.1
Definitions and Elements of AEs .............................................................................47
10.1.1
SAEs...........................................................................................................49
10.1.2
Special Interest AEs....................................................................................50
10.2
AE Procedures.........................................................................................................50
10.2.1
Assigning Severity/Intensity of AEs............................................................50
10.2.2
Assigning Causality of AEs.........................................................................51
10.2.3
Start Date....................................................................................................51
10.2.4
End Date.....................................................................................................51
10.2.5
Pattern of Adverse Event (Frequency).........................................................51
10.2.6
Action Taken With Study Treatment ...........................................................51
10.2.7
Outcome .....................................................................................................52
10.2.8
Collection and Reporting of AEs, SAEs, Special Interest AEs, and 
Abnormal LFTs...........................................................................................52
10.2.8.1
Collection Period....................................................................................52
10.2.8.2
Reporting AEs........................................................................................52
10.2.8.3
Reporting SAEs......................................................................................53
10.2.8.4
Reporting Special Interest AEs ...............................................................54
10.2.8.5
Reporting of Abnormal LFTs .................................................................54
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................54
11.0
STATISTICAL METHODS..........................................................................................55
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Study ID TAK-954-1009
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11.1
Statistical and Analytical Plans ................................................................................55
11.1.1
Analysis Sets...............................................................................................55
11.1.1.1
Safety Set ...............................................................................................55
11.1.1.2
PK Set....................................................................................................55
11.1.1.3
PD Set....................................................................................................55
11.1.2
Analysis of Demography and Other Baseline Characteristics.......................55
11.1.3
Safety Analysis ...........................................................................................55
11.1.3.1
AEs ........................................................................................................56
11.1.3.2
Clinical Laboratory Evaluation...............................................................56
11.1.3.3
Vital Signs..............................................................................................56
11.1.3.4
ECGs......................................................................................................56
11.1.3.5
Other Safety Parameters .........................................................................56
11.1.4
PK Analysis ................................................................................................56
11.1.5
PD Analysis ................................................................................................56
11.2
Interim Analysis and Criteria for Early Termination ................................................57
11.3
Determination of Sample Size..................................................................................57
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................58
12.1
Study-Site Monitoring Visits ...................................................................................58
12.2
Protocol Deviations..................................................................................................58
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................58
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................59
13.1
IRB and/or IEC Approval ........................................................................................59
13.2
Participant Information, Informed Consent, and Participant Authorization...............60
13.3
Participant Confidentiality .......................................................................................61
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................61
13.4.1
Publication and Disclosure..........................................................................61
13.4.2
Clinical Study Registration..........................................................................62
13.4.3
Clinical Study Results Disclosure................................................................62
13.5
Insurance and Compensation for Injury....................................................................62
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................63
14.1
Administrative Information......................................................................................63
14.1.1
Study Contact Information ..........................................................................63
14.1.2
Investigator Agreement ...............................................................................64
14.1.3
Study-Related Responsibilities....................................................................65
14.1.4
Protocol Amendment 01 Summary of Changes ...........................................65
14.1.5
List of Abbreviations...................................................................................65
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Study ID TAK-954-1009
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15.0
DATA HANDLING AND RECORDKEEPING............................................................68
15.1
CRFs (Electronic and/or Paper)................................................................................68
15.2
Record Retention .....................................................................................................68
16.0
REFERENCES..............................................................................................................70
17.0
APPENDICES...............................................................................................................71
LIST OF IN-TEXT TABLES
Table 6.a
Planned TAK-954 and Placebo Doses................................................................27
Table 6.b
Mean (SD) Actual and Predicted Exposure Parameters for TAK-954 after Oral 
and IV dosing.....................................................................................................29
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................34
Table 9.a
Sequence Groups ...............................................................................................39
Table 9.b
Primary Specimen Collections ...........................................................................43
Table 9.c
Pharmacokinetics Sample Collection Time Window ..........................................44
Table 10.a
Takeda Medically Significant AE List................................................................50
LIST OF IN-TEXT FIGURES
Figure 2.a
Schematic of Study Design ................................................................................14
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................72
Appendix B
Elements of the Participant Informed Consent....................................................74
Appendix C
Investigator Consent to the Use of Personal Information ....................................77
Appendix D
Pregnancy and Contraception.............................................................................78
Appendix E
Detailed Description of Amendments to Text.....................................................81
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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Study ID TAK-954-1009
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1.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc. a wholly owned subsidiary of 
Takeda Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge, Massachusetts USA 02139
Telephone: +1 (617) 679-7000
Compound:
TAK-954
Study Identifier: TAK-954-1009
Phase: 1
Protocol Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, 3-Period, 
Incomplete Block Design Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
TAK-954 in Healthy Adult Participants.
Study Design:
This is a double-blind, placebo-controlled, single ascending intravenous (IV) dose, 3-period, incomplete block design 
study to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of TAK-954 at 
higher IV doses than those previously studied. In this Phase 1 study, healthy adult participants will attend a screening 
visit within 28 days prior to the first dose.
Participants will be randomized to one of 3 treatment sequences as detailed in the table below. In each sequence, each 
participant will receive 2 doses of the active drug (out of 3 evaluated dose levels) in an ascending order and 1 dose of 
placebo. A sample size of 6 participants is proposed based on empirical considerations.
Period 1
Period 2
Period 3
Sequence
Day 1
(Lead-in)
Day 2
(Treatment)
Day 1
(Lead-in)
Day 2
(Treatment)
Day 1
(Lead-in)
Day 2
(Treatment)
Sequence 1 
(n=2)
Placebo
Placebo
TAK-954
Treatment B
TAK-954
Treatment C
Sequence 2 
(n=2)
TAK-954
Treatment A
Placebo
Placebo
TAK-954
Treatment C
Sequence 3 
(n=2)
TAK-954
Treatment A
TAK-954
Treatment B
Placebo
Placebo
Lead-in TAK-954: 0.1 mg TAK-954 IV infusion.
Treatment A: 0.5 mg TAK-954 IV infusion.
Treatment B: 1 mg TAK-954 IV infusion.
Treatment C: 2 mg TAK-954 IV infusion.
On Day 1 of each period, each participant will receive a lead-in dose of 0.1 mg TAK-954 (if scheduled to receive a 
dose of active drug on Day 2 of that period as per the randomization schedule) or placebo (if scheduled to receive a 
placebo on Day 2 of that period as per the randomization schedule) as a 60 minutes IV infusion. On Day 2 of each 
period, participants will receive either a single dose of 0.5 mg, 1 mg, or 2 mg TAK-954 or placebo as a 60-minute 
infusion as per the randomization schedule.
Safety will be assessed by monitoring for adverse events (AEs), vital signs, orthostatic vital signs, electrocardiograms 
(ECGs), safety laboratory assessments, and physical examinations throughout each dosing period. Blood (for plasma) 
samples for assessment of TAK-954 concentrations will be collected at selected times from predose through to 9 hours 
after each lead-in dose (Day 1). Blood (for plasma) samples for assessment of TAK-954 concentrations will also be 
collected at selected times from predose through 336 hours (Day 16) after each Day 2 dose. Urine samples for 
assessment of TAK-954 concentrations will also be collected at selected times from predose through 36 hours (Day 3) 
after each Day 2 dose.
. The time to first stool 
will be recorded following dosing on Day 1 until prior to dosing on Day 2 and following dosing on Day 2. The number 
of stools per day and stool form (Bristol Stool Form Scale) will be recorded following dosing on Day 1 until prior to 
dosing on Day 2, and for 36 hours following Day 2 dosing.
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TAK-954
Study ID TAK-954-1009
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Protocol Incorporating Amendment No. 01
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The last dose in the previous period and the first dose of the next period will be separated by a minimum of 16 days.
The starting dose of TAK-954 on Day 2 (Period 1) will be 0.5 mg, which is the highest dose previously used in a 
completed study following IV administration. Subsequent doses will be chosen based on emerging data; the currently 
proposed doses are 1 mg and 2 mg. Dose escalation to the next dose level (ie, next period) will not take place until the 
Investigator and the Sponsor have determined that adequate safety/tolerability from the previous period has been 
demonstrated to permit proceeding to the next dose level. Additional cohort(s) (approximately 6 participants per 
cohort) may be enrolled if it is deemed appropriate by the Investigator and the Sponsor to repeat a dose level or to 
study an interim dose level (lower than those planned) in a new cohort.
Day 16 of Period 3 will also be considered as the follow-up visit for participants who complete the study. All 
participants who received at least 1 dose of study drug or placebo and withdraw from the study early will return for a 
follow-up visit, 10-14 days after the last dose administration.
Study Primary Objectives:
!
To evaluate the safety and tolerability of single ascending IV doses of TAK-954.
!
To evaluate the PK of single ascending IV doses of TAK-954.
Secondary Objective:
!
To evaluate the PD effect of single ascending IV doses of TAK-954 on the gastrointestinal (GI) motility in healthy 
participants while in confinement.
Study Participant Population: Healthy male and female participants aged 18 to 55 years inclusive. Body Mass Index 
(BMI) 18.0-32.0 kg/m2, inclusive, body weight ≥50 kg. 
Planned Number of Participants:
6
Additional cohort(s) (approximately 6 participants per 
cohort) may be enrolled if it is deemed appropriate by 
the Investigator and the Sponsor to repeat a dose level 
or to study an interim dose level (lower than those 
planned) in a new cohort.
Planned Number of Sites:
1
Dose Levels:
Day 1 (Lead-in):
0.1 mg TAK-954 (100 mL x 0.001 mg/mL TAK-954 
solution for IV administration)
Placebo will be administered as 100 ml saline solution 
for IV infusion
Lead-in treatment (ie, TAK-954 or placebo) will match 
the scheduled treatment (TAK-954 or placebo) to be 
received on Day 2 of that period as per the 
randomization schedule.
Route of Administration:
IV
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Study ID TAK-954-1009
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Protocol Incorporating Amendment No. 01
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Day 2 (Treatment):
Treatment A: 
0.5 mg TAK-954 (100 mL x 0.005 mg/mL TAK-954 
solution for IV administration)
Treatment B: 
1 mg * TAK-954 (100 mL x 0.01 mg/mL TAK-954 
solution for IV administration)
Treatment C: 
2 mg * TAK-954 (100 mL x 0.02 mg/mL TAK-954 
solution for IV administration)
Placebo will be administered as 100 ml saline solution 
for IV infusion.
* Dose levels may be changed based on emerging data
Duration of Treatment:
On Day 1 of each period, each participant will receive a 
lead-in dose of 0.1 mg TAK-954 or placebo as a 
60-minute IV infusion. On Day 2 of each period, 
participants will receive a single dose of either 
TAK-954 (if received the lead-in dose of TAK-954 on 
Day 1 of that period) or placebo (if received placebo on 
Day 1 of that period) as a 60-minute infusion.
Planned Study Duration:
Approximately 73 days including screening period and 
follow-up visit.
Criteria for Inclusion:
In order to be eligible for study participation, participants must: 
1.
Healthy, adult, male or female, 18-55 years of age, inclusive, at screening. 
2.
Body mass index (BMI) ≥18 and ≤32.0 kg/m2, weighing ≥50 kg at screening. 
3.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital 
signs, orthostatic vital signs, or ECGs, as deemed by the Investigator or designee.
4.
Continuous nonsmoker who has not used nicotine- containing- products for at least 3 months prior to the first dose 
and throughout the study based on participant self-reporting.
5.
For a male or female of childbearing potential, use an acceptable birth control methods as indicated in 
Appendix D.
6.
Understands the study procedures in the informed consent form (ICF) and be willing and able to comply with the 
protocol.
Criteria for Exclusion:
The participant must be excluded from participating in the study if the participant: 
1.
Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the 
Investigator or designee.
3.
History of any illness that, in the opinion of the Investigator or designee, might confound the results of the study 
or poses an additional risk to the participant by their participation in the study.
4.
History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing.
5.
History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds.
6.
History or presence of:

risk factors for Torsade de Pointes (eg, heart failure, unexplained syncope, cardiomyopathy, or family 
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Study ID TAK-954-1009
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history of Long QT Syndrome);

family history of sudden death;

sick sinus syndrome, second or third degree atrioventricular (AV) block, myocardial infarction, pulmonary 
congestion, symptomatic or significant cardiac arrhythmia, prolonged heart rate corrected QT interval by 
Fredericia (QTcF) interval, or conduction abnormalities;

cholecystectomy;

orthostatic hypotension or orthostatic vital sign results at screening with a decrease in systolic >20 mmHg or 
decrease in diastolic >10 mmHg, and increase in pulse of >20 bpm.
7.
Female participants with a positive pregnancy test or who are lactating.
8.
Positive urine drug or alcohol results at screening or first check in-.
9.
Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or 
hepatitis C virus (HCV).
10. Seated blood pressure is less than 100/60 mmHg or greater than 140/90 mmHg at screening.
11. QTcF interval is >450 msec (males and females) or has ECG findings deemed abnormal with clinical significance 
by the Investigator or designee at screening or first check-in, including:

T wave forms which make accurate QT measurement difficult;

Absence of regular atrial or the presence of junctional rhythm;

Abnormal sinus rhythm (heart rate <55 bpm or >100 bpm);

PR interval >210 msec, or QRS complex >110 msec.
12. Unable to refrain from or anticipates the use of:

Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements 
beginning 14 days prior to the first dosing and throughout the study. After randomization, acetaminophen 
(up to 2 g per 24 hours) may be administered at the discretion of the Investigator or designee. Acceptable 
birth control methods as described in Appendix D will be allowed.

Any drugs known to be significant inducers of Cytochrome P450 (CYP) 3A4 enzymes and/or P-gp, 
including St. John’s Wort, for 28 days prior to the first dosing and throughout the study. 

Serotonin antagonists, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin and 
norepinephrine reuptake inhibitors, gamma-aminobutyric acid antagonists, and N-methyl-D-aspartate 
receptor antagonists for 14 days prior to the first dosing and throughout the study.

Serotonin agonists for 28 days prior to the first dosing and throughout the study.
Appropriate sources (eg, Flockhart Table™) will be consulted to confirm lack of PK/PD interaction with study 
drug.
13. Participant has infrequent bowel movements (less than approximately once per day) within 30 days prior to first 
dosing.
14. Recent history of abnormal bowel movements, such as diarrhea, loose stools, or constipation, within 2 weeks of 
first dosing.
15. Has been on a diet incompatible with the on study- diet, in the opinion of the Investigator or designee, within the 
30 days prior to the first dosing and throughout the study.
16. Donation of blood or significant blood loss within 56 days prior to the first dosing.
17. Plasma donation within 7 days prior to the first dosing.
18. Participation in another clinical study within 30 days prior to the first dosing. The 30-day window will be derived 
from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of Period 1 
of the current study.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study ID TAK-954-1009
Page 11 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study are:
The following safety parameters of TAK-954 derived after a single dose of TAK-954 on Day 2 of each treatment 
period:
!
Treatment emergent AE (TEAE) assessments.
!
Vital signs.
!
12-lead ECG.
!
Clinical laboratory testing (hematology, serum chemistry and urinalysis).
The following plasma PK parameters of TAK-954 derived after a single dose of TAK-954 on Day 2 of each treatment 
period:
!
AUC0-t: Area under the plasma concentration-time curve from time 0 to time of the last quantifiable 
concentration.
!
AUC0-inf: Area under the plasma concentration-time curve from time 0 to infinity.
!
Ceoi: Observed plasma concentration at the end of infusion.
!
CL: Clearance.
!
Vz: Volume of distribution.
The following urine PK parameters of TAK-954 derived after a single dose of TAK-954 on Day 2 of each treatment 
period
!
Ae: Amount of drug excreted in urine.
!
fe: Fraction of IV dose excreted in urine.
!
CLR: Renal clearance.
The secondary endpoints will be assessed through evaluation of the following parameters: 
The following PD parameters derived after a single dose of TAK-954 on Day 2 of each treatment period
!
Time to first stool.
!
Number of stools per day.
!
Stool form (Bristol Stool Form Scale).
The exploratory endpoints will be assessed through evaluation of the following parameters:
Propert
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CCI


TAK-954
Study ID TAK-954-1009
Page 12 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Statistical Considerations:
Safety:
Quantitative safety data as well as the difference to baseline, when appropriate, will be summarized using the 
appropriate descriptive statistics.
Pharmacokinetics:
Individual TAK-954 
 plasma and urine concentration data, as appropriate, and PK parameters will be 
listed by participant and treatment, and summarized by treatment (TAK-954 plasma concentrations and PK 
parameters) and nominal time (TAK-954 plasma concentrations).
Statistical analyses of additional plasma PK parameters may be performed, if appropriate.
Dose proportionality will be assessed graphically.
Pharmacodynamics:
Time to first stool, number of stools per day, and stool consistency (form) will be reported using descriptive and 
summary statistics.
Sample Size Justification: 
Approximately 6 participants will be enrolled in this study. This sample size is based on empirical considerations and 
is considered adequate for the objectives of this study.
Property of Takeda: For non-commercial use only and subj
ubjbject to the applicable Terms of Use
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CCI


TAK-954
Study ID TAK-954-1009
Page 13 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
2.0
STUDY SCHEMATIC
Pretreatment
Treatment Periods 1-3
Study Exit (a)
Follow Up (b)
Screening
Check-in and 
Predose 
Assessments
Lead-in Dose and 
Study Assessments
Treatment Dosing 
and Study 
Assessments
Safety and PK 
Assessments
Within 28 days prior 
to first dosing
Day -1
Day 1
Day 2
Day 3
Days 4-16
Day 16 of 
Treatment 
Period 3
14 days after last 
dose
Outpatient Visit
Confinement (a) (c) 
Outpatient Visits (c)
(a) At all times, a participant may be required to remain at the clinical research unit for longer at the discretion of the Investigator or designee.
(b) Day 16 of Period 3 will also be considered as the follow-up visit for participants who complete the study. All participants who received at least 1 dose of study 
drug or placebo and withdraw from the study early will return for a follow-up visit 10-14 days after the last dose administration.
(c) Participants will start the confinement on Day -1 and be released from confinement after Day 3 study assessments are complete and will return to the study site 
for subsequent safety and PK assessments as per the scheduled of study procedures (Section 3.0); There will be a washout period of at least 16 days between the 
last dose in the previous period and the first dose of the next period.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study ID TAK-954-1009
Page 14 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Figure 2.a
Schematic of Study Design
TAK-954/
Placebo
TAK-954 
PK
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study ID TAK-954-1009
Page 15 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
3.0
SCHEDULE OF STUDY PROCEDURES
3.1
Screening and Period 1
Screening a
Study Period 1 b
Day
-1
Day
1
Day
2
Day
3
Hours relative to start of infusion on Day 1
Hours relative to start of infusion on Day 2
Check-in
Predose
0
1
1.083
1.25
3
9
Predose
0
0.5
1
2
4
6
12
24
36
Administrative Procedures
Informed Consent (including Future 
Biomedical Research)
X
Inclusion/Exclusion Criteria
X
Medical History
X
Prior/Concomitant Medication Review
X------------------------------------------------------ Continuous -----------------------------------------------------------------------------X
Clinic Procedures/Assessments
Full Physical Examination
X
Abbreviated Physical Examination
X
X
Height
X
Weight
X
X
12-Lead ECG
X
X
X
X
X
X
X
X
X
X
Orthostatic Vital Signs (HR, BP)
X
X
X
X
X
X
X
X
X
Vital Signs (HR, BP)
X
Vital signs (RR and T)
X
X
X
X
TAK-954 / Placebo Administration
X
X
Adverse Events Monitoring
X---------------------------------------------------------- Continuous -----------------------------------------------------------------------------X
Laboratory Procedures/Assessments
Hematology, Chemistry c, Urinalysis
X
X
X
X
Serum FSH - if applicable
X
Urine Drug Screen
X
X
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-954
Study ID TAK-954-1009
Page 16 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Screening a
Study Period 1 b
Day
-1
Day
1
Day
2
Day
3
Hours relative to start of infusion on Day 1
Hours relative to start of infusion on Day 2
Check-in
Predose
0
1
1.083
1.25
3
9
Predose
0
0.5
1
2
4
6
12
24
36
Urine Alcohol Screen
X
X
HIV/Hepatitis Screen
X
Blood for DNA analysis (optional)
Xd
Serum Pregnancy Test (hCG) – Female 
Participants Only
X
X
Pharmacokinetic Evaluations
Blood for Plasma TAK-954 (
 
)
X
X e
X
X
X
X
X
X
X e
X
X
X
X
X
X
Urine for Urinary TAK-954 
 
X------------------------------------------------- Continuous f -------------------------------------------------X
Pharmacodynamic Evaluations
Time to Onset of Defecation
X-------------- Continuous ------------- X
X  --------------- Continuous -------------- X
Number of Stools per Day
X-------------- Continuous ------------- X
X  --------------- Continuous -------------- X
Stool Form (Bristol Stool Form Scale)
X-------------- Continuous ------------- X
X  --------------- Continuous -------------- X
Other
Confinement
X------------------------------------------------------- Continuous ----------------------------------------------------------X
Visit and Return Visits
X
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
le 
ab
ica
Hours
Hour
ap
Predose
Predo
e
th
o t
to
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ctctct
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TAK-954
Study ID TAK-954-1009
Page 17 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Study Period 1
Day 8
Day 10
Day 12
Day 14
Day 16
Hours relative to start of infusion on Day 2
144
192
240
288
336
Administrative Procedures
Prior/Concomitant Medication Review
X------------------------------------------ Continuous -----------------------------------------------X
Clinic Procedures/Assessments
12-Lead ECG
X
X
X
X
Orthostatic Vital Signs (HR, BP) 
X
X
X
X
Adverse Events Monitoring
X------------------------------------------ Continuous -----------------------------------------------X
Pharmacokinetic Evaluations
Blood for Plasma TAK-954 
 
X
X
X
X
X
Other
Visit and Return Visits
X
X
X
X
X
a.
Within 28 days prior to the first study drug administration. 
b.
There will be a washout period of at least 16 days between the last dose in the previous period and the first dose of the next period.
c.
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts or rechecks, participants may not have fasted for 8 hours 
prior to the serum chemistry sample is taken.
d.
DNA sample should be obtained after dosing (or with the next scheduled blood draw) on randomized participants only.
e.
To be performed at the end of infusion.
f.
Urine will be collected at predose (spot sample) and from 0-12, and 12-24 hours postdose on Day 1 and from 0-12, 12-24, and 24-36 hours on Day 2.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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TAK-954
Study ID TAK-954-1009
Page 18 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
3.2
Periods 2 and 3
Study Periods 2 and 3 a
Day
-1
Day 1
Day 2
Day 3
Hours relative to start of infusion on Day 1
Hours relative to start of infusion on Day 2
Check-in
Predose
0
1
1.083
1.25
3
9
Predose
0
0.5
1
2
4
6
12
24
36
Administrative Procedures
Prior/Concomitant Medication Review
X------------------------------------------------------- Continuous -------------------------------------------------------------------------X
Clinic Procedures/Assessments
Abbreviated Physical Examination
X
X
Weight
X
X
12-Lead ECG
X
X
X
X
X
X
X
X
X
Orthostatic Vital Signs (HR, BP) 
X
X
X
X
X
X
X
X
Vital Signs (HR, BP)
X
Vital signs (RR and T)
X
X
X
TAK-954 / Placebo Administration
X
X
Adverse Events Monitoring
X----------------------------------------------------------- Continuous ----------------------------------------------------------------X
Laboratory Procedures/Assessments
Hematology, Chemistry b, Urinalysis
X
X
X
Urine Drug Screen 
X
Urine Alcohol Screen
X
Serum Pregnancy Test (hCG) – Female 
Participants Only
X
Pharmacokinetic Evaluations
Blood for Plasma TAK-954 
 
)
X
X c
X
X
X
X
X
X
X c
X
X
X
X
X
X
Urine for Urinary TAK-954 
 
)
X---------------------------------------------------- Continuous d ---------------------------------------------------------X
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TAK-954
Study ID TAK-954-1009
Page 19 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Study Periods 2 and 3 a
Day
-1
Day 1
Day 2
Day 3
Hours relative to start of infusion on Day 1
Hours relative to start of infusion on Day 2
Check-in
Predose
0
1
1.083
1.25
3
9
Predose
0
0.5
1
2
4
6
12
24
36
Pharmacodynamic Evaluations
Time to Onset of Defecation
X------------------- Continuous ------------------- X
X  --------------- Continuous -------------- X
Number of Stools per Day
X------------------- Continuous ------------------- X
X  --------------- Continuous -------------- X
Stool Form (Bristol Stool Form Scale)
X------------------- Continuous ------------------- X
X  --------------- Continuous -------------- X
Other
Confinement
X--------------------------------------------------------- Continuous -------------------------------------------------------------------X
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TAK-954
Study ID TAK-954-1009
Page 20 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Study Periods 2 and 3 a
Follow-up (Day 16 
of Period 3 / 
10-14 days 
post last dose) / 
Early Term
Day 8
Day 10
Day 12
Day 14
Day 16
Hours relative to start of infusion on Day 2
144
192
240
288
336
Administrative Procedures
Prior/Concomitant Medication Review
X----------------------------------------------- Continuous ---------------------------------------------X
Clinic Procedures/Assessments
Full Physical Examination
X
Weight
X
12-Lead ECG
X
X
X
X
X
Orthostatic Vital Signs (HR, BP) 
X
X
X
X
X
Vital signs (HR, BP)
X
Vital signs (RR, and T)
X
Adverse Events Monitoring
X------------------------------------------------ Continuous --------------------------------------------X
Pharmacokinetic Evaluations
Blood for Plasma TAK-954 
 
X
X
X
X
X
Other
Visit and return visits
X
X
X
X
X
a.
There will be a washout period of at least 16 days between the last dose in the previous period and the first dose of the next period.
b.
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts or rechecks, participants may not have fasted for 8 hours prior to the serum 
chemistry sample is taken.
c.
To be performed at the end of infusion.
d.
Urine will be collected at predose (spot sample) and from 0-12, and 12-24 hours postdose on Day 1 and from 0-12, 12-24, and 24-36 hours on Day 2.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
le 
ab
y 14
14
ica
on Day 2
n Day 2
pp
288
288
ap
th
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CCI


TAK-954
Study ID TAK-954-1009
Page 21 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
4.0
INTRODUCTION
4.1
Background
TAK-954 is a small molecule 5-hydroxytryptamine receptor 4 (5-HT4) agonist that exhibits 
prokinetic activity throughout the GI tract and is being developed for the treatment of disorders of 
reduced GI motility to accelerate GI recovery post-surgery (post-operative gastrointestinal 
dysfunction).
TAK-954 has been investigated in healthy participants at single oral doses from 0.1 to 20 mg, 
multiple oral doses from 0.2 to 10 mg QD for 10 days, a single IV infusion over 60 min of 0.2 mg 
in each of two periods in a crossover drug-drug interaction study and a single IV infusion of 0.1 mg 
followed by multiple doses of 0.5 mg for 3 days and multiple IV doses of 0.5 mg QD for 5 days. 
After single and multiple IV infusion dosing in healthy participants (0.2 mg and 0.1 single dose 
and 0.5 mg multiple doses over 1 hour), TAK-954 concentrations declined in a biphasic manner, 
with mean t1/2 value of 22.6 hours, CL values of 7.17 L/h (119.5 mL/min) and Vz values of 
230.37 L following single 0.2 mg dose. TAK-954 steady state was achieved by Day 3, with 
minimal accumulation of TAK-954 after multiple IV dosing of 0.5 mg. The increase in exposure 
from the 0.1 mg to 0.5 mg IV dose was approximately dose proportional, and the mean amount of 
TAK-954 excreted unchanged in urine on Day 5 ranged from 27.7% to 31.6%. A single IV dose of 
0.5 mg TAK-954 has also been investigated in critically ill patients with enteral feeding 
intolerance and compared to metoclopramide. In patients who were critically ill and received 
0.5 mg by IV infusion, the exposure was slightly less (Cmax 5040 pg/mL and AUC0-24 23,200 
pg·h/mL) compared to that observed in healthy participants (Cmax 6920 pg/mL and AUC0-24 
41,500 pg·h/mL) following administration of a single 0.5 mg IV infusion.
Clinical Safety
TAK-954 was generally well tolerated at doses of up to 10 mg (oral single dose) and multiple 
doses of up to 5 mg (orally for 10 days) or doses of 0.5 mg (IV for 5 days). No serious adverse 
events (SAEs) were reported across all Phase 1 studies. The most common AEs in participants 
receiving TAK-954 regardless of dose were headache, nausea, vomiting, diarrhea, and postural 
dizziness (IV dose only) with no clear exposure response. No clinically relevant trends in clinical 
laboratory data, physical examinations, or ECGs (including QT interval data) were observed after 
single or repeat oral or IV dosing. Although there were transient asymptomatic increases in heart 
rate associated with TAK-954 administration all events resolved spontaneously, none were 
considered clinically significant by the investigator, and a dose response was not evident. Adverse 
events associated with cardiovascular systems were dizziness, postural hypotension, and 
tachycardia. These were usually of short duration and resolved spontaneously. In the single 
ascending oral dose study, junctional rhythm was reported in 4 participants: 2 receiving 1 mg 
(isolated occurrences at 24 hours and 36 hours after dosing), and 2 receiving 20 mg (isolated 
occurrence at 24 hours and in 1 of the 2, multiple occurrences starting at 8 hours after dosing). 
ECGs were collected at the following time points: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours after 
dosing. There appeared to be a lack of an obvious dose related effect, the findings were far 
removed from time to maximum concentration (1-2 hours postdose), and in 3 of the 4 participants 
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TAK-954
Study ID TAK-954-1009
Page 22 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
the finding was isolated to a single ECG time point. Dose escalation in the study was stopped at 
20 mg, according to the protocol-specified stopping rules, because of the occurrence of two AEs of 
moderate orthostatic hypotension. In the multiple ascending oral dose study, no ECG findings of 
significance were reported in the first 3 cohorts (0.2 mg, 1 mg, and 5 mg, or placebo for 10 days). 
However, in Cohort 4 (10 mg), asymptomatic intermittent AV dissociation was reported in 2 of 
3 participants. The two participants had bradycardia approximately 50 bpm at baseline. One hour 
after receiving the first dose of TAK-954, both participants developed intermittent AV 
dissociation. They both received additional doses on study day 2 before being discontinued from 
the study.
Refer to the Investigator’s Brochure (IB) for detailed background information on TAK-954 [1].
4.2
Rationale for the Proposed Study
The IV formulation of TAK-954 was assessed at doses ranging from 0.1 to 0.5 mg with 0.5 mg for 
5 days being the maximum IV dose investigated to date. TAK-954 was generally well tolerated. 
This study will further explore the safety, tolerability, PD, and PK of IV doses of TAK-954 at 
higher dose levels to guide the selection of a supratherapeutic dose. This information is needed in 
order to design a future study investigating the potential of TAK-954 to prolong the QTc interval.
4.3
Benefit/Risk Profile
The doses of TAK-954 administered in this study are not anticipated to induce any potential risk or 
benefit to participants participating in this study, as the predicted exposure levels are expected to 
be lower than the exposure levels found safe and well tolerated following oral dose administration 
of TAK-945 (see Section 6.3.2).
The safety monitoring practices employed by this protocol (ie, AE questioning, 12-lead ECG, vital 
signs, orthostatic vital signs, clinical laboratory tests, and physical examinations) are adequate to 
protect the participants’ safety and should detect all expected TEAEs. In addition, a lead-in dose 
on Day 1 will be administered prior to receiving the full dose on Day 2 in order to reduce postural 
hypotension adverse event. Based on the observation in a previous multiple dose IV study 
(Theravance 0095), AE’s (moderate postural dizziness) seen on Day 1 after the 0.5 mg dose were 
not found when the Day 1 dose was reduced to 0.1 mg followed by 0.5 mg doses on Days 2 
through 5.
There will be no direct health benefit for study participants from receipt of study drug. An indirect 
health benefit to the healthy participants enrolled in this study is the free medical tests received at 
screening and during the study.
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TAK-954
Study ID TAK-954-1009
Page 23 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
TAK-954 will be sufficiently safe and well-tolerated to permit continued clinical investigation.
5.2
Study Objectives
5.2.1
Study Primary Objectives
The primary objectives of the study are:
!
To evaluate the safety and tolerability of single ascending IV doses of TAK-954.
!
To evaluate the PK of single ascending IV doses of TAK-954.
5.2.2
Study Secondary Objective
The secondary objective of the study is:
!
To evaluate the PD effect of single ascending IV doses of TAK-954 on the GI motility in 
healthy participants while in confinement.
5.2.3
Study Exploratory Objectives
5.3
Endpoints
5.3.1
Primary Endpoints
The primary endpoints of the study are:
The following safety parameters of TAK-954 derived after a single dose of TAK-954 on Day 2 of 
each treatment period:
!
TEAE assessments.
!
Vital signs.
!
12-lead ECG.
!
Clinical laboratory testing (hematology, serum chemistry and urinalysis).
The following plasma PK parameters of TAK-954 derived after a single dose of TAK-954 on 
Day 2 of each treatment period:
!
AUC0-t: Area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration.
Property of Takeda: For non-com
points
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oints of t
ints of
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safety y p
ment peri
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of TAK-
of TA
doses of 
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CCI
CCI


TAK-954
Study ID TAK-954-1009
Page 24 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
!
AUC0-inf: Area under the plasma concentration-time curve from time 0 to infinity, calculated 
using the observed value of the last quantifiable concentration.
!
Ceoi: Observed plasma concentration at the end of infusion.
!
CL: Total clearance after intravenous administration, calculated using the observed value of 
the last quantifiable concentration.
!
Vz: Volume of distribution during the terminal disposition phase after intravenous 
administration, calculated using the observed value of the last quantifiable concentration.
The following urine PK parameters of TAK-954 derived after a single dose of TAK-954 on Day 2 
of each treatment period
!
Ae: Amount of unchanged drug excreted in urine.
!
fe: Fraction of IV dose excreted in the urine.
!
CLR: Renal clearance.
5.3.2
Secondary Endpoints 
The secondary endpoint includes: 
The following PD parameters derived after a single dose of TAK-954 on Day 2 of each treatment 
period
!
Time to first stool.
!
Number of stools per day.
!
Stool form (Bristol Stool Form Scale).
5.3.3
Exploratory Endpoints
Propert
ommercial use only and subject to the applicable Terms of Use
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TAK-954
Study ID TAK-954-1009
Page 25 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Property of Takeda: For non-commercial use only and subject to the ap
 Use
CCI
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TAK-954
Study ID TAK-954-1009
Page 26 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a double-blind, placebo-controlled, single ascending IV dose, 3-period, incomplete block 
design study to investigate the safety, tolerability and PK, and PD of TAK-954 at higher IV doses 
than those previously studied. In this Phase 1 study, healthy adult participants will attend a 
screening visit within 28 days prior to the first dose.
Participants will be randomized to one of 3 treatment sequences as detailed in the table below. In 
each sequence (see Section 9.1.1.1), each participant will receive 2 doses of the active drug (out of 
3 evaluated dose levels) in an ascending order and 1 dose of placebo. A sample size of 
6 participants is proposed based on empirical considerations. 
On Day 1 of each period, each participant will receive a lead-in dose of 0.1 mg TAK-954 (if 
scheduled to receive a dose of active drug on Day 2 of that period as per the randomization 
schedule) or placebo (if scheduled to receive a placebo on Day 2 of that period as per the 
randomization schedule) as a 60-minute IV infusion. On Day 2 of each period, participants will 
receive either a single dose of 0.5 mg, 1 mg, or 2 mg TAK-954 or placebo as a 60-minute infusion 
as per the randomization schedule.
Safety will be assessed by monitoring for AEs, vital signs, orthostatic vital signs, ECGs, safety 
laboratory assessments, and physical examinations throughout each dosing period. Blood (for 
plasma) samples for assessment of TAK-954 concentrations will be collected at selected times 
from predose through to 9 hours after each lead-in dose (Day 1). Blood (for plasma) samples for 
assessment of TAK-954 concentrations will also be collected at selected times from predose 
through 336 hours (Day 16) after each Day 2 dose. Urine samples for assessment of TAK-954 
concentrations will also be collected at selected times from predose through 36 hours (Day 3) after 
each Day 2 dose.
. The 
time to first stool will be recorded following dosing on Day 1 until prior to dosing on Day 2 and 
following dosing on Day 2. The number of stools per day and stool form (Bristol Stool Form 
Scale) will be recorded following dosing on Day 1 until prior to dosing on Day 2, and for 36 hours 
following Day 2 dosing.
The last dose in the previous period and the first dose of the next period will be separated by a 
minimum of 16 days.
The starting dose of TAK-954 on Day 2 (Period 1) will be 0.5 mg, which is the highest dose 
previously used in a completed study following IV administration. Subsequent doses will be 
chosen based on emerging data; the currently proposed doses are 1 mg and 2 mg (see Table 6.a). 
Dose escalation to the next dose level (ie, next period) will not take place until the Investigator and 
the Sponsor have determined that adequate safety/tolerability from the previous period has been 
demonstrated to permit proceeding to the next dose level. Additional cohorts (approximately 6 
participants per cohort) may be enrolled if it is deemed appropriate by the Investigator and the 
Sponsor to repeat a dose level or to study an interim dose level (lower than those planned) in a new 
cohort. For dose escalation and stopping rules see Section 6.2. 
Property of Takeda: For non-c
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Day 16 of Period 3 will also be considered as the follow-up visit for participants who complete the 
study. All participants who received at least 1 dose of study drug or placebo and withdraw from the 
study early will return for a follow-up visit, 10-14 days after the last dose administration.
Table 6.a
Planned TAK-954 and Placebo Doses
Dose
Infusion Duration
Lead-in
0.1 mg (100 mL x 0.001 mg/mL)
60 min
Treatment A
0.5 mg (100 mL x 0.005 mg/mL)
60 min
Treatment B (a)
1 mg (100 mL x 0.01 mg/mL)
60 min
Treatment C (a)
2 mg (100 mL x 0.02 mg/mL)
60 min
Placebo
100 mL
60 min
(a) The starting dose on Day 2 of Period 1 will be 0.5 mg, which is the highest dose previously used in a completed 
study following IV administration. Subsequent doses will be chosen based on emerging data; the currently proposed 
doses are 1 mg and 2 mg. Dose escalation to the next dose level (ie, next period) will not take place until the 
Investigator and the Sponsor have determined that adequate safety/tolerability from the previous period has been 
demonstrated to permit proceeding to the next dose level. Additional cohort(s) (approximately 6 participants per 
cohort) may be enrolled if it is deemed appropriate by the Investigator and the Sponsor to repeat a dose level or to 
study an interim dose level (lower than those planned) in a new cohort. For dose escalation see Section 6.2.
6.2
Dose Escalation
A decision to proceed to the next higher dose administration (next period) will be made by the 
Investigator and Sponsor representative(s) who will review all pertinent blinded safety/tolerability 
(eg, physical examinations, vital signs assessments, orthostatic vital signs, 12-lead ECGs, clinical 
laboratory tests, and AEs) data through at least 10 days following Day 2 dosing in each period for 
at least 75% of participants from the current period and those from all previous periods, as 
applicable.
Additional cohort(s) (approximately 6 participants per cohort) may be enrolled if it is deemed 
appropriate by the Investigator and the Sponsor to repeat a dose level or to study an interim dose 
level (lower than those planned) in a new cohort. 
When applicable, a written statement fully documenting the reasons for study termination will be 
provided to the Institutional Review Board (IRB).
6.3
Rationale for Study Design, Dose, and Endpoints
6.3.1
Rationale of Study Design 
A randomized, double-blind, placebo-controlled design has been selected to allow for unbiased 
analysis of safety and tolerability data following single doses. A lead-in dose on Day 1 will be 
administered prior to receiving the treatment dose on Day 2 in order to reduce postural 
hypotension adverse event. The starting treatment dose (Day 2) was selected to ensure the safety of 
the participants and is supported by previous clinical studies. The different dose levels will be 
studied in a dose escalation study design, in order to define doses that are anticipated to be safe. 
Dose escalation will be based on safety and tolerability from previous periods.
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Participants will be randomized to treatment sequences to minimize assignment bias and a 
crossover design is used to reduce the residual variability as every participant acts as their own 
control. However, an incomplete block design where the 4 treatment (3 active and 1 placebo) will 
be randomized to 3-period instead of 4-period is proposed; all participants will receive placebo 
treatment but will be randomized to receive 2 out of 3 treatment dose (see Table 9.a). This will 
provide the same information as full design but in a shorter timeframe. As safety and tolerability is 
the primary endpoint, the study will be double-blinded.
6.3.2
Rationale for Dose 
6.3.2.1
Starting Dose for This Study
The starting dose (Day 2) in Period 1 of this study is 0.5 mg IV, which is the maximum IV dose of 
TAK-954 reported from a completed study to date. Ongoing clinical studies (TAK-954-2003) 
have administered 1 mg infusion of TAK-954 over 60 min. Results for these studies are pending.
A lead-in dose of 0.1 mg will be administered on Day 1 for participants randomized to receive 
TAK-954 on Day 2 to alleviate moderate postural dizziness as reported in previous studies.
6.3.2.2
Maximum Dose/Exposure for This Study
The maximum tolerated oral doses of TAK-954 were 10 mg single dose, and 5 mg QD multiple 
doses for 10 days. Single oral doses of 20 mg were associated with moderate orthostatic 
hypotension (2 of 6 participants), and 2 of 3 participants with bradycardia at baseline discontinued 
multiple oral doses of 10 mg QD due to intermittent AV dissociation AEs that started 
approximately one-hour post dosing on first day. Currently, the highest dose being investigated for 
the inpatient use only is 0.5 mg administered IV QD for up to 10 days (TAK-954-2004). In 
addition, 1 mg is being investigated in Study TAK-954-2003.
Mean (standard deviation [SD]) TAK-954 exposure parameters (Cmax and AUC), from oral and IV 
doses are presented in Table 6.b. Exposures predicted from regression of IV data (Studies 
Theravance 0095 and TAK-954-1004) are also shown in Table 6.b. Assuming dose proportional 
PK, the predicted Cmax and AUC parameters for TAK-954 following the proposed maximum dose 
(2 mg IV) in this study are lower than those observed at oral doses associated with dose-limiting 
arrhythmia events.
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Table 6.b
Mean (SD) Actual and Predicted Exposure Parameters for TAK-954 after 
Oral and IV dosing
Route
Study
N
Dose/Regimen
Cmax
(ng/mL)
AUC (ng•h/mL)
Oral
Theravance 0060
6
10 mg single dose
94.4 (47.0)
1017 (327)a
6
20 mg single dose
223 (60.0)
2462 (617)a
Theravance 0061
6
5 mg QD (Day 1)
19.0 (8.2)
211 (n=2)a
5
5 mg QD (Day 10)
27.7 (5.2)
387 (830)b
3
10 mg QD (Day 1)
56.5 (20.3)
498 (n=1)a
1
10 mg QD (Day 10)
64.6
796 b
IV
Theravance 0095
6
0.1 mg (Day 1)
1.2 (0.3)
15.3 (n=1)
TAK-954-1004
0.2 mg single dose
2.64 (0.4)
28.6 (6.6)a
Theravance 0095
0.5 mg (Day 1)
6.9 (2.1)
50.6 (5.4) c
Not applicable
Predicted
2 mg single dose
~28
~171a
Predicted
3 mg single dose
~41
~255 a
a
AUC0-inf.
b
AUCtau.
c
AUClast.
6.3.3
Rationale for Endpoints
6.3.3.1
Safety Endpoints 
The key safety endpoints are typical for Phase 1 studies and will be assessed through monitoring of 
adverse events, vital signs, orthostatic vital signs, ECGs, laboratory assessments and physical 
examinations.
6.3.3.2
Pharmacokinetic Endpoints
The pharmacokinetic endpoints are standard for this type of study.
6.3.3.3
Pharmacodynamic Endpoints 
Time to onset of defecation, number of stools per day, and stool consistency (form) are indicators 
of GI transit.
6.3.4
Future Biomedical Research
Biomarker samples for DNA collected in this study may be used to understand how individual 
genetic variation in participants impacts their study drug treatment response. This information may 
also be used, for example, to develop a better understanding of the safety and efficacy of TAK-954 
and other study drugs, to increase understanding of the disease/condition being studied and other 
related conditions, gain a better understanding of the drug pharmacology and for generating 
information needed for research, development, and regulatory approval of tests to predict response 
to TAK-954.
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6.3.5
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the primary assessment is safety, tolerability, and PK. The blood collection for 
plasma concentrations for TAK-954 are required to be collected as close to the scheduled times 
defined in this protocol as possible.
6.4
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The starting dose of TAK-954 on Day 2 will be 0.5 mg. Subsequent doses will be chosen based on 
emerging data; the currently proposed doses are 1 mg and 2 mg. Dose escalation to the next dose 
level (ie, next period) will not take place until the Investigator and the Sponsor have determined 
that adequate safety/tolerability from the previous period has been demonstrated to permit 
proceeding to the next dose level. Additional cohorts (approximately 6 participants per cohort) 
may be enrolled if it is deemed appropriate by the Investigator and the Sponsor to repeat a dose 
level or to study an interim dose level (lower than those planned) in a new cohort. For additional 
details regarding dose escalation and stopping rules see Section 6.2.
6.5
Study Beginning and End/Completion
6.5.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of screening (ie, signing of the ICF) of 
the first participant.
6.5.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled study procedure (ie, Day 16 of Period 3 
for participants who complete the study) as outlined in the Schedule of Study Procedures 
(Section 3.0). For a participant who received at least 1 dose of study drug or placebo and withdraw 
from the study early, the end of study is defined as the follow-up visit (ie, 10-14 days after the last 
dose administration).
6.5.3
Definition of Study Completion
The end of the study is scheduled after completion of the evaluations in Day 16 of Period 3 for the 
last participant in the study.
This time period may change in the event that the study is terminated early or the last participant is 
lost to follow-up, or if additional cohorts are enrolled to repeat a dose level or to study an interim 
dose level.
6.5.4
Definition of Study Discontinuation
In consultation with the Sponsor, Celerion reserves the right to terminate the study in the interest 
of participant welfare.
The Sponsor reserves the right to suspend or terminate the study at any time.
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6.5.5
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

Study stopping rule for termination of the study (Section 6.2) is met.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk is no 
longer acceptable for participants participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises participant safety.
6.5.6
Criteria for Premature Termination or Suspension of a Site
NA
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS
7.1
Inclusion Criteria 
1. Healthy, adult, male or female, 18--55 years of age, inclusive, at screening.
2. Body mass index (BMI) ≥18 and ≤32.0 kg/m2, weighing ≥50 kg at screening.
3. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs, orthostatic vital signs, or ECGs, as deemed by the Investigator 
or designee.
4. Continuous non-smoker who has not used nicotine-containing products for at least 3 months 
prior to the first dose and throughout the study, based on participant self-reporting.
5. For a male or female of childbearing potential, use an acceptable birth control method as 
indicated in Appendix D.
6. Understands the study procedures in the ICF and be willing and able to comply with the 
protocol.
7.2
Exclusion Criteria
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical or psychiatric condition or disease in the 
opinion of the Investigator or designee.
3. History of any illness that, in the opinion of the Investigator or designee, might confound the 
results of the study or poses an additional risk to the participant by their participation in the 
study.
4. History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing. 
5. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related 
compounds.
6. History or presence of:

risk factors for Torsade de Pointes (eg, heart failure, unexplained syncope, 
cardiomyopathy, or family history of Long QT Syndrome);

family history of sudden death;

sick sinus syndrome, second or third degree AV block, myocardial infarction, pulmonary 
congestion, symptomatic or significant cardiac arrhythmia, prolonged QTcF interval, or 
conduction abnormalities;

cholecystectomy;
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
orthostatic hypotension or orthostatic vital sign results at screening with a decrease in 
systolic >20 mmHg or decrease in diastolic >10 mmHg, and increase in pulse of >20 bpm.
7. Female participants with a positive pregnancy test or who are lactating.
8. Positive urine drug or alcohol results at screening or first check-in.
9. Positive results at screening for HIV, HBsA) or HCV.
10. Seated blood pressure is less than 100/60 mmHg or greater than 140/90 mmHg at screening.
11. QTcF interval is >450 msec (males and females) or has ECG findings deemed abnormal with 
clinical significance by the Investigator or designee at screening or first check-in including:

T wave forms which make accurate QT measurement difficult;

Absence of regular atrial or the presence of junctional rhythm;

Abnormal sinus rhythm (heart rate <55 bpm or >100 bpm);

PR interval >210 msec, or QRS complex >110 msec.
12. Unable to refrain from or anticipates the use of:

Any drug, including prescription and non-prescription medications, herbal remedies, or 
vitamin supplements beginning 14 days prior to the first dosing and throughout the study. 
After randomization, acetaminophen (up to 2 g per 24 hours) may be administered at the 
discretion of the Investigator or designee. Acceptable birth control methods as described in 
Appendix D will be allowed.

Any drugs known to be significant inducers of CYP3A4 enzymes and/or P-gp, including 
St. John’s Wort, for 28 days prior to the first dosing and throughout the study.

Serotonin antagonists, monoamine oxidase inhibitors, selective serotonin reuptake 
inhibitors, serotonin and norepinephrine reuptake inhibitors, gamma-aminobutyric acid 
antagonists, and N-methyl-D-aspartate receptor antagonists for 14 days prior to the first 
dosing and throughout the study.

Serotonin agonists for 28 days prior to the first dosing and throughout the study.
Appropriate sources (eg, Flockhart Table™) will be consulted to confirm lack of PK/PD 
interaction with study drug.
13. Participant has infrequent bowel movements (less than approximately once per day) within 
30 days prior to first dosing.
14. Recent history of abnormal bowel movements, such as diarrhea, loose stools, or constipation, 
within 2 weeks of first dosing.
15. Has been on a diet incompatible with the onstudy- diet, in the opinion of the Investigator or 
designee, within the 30 days prior to the first dosing and throughout the study.
16. Donation of blood or significant blood loss within 56 days prior to the first dosing.
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17. Plasma donation within 7 days prior to the first dosing.
18. Participation in another clinical study within 30 days prior to the first dosing. The 30-day 
window will be derived from the date of the last blood collection or dosing, whichever is later, 
in the previous study to Day 1 of Period 1 of the current study.
7.3
Excluded Medications, Supplements, Dietary Products 
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.2. After 
the randomization, acetaminophen (up to 2 g per 24 hours) may be administered at the discretion 
of the Investigator or designee. Acceptable birth control methods as described in Appendix D will 
be allowed.
If deviations occur, the Investigator or designee in consultation with the Sponsor if needed will 
decide on a case by- -case basis whether the participant may continue participation in the study.
All medications taken by participants during the course of the study will be recorded.
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in 
Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Randomization 
(Days -28 to predose [Day 1])
Post-Randomization (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing
Prohibited from 48 hours prior to 
first dosing in each period and 
throughout the period of PK 
sample collection in each 
Treatment period.
Xanthine and/or caffeine
Prohibited from 24 hours prior to first dosing a
Prohibited from 24 hours prior to 
first dosing in each period and 
throughout the period of PK 
sample collection in each 
Treatment period a.
Nicotine
Prohibited from 3 month prior to first dosing
Prohibited until end of PK 
collection in Treatment Period 3.
Medications
See Sections 7.2 and 7.3
See Sections 7.2 and 7.3
Food substance
Grapefruit/Seville orange
Prohibited from 14 days prior to first dosing
Prohibited until end of PK 
collection in Treatment Period 3.
a small amounts of caffeine derived from normal foodstuffs eg, 250 mL/8 oz./1 cup decaffeinated coffee or other 
decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. chocolate bar, per day, would not be 
considered a deviation to this restriction.
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7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
When confined to the CRU, water will be allowed ad libitum. Other fluids may be given as part of 
meals and snacks but will be restricted at all other times throughout the confinement period. 
Participants will fast overnight for at least 8 hours prior to each dose and will remain fasted until at 
least 4 hours postdose.
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, participants will be required to fast from all 
food and drink except water between meals and snacks.
Each meal and/or snacks served at the CRU will be standardized and will be similar in caloric 
content and composition, and will be taken at approximately the same time in each period.
7.4.2
Activity
Participants will remain seated or semi-reclined for the duration of the infusion and for the first 
4 hours postdose, except when they are supine or semi-reclined for study procedures. Participants 
will then resume normal activity.
However, should AEs occur at any time, participants may be placed in an appropriate position or 
will be permitted to lie down.
Specific measures will be taken to prevent the participant from missing a urine collection and/or 
defecation by strictly controlling and providing access to designated restrooms only. Participants 
will be asked to void prior to entering the shower.
Participants will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until completion of the 
study.
7.5
Criteria for Discontinuation or Withdrawal of a Participant
Participants are free to withdraw from the study at any time for any reason. 
In addition, participants may be withdrawn from the study by the investigator or designee for the 
following reasons:

AEs;

Positive urine drug or alcohol results;

Positive pregnancy test;

Difficulties in blood collection.
A participant may be withdrawn by the investigator (or designee) or the Sponsor if enrollment into 
the study is inappropriate, the study plan is violated, or for administrative and/or other safety 
reasons.
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7.6
Procedures for Discontinuation or Withdrawal of a Participant
The Investigator may discontinue a participant’s study participation at any time during the study 
when the participant meets the study termination criteria described in Section 7.5. In addition, a 
participant may discontinue his or her participation without giving a reason at any time during the 
study. Should a participant’s participation be discontinued, the primary criterion for termination 
must be recorded by the investigator. In addition, efforts should be made to perform all procedures 
scheduled for the end-of-study or early termination as described in Section 3.0.
7.7
Participant Replacement
Discontinued participants may be replaced at the discretion of the Sponsor and the Investigator.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
TAK-954 0.1 mg or placebo will be administered as a single IV lead-in dose on Day 1 followed by 
a single IV dose of TAK-954, or placebo on Day 2 of each study period (as per randomization 
sequence). See Table 6.a and Table 9.a for detailed description of treatments and treatment 
sequences, respectively.
The TAK-954 will be supplied in sealed cartons containing 1 single-use vial. The vial contains 
solution for infusion. The drug product is prepared in the CRU pharmacy as an IV solution. The 
solution will be prepared and labeled by licensed pharmacy staff according to the procedures 
outlined in the pharmacy manual. 
A saline solution for IV infusion will be used as placebo for the study. 
8.1.1
Clinical Study Drug Labeling
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of TAK-954 to allow completion of this study.
Celerion will provide sufficient quantities of saline solutions to allow completion of the study. The 
same lot number will be used throughout the study. 
The lot numbers and expiration dates (where available) of the study drugs supplied will be 
recorded in the final report.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied. All TAK-954 products will be prepared and labeled by licensed pharmacy staff 
according to the procedures outlined in the pharmacy manual.
8.1.3
Clinical Study Drug Blinding
This is a double-blind, placebo controlled study.
8.1.4
Randomization Code Creation and Storage 
A computerized randomization scheme will be created by a Celerion statistician (who will not be 
involved in the analysis of the study data) and it shall be considered blinded (as per the following).
The randomization is available only to the CRU pharmacy staff that is preparing the drug who will 
not be involved in any other aspect of the study including administration of the drug. It will not be 
made available to the Sponsor, participants, or members of the staff responsible for the monitoring 
and evaluation of safety assessments.
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In the absence of a medical emergency, the blinded randomization for this study will not be 
revealed until all data are entered in the database, edits checks are performed, queries closed, case 
report forms (CRFs) signed by the Investigator, and the database is officially locked.
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
One set of sealed envelopes containing the randomization code will be supplied to the Investigator 
or designee at the start of the study.
Breaking of the blind is expressly forbidden except in the event of a medical emergency where the 
identity of the drug must be known in order to properly treat the participant or in the event of an 
interim analysis. 
In the event of a medical emergency, it is requested that the Investigator or designee make every 
effort to contact the Study Monitor or designee prior to breaking the blind. If breaking the blind is 
required because of a medical emergency, the treatment identity would be revealed by the 
Investigator or designee, for that participant only. In the event that the emergency is one, in which 
it appears that the other participants may be at imminent risk, the blind may be broken for all 
participants dosed at that dose level. The unblinding will be properly documented in the study file.
In all cases where the code is broken, the Investigator or designee should record the date and 
reason for code breaking.
At the end of the study, envelopes will be retained or destroyed according to site procedures unless 
specified otherwise by the Sponsor.
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
Records will be made of the receipt and dispensing of the study drugs supplied. At the conclusion 
of the study, any unused TAK-954 study drug will be retained by Celerion, returned to the Sponsor 
or designee, or destroyed, as per Sponsor instructions. If no supplies remain, this fact will be 
documented in the pharmacy product accountability records.
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9.0
STUDY PROCEDURES
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the participants in non-technical terms. Participants will be required to read, sign and 
date an ICF summarizing the discussion prior to screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care.
Participants will be given a copy of their signed ICF.
9.1.1.1
Assignment of Screening and Randomization Numbers 
Each participant will be assigned a unique identification number upon screening. Participants who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique randomization identification number at the time of the first dosing, different from the 
screening number, and will receive the corresponding product.
Participants will be randomized to 1 of 3 treatment sequences in a 1:1:1 ratio. The sequences to be
used in the randomization are detailed in Table 9.a below. Participants will receive placebo and 2 
of the 3 TAK-954 doses.
Table 9.a
Sequence Groups
Sequence
Period 1
Period 2
Period 3
Day 1
(Lead-in)
Day 2
(Treatment)
Day 1
(Lead-in)
Day 2
(Treatment)
Day 1
(Lead-in)
Day 2
(Treatment)
Sequence 1 
(n=2)
Placebo
Placebo
TAK-954
Treatment B
TAK-954
Treatment C
Sequence 2 
(n=2)
TAK-954
Treatment A
Placebo
Placebo
TAK-954
Treatment C
Sequence 3 
(n=2)
TAK-954
Treatment A
TAK-954
Treatment B
Placebo
Placebo
If replacement participants are used, the replacement participant number will be 100 more than the 
original (eg, Participant No. 101 will replace Participant No. 1).
9.1.1.2
Study Drug Assignment
This is a 3-period, incomplete block design study. Participants will receive placebo and 2 of the 
3 TAK-954 doses as detailed in Section 6.1.
9.1.2
Inclusion and Exclusion 
Participants will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0.
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9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of 
tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 7.2 and in Section 7.3. All 
medications taken by participants during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3.0) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the investigator or designee and/or the Sponsor 
for reasons related to participant safety.
For this study, safety, tolerability and the collection of blood for plasma concentrations for 
TAK-954 is a critical parameter and are required to be collected as close to the scheduled times 
defined in this protocol as possible. During infusion, blood samples should be collected from the 
contralateral arm opposite the infusion site. -All other procedures should be completed as close to 
the prescribed/scheduled time as possible, but can be performed prior or after the 
prescribed/scheduled time.
9.2.1
Physical Examination
Physical examinations will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0).
An abbreviated physical examination will include at the minimum, examination of respiratory, 
cardiovascular, and GI systems, with the option for further examination of additional systems as 
necessary based on reported symptoms/AEs.
Symptom-driven physical examinations may be performed at other times, if deemed necessary by 
the investigator or designee.
9.2.2
Height and Weight
Body height (cm) and weight (kg) will be reported as outlined in the Schedule of Study Procedures 
(Section 3.0).
9.2.3
BMI
BMI will be calculated based on the height and weight measured at screening.
9.2.4
Vital Signs
Single measurements of body temperature, respiratory rate, blood pressure and heart rate, 
orthostatic blood pressure and heart rate, will be measured as outlined in the Schedule of Study 
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Procedures (Section 3.0). Additional vital signs may be taken at any other times, if deemed 
necessary.
Blood pressure and heart rate measurements will be performed with participants in a seated 
position, except when they are supine or semi-reclined because of study procedures and/or AEs 
(eg, nausea, dizziness) or if deemed necessary by the investigator or designee.
For orthostatic vital signs (heart rate and blood pressure), participants should be seated and then 
stand upright prior to measurement of orthostatic vital signs, as per Celerion standard operating 
procedures.
Vital signs will be measured prior to Day 1 dosing of each period for the predose time point. At all 
other predose time points vital signs will be measured within 2 hours prior to dosing. When 
scheduled postdose, vital signs will be performed within approximately 15 minutes of the 
scheduled time point.
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional ECGs may be taken at any other times, if deemed necessary by the 
investigator or designee.
ECGs will be performed with participants in a supine position. All ECG tracings will be reviewed 
by the investigator or designee.
ECGs will be measured prior to Day 1 dosing of each period for the predose time point. At all other 
predose time points vital signs will be measured within 2 hours prior to dosing. When scheduled 
postdose, ECGs will be performed within approximately 20 minutes of the scheduled time point.
9.2.6
Study Drug Administration
TAK-954 IV solution will be provided as described in Section 8.1.
Lead-in dose and drug treatments are described in Table 6.a.
The IV dose will be administered over approximately 60 minutes. The start and end time of the IV 
infusion will be recorded.
Hour 0 on Day 1 (Lead-in) will be defined as the start of IV infusion on Day 1. Hour 0 on Day 2 
(Treatment) will be defined as the start of IV infusion on Day 2.
The pharmacy at the CRU will provide the IV dose ready for the 60 minute infusion in individual 
unit dose containers for each participant and for each study period, as per the randomization 
scheme (Table 9.a).
9.2.7
AE Monitoring
Participants will be monitored throughout the study for adverse reactions to the study formulations 
and/or procedures as described in Section 10.0.
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9.2.8
Laboratory Procedures and Assessments
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the investigator or designee.
9.2.8.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total and differential leukocyte count
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, participants may not have fasted for 8 hours prior to the serum chemistry sample is 
taken.
Chemistry evaluations will consist of the following standard chemistry panel
Blood Urea Nitrogen
Sodium
Bilirubin (total and direct)
Potassium
Alkaline phosphatase
Chloride
Aspartate aminotransferase
Glucose 
Alanine aminotransferase (ALT)
Creatinine *
Albumin
* At screening, creatinine clearance will be calculated using the Cockcroft Gault formula.
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
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Other 
HIV test
Urine drug screen
–
Opiates (includes morphine, heroin 
(diacetylmorphine), codeine, 6-acetylmorphine, 
dihydrocodeine, hydrocodone, thebaine, and, 
hydromorphone)
–
Amphetamines
–
Barbiturates
–
Benzodiazepines
–
Cocaine
–
Cannabinoids
HBsAg
HCV
Urine alcohol screen
Serum pregnancy test (human chorionic gonadotropin 
[hCG])
9.3
PK, PD, and Biomarkers Samples
Primary specimen collection parameters are provided in Table 9.b. Instructions for plasma, blood 
and urine samples processing and handling will be provided in a separate document(s).
Table 9.b
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for TAK-954 PK 
Blood
Plasma
Plasma sample for PK analysis
Mandatory
Blood for DNA analysis
Blood
DNA
Biomarker analysis
Optional
Urine sample for TAK-954 
 
Urine
Urine
Urine sample for PK analysis
Mandatory
9.3.1
PK Measurements 
All plasma and urine samples from all participants receiving active drug will be analyzed. Only the 
Day 2 predose and end of infusion (1 hour postdose) plasma samples will be analyzed from 
participants when receiving placebo treatment. No urine sample from participants receiving 
placebo will be analyzed.
The PK parameters of TAK-954 will be derived using non-compartmental analysis methods and 
will be determined from the concentration-time data for all evaluable participants. Actual 
sampling times, rather than scheduled sampling times, will be used in all PK computations 
involving sampling times. A more detailed description will be given in the clinical pharmacology 
analysis plan (CPAP).
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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9.3.1.1
Plasma for PK Measurements
No PK parameters will be calculated for participants with detectable at 2 or fewer consecutive time 
points. 
Individual and mean plasma concentration-time curves (both linear and log-linear) will be 
included in the final report.
Other PK parameters may be calculated, if deemed necessary, for the interpretation of the data. All 
efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. 
However, samples obtained within the time windows indicated in Table 9.c will not be captured as 
a protocol deviation, as long as the exact time of dosing and the sample collection is noted on CRF.
Table 9.c
Pharmacokinetics Sample Collection Time Window
Time window (minutes)
Nominal Sample Time
Up to 30 minutes prior to dose
Predose
±2
Immediately post start of infusion to 1.25 hours
±5
>1.25 hours to 6 hours
±10
>6 hours to 36 hours
±30
>36 hours
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9.3.1.2
Urine for PK Measurements
9.3.2
PD Measurements 
The time to first stool and number of stools per day will be recorded. Stool samples will be 
collected and stool form (Bristol Stool Form Scale) will be assessed by the appropriate qualified 
clinic staff. Stool samples will not be stored and will be discarded following the recording of PD 
evaluations.
The following parameters derived following dosing on Day 1 until prior to Day 2 dosing and 
following dosing on Day 2 of each treatment period will be assessed:
!
Time to first stool.
!
Number of stools per day.
!
Stool form (Bristol Stool Form Scale).
9.3.3
Biomarkers Measurements 
Blood samples for DNA will be collected to identify biomarkers that are predictive of efficacy, 
resistance to and or safety of treatment with TAK-954 and for genotyping variations in genes 
encoding drug metabolizing enzymes (DME) or drug transporters that might be implicated in 
TAK-954 disposition.
All biomarkers samples collected will be stored by the Sponsor or bioanalytical facility for 
15 years following the last dosing. Tubes will be identified with a barcode using an appropriate 
label. Samples will not be submitted to a public database. The sponsor and contract research 
organizations involved in the clinical conduct, bioanalytical analyses and PK and statistical 
analyses of the data will have access to the samples and /or the data that resulted from the analysis, 
if performed. By signing the ICF, participants agree to the possible future analysis of these 
samples. At any time, the participants can contact the clinical research unit (CRU) staff to 
requested destruction of the samples. Any additional research on these samples unspecified by this 
protocol will require approval from the participants.
Property of Takeda: For non-commercial use only and subject to th
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9.3.4
Confinement
In each treatment period, participants will be housed on Day -1, at the time indicated by the CRU
until after the 36-hour blood draw and/or study procedures on Day 3. Participants will return for 
study procedures as indicated in the Schedule of Study Procedures (Section 3.0).
At all times, a participant may be required to remain at the CRU for longer at the discretion of the 
Investigator or designee.
As per site preference, participants may be confined throughout the washout period(s). If the 
washout period is exactly 14 days, Days 15 and 16 of Period 1 and/or Period 2 may occur on 
Days -1 and 1 of Period 2 and/or Period 3, respectively.
Day 16 of Period 3 will also be considered as the follow-up visit for participants who complete the 
study. All participants who received at least 1 dose of study drug or placebo and withdraw from the 
study early will return for a follow-up visit, 10-14 days after the last dose administration.
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation participant who 
has signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the participant experiences a worsening or 
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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 participant 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 participant has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the participant 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 participant experiences a change in the severity of an AE that is not associated with a 
change in study medication, the event should be captured once with the maximum severity 
recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the participant’s medical condition 
should not be recorded as AEs but should be documented in the participant’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 participant, at a dose above that which is assigned to that individual 
participant 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.
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
All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the CRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.

In the event of drug overdose, the participant should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the participant was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the participant to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2 Special Interest AEs
NA
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Moderate:
An adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
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10.2.2 Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the participant 
and/or investigator.
10.2.4 End Date 
The end date of the AE is the date at which the participant recovered, the event resolved but with 
sequelae or the participant died.
10.2.5 Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the participant died, dosing with study medication had not 
yet started or dosing with study medication was already stopped before the onset of the AE.

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Drug interrupted – the dose was interrupted due to the particular AE.
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10.2.7 Outcome 

Recovered/resolved – participant 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 participant 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 
participant died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae – the participant 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 participant’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 liver function tests [LFTs])
will commence at the time the participant signs the informed consent. Routine collection of AEs 
will continue until the follow-up visit on Day 16 of Period 3 or 10-14 days following the last study 
drug administration for participants who withdraw from the study early. For participants who 
discontinue prior to the administration of study medication, AEs will be followed until the 
participant 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. 
Participants may report AEs occurring at any other time during the study. Participants 
experiencing an SAE prior to the first exposure to investigational product must be monitored until 
the symptoms subside and any clinically relevant changes in laboratory values have returned to 
Baseline or there is a satisfactory explanation for the change. Non-serious AEs that begin prior to 
the first exposure to investigational product, related or unrelated to the study procedure, need not 
be followed-up for the purposes of the protocol.
All participants 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
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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 CRF, whether or not 
the investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event:

Event term;

Start and end date and time;

Pattern of AE (frequency);

Severity/Intensity;

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]);

Action taken with study drug;

Outcome of event;

Seriousness.
10.2.8.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:
A short description of the event and the reason why the event is categorized as serious;

Participant identification number;

Investigator’s name;

Name of the study medication(s);

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
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SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4 Reporting Special Interest AEs 
NA
10.2.8.5 Reporting of Abnormal LFTs
If a participant is noted to have ALT or AST elevated >3 × upper limit of normal (ULN) on 
2 consecutive occasions, the abnormality should be recorded as an AE. In addition, an LFT 
Increases CRF must be completed providing additional information on relevant recent history, risk 
factors, clinical signs and symptoms and results of any additional diagnostic tests performed.
If a participant is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, 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 participant details and possible alternative etiologies, such as acute viral hepatitis A or B 
or other acute liver disease. Follow-up laboratory tests as described in Section 9.2.8 must also be 
performed. In addition, an LFT Increases CRF must be completed and transmitted with the Takeda 
SAE form (as per Section 10.2.9). 
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
Sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
All statistical analysis of the study will be performed using the statistical software, SAS 
version 9.3 or higher Details concerning the standards for precision, decimals, descriptive 
statistics will be in the Statistical Analysis Plan (SAP).
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a SAP. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. Additional statistical 
analyses other than those described in this section may be performed if deemed appropriate.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
All participants who received at least one dose of the study drug (active or placebo) will be 
included in the safety evaluations.
11.1.1.2 PK Set
Samples from all participants will be assayed even if the participants do not complete the study. 
All participants who comply sufficiently with the protocol and display an evaluable PK profile (eg, 
exposure to treatment, availability of measurements and absence of major protocol violations) will 
be included in the statistical analyses.
11.1.1.3 PD Set
All participants who received at least one dose of the study drug (active or placebo) and have at 
completed at least 1 PD sampling period and/or have at least 1 evaluable parameter will be 
included in the PD evaluations.
11.1.2 Analysis of Demography and Other Baseline Characteristics
Continuous demographic data (ie, age, weight, height, and BMI) will be listed and summarized 
using appropriate summary statistics. Categorical demographic data (ie, gender, race, and 
ethnicity) will also be listed and tabulated.
11.1.3 Safety Analysis
All safety data will be populated in the individual CRFs and listed by participant.
Dosing dates and times (including beginning and end of infusion) will be listed by participant.
Quantitative safety data as well as the difference to baseline, when appropriate, will be 
summarized using the appropriate descriptive statistics.
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11.1.3.1 AEs
AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) available at Celerion and summarized by treatment for the number of participants 
reporting the TEAE and the number of TEAEs reported. A by-participant AE data listing including 
verbatim term, coded term, treatment, severity, and relationship to treatment will be provided.
11.1.3.2 Clinical Laboratory Evaluation
Clinical laboratory results will be summarized by treatment and point of time of collection and a 
shift table describing out of normal range shifts will be provided.
11.1.3.3 Vital Signs
Vital signs assessments will be summarized by treatment and point of time of collection.
11.1.3.4 ECGs
ECGs will be summarized by treatment and point of time of collection.
11.1.3.5 Other Safety Parameters
Physical examination findings will be presented in the data listings.
Medical history, and concurrent conditions will be coded using the MedDRA® and concomitant 
medications will be coded using the World Health Organization (WHO) drug dictionary and will 
be listed by participant.
11.1.4 PK Analysis
Descriptive statistics will be provided for the TAK-954 
 concentrations, as 
applicable, and PK parameters (plasma and urine) using appropriate summary statistics to be fully 
specified in the CPAP.
PK parameters for plasma concentrations will be calculated as described in Section 9.3.1.1 and for 
urine, as described in Section 9.3.1.2, respectively.
Dose proportionality will be assessed graphically.
11.1.5 PD Analysis
Descriptive statistics will be provided for time to first stool and number of stools per day using 
appropriate summary statistics to be fully specified in the SAP.
Stool form (using Bristol Stool Form Scale [Lewis SJ, Heaton KW. Stool form scale as a useful 
guide to intestinal transit time. Scand J Gastroenterol. 1997 Sep;32(9):920-4.Lewis and Heaton 
1997]) will be listed.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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11.2
Interim Analysis and Criteria for Early Termination
A blinded safety and tolerability assessment will be conducted by the Investigator and sponsor 
representative(s) prior to proceeding to the next higher dose level (next period) according to the 
dose escalation and stopping rules outlined in Section 6.2.
11.3
Determination of Sample Size
The sample size of 6 healthy male and female participants is empirical, was selected without 
statistical considerations, and is deemed adequate to meet the study objectives. Additional cohorts 
(approximately 6 participants per cohort) may be enrolled if it is deemed appropriate by the 
Investigator and the Sponsor to repeat a dose level or to study an interim dose level (lower than 
those planned) in a new cohort.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the CRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be participant 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, participant medical records, informed consent documentation, 
and review of CRFs and associated source documents. It is important that the investigator and 
other study personnel are available during the monitoring visits and that sufficient time is devoted 
to the process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study participants. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or exclusion 
criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the participant, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be participant to quality assurance audits by the Sponsor or designees. In 
this circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the Sponsor should be notified 
immediately. The investigator guarantees access for quality assurance auditors to all study 
documents as described in Section 12.1.
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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Conference on Harminsation (ICH) Harmonised Tripartite 
Guideline for GCP. Each investigator will conduct the study according to applicable local or 
regional regulatory requirements and align his or her conduct in accordance with the 
“Responsibilities of the Investigator” that are listed in Appendix A. The principles of Helsinki are 
addressed through the protocol and through appendices containing requirements for informed 
consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The Sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the ICF, and, if applicable, participant recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and participant 
informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. The Sponsor will ship drug/notify site once the Sponsor has confirmed the adequacy 
of site regulatory documentation and, when applicable, the Sponsor has received permission from 
competent authority to begin the study. Until the site receives drug/notification no protocol 
activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by participants, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the Sponsor or its 
designee.
Participant incentives should not exert undue influence for participation. Payments to participants 
must be approved by the IRB or IEC and Sponsor.
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13.2
Participant Information, Informed Consent, and Participant 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 ICF, participant authorization form (if applicable), and 
participant information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the participant’s personal and personal health information for purposes of 
conducting the study. The ICF and the participant 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 ICF 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 or IEC approval of the ICF 
and, if applicable, the participant authorization form. The ICF, participant authorization form (if 
applicable), and participant information sheet (if applicable) must be approved by both the IRB or 
IEC and the Sponsor prior to use.
The ICF, participant authorization form (if applicable), and participant information sheet (if 
applicable) must be written in a language fully comprehensible to the prospective participant. It is 
the responsibility of the investigator to explain the detailed elements of the ICF, participant 
authorization form (if applicable), and participant information sheet (if applicable) to the 
participant. Information should be given in both oral and written form whenever possible and in 
the manner deemed appropriate by the IRB or IEC. In the event the participant is not capable of 
rendering adequate written informed consent, then the participant’s legally acceptable 
representative may provide such consent for the participant in accordance with applicable laws and 
regulations.
The participant, or the participant’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 participant, or the participant’s legally acceptable representative, determines he or 
she will participate in the study, then the ICF and participant authorization form (if applicable) 
must be signed and dated by the participant, or the participant’s legally acceptable representative, 
at the time of consent and prior to the participant entering into the study. The participant or the 
participant’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 ICF 
and participant authorization (if applicable) at the time of consent and prior to participant entering 
into the study; however, the Sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original ICF, participant authorization form (if applicable), and participant 
information sheet (if applicable) will be stored in the investigator’s site file. The investigator must 
document the date the participant signs the informed consent in the participant’s medical record. 
Copies of the signed ICF, the signed participant authorization form (if applicable), and participant 
information sheet (if applicable) shall be given to the participant.
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All revised ICFs must be reviewed and signed by relevant participants or the relevant participant’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 participant’s medical record, and the 
participant should receive a copy of the revised ICF.
Participants who consented and provided a sample for DNA analysis can withdraw their consent 
and request disposal of a stored sample at any time prior to analysis. Notify Sponsor of consent 
withdrawal.
13.3
Participant Confidentiality
The Sponsor and designees affirm and uphold the principle of the participant’s right to protection 
against invasion of privacy. Throughout this study, a participant’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 participant attributes, such as sex, age, or 
date of birth, and participant initials may be used to verify the participant and accuracy of the 
participant’s unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the participant’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 participant’s study 
participation, and autopsy reports. Access to a participant’s original medical records requires the 
specific authorization of the participant as part of the informed consent process (see Section 13.2).
Copies of any participant source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, participant name, address, and other identifier 
fields not collected on the participant’s CRF).
13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
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this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2 Clinical Study Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting study
information. Once participants 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 participant 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 trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each participant in the study must be insured in accordance with the regulations applicable to the 
site where the participant 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 
participants. Refer to the study site agreement regarding the Sponsor’s policy on participant 
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 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
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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 participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 (R2) Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events 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/Provence)
Location of Facility (Country)
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14.1.3 Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.4 Protocol Amendment 01 Summary of Changes
Rationale for Amendment No. 01
The purpose of this amendment is to update the protocol to update the period of PD assessments 
(time to onset of defecation, number of stool per day, and stool form) on Day 1 from predose only 
to following dosing on Day 1 until prior to dosing on Day 2, to allow assessment of the effect of the 
lead-in dose on GI transit. A clarification was also made to indicate that stool will be collected and 
stool form will be assessed by the appropriate qualified clinic staff. 
In addition, the following changes were also applied:

Addition of postdose ECG and orthostatic vital signs measurements.

Removal of indication for infusion site assessments.

Correction of discrepancy in the indication in inclusion criteria #3 between Section 1.0 Study 
Summary (under Criteria for Inclusion) and Section 7.1 – Inclusion Criteria.

Correction of discrepancy in the primary endpoints between Section 1.0 – Study Summary 
(under Main Criteria for Evaluation and Analysis) and Section 5.3.1 – Primary Endpoints.

Clarification of the restriction period for alcohol and xanthine and/or caffeine in Section 7.3 -
Excluded Medications, Supplements, Dietary Products.

Clarification of the arm from which blood sampling should be conducted during drug infusion.

Update the PK sample collection deviation window to include specific deviation windows to 
different postdose sampling times.
For specific descriptions of text changes and where the changes are located, see Appendix E.
14.1.5 List of Abbreviations
AE
Adverse event
Ae
Amount of drug excreted in urine
ALT
Alanine aminotransferase
AUC
Area under the concentration-time curve
AUClast
Area under the concentration-time curve, from time 0 to the last observed non-zero 
concentration
AUC0-24
Area under the concentration-time curve, from time 0 to the 24-hour time point
AUC0-inf
Area under the concentration-time curve, from time 0 extrapolated to infinity
AV
Atrioventricular
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BMI
Body mass index
bpm
Beats per minute
Ceoi
Concentration at end of infusion
CFR
Code of Federal Regulations
CI
Confidence interval
CL
Clearance
CLR
Renal clearance
cm
Centimeter
Cmax
Maximum observed concentration 
CPAP
Clinical pharmacology analysis plan
CRF
Case report form
CRU
Clinical Research Unit
CYP
Cytochrome P450
ECG
Electrocardiogram
fe
Fraction of IV dose excreted in urine 
g
Gram
GCP
Good Clinical Practice
GI
Gastrointestinal
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
Intravenous
kg
Kilogram
LFT
Liver function test
m2
Meters squared
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
min
Minute
mL
Milliliter
mmHg
Millimeter of mercury
msec
Millisecond
MTD
Maximum tolerated dose
NA
Not applicable
ng
Nanogram
P-gp
P-glycoprotein
PD
Pharmacodynamic(s)
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pg
Picogram
PK
Pharmacokinetic(s)
QD
Once daily
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SUSARs
Suspected unexpected serious adverse reactions
t½
Apparent first-order terminal elimination half-life
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
US
United States
USA
United States of America
Vz
Volume of distribution
WHO
World Health Organization
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA®. Drugs will be 
coded using the WHO drug dictionary.
15.1
CRFs (Electronic and/or Paper)
Completed CRFs are required for each participant who signs an informed consent.
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the PI. The 
final signed CRFs are provided to the Sponsor on CD.
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 Investigator must review the CRFs for completeness and accuracy and must sign and date the 
appropriate CRFs as indicated. Furthermore, the investigator must retain full responsibility for the 
accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the CRFs should be made by the investigator with use of change and modification records of the 
CRFs. The Investigator must review the data change for completeness and accuracy, and must sign 
and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the participant’s 
medical and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed 
CRFs are the sole property of the Sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the Sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating participants, medical records, temporary media such as thermal sensitive paper, 
source worksheets, all original signed and dated ICFs, participant authorization forms regarding 
the use of personal health information (if separate from the ICFs), electronic copy of CRFs, 
including the audit trail, and detailed records of drug disposition to enable evaluations or audits 
from regulatory authorities, the Sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original in 
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the participant’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.
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16.0
REFERENCES
1. TAK-954. Millennium Pharmaceuticals, Inc. Global Investigator Brochure. Edition 2.0, 
March 2018.
2. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920-4.
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17.0
APPENDICES
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Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are participant 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 participants, prior to the receipt of 
written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to participants. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each participant who participates in the study, and 
document the date of consent in the participant’s medical chart. Valid informed consent is the 
most current version approved by the IRB/IEC. Each ICF should contain a participant 
authorization section that describes the uses and disclosures of a participant’s personal 
information (including personal health information) that will take place in connection with the 
study. If an ICF does not include such a participant authorization, then the investigator must 
obtain a separate participant authorization form from each participant or the participant’s 
legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the Sponsor that all investigations have been discontinued or 
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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 Participant Informed Consent
In seeking informed consent, the following information shall be provided to each participant:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the participant’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 participants involved in the study.
7. A description of the participant’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 participant may receive.
11. A description of any reasonably foreseeable risks or discomforts to the participant and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the participant or to others that reasonably may be expected 
from the research. When there is no intended clinical benefit to the participant, the participant 
should be made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the participant and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the 
participant will be maintained, and a note of the possibility that regulatory agencies, auditor(s), 
IRB/IEC, and the monitor may inspect the records. By signing a written ICF, the participant or 
the participant’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 participant for participating in the study.
17. The anticipated expenses, if any, to the participant for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), participant’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the participant.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the participant otherwise is entitled, and that the participant or the 
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participant’s legally acceptable representative may discontinue participation at any time 
without penalty or loss of benefits to which the participant is otherwise entitled.
20. The consequences of a participant’s decision to withdraw from the research and procedures for 
orderly termination of participation by the participant.
21. A statement that the participant or the participant’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
participant’s willingness to continue participation in the study.
22. A statement that results of DNA analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the participant’s participation in the 
study may be terminated.
24. A written participant authorization (either contained within the ICF or provided as a separate 
document) describing to the participant the contemplated and permissible uses and disclosures 
of the participant’s personal information (including personal health information) for purposes 
of conducting the study. The participant authorization must contain the following statements 
regarding the uses and disclosures of the participant’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
participants 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 participants 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 participant’s identity will remain confidential in the event that study results are 
published.
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25. Female participants of childbearing potential (eg, nonsterilized, premenopausal female 
participants) who are sexually active must use highly effective contraception (as defined in the 
informed consent) from signing the informed consent and throughout the duration of the study, 
and for 30 days after the last dose of study drug. Regular pregnancy tests will be performed 
throughout the study for all female participants of childbearing potential. If a participant is 
found to be pregnant during study, study drug will be discontinued and the investigator will 
offer the participant the choice to receive unblinded treatment information. 
26. Male participants must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 90 days after 
the last dose of study drug. If the partner of the participant is found to be pregnant during the 
study, the investigator will offer the participant the choice to receive unblinded treatment 
information. 
27. A statement that clinical trial information from this study will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical 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 
Animal studies for TAK-954 have demonstrated embryotoxicity and there is a lack of adequate 
reproductive toxicity data in humans. Given that TAK-954 did not exhibit genotoxic potential in 
the standard battery of genotoxicity assays and the terminal disposition phase half-life of 
TAK-954, the duration of contraception for 30 days is considered acceptable. This is in line with
the Clinical Trials Facilitation Group “Recommendations related to contraception and pregnancy 
testing in clinical trials” [CTFG, 2014].
Females of reproductive potential, as well as fertile men and their partners who are female of 
reproductive potential, must agree to abstain from sexual intercourse or to use 2 highly effective 
forms of contraception from the time of giving informed consent, during the study, and for 30 days 
(females and males) following the last dose of study drug. An effective form of contraception is 
defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier 
method (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel) 
or male partner sterilization.
The following definitions apply for contraception and pregnancy avoidance procedures:
A woman is considered a woman of childbearing potential (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.
Sterilized males should be at least 1 year postbilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
Pregnancy
If any subject is confirmed to be pregnant during the study, she should be withdrawn and TAK-954 
should be immediately discontinued. In addition, any pregnancies in the partner of a male subject 
during the study or for 30 days after the last dose should also be recorded following authorization 
from the subject’s partner. A pregnancy notification form should be submitted within 24 hours of 
learning of the pregnancy.
If the female subject and/or female partner of a male subject agree 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.
All pregnancies, including female partners of male subjects, in subjects on active study drug will 
be followed up to final outcome using the pregnancy form. 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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The following procedures apply for contraception and pregnancy avoidance.
Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this study, where medications and devices containing hormones are included, the 
only acceptable methods of contraception are:

Non-Hormonal Methods: 
–
Intrauterine device (IUD).
–
Bilateral tubal occlusion.
–
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 
participant. 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 30 days after last 
dose.

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 shorter till she has been 
on contraceptive for 3 months;

oral.

Injectable.

Implantable.
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28. 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.
29. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
Reference:
Clinical Trials Facilitation Group, Recommendations related to contraception and pregnancy 
testing in clinical trials. Sep 2014.
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Appendix E
Detailed Description of Amendments to Text
Change 1. Update collection period of PD measurements on Day 1 from predose on Day 1 to 
following dosing on Day 1 through prior to dosing on Day 2.
The primary change occurs in Section 1.0 – Study Summary, under Study Design (last sentence in
the fourth paragraph) and in Section 6.1 – Study Design (last sentence in the fourth paragraph).
Initial 
wording:
The time to first stool will be recorded postdose on Day 2 and number of stools per 
day and stool form (Bristol Stool Form Scale) will be recorded for 36 hours postdose 
on Day 2.
Amended 
or new 
wording:
The time to first stool will be recorded following dosing on Day 1 until prior to 
dosing on Day 2 and following dosing on Day 2. The number of stools per day and 
stool form (Bristol Stool Form Scale) will be recorded following dosing on Day 1 
until prior to dosing on Day 2 and for 36 hours following Day 2 dosing.
Rationale for Change:
Extend the collection time for PD measurements on Day 1 to allow the assessment of the effect of 
the lead-in dose on GI transit time.
Other Sections Affected:
Section 3.1 – Screening and Period 1 and Section 3.2 – Periods 2 and 3 (under Section 3.0 -
Schedule of Study Procedures).
Initial 
wording:
(…)
Study Period 
(…)
Day 1
Day 2
Hours relative to start of infusion on 
Day 1
Hours 
relative to 
start of 
infusion 
on Day 2
Predose
0
1
1.083
1.25
3
9
Predose
Pharmacodynamic Evaluations
Time to Onset of Defecation
X
Number of Stools per Day
X
Stool Form (Bristol Stool Form 
Scale)
X
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Amended or 
new 
wording:
(…)
Study Period 
(…)
Day 1
Day 2
Hours relative to start of infusion on Day 1
Hours 
relative 
to start 
of 
infusion 
on Day 2
Predose
0
1
1.083
1.25
3
9
Predose
Pharmacodynamic Evaluations
Time to Onset of Defecation
X  -------------  Continuous  ------------X
Number of Stools per Day
X  ---------------  Continuous  ----------X
Stool Form (Bristol Stool Form 
Scale)
X  --------------  Continuous  -----------X
Section 9.3.2– PD measurements
Initial 
wording:
The following parameters derived after TAK-954 administration on Day 2 of each 
treatment period will be assessed:
Amended or 
new 
wording:
The following parameters derived following dosing on Day 1 until prior to Day 2 
dosing and following dosing on Day 2 of each treatment period will be assessed:
Change 2. Addition of text to indicate that stool samples will be collected and stool form will be 
assessed by the appropriate qualified clinic staff, and that stool samples will not be stored and will 
be discarded following the recording of PD evaluations.
The primary change occurs in Section 9.3.2 – PD Measurements.
Amended 
or new 
wording:
The time to first stool and number of stools per day will be recorded. Stool samples 
will be collected and stool form (Bristol Stool Form Scale) will be assessed by the 
appropriate qualified clinic staff. Stool samples will not be stored and will be 
discarded following the recording of PD evaluations.
Rationale for Change: 
Clarifies the stool collection, form assessment, and sample handling processes.
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Change 3. Update of the PD analysis language to clarify that stool form assessments results will be 
listed, and no summary statistics will be conducted.
The primary change occurs in Section 11.1.5 - PD Analysis.
Initial 
wording:
Descriptive statistics will be provided for time to first stool, number of stools per 
day, and stool form using appropriate summary statistics to be fully specified in the 
SAP.
Stool form (using Bristol Stool Form Scale [Lewis SJ, Heaton KW, 1997]) will be 
summarized by treatment and point of time of collection.
Amended 
or new 
wording:
Descriptive statistics will be provided for time to first stool and number of stools per 
day using appropriate summary statistics to be fully specified in the SAP.
Stool form (using Bristol Stool Form Scale [Lewis SJ, Heaton KW, 1997]) will be
listed.
Rationale for Change: 
Due to the qualitative nature of the stool form assessment, summary statistics will not provide an 
added value for data interpretation.
Change 4. Addition of postdose ECG and orthostatic vital signs measurements.
The primary change occurs in Sections 3.1- Screening and Period 1 and Section 3.2– Periods 2 and 
3.
Initial 
wording:
(…)
Study Period 
Day
1
Day
2
Day
3
Hours relative to start of infusion 
on Day 1
Hours relative to start of infusion on Day 2
Pre
dose
0
1
1.083
1.25
3
9
Pre
dose
0
0.5
1
2
4
6
12
24
36
12-Lead ECG
X
X
Orthostatic Vital 
Signs (HR, BP)
X
X X
X
X
Study Period 
Day 8
Day 10
Day 12
Day 14
Day 16
Hours relative to start of infusion on Day 2
144
192
240
288
336
Orthostatic Vital Signs (HR, BP) 
X
X
X
X
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Amended 
or new 
wording:
(…)
Study Period 1 b
Day
1
Day
2
Day
3
Hours relative to start of infusion 
on Day 1
Hours relative to start of infusion on Day 2
Pre
dose
0
1
1.083
1.25
3
9
Pre
dose
0
0.5
1
2
4
6
12
24
36
12-Lead ECG
X
X
X
X
X X
X
X
Orthostatic Vital 
Signs (HR, BP)
X
X
X
X X
X
X
Study Period 
Day 8
Day 10
Day 12
Day 14
Day 16
Hours relative to start of infusion on Day 2
144
192
240
288
336
12-Lead ECG
X
X
X
X
Orthostatic Vital Signs (HR, BP) 
X
X
X
X
Rationale for Change: 
ECG and orthostatic vital signs measurements were added to improve the subjects’ safety.
Other Sections Affected:
Section 9.2.5 - 12-Lead ECG (sentence added to the last paragraph).
Initial 
wording:
ECGs will be measured prior to Day 1 dosing of each period for the predose time 
point. At all other predose time points vital signs will be measured within 2 hours 
prior to dosing.
Amended 
or new 
wording:
ECGs will be measured prior to Day 1 dosing of each period for the predose time 
point. At all other predose time points vital signs will be measured within 2 hours 
prior to dosing. When scheduled postdose, ECGs will be performed within 
approximately 20 minutes of the scheduled time point.
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Change 5. Removal of indication for infusion site assessments.
The primary change occurs in Section 9.2.6 – Infusion Site Evaluation.
Initial 
wording:
9.2.6 – Infusion Site Reaction
In monitoring AEs, special attention will be paid to potential infusion site reactions 
(ie, local tolerability). Infusion site reactions will be evaluated as outlined in the 
Schedule of Study Procedures (Section 3.0) and any abnormal findings will be 
reported as AEs.
Amended 
or new 
wording:
(section removed)
Rationale for Change: 
Infusion site reaction will be assessed as part of AE monitoring and not at schedule time points. As 
such, the section was removed.
Other Sections Affected:
Section 1.0– Study Summary, under Study Design (first sentence in the fourth paragraph) and 
Section 6.1 – Study Design (first sentence in the fourth paragraph).
Initial 
wording:
Safety will be assessed by monitoring for adverse events (AEs), vital signs, 
orthostatic vital signs, electrocardiograms (ECGs), infusion site assessment, safety 
laboratory assessments, and physical examinations throughout each dosing period.
Amended 
or new 
wording:
Safety will be assessed by monitoring for adverse events (AEs), vital signs, 
orthostatic vital signs, electrocardiograms (ECGs), safety laboratory assessments, 
and physical examinations throughout each dosing period.
Change 6. Correction of discrepancy in Inclusion criteria #3 between Section 1.0 – Study 
Summary (under Criteria for Inclusion) and Section 7.1 – Inclusion Criteria.
The primary change occurs in Section 7.1 – Inclusion criteria.
Initial 
wording:
Medically healthy with no clinically significant medical history, physical 
examination, laboratory profiles, vital signs or ECGs, as deemed by the Investigator 
or designee.
Amended 
or new 
wording:
Medically healthy with no clinically significant medical history, physical 
examination, laboratory profiles, vital signs, orthostatic vital signs, or ECGs, as 
deemed by the Investigator or designee.
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TAK-954
Study ID TAK-954-1009
Page 86 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Rationale for Change: 
Orthostatic vital signs are assessed as part eligibility assessments at screening and as such, the 
indication for orthostatic vital signs was added to Inclusion criteria #3 in Section 7.1 – Inclusion 
criteria to correct the discrepancy with the correct indication in Section 1.0 – Study Summary 
(under Criteria for Inclusion). 
Change 7. Removal of physical examination from the primary endpoints in Section 1.0 – Study 
Summary (under Main Criteria for Evaluation and Analysis) to correct a discrepancy with 
Section 5.3.1 – Primary Endpoints.
The primary change occurs in Section 7.1 – Inclusion criteria.
Initial 
wording:
The following safety parameters of TAK-954 derived after a single dose of 
TAK-954 on Day 2 of each treatment period:

Treatment emergent AE (TEAE) assessments.

Vital signs.

12-lead ECG.

Clinical laboratory testing (hematology, serum chemistry and urinalysis).

Physical Examinations
Amended 
or new 
wording:
The following safety parameters of TAK-954 derived after a single dose of 
TAK-954 on Day 2 of each treatment period:

Treatment emergent AE (TEAE) assessments.

Vital signs.

12-lead ECG.

Clinical laboratory testing (hematology, serum chemistry and urinalysis).
Rationale for Change: 
Physical examinations are assessed as during the study but are not considered a primary endpoint 
and as such, was removed from the primary endpoints in Section 1.0 – Study Summary (under 
Main Criteria for Evaluation and Analysis) to correct the discrepancy with the correct indication in 
Section 5.3.1 – Primary Endpoints.
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TAK-954
Study ID TAK-954-1009
Page 87 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Change 8. Clarification of restriction period for alcohol and xanthine and/or caffeine
post-randomization (Day 1) to Follow-up.
The primary change occurs in Section 7.3 - Excluded Medications, Supplements, Dietary Products
(under Table 7.a).
Initial 
wording:
Category
(…)
Post-Randomization (Day 1) to Follow-Up 
Alcohol
Prohibited in each period and throughout the period of PK 
sample collection in each Treatment period.
Xanthine and/or 
caffeine
Prohibited in each period and throughout the period of PK 
sample collection in each Treatment period.
Amended 
or new 
wording:
Category
(…)
Post-Randomization (Day 1) to Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing in each 
period and throughout the period of PK sample collection 
in each Treatment period.
Xanthine and/or 
caffeine
Prohibited from 24 hours prior to first dosing in each 
period and throughout the period of PK sample collection 
in each Treatment period.
Rationale for Change: 
Clarify that the restriction period prior to first dose (i.e. 48 hours for alcohol and 24 hours for 
xanthine and/or caffeine) is applicable to each study period.
Change 9. Addition of language to clarify that during infusion, blood samples should be collected 
from the contralateral arm opposite the infusion site.
The primary change occurs in Section 9.2 - Clinical Procedures and Assessments (second 
paragraph).
Initial 
wording:
For this study, safety, tolerability and the collection of blood for plasma 
concentrations for TAK-954 is a critical parameter and are required to be collected 
as close to the scheduled times defined in this protocol as possible. All other 
procedures should be completed as close to the prescribed/scheduled time as 
possible, but can be performed prior or after the prescribed/scheduled time.
Amended 
or new 
wording:
For this study, safety, tolerability and the collection of blood for plasma 
concentrations for TAK-954 is a critical parameter and are required to be collected 
as close to the scheduled times defined in this protocol as possible. During infusion, 
blood samples should be collected from the contralateral arm opposite the infusion 
site. All other procedures should be completed as close to the prescribed/scheduled 
time as possible, but can be performed prior or after the prescribed/scheduled time.
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TAK-954
Study ID TAK-954-1009
Page 88 of 88
Protocol Incorporating Amendment No. 01
11 March 2019
Rationale for Change: 
For consistency in blood sample collection, it is clarified that during infusion, blood samples 
should be collected from the contralateral arm opposite the infusion site.
Change 10. Removal of the general deviation window (10%) for PK sampling with a table that 
includes different and more strict deviation windows based on the nominal sampling time.
The primary change occurs in Section 9.3.1.1 - Plasma for PK Measurements (last paragraph).
Initial 
wording:
Other PK parameters may be calculated, if deemed necessary, for the interpretation 
of the data. All efforts will be made to obtain the PK samples at the exact nominal 
time relative to dosing. However, samples obtained within 10% of the nominal time 
from dosing will not be captured as a protocol deviation, as long as the exact time of 
dosing and the sample collection is noted on CRF.
Amended
or new 
wording:
Other PK parameters may be calculated, if deemed necessary, for the interpretation 
of the data. All efforts will be made to obtain the PK samples at the exact nominal 
time relative to dosing. However, samples obtained within the time windows 
indicated in Table 9.c will not be captured as a protocol deviation, as long as the 
exact time of dosing and the sample collection is noted on CRF.
Table 9.c
Pharmacokinetics Sample Collection Time Window
Time window (minutes)
Nominal Sample Time
Up to 30 minutes prior to dose
Predose
±2
Immediately post start of infusion to 1.25 hours
±5
>1.25 hours to 6 hours
±10
>6 hours to 36 hours
±30
>36 hours
Rationale for Change: 
Clarify and tighten the allowed deviation window for sample collection to guaranty a closer 
association between the nominal and actual sampling time.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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PPD

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, 
3-Period, Incomplete Block Design Study to Investigate the Safety, Tolerability,
Pharmacokinetics and Pharmacodynamics of TAK-954 in Healthy Adult Participants.
NCT Number: NCT03870555
SAP Approve Date:  18 March 2019
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-954-1009
CELERION STUDY NUMBER: CA27260
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, 
3-Period, Incomplete Block Design Study to Investigate the Safety, Tolerability,
Pharmacokinetics and Pharmacodynamics of TAK-954 in Healthy Adult Participants
Version: Final
Date: 18 March 2019
Prepared by:
Based on:
Protocol Dated: 07 February 2019
Protocol Amendment 1 Dated: 08 March 2019
Property 
 non-c
ed: 07
ed: 07
mend
men
only and subject to the applicable Terms of Use
d, Singl
, Sing
ate the S
ate the 
54 in He
4 in H
h 2019
h 2019
PPD


TAK-954-1009
Celerion Study Number CA27260
Page 2 of 21
Statistical Analysis Plan Final
18 March 2019
1.1
Approval Signatures
Study Title:
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single 
Ascending Dose, 3-Period, Incomplete Block Design Study to Investigate 
the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 
TAK-954 in Healthy Adult Participants
Date
Property of Takeda: For non-commercial use only and sub
the applicable Terms of Use
te
Date
Dat
pp
PPD


TAK-954-1009
Celerion Study Number CA27260
Page 3 of 21
Statistical Analysis Plan Final
18 March 2019
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
Hypothesis.................................................................................................................7
4.2
Primary Objectives ....................................................................................................7
4.3
Secondary Objective..................................................................................................7
4.4
Exploratory Objectives ..............................................................................................7
4.5
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
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
Study Definitions ...............................................................................................14
7.1.2
Definition of Study Days....................................................................................14
7.2
Analysis Sets ...........................................................................................................14
7.3
Disposition of Subjects ............................................................................................14
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................15
7.6
Medication History and Concomitant Medications...................................................15
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 ...............................................................................16
7.10
Other Outcomes.......................................................................................................17
7.11
Safety Analysis........................................................................................................17
7.11.1 Adverse Events ..................................................................................................17
7.11.2 Clinical Laboratory Evaluations .........................................................................18
7.11.3 Vital Signs .........................................................................................................18
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TAK-954-1009
Celerion Study Number CA27260
Page 4 of 21
Statistical Analysis Plan Final
18 March 2019
7.11.4 12-Lead ECGs ...................................................................................................19
7.11.5 Physical Exams..................................................................................................20
7.11.6 Overdose............................................................................................................20
7.12
Interim Analysis ......................................................................................................20
7.13
Preliminary Analysis................................................................................................20
7.14
Changes in the Statistical Analysis Plan...................................................................21
8.0
REFERENCES..............................................................................................................21
LIST OF IN-TEXT TABLES
Table 4.a
Sequence Groups for the Planned Doses of TAK-954 and Placebo.......................8
Table 7.a
Collection of Blood and Urine Samples for Pharmacokinetic Analysis...............16
Table 7.b
Collection of Stool Samples for Pharmacodynamic Analysis..............................17
Table 7.c
Collection of Vital Signs and Orthostatic Vital Signs .........................................19
Table 7.d
Collection of Electrocardiograms .......................................................................20
LIST OF IN-TEXT FIGURES
Figure 4.a
Study Schematic ..................................................................................................9
Figure 4.b
Schematic of Study Design ................................................................................10
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TAK-954-1009
Celerion Study Number CA27260
Page 5 of 21
Statistical Analysis Plan Final
18 March 2019
3.0
LIST OF ABBREVIATIONS
Ae
Amount of drug excreted in urine
AE
adverse event
AUC
area under the curve
AUC0-24
area under the plasma concentration-time curve from time 0 to 24 hours 
postdose
AUC0-inf
area under the plasma concentration-time curve from time 0 extrapolated 
to infinity
AUC0-t
area under the plasma concentration-time curve from time 0 to time of the 
last quantifiable concentration.
BLQ
below the limit of quantitation
BMI
body mass index
Ceoi
Concentration at the end of infusion
CI
confidence interval
CL
total plasma clearance of drug after IV administration (parent only)
CLR
renal clearance calculated as CLR = Ae/AUC where both Ae and AUC 
are determined over matched time interval
CPAP
Clinical Pharmacology Analysis Plan
CRF
case report form
CRU
clinical research unit
CS
clinically significant
CSR
clinical study report
CV
coefficient of variation
DMP
Data Management Plan
ECG
electrocardiogram
eCRF
electronic case report form
fe
fraction of IV dose excreted in urine
Geom CV
geometric coefficient of variation
Geom Mean
geometric mean
ICF
informed consent form
ICH
International Conference on Harmonisation
λz
Terminal disposition phase rate constant
ln
natural log
LSM
least-square means
Mean
arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
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TAK-954-1009
Celerion Study Number CA27260
Page 6 of 21
Statistical Analysis Plan Final
18 March 2019
PD
pharmacodynamics
PI
Principal Investigator
PK
pharmacokinetics
SAE
serious adverse event
SD
standard deviation
SEM
standard error of the mean
SOC
system organ class
t½
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TFL
tables, figures and listings
Tmax
time of maximum observed plasma concentration
Vz
volume of distribution during the terminal elimination phase after IV 
administration (parent only)
WHO
World Health Organisation
Note: The words ‘subject’ and ‘participant’ are used interchangeably in this statistical analysis 
plan.
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TAK-954-1009
Celerion Study Number CA27260
Page 7 of 21
Statistical Analysis Plan Final
18 March 2019
4.0
OBJECTIVES
4.1
Hypothesis
TAK-954 1 and 2 mg by IV infusion will be sufficiently safe and well-tolerated to permit use for 
clinical investigation.
4.2
Primary Objectives
!
To evaluate the safety and tolerability of single ascending IV doses of TAK-954.
!
To evaluate the PK of single ascending IV doses of TAK-954.
4.3
Secondary Objective
To evaluate the PD effect of single ascending IV doses of TAK-954 on the GI motility in healthy 
participants while in confinement.
4.4
Exploratory Objectives
4.5
Study Design
This is a double-blind, placebo-controlled, single ascending IV dose, 3-period, incomplete block 
design study to investigate the safety, tolerability and PK, and PD of TAK-954 at higher IV 
doses than those previously studied. In this Phase 1 study, healthy adult participants will attend a 
screening visit within 28 days prior to the first dose.
Participants will be randomized to one of 3 treatment sequences as detailed in the Table 4.a
below. In each sequence, each participant will receive 2 doses of the active drug (out of 3 
evaluated dose levels) in an ascending order and 1 dose of placebo. A sample size of 6 
participants is proposed based on empirical considerations.
Property of Takeda: For non-commercial use
 subject to the applicable Terms of Use
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TAK-954-1009
Celerion Study Number CA27260
Page 8 of 21
Statistical Analysis Plan Final
18 March 2019
Table 4.a
Sequence Groups for the Planned Doses of TAK-954 and Placebo
Sequence
Period 1
Period 2
Period 3
Day 1
(Lead-in)
Day 2
(Treatment)
Day 1
(Lead-in)
Day 2
(Treatment)
Day 1
(Lead-in)
Day 2
(Treatment)
Sequence 1 
(n=2)
Placebo
Placebo
Lead-in
TAK-954
Treatment B
Lead-in
TAK-954
Treatment C
Sequence 2 
(n=2)
Lead-in
TAK-954
Treatment A
Placebo
Placebo
Lead-in
TAK-954
Treatment C
Sequence 3 
(n=2)
Lead-in
TAK-954
Treatment A
Lead-in
TAK-954
Treatment B
Placebo
Placebo
Lead-in TAK-954: 0.1 mg (100 mL x 0.001 mg/mL) TAK-954 IV infusion.
Treatment A: 0.5 mg (100 mL x 0.005 mg/mL) TAK-954 IV infusion.
Treatment B: 1 mg (100 mL x 0.01 mg/mL) TAK-954 IV infusion.
Treatment C: 2 mg (100 mL x 0.02 mg/mL) TAK-954 IV infusion.
Placebo: 100 mL.
On Day 1 of each period, each participant will receive a lead-in dose of 0.1 mg TAK-954 (if 
scheduled to receive a dose of active drug on Day 2 of that period as per the randomization 
schedule) or placebo (if scheduled to receive a placebo on Day 2 of that period as per the 
randomization scheme) as a 60 min IV infusion. On Day 2 of each period, participants will 
receive either a single dose of 0.5 mg, 1 mg, or 2 mg TAK-954 or placebo as a 60-minute 
infusion as per the randomization schedule.
The starting dose of TAK-954 on Day 2 (Period 1) will be 0.5 mg, which is the highest dose 
previously used in a completed study following IV administration. Subsequent doses will be 
chosen based on emerging data; the currently proposed doses are 1 mg and 2 mg. Dose 
escalation to the next dose level (ie, next period) will not take place until the Investigator and the 
Sponsor have determined that adequate safety/tolerability from the previous period has been 
demonstrated to permit proceeding to the next dose level. Additional cohorts (approximately 6 
participants per cohort) may be enrolled if it is deemed appropriate by the Investigator and the 
Sponsor to repeat a dose level or to study an interim dose level (lower than those planned) in a 
new cohort. The last dose in the previous period and the first dose of the next period will be 
separated by a minimum of 16 days.
In each treatment period, participants will be housed on Day -1, at the time indicated by the 
clinical research unit (CRU) until after the 36-hour blood draw and/or study procedures on 
Day 3. At all times, a participant may be required to remain at the CRU for longer at the 
discretion of the Investigator or designee. As per site preference, participants may be confined 
throughout the washout period.
Day 16 of Period 3 will also be considered as the follow-up visit for participants who complete 
the study. All participants who received at least 1 dose of study drug or placebo and withdraw 
from the study early will return for a follow-up visit, 10-14 days after the last dose 
administration.
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TAK-954-1009
Celerion Study Number CA27260
Page 9 of 21
Statistical Analysis Plan Final
18 March 2019
When confined to the CRU, water will be allowed ad libitum. Participants will fast overnight for 
at least 8 hours prior to each dose and will remain fasted until at least 4 hours postdose. When 
confined, standard meals and snacks will be provided at appropriate times, except when they are 
required to fast. When confined in CRU, participants will be required to fast from all food and 
drink except water between meals and snacks. Participants will remain seated or semi-reclined 
for the duration of the infusion and for the first 4 hours postdose, except when they are supine or 
semi-reclined for study procedures. Participants will then resume normal activity.
Blood samples for assessment of plasma TAK-954 concentrations will be collected at selected 
times from predose through to 9 hours after each lead-in dose (Day 1). Blood samples for 
assessment of plasma TAK-954 concentrations will also be collected at selected times from 
predose through 336 hours (Day 16) after each Day 2 dose. Urine samples for assessment of 
urinary TAK-954 concentrations will also be collected at selected times from predose through 24 
hours (Day 2) after each lead-in Day 1 dose and from predose through 36 hours (Day 3) after 
each Day 2 dose. 
 
The time to first stool will be recorded after dosing on Day 1 until prior to Day 2 
dosing and postdose Day 2. The number of stools per day and stool form (Bristol Stool Form 
Scale) will be recorded after dosing on Day 1 until prior to dosing on Day 2 and for 36 hours 
postdose on Day 2.
A schematic of the study design is included as Figure 4.a and Figure 4.b.
Figure 4.a
Study Schematic 
Pretreatment
Treatment Periods 1-3
Study 
Exit (a)
Follow Up 
(b)
Screening
Check-in 
and Predose 
Assessments
Lead-in Dose 
and Study 
Assessments
Treatment 
Dosing and 
Study 
Assessments
Safety and PK 
Assessments
Within
28 days prior 
to first dosing
Day -1
Day 1
Day 2
Day 3
Days 
4-16
Day 16 of 
Treatment 
Period 3
14 days 
after last 
dose
Outpatient 
Visit
Confinement (a) (c) 
Outpatient Visits (c)
(a) At all times, a participant may be required to remain at the clinical research unit for longer at the discretion of the 
Investigator or designee.
(b) Day 16 of Period 3 will also be considered as the follow-up visit for participants who complete the study. All 
participants who received at least 1 dose of study drug or placebo and withdraw from the study early will return for a 
follow-up visit 10-14 days after the last dose administration.
(c) Participants will start the confinement on Day -1 and be released from confinement after Day 3 study 
assessments are complete and will return to the study site for subsequent safety and PK assessments as per the 
scheduled of study procedures. There will be a washout period of at least 16 days between the last dose in the 
previous period and the first dose of the next period.
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Statistical Analysis Plan Final
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Figure 4.b
Schematic of Study Design
TAK-954/
Placebo
TAK-954 
PK
Safety will be assessed by monitoring for AEs, vital signs, orthostatic vital signs, ECGs, safety 
laboratory assessments, and physical examinations throughout each dosing period. 
A decision to proceed to the next higher dose administration (next period) will be made by the 
Investigator and Sponsor representative(s) who will review all pertinent blinded 
safety/tolerability (eg, physical examinations, vital signs assessments, orthostatic vital signs, 
12-lead ECGs, clinical laboratory tests, and AEs) data through at least 10 days following Day 2 
dosing in each period for at least 75% of participants from the current period and those from all 
previous periods, as applicable.
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoints of the study are the following safety parameters of TAK-954 derived after 
a single dose of TAK-954 on Day 2 of each treatment period:

Treatment-emergent adverse event (TEAE) assessments.

Vital signs and orthostatic vital signs.

12-lead ECG.

Clinical laboratory testing (hematology, serum chemistry, and urinalysis).
The following plasma PK parameters of TAK-954 derived after a single dose of TAK-954 on 
Day 2 of each treatment period:

AUC0-t: Area under the plasma concentration-time curve from time 0 to time of the last 
quantifiable concentration.

AUC0-inf: Area under the plasma concentration-time curve from time 0 to infinity, 
calculated using the observed value of the last quantifiable concentration.
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Statistical Analysis Plan Final
18 March 2019
!
Ceoi: Observed plasma concentration at the end of infusion.
!
CL: Total clearance after intravenous administration, calculated using the observed value of 
the last quantifiable concentration.
!
Vz: Volume of distribution during the terminal disposition phase after intravenous 
administration, calculated using the observed value of the last quantifiable concentration.
The following urine PK parameters of TAK-954 derived after a single dose of TAK-954 on 
Day 2 of each treatment period:
!
Ae: Amount of unchanged drug excreted in urine.
!
Fe: Fraction of IV dose excreted in the urine.
!
CLR: Renal clearance.
5.2
Secondary Endpoints
The secondary endpoints of the study are the following PD parameters derived after a single dose 
of TAK-954 on Day 2 of each treatment period:
!
Time to first stool.
!
Number of stools per day.
!
Stool from (Bristol Stool Form Scale).
5.3
Exploratory Endpoints
Propert
al use only and subject to the applicable Terms of Use
ration.
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Statistical Analysis Plan Final
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6.0
DETERMINATION OF SAMPLE SIZE
The sample size of 6 healthy male and female participants is empirical, was selected without 
statistical considerations, and is deemed adequate to meet the study objectives. Additional 
cohorts (approximately 6 participants per cohort) may be enrolled if it is deemed appropriate by 
the Investigator and the Sponsor to repeat a dose level or to study an interim dose level (lower 
than those planned) in a new cohort.
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All PK analyses will be conducted using Phoenix® WinNonlin® Version 7.0, or higher. All 
statistical analyses will be conducted using SAS® Version 9.3, or higher. All data recorded on the 
CRF will be listed by participant. All tables, figures and listings (TFLs) shells and numbering list 
specified in the Clinical Pharmacology Analysis Plan (CPAP) will be included.
The concentration data will be used as reported by the respective bioanalytical groups without 
rounding for all analyses. Arithmetic mean (mean), median, and geometric mean (Geom Mean) 
values will be presented to 1 more level of precision than the individual values. Standard 
deviation (SD) and standard error of the mean (SEM) will be presented to 2 more levels of 
precision than the individual values. Minimum and maximum values will be presented to the 
same precision as the individual values. Arithmetic percent coefficient of variation (CV%) and 
geometric percent coefficient of variation (Geom CV%) will be presented to 1 decimal place. 
Dose proportionality will be assessed graphically.
Concentration values below the limit of quantitation (BLQ) will be presented as ‘BLQ’ in the 
concentration table listings and footnoted accordingly. BLQ values will be treated as zero for the 
calculation of summary statistics, the generation of concentration plots, and the calculation of PK 
parameters, unless they are obvious outliers (eg, BLQ value between 2 measurable values), in 
which case they will be treated as missing. In the tables presenting summary statistics of 
concentration-time series, the total number of values (n) and the number of values that are above 
the level of quantification (LOQ) will be presented to allow appropriate interpretation of the 
data. A statement similar as “all values reported BLQ have been replaced with zero” will be 
included as footnote to the appropriate figures.
For the calculation of PK parameters, if actual times are missing, nominal times will be used 
instead.
Property of Takeda: For non-commercial use only and subject to the applicable erms of Use
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A participant’s PK parameter data will be included in the listings but excluded from the 
descriptive statistics and dose proportionality plots if one or more of the following criteria are 
met: 

A predose (0 hr) concentration is greater than 5% of that participant’s maximum 
concentration value in that period.

A participant did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist).

A participant deviates substantially from the protocol defined study procedures including but 
not limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist).
The details on PK parameter calculations will be outlined in the CPAP including specifics on the 
following:

Insufficient data to determine a reliable t½ value and other terminal disposition phase rate 
constant dependent parameters.

PK parameters presented by treatment, including the units, precision, and summary statistics 
that will be presented in in-text and end-of-text tables.

Concentration data presented by treatment, including the units, precision, and summary 
statistics that will be presented in end-of-text tables.

Concentration data file used for PK analysis.

PK parameter WinNonlin® output file used to generate the TFLs.

Arithmetic mean concentration-time figures presented as in-text and end-of-text figures.

Individual concentration-time figures presented in Appendix 16.2.6.
For PD data, descriptive statistics (mean, SD, minimum, median, and maximum) will be 
provided by treatment and time point for continuous data. Listing will be provided for 
categorical data.
For demographic data where appropriate, variables will be summarized descriptively by 
treatment sequence and overall. For the categorical variables, the count and proportions of each 
possible value will be tabulated by treatment sequence, and overall, where applicable. The 
denominator for the proportion will be based on the number of participants who provided non 
missing responses to the categorical variable. For continuous variables, the number of 
participants with non-missing values, mean, SD, minimum, median, and maximum values will 
be tabulated.
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7.1.1
Study Definitions
7.1.2
Definition of Study Days
Day 1 (lead-in) for each period is defined as the date on which a participant is administered their 
first dose of the study drug(s) in each period. Other study days are defined relative to Day 1 with 
Day -1 being the day prior to Day 1 of each period. Study day prior to the first dose of each 
treatment will be calculated as: date of assessment/event - date of treatment (Day 1); study day 
on or after the date of first dose will be calculated as: date of assessment/event - date of treatment 
(Day 1) + 1.
7.2
Analysis Sets
Safety Set:
All participants who received at least one dose of the study drug(s) (active or placebo) will be 
included in the safety set. Participants in this analysis set will be used for demographic, baseline 
characteristics and safety summaries.
PK Set:
Samples from all participants will be assayed even if the participants do not complete the study. 
All participants who comply sufficiently with the protocol and display an evaluable PK profile 
(eg, exposure to active treatment, availability of measurements and absence of major protocol 
violations) will be included in the PK statistical summaries. In terms of criteria for evaluable 
participants, please see CPAP.
PD Set:
All participants who received at least one dose of the study drug(s) (active or placebo) and have 
at completed at least 1 PD sampling period and/or have at least 1 evaluable parameter will be 
included in the PD summaries.
7.3
Disposition of Subjects
Disposition of participants (number of participants dosed, completed the study, discontinued 
from the study, and reason(s) for discontinuation) will be summarized for each treatment 
sequence and overall. Study completion status, including reason for discontinuation, will also be 
listed by participant. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment sequence and overall. 
Summary statistics (number of participants [n], mean, SD, minimum, median, and maximum) 
will be generated for continuous variables (age [calculated from the date of signed Informed 
Consent Form [ICF], weight, height and body mass index [BMI]) and the number and percentage 
of participants within each category will be presented for categorical variables (sex, race, and 
ethnicity). Height, weight, and BMI collected at screening will be used in the baseline 
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summaries. Demographics data will also be listed as recorded on the CRF, including the date of 
informed consent. 
7.5
Medical History and Concurrent Medical Conditions
Medical history to be obtained will include any significant conditions or diseases relevant to the 
disease under study that resolved at or before signing the ICF. Concurrent medical conditions are 
those significant ongoing conditions or diseases that are present at signing the ICF. Each 
participant’s medical history and concurrent medical conditions will be listed. Any medical 
condition started after taking the study drug will be classified as an adverse event. The medical 
history listing will include whether the event was medical or surgical, the body system or organ 
class involved, start date (if known) and end date or whether the condition was ongoing, and a 
description of the condition or event. There will be no statistical analysis of medical history.
7.6
Medication History and Concomitant Medications
Medication history to be obtained includes any medication relevant to eligibility criteria and
efficacy/safety evaluation stopped at or within 28 days prior to signing the ICF. Concomitant 
medication includes any medication other than study drug taken at any time between time of 
signing the ICF through the end of the study (including follow-up visit). All medication history 
and concomitant medications recorded during the study will be coded with the World Health 
Organization (WHO) Dictionary, as described in the Data Management Plan (DMP), and listed. 
If appropriate, the listing will include the medication name, coded term, dosage, route of 
administration, start date and time (if known), end date and time, or whether it continued after 
study completion, and indication for use. 
7.7
Study Drug Exposure and Compliance
Not applicable.
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Blood and urine samples for PK analysis of TAK-954 will be collected as specified in Table 7.a
following administration of different treatments on Days 1 and 2 of each period under fasted 
conditions.
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Table 7.a
Collection of Blood and Urine Samples for Pharmacokinetic Analysis
Sample 
Type
Dosing Day
Time (hours)
(Periods 1, 2 and 3)
Plasma
1
Predose and at 1, 1.083, 1.25, 3, and 9 hours postdose.
Plasma
2
Predose and at 0.5, 1, 2, 4, 6, 12, 24, 36, 144, 192, 240, 288, and 336 hours
postdose.
Urine
1
Predose (spot sample), 0-12 and 12-24 hours
Urine
2
0-12, 12-24, and 24-36 hours
The actual date and time of sample collection will be recorded on the source document and 
electronic case report form (eCRF).
Placebo data will be listed (if provided) and will not be included in any summary analyses.
The PK parameters of TAK-954 will be listed in the CPAP for this study and will be determined 
from the concentration-time profiles for participants in the PK set using a noncompartmental 
analysis method. Actual sampling times, rather than scheduled sampling times, will be used in all 
computations involving sampling times. If actual sample times are missing, nominal times may 
be used.
Concentrations will be listed and summarized descriptively by PK sampling time. Summary will 
be done by treatment using the summary statistics listed in the CPAP. Excluded concentrations 
will be presented and footnoted as such in the concentration table listings, and those values will 
be excluded from the descriptive summary statistics. Individual participant and arithmetic mean 
profiles of the concentration-time data will be plotted by treatment on linear (with and without 
SD) and semi-log scales. For summary statistics and arithmetic mean plots by sampling time, the 
nominal PK sampling time will be used, for individual participant plots by time, the actual PK 
sampling time will be used. 
PK parameters will be summarized descriptively by treatment using the summary statistics listed 
in the CPAP. Excluded parameters will be presented and footnoted as such in the PK parameter 
table listings, and those values will be excluded from the descriptive summary statistics. Dose 
proportionality will be assessed graphically by plotting the natural-log (ln)-transformed PK 
parameters (AUC0-t, AUC0-inf, AUC0-24, and Ceoi) against the ln-transformed dose levels. 
Excluded parameters will not be included in the dose proportionality plots. 
No inferential statistical analysis will be performed to assess period or sequence effects.
7.9.2
Pharmacodynamic Analysis
Stool samples for PD analysis of TAK-954 will be collected as specified in Table 7.b following 
administration of different treatments on Days 1 and 2 of each period under fasted conditions.
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Table 7.b
Collection of Stool Samples for Pharmacodynamic Analysis
Sample 
Type
Dosing Day
Time (hours)
(Periods 1, 2 and 3)
Stool
1 
Day 1 postdose through Day 2 predose 
Stool
2
Day 2 dosing through 36 hours postdose.
The time to first stool will be recorded after dosing on Day 1 until prior to Day 2 dosing and 
postdose Day 2. The number of stools per day and stool form (Bristol Stool Form Scale) will be 
recorded after dosing on Day 1 until prior to dosing on Day 2 and for 36 hours postdose on 
Day 2. Descriptive statistics will be provided for time to first stool and number of stools as 
recorded in the CRF by treatment and dosing day. Stool form type will be listed by subject and 
time point.
Additional analyses may be performed, if deemed appropriate. 
7.10
Other Outcomes
Not applicable.
7.11
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, severity and type of TEAEs, changes from 
baseline in the participants’ clinical laboratory results, vital signs, orthostatic vital signs, and 
ECG’s using the safety set. Reasons for discontinuation will be tabulated. All clinical safety data 
will be listed by participant and assessment time points, including rechecks, unscheduled 
assessments, and early termination, chronologically. 
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators.
7.11.1 Adverse Events 
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity (mild, moderate or severe), relationship to study drug (related or not 
related), action relative to the study drug, and procedures. All AEs occurring during this study 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®), as described 
in the DMP. However, only TEAEs occurring after administration of the first dose of study drug 
and through the follow-up visit (Day 16 of Period 3 or 10 – 14 days after the last dose of 
investigational product administration for participants who withdraw from the study early) will 
be summarized. A TEAE is defined as an AE that is starting or worsening at the time of or after 
study drug administration. 
For each treatment, TEAEs will be coded using MedDRA® and tabulated by System Organ Class 
(SOC) and Preferred Term. Summary tables will include number of participants reporting the AE 
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and as percent of safety set by treatment. The most commonly reported TEAEs (ie, those events 
reported by >5% of all participants in each treatment, excluding SAEs) will also be summarized. 
For the list of all AE summary tables see CPAP.
In addition, TEAEs will be summarized as number of AEs and percentage of AEs for each 
treatment for the overview of TEAEs. 
Additional TEAE summary tables will be presented by severity and relationship to study drug. If 
a participant has multiple AEs with different severity levels within the same term, the participant 
will be counted in the most severe category only. If a participant has both related and unrelated 
AEs with the same term, the participant will be counted as having related TEAEs only. 
Should any SAEs occur they will be summarized the same way as TEAE. All AEs will be 
displayed in the data listings and TEAEs will be discussed in the text of the study report. 
7.11.2 Clinical Laboratory Evaluations
Hematology, serum chemistry, and urinalysis will be performed at screening, check-in (Day -1), 
Day 2 Predose and 24 hours post-Day 2 dosing in each period. In addition, laboratory safety tests 
may be performed at various unscheduled time points, if deemed necessary by the Principal 
Investigator (PI).
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by treatment and assessment time 
points. Change from baseline will be summarized in a similar way. Baseline is defined as the last 
assessment including rechecks taken prior to dosing on Day 1 in each period (Day -1 Check-in). 
For each laboratory test, a shift table will be developed comparing the frequency of the results at 
treatment baseline (above normal (H), normal (N), or below normal (L)) with those postdose 
time points for each regimen. For urinalysis tests, the categories are normal (N) and abnormal 
(A). Out-of-range values and corresponding recheck results will be listed. 
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. If a value fails the reference range, it will 
automatically be compared to a clinically significant (CS) range. If the value falls within the CS 
range, it will be noted as “N” for not clinical significant. If the value fails the CS range, it will be 
flagged with a “Y” which prompts the PI to determine how the out-of-range value should be 
followed using 4 Investigator flags: "N", not clinically significant, "R", requesting a recheck, "^", 
checking at the next scheduled visit, or "Y", clinically significant. All clinically significant 
laboratory tests, as indicated by the PI (either in the PI flag or in PI comments), and the 
corresponding values will be listed by participant. All clinical laboratory data will be presented 
in by-subject data listings.
7.11.3 Vital Signs
Single measurements and orthostatic vital signs will be collected as outlined in Table 7.c. 
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Table 7.c
Collection of Vital Signs and Orthostatic Vital Signs
Measurement Type
Period
Day
Time Point
Orthostatic Vital Signs (Heart Rate and 
Blood Pressure)
Screen
1, 2, 3
-1 
1
1 and 3 hours postdose
2
Predose and 1, 2, 6, 24 hours postdose
8, 10, 12, 14
3
16 or ET*
Vital Signs (Heart Rate and Blood 
Pressure)
1, 2, 3
1
Predose
3
16 or ET*
Vital Signs (Respiratory Rate and 
Temperature)
Screen
1, 2, 3
1
Predose
2
Predose and 24 hours postdose
3
16 or ET*
* ET = Early termination.
Additional unscheduled vital signs measurements may be taken at other times, if deemed 
necessary by the PI.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for vital 
sign results (seated and standing measurements will be reported separately) and orthostatic 
change in blood pressure and heart rate by treatment and time point of collection. Change from 
baseline will be summarized in a similar way. Orthostatic change in vital signs (ie, seated and 
standing blood pressure and pulse rate) is defined as the difference between the measurement 
collected in the standing position and the measurement collected in the seated position (ie, 
Standing – Seated). Baseline is defined as the last assessment including rechecks taken prior to 
Day 1 dosing in each period (Day 1 Predose for seated vital signs and Day -1 check-in for 
orthostatic vital signs). Vital signs will also be displayed in a data listing by participant.
7.11.4 12-Lead ECGs
Standard 12-lead ECGs will be recorded as outlined in Table 7.d. 
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Statistical Analysis Plan Final
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Table 7.d
Collection of Electrocardiograms
Measurement Type
Period
Day
Time Point
12-Lead ECG
Screen
1, 2, 3
-1 
1
Predose and 1, 3 hours postdose
2
Predose and 1, 2, 6, 24 hours postdose
8, 10, 12, 14
3
16 or ET*
* ET = Early termination.
Additional unscheduled ECGs may be recorded at other times if deemed necessary by the PI. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results and change from baseline by treatment and time point of collection. Baseline is defined as 
the last assessment including rechecks taken prior to Day 1 dosing in each period (Day 1 
Predose). ECG data will also be displayed in a data listing by participant.
7.11.5 Physical Exams
A full physical exam will be performed at screening and Day 16 of Period 3 or upon early 
termination. Abbreviated physical examinations will be performed at check-in (Day -1) and 24 
hours post-Day 2 dosing in each period. Symptom driven physical exams may be performed at 
other times at the discretion of the PI. Physical exam findings, as recorded on the CRF, will be 
presented in a data listing by participant. Reproductive system findings will also be listed by 
participant.
7.11.6 Overdose 
All cases of overdose will be presented in a data listing by participant. Any AEs associated with 
overdose will be documented as AEs. 
7.12
Interim Analysis
A blinded safety and tolerability assessment will be conducted by the Investigator and sponsor 
representative(s) prior to proceeding to the next higher dose level (next period) according to the 
dose escalation and stopping rules.
7.13
Preliminary Analysis
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Statistical Analysis Plan Final
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7.14
Changes in the Statistical Analysis Plan 
There are no changes in the statistical analysis plan from the protocol analysis.
8.0
REFERENCES
Not applicable.
Property of Takeda: For non-commercial use only and subject to the applicable Term
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