Conditions: Healthy Participants
Keywords: Drug Therapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the effect of the potent CYP3A4 inhibitor itraconazole on the single-dose PK of TAK-954.

Detailed description:
The drug being tested in this study is called TAK-954. TAK-954 is being tested in healthy participants in order to evaluate the effect of the potent CYP3A4 inhibitor itraconazole on the single-dose PK of TAK-954.

The study will enroll approximately 10 participants. Participants will receive the following treatment sequences:

• TAK-954 0.2 mg; Itraconazole 200 mg + TAK-954 0.2 mg

Participants will be given an intravenous infusion of TAK-954 on Day 1 of First Intervention Period (6 days) followed by minimum 7-day washout period, after which participants will be given Itraconazole capsule on Days 1 to 8 along with TAK-945 infusion on Day 4 of Second Intervention Period (9 days).

This single center trial will be conducted in the United States. The overall duration to participate in this study is 7 to 8 weeks. Participants will visit the clinic on Day -1 and remained confined until Day 6 (First Intervention Period) and Day 9 (Second Intervention Period). Participants will return for a Follow-up Visit 10 to 14 days after last dose of study drug (approximately up to Day 34).

Arms:
arm 1: TAK-954 0.2 milligram (mg), infusion, intravenously, once on Day 1 of First Intervention Period, followed by a minimum of 7-day washout period, further followed by Itraconazole 200 mg, capsule, orally, once daily on Days 1 to 8 along with TAK-954 0.2 mg, infusion, intravenously on Day 4 of Second Intervention Period.

Interventions: intervention 1: TAK-954 intervention 2: Itraconazole
Intervention descriptions: intervention 1: TAK-954 Infusion intervention 2: Itraconazole Capsule

Protocol document:
Prot_000.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A Single-Sequence, Open-Label, 2-Period Crossover Trial to Evaluate the Effect of the 
Potent Cytochrome P-450 3A4 Inhibitor Itraconazole on the Pharmacokinetics of TAK-954 in 
Healthy Adult Subjects
NCT Number: NCT03173170
Protocol Approve Date: 03 May 2017
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Single-Sequence, Open-Label, 2-Period Crossover Trial to Evaluate the Effect of the 
Potent Cytochrome P-450 3A4 Inhibitor Itraconazole on the Pharmacokinetics of TAK-954 
in Healthy Adult Subjects
Sponsor:
Takeda Development Center Americas, Inc. 
Trial Number:
TAK-954-1004
Compound:
TAK-954
Date:
03 May 2017
Version/Amendment 
Number:
Initial Version
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the trial.


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TABLE OF CONTENTS
1.0
TRIAL SUMMARY........................................................................................................7
2.0
TRIAL SCHEMATIC .....................................................................................................9
3.0
SCHEDULE OF TRIAL PROCEDURES......................................................................10
4.0
INTRODUCTION.........................................................................................................12
4.1
Background .............................................................................................................12
4.2
Rationale for the Proposed Trial...............................................................................12
4.3
Benefit/Risk Profile .................................................................................................12
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................14
5.1
Objectives................................................................................................................14
5.1.1
Primary Objective .......................................................................................14
5.1.2
Secondary Objective ...................................................................................14
5.1.3
Exploratory Objectives................................................................................14
5.2
Endpoints.................................................................................................................14
5.2.1
Primary Endpoint........................................................................................14
5.2.2
Safety Endpoints.........................................................................................14
5.2.3
Exploratory Endpoints.................................................................................14
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................16
6.1
Trial Design.............................................................................................................16
6.2
Rationale for Trial Design, Dose, and Endpoints......................................................16
6.2.1
Rationale of Trial Design and Dose.............................................................16
6.2.2
Rationale for Endpoints...............................................................................18
6.2.2.1
PK..........................................................................................................18
6.2.2.2
Safety Endpoints ....................................................................................18
6.2.2.3
Exploratory Endpoints............................................................................18
6.2.3
Critical Procedures Based on Trial Objectives: Timing of Procedures .........18
6.3
Trial Beginning and End/Completion.......................................................................18
6.3.1
Definition of Beginning of the Trial ............................................................18
6.3.2
Definition of End of the Trial......................................................................18
6.3.3
Definition of Trial Discontinuation..............................................................19
6.3.4
Criteria for Premature Termination or Suspension of the Trial.....................19
6.3.4.1
Criteria for Premature Termination or Suspension of Trial Sites .............19
6.3.4.2
Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Trial Site(s)....................................................................19
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............20


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7.1
Inclusion Criteria .....................................................................................................20
7.2
Exclusion Criteria ....................................................................................................21
7.3
Excluded Medications, Supplements, and Dietary Products .....................................22
7.4
Diet, Fluid, and Activity ..........................................................................................22
7.4.1
Diet and Fluid .............................................................................................22
7.4.2
Activity.......................................................................................................23
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................23
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................24
7.7
Subject Replacement................................................................................................24
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................25
8.1
Clinical Trial Drug...................................................................................................25
8.1.1
Clinical Trial Drug Labeling .......................................................................25
8.1.2
Clinical Trial Drug Inventory and Storage...................................................25
8.1.3
Clinical Trial Drug Blinding........................................................................25
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs ........................25
8.1.5
Ancillary Supplies.......................................................................................25
9.0
TRIAL PROCEDURES.................................................................................................26
9.1
Administrative Procedures.......................................................................................26
9.1.1
Informed Consent Procedure.......................................................................26
9.1.2
Assignment of Screening Numbers..............................................................26
9.1.3
Inclusion and Exclusion Criteria..................................................................26
9.1.4
Medical History/Demographics...................................................................26
9.1.5
Prior and Concomitant Medication Review .................................................26
9.1.6
Physical Examinations ................................................................................26
9.1.7
Vital Sign Measurements ............................................................................27
9.1.8
Height and Weight ......................................................................................27
9.1.9
BMI ............................................................................................................27
9.1.10
12-Lead ECG..............................................................................................27
9.1.11
AE Monitoring............................................................................................28
9.2
Laboratory Procedures and Assessments..................................................................28
9.2.1.1
Clinical Laboratory Tests........................................................................28
9.2.1.2
Screening ...............................................................................................29
9.3
PK and PGx Samples...............................................................................................30
9.3.1
PK Evaluations ...........................................................................................30
9.3.2
PGx Measurements .....................................................................................31


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9.3.2.1
Blood Sample for DNA and RNA PGx Measurements ...........................31
9.3.2.2
Biological Sample Retention and Destruction.........................................31
9.4
Trial Drug Administration........................................................................................32
9.5
Confinement ............................................................................................................32
10.0
ADVERSE EVENTS ....................................................................................................34
10.1
Definitions and Elements of AEs .............................................................................34
10.1.1
SAEs...........................................................................................................36
10.2
AE Procedures.........................................................................................................37
10.2.1
Assigning Severity/Intensity of AEs............................................................37
10.2.2
Assigning Causality of AEs.........................................................................37
10.2.3
Assigning Relationship to Trial Procedures.................................................37
10.2.4
Start Date....................................................................................................37
10.2.5
Stop Date ....................................................................................................37
10.2.6
Frequency ...................................................................................................37
10.2.7
Action Concerning Trial Drug.....................................................................38
10.2.8
Outcome .....................................................................................................38
10.2.9
Collection and Reporting of AEs, SAEs, and Abnormal LFTs.....................38
10.2.9.1
Collection Period....................................................................................38
10.2.9.2
Reporting AEs........................................................................................38
10.2.9.3
Reporting SAEs......................................................................................39
10.2.9.4
Reporting of Abnormal LFTs .................................................................40
10.2.10
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................40
11.0
STATISTICAL METHODS..........................................................................................41
11.1
Statistical and Analytical Plans ................................................................................41
11.1.1
Analysis Sets...............................................................................................41
11.1.2
Analysis of Demographics and Other Baseline Characteristics ....................41
11.1.3
PK Analysis ................................................................................................41
11.1.4
Safety Analysis ...........................................................................................42
11.1.4.1
AEs ........................................................................................................42
11.1.4.2
Clinical Laboratory Evaluation...............................................................42
11.1.4.3
Vital Signs..............................................................................................42
11.1.4.4
ECGs......................................................................................................42
11.2
Interim Analysis and Criteria for Early Termination ................................................43
11.3
Determination of Sample Size..................................................................................43
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................44


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12.1
Trial-Site Monitoring Visits.....................................................................................44
12.2
Protocol Deviations..................................................................................................44
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................44
13.0
ETHICAL ASPECTS OF THE TRIAL .........................................................................45
13.1
IRB and/or IEC Approval ........................................................................................45
13.2
Subject Information, Informed Consent, and Subject Authorization .........................46
13.3
Subject Confidentiality ............................................................................................47
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................47
13.4.1
Publication and Disclosure..........................................................................47
13.4.2
Clinical Trial Registration...........................................................................48
13.4.3
Clinical Trial Results Disclosure .................................................................48
13.5
Insurance and Compensation for Injury....................................................................48
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................49
14.1
Administrative Information......................................................................................49
14.1.1
Trial Contact Information............................................................................49
15.0
INVESTIGATOR AGREEMENT.................................................................................50
15.1.1
Trial-Related Responsibilities .....................................................................51
15.1.2
List of Abbreviations...................................................................................51
16.0
DATA HANDLING AND RECORDKEEPING............................................................53
16.1
eCRFs......................................................................................................................53
16.2
Record Retention .....................................................................................................53
17.0
REFERENCES..............................................................................................................55
18.0
APPENDICES...............................................................................................................56
LIST OF IN-TEXT TABLES
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................22
Table 9.a
Primary Specimen Collections ...........................................................................30
Table 10.a
Takeda Medically Significant AE List................................................................36


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LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................56
Appendix B
Elements of the Subject Informed Consent.........................................................58
Appendix C
Investigator Consent to Use of Personal Information..........................................61
Appendix D
Pregnancy and Contraception.............................................................................62


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1.0
TRIAL SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. 
Compound:
TAK-954
Study Number: TAK-954-1004
Phase: 1
Protocol Title: A Fixed Sequence, Open-Label, 2-Period Crossover Trial to Evaluate the Effect of the Potent 
Cytochrome P-450 3A4 Inhibitor Itraconazole on the Pharmacokinetics of TAK-954 in Healthy Adult Subjects
Trial Design:
This is a phase 1, single-sequence, open-label, 2-period crossover trial in approximately 10 healthy male and female 
(non–childbearing potential) subjects aged 18 and 55 years (inclusive). The trial is designed to investigate the effect of 
a potent cytochrome P-450 (CYP) 3A4 inhibitor (itraconazole) on the pharmacokinetics (PK) of TAK-954. TAK-954 
will be administered as a single 60-minute intravenous (IV) infusion.
The trial will include a Screening Visit, Trial Period 1 (6 days), a washout (a minimum of 7 days between doses in 
Period 1 Day 1 and Period 2 Day 1), Trial Period 2 (9 days), and a Follow-up Visit. Eligible subjects will be allocated 
to the trial treatment by non-random assignment on Day 1 of Trial Period 1 and will receive a 0.2 mg single dose 
TAK-954 IV on this day and on Day 4 of Trial Period 2 at approximately the same time (between 0600 and 0900). In 
Trial Period 2, subjects will receive 200 mg once daily (QD) itraconazole orally on Days 1 to 8 at approximately the 
same time (between 0600 and 0900) and a single dose of 0.2 mg TAK-954 on Day 4. Itraconazole will be administered 
as 2 x 100 mg capsules. After completion of the trial (or after subject withdrawal), all subjects will return for a 
Follow-up Visit 10 to 14 days after their last dose of trial drug.
Primary Objective:

To evaluate the effect of the potent CYP3A4 inhibitor itraconazole on the single-dose PK of TAK-954.
Secondary Objectives:

To evaluate the safety of a single IV dose of TAK-954 in the presence and absence of a potent CYP3A4 inhibitor.
Subject Population: Healthy male and female (non–childbearing potential) subjects.
Number of Subjects:
Approximately 10 subjects will complete this trial.
Number of Sites:
1 site
Dose Levels:

TAK-954 0.2 mg

Itraconazole 200 mg QD
Route of Administration:

TAK-954 IV 

Itraconazole oral
Duration of Treatment:
Two doses of TAK-954.
Eight doses of itraconazole.
Period of Evaluation:
Approximately 7 to 8 weeks
Main Criteria for Inclusion:
Healthy male and female (non–childbearing potential) subjects who are aged 18 to 55 years, inclusive, with a body 
mass index (BMI) between 18 to 30 kg/m2, and a body weight >50 kg.
Main Criteria for Exclusion:
Subjects who have a history of clinically significant endocrine, gastrointestinal (GI [including motility disorder and 
intestinal obstruction]), cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or 
major neurological (including stroke and chronic seizures) abnormalities or diseases will be excluded from the trial.


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Endpoints and Criteria for Evaluation:
Primary endpoints:
Plasma PK parameters (maximum observed concentration [Cmax] and area under the concentration-time curve from 
time 0 to infinity, calculated using the observed value of the last quantifiable concentration [AUC∞]) for TAK-954 will 
be analyzed on Day 1 of Trial Period 1 and on Day 4 of Trial Period 2.
Safety endpoints: 
Safety and tolerability will be assessed through physical examinations, electrocardiograms (ECGs), vital signs, and 
laboratory assessments as well as collection of spontaneous adverse events.
Statistical Considerations:
Pharmacokinetics:
The PK parameters of TAK-954 (and metabolites, if possible) will be summarized by regimen using descriptive 
statistics. Linear and semilogarithmic plots of the mean and individual concentration-time curves will be provided. 
Individual plasma concentration and PK parameter data will be presented in the data listing. 
For evaluation of potential effect of itraconazole on TAK-954 PK, paired t-tests and associated confidence intervals 
will be determined on the natural logarithms of Cmax and AUCs to assess the exposure between regimens (TAK-954 
alone and TAK-954 with itraconazole). The geometric mean of the relative bioavailability of the TAK-954 with 
itraconazole regimen relative to the TAK-954 alone regimen and the associated 90% confidence intervals will be 
determined by exponentiating the appropriate estimates for the difference between regimens in the log-transformed 
parameters.
Safety:
Safety data will be presented by regimen. Treatment-emergent adverse events (TEAEs) will be summarized by causal 
relationship to the trial drug and by intensity. Clinical laboratory variables, ECGS, and vital signs parameters 
(uncorrected and corrected QT intervals, PR, and QRS and heart rate) will be summarized with descriptive statistics 
for period baseline, postdose, and change from period baseline to postdose values.
Sample Size Justification: 
Approximately 10 subjects will complete this trial. With this sample size, a 2-sided 95.0% CI for the geometric mean 
ratio of Cmax for TAK-954 when administered with and without itraconazole will have 90% probability of excluding 
1.25 (the upper bound of the bioequivalence range) if itraconazole increases the Cmax for TAK-954 by at least 50%. 
This calculation assumes that the CI is based on the t statistic, that the distance from the mean to the lower bound of the 
CI on the natural-log scale is 0.182, and that the true SD of differences on the natural-log scale is 0.187 as estimated 
from Cmax values reported for Cohort 1 in Theravance Protocol No. 0095. Assuming the intrasubject variation 
observed for area under the concentration-time from 0 to t in that cohort (SD=0.129), a 2-sided 95.0% CI for the 
geometric mean ratio of AUC∞for TAK-954 when administered with and without itraconazole will have greater than 
99% probability of excluding 1.25 if itraconazole increases AUC∞ for TAK-954 by at least 50%. 
Subjects who drop out may be replaced at the discretion of the investigator in consultation with the sponsor. 


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2.0
TRIAL SCHEMATIC
PK=pharmacokinetic.


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3.0
SCHEDULE OF TRIAL PROCEDURES
Assessment
Screening
Trial Period 1 (a)
Trial Period 2
Follow-up/Early 
Termination
Day
-28 to -2
-1
1
2
3
4 to 6
-1
1
2 to 3
4
5
6
7
8
9
10-14 days after last 
dose of trial drug
Administrative Procedures
Informed consent 
X
Inclusion/exclusion criteria
X
X
Medical history/demographics
X
Prior and concomitant 
medication review
--------------------------------------------Continuous review-------------------------------------------------
Clinic Procedures/Assessments
Full physical examination
X
X
X
Semirecumbent vital signs (heart 
rate [HR], systolic blood 
pressure [SBP] and diastolic 
blood pressure [DBP]
X
X(b)
X
X
X
X
X
X
(b)
X
X
X
X
Vital signs (respiratory rate, oral 
[at the floor of the 
mouth]/tympanic temperature) 
rate
X
X(b)
X
Height
X
Weight
X
Body mass index (BMI)
X
Standard 12-lead 
electrocardiogram (ECG)
X
X(b)
X
X
X
(b)
X
X
Adverse event (AE) monitoring
---------------------------------------------Continuous review-------------------------------------------------
Laboratory Procedures/Assessments
Serum chemistry
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Serum follicle-stimulating 
X
CCI


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Assessment
Screening
Trial Period 1 (a)
Trial Period 2
Follow-up/Early 
Termination
Day
-28 to -2
-1
1
2
3
4 to 6
-1
1
2 to 3
4
5
6
7
8
9
10-14 days after last 
dose of trial drug
hormone (FSH)
Urine drug screen
X
X
X
Urine alcohol test/alcohol breath 
test (d)
X
X
X
HIV test
X
Hepatitis panel
X
Pharmacokinetics (PK) Evaluations
Plasma samples for TAK-954 (e)
X
X
X
X
X
X
X
X
X
X
Urine sample for TAK-954 PK 
(f)
X
X
X
X
X
X
Pharmacogenomic (PGx) Evaluations
Blood sample for DNA PGx 
X
Blood sample for RNA PGx 
X
Drug Administration
TAK-954 dosing 
X
X
Itraconazole dosing 
X
X
X
X
X
X
X
Other
Confinement
X
X
X
X
X
X
X
X
X
X
Meals 
X
X
X
X
X
X
X
X
X
X
X
(a) A minimum of 7 days between doses in Period 1 Day 1 and Period 2 Day 1. 
(b) Assessments at predose (within 30 minutes), 1, 2, 4, 8, and 12 hours postdose (relative to TAK-954 start of infusion).
(c)
(d) An alcohol breath test may be performed at the discretion of the investigator.
(e) Time points for PK blood samples for TAK-954: predose (within 30 minutes), and 0.33, 0.5, 0.67, 1 (just after the end of infusion), 1.5, 2, 3, 4, 6, 12, 24, 36, 48, 72, 96, and 
120 hours postdose (relative to TAK-954 start of infusion).
(f) Urine collected at predose, 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours relative to TAK-954 infusion start in Trial Periods 1 and 2.
CCI


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4.0
INTRODUCTION
4.1
Background
Critically ill patients who require enteral feeding frequently have reduced gastrointestinal (GI) 
motility, develop enteral feeding intolerance, which can lead to several complications including 
not meeting daily calorie and protein requirements [1]. The addition of malnutrition in these 
patients is associated with impairment of immunological function, increased risk of infection, 
prolongation of mechanical ventilation, increased length of intensive care unit and hospital stay,
and ultimately higher mortality [2,3]. 
TAK-954 is being developed for short-term use with enteral feeding to treat critically ill patients 
with enteral feeding intolerance. TAK-954 is a highly selective and potent serotonin type 4 
(5-HT4) receptor agonist that exhibits prokinetic activity throughout the GI tract [4]. 
TAK-954 has been investigated in healthy subjects at single oral doses from 0.1 to 20 mg, multiple 
oral doses from 0.2 to 10 mg daily for 10 days, and multiple intravenous (IV) doses from 0.1 to 
0.5 mg daily for 5 days. TAK-954 has been shown to undergo oxidative metabolism in vitro in 
human liver microsomes, although it was relatively stable when incubated with cryopreserved 
human hepatocytes (half-life [t1/2]) >17 hours).
The purpose of this trial is to investigate the effect of a potent CYP3A4 inhibitor on the PK of IV 
TAK-954 in healthy males and females. Itraconazole has been chosen as it is recommended by the 
Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a suitable 
potent cytochrome P-450 (CYP) 3A4 inhibitor for use in drug-drug interaction (DDI) studies. An 
IV dose of 0.2 mg TAK-954 daily has been selected as a dose that is predicted to be within the 
clinically relevant range, but is lower than the maximum multiple IV dose (0.5 mg) that has been 
investigated so far, to allow for any increases in exposure that may be observed with metabolic 
inhibition.
Please refer to the TAK-954 Investigator’s Brochure for complete information on the 
investigational product and the most recent itraconazole product insert for the appropriate region.
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
the applicable regulatory requirement(s).
4.2
Rationale for the Proposed Trial
This is a phase 1, single-sequence, open-label, 2-period crossover trial in 10 healthy male and 
female (non–childbearing potential) subjects. The trial is designed to investigate the effect of a 
potent CYP3A4 inhibitor (itraconazole) on the PK of TAK-954. TAK-954 will be administered as 
a single 60-minute IV infusion.
4.3
Benefit/Risk Profile
As this is a trial in healthy subjects, there is no expected clinical benefit to the trial participants. 
Potential risks are based on clinical findings, the mechanism of action, and nonclinical findings. 


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There is minimal risk associated with trial procedures including phlebotomy (limited to <500 mL) 
and noninvasive procedures including vital sign assessments and ECGs. The principal mitigation 
for these risks includes appropriate selection of the trial populations, the CRU setting, which 
permits close monitoring and rapid institution of appropriate care as needed, and the specified 
monitoring procedures. Overall, the risk:benefit is considered appropriate for this trial.


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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of the trial is to evaluate the effect of the potent CYP3A4 inhibitor 
itraconazole on the single-dose PK of TAK-954.
5.1.2
Secondary Objective
The secondary objectives of the trial are to evaluate the safety of single-dose IV doses of TAK-954 
in the presence and absence of a potent CYP3A4 inhibitor.
5.1.3
Exploratory Objectives
Exploratory objectives of this trial include: 
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint of the trial is the following PK parameters on Day 1 of Trial Period 1 and 
Day 4 of Trial Period 2:
!
Maximum observed concentration (Cmax).
!
Area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value of the last quantifiable concentration (AUC∞).
5.2.2
Safety Endpoints
Safety endpoints include the following: 
Safety and tolerability will be assessed through physical examinations, ECGs, vital signs, and 
laboratory assessments, and collection of spontaneous AEs.
5.2.3
Exploratory Endpoints
Exploratory endpoints will be assessed through the following parameters: 
PK parameters:
CCI
CCI


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Pharmacodynamic parameters:
CCI
CCI


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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
This is a phase 1, single-sequence, open-label, 2-period crossover trial in approximately 
10 healthy male and female (non–childbearing potential) subjects. The trial is designed to 
investigate the effect of a potent CYP3A4 inhibitor (itraconazole) on the PK of TAK-954. 
TAK-954 0.2 mg will be administered as a single 60-minute IV infusion. 
The trial will include a Screening Visit, Trial Period 1 (6 days), a washout (a minimum of 7 days 
between doses in Period 1 Day 1 and Period 2 Day 1), Trial Period 2 (9 days), and a Follow-up 
Visit. Blood samples for assessment of TAK-954 concentrations will be collected before each dose 
of TAK-954 and at intervals up to 120 hours after the last dose of trial drug in each trial period. 
Samples may be assayed for TAK-954 metabolites. TAK-954 and its metabolites will also be 
assayed in urine, data permitting and if deemed possible.
Whole blood samples for DNA PGx analysis and RNA isolation will be collected predose on 
Day 1of Trial Period 1. 
Safety will be assessed by monitoring for AEs, ECGs, vital signs, safety laboratory tests, and 
physical examinations throughout each dosing period. 
After completion of the trial (or after subject withdrawal), all subjects will return for a Follow-up 
Visit, approximately 10 to 14 days after their last dose of trial drug.
6.2
Rationale for Trial Design, Dose, and Endpoints
6.2.1
Rationale of Trial Design and Dose
TAK-954 is a small molecule, 5-HT4 agonist. TAK-954 has been investigated in healthy subjects 
at single oral doses from 0.1 to 20 mg, multiple oral doses from 0.2 to 10 mg once daily (QD) for 
10 days, and multiple IV doses from 0.1 to 0.5 mg QD for 5 days. A single IV dose of 0.5 mg 
TAK-954 has also been investigated in critically ill patients with enteral feeding intolerance and 
compared with metoclopramide. After multiple IV infusion dosing in healthy subjects (0.1 and 
0.5 mg with a 1-hour infusion), TAK-954 concentrations declined in a biphasic manner, with mean 
t1/2 values ranging from 18.0 to 18.9 hours on Day 5. 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%. In 
subjects who were critically ill and received 0.5 mg by IV infusion, the PK exposure was slightly 
lower relative to that observed in healthy subjects.
Two active metabolites were identified nonclinically, but TAK-954 was not extensively 
metabolized to either of these metabolites after oral dosing (mean Cmax and area under the 
concentration-time curve from time 0 to 48 hours metabolite to parent ratios ranged from 0.0008 to 
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0.004). Renal excretion of these metabolites was also low with concentrations in urine generally 
below the limit of detection. Evidence of GI prokinetic activity in healthy subjects (increased 
bowel movement frequency, looser stool consistency, and decreased time to first bowel 
movement) was observed at all dose levels after receiving single and multiple doses (oral and IV). 
In 7 subjects who were critically ill, scintigraphy data qualitatively suggest TAK-954 decreases 
gastric emptying time after a liquid meal.
After multiple oral doses in healthy subjects, TAK-954 was generally well tolerated at doses up to 
5 mg QD for 10 days. There were no SAEs and the overall incidence of AEs reported for the 
TAK-954 dose groups was similar to that for the placebo group. All AEs were mild or moderate. 
The most commonly reported treatment-related AEs in TAK-954 subjects overall were headache 
and diarrhea. No dose-related trends were evident in the AE data across the 0.2, 1, or 5 mg dose
groups, but 2 of 3 subjects receiving 10 mg were discontinued because of an AE (mild intermittent 
atrioventricular dissociation, which resolved without intervention). There were no safety signals in 
the clinical laboratory or respiratory rate data after multiple dose administration. Mean blood 
pressure (BP) and heart rate (HR) remained in the normal range for all groups throughout the trial. 
However, there was a trend toward lower BP and elevated HR in the standing position for 
TAK-954 subjects, but no dose response was apparent. In addition, there was one AE related to BP 
(orthostatic hypotension in a subject who received 5 mg TAK-954).
After IV doses in healthy subjects, TAK-954 was generally well tolerated at doses ranging from 
0.1 to 0.5 mg QD for 5 consecutive days. No serious adverse events (SAEs) were reported. The 
most common AEs (ie, headache and postural dizziness) were not clinically significant and 
resolved spontaneously. Among the AEs reported, 3 subjects experienced modest and transient 
cardiovascular AEs upon standing after the first dose (ie, postural tachycardia and postural 
dizziness) that resolved spontaneously, and were not observed upon challenge. After single 
infusions of TAK-954 0.5 mg in subjects who were critically ill with enteral feeding intolerance, 
no subjects had an AE that led to trial discontinuation or interruption of treatment. Vital sign 
changes from Baseline noted during treatment were minimal and typical of critically ill subjects. 
No clinically relevant changes in ECGs in either treatment group were observed.
TAK-954 has been shown to undergo oxidative metabolism in vitro in human liver microsomes, 
though it was relatively stable when incubated with cryopreserved human hepatocytes (t1/2
>17 hours).
The purpose of this trial is to investigate the effect of a potent CYP3A4 inhibitor on the PK of IV 
TAK-954 in healthy subjects. Itraconazole has been chosen as it is recommended by the FDA and 
EMA as a suitable potent CYP3A4 inhibitor for use in DDI studies. An IV dose of 0.2 mg 
TAK-954 has been selected as a dose that is predicted to be within the clinically relevant range, but 
is lower than the maximum multiple IV dose (0.5 mg) that has been investigated so far, to allow for 
any increases in exposure that may be observed with metabolic inhibition. 


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6.2.2
Rationale for Endpoints
6.2.2.1
PK 
The primary endpoint for this trial consists of standard PK variables (Cmax and AUC∞) to 
determine the effect of itraconazole on the PK of TAK-954 in healthy subjects.
6.2.2.2
Safety Endpoints
Key safety endpoints will be assessed through monitoring of AEs, vital signs, ECGs, clinical 
laboratory results, and physical examinations.
6.2.2.3
Exploratory Endpoints
6.2.3
Critical Procedures Based on Trial Objectives: Timing of Procedures
For this trial, the collections of the blood samples for TAK-954 (PK) are the critical procedures. 
!
At any postdose time point, the blood samples for TAK-954 (PK) needs to be collected as close 
to the exact nominal time point as possible.
!
All other procedures should be completed as close as possible, either before or after the 
prescribed/scheduled time.
–
ECG and vital signs measurements should be performed before the nominal time of the 
TAK-954 (PK) if scheduled together.
!
The order of priority can be changed during the trial with joint agreement of the investigator 
and the sponsor.
!
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
6.3
Trial Beginning and End/Completion
6.3.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signs the trial informed consent form.
6.3.2
Definition of End of the Trial
The overall trial ends when the last subject completes the last planned or follow-up 
visit/interaction associated with a planned visit (this can be a phone contact), discontinues from the 
trial or is lost to follow-up (ie, the investigator is unable to contact the subject).
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6.3.3
Definition of Trial Discontinuation
Trial discontinuation because of nonsafety reasons, such as:

A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical trial 
using the trial treatment(s) results in the trial being stopped for a non–safety-related reason. 

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this trial 
become available and results in the trial being stopped for a non–safety-related reason. 

The trial is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Trial discontinuation because of safety reasons: 

Early trial termination because of unanticipated concerns of safety to the trial subjects arising 
from clinical or preclinical trials with the trial treatment(s), comparator(s), drug(s) of the same 
class, or methodology(ies) used in this trial.
6.3.4
Criteria for Premature Termination or Suspension of the Trial
6.3.4.1
Criteria for Premature Termination or Suspension of Trial Sites
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the trial, or as otherwise permitted by the contractual agreement.
6.3.4.2
Procedures for Premature Termination or Suspension of the Trial or the Participation of 
Trial Site(s)
In the event that the sponsor, an institutional review board (IRB), or regulatory authority elects to 
terminate or suspend the trial or the participation of an investigational site, a trial-specific 
procedure for early termination or suspension will be provided by the sponsor; the procedure will 
be followed by applicable investigational sites during the course of termination or trial suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must:
1. Understand the trial procedures and agree to participate by providing written informed 
consent.
2. Be willing and able to comply with all trial procedures and restrictions.
3. Be a man or woman (with no child bearing potential) aged 18 to 55 years, inclusive, at the 
Screening Visit. 
4. Have a BMI ≥18 and ≤30 kg/m2 and a body weight >50 kg at the Screening Visit.
5. Be a nonsmoker who has not used tobacco- or nicotine-containing products (eg, nicotine 
patch) for at least 6 months before administration of the initial dose of trial drug/invasive 
procedure.
6. Be judged to be in good health by the investigator, based on clinical evaluations including 
laboratory safety tests, medical history, physical examination, 12-lead ECG, and vital sign 
measurements performed at the Screening Visit and before administration of the initial dose of 
trial drug.
7. Meet the following birth control requirements:
–
Is a male subject who is sterile or agrees to use an appropriate method of contraception, 
including a condom with or without spermicidal cream or jelly, from trial drug 
administration on the first day of the first dose until 5 half-lives plus 90 days after 
administration of the last dose of trial drug. No restrictions are required for a vasectomized 
male subject provided the subject is at least 1 year post–bilateral vasectomy procedure 
before trial drug administration on the first day of the first dose. A male subject whose 
vasectomy procedure was performed less than 1 year before trial drug administration on 
the first day of the first dose must follow the same restrictions as a nonvasectomized man. 
Appropriate documentation of surgical procedure should be provided.
–
Is a male subject who agrees to not donate sperm from trial drug administration on the first 
day of the first dose until 5 half-lives plus 90 days after administration of the last dose of 
trial drug.
–
Is a female subject with no childbearing potential, defined by at least 1 of the following 
criteria:
a) Postmenopausal (defined as 12 months of spontaneous amenorrhea in females aged 
>45 years, 6 months of spontaneous amenorrhea in females aged >45 years with serum 
FSH levels >40 mIU/mL). Appropriate documentation of FSH levels is required.
b) Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate 
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c) Had a tubal ligation with appropriate documentation of surgical procedure.
d) Has a congenital condition resulting in no uterus.
7.2
Exclusion Criteria
The subject must be excluded from participating in the trial if the subject: 
1. Has a history of clinically significant endocrine, gastrointestinal (including motility disorder 
and intestinal obstruction), cardiovascular, hematological, hepatic, immunological, renal, 
respiratory, genitourinary, or major neurological (including stroke and chronic seizures) 
abnormalities or diseases.
2. Has participated in another investigational trial within 4 weeks before the pretrial (Screening) 
visit. The 4-week window will be derived from the date of the last trial procedure and/or AE 
related to the trial procedure in the previous trial to the pretrial/Screening Visit of the current 
trial. 
3. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the sponsor.
4. Has a history of cancer (malignancy).
5. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy) or 
has had an anaphylactic reaction or significant intolerability to prescription or nonprescription 
drugs or food.
6. Has a positive alcohol or drug screen.
7. Is a lactating/nursing woman.
8. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 8 weeks of 
the first dose of trial drug.
9. Has a known hypersensitivity to any component of the formulation of TAK-954 or related 
compounds, or to itraconazole (see Product Insert).
10. Is unable to refrain from or anticipates the use of any medication, including prescription and 
nonprescription drugs or herbal remedies, beginning approximately 7 days before 
administration of the initial dose of trial drug, throughout the trial (including washout intervals 
between trial periods), until the Follow-up Visit. There may be certain medications that are 
permitted, see Section 7.3.
11. Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass
is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled 
spirits [29.5 mL/1 ounce] per day).
12. Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately 
equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated 
beverages per day.
13. Has a substance abuse disorder.


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7.3
Excluded Medications, Supplements, and Dietary Products
Use of excluded agents (prescription or nonprescription) or dietary products is outline in Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Enrollment 
(Days -28 to Predose [Day 1])
Randomization Post-Enrollment 
(Day 1) to Follow-up Visit
Tobacco- and 
nicotine-containing 
products
Completely restricted
Completely restricted
Cannabis products
Completely restricted
Completely restricted 
Alcohol
Completely restricted 7 days before 
dosing
Completely restricted 7 days before 
dosing 
At all other times no more than 
3 units/day
Xanthine and/or caffeine
Completely restricted 24 hours before 
dosing
Completely restricted 24 hours before 
dosing 
At all other times no more than 
6 units/day
Medications
Completely restricted 7 days before 
dosing
Completely restricted (a)
Food substance
Grapefruit /grapefruit juice
Completely restricted 7 days before 
dosing
Completely restricted
Fruit
No restriction
No restriction
Fruit juice
No restriction
Dosing will occur without consumption 
of fruit juice. Fruit juice is restricted 4 
hours after dosing.
Mustard green (b)
Completely restricted 7 days before 
dosing
Completely restricted
Charbroiled meat
Completely restricted 7 days before 
dosing
Completely restricted
(a) If medications are required to treat an AE, certain medications may be allowed after discussion and agreement 
between the sponsor and principal investigator.
(b) Mustard green family includes kale, broccoli, watercress, collard greens, kohlrabi, Brussel sprouts, and mustard. 
7.4
Diet, Fluid, and Activity 
7.4.1
Diet and Fluid
Subjects must abstain from all food and drink (except water) at least 8 hours before any safety 
laboratory evaluations. 
Water is permitted until 1 hour before TAK-954 and itraconazole administration. Water may be 
consumed without restrictions beginning 1 hour after TAK-954 and itraconazole dosing. 


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Subjects will receive a standard (moderate-fat) breakfast 1.5 hours before TAK-954 dosing in 
Trial Period 1 and 30 minutes before itraconazole dosing in Trial Period 2. Lunch will be provided 
approximately 4 hours after TAK-954 dosing or 5.5 hours after itraconazole dosing, as applicable, 
on all days. Dinner will be provided approximately 9 or 10 hours after TAK-954 or itraconazole 
dosing, respectively, on all days. An evening snack will also be permitted. The caloric content and 
composition of meals will be the same in each trial period. After the 24-hour postdose (Day 1 of 
Trial Period 1 and Day 4 of Trial Period 2) procedures have been completed, subsequent meals and 
snacks will be unrestricted in caloric content, composition, and timing.
7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (eg, weight lifting, running, 
bicycling) from the Screening Visit until the Follow-up Visit.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
1. The subject experiences an AE that requires early termination because continued participation 
imposes an unacceptable risk to the subject’s health or the subject is unwilling to continue 
because of the AE.
2. Liver Function Test (LFT) Abnormalities
In multidose studies, trial drug should be discontinued immediately with appropriate clinical 
follow-up (including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 10.2.9.4), if the following circumstances occur at any time 
during trial drug treatment:
–
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 times the upper 
limit of normal (ULN), or
–
ALT or AST >5×ULN and persists for more than 2 weeks, or
–
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or 
international normalized ratio >1.5, or
–
ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%).
3. Significant protocol deviation. The discovery that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.
4. Lost to follow-up. The subject did not return to the clinic, and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
5. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the trial. The reason for withdrawal, if provided, should be recorded in the 
electronic case report form (eCRF). 


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Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal because of 
an AE should not be recorded in the “voluntary withdrawal” category).
6. Trial termination. The sponsor, IRB, or regulatory agency terminates the trial.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s trial participation at any time during the trial when 
the subject meets the trial termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the trial. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. 
7.7
Subject Replacement
If a subject discontinues from the trial, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and sponsor. The trial site should contact the sponsor for the 
replacement of subject’s treatment assignment and allocation number. 


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
8.1
Clinical Trial Drug 
Details regarding the composition and extemporaneous preparation of the active ingredient are 
found in the Pharmacy Manual, Compounding Instructions, and/or similar documents. Clinical 
trial drug will be packaged to support enrollment and replacement subjects as required. When a 
replacement subject is required, the sponsor needs to be contacted before dosing.
Itraconazole will be supplied by the trial site.
8.1.1
Clinical Trial Drug Labeling
Clinical trial drug packaging will be affixed with a clinical label in accordance with regulatory 
requirements.
8.1.2
Clinical Trial Drug Inventory and Storage
Clinical trial drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Inventory (receipt and dispensing) of trial drug must be recorded by an 
authorized person at the trial site. 
8.1.3
Clinical Trial Drug Blinding
This is an open-label trial; therefore, the sponsor, investigator, and subject will know the treatment 
administered.
8.1.4
Accountability and Destruction of Sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the clinical trial drug received from 
the sponsor or designee, the amount dispensed to and returned by the subjects, and the amount 
remaining at the conclusion of the trial. For all trial sites, the local country sponsor personnel or 
designee will provide appropriate documentation that must be completed for clinical trial drug 
accountability, return, and destruction. 
8.1.5
Ancillary Supplies
All ancillary supplies will be provided by either the site or Takeda, based upon availability. If 
provided by Takeda, unused ancillary supplies will be accounted for and disposed of as directed by 
Takeda or a Takeda designee.


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9.0
TRIAL PROCEDURES
The following sections describe the trial procedures and data to be collected as indicated in the 
Schedule of Trial Procedures (Section 3.0). For each procedure, subjects are to be assessed by the 
same investigator or site personnel whenever possible. Please note that it may become necessary to 
perform the following procedures at unscheduled time periods, per the discretion of the 
investigator. For information regarding procedures that are scheduled concurrently, see 
Section 6.3.4.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject entering into the trial and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Section 13.2. 
In the case where subjects have screening assessments performed prior to the trial, the data from 
the general/site screening could be included/used in the trial for those who were enrolled, as long 
as the procedure was performed within the protocol screening/enrollment window. A generic site 
screening form may be used.
9.1.2
Assignment of Screening Numbers
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur before allocation. Each subject will be assigned only 1 
screening number. Screening numbers must not be re-used for different subjects. Any subject who 
is screened multiple times will be assigned a new screening number for each screening event.
9.1.3
Inclusion and Exclusion Criteria 
Each subject is assessed according to the eligibility criteria provided in Section 7.0.
9.1.4
Medical History/Demographics
Qualified site personnel are to collect subject significant medical history (past and ongoing) per 
the site’s standard of care and appropriate clinical judgment as well as subject demographics. 
9.1.5
Prior and Concomitant Medication Review
Medications are defined as prescription and over-the-counter drugs, vitamin supplements, 
nutraceuticals, and oral herbal preparations. Qualified site personnel are to review subject 
medication use. 
9.1.6
Physical Examinations
Qualified site personnel will conduct physical examinations.


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9.1.7
Vital Sign Measurements
Body temperature will be measured with an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (eg, oral or tympanic) must be used for all subsequent 
measurements for each individual subject and should be the same for all subjects.
Subjects should rest in a semirecumbent position for at least 5 minutes before having vital sign 
measurements obtained. Vital signs will include HR, systolic blood pressure, and diastolic blood 
pressure. The same method (eg, same and appropriately sized cuff, manual, or automated) must be 
used for all measurements for each individual subject and should be the same for all subjects. 
Subjects will continue to rest in a semirecumbent position from the time of dosing until 4 hours 
postdose except to stand for the measurement of standing vital signs (if needed) or other 
trial-related procedure. 
9.1.8
Height and Weight
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed.
9.1.9
BMI
BMI equals a person’s weight in kilograms divided by height in meters squared (BMI=kg/m2). 
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed. 
BMI will be rounded to the nearest whole number according to the standard convention of 
0.1 to 0.4 round down and 0.5 to 0.9 round up.
9.1.10 12-Lead ECG
Special care must be taken for proper lead placement by qualified personnel. Skin should be clean 
and dry before lead placement. Subjects may need to be shaved to ensure proper lead placement. 
Female subjects may need to remove their bras. 
Subjects should be resting in a semirecumbent position for at least 5 minutes before each ECG 
measurement.
QT intervals with Fridericia correction method (QTcF) will be used to calculate QT intervals in 
this trial.
Before each trial period, a predose ECG will be obtained within approximately 30 minutes before 
dosing. This measurement will be used as the baseline. The principal investigator should arrange 
to have a trial cardiologist available as needed to review ECG tracings with abnormalities.
If a subject demonstrates an increase in QTcF interval ≥40 msec compared with a predose baseline 
measurement, the ECG will be repeated within 5 minutes. The average value of the QTcF interval 
from the 2 ECGs will represent the value at that time point. If the average QTcF interval increase 
from Baseline for any postdose time point is ≥40 msec, the subject will continue to be monitored 
by repeat 12-lead ECGs every 60 minutes for at least 4 hours or until the QTcF is within 40 msec of 
the baseline value. If prolongation of the QTcF interval ≥40 msec persists, a consultation with a 
trial cardiologist may be appropriate and the sponsor should be notified.


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If the QTcF interval is ≥500 msec, the sponsor should be notified and the ECGs should be 
reviewed by a cardiologist. The subject should be telemetry-monitored (until the QTcF is 
<500 msec) or should be considered for transfer to a location where closer monitoring is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias noted on 
telemetry, the subject should be immediately transferred to an acute care setting for definitive 
therapy. 
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in place or 
mark the position of the electrodes for subsequent ECGs. To mark the position of the electrodes, 
12-lead electrode sites will be marked on the skin of each subject with an ECG skin marker pen to 
ensure reproducible electrode placement.
The following ECG parameters will be recorded: HR, PR-interval, QRS-duration, QT-interval, 
QTcF-interval, and the interpretation of the ECG profile by the principal investigator.
9.1.11 AE Monitoring
AE monitoring begins after signing of informed consent. Changes in subject health status from 
baseline assessment to trial drug administration should be captured in the subject’s medical 
history. A complete description of AE collections and procedures is provided in Section 10.0.
9.2
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be taken after a minimum 8-hour overnight fast on the days stipulated in the Schedule 
of Trial Procedures (Section 3.0).
9.2.1.1
Clinical Laboratory Tests
Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase
ALT
AST
Blood urea nitrogen
Calcium
Bicarbonate
Chloride
Creatinine
Glucose
Gamma-glutamyl transferase
Sodium
Potassium
Bilirubin (total), if above ULN, will be fractionated
Protein (total)


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Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells [RBCs])
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs]) with absolute 
differential
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrite
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of 
RBC/high-power field, WBC/high-power field, and casts.
Urine Drug Screen
A urine drug screen will include the following tests: 
Amphetamines
3,4-methylenedioxy-methamphetamine (MDMA)
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
Alcohol Screen
Subjects will undergo a urine alcohol test. An alcohol breath test may be performed at the 
discretion of the investigator.
9.2.1.2
Screening
Serum
Serum evaluations will include the following tests:
HIV test
FSH (females only)
Hepatitis panel, including HBsAg and anti-HCV


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9.3
PK and PGx Samples
A portion of the DNA sample will be analyzed for the presence of allelic variants in drug 
metabolizing enzymes, drug transporters, or putative drug targets that may contribute to the 
variability in the PK of TAK-954 (Drug Metabolism Enzymes and Transporters. 
As PGx is an evolving science, many genes and their functions are not yet fully understood. Future 
data may suggest a role of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development on stored samples.
Samples for PK analysis will be collected as specified in the Schedule of Trial Procedures 
(Section 3.0). Please refer to the Laboratory Manual for information on the collection, processing, 
and shipment of samples to the central laboratory. 
It is anticipated that the total blood volume drawn for the trial will be approximately 300 mL. 
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended 
Use
Sample 
Collection
Plasma sample for TAK-954 PK
Plasma
PK measurements
Mandatory
Urine sample for TAK-954 PK
Urine
PK measurements
Mandatory
Blood sample for DNA PGX
Blood
DNA
PGx measurements
Mandatory
Blood sample for RNA PGX
Blood
RNA
PGx measurements
Mandatory
9.3.1
PK Evaluations 
The PK parameters of TAK-954 will be derived using noncompartmental analysis methods and 
will be determined from the concentration-time data for all evaluable subjects. Actual sampling 
times, rather than scheduled sampling times, will be used in all PK computations involving 
sampling times. A more detailed description will be given in the clinical pharmacology analysis 
plan.
The following plasma PK parameters for TAK-954 will be calculated on Day 1 of Trial Period 1 
and Day 4 of Trial Period 2: 

Cmax
.

AUC∞
.

t1/2
.
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 


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protocol deviation, as long as the exact date and time of the dosing and sample collection is noted 
on eCRF.
9.3.2
PGx Measurements
9.3.2.1
Blood Sample for DNA and RNA PGx Measurements
When sampling of whole blood for PGx analysis occurs, every subject must sign an informed 
consent/be consented in order to participate in the trial. PGx is a component of the trial; 
participation is mandatory.
PGx is the study of variations of DNA and RNA characteristics as related to drug response. There 
is increasing evidence that an individual’s genetic background may impact the PK (absorption, 
distribution, metabolism, and excretion), pharmacodynamics (pharmacologic effects), and/or the 
clinical outcome (efficacy and/or safety).
PGx research in this trial may be conducted to understand how individual genetic variation in 
subjects impacts their trial drug treatment response. This information may be also be used, for 
example, to develop a better understanding of the safety and efficacy of TAK-954 and other trial 
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. 
Whole blood samples for DNA and RNA isolation will be collected from each consented subject in 
the trial. If necessary and feasible, a second aliquot of blood may be taken at a later time point if 
isolation of DNA from the first sample was not successful or possible.
Since PGx is an evolving science, many genes and their functions are not yet fully understood. 
Future data may suggest a role of these genes in drug response, which may lead to additional 
hypothesis-generating exploratory research and diagnostic development on stored samples.
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
9.3.2.2
Biological Sample Retention and Destruction
In this trial, specimens for genome/gene analysis will be collected as described in the Laboratory 
Manual. The genetic material will be initially stored at the vendor, or a comparable laboratory, 
under contract to Takeda, with validated procedures in place, and then preserved and retained at 
the vendor, or a comparable laboratory with validated procedures in place, for up to but not longer 
than 15 years from the end of the trial when the trial report is signed, or if less, the maximum 
period permitted under applicable law or until consent is withdrawn.
CCI


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The sponsor and vendors working with the sponsor will have access to the samples collected and 
any test results. All samples collected during the trial will be stored securely with limited access 
and the sponsor will require anyone who works with the samples to agree to hold the research 
information and any results in confidence.
The sample will be labeled with a unique sample identifier as in the main trial but using a code that 
is different from the code attached to the health information and other clinical test results collected 
in the trial. The sample and data are linked to personal health information with code numbers; the 
samples are stripped of all personal identifying information but a key linking the samples to 
clinical analysis data exists. This link means that the subject may be identified but only indirectly. 
The sample identifier will be kept secure by or on behalf of the sponsor.
Subjects who consented and provided a PD sample for DNA and RNA analysis can withdraw their 
consent at any time and request disposal of a stored sample. Any remaining sample that can be 
identified as coming from the subject will be destroyed. The trial doctor and sponsor may continue 
to use and distribute any information and test results gathered before the request to withdraw.
9.4
Trial Drug Administration
Eligible subjects will be allocated to trial treatment by non-random assignment on Day 1 of Trial 
Period 1 and will receive a 0.2 mg single-dose TAK-954 IV on this day and on Day 4 of Trial 
Period 2 at approximately the same time (between 0600 and 0900). In Trial Period 2, subjects will 
receive 200 mg QD itraconazole orally on Days 1 to 8 at approximately the same time (between 
0600 and 0900). Itraconazole will be administered as 2 x 100 mg capsules and witnessed by the 
investigator and/or trial staff. The bioavailability of itraconazole when administered as capsules is 
increased under fed compared with fasted conditions and therefore, itraconazole will be 
administered after a standard (moderate-fat) breakfast (consumed within 30 minutes before 
dosing). The TAK-954 infusion will start 1 hour after itraconazole administration on Day 4 of 
Trial Period 2. To maintain similar conditions in each trial period, subjects will also receive a 
standard (moderate-fat) breakfast 1.5 hours before TAK-954 IV administration in Trial Period 1.
9.5
Confinement
Period 1:
Subjects will report to the clinical research unit (CRU) on Day -1, the day before the scheduled day 
of administration of the trial drug at the discretion of the investigator. Subjects will remain in the 
unit until after the PK sample collection at 48 hours after TAK-954 dosing (the morning of Day 3) 
and will return to the clinic for PK sample collection at 72, 96, and 120 hours. At the discretion of 
the investigator, subjects may be requested to remain in the CRU longer.


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Period 2:
Subjects will report to the CRU on Day -1, the day before the scheduled day of administration of 
the trial drug at the discretion of the investigator. Subjects will remain in the unit until after the PK 
sample collection at 72 hours after TAK-954 dosing (the morning of Day 7). Subjects will return to 
the clinic for PK sample collection at 96 and 120 hours and itraconazole administration at 96 hours 
(Day 8). At the discretion of the investigator, subjects may be requested to remain in the CRU 
longer.


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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 subject who has 
signed informed consent to participate in a trial; 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 underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of trial 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 to be AEs if they are 
judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation, or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, x-ray) should NOT be recorded as an AE unless related to 
a trial procedure. However, if the subject experiences a worsening or complication of such a 


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concurrent medical history condition, the worsening or complication should be recorded 
appropriately as an AE (worsening or complication occurs after informed consent is signed). 
Investigators should ensure that the event term recorded captures the change in the condition 
(eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
trial medication or after any change in trial medication, the worsening or complication should 
be recorded as a new AE. Investigators should ensure that the AE term recorded captures the 
change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in trial medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled before signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) because of a worsening of the pre-existing condition, the worsening of the 
condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a trial subject, at a dose above that which is assigned to that individual subject 
according to the trial protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the eCRF, in order to capture this important safety information consistently in the 


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database. AEs associated with an overdose will be documented on the AE CRF(s) according to 
Section 10.2.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.9.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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


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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.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.2.2 Assigning Causality of AEs
The relationship of each AE to trial 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 possible involvement of the drug can be 
argued, 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 drugs and concurrent treatments.
10.2.3 Assigning Relationship to Trial Procedures
Relationship (causality) to trial procedures should be determined for all AEs.
The relationship should be assessed as “Related” if the investigator considers that there is 
reasonable possibility that an event is because of a trial procedure. Otherwise, the relationship 
should be assessed as “Not Related”.
10.2.4 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.5 Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.2.6 Frequency 
Episodic AEs (eg, headache) or those that occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.


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10.2.7 Action Concerning Trial Drug 

Drug withdrawn: a trial medication is stopped because of the particular AE.

Dose not changed: the particular AE did not require stopping a trial medication.

Unknown: only to be used if it has not been possible to determine what action has been taken.

Not applicable: a trial medication was stopped for a reason other than the particular AE, for 
example, the trial has been terminated, the subject died, dosing with trial medication was 
already stopped before the onset of the AE.
10.2.8 Outcome 

Recovered/resolved: subject returned to first assessment status with respect to the AE.

Recovering/resolving: the intensity is lowered by one or more stages; the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved: there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms, or laboratory value on the last day of the observed 
trial period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Resolved with sequelae: the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal: an AE that is considered as the cause of death.

Unknown: the course of the AE cannot be followed up because of hospital change or residence 
change at the end of the subject’s participation in the trial.
10.2.9 Collection and Reporting of AEs, SAEs, and Abnormal LFTs
10.2.9.1 Collection Period
Collection of AEs (ie, AEs, SAEs, and abnormal LFTs) will commence at the time the subject 
signs the informed consent. Routine collection of AEs will continue until the Follow-up Visit 
10-14 days after the last dose of trial drug. For subjects who discontinue before the administration 
of trial medication, AEs will be followed until the subject discontinues trial participation. 
10.2.9.2 Reporting AEs
At each trial visit, the investigator will assess whether any subjective AEs have occurred. A neutral 
question, such as “How have you been feeling since your last visit?” may be asked. Subjects may 
report AEs occurring at any other time during the trial. Subjects experiencing an SAE before the 


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first exposure to investigational product must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to Baseline or there is a satisfactory 
explanation for the change. Nonserious AEs that begin before the first exposure to investigational 
product, related or unrelated to the trial procedure, need not be followed-up for the purposes of the 
protocol.
All subjects experiencing AEs, whether considered associated with the use of the trial medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and stop date and time.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of trial 
medication(s) (related or not related).

Investigator’s opinion of the causal relationship to trial procedure(s), including the details of 
the suspected procedure.

Action concerning trial medication.

Outcome of event.

Seriousness.
10.2.9.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the trial 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.


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Any SAE spontaneously reported to the investigator after the AE collection period should be 
reported to the sponsor if considered related to trial participation.
Reporting of SAEs that begin before the first administration of investigational product will follow 
the same procedure for SAEs occurring on treatment.
SAE Follow-up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.9.4 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF 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 subject 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 10.2.9.3. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.2 must also be 
performed. In addition, an LFT Increases eCRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.10). 
10.2.10 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 
Independent Ethics Committees (IECs), as applicable, in accordance with national regulations in 
the countries where the trial 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 trial. 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
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all trial objectives.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the trial database, subject evaluability, or appropriateness of the 
planned statistical methods.
11.1.1
Analysis Sets
Safety Set
The safety set will consist of all subjects who are enrolled and receive at least 1 dose of trial drug. 
Subjects in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries.
PK Set
The PK set will consist of all subjects who are enrolled and receive at least 1 dose of trial drug and 
have at least 1 measurable TAK-954 plasma concentration. All subjects with valid PK parameter 
estimates will be included in the summaries and analyses for that parameter.
If any subject is found to be noncompliant with the dosing schedule or has incomplete data, a 
decision will be made on a case-by-case basis as to whether that subject should be included in the 
PK analyses; however, data for all subjects will be presented in the data listings.
11.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for all subjects. Summary statistics 
(number of subjects, mean, SD, median, minimum, and maximum) will be presented for 
continuous variables (eg, age, weight, and BMI), and the number and percentage of subjects within 
each category will be presented for categorical variables (eg, sex, ethnicity, and race). Individual 
subject demographic and baseline characteristic data will be provided in the data listings.
11.1.3
PK Analysis
Concentrations of TAK-954 and any measured metabolites will be summarized by regimen over 
each scheduled sampling time using descriptive statistics.
The amount of TAK-954 and any measured metabolites excreted in urine will be summarized by 
regimen using descriptive statistics. 
Individual plasma and urine concentration versus time data will be presented in a data listing. 
Plasma and urine PK parameters of TAK-954 and any measured metabolites will be summarized 
by regimen using descriptive statistics. 


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For evaluation of potential effect of itraconazole on TAK-954 PK, paired t-tests and associated CIs 
will be determined on the natural logarithms of Cmax and area under the concentration-time curses 
to assess the exposure between regimens (TAK-954 alone and TAK-954 with itraconazole). The 
geometric mean of the relative bioavailability of the TAK-954 with itraconazole regimen relative 
to the TAK-954 alone regimen and the associated 90% CIs will be determined by exponentiating 
the appropriate estimates for the difference between regimens in the log-transformed parameters.
A more detailed analysis will be presented in the SAP. Additional analyses will be included, if 
appropriate.
11.1.4
Safety Analysis
The safety set will be used for all summaries of safety parameters. These summaries will be 
presented by TAK-954 alone, itraconazole alone, and TAK-954 with itraconazole.
11.1.4.1 AEs
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse events (TEAEs) 
with onset occurring within 30 days (onset date minus last date of dose +1≤30) after the last dose 
of trial drug will be included in the summary tables. All AEs will be in the listings. TEAEs will be 
summarized by SOC and PT. The following summary tables will be included in the report: 
summary of TEAEs and drug-related AEs, relationship of AEs to trial drug (related vs not related), 
severity of AEs, and related SAEs. Data listings will be provided for all AEs including TEAEs, 
AEs leading to trial drug discontinuation, and SAEs. 
11.1.4.2 Clinical Laboratory Evaluation
Baseline, postdose, and change from Baseline to postdose laboratory data will be summarized by 
regimen. All clinical laboratory data will be provided in the data listings.
11.1.4.3 Vital Signs
Baseline, postdose, and changes from Baseline in vital sign measurements will be summarized. All 
vital sign data will be provided in the data listings.
11.1.4.4 ECGs
Baseline, postdose, and changes from Baseline in quantitative ECG parameters will be 
summarized by regimen. Shift tables for each will be generated to show the investigator’s ECG 
interpretations at each postdose collection by the interpretation at Baseline.
All ECG data will be provided in the data listings.


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11.2
Interim Analysis and Criteria for Early Termination
No formal interim analyses will be conducted. 
11.3
Determination of Sample Size
Approximately 10 subjects will complete this trial. With this sample size, a 2-sided 95.0% CI for 
the geometric mean ratio of Cmax for TAK-954 when administered with and without itraconazole 
will have 90% probability of excluding 1.25 (the upper bound of the bioequivalence range) if 
itraconazole increases the Cmax for TAK-954 by at least 50%. This calculation assumes that the CI 
is based on the t statistic, that the distance from the mean to the lower bound of the CI on the 
natural-log scale is 0.182, and that the true SD of differences on the natural-log scale is 0.187 as 
estimated from Cmax values reported for Cohort 1 in Theravance Protocol No. 0095. Assuming the 
intrasubject variation observed for area under the concentration-time curve from time 0 to time t in 
that cohort (SD=0.129), a 2-sided 95.0% CI for the geometric mean ratio of AUC∞for TAK-954 
when administered with and without itraconazole will have greater than 99% probability of 
excluding 1.25 if itraconazole increases AUC∞for TAK-954 by at least 50%. 
Subjects who drop out may be replaced at the discretion of the sponsor in consultation with the 
investigator. Subjects who replace dropouts will begin the trial as a new subject in Trial Period 1. 


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Trial-Site Monitoring Visits
Monitoring visits to the trial site will be made periodically during the trial to ensure that all aspects 
of the protocol are followed. Source documents will be reviewed for verification of data recorded 
on the eCRFs. Source documents are defined as original documents, data, and records. The 
investigator and trial site guarantee access to source documents by the sponsor or its designee and 
by the IRB or IEC.
All aspects of the trial and its documentation will be subject to review by the sponsor or the 
sponsor’s designee, including but not limited to the Investigator’s Binder, trial drug, subject 
medical records, informed consent documentation, and review of eCRFs and associated source 
documents. It is important that the investigator and other trial 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 trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary trial assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The trial site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the trial. In 
addition, there is the possibility that this trial 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 
trial 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 trial 
documents as described in Section 12.1.


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13.0
ETHICAL ASPECTS OF THE TRIAL
This trial 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 Harmonisation (ICH) Harmonised Tripartite 
Guideline for GCP. Each investigator will conduct the trial 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 trial, 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 
because of privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the trial (ie, before shipment of the sponsor-supplied drug or trial-specific 
screening activity). The IRB or IEC approval must refer to the trial by exact protocol title, number, 
and version date; identify versions of other documents (eg, informed consent form) reviewed; and 
state the approval date. The sponsor will ship drug/notify site once the sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the trial. Until the site receives drug/notification no 
protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the trial at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the trial. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the trial, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor before use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the trial, and (2) decide whether or not to participate in the trial. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the trial, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the trial. The subject or the subject’s legally acceptable 
representative should be instructed to sign using their legal names, not nicknames, using blue or 
black ballpoint ink. The investigator must also sign and date the informed consent form and 
subject authorization (if applicable) at the time of consent and before subject entering into the trial; 
however, the sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time before analysis. Notify the 
sponsor of consent withdrawal.
13.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this trial, a subject’s source data will only be linked to the 
sponsor’s clinical trial database or documentation via a unique identification number. As permitted 
by all applicable laws and regulations, limited subject attributes, such as sex, age, or date of birth, 
and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s trial participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
13.4
Publication, Disclosure, and Clinical Trial 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 trial. During and after the trial, only the sponsor may make trial 
information available to other trial investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical trial site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or trial results, other 
than trial recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the trial (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 Trial 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 the trial, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for American investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial 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 Trial 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 subject in the trial must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical trial insurance against the risk of injury to trial subjects. Refer to the 
trial site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee.


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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Trial Contact Information 
Contact Type/Role
Contact
SAE and pregnancy reporting
Pharmacovigilance
Takeda Development Center Americas, Inc.
Fax: 224-554-1052


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15.0
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 trial in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of trial subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.10 of this protocol.

Terms outlined in the trial site agreement.

Responsibilities of the Investigator (Appendix A).
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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15.1.1 Trial-Related Responsibilities 
The sponsor will perform all trial-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific trial-related activities 
will perform these activities in full or in partnership with the sponsor.
15.1.2 List of Abbreviations
5-HT4
serotonin type 4
β-hCG
β–human chorionic gonadotropin
AE
adverse event
Aet
amount of drug excreted in urine from time 0 to time t
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUClast
area under the concentration-time curve from time 0 to the last measurable time point.
AUCt
area under the concentration-time curve from time 0 to time t.
AUC∞
area under the concentration-time curve from time 0 to infinity.
BMI
body mass index
CFR
Code of Federal Regulations
CLR
renal clearance
Cmax
maximum observed concentration
CRU
clinical research unit
CV
coefficient of variation
CYP
cytochrome P-450
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
DDI
drug-drug interaction
ECG
electrocardiogram
eCRF
electronic case report form
EFI
enteral feeding intolerance
EMA
European Medicines Agency
fe
fraction of administered dose of drug excreted in urine
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
HR
heart rate
ICH
International Conference on Harmonisation
ICU
intensive care unit
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous


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LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PT
preferred term
QD
once daily
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
t1/2
terminal elimination half-life
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WBC
white blood cell


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16.0
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 World Health Organization Drug Dictionary.
16.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this trial to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical trial database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator using change and modification records of the 
eCRFs. The principal investigator must review the data change for completeness and accuracy, 
and must sign and date. 
eCRFs will be reviewed for completeness and acceptability at the trial site during periodic visits by 
trial monitors. The sponsor or its designee will be permitted to review the subject’s medical and 
hospital records pertinent to the trial to ensure accuracy of the eCRFs. The completed eCRFs are 
the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
16.2
Record Retention
The investigator agrees to keep the records stipulated in Section 16.1 and those documents that 
include (but are not limited to) the trial-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 


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documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 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 trial 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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17.0
REFERENCES
1. Barton RG. Nutrition support in critical illness. American Society for Parenteral and Enteral 
Nutrition 1994;168:659-64.
2. Harrington L. Nutrition in critically ill adults: key processes and outcomes. Crit Care Nurs Clin 
North Am 2004;16(4):459-65.
3. Slone DS. Nutritional support of the critically ill and injured patient. Crit Care Clin 
2004;20(1):135-57.
4. Beattie DT, Armstrong SR, Vickery RG, Tsuruda PR, Campbell CB, Richardson C, et al. The 
Pharmacology of TD-8954, a Potent and Selective 5-HT(4) Receptor Agonist with 
Gastrointestinal Prokinetic Properties. Front Pharmacol 2011;2:25.


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18.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this trial.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the trial 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 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that trial-related procedures, including trial specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the trial are informed of 
these obligations.
6. Secure prior approval of the trial and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the trial to the 
IRB/IEC, and issue a final report within 3 months of trial completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the trial, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
trial. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the trial, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 


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2 years after notification by the sponsor that all investigations have been discontinued or that 
the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the trial involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the trial.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the trial.
9. A description of the possible side effects of the treatment that the subject may receive.
10. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
11. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
12. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
13. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
14. 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.
15. The anticipated prorated payment(s), if any, to the subject for participating in the trial.
16. The anticipated expenses, if any, to the subject for participating in the trial.
17. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
18. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.


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19. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
20. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial.
21. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the sponsor to do so.
22. The foreseeable circumstances or reasons under which the subject’s participation in the trial 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the trial. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the trial medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the trial to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that trial results are 
published.
24. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening, throughout the duration of the trial, and for 5 half-lives plus 90 days after last dose 
of trial medication. 


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25. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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Appendix C
Investigator Consent to 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 trial and/or other clinical studies.

Management, monitoring, inspection, and audit of the trial.

Analysis, review, and verification of the trial results.

Safety reporting and pharmacovigilance relating to the trial.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the trial.

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 trial medication.

Inspections and investigations by regulatory authorities relating to the trial.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of trial records.

Posting investigator site contact information, trial 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.


TAK-954
Study No. TAK-954-1004
Page 62 of 63
Protocol 
03 May 2017
CONFIDENTIAL
Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Female Subjects and Their Male Partners
Female subjects of childbearing potential are excluded from this trial; there are no requirements 
for contraception or pregnancy avoidance.
Male Subjects and Their Female Partners
From signing of informed consent, throughout the duration of the trial, and for 5 half-lives PLUS 
90 days after the last dose of trial drug, nonsterilized** male subjects who are sexually active with 
a female partner of childbearing potential must use barrier contraception (eg, condom with or 
without spermicidal cream or jelly). In addition, they must be advised not to donate sperm during 
this period. Women of childbearing potential who are partners of male subjects are also advised to 
use additional contraception as shown in the list containing highly effective/effective 
contraception below.
** Sterilized males should be at least 1 year post–bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
1. Highly effective methods of contraception are defined as “those, alone or in combination, that 
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and 
correctly). In this trial, where medications and devices containing hormones are included, 
females of childbearing potential who are partners of male subjects are advised to use 
additional contraception chosen from the list below: 

Nonhormonal methods: 
–
Intrauterine device.
–
Bilateral tubal occlusion. 

Hormonal methods: 
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months before the first dose of trial drug.
Oral. 
Intravaginal (eg, ring).
Transdermal. 
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months before the first dose of trial drug.
Oral. 
Injectable.


TAK-954
Study No. TAK-954-1004
Page 63 of 63
Protocol 
03 May 2017
CONFIDENTIAL
Implantable.
2. Since genotoxicity/teratogenicity/embryotoxicity is unlikely to be caused by the 
investigational drug, additional effective methods of contraception (there may be a higher than 
1% failure rate) that may be chosen by the female partner of a male subject are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams).

Progestogen only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action. 
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
4. Male subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy and 
sperm donation during the course of the trial.
5. Male subjects will receive continued guidance with respect to the avoidance of pregnancy and 
sperm donation as part of the trial procedures. Such guidance should include a reminder of the 
following:

Contraceptive requirements of the trial.

Reasons for use of barrier methods (ie, condom) in males with pregnant partners.

Assessment of subject compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit?


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PPD

SAP_001.pdf: 
This may include, but is not limited to, redaction of the following: 


• 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 Fixed Sequence, Open-Label, 2-Period Crossover Trial to Evaluate the Effect of the 
Potent Cytochrome P-450 3A4 Inhibitor Itraconazole on the Pharmacokinetics of TAK-954 in 
Healthy Adult Subjects
NCT Number: NCT03173170
SAP Approve Date: 08 August 2017
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 information or company confidential information. 
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-954-1004
A Fixed Sequence, Open-Label, 2-Period Crossover Trial to Evaluate the Effect of the Potent 
Cytochrome P-450 3A4 Inhibitor Itraconazole on the Pharmacokinetics of TAK-954 in Healthy 
Adult Subjects
PHASE 1
Version: Final
Date: 08 August 2017
Prepared by:
Based on:
Protocol Version: Original
Protocol Date: 03 May 2017
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


TAK-954-1004
Page 2 of 23
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


TAK-954-1004
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Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Study Definitions ...............................................................................................11
7.1.2
Definition of Study Days....................................................................................11
7.1.3
Definition of Study Visit Windows ....................................................................11
7.1.4
Conventions for Missing Adverse Event Dates...................................................11
7.1.5
Conventions for Missing Concomitant Medication Dates...................................11
7.1.6
Conventions for Missing Data............................................................................11
7.2
Analysis Sets ...........................................................................................................12
7.3
Disposition of Subjects ............................................................................................12
7.4
Demographic and Other Baseline Characteristics.....................................................12
7.5
Medical History and Concurrent Medical Conditions...............................................12
7.6
Medication History and Concomitant Medications...................................................13
7.7
Study Drug Exposure and Compliance.....................................................................13
7.8
Efficacy Analysis.....................................................................................................13
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................13
7.9.1
Pharmacokinetic Analysis ..................................................................................13
7.9.2
Pharmacodynamic Analysis ...............................................................................14
7.10
Other Outcomes.......................................................................................................15
7.11
Safety Analysis........................................................................................................15
7.11.1 Adverse Events ..................................................................................................15
7.11.2 Clinical Laboratory Evaluations .........................................................................16
7.11.3 Vital Signs .........................................................................................................16


TAK-954-1004
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Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
7.11.4 12-Lead ECGs ...................................................................................................17
7.11.5 Other Observations Related to Safety.................................................................17
7.12
Interim Analysis ......................................................................................................17
7.13
Changes in the Statistical Analysis Plan...................................................................17
8.0
REFERENCES..............................................................................................................18
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................19
Appendix B
Criteria for Identification of Markedly Abnormal Laboratory Values .................21
Appendix C
Criteria for Markedly Abnormal Vital Signs.......................................................22
Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters..........23


TAK-954-1004
Page 5 of 23
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
3.0
LIST OF ABBREVIATIONS
5-HT4
serotonin type 4
β-hCG
β–human chorionic gonadotropin
AE
adverse event
Aet
amount of drug excreted in urine from time 0 to time t
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUClast
area under the concentration-time curve from time 0 to the last measurable time 
point.
AUCt
area under the concentration-time curve from time 0 to time t.
AUC∞
area under the concentration-time curve from time 0 to infinity.
BMI
body mass index
CFR
Code of Federal Regulations
CLR
renal clearance
Cmax
maximum observed concentration
CRU
clinical research unit
CV
coefficient of variation
CYP
cytochrome P-450
DBP
diastolic blood pressure
DNA
deoxyribonucleic acid
DDI
drug-drug interaction
ECG
electrocardiogram
eCRF
electronic case report form
EFI
enteral feeding intolerance
EMA
European Medicines Agency
fe
fraction of administered dose of drug excreted in urine
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
HR
heart rate
ICH
International Conference on Harmonisation
ICU
intensive care unit
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose


TAK-954-1004
Page 6 of 23
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
PGx
pharmacogenomics
PK
pharmacokinetic(s)
PT
preferred term
QD
once daily
QTcF
QT interval with Fridericia correction method
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
t1/2
terminal elimination half-life
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WBC
white blood cell


TAK-954-1004
Page 7 of 23
Statistical Analysis Plan
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CONFIDENTIAL
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective of the trial is to evaluate the effect of the potent CYP3A4 inhibitor 
itraconazole on the single-dose PK of TAK-954.
4.2
Secondary Objectives
The secondary objectives of the trial are to evaluate the safety of single-dose IV doses of 
TAK-954 in the presence and absence of a potent CYP3A4 inhibitor.
4.3
Exploratory Objectives
Exploratory objectives of this trial include:
4.4
Study Design
This is a phase 1, single-sequence, open-label, 2-period crossover trial in approximately 10 
healthy male and female (non–childbearing potential) subjects. The trial is designed to 
investigate the effect of a potent CYP3A4 inhibitor (itraconazole) on the PK of TAK-954. 
TAK-954 0.2 mg will be administered as a single 60-minute IV infusion. 
The trial will include a Screening Visit, Trial Period 1 (6 days), a washout (a minimum of 7 days 
between doses in Period 1 Day 1 and Period 2 Day 1), Trial Period 2 (9 days), and a Follow-up 
Visit. 
On Day 1 of Trial Period 1 subjects will receive a 0.2 mg single-dose TAK-954 IV on this day 
and on Day 4 of Trial Period 2 at approximately the same time (between 0600 and 0900). In 
Trial Period 2, subjects will receive 200 mg QD itraconazole orally on Days 1 to 8 at 
approximately the same time (between 0600 and 0900). Itraconazole will be administered as 2 x 
100 mg capsules.
Blood samples for assessment of TAK-954 concentrations will be collected before each dose of 
TAK-954 and at intervals up to 120 hours after the last dose of trial drug in each trial period. 
Samples may be assayed for TAK-954 metabolites. TAK-954 and its metabolites will also be 
assayed in urine, data permitting and if deemed possible. 
Whole blood samples for DNA PGx analysis and RNA isolation will be collected predose on 
Day 1of Trial Period 1.
Safety will be assessed by monitoring for AEs, ECGs, vital signs, safety laboratory tests, and 
physical examinations throughout each dosing period.
CCI


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Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
After completion of the trial (or after subject withdrawal), all subjects will return for a Follow-up 
Visit, approximately 10 to 14 days after their last dose of trial drug.
CCI


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Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
5.0
ANALYSIS ENDPOINTS
The primary endpoint of the trial is the following PK parameters on Day 1 of Trial Period 1 and 
Day 4 of Trial Period 2:
!
Maximum observed concentration (Cmax).
!
Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞).
Safety endpoints include the following:
Safety and tolerability will be assessed through physical examinations, ECGs, vital signs, and 
laboratory assessments, and collection of spontaneous AEs.
Exploratory endpoints will be assessed through the following parameters:
PK parameters:
Pharmacodynamic parameters:
CCI
CCI


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Page 10 of 23
Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
6.0
DETERMINATION OF SAMPLE SIZE
Approximately 10 subjects will complete this trial. With this sample size, a 2-sided 95.0% CI for 
the geometric mean ratio of Cmax for TAK-954 when administered with and without 
itraconazole will have 90% probability of excluding 1.25 (the upper bound of the bioequivalence 
range) if itraconazole increases the Cmax for TAK-954 by at least 50%. This calculation 
assumes that the CI is based on the t statistic, that the distance from the mean to the lower bound 
of the CI on the natural-log scale is 0.182, and that the true SD of differences on the natural-log 
scale is 0.187 as estimated from Cmax values reported for Cohort 1 in Theravance Protocol No. 
0095. Assuming the intrasubject variation observed for area under the concentration-time curve 
from time 0 to time t in that cohort (SD=0.129), a 2-sided 95.0% CI for the geometric mean ratio 
of AUC∞for TAK-954 when administered with and without itraconazole will have greater than 
99% probability of excluding 1.25 if itraconazole increases AUC∞for TAK-954 by at least 50%.
Subjects who drop out may be replaced at the discretion of the sponsor in consultation with the 
investigator. Subjects who replace dropouts will begin the trial as a new subject in Trial Period 1.


TAK-954-1004
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Continuous data will be summarized using descriptive statistics, including the number of 
subjects, mean, standard deviation (SD), median, minimum, and maximum. The coefficient of 
variation (%CV) and geometric mean will be included in the summary of continuous data where 
indicated. Categorical data will be summarized as the number and percentage of subjects in each 
category.
Arithmetic means, geometric means, and medians will be presented to 1 more decimal place than 
the recorded data, and SDs will be presented to 2 more decimal places than the recorded data, 
where appropriate. Where applicable, confidence intervals about a parameter estimate will be 
presented using the same number of decimal places as the parameter estimate and p-values will 
be rounded to 3 decimal places prior to assessment of statistical significance.
All study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings. In addition, the actual day relative to the first dose will be presented, where applicable.
All statistical analyses will be performed using the SAS System® Version 9.4.
7.1.1
Study Definitions
There are no study-specific definitions.
7.1.2
Definition of Study Days
Study Day 1 is defined as the date of the first dose of study drug, as recorded on the electronic 
case report form (eCRF) dosing page. Other study days are defined relative to Study Day 1, with 
Day 1 being Study Day 1 and Day -1 being the day prior to Study Day 1. Study days prior to the 
first dose of study drug will be calculated as: {date of assessment/event – date of first dose of 
study drug}. Study days on or after the first dose of study drug will be calculated as: {date of 
assessment/event – date of first dose of study drug + 1}.
7.1.3
Definition of Study Visit Windows
There will be no visit windowing.
7.1.4
Conventions for Missing Adverse Event Dates
There will be no imputation of incomplete or missing adverse event dates.
7.1.5
Conventions for Missing Concomitant Medication Dates
There will be no imputation of incomplete or missing concomitant medication dates.
7.1.6
Conventions for Missing Data
There will be no imputation of incomplete or missing data. 


TAK-954-1004
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Statistical Analysis Plan
08 August 2017
CONFIDENTIAL
Plasma concentrations that are below the lower limit of quantification (< LLOQ) will be treated 
as zero in the summarization of concentration values and derivation of PK parameters.
7.2
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data:

Safety Analysis Set: The safety analysis set will consist of all subjects who are randomized
and received at least 1 dose of study drug. Subjects in this analysis set will be used for 
demographic, baseline characteristics, and safety summaries.

Pharmacokinetic Set: The PK set will consist of all subjects who received at least 1 dose of 
study drug and have at least 1 measurable plasma concentration.
If any subjects are found to be noncompliant in dosing schedule or with incomplete data, a 
decision will be made on a case-by-case basis as to their inclusion in the analysis but will be 
presented in the subject listings.
Number of subjects in each analysis set will be tabulated. 
7.3
Disposition of Subjects
Study Information, including date of first subject signing Informed Consent Form (ICF), date of 
first/last study drug, date of last subject’s last visit/contact, date of last subject’s last procedure 
for collection of data for primary endpoint, Medical Dictionary for Drug Regulatory Activities 
(MedDRA) Version, World Health Organization Drug Dictionary (WHODrug) Version, and 
SAS Version, will be tabulated.
The eligibility of subjects will be summarized, along with the primary reasons of screen failure 
as recorded in eCRF.
Disposition of all enrolled subjects will be tabulated. Categories will include:

Subjects who completed the study 

Subjects who prematurely discontinued study 
Primary reasons for discontinuing study, as entered on the eCRF will be tabulated. 
7.4
Demographic and Other Baseline Characteristics
Demographic and study baseline characteristics, including age at informed consent, gender, 
ethnicity, race, height (cm), weight (kg) and body mass index (kg/m2), will be summarized. 
There will be no inferential analysis of demographic and baseline characteristics.
7.5
Medical History and Concurrent Medical Conditions
Medical history is defined as significant conditions or diseases that resolved at or prior to the 
time of informed consent. Concurrent medical conditions are defined as significant conditions or 
diseases that are present at signing of informed consent.


TAK-954-1004
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Statistical Analysis Plan
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CONFIDENTIAL
Medical history and concurrent medical conditions will be coded using the MedDRA coding 
system.
Medical history and concurrent medical conditions will be listed by site and subject number.
There will be no summary or inferential analysis of medical history and concurrent medical 
conditions.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 28 days prior to signing of informed consent. Concomitant medication is any drug 
given in addition to the study drug, taken at any time from signing of informed consent through 
the end of study.
Medication history and concomitant medications will be coded using the WHODrug.
Listings for medication history and concomitant medications will be produced by site and subject 
number. 
There will be no summary or inferential analysis of medication history and concomitant 
medications.
7.7
Study Drug Exposure and Compliance
All doses of study medication will be at the clinc. Dosing data, including dosing time will be 
provided by subject and visit in the listings.
Daily meals during confinement in each period will be reported in the data listings.
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Blood samples for PK analysis of TAK-954 are obtained relative to the dose on Day 1 of Period 
1 and Day 4 of Period 2 at the following times: predose (within 30 minutes), and 0.33, 0.5, 0.67, 
1 (just after the end of infusion), 1.5, 2, 3, 4, 6, 12, 24, 36, 48, 72, 96, and 120 hours postdose 
(relative to TAK-954 start of infusion).
The concentration of TAK-954 (and metabolites THRX-513466 and THRX-913682) in plasma 
will be summarized by regimen over each scheduled sampling time point using descriptive 
statistics (arithmetic mean, SD, CV%, median, minimum and maximum). Individual plasma
concentration data versus time will be presented in a data listing.
In addition, the figures for mean plasma concentrations of TAK-954 (and any measured 
metabolites) versus time (linear and semi-log scale) will be generated. 


TAK-954-1004
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Statistical Analysis Plan
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CONFIDENTIAL
Urine is collected at predose, 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours relative to TAK-954 
infusion start in Trial Periods 1 and 2. The amount of TAK-954 (and any measured metabolites) 
recovered in urine will be summarized by regimen over each scheduled sampling interval using 
descriptive statistics (arithmetic mean, SD, CV%, median, minimum and maximum). Individual 
urine collection information including volume, concentration, and amount recovered will be 
presented in a data listing.
The plasma PK parameters determined are Cmax, AUC∞, AUClast, t1/2, CL, and Vz. The ratio of 
metabolite parameter to TAK-954 parameter will also be determined for Cmax and AUC. The 
urinary PK parameters determined are Aet, fe, and CLr. Descriptive statistics (N, mean, SD, 
CV%, median, minimum and maximum) will be used to summarize the PK parameters for
TAK-954 (and metabolites THRX-513466 and THRX-913682) by regimen. In addition, 
geometric mean will be computed for Cmax and AUC parameters. Additional plasma and/or 
urine PK parameters may be calculated if necessary, in accordance with the Clinical
Pharmacology Analysis Plan (CPAP). All pharmacokinetic parameters calculated will be 
provided in a data listing.
Box plots for Cmax and AUC∞will be generated by regimen.
For evaluation of potential effect of itraconazole on TAK-954 PK, paired t-tests and associated 
CIs will be determined on the natural logarithms of Cmax and area under the concentration-time 
curve (AUC∞and AUClast) to assess the exposure between regimens (TAK-954 alone and 
TAK-954 with itraconazole). This paired t-test (one-sample t-test) will be performed on the 
differences (TAK-954 with itraconazole minus TAK-954 alone) of the natural logarithm 
transformed parameters for the two regimens. The relative bioavailability estimate and the 90% 
confidence intervals for relative bioavailability will be obtained by exponentiating the estimated 
difference and the 90% confidence intervals for the estimated difference between regimens in the 
log-transformed parameters. 
Additional analyses may be performed if appropriate.
7.9.2
Pharmacodynamic Analysis
CCI


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7.10
Other Outcomes
Not Applicable.
7.11
Safety Analysis
Safety analyses include adverse events (AEs), clinical laboratory parameters, vital sign 
parameters, and 12-lead electrocardiogram (ECG) results.
All summaries of safety data are based on subjects in the Safety Analysis Set. 
7.11.1 Adverse Events
A treatment -emergent adverse event (TEAE) will be defined as an AE or serious adverse event 
(SAE) that started or worsened after first study drug administration and within 30 days of last 
dose of study drug (onset date – date of last dose + 1 ≤30). A TEAE will be attributed to a 
regimen if the TEAE occurs after administration of the study drug in a period and up to just prior 
to study drug administration in the next period. A TEAE that occurs after administration of the 
study drug in the last period and up to 30 days after the last study drug dose is attributed to the 
regimen received in the last period. All AE verbatim terms will be coded by system organ class
(SOC) and preferred term using (PT) the MedDRA coding system.
TEAEs will be summarized by regimen (TAK-954 alone, itraconazole alone, and TAK-954 with 
itraconazole) and overall. The tables will include the number and percentage (N [%]) of subjects 
reporting any event for that term. The following TEAE tables will be summarized. 
–
Overview of TEAEs.
–
TEAEs by SOC and PT at subject and event level.
–
Subject Mappings for TEAEs.
–
TEAEs by PT.
–
Relationship of TEAEs to Study Drug by SOC and PT.
–
Drug-Related TEAEs by SOC and PT.
–
Severity of TEAEs by SOC and PT.
–
Severity of Drug-Related TEAEs by SOC and PT.
In addition, pretreatment events (PTEs) will be summarized overall by SOC and PT.
For each regimen and overall, subjects reporting more than one occurrence for a term (SOC or 
PT) being summarized will be counted only once using the most extreme incident (most severe 
for the severity tables and related for the relationship to study drug tables).
Data listings will be provided for all TEAEs, PTEs, TEAEs that led to study discontinuation, 
TEAEs that led to abnormal liver functions, SAEs, AEs that resulted in death, and AEs occurring 
more than 30 days after the last dose of study medication.


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CONFIDENTIAL
7.11.2 Clinical Laboratory Evaluations
Clinical safety laboratory tests for this study are listed below. The schedule of clinical laboratory 
collections is presented in Appendix A.
Individual results for hematology and chemistry laboratory tests that meet the Takeda predefined 
laboratory markedly abnormal value (MAV) criteria in Appendix B will be presented in a data 
listing. If a subject has a MAV for a particular laboratory test, all visits for that subject for that 
parameter will be listed. 
All clinical laboratory data will be presented in both SI and conventional units in the data 
listings. Laboratory data outside of the normal reference range will be listed. Out of normal 
range values and MAVs will be flagged in data listings.
7.11.3 Vital Signs
Vital sign measurements include body temperature, pulse, respiratory rate, and blood pressure.
Refer to Appendix A for scheduled vital signs measurement visits.


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Statistical Analysis Plan
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CONFIDENTIAL
Individual results for vital sign measurements that meet the Takeda predefined vital signs MAV 
criteria in Appendix C will be presented in a data listing. If a subject has a MAV for a particular 
vital sign parameter, all visits for that subject for that parameter will be listed. 
All vital sign data will be presented in the listings. Vital sign MAVs will be flagged in the 
listings.
7.11.4 12-Lead ECGs
The scheduled 12-lead ECG data will be collected according to Appendix A. The ECG 
parameters include heart rate, PR interval, QRS interval, QT interval, and QTc interval 
(Fredericia’s correction).
Individual results for 12-lead ECG measurements that meet the Takeda predefined 12-lead ECG 
MAV criteria in Appendix D will be presented in a data listing. If a subject has a MAV for a 
particular ECG parameter, all visits for that subject for that parameter will be listed. 
All ECG data will be presented in the listings. ECG MAVs will be flagged in the listings.
7.11.5 Other Observations Related to Safety
Physical examination information will be presented in the listings. No summary tables will be 
provided.
All cases of overdose will be listed.
7.12
Interim Analysis
Not applicable. 
7.13
Changes in the Statistical Analysis Plan 
None.


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Statistical Analysis Plan
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8.0
REFERENCES


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Statistical Analysis Plan
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Appendix A
Schedule of Study Procedures


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Statistical Analysis Plan
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Appendix A
Schedule of Study Procedures (continued)


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Appendix B
Criteria for Identification of Markedly Abnormal Laboratory Values 
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
< 0.8 × LLN
> 1.2 × ULN
Hematocrit
Both
< 0.8 × LLN
> 1.2 × ULN
RBC count 
Both
< 0.8 × LLN 
> 1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
GGT
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
Albumin
Conventional 
<2.5 g/dL
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
>177 mol/L
Blood urea nitrogen
Conventional 
>30 mg/dL
SI
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
SI
<3.0 mmol/L
>6.0 mmol/L
Glucose
Conventional
< 50 mg/dL
>350 mg/dL
SI
< 2.8 mmol/L
>19.4 mmol/L
Chloride
Conventional
< 75 mEq/L
>126 mmol/L
SI
< 75 mmol/L
>126 mmol/L
Bicarbonate
Conventional 
< 8.0 mEq/L
SI
< 8.0 mmol/L
Calcium
Conventional 
< 7.0 mg/dL
>11.5 mg/dL
SI 
< 1.75 mmol/L
>2.88 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of
normal, ULN=upper limit of normal.


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Appendix C
Criteria for Markedly Abnormal Vital Signs
Parameter
Unit
Lower Criteria
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85
>180 
Diastolic blood pressure
mm Hg
<50
>110
Body temperature
oC
< 35.6
>37.7


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Appendix D
Criteria for Markedly Abnormal Values for the 12-Lead ECG Parameters
Parameter
Lower Criteria
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
QT Interval
≤300 milliseconds
≥460 milliseconds
QTcF Interval
≤300 milliseconds
≥500 milliseconds OR 
≥30 milliseconds change from baseline and
≥450 milliseconds
PR
≤120 milliseconds
≥200 milliseconds
QRS
≤60 milliseconds
≥120 milliseconds


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