Clinical trial NCT03500224
Conditions: Healthy Volunteers
Keywords: Drug therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2018-04-30; Completion date: 2018-06-01
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the mass balance, routes of elimination and characterize the metabolic profiles of a single intravenous dose of \[14C\]-TAK-954, identify major circulating and excreted metabolites. This study will also determine the single-dose PK of total radioactivity, TAK-954 and its metabolites where possible.

Detailed description:
The drug being tested in this study is called TAK-954. This study will assess the mass balance, metabolic profiles and routes of elimination of single intravenous dose of \[14C\]-TAK-954, and will determine the major circulating and excreted metabolites and single-dose PK of total radioactivity, TAK-954, THRX513466, and THRX 913682 in healthy male participants.

The study will enroll approximately 6 participants. All participants will receive a single dose of \[14C\]-TAK-954 0.5 mg on Day 1.

This single-center trial will be conducted in Netherlands. The overall time to participate in this study is approximately 6 to 7 weeks. Participants will make a final visit to the clinic 15 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: \[14C\]-TAK-954 0.5 milligram (mg), (containing approximately 1.5 microcurie \[µCi\] of radioactive tracer), administered as 60-minute infusion, intravenously, once on Day 1.
Interventions: intervention 1: [14C]-TAK-954
Intervention descriptions: intervention 1: \[14C\]-TAK-954 intravenous infusion.

Protocol documents:
Prot_000.pdf: 


•
Title: A Phase 1, Open-label, Single Intravenous Infusion Dose Study to Evaluate the Mass
Balance, Pharmacokinetics, Metabolism, and Excretion of TAK-954 Containing
Microtracer ([14C]-TAK-954) in Healthy Adult Male Subjects
NCT Number: NCT03500224
Protocol Approve Date: 26 March 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Open-label, Single Intravenous Infusion Dose Study to Evaluate the Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of TAK-954 Containing 
Microtracer ([14C]-TAK-954) in Healthy Adult Male Subjects
Study Identifier:
TAK-954-1005
Compound:
TAK-954
Date:
26 March 2018
Version/Amendment 
Number:
Initial
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 study.


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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC....................................................................................................9
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................10
4.0
INTRODUCTION.........................................................................................................13
4.1
Background .............................................................................................................13
4.2
Rationale for the Proposed Study.............................................................................14
4.3
Benefit-Risk Profile .................................................................................................14
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................15
5.1
Trial Objectives .......................................................................................................15
5.1.1
Trial Primary Objectives ....................................................................................15
5.1.2
Trial Secondary Objective..................................................................................15
5.2
Endpoints.................................................................................................................15
5.2.1
Primary Endpoints .............................................................................................15
5.2.2
Secondary Endpoints..........................................................................................16
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................17
6.1
Trial Design.............................................................................................................17
6.2
Rationale for Trial Design, Dose, and Endpoints......................................................17
6.2.1
Rationale for Trial Design..................................................................................17
6.2.2
Rationale for Dose .............................................................................................18
6.2.3
Rationale for Subject Population........................................................................18
6.2.4
Rationale for Endpoints......................................................................................18
6.2.5
Critical Procedures Based on Trial Objectives: Timing of Procedures ................18
6.3
Trial Design/Dosing/Procedure Modifications Permitted Within Protocol 
Parameters...............................................................................................................18
6.4
Trial Beginning and End/Completion.......................................................................19
6.4.1
Definition of Beginning of the Trial ...................................................................19
6.4.2
Definition of End of the Trial.............................................................................19
6.4.3
Definition of Trial Completion...........................................................................19
6.4.4
Definition of Trial Discontinuation ....................................................................19
6.4.5
Criteria for Premature Termination or Suspension of the Trial............................20
6.4.6
Criteria for Premature Termination or Suspension of a Site................................20
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............21
7.1
Inclusion Criteria .....................................................................................................21
7.2
Exclusion Criteria ....................................................................................................21


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7.3
Excluded Medications, Supplements, Dietary Products............................................22
7.3.1
Concomitant Medications...................................................................................22
7.3.2
Fruit Juice ..........................................................................................................23
7.3.3
Alcohol..............................................................................................................23
7.3.4
Caffeine .............................................................................................................23
7.3.5
Smoking ............................................................................................................23
7.4
Diet, Fluid, and Activity ..........................................................................................23
7.4.1
Diet and Fluid ....................................................................................................23
7.4.2
Activity..............................................................................................................23
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................24
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................24
7.7
Subject Replacement................................................................................................24
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................25
8.1
Clinical Study Drug .................................................................................................25
8.1.1
Clinical Study Drug Labeling.............................................................................25
8.1.2
Clinical Study Drug Inventory and Storage ........................................................25
8.1.3
Clinical Study Drug Blinding.............................................................................25
8.1.4
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................25
8.1.5
Accountability and Destruction of sponsor-Supplied Drugs................................25
9.0
STUDY PROCEDURES...............................................................................................26
9.1
Administrative Procedures.......................................................................................26
9.1.1
Informed Consent Procedure..............................................................................26
9.1.2
Inclusion and Exclusion .....................................................................................26
9.1.3
Medical History/Demography ............................................................................26
9.1.4
Concomitant Medications...................................................................................26
9.2
Clinical Procedures and Assessments.......................................................................27
9.2.1
Full Physical Exam ............................................................................................27
9.2.2
Height and Weight .............................................................................................27
9.2.3
BMI ...................................................................................................................27
9.2.4
Vital Signs .........................................................................................................27
9.2.5
12-Lead ECG.....................................................................................................27
9.2.6
Study Drug Administration ................................................................................28
9.2.7
AE Monitoring...................................................................................................28
9.2.8
Laboratory Procedures and Assessments ............................................................28
9.3
PK Samples .............................................................................................................30


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9.3.1
PK Evaluations ..................................................................................................31
9.3.2
Confinement ......................................................................................................33
10.0
ADVERSE EVENTS ....................................................................................................34
10.1
Definitions and Elements of AEs .............................................................................34
10.1.1 SAEs..................................................................................................................36
10.2
AE Procedures.........................................................................................................36
10.2.1 Assigning Severity/Intensity of AEs...................................................................36
10.2.2 Assigning Causality of AEs................................................................................37
10.2.3 Start Date...........................................................................................................37
10.2.4 End Date............................................................................................................37
10.2.5 Pattern of AE (Frequency) .................................................................................37
10.2.6 Action Taken With Study Treatment..................................................................37
10.2.7 Outcome ............................................................................................................37
10.2.8 Collection and Reporting of AEs, SAEs, and Abnormal LFTs............................38
10.2.9 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 Demography and Other Baseline Characteristics .............................41
11.1.3 PK and Radioactivity Analysis...........................................................................41
11.1.4 Safety Analysis ..................................................................................................42
11.2
Interim Analysis and Criteria for Early Termination ................................................42
11.3
Determination of Sample Size..................................................................................42
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................43
12.1
Study-Site Monitoring Visits ...................................................................................43
12.2
Protocol Deviations..................................................................................................43
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................43
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................44
13.1
IRB/IEC Approval...................................................................................................44
13.2
Subject Information, Informed Consent, and Subject Authorization .........................44
13.3
Subject Confidentiality ............................................................................................45
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................46
13.4.1 Publication and Disclosure.................................................................................46
13.4.2 Clinical Trial Registration..................................................................................46
13.4.3 Clinical Trial Results Disclosure ........................................................................47


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13.5
Insurance and Compensation for Injury....................................................................47
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................48
14.1
Administrative Information......................................................................................48
14.1.1 Investigator Agreement......................................................................................49
14.1.2 List of Abbreviations .........................................................................................49
15.0
DATA HANDLING AND RECORDKEEPING............................................................51
15.1
CRFs (Electronic and Paper)....................................................................................51
15.2
Record Retention .....................................................................................................51
16.0
REFERENCES..............................................................................................................53
17.0
APPENDICES...............................................................................................................54
LIST OF IN-TEXT TABLES
Table 9.a
Primary Specimen Collections ...........................................................................31
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................54
Appendix B
Elements of the Subject Informed Consent.........................................................56
Appendix C
Investigator Consent to the Use of Personal Information ....................................58


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1.0
STUDY SUMMARY
Name of sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of 
Takeda Pharmaceutical Company Limited
Please note: Millennium Pharmaceuticals, Inc, a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited, may be 
referred to in this protocol as “Millennium,” “sponsor,” or 
“Takeda”.
Compound:
TAK-954
Study Identifier: TAK-954-1005
Phase: 1
Protocol Title: A Phase 1, Open-label, Single Intravenous Infusion Dose Study to Evaluate the Mass Balance, 
Pharmacokinetics, Metabolism, and Excretion of TAK-954 Containing Microtracer ([14C]-TAK-954) in Healthy 
Adult Male Subjects
Trial Design: 
This is a phase 1, open-label study in 6 healthy male subjects. The study will include a screening visit, a treatment 
period, and a follow-up period. At least 6 subjects will be dosed in the study. 
Subjects will complete the screening visit within approximately 28 days before study drug administration. 
Eligible subjects will be enrolled into the study and will receive a single 60-minute intravenous (IV) infusion of 0.5 mg 
TAK-954 containing a microtracer of [14C]-TAK-954 (~1.5 μCi). 
Subjects will be confined from admission for a minimum of 7 days. If the recovery of radioactivity has not met the 
target conditions specified below, a subject’s duration of confinement may be maximally extended to Day 15 (336 
hours postdose). Should the duration of confinement be extended, clinical assessments planned at discharge will be 
rescheduled accordingly. 
An individual subject will be discharged from the clinic when at least 1 of the following criteria has been met for that 
subject: 
1.
≥90% of the administered radioactivity has been recovered in excreta.
2.
Excreta samples from 2 consecutive days contain <1% of the administered radioactivity. 
Safety will be assessed by monitoring for adverse events (AEs), vital signs, electrocardiograms (ECGs), clinical 
laboratory results, and physical examinations.
Trial Primary Objective:
The primary objectives of the study are:

To determine the mass balance and routes of elimination of a single IV dose of TAK-954 containing microtracer 
([14C]-TAK-954).

To characterize the metabolic profiles following single-dose IV administration of TAK-954 containing 
microtracer ([14C]-TAK-954) and identify major circulating and excreted metabolites.

To determine the single-dose pharmacokinetics (PK) of total radioactivity, TAK-954, THRX513466, and THRX 
913682, where possible.
Secondary Objectives:
The secondary objective of the study is to evaluate the safety and tolerability of a single IV dose of TAK-954 
containing microtracer ([14C]-TAK-954) in healthy male subjects.
Trial Subject Population: Healthy male subjects, aged 18 to 55 years, inclusive.
Planned Number of Subjects:
At least 6 subjects
Planned Number of Sites:
1 site


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Dose Level:
0.5 mg TAK-954 IV containing a microtracer of 
[14C]-TAK-954 (~1.5 μCi).
Route of Administration:
IV
Duration of Treatment:
Single dose
Planned Trial Duration:
Up to approximately 6 to 7 weeks
Main Criteria for Inclusion:
To be eligible for study participation, subjects must: 

Be a man aged 18 to 55 years, inclusive, at the screening visit. 

Have a body mass index ≥18 and ≤30 kg/m2 and a body weight >50 kg at the screening visit.

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.

Be judged to be in good health by the investigator on the basis of 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.

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, 
from the first dose of study drug until 30 days after the last dose of study drug. No restrictions are required for 
a vasectomized male subject provided that the subject is at least 1 year postbilateral vasectomy procedure 
before the first dose of study drug. A male subject whose vasectomy procedure was performed less than 1 
year before the first dose of study drug must follow the same restrictions as a nonvasectomized man. 
Appropriate documentation of surgical procedure should be provided. 
–
Is a male subject who agrees to not donate sperm from trial drug administration on the first day of the first 
dose until 30 days after the last dose of study drug.
Main Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject: 

Has participated in another investigational trial within 4 weeks (or based on local regulations) before the pretrial 
visit (screening). This window will be derived from the date of the last trial procedure or AE related to the trial 
procedure in the previous trial to the pretrial/screening visit of the current trial. 

Has total 14C radioactivity measured by accelerator mass spectrometry in plasma (during screening) exceeding 
14C/12C ratio 1.1E-12.

Participated in any study with a radiation dose above 0.1 MBq or radiation burden above 0.1 mSv within 1 year 
before screening.

Was exposed to significant radiation (eg, serial x-ray or computed tomography scans, barium meal, current 
employment in a job requiring radiation exposure monitoring) within 12 months before check-in.

Irregular defecation pattern (less than once per 2 days).
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study are:
1.
Percentage of administered radioactive dose recovered in urine and feces and cumulative recovery in urine and 
feces combined. 
2.
TAK-954 and metabolites (if any) expressed as a percentage of total radioactivity in plasma and as a percentage of
dose in urine and in feces.
3.
Concentration of total radioactivity in whole blood and plasma.
4.
PK parameters to describe the single-dose PK, postdose on Day 1, for a) total radioactivity in whole blood and 
plasma, b) TAK-954 in plasma, c) THRX513466 and THRX 913682 in plasma (where possible):


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–
Maximum observed concentration (Cmax).
–
Area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast).
–
Area under the concentration-time curve from time 0 to infinity (AUC∞).
–
Time of first occurrence of Cmax (tmax).
–
t1/2z.
–
Total clearance after IV administration (TAK-954 only).
–
Volume of distribution during the terminal disposition phase after IV administration (Vz) (TAK-954 only).
–
Amount of total radioactivity and TAK-954 excreted in urine and radioactivity only for feces from 0 to time 
t (Aet).
–
Fraction of TAK-954 dose and total radioactivity excreted in urine and radioactivity only for feces from time 
0 to time t (fet).
Secondary endpoints include: 
1.
The ratio of total radioactivity in whole blood and plasma.
2.
The ratio of plasma TAK-954 to total radioactivity in plasma.
3.
Safety: 
–
Percentage of subjects who experience at least 1 treatment-emergent AE.
–
Percentage of subjects who discontinue because of an AE.
Statistical Considerations:
Concentration Data:
Plasma concentration of TAK-954 and its metabolites and total radioactivity in whole blood and plasma at each 
scheduled timepoint will be summarized using descriptive statistics. Mass balance will be assessed by the percentage
and cumulative percentage of administered radioactive dose recovered in urine and in feces and their combined total at 
appropriate intervals. Descriptive statistics will be used.
Mean and individual cumulative excretion of radioactivity in urine and in feces and their combined total by time curve 
will be displayed.
Individual percentage and cumulative percentage will be presented in data listings. 
All concentration data will be listed.
PK:
Descriptive statistics will be used to summarize the PK parameters. All PK parameter data will be listed. Statistical 
analyses will be performed if appropriate. 
Circulatory and excretory metabolite profiles will be established for each subject. Metabolites will be presented as a 
mean percentage of total radioactivity and/or dose. Descriptive statistics will be used.
Sample Size Justification:
The sample size (n = 6) is based on the consideration that radioactivity is being administered to healthy subjects and 
that generally 6 subjects is sufficient to characterize the endpoints described in the protocol and is accepted by 
regulatory agencies.


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2.0
STUDY SCHEMATIC
Abbreviation: IV, intravenous.


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3.0
SCHEDULE OF STUDY PROCEDURES 
Assessment
Screening
Trial Days
Follow-up/
Early 
Termination
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9-15
Day 15 
±2 Days 
Hours Postdose
0
24
48
72
96
120
144
168
192-336
Administrative Procedures
Informed consent 
X
Inclusion/exclusion criteria
X
X
Medication history
X
Prior and concomitant medication 
review
----------------------------------------------Continuous monitoring-------------------------------------------------
Clinic Procedures/Assessments
Full physical exam
X
X a
X
Semirecumbent vital signs (heart rate, 
systolic blood pressure, and diastolic 
blood pressure)
X
X b
X
X
Vital signs (respiratory rate and oral or 
tympanic temperature)
X
X b
X
Height
X
Weight 
X
X
Body mass index
X
Standard 12-lead electrocardiogram
X
X b
X
X
Adverse event monitoring
--------------------------------------------------------Continuous monitoring-------------------------------------------------
Laboratory Procedures/Assessments
Serum chemistry
X
X a
X
Hematology
X
X a
X
Urinalysis
X
X a
X
Urine drug screen
X
X a
Alcohol screen
X
X a
HIV test
X


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Assessment
Screening
Trial Days
Follow-up/
Early 
Termination
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9-15
Day 15 
±2 Days 
Hours Postdose
0
24
48
72
96
120
144
168
192-336
Hepatitis panel
X
Pharmacokinetics (PK) Evaluations
Blood collection for total radioactivity 
in whole blood and plasma, TAK-954 
in plasma, and metabolite profiling c
X----------------------------------------------------------------------------------X
Urine collection for total radioactivity, 
TAK-954 concentrations, and 
metabolite profiling d
X
X---------------------------------------------------------------------------------X
Emesis e
X
Feces collection for total radioactivity 
and metabolite profiling f
X
X---------------------------------------------------------------------------------X 
Total 14C radioactivity measured by 
accelerator mass spectrometry (AMS) 
in plasma.
X
Drug Administration
[14C]-TAK-954 dosing
X
Other
Confinement
X
X
X
X
X
X
X
X
X g
X g
a Within 24 hours before dosing on Day 1. 
b Assessments predose (between waking up and the start of the infusion) and at the end of the infusion.
c PK blood samples (for total radioactivity in whole blood and plasma and TAK-954 in plasma) are collected predose (within 30 minutes) and at 0.5, 1 (at end of 
infusion), 1.5, 2, 3, 4, 6, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose and every 24 hours thereafter while the subject is confined. Blood samples for 
metabolite profiling will be collected predose and at 1 (at end of infusion), 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose and every 24 hours thereafter 
while the subject is confined.
d Urine will be collected predose (spot sample -12 to 0 hours) and at 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours and every 24 hours 
thereafter while the subject is confined.
e If emesis occurs within 8-10 hours after dosing, vomitus will be collected in a preweighed container assigned to each subject, reweighed, and submitted for 
analysis of total radioactivity.
f Feces will be collected predose (last stool before dosing), and all samples produced up to at least 168 hours postdose (to be pooled in 24-hour intervals) and every 


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24 hours thereafter will be collected while the subject is confined.
g Subjects will be confined only if requirements for discharge are not met.


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4.0
INTRODUCTION
4.1
Background
TAK-954 is a small molecule, highly selective serotonin subtype 4 agonist being investigated for 
potential use in the treatment of gastrointestinal motility disorders. Takeda is developing TAK-954 
for the treatment of reduced gastrointestinal motility, particularly in settings where an intravenous 
(IV) formulation is advantageous, such as critically ill patients within intensive care units who 
develop intolerance of enteral feeding support.
Nonclinical mass-balance studies in rats and dogs after 0.5 mg/kg IV dosing of [14C]-TAK-954 
(carbon-14-TAK-954) indicate that radioactivity was predominantly excreted in the feces (66.2% 
in rats and 79.4% in dogs), with urinary excretion being lower (32.7% in rats and 14.4% in dogs). 
The biliary excretion in rats constituted 40.4% of the IV dose. 
TAK-954 was relatively stable when incubated in cryopreserved rat, dog, and human hepatocytes, 
with half-lives of 5.8, 8.8, and >17 hours, respectively. Furthermore, 2 active metabolites 
identified nonclinically (THRX513466 and THRX913682), were observed clinically following 
oral dosing, but mean maximum observed concentration (Cmax) and area under the 
concentration-time curve from time 0 to 48 hours metabolite-to-parent ratios ranged from 0.0008 
to 0.004. Renal excretion of these metabolites was also low, with concentrations in urine generally 
being below the limit of detection. 
TAK-954 has been investigated in healthy subjects at single oral doses from 0.1 to 20 mg 
(maximum tolerated dose [MTD] 10 mg), multiple oral doses from 0.2 to 10 mg once daily (QD) 
for 10 days (MTD 5 mg), 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. After multiple IV infusion dosing in healthy subjects (0.1 and 0.5 mg over 1 hour), 
TAK-954 concentrations declined in a biphasic manner, with mean terminal disposition phase 
half-life (t1/2z) 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 doses 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 28% to 32%. 
In subjects who were critically ill and received 0.5 mg by IV infusion, the TAK-954 exposure was 
lower relative to that observed in healthy subjects. The average percentage of plasma protein 
binding was 56% in human plasma.
Following 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 adverse events (AEs) (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 following the first dose (postural tachycardia and 
postural dizziness); these resolved spontaneously and were not observed upon challenge. 
Following single infusions of TAK-954 of 0.5 mg in subjects who were critically ill with enteral 
feeding intolerance, no subject had an AE that led to study discontinuation or interruption of 
treatment. Vital sign changes from baseline noted over the course of treatment were minimal and 


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typical of critically ill subjects. No clinically relevant changes in electrocardiograms (ECGs) in 
either treatment group were observed. 
4.2
Rationale for the Proposed Study
This radiolabeled human mass-balance study will characterize the overall disposition and 
biotransformation of TAK-954. The study design involves a microtracer 14C dose, with sample 
analysis done primarily by highly sensitive accelerator mass spectrometry (AMS). The AMS 
technique will provide adequate sensitivity to assess quantitative disposition of TAK-954 in 
humans. The rationale for using a microtracer 14C dose is as follows: Conducting a human 
mass-balance study with a traditional radioactive dose (100 μCi) requires [14C]-TAK-954–specific 
activity of 200 µCi/mg. Preliminary stability results with radioactive material prepared at 
~127 µCi/mg suggested a significant decrease in radiochemical purity, even after storing at -80°C 
over a 4-month period, and the instability is considered to be due to highly specific activity. 
Because the time required for completion of the human mass-balance and metabolite 
profiling/identification studies is approximately 6 to 9 months, the radiolabeled material would 
have to be stable until the analysis is complete. To avoid highly specific activity material and the 
ensuing radiochemical instability, for the human mass-balance study, a microtracer approach with 
approximately 3 µCi/mg has been adopted. The stability of the microtracer (approximately 
3 µCi/mg) will be established before dosing human subjects.
4.3
Benefit-Risk Profile
As this trial will be conducted in healthy subjects, there is no expected clinical benefit to trial 
participants.
Potential risks of TAK-954 use include findings from prior studies. There were no SAEs or severe 
AEs observed in 2 oral dose studies in healthy subjects, Studies 0060 and 0061. Following 
multiple IV doses in healthy subjects in Study 0095, TAK-954 was generally well tolerated at 
doses ranging from 0.1 to 0.5 mg QD for 5 consecutive days. No SAEs were reported. The most 
common AEs (headache and postural dizziness) were not serious and resolved with treatment 
discontinuation. The radioactive burden due to approximately 1.5 μCi of total 14C planned to be 
administered per subject is considered to pose negligible additional risk above the background 
cosmic radiation, so no dosimetry estimation is necessary.
Overall, the benefit-risk profile is considered appropriate for this study.


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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Trial Objectives
5.1.1
Trial Primary Objectives
The primary objectives of the study are:

To determine the mass balance and routes of elimination of a single IV dose of TAK-954 
containing microtracer ([14C]-TAK-954).

To characterize the metabolic profiles following single-dose IV administration of TAK-954 
containing microtracer ([14C]-TAK-954) and identify major circulating and excreted 
metabolites.

To determine the single-dose pharmacokinetics (PK) of total radioactivity, TAK-954, 
THRX513466, and THRX 913682, where possible.
5.1.2
Trial Secondary Objective
The secondary objective of the study is to evaluate the safety and tolerability of a single IV dose of 
TAK-954 containing microtracer ([14C]-TAK-954) in healthy male subjects.
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints of the study are:

Percentage of administered radioactive dose recovered in urine and feces and cumulative 
recovery in urine and feces combined. 

TAK-954 and metabolites (if any) expressed as a percentage of total radioactivity in plasma 
and as a percentage of dose in urine and in feces.

Concentration of total radioactivity in whole blood and plasma.

PK parameters to describe the single-dose PK, postdose on Day 1, for a) total radioactivity in 
whole blood and plasma, b) TAK-954 in plasma, and c) THRX513466 and THRX 913682 in 
plasma (where possible):
–
Cmax.
–
Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast).
–
Area under the concentration-time curve from time 0 to infinity (AUC∞).
–
Time of first occurrence of Cmax (tmax).
–
t1/2z.


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–
Total clearance after IV administration (CL) (TAK-954 only).
–
Volume of distribution during the terminal disposition phase after IV administration (Vz) 
(TAK-954 only).
–
Amount of total radioactivity and TAK-954 excreted in urine and radioactivity only for 
feces from 0 to time t (Aet).
–
Fraction of TAK-954 dose and total radioactivity excreted in urine and radioactivity only 
for feces from time 0 to time t (fet).
5.2.2
Secondary Endpoints 
Secondary endpoints include: 

The ratio of total radioactivity in whole blood and plasma.

The ratio of plasma TAK-954 to total radioactivity in plasma.

Safety: 
–
Percentage of subjects who experience at least 1 treatment-emergent AE.
–
Percentage of subjects who discontinue because of an AE.


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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
This is a phase 1, open-label study in 6 healthy male subjects. The study will include a screening 
visit, a treatment period, and a follow-up period. At least 6 subjects will be dosed in the study. The 
site should have alternate subjects available on the dosing day in case a subject is discontinued on 
Day 1.
Subjects will complete the screening visit within approximately 28 days before study drug 
administration. 
Eligible subjects will be enrolled into the study and will receive a single 60-minute IV infusion of 
0.5 mg TAK-954 containing a microtracer of [14C]-TAK-954 (~1.5 μCi). For standardization 
purposes, study drug will be administered following at least 2 hours of fasting. 
Subjects will be confined from admission for a minimum of 7 days. If the recovery of radioactivity 
has not met the target conditions specified below, a subject’s duration of confinement may be 
maximally extended to Day 15 (336 hours postdose). Should the duration of confinement be 
extended, clinical assessments planned at discharge will be rescheduled accordingly. 
An individual subject will be discharged from the clinic when at least 1 of the following criteria 
has been met for that subject: 
1. ≥90% of the administered radioactivity has been recovered in excreta.
2. Excreta samples from 2 consecutive days contain <1% of the administered radioactivity. 
Discharge/stopping criteria will be assessed daily by liquid scintillation counting or using AMS 
until target conditions have been met, but ultimately, a subject’s duration of confinement will not 
extend beyond Day 15 (336 hours postdose). 
Specific measures should be taken to prevent the subject from missing a fecal or urine collection 
by strictly controlling and providing access to designated restrooms only.
Safety will be assessed by monitoring for AEs, vital signs, ECGs, clinical laboratory results, and 
physical examinations.
Follow-up visit procedures will be performed on the last possible day (15 days after the start of the 
infusion) of discharge; subjects who meet the stopping criteria before this day will be asked to 
return for a follow-up visit on Day 15 (±2 days).
6.2
Rationale for Trial Design, Dose, and Endpoints
6.2.1
Rationale for Trial Design 
This trial has a standard design for assessing mass balance, metabolic profiles, and routes of 
elimination. The duration of sampling was chosen on the basis of the plasma elimination half-life 
for the parent drug (approximately 19 hours in healthy subjects), and observations from 
nonclinical tissue distribution and mass-balance studies.


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6.2.2
Rationale for Dose
A single dose of 0.5 mg was chosen for the following reasons: a 0.5 mg IV dose is likely to be in 
the therapeutic range, and on the basis of previous clinical experience with this compound, this 
dose (and associated systemic exposure) has an acceptable safety profile in healthy subjects. The 
radioactive burden due to approximately 1.5 μCi of total 14C planned to be administered per 
subject is considered to pose negligible additional risk above the background cosmic radiation, so
no dosimetry estimation is necessary.
6.2.3
Rationale for Subject Population
The study involves a small amount of radioactivity; therefore, only adult males are included in the 
trial.
6.2.4
Rationale for Endpoints
6.2.4.1
Safety Endpoints
Key safety endpoints will be assessed through monitoring of AEs, vital signs, ECGs, laboratory 
assessments, and physical examinations.
6.2.4.2
PK Endpoints
The PK endpoints described are standard for this type of study.
6.2.5
Critical Procedures Based on Trial Objectives: Timing of Procedures 
For this trial, the collections of the blood, urine, and feces samples are the critical procedures.
During the treatment period, where multiple procedures are scheduled at the same time point(s) 
relative to dosing, the following chronology of events should be adhered to, where possible:

Vital signs and 12-lead EGC should be obtained as close as possible to the scheduled time but 
before any blood specimen collection.

PK blood specimens should be obtained at scheduled time.

All other procedures should be obtained as close as possible to the scheduled time but may be 
obtained before or after any blood specimen collection.

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 Design/Dosing/Procedure Modifications Permitted Within Protocol Parameters
This is a phase 1 assessment of TAK-954 in humans, and the PK, pharmacodynamic, and safety 
profiles of the compound are still being elucidated. This protocol is written with some flexibility to 


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accommodate the inherent dynamic nature of phase 1 clinical trials. Modifications to the clinical or 
laboratory procedures currently outlined below may be required to achieve the scientific goals of 
the trial objectives or to ensure appropriate safety monitoring of the trial subjects.
Up to an additional 50 mL of blood may be drawn. The total blood volume withdrawn from any 
single subject will not exceed the total maximum allowable volume during the subject’s
participation in the trial. 
It is understood that the current trial may employ some or none of the alterations described above. 
Any alteration made to this protocol to meet the trial objectives must be detailed by the sponsor in 
a letter to the trial master file and forwarded to the investigator for retention. The letter may be 
forwarded to the institutional review board (IRB)/independent ethics committee (IEC) at the 
discretion of the investigator.
6.4
Trial Beginning and End/Completion
6.4.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signs the trial informed consent form (ICF).
6.4.2
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).
6.4.3
Definition of Trial Completion
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).
6.4.4
Definition of Trial Discontinuation
Trial discontinuation because of nonsafety reasons, such as:

A finding (eg, PK, pharmacodynamics, 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 result 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 about the safety of the trial subjects arising from clinical or nonclinical trials with the trial 
treatment(s), comparator(s), drug(s) of the same class, or methodology(ies) used in this trial.


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6.4.5
Criteria for Premature Termination or Suspension of the Trial
6.4.5.1
Criteria for Premature Termination or Suspension of Trial 
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of Good Clinical Practice (GCP), the protocol, or a contractual 
agreement; is unable to ensure adequate performance of the trial; or as otherwise permitted by the 
contractual agreement.
6.4.5.2
Procedures for Premature Termination or Suspension of the Trial
If the sponsor, an IRB, or a 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 termination or trial suspension.
6.4.6
Criteria for Premature Termination or Suspension of a Site
6.4.6.1
Criteria for Premature Termination or Suspension of a Site 
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, the protocol, or a contractual agreement; or is unable to 
ensure adequate performance of the trial; or as otherwise permitted by the contractual agreement.
6.4.6.2
Procedures for Premature Termination or Suspension of a Site
If the sponsor, an IRB/IEC, or a 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 termination or trial suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
To be eligible for study participation, subjects 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 aged 18 to 55 years, inclusive, at the screening visit. 
4. Have a body mass index (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.
6. Be judged to be in good health by the investigator on the basis of 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, from the first dose of study drug until 30 days after the last dose of 
study drug. No restrictions are required for a vasectomized male subject provided that the 
subject is at least 1 year postbilateral vasectomy procedure before the first dose of study 
drug. A male subject whose vasectomy procedure was performed less than 1 year before 
the first dose of study drug must follow the same restrictions as a nonvasectomized man. 
Appropriate documentation of surgical procedures 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 30 days after the last dose of study drug.
7.2
Exclusion Criteria
The subject must be excluded from participating in the study if the subject: 
1. Has participated in another investigational trial within 4 weeks (or based on local regulations) 
before the pretrial visit (screening). This window will be derived from the date of the last trial 
procedure or AE related to the trial procedure in the previous trial to the pretrial/screening visit 
of the current trial. 
2. Is an employee or immediate family member (eg, spouse, parent, child, sibling) of the sponsor 
or clinical site.
3. Has a history of cancer (malignancy).


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4. Has a history of significant multiple or severe allergies (eg, food, drug, latex allergy) or has 
had an anaphylactic reaction or significant intolerability to prescription or nonprescription 
drugs or food.
5. Has a positive alcohol or drug screen.
6. Has a positive test result for hepatitis B surface antigen, hepatitis C virus (HCV) antibody, or 
HIV antibody/antigen at the screening visit. Note: Subjects with positive hepatitis B virus
(HBV) or HCV serology may be enrolled if quantitative polymerase chain reaction for HBV or 
HCV RNA is negative.
7. Had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 8 weeks 
before the first dose of study drug.
8. Has a known hypersensitivity to any component of the formulation of TAK-954 or related 
compounds.
9. 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, until the follow-up visit; see 
Section 7.3.
10. Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass 
is approximately equivalent to beer 354 mL/12 oz, wine 118 mL/4 oz, or distilled spirits 29.5 
mL/1 oz).
11. 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.
12. Has a substance abuse disorder.
13. Has total 14C radioactivity measured by AMS in plasma (during screening) exceeding 14C/12C 
ratio 1.1E-12.
14. Participated in any study with a radiation dose above 0.1 MBq or radiation burden above 
0.1 mSv within 1 year before screening.
15. Was exposed to significant radiation (eg, serial x-ray or computed tomography scans, barium 
meal, current employment in a job requiring radiation exposure monitoring) within 12 months 
before check-in.
16. Irregular defecation pattern (less than once per 2 days).
7.3
Excluded Medications, Supplements, Dietary Products 
7.3.1
Concomitant Medications
The use of concomitant medications (see Section 9.1.4) after enrollment (ie, Day 1) until the 
follow-up visit is not permitted. Subjects must be instructed not to take any medications without 


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first consulting the investigator. Any concomitant medication use must first be discussed with the 
sponsor, unless the investigator or designee believes that immediate administration is necessary.
The occasional use of acetaminophen (approximately <1 g/day) is allowed.
7.3.2
Fruit Juice
Subjects will refrain from consuming grapefruit juice, grapefruits, and products containing 
grapefruit beginning approximately 2 weeks before administration of the initial dose of study drug, 
throughout the trial, until the follow-up visit.
Subjects also will refrain from consuming all juices 24 hours before and after administration of the 
study drug. Consumption of all fruits other than grapefruit is allowed on all days of the trial.
7.3.3
Alcohol
Subjects will refrain from consuming alcohol 7 days before the screening visit and follow-up visit 
and starting 7 days before and until after the last PK blood sample has been collected. At all other 
times, alcohol consumption is limited to no more than approximately 3 alcoholic beverages or 
equivalent (1 alcoholic beverage is approximately equivalent to beer 354 mL/12 oz, wine 
118 mL/4 oz, or distilled spirits 29.5 mL/1 oz) per day.
7.3.4
Caffeine
Subjects will refrain from consuming caffeinated beverages starting 24 hours before and until after 
the last PK blood sample has been collected and for 24 hours before the screening visit and 
follow-up visit. At all other times, caffeinated beverages or xanthine-containing products will be 
limited to amounts of no more than 6 units per day (1 unit = 120 mg of caffeine).
7.3.5
Smoking
Smoking is not permitted during the trial.
7.4
Diet, Fluid, and Activity 
7.4.1
Diet and Fluid
Subjects will fast (no food or drink except water) for at least 2 hours before study drug dosing. 
Water is permitted until 1 hour before TAK-954 administration. Water may be consumed without 
restrictions beginning 1 hour after TAK-954 dosing.
Lunch, dinner, and snacks will be provided on Day 1. Breakfast, lunch, dinner, and morning and 
afternoon snacks will be provided on all other domiciled days.
7.4.2
Activity
Subjects will avoid unaccustomed strenuous physical activity (eg, weight lifting, running, 
bicycling) from the screening visit until administration of the study drug, throughout the trial, until 
the follow-up visit.


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7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the electronic case report form (eCRF) using the following categories. 
1. Treatment discontinuation due to an AE: The subject has experienced an AE that requires early 
termination because continued participation poses an unacceptable risk to the subject’s health 
or the subject is unwilling to continue in the study because of the AE. 
2. Significant protocol deviation: The discovery that the subject did not meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.
3. Lost to follow-up: The subject did not return to the clinic, and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents. 
4. Voluntary withdrawal: The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF.
5. Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (eg, withdrawal due to an 
AE should not be recorded in the voluntary withdrawal category).
6. Study termination: The sponsor, IRB, IEC, or regulatory agency terminates the study.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
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 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. 


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
Details regarding the composition and extemporaneous preparation of the active drug are found in 
the pharmacy manual. Clinical study drug will be packaged to support enrollment and replacement 
subjects as required. When a replacement subject is required, the sponsor must be contacted before
dosing.
8.1.1
Clinical Study Drug Labeling
Clinical study drug will be affixed with a clinical label in accordance with regulatory 
requirements.
8.1.2
Clinical Study Drug Inventory and Storage
Clinical study drug must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Inventory (receipt and dispensing) of study drug must be recorded by an 
authorized, unblinded person at the trial site.
8.1.3
Clinical Study Drug Blinding
This is an open-label trial.
8.1.4
Clinical Trial Blind Maintenance/Unblinding Procedure
This is an open-label trial.
8.1.5
Accountability and Destruction of sponsor-Supplied Drugs
The investigator is responsible for keeping accurate records of the clinical study drug received 
from the sponsor or designee 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 study drug accountability, return, and destruction.


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9.0
STUDY PROCEDURES
The following sections describe the trial procedures to be performed and data to be collected as 
indicated in the schedule of study procedures (Section 3.0). For each procedure, subjects are to be 
assessed by the same investigator or site personnel whenever possible. Please note that it may 
become necessary to perform the following procedures at unscheduled time periods, at the 
investigator’s discretion.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained before the subject enters the trial and before any 
protocol-directed procedures are performed. The requirements of informed consent are described 
in Appendix B.
9.1.1.1
Assignment of Screening and Subject 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 enrollment. Each subject will be assigned only 
1 screening number. Screening numbers must not be reused for different subjects. Any subject 
who is screened multiple times will be assigned a new screening number for each screening event.
All eligible subjects will receive a subject number. The subject number identifies the subject for all 
procedures occurring after enrollment. Once a subject number is assigned to a subject, it can never 
be reassigned to another subject. A single subject cannot be assigned more than 1 subject number.
9.1.1.2
Study Drug Assignment
On Day 1, subjects will be assigned a subject number in ascending numerical order at the clinical 
site. The subject number determines the order in which the subjects will receive TAK-954. 
9.1.2
Inclusion and Exclusion 
Each subject will be assessed according to the eligibility criteria provided in Section 7.0.
9.1.3
Medical History/Demography
Qualified site personnel will collect subject significant medical history (past and concurrent 
medical conditions), per the site’s standard of care and appropriate clinical judgment, and subject 
demographics.
9.1.4
Concomitant Medications
Qualified site personnel will review each subject’s prior and concomitant medication use. 
Medications are defined as prescription and over-the-counter drugs, vaccines, supplements, 
nutraceuticals, and oral herbal preparations.


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9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Exam
Qualified site personnel will conduct full physical examinations.
A neurological assessment will be part of the physical examination and mainly will consist of tests 
of sensory and motor functions (eg, reflexes, coordination, and gait).
9.2.2
Height and Weight
Body weight and height will be obtained with the subject’s shoes off and jacket or coat removed.
9.2.3
BMI
BMI equals a subject’s weight in kilograms divided by height in meters squared (BMI = kg/m2). 
BMI will be rounded to the nearest whole number according to the standard convention of 0.1 to 
0.4, round down, and 0.5 to 0.9, round up.
9.2.4
Vital Signs
Body temperature will be measured with an oral (temperature taken at floor of the mouth) or 
tympanic thermometer. The same method (ie, oral or tympanic) must be used for all subsequent 
measurements for each subject and should be the same for all subjects.
Subjects should rest in a semirecumbent position for at least 5 minutes before vital signs are 
measured. Vital signs will include heart rate, respiratory rate, and systolic and diastolic blood 
pressure. The same method (eg, same size cuff, manual or automated) must be used for all 
measurements for each subject and should be the same for all subjects.
Subjects should continue to rest in a semirecumbent position from the time of dosing until 4 hours 
postdose, except to stand for the measurement of standing vital signs (if needed) or other 
trial-related procedures.
9.2.5
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. 
Subjects should be resting in a semirecumbent position for at least 5 minutes before each ECG 
measurement.
QT intervals with Fridericia correction method (QTcF intervals) will be calculated in this trial.
An ECG will be obtained at screening. This measurement will be used as the baseline assessment. 
The principal investigator should arrange to have a trial cardiologist available as needed to review 
ECG tracings with abnormalities. 
During the treatment period, if a subject demonstrates an increase in QTcF interval 
≥40 milliseconds compared with a predose baseline measurement, the ECG will be repeated 


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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 milliseconds, the subject will continue to be monitored by repeat 12-lead ECGs every 
60 minutes for at least 4 hours or until the QTcF interval is within 40 milliseconds of the baseline 
value. If prolongation of the QTcF interval ≥40 milliseconds persists, a consultation with a trial 
cardiologist may be appropriate, and the sponsor should be notified.
If the QTcF interval is ≥500 milliseconds, the sponsor should be notified, and the ECGs should be 
reviewed by a cardiologist. The subject should be monitored by telemetry (until the QTcF interval 
is <500 milliseconds) or should be considered for transfer to a location where closer monitoring is 
available.
If the subject has unstable hemodynamics or any clinically significant dysrhythmias noted by 
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 to 
ensure reproducible electrode placement.
The following ECG parameters will be recorded: heart rate, PR interval, QRS interval, QT interval, 
QTcF interval, and the interpretation of the ECG profile by the principal investigator.
9.2.6
Study Drug Administration
On Day 1 of the treatment period, study drug (a single dose of TAK-954) will be administered as 
described in Section 6.1.
9.2.7
AE Monitoring
AE monitoring begins after signing of the ICF. Changes in subject health status from the baseline 
assessment until study drug administration should be captured in the subject’s medical history. A 
complete description of AE collection and procedures is provided in Section 10.0.
9.2.8
Laboratory Procedures and Assessments
Laboratory samples will be collected in accordance with acceptable laboratory procedures. 
Samples will be taken on the days indicated in the schedule of study procedures (Section 3.0).


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9.2.8.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells [RBCs])
Hemoglobin
Hematocrit
Platelets
Leukocytes (white blood cells [WBCs]) with absolute 
differential
Chemistry 
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Alkaline phosphatase
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride
Creatinine
Glucose
γ-glutamyl transferase (GGT)
Sodium
Potassium
Bilirubin (total), if above ULN total bilirubin will be 
fractionated
Protein (total)
Abbreviations: ULN, upper limit of normal.
If subjects experience ALT or AST >3 × the upper limit of normal (ULN), follow-up laboratory 
tests (at a minimum, serum alkaline phosphatase, alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], total bilirubin, and γ-glutamyl transferase) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted.
If ALT or AST remains elevated >3 × ULN on these 2 consecutive occasions, the investigator 
must contact the medical monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study drug, and discussion of the relevant subject details and possible 
alternative etiologies. The abnormality should be recorded as an AE.
Refer to Section 7.5 for subject discontinuation criteria regarding abnormal liver function tests 
(LFTs) and Section 10.2.8.4 for guidance on reporting abnormal LFTs.
Urinalysis
Urinalysis will consist of the following tests:
Protein
Glucose
Blood
Nitrite


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Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of red blood 
cells/high-power field, white blood cells/high-power field, and casts.
9.2.8.2
Diagnostic Screening
The serum diagnostic screening assessment will include the following tests:
HIV
Hepatitis screen (HBsAg, HCV antibody)
Abbreviations: HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus.
Alcohol Screen
Subjects will undergo an alcohol breath test. A urine alcohol test may be performed at the 
discretion of the investigator.
Urine
The urine drug screening assessment will include the following tests:
Amphetamines
MDMA
Barbiturates
Methadone/metabolite
Benzodiazepines
Opiates
Buprenorphine/metabolite
Oxycodone/oxymorphone
Cannabinoids
Phencyclidine
Cocaine/metabolites
Abbreviations: MDMA, 3,4-methylenedioxy-methamphetamine.
9.3
PK Samples
Samples for total radioactivity concentration determination in whole blood, plasma, urine, and 
feces, and the determination of concentration of TAK-954 in plasma and urine will be collected as 
specified in the schedule of study procedures (Section 3.0). Refer to the laboratory manual for 
information on collecting, processing, and shipping samples to the central laboratory. 
A detailed PK analysis plan will be prepared before PK parameter computation. 
It is anticipated that the total blood volume drawn in this trial will be approximately 400 mL.


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Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary Specimen
Description of Intended Use
Sample 
Collection
Plasma sample for TAK-954 PK
Plasma
PK measurement
Mandatory
Urine sample for TAK-954 PK
Urine
PK measurements
Mandatory
Plasma, urine, and feces for 
metabolite profiles
Plasma/urine/feces
Metabolic profiling
Mandatory
Blood and plasma sample for total 
radioactivity
Blood and plasma
Total radioactivity
Mandatory
Feces samples for total radioactivity
Feces
Total radioactivity
Mandatory
Abbreviation: PK, pharmacokinetics.
9.3.1
PK Evaluations
The following parameters for TAK-954 and/or total radioactivity will be calculated. The PK 
parameters for TAK-954 and/or total radioactivity 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 and both plasma and whole blood PK 
parameters for radioactivity will be calculated:

Cmax.

AUClast.

AUC∞.

tmax.

t1/2z.

CL (TAK-954 only).

Vz (TAK-954 only).
The following urinary PK parameters will be calculated for both TAK-954 and radioactivity:

Aet.

fet.
The following fecal parameter will be calculated for total radioactivity:

fet.


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The following radioactivity parameters/profiles will be calculated:

Cumulative recovery (% urine, % feces, and percentage of total radioactivity in urine and feces 
over the entire period of collection).

TAK-954 metabolite profiles in plasma, urine, and feces.
Other PK parameters may be calculated if deemed necessary for the interpretation of the data 
including PK parameters for the metabolites THRX513466 and THRX 913682, if possible.
Radioactivity in plasma will be measured and reported in unchanged drug equivalents per volume 
of plasma (eg, ng-eq/mL). Noncompartmental PK parameters (tmax, Cmax, AUClast, AUC∞, t1/2z) 
will be calculated from the plasma radioactivity concentration-time data. 
Unchanged drug and metabolite concentrations in plasma will be measured and reported in mass 
per volume of plasma (eg, ng/mL), and the percentage of total radioactivity associated with 
TAK-954 and metabolites will be calculated. Noncompartmental PK parameters (including tmax, 
Cmax, AUClast, AUC∞, CL (TAK-954 only), Vz (TAK-954 only), t1/2z) will be calculated from the 
plasma concentration-time data.
Radioactivity in whole blood will be measured and reported in unchanged drug equivalents per 
volume of blood (eg, μg-eq/mL). The total radioactivity ratio of whole blood to plasma will be 
calculated.
Radioactivity in urine will be measured and reported as the percentage of the administered 
radioactivity excreted at each time interval and the total percentage of dose excreted in urine.
The percentage of total radioactivity associated with TAK-954 and metabolites (where possible) 
will be calculated. Renal clearance of unchanged drug may also be calculated (if appropriate).
Radioactivity in feces will be measured and reported as the percentage of the administered 
radioactivity excreted at each time interval and the total percentage of dose excreted in feces.
The percentage of total radioactivity associated with TAK-954 and metabolites (where possible) 
will be calculated.
For metabolite profiling of urine and feces, samples collected at different time intervals for each 
subject will be pooled. Pooling will occur in proportion to the amount (weight or volume) of 
excreta collected in each sampling period.
PK Assessments
It is extremely important to quantitatively collect all scheduled blood, urine, and feces samples. 
The separate collection of urine and feces is critical to the success of this study. If urine and feces 
become mixed at any collection, note the weight and add the feces-contaminated urine to the feces 
collection. Samples missed or lost for any reason should be documented.
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 (eg, within 6 minutes of a 60-minute 
sample) from dosing will not be recorded as a protocol deviation. The exact collection time of all 
samples must be noted on the source document and data collection tool (eCRF).


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Detailed instructions for processing plasma samples will be provided to the site before the 
initiation of the study. Samples will be analyzed for TAK-954 and 2 of the standard metabolites 
using a validated analytical method. 
Detailed instructions for processing plasma radioactivity samples will be provided to the site 
before the initiation of the study. Samples will be assayed for radioactivity using the clinical 
research unit’s standard operating procedures.
9.3.1.1
Blood Collection for Total Radioactivity and TAK-954 PK 
More detailed sample handling information can be found in the TAK-954-1005 laboratory manual 
for all the following sections. 
9.3.1.2
Blood Collection for Metabolite Profiling
More detailed sample handling information can be found in the TAK-954-1005 laboratory manual 
for all the following sections. 
9.3.1.3
Urine Collection for Total Radioactivity and Metabolic Profiling
More detailed sample handling information can be found in the TAK-954-1005 laboratory manual 
for all the following sections. 
9.3.1.4
Fecal Collection for Total Radioactivity and Metabolic Profiling
More detailed sample handling information can be found in the TAK-954-1005 laboratory manual 
for all the following sections. 
9.3.1.5
Unscheduled Sample Collection
More detailed sample handling information can be found in the TAK-954-1005 laboratory manual 
for all the following sections. 
9.3.1.6
Emesis
More detailed sample handling information can be found in the TAK-954-1005 laboratory manual. 
9.3.2
Confinement
Subjects will be confined from admission for a minimum of 7 days. If the recovery of radioactivity 
has not met the target conditions specified below, a subject’s duration of confinement may be 
maximally extended to Day 15 (336 hours postdose). Should the duration of confinement be 
extended, clinical assessments planned at discharge will be rescheduled accordingly. 
A subject will be discharged from the clinic when at least 1 of the following criteria has been met 
for that subject: 

≥90% of the administered radioactivity has been recovered in excreta.

Excreta samples from 2 consecutive days contain <1% of the administered radioactivity. 


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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 study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for preexisting conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) and symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, signs and symptoms should be recorded
appropriately as an AEs.
Laboratory values and ECG findings:

Changes in laboratory values and ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). Laboratory 
retests and continued monitoring of an abnormal value are not considered interventions. 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), only the diagnosis should be 
reported appropriately as an AE.
Preexisting conditions:

A preexisting condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, x-ray) should NOT be recorded as an AE unless related to 
a study procedure. However, if the subject experiences a worsening or complication of such a 


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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 preexisting episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should be captured as an AE only if the episodes become more frequent, serious, or 
severe in nature, and 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 be captured as an AE only if occurring to a greater extent 
than 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 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, worsening of…).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once, with the maximum severity recorded.
Preplanned surgeries and 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 worsening of the preexisting 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 and procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the sponsor.


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
All cases of overdose (with or without associated AEs) will be documented on an overdose 
page of the eCRF to capture this important safety information consistently in the database. AEs 
associated with an overdose will be documented on AE eCRFs according to Section 10.0.

SAEs of overdose should be reported according to the procedure outlined in Section 10.2.8.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE-THREATENING.
–
The term life-threatening refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
–
May require intervention to prevent items 1 through 5 above.
–
May expose the subject to danger, even though the event is not immediately 
life-threatening or fatal or does not result in hospitalization.
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living.
Moderate:
An AE that is usually alleviated with additional specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but 
posing no significant or permanent risk of harm to the research participant.
Severe:
An AE that interrupts usual activities of daily living or significantly affects clinical 
status, or may require intensive therapeutic intervention.


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10.2.2 Assigning Causality of AEs
The relationship of each AE to study medication will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug 
(including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility; ie, the relationship cannot be ruled 
out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs, and concurrent treatments, may also be 
responsible.
Not related:
An AE that does not follow a reasonable temporal sequence from administration of 
a drug and/or can reasonably be explained by other factors, such as underlying 
diseases, complications, concomitant medications, and concurrent treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject or 
investigator.
10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae, or the subject died.
10.2.5 Pattern of AE (Frequency) 
Episodic AEs (eg, headache) or those that occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Study Treatment

Drug withdrawn: A study medication is stopped because of the particular AE.

Dose not changed: The particular AE did not require stopping a study medication.

Unknown: To be used only if it is not possible to determine what action has been taken.

Not applicable: A study medication was stopped for a reason other than the particular AE;
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started, or dosing with study medication was already stopped before the onset of the AE.

Dose reduced: The dose was reduced because of the particular AE.

Dose increased: The dose was increased because of the particular AE.

Drug interrupted: The dose was interrupted because of the particular AE.
10.2.7 Outcome 

Recovered/resolved: The subject returned to first assessment status with respect to the AE.


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
Recovering/resolving: The intensity is lowered by one or more stages: The diagnosis or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved but has not 
returned to the normal range or to the baseline value; the subject died from a cause other than 
the particular AE with the condition remaining recovering/resolving.

Not recovered/not resolved: There is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, signs/symptoms, or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining not recovered/not 
resolved.

Recovered/resolved with sequelae: The subject recovered from an acute AE but was left with 
permanent/significant impairment, eg, recovered from a cardiovascular accident but with some 
persisting paresis.

Fatal: an AE that is considered as the cause of death.

Unknown: The course of the AE cannot be followed up because of hospital change or 
residence change at the end of the subject’s participation in the study.
10.2.8 Collection and Reporting of AEs, SAEs, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (AEs, SAEs, and abnormal LFTs) will commence when the subject signs the 
informed consent. Routine collection of AEs will continue until the follow-up visit on day 15 
(±2 days). For subjects who discontinue before the administration of study medication, AEs will 
be followed until the subject discontinues study participation. 
10.2.8.2 Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?”, may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE before the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to baseline, or until 
there is a satisfactory explanation for the change. Nonserious AEs that begin before the first 
exposure to investigational product, related or unrelated to the study procedure, need not be 
followed up for the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline, or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.


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
Start and end date and time.

Pattern of AE (frequency).

Severity/intensity.

Causality (investigator’s opinion of the causal relationship between the event and 
administration of study drug).

Action taken with trial drug.

Outcome of event.

Seriousness.
10.2.8.3 Reporting SAEs
When an SAE occurs during 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 after first onset or notification of the event. The information should be completed 
as fully as possible but must contain, at a minimum:

A short description of the event and the reason the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication.

Causality assessment.
The SAE form should be transmitted within 24 hours.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of SAEs that begin before the first administration of investigational product will follow 
the same procedure as SAEs occurring on treatment.
SAE Follow-up
If information not available at the time of the first report later becomes available, the investigator 
should complete a follow-up SAE form or provide other written documentation and fax it 
immediately within 24 hours after receipt. Copies of any relevant data from the hospital notes (eg, 
ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the addressee, if 
requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.


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10.2.8.4 Reporting 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 
per Section 10.2.8.3. The investigator must contact the sponsor’s 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 9.2.8 must also be 
performed. In addition, an LFT increases eCRF must be completed and transmitted with the 
Takeda SAE form. 
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues that 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 product administration or in the overall 
conduct of the trial. The investigational site also will forward a copy of all expedited reports to the 
site’s 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 will be prepared and finalized before database lock. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
The safety analysis set will include subjects who are enrolled in the study and receive at least 
1 dose of study drug. Subjects in this analysis set will be used for demographic and safety 
summaries.
11.1.1.2 PK Set
The PK analysis set will consist of all subjects in the safety analysis set with sufficient 
concentration data to facilitate the derivation of at least 1 PK parameter from the 
concentration-time data. All subjects who have a valid PK parameter estimated will be included in 
the analyses and summary statistics for that parameter. 
All subjects who have valid concentration data at a scheduled sample collection time will be 
included in the summary statistics.
11.1.2 Analysis of Demography and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized using the safety analysis set. 
Summary statistics (number of subjects, mean, SD, median, minimum, and maximum) will be 
generated for continuous variables (eg, age and weight), and the number and percentage of 
subjects within each category will be presented for categorical variables (eg, gender, ethnicity, and 
race).
The number and percentage of subjects who are enrolled, complete the study visit, those who 
discontinue early, and each reason for discontinuation will be summarized. 
11.1.3 PK and Radioactivity Analysis
11.1.3.1 Concentration Data
Plasma concentration of TAK-954 and its metabolites and total radioactivity in whole blood and 
plasma at each scheduled time point will be summarized using descriptive statistics.
Mass balance will be assessed by the percentage and cumulative percentage of administered 
radioactive dose recovered in urine and in feces and their combined total at appropriate intervals. 
Descriptive statistics will be used.


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Mean and individual cumulative excretion of radioactivity in urine and in feces and their combined 
total by time curve will be displayed.
Individual percentage and cumulative percentage will be presented in data listings. 
All concentration data will be listed.
11.1.3.2 PK Parameters
Descriptive statistics will be used to summarize the PK parameters. All PK parameter data will be 
listed. Statistical analyses will be performed if appropriate.
11.1.3.3 Metabolites
Circulatory and excretory metabolite profiles will be established for each subject. Metabolites will 
be presented as a mean percentage of total radioactivity and/or dose. Descriptive statistics will be 
used.
11.1.4 Safety Analysis
All safety assessments, including AEs, clinical laboratory evaluations, vital signs, and ECG 
findings, will be presented in the data listings and summarized using descriptive statistics for all 
subjects in the safety analysis set, where appropriate.
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Data 
will be summarized using Preferred Term and primary System Organ Class.
11.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
11.3
Determination of Sample Size
No formal sample size calculations have been performed. The sample size (n = 6) is based on the 
consideration that radioactivity is being administered to healthy subjects and that generally 
6 subjects is sufficient to characterize the endpoints described in the protocol and is accepted by 
regulatory agencies.


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or the 
sponsor’s designee (as long as blinding is not jeopardized) including, but not limited to, the 
investigator’s binder, trial drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except when necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that require 
deviation from protocol-specified procedures, the investigator should consult the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (prospectively approved deviations) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the United States [US] Food and Drug Administration [FDA], 
the United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). The sponsor should be notified immediately if the study 
site is contacted for an inspection by a regulatory body. The investigator guarantees access for 
quality assurance auditors to all study documents as described in Section 12.1.


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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the International Council on Harmonisation (ICH) Harmonised Tripartite Guideline for GCP. 
Each investigator will conduct the study according to applicable local or regional regulatory 
requirements and align his or her conduct in accordance with the responsibilities of the 
investigator 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/IEC Approval
This study will be conducted in accordance with the protocol and with the consensus ethical 
principles derived from international guidelines, including the Declaration of Helsinki and 
CIOMS (Council for International Organizations of Medical Sciences) International Ethical 
Guidelines, ICH GCP guidelines, and laws and regulations applicable to clinical studies (including 
US 21 Code of Federal Regulations [CFR] and European Union Clinical Trials Directive
2001/20/EC).

The protocol, ICFs, investigator’s brochure, and other relevant supporting documents (eg, 
advertisements, information on payments and compensation available to subjects) must be 
submitted to an IRB/IEC by the investigator. Written approval of the protocol from the 
IRB/IEC must be obtained before the study is initiated, ie, the first subject signs the study ICF. 

The study cannot be initiated until notification is received from the sponsor.

Any amendment to the protocol, except when necessary to eliminate an immediate hazard to 
study participants, requires IRB/IEC written approval before implementation.

If required by country or regional regulations or procedures, approval from the competent 
regulatory authority will be obtained before commencement of the study or implementation of 
an amendment. 

The investigator will be responsible for the following:
–
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC.
–
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures.
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 ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 


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disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, and the date informed consent is given. 
The ICF will detail the requirements of the participant and the fact that participants are free to 
withdraw at any time without giving a reason and without prejudice to further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF
and, if applicable, the subject authorization form. The ICF, 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 ICF, 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 ICF, 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. If the subject is not capable of rendering adequate written informed 
consent, then the subject’s legally acceptable representative may provide such consent for the 
subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to 
(1) inquire about details of the study, and (2) decide whether to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines that the subject will 
participate in the study, then the ICF 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 enters into the study. The subject or the subject’s legally acceptable 
representative should be instructed to sign using their legal names, not nicknames, using a blue or 
black ballpoint pen. The investigator must also sign and date the ICF and subject authorization (if 
applicable) at the time of consent and before the subject enters into the study; however, the sponsor 
may allow a designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, 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 ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs 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 ICF.
13.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will be linked only to 
the sponsor’s clinical study database or documentation via a unique identification number. As 


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permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, 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, US FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents) including, but not limited to, laboratory test result reports, ECG reports, admission and 
discharge summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific authorization 
by 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 (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 study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail.
13.4.2 Clinical Trial Registration 
To ensure that information on clinical 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 or other 
publicly accessible websites before the start of the study, as defined in Takeda Policy/Standard. 
Takeda contact information, along with investigator’s city, state (for US investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers with locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 


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information. Once subjects receive investigator contact information, they may call the site to 
request 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, the caller should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with 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 regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the clinical study site agreement regarding the sponsor’s policy on subject compensation and 
treatment for injury. The investigator should contact the sponsor or sponsor’s designee with any
questions regarding this policy.


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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
Trial contact numbers can be found in the study manual, the communication plan, or other similar 
documents provided to the site.


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14.1.1 Investigator Agreement
I confirm that I have read and that I understand this protocol, the investigator’s brochure, package 
insert, and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and to protect the rights, safety, privacy, and 
well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.2.9 of this protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
14.1.2 List of Abbreviations
14C
carbon-14
AE
adverse event
Aet
Amount of total radioactivity and/or TAK-954 excreted in urine/feces from 0 to time t
ALT
alanine aminotransferase
AMS
accelerator mass spectrometry
AST
aspartate aminotransferase


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AUC∞
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration
BMI
body mass index
CFR
Code of Federal Regulations
CL
total clearance after intravenous administration
Cmax
maximum observed concentration
ECG
electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
fet
fraction of TAK-954 dose and/or total radioactivity excreted in urine/feces from time 0 to 
time t
GCP
Good Clinical Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
PK
pharmacokinetics
QD
once daily
QTcF
QT interval with Fridericia correction method
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reactions
t1/2z
terminal disposition phase half-life
tmax
time of first occurrence of maximum observed concentration
ULN
upper limit of normal
US
United States
VZ
volume of distribution during the terminal disposition phase after intravenous 
administration


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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the data management plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the data entry process, computer logic checks will be run to identify items, 
such as inconsistent dates, missing data, and questionable values. Queries may be issued by 
Takeda personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator 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 study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), eCRFs including the audit trail, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities, the 
sponsor, or its designees. Any source documentation printed on degradable thermal-sensitive 


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paper should be photocopied by the site and filed with the original in the subject’s chart to ensure 
long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain essential 
documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of a 
marketing application for a specified drug indication being investigated or, if an application is not 
approved, until at least 2 years after the investigation is discontinued and regulatory authorities are 
notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until an 
amount of time specified by applicable regulatory requirements or for a time specified in the 
clinical study site agreement between the investigator and sponsor.
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.


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16.0
REFERENCES
Not applicable


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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the Statement of Investigator (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. A valid ICF is the most current version 
approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 


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


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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. Identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A 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, auditors, IRBs/IECs, 
and the medical monitor may inspect the records. By signing a written ICF, 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 payments, if any, to the subject for participating in the study.
16. The anticipated expenses, if any, to the subject for participating in the study.
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 or the subject’s 
legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.


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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 study.
21. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
22. A written subject authorization (either contained within the ICF or provided as a separate 
document) describing to the subject the contemplated and permissible uses and disclosures of 
the subject’s personal information (including personal health information) for purposes of 
conducting the study. The subject authorization must contain the following statements 
regarding the uses and disclosures of the subject’s personal information:
a) 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, 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) Personal information (including personal health information) may be added to Takeda’s 
research databases for purposes of developing a better understanding of the safety and 
effectiveness of the study medication(s), studying other therapies for patients, developing a 
better understanding of disease, and improving the efficiency of future clinical studies.
d) Subjects agree not to restrict the use and disclosure of their personal information (including 
personal health information) upon withdrawal from the study to the extent that the 
restricted use or disclosure of such information may impact the scientific integrity of the 
research.
e) The subject’s identity will remain confidential if study results are published.
23. Male subjects must use highly effective contraception (as defined in the informed consent) and 
avoid sperm donation from signing the informed consent throughout the duration of the study 
and for 30 days after the last dose of study drug. If the partner or wife of the subject is found to 
be pregnant during the study, the investigator will offer the subject the choice to receive 
treatment information. 
24. A statement that clinical trial information from this trial will be disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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PPD

SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Open-label, Single Intravenous Infusion Dose Study to Evaluate the Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of TAK-954 Containing Microtracer 
([14C]-TAK-954) in Healthy Adult Male Subjects
NCT Number:  NCT03500224
SAP Approve Date: 18 October 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-954-1005
A Phase 1, Open-label, Single Intravenous Infusion Dose Study to Evaluate the Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of TAK-954 Containing 
Microtracer ([14C]-TAK-954) in Healthy Adult Male Subjects
PHASE 1
Version: Final
Date: 18 October 2018
Prepared by:
Based on:
Protocol Version: Initial
Protocol Date: 26 March 2018
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


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1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


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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 .................................................................................................................6
4.1
Primary Objectives ....................................................................................................6
4.2
Secondary Objectives.................................................................................................6
4.3
Study Design .............................................................................................................6
5.0
ANALYSIS ENDPOINTS...............................................................................................8
5.1
Primary Endpoints .....................................................................................................8
5.2
Secondary Endpoints .................................................................................................8
6.0
DETERMINATION OF SAMPLE SIZE.........................................................................9
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................10
7.1
General Principles....................................................................................................10
7.1.1
Study Definitions ...............................................................................................10
7.1.2
Definition of Study Days....................................................................................10
7.1.3
Definition of Study Visit Windows ....................................................................10
7.1.4
Conventions for Missing Adverse Event Dates...................................................10
7.1.5
Conventions for Missing Data............................................................................11
7.2
Analysis Sets ...........................................................................................................11
7.3
Disposition of Subjects ............................................................................................11
7.4
Demographic and Other Baseline Characteristics.....................................................11
7.5
Medical History and Concurrent Medical Conditions...............................................12
7.6
Medication History and Concomitant Medications...................................................12
7.7
Study Drug Exposure and Compliance.....................................................................12
7.8
Efficacy Analysis.....................................................................................................12
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................12
7.9.1
Pharmacokinetic Analysis ..................................................................................13
7.9.2
Pharmacodynamic Analysis ...............................................................................14
7.10
Other Outcomes.......................................................................................................14
7.11
Safety Analysis........................................................................................................15
7.11.1 Adverse Events ..................................................................................................15
7.11.2 Clinical Laboratory Evaluations .........................................................................16
7.11.3 Vital Signs .........................................................................................................16


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7.11.4 12-Lead ECGs ...................................................................................................16
7.11.5 Other Observations Related to Safety.................................................................16
7.12
Interim Analysis ......................................................................................................16
7.13
Changes in the Statistical Analysis Plan...................................................................17
8.0
REFERENCES..............................................................................................................18
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................19


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
CV
coefficient of variation
CRF
case report form
ECG
electrocardiogram
HR
heart rate
LLN
lower limit of normal
MAV
markedly abnormal values
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PK
pharmacokinetics
PT
preferred term
QTcF
QT interval with Fridericia correction method
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SI
International System of Units
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WBC
white blood cell
WHODrug
World Health Organization Drug Dictionary


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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objectives of the study are:

To determine the mass balance and routes of elimination of a single IV dose of TAK-954 
containing microtracer ([14C]-TAK-954).

To characterize the metabolic profiles following single-dose IV administration of TAK-954 
containing microtracer ([14C]-TAK-954) and identify major circulating and excreted 
metabolites.

To determine the single-dose pharmacokinetics (PK) of total radioactivity, TAK-954, 
THRX513466, and THRX 913682, where possible.
4.2
Secondary Objectives
The secondary objective of the study is to evaluate the safety and tolerability of a single IV dose 
of TAK-954 containing microtracer ([14C]-TAK-954) in healthy male subjects.
4.3
Study Design
This is a phase 1, open-label study in 6 healthy male subjects. The study will include a screening 
visit, a treatment period, and a follow-up period. At least 6 subjects will be dosed in the study. 
The site should have alternate subjects available on the dosing day in case a subject is 
discontinued on Day 1.
Subjects will complete the screening visit within approximately 28 days before study drug 
administration. 
Eligible subjects will be enrolled into the study and will receive a single 60-minute IV infusion 
of 0.5 mg TAK-954 containing a microtracer of [14C]-TAK-954 (~1.5 μCi). For standardization 
purposes, study drug will be administered following at least 2 hours of fasting. 
Subjects will be confined from admission for a minimum of 7 days. If the recovery of 
radioactivity has not met the target conditions specified below, a subject’s duration of 
confinement may be maximally extended to Day 15 (336 hours postdose). Should the duration of 
confinement be extended, clinical assessments planned at discharge will be rescheduled 
accordingly. 
An individual subject will be discharged from the clinic when at least 1 of the following criteria 
has been met for that subject: 
1. ≥90% of the administered radioactivity has been recovered in excreta.
2. Excreta samples from 2 consecutive days contain <1% of the administered radioactivity. 
Discharge/stopping criteria will be assessed daily by liquid scintillation counting or using AMS 
until target conditions have been met, but ultimately, a subject’s duration of confinement will not 
extend beyond Day 15 (336 hours postdose). 


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Specific measures should be taken to prevent the subject from missing a fecal or urine collection 
by strictly controlling and providing access to designated restrooms only.
Safety will be assessed by monitoring for AEs, vital signs, ECGs, clinical laboratory results, and 
physical examinations.
Follow-up visit procedures will be performed on the last possible day (15 days after the start of 
the infusion) of discharge; subjects who meet the stopping criteria before this day will be asked 
to return for a follow-up visit on Day 15 (±2 days).


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints of the study are:

Percentage of administered radioactive dose recovered in urine and feces and cumulative 
recovery in urine and feces combined. 

TAK-954 and metabolites (if any) expressed as a percentage of total radioactivity in plasma 
and as a percentage of dose in urine and in feces.

Concentration of total radioactivity in whole blood and plasma.

PK parameters to describe the single-dose PK, postdose on Day 1, for a) total radioactivity in 
whole blood and plasma, b) TAK-954 in plasma, and c) THRX513466 and THRX 913682 in 
plasma (where possible):
–
Cmax.
–
Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast).
–
Area under the concentration-time curve from time 0 to infinity (AUC∞).
–
Time of first occurrence of Cmax (tmax).
–
t1/2z.
–
Total clearance after IV administration (CL) (TAK-954 only).
–
Volume of distribution during the terminal disposition phase after IV administration (Vz) 
(TAK-954 only).
–
Amount of total radioactivity and TAK-954 excreted in urine and radioactivity only for 
feces from 0 to time t (Aet).
–
Fraction of TAK-954 dose and total radioactivity excreted in urine and radioactivity only 
for feces from time 0 to time t (fet).
5.2
Secondary Endpoints 
Secondary endpoints include: 

The ratio of total radioactivity in whole blood and plasma.

The ratio of plasma TAK-954 to total radioactivity in plasma.

Safety: 
–
Percentage of subjects who experience at least 1 treatment-emergent AE.
–
Percentage of subjects who discontinue because of an AE.


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6.0
DETERMINATION OF SAMPLE SIZE
No formal sample size calculations have been performed. The sample size (n = 6) is based on the 
consideration that radioactivity is being administered to healthy subjects and that generally 6 
subjects is sufficient to characterize the endpoints described in the protocol and is accepted by 
regulatory agencies.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Continuous data will be summarized using number of subjects (N), mean, standard deviation 
(SD), median, minimum, and maximum, where appropriate. Where indicated, percent of 
coefficient of variation (%CV) and geometric mean, will also be included in the summary of 
continuous data. Categorical data will be summarized using the number and percent of subjects 
(N [%]) for each category where appropriate.
Unless otherwise stated, Baseline will be defined as last observation prior to administration of 
the study drug.
In general, the presentation of decimal points will follow the following rules as appropriate: 
minimum and maximum values will be presented using the same number of decimal places as 
the recorded data. 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. 
All statistical analyses will be performed using the SAS System® Version 9.4 or higher.
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
All data will be categorized on the basis of the scheduled visit at which they are collected. These 
visit designators are predefined values that appear as part of the visit tab in the eCRF.
7.1.4
Conventions for Missing Adverse Event Dates
When calculating the duration/ onset of adverse events (AE), any AEs with start and/ or end 
times that are partially or completely missing will be imputed as follows:

If start time is missing, then impute to 00:01.

If end time is missing, then impute to 23:59.
There will be no imputation of incomplete or missing adverse event dates.


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7.1.5
Conventions for Missing Data
There will be no imputation of incomplete or missing data. Inclusion of subjects who are 
noncompliant with the dosing or who have incomplete data, will be made on a case-by-case 
basis. 
Plasma or urine concentrations that are below the limit of quantification (< BLQ) will be treated 
as zero in the summarization of concentration values and derivation of PK parameters. They will 
be flagged in the data listings; however, deviations from this convention may be considered on a 
case-by-case basis.
7.2
Analysis Sets
Safety Set
The Safety Analysis Set will include subjects who are enrolled in the study and received at least 
1 dose of study drug. Subjects in this analysis set will be used for demographic, baseline 
characteristic and safety summaries.
Pharmacokinetic (PK) Set
The PK analysis set will consist of all subjects in the safety analysis set with sufficient 
concentration data to facilitate the derivation of at least 1 PK parameter from the concentration-
time data. All subjects who have a valid PK parameter estimated will be included in the analyses 
and summary statistics for that parameter. 
All subjects who have valid concentration data at a scheduled sample collection time will be 
included in the summary statistics.
7.3
Disposition of Subjects
The number and percentage of subjects who are enrolled, complete the study drug and study 
visits, who prematurely discontinue study drug and/or study visits and each reason for 
discontinuation will be summarized. Subjects’ study completion data, including reasons for 
premature termination, will be listed. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for subjects in the safety set. 
Descriptive statistics (number of subject (N), mean, SD, median, minimum and maximum) will 
be generated for continuous demographic variables and baseline characteristics variables (e.g., 
age, height, weight, and BMI), and the number and percentage of subjects in each class of the 
categorical demographic variables and baseline characteristics variables (e.g., gender, ethnicity 
and race of the subject) will be tabulated. Individual subject demographic and baseline 
characteristics data will be listed.
There will be no inferential analysis of demographic and baseline characteristics.


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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 or ongoing at signing of informed consent.
Medical history and concurrent medical conditions will be coded by system organ class and 
preferred term using the Medical Dictionary for Regulatory Activities (MedDRA, version 21.0 or 
higher). No summary statistics for medical history and concurrent medical conditions will be 
provided.
Medical history and concurrent medical conditions will be listed by subject number. The listing 
will contain subject identifier, system organ class (SOC), preferred term (PT), whether there was 
any medical history or concurrent condition, and, if yes, a detail of the medical history or 
concurrent condition.
There will be no 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 7 days prior to administration of the initial dose. Concomitant medications are recorded 
on the eCRF and include any medications, other than study drug, taken at any time from signing 
of informed consent through the end of the study. No summary statistics for medication history 
and concomitant medications will be provided.
All medication history and concomitant medications will be listed by site and subject number. 
The listings will contain subject identifier, World Health Organization Drug Dictionary 
(WHODrug) preferred medication name, dose, unit, frequency, route, start date, stop date, 
whether the medication was ongoing, and reason for use. No inferential statistics will be 
presented. 
Medication history and concomitant medications will be coded using the WHODrug Global B2
or higher.
7.7
Study Drug Exposure and Compliance
The date, start and end of infusion time of study drug for each subject will be reported in the data 
listings. Summaries of TAK-954 PK data will be provided; details can be found in section 7.9. 
No other summaries of the extent of exposure to study drug or compliance calculations are 
planned.
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
All PK summaries and analyses will be based on the PK set. 


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Samples for total radioactivity concentration determination in whole blood, plasma, urine, and 
feces, the determination of concentration of TAK-954 in plasma and urine, and metabolite 
profiling in plasma, urine and feces will be collected as specified in the Schedule of Study 
Procedure (see Appendix A).
7.9.1
Pharmacokinetic Analysis
7.9.1.1
TAK-954 Concentration and Total Radioactivity Data 
Descriptive statistics (n, mean, SD, geometric mean, coefficient of variation (%CV), median, 
minimum, and maximum) will be used to summarize plasma concentration of TAK-954 and its 
metabolites and total radioactivity in whole blood and plasma at each scheduled time point, 
respectively. Linear and semi-logarithmic mean and individual plots of plasma concentration of 
TAK-954 and total radioactivity will be displayed by time, respectively. Nominal sampling 
times, rather than actual times, will be used in generating mean concentration-by-time curves; 
while actual sampling times will be used in individual plots.
The ratio of total radioactivity in whole blood to plasma, and the ratio of plasma TAK-954 to 
total radioactivity in plasma will be derived and summarized at each time point.
Individual plasma concentration data will be listed.
7.9.1.2
PK Parameters
The following parameters for TAK-954 and/or total radioactivity will be calculated. The PK 
parameters for TAK-954 and/or total radioactivity 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 and both plasma and whole blood PK 
parameters for radioactivity will be calculated, using Phoenix WinNonlin:

Cmax.

AUClast.

AUC∞.

tmax.

t1/2z.

CL (TAK-954 only).

Vz (TAK-954 only).
The following urinary PK parameters will be calculated for both TAK-954 and radioactivity:

Aet.


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
fet.

CLR(TAK-954 only)
The following fecal parameter will be calculated for total radioactivity:

Aet.

fet.
Other PK parameters may be calculated if deemed necessary for the interpretation of the data 
including PK parameters for the metabolites THRX513466 and THRX 913682, if possible.
Descriptive statistics (N, mean, SD, %CV, median, minimum and maximum) will be used to 
summarize the PK parameters. In addition, geometric means will be calculated. 
Additional analyses may be performed as deemed appropriate.
All PK parameter data will be listed.
7.9.1.3
Radioactivity Parameters/ Profiles
The following radioactivity parameters/profiles will be calculated:

Cumulative recovery (% urine, % feces, and percentage of total radioactivity in urine and 
feces over the entire period of collection).

TAK-954 metabolite profiles in plasma, urine, and feces.
Mass balance will be assessed by percent and cumulative percent of administered radioactivity 
dose recovered in urine, feces and their combined total at appropriate time points. 
Descriptive statistics (N, mean, SD, %CV, median, minimum and maximum) will be 
summarized by each scheduled timepoint. 
Linear mean and individual cumulative excretion of radioactivity in urine, feces, and their 
combined total by time curve will be displayed. 
Individual percentage and cumulative percentage will be presented in data listings. 
Circulatory metabolite profiles will be established for each subject, while pooled excretory 
metabolite profiles will be obtained. Metabolites will be presented as a mean percentage of total 
radioactivity and/or dose. Descriptive statistics will be summarized. 
The results of metabolite profiling will be included in a separate report.
7.9.2
Pharmacodynamic Analysis
Not applicable. 
7.10
Other Outcomes
Not applicable. 


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7.11
Safety Analysis
Safety analyses include AEs, clinical laboratory evaluations, vital sign results, 12-lead ECG 
results, and other safety parameters. The safety set will be used for all summaries of safety 
parameters.
7.11.1 Adverse Events
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study; it does not necessarily have to 
have a causal relationship with study participation. A treatment-emergent adverse event (TEAE) 
is defined as any sign, symptom, syndrome, or new illness, regardless of relationship to study 
drug, which occurs on or after the administration of the study drug and no more than 30 days 
after receiving the study drug (onset date minus date of last dose +1 ≤30). A TEAE may also be 
a pretreatment AE or a concurrent medical condition diagnosed prior to the date of study drug 
that increases in severity after the start of dosing. Any event with partially or completely missing 
onset date information will be considered treatment emergent unless the available information 
indicates that the onset occurred outside the window (onset date - date of last dose +1 > 30) or 
onset date prior to the first dose.
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA, version 21.0 or higher).
AEs are recorded in the eCRF as being related or not related to study drug and study procedure. 
AEs that are recorded as related to study drug and/or study procedure will be summarized 
separately. AEs will also be presented by intensity/severity (mild, moderate, and severe). 
When calculating the frequency and percentage of subjects who reported AEs, a subject will be 
counted only once for each SOC or PT when multiple AEs are coded to the same SOC or PT. 
AEs with missing intensity will be listed as such in the AE listings, however, will be summarized 
as severe in summary tables. If the relationship of an event is missing, the relationship for the 
event will be considered to have been related.
The TEAE summary tables will include numbers and percentages of subjects experiencing at 
least one TEAE by SOC and PT and will be tabulated. The following is a list of TEAE summary 
tables to be generated: 
–
Overview of TEAEs.
–
TEAEs by SOC and PT
–
Serious TEAEs by SOC and PT
–
Drug-Related TEAEs by SOC and PT.
Also, non-treatment-emergent AEs will be summarized by SOC and PT. Data listings will be 
provided for all AEs including TEAEs, AEs leading to trial drug discontinuation, and SAEs. 


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7.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests will be assessed using the Safety Set and will be evaluated and presented 
using International System of Units (SI) units unless otherwise stated. Refer to Appendix A for 
scheduled clinical laboratory test measurements.
For hematology and chemistry tests, descriptive statistics (N, mean, median, SD, minimum and 
maximum) will be summarized for baseline, post-baseline, and change from baseline values by 
study visit. Only the scheduled measurements will be included in the summary. No inferential 
statistics will be presented.
Listings of all clinical safety laboratory data will be provided and will be presented in both SI 
and conventional units. Laboratory data outside of the normal reference range will be indicated 
in the listings and flagged. The listing will include site number, subject identifier, age (at 
informed consent), gender, study visit, and sample collection date.
7.11.3 Vital Signs
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be used to 
summarize vital sign parameters at baseline, each post-baseline visit, and change from baseline 
to each post-baseline visit. Only the scheduled visits will be included in the summary. No 
inferential statistics will be presented.
All vital sign results for all subjects in the Safety Set will be listed by subject in the data listings 
and abnormal values will be flagged.
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 QTcF interval, and the 
interpretation of the ECG profile by the principal investigator.
Descriptive statistics (N, mean, SD, median, minimum, and maximum) of ECG parameters will 
be presented for baseline, each post-baseline visit, and changes from baseline in quantitative 
ECG parameters to each post-baseline visit. Only the scheduled measurements will be included 
in the summary. No inferential statistics will be presented.
All ECG data will be presented in the listings. Abnormal values will be flagged in the listings. 
7.11.5 Other Observations Related to Safety
Not applicable. 
7.12
Interim Analysis
Not applicable.


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7.13
Changes in the Statistical Analysis Plan 
Based on consultation with pharmacovigilance, the last pre-dose value will be used as the 
Baseline for ECG summaries, rather than Screening as stated in the protocol. Based on 
discussion with the team, instead of the individual excretory metabolite profiles, pooled 
excretory metabolite profiles will be established. 


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8.0
REFERENCES
1. A Phase 1, Open-label, Single Intravenous Infusion Dose Study to Evaluate the Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of TAK-954 Containing Microtracer 
([14C]-TAK-954) in Healthy Adult Male Subjects, Millennium Pharmaceuticals, Inc., Initial. 
Trial No. TAK-954-1005, dated 26 March, 2018.


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Appendix A
SCHEDULE OF STUDY PROCEDURES 
Assessment
Screening
Trial Days
Follow-up/ 
Early 
Termination
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9-15
Day 15 
±2 Days 
Hours Postdose
0
24
48
72
96
120
144
168
192-336
Administrative Procedures
Informed consent 
X
Inclusion/exclusion criteria
X
X
Medication history
X
Prior and concomitant medication review
----------------------------------------------Continuous monitoring-------------------------------------------------
Clinic Procedures/Assessments
Full physical exam
X
X a
X
Semirecumbent vital signs (heart rate, 
systolic blood pressure, and diastolic 
blood pressure)
X
X b
X
X
Vital signs (respiratory rate and oral or 
tympanic temperature)
X
X b
X
Height
X
Weight 
X
X
Body mass index
X
Standard 12-lead electrocardiogram
X
X b
X
X
Adverse event monitoring
--------------------------------------------------------Continuous monitoring-------------------------------------------------
Laboratory Procedures/Assessments
Serum chemistry
X
X a
X
Hematology
X
X a
X
Urinalysis
X
X a
X
Urine drug screen
X
X a
Alcohol screen
X
X a
HIV test
X
Hepatitis panel
X
Pharmacokinetics (PK) Evaluations
Blood collection for total radioactivity in 
X----------------------------------------------------------------------------------X


TAK-954-1005
Page 20 of 20
Statistical Analysis Plan Final
18 October 2018
CONFIDENTIAL
Assessment
Screening
Trial Days
Follow-up/ 
Early 
Termination
Day
-28 to -2
-1
1
2
3
4
5
6
7
8
9-15
Day 15 
±2 Days 
Hours Postdose
0
24
48
72
96
120
144
168
192-336
whole blood and plasma, TAK-954 in 
plasma, and metabolite profiling c
Urine collection for total radioactivity, 
TAK-954 concentrations, and metabolite 
profiling d
X
X---------------------------------------------------------------------------------X
Emesis e
X
Feces collection for total radioactivity and 
metabolite profiling f
X
X---------------------------------------------------------------------------------X
Total 14C radioactivity measured by 
accelerator mass spectrometry (AMS) in 
plasma.
X
Drug Administration
[14C]-TAK-954 dosing
X
Other
Confinement
X
X
X
X
X
X
X
X
X g
X g
a Within 24 hours before dosing on Day 1. 
b Assessments predose (between waking up and the start of the infusion) and at the end of the infusion.
c PK blood samples (for total radioactivity in whole blood and plasma and TAK-954 in plasma) are collected predose (within 30 minutes) and at 0.5, 1 (at end of infusion), 1.5, 2, 
3, 4, 6, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose and every 24 hours thereafter while the subject is confined. Blood samples for metabolite profiling will be collected 
predose and at 1 (at end of infusion), 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose and every 24 hours thereafter while the subject is confined.
d Urine will be collected predose (spot sample -12 to 0 hours) and at 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours and every 24 hours thereafter 
while the subject is confined.
e If emesis occurs within 8-10 hours after dosing, vomitus will be collected in a preweighed container assigned to each subject, reweighed, and submitted for analysis of total 
radioactivity.
f Feces will be collected predose (last stool before dosing), and all samples produced up to at least 168 hours postdose (to be pooled in 24-hour intervals) and every 24 hours 
thereafter will be collected while the subject is confined.
g Subjects will be confined only if requirements for discharge are not met.


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