Clinical trial NCT03237156
Conditions: Japanese Healthy Adult Male Participants
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2017-08-07; Completion date: 2017-10-07
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of TAK-906 in Japanese healthy male participants.

Detailed description:
The drug being tested in this study is called TAK-906. TAK-906 is being tested in healthy participants in order to evaluate safety and tolerability of single and multiple oral doses of TAK-906 in Japanese healthy male participants.

The study will enroll approximately 24 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in Cohort 1 or Cohort 3. Study drug will be administered in a double-blind manner which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need), orally, once daily on Day 1 as Single Dose Period and twice daily from Day 3 to 7 as Multiple Dose Period:

* TAK-906 50 mg (Cohort 1)
* TAK-906 100 mg (Cohort 2)
* TAK-906 10 mg (Cohort 3)
* Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient

Cohort 2 will be conducted after the completion of Cohort 1. This will be conducted in Japan.

Arms: arm 1: TAK-906 50 milligram (mg) capsules, orally, once daily on Day 1 as Single Dose Period followed by TAK-906 50 mg capsules, orally, twice daily from Day 3 to 7 as Multiple Dose Period. arm 2: TAK-906 Placebo capsules, orally, once daily on Day 1 as Single Dose Period followed by TAK-906 Placebo capsules, orally, twice daily from Day 3 to 7 as Multiple Dose Period. arm 3: TAK-906 100 mg capsules, orally, once daily on Day 1 as Single Dose Period followed by TAK-906 100 mg capsules, orally, twice daily from Day 3 to 7 as Multiple Dose Period. Cohort 2 will be conducted after Cohort 1. arm 4: TAK-906 Placebo capsules, orally, once daily on Day 1 as Single Dose Period followed by TAK-906 Placebo capsules, orally, twice daily from Day 3 to 7 as Multiple Dose Period. Cohort 2 will be conducted after Cohort 1. arm 5: TAK-906 10 mg capsules, orally, once daily on Day 1 as Single Dose Period followed by TAK-906 10 mg capsules, orally, twice daily from Day 3 to 7 as Multiple Dose Period. arm 6: TAK-906 Placebo capsules, orally, once daily on Day 1 as Single Dose Period followed by TAK-906 Placebo capsules, orally, twice daily from Day 3 to 7 as Multiple Dose Period.
Interventions: intervention 1: TAK-906 intervention 2: TAK-906 Placebo
Intervention descriptions: intervention 1: TAK-906 capsules. intervention 2: Placebo capsules.

Protocol documents:
Prot_000.pdf: 
 
 
Title: A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending 
Dose, Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of TAK-906 in Japanese Healthy Male Subjects 
 
NCT Number: NCT03237156 
Protocol Approve Date: 06-Jun-2017 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
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. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


TAK-906
Study No. TAK-906-1004
Page 1 of 71
Protocol 
6 June 2017
CONFIDENTIAL
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose, 
Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of TAK-906 in Japanese Healthy Male Subjects
Phase 1 TAK-906 Single and Multiple Ascending Dose Study 
in Japanese Healthy Male Subjects
Study Identifier:
TAK-906-1004
Compound:
TAK-906 (investigational ingredient code in Japan: TAK-906M)
Date:
6 June 2017
Version/Amendment 
Number:
Initial Version
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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Study No. TAK-906-1004
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CONFIDENTIAL
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 .................................................................................................15
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................16
5.1
Hypothesis...............................................................................................................16
5.2
Trial Objectives .......................................................................................................16
5.2.1
Trial Primary Objective......................................................................................16
5.2.2
Trial Secondary Objective..................................................................................16
5.2.3
Trial Exploratory Objectives ..............................................................................16
5.3
Endpoints.................................................................................................................16
5.3.1
Primary Endpoint...............................................................................................16
5.3.2
Secondary Endpoints..........................................................................................16
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................18
6.1
Trial Design.............................................................................................................18
6.2
Dose Escalation .......................................................................................................19
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................20
6.3.1
Rationale of Trial Design ...................................................................................20
6.3.2
Rationale for Dose .............................................................................................20
6.3.3
Rationale for Endpoints......................................................................................21
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures ................22
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................22
6.5
Trial Beginning and End/Completion.......................................................................23
6.5.1
Definition of Beginning of the Trial ...................................................................23
6.5.2
Definition of End of the Trial.............................................................................23
6.5.3
Definition of Trial Discontinuation ....................................................................23
6.5.4
Criteria for Premature Termination or Suspension of the Trial............................23
6.5.5
Criteria for Premature Termination or Suspension of an Investigational Site ......24
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............25
7.1
Inclusion Criteria .....................................................................................................25


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CONFIDENTIAL
7.2
Exclusion Criteria ....................................................................................................25
7.3
Excluded Medications, Supplements, Dietary Products............................................28
7.4
Diet, Fluid, Activity.................................................................................................28
7.4.1
Diet and Fluid ....................................................................................................28
7.4.2
Activity..............................................................................................................29
7.5
Documentation of Subjects Failure ..........................................................................30
7.6
Criteria for Discontinuation or Withdrawal of a Subject...........................................30
7.7
Procedures for Discontinuation or Withdrawal of a Subject......................................31
7.8
Subject Replacement................................................................................................31
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................32
8.1
Clinical Study Drug .................................................................................................32
8.1.1
Clinical Study Drug Labeling.............................................................................32
8.1.2
Clinical Study Drug Inventory and Storage ........................................................32
8.1.3
Clinical Study Drug Blinding.............................................................................33
8.1.4
Randomization Code Creation and Storage ........................................................33
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure ....................................33
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs...............................33
9.0
STUDY PROCEDURES...............................................................................................35
9.1
Administrative Procedures.......................................................................................35
9.1.1
Informed Consent Procedure..............................................................................35
9.1.2
Inclusion and Exclusion .....................................................................................35
9.1.3
Medical History/Demography ............................................................................36
9.1.4
Concomitant Medications...................................................................................36
9.2
Clinical Procedures and Assessments.......................................................................36
9.2.1
Full Physical Exam ............................................................................................36
9.2.2
Height and Weight .............................................................................................36
9.2.3
BMI ...................................................................................................................36
9.2.4
Vital Signs .........................................................................................................37
9.2.5
12-Lead ECG.....................................................................................................37
9.2.6
Study Drug Administration ................................................................................37
9.2.7
AE Monitoring...................................................................................................38
9.2.8
Laboratory Procedures and Assessments ............................................................38
9.3
PK, PD, and 
.......................................................................................40
9.3.1
PK Measurements..............................................................................................40
9.3.2
PD Measurements..............................................................................................42
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CONFIDENTIAL
9.3.3
............................................................................................43
9.3.4
Confinement ......................................................................................................44
10.0
ADVERSE EVENTS ....................................................................................................45
10.1
Definitions and Elements of AEs .............................................................................45
10.1.1 SAEs..................................................................................................................47
10.2
AE Procedures.........................................................................................................48
10.2.1 Assigning Severity/Intensity of AEs...................................................................48
10.2.2 Assigning Causality of AEs................................................................................48
10.2.3 Assigning Causality of AEs to Study Procedures................................................49
10.2.4 Start Date...........................................................................................................49
10.2.5 End Date............................................................................................................49
10.2.6 Pattern of Adverse Event (Frequency)................................................................49
10.2.7 Action Taken With Study Treatment..................................................................49
10.2.8 Outcome ............................................................................................................49
10.2.9 Collection and Reporting of AEs, SAEs, and Abnormal LFTs............................50
10.2.10
Safety Reporting to Investigators, IRBs, and Regulatory Authorities ............52
11.0
STATISTICAL METHODS..........................................................................................53
11.1
Statistical and Analytical Plans ................................................................................53
11.1.1 Analysis Sets......................................................................................................53
11.1.2 Analysis of Demography and Other Baseline Characteristics .............................53
11.1.3 PK Analysis .......................................................................................................53
11.1.4 PD Analysis .......................................................................................................54
11.1.5 Safety Analysis ..................................................................................................54
11.2
Interim Analysis and Criteria for Early Termination ................................................54
11.3
Determination of Sample Size..................................................................................55
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................56
12.1
Investigational Site Monitoring Visits......................................................................56
12.2
Protocol Deviations..................................................................................................56
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................56
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................57
13.1
IRB Approval ..........................................................................................................57
13.2
Subject Information, Informed Consent, and Subject Authorization .........................57
13.3
Subject Confidentiality ............................................................................................58
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................59
13.4.1 Publication and Disclosure.................................................................................59
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CONFIDENTIAL
13.4.2 Clinical Trial Registration..................................................................................59
13.4.3 Clinical Trial Results Disclosure ........................................................................59
13.5
Insurance and Compensation for Injury....................................................................59
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................61
14.1
Administrative Information......................................................................................61
14.1.1 Study Contact Information .................................................................................61
14.1.2 INVESTIGATOR AGREEMENT......................................................................61
14.1.3 Study-Related Responsibilities...........................................................................61
14.1.4 List of Abbreviations .........................................................................................61
15.0
DATA HANDLING AND RECORDKEEPING............................................................63
15.1
eCRFs......................................................................................................................63
15.2
Record Retention .....................................................................................................64
16.0
REFERENCES..............................................................................................................65
17.0
APPENDICES...............................................................................................................66
LIST OF IN-TEXT TABLES
Table 6.a
Summary of Dose Cohorts .................................................................................19
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................28
Table 7.b
Overview of Diet/Meal Considerations ..............................................................29
Table 9.a
Number of Capsules per Dose............................................................................38
Table 9.b
Primary Specimen Collections ...........................................................................40
Table 9.c
Collection of Blood Samples for PK Analysis ....................................................42
Table 9.d
Collection of Urine Samples for PK Analysis.....................................................42
Table 9.e
Collection of Blood Samples for PD Analysis ....................................................43
Table 10.a
Takeda Medically Significant AE List................................................................48
LIST OF IN-TEXT FIGURES
Figure 2.a
Schematic of Trial Design....................................................................................9
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................66
Appendix B
Pregnancy and Contraception.............................................................................67
Appendix C
Acceptable Time Window for Study Procedure..................................................69


TAK-906
Study No. TAK-906-1004
Page 6 of 71
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CONFIDENTIAL
1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company Limited
Compound:
TAK-906
Study Identifier: TAK-906-1004
Phase: 1
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose, Phase 1 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-906 in Japanese 
Healthy Male Subjects
Trial Design:
This is a phase 1, randomized, double-blind, placebo-controlled, single and multiple ascending dose, parallel-group 
study in up to 3 cohorts of Japanese healthy male subjects, to assess the safety, tolerability, pharmacokinetics (PK) and 
pharmacodynamics (PD) of TAK-906.
Each cohort will consist of 8 subjects where 6 subjects will be randomized to receive TAK-906 and 2 subjects will be 
randomized to receive matching placebo. The study population will be 24 Japanese healthy male subjects. The 
randomized subjects will receive a single dose of blinded study drug on Day 1 followed by multiple doses of blinded 
study drug twice daily (BID) for 5 days from Day 3 to Day 7, except that an evening dose of study drug will not be 
administered on Day 7. If a subject discontinues from the trial, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and Sponsor. The investigational site should contact the Sponsor for the replacement 
subject’s medication identification number.
In Cohorts 1 and 2, subjects will be randomized to receive TAK-906 maleate 50 mg, 100 mg, or matching placebo. In 
Cohort 3, subjects will be randomized to receive TAK-906 maleate 10 mg, or matching placebo. For each cohort, 
follow-up assessments will occur on Day 14 which is 7 days after completion of the last treatment dose. Dose 
escalation to Cohort 2 will be based on a full blinded review of safety and tolerability data until follow-up assessments 
from Cohort 1. Cohort 3 will be conducted in parallel with Cohort 1 or 2. Dose level in Cohort 2 may be changed 
within the range up to 100 mg, as appropriate, based on safety and pharmacokinetic data in preceding cohorts, ie, 
50 mg BID in Cohort 1 or 10 mg BID in Cohort 3 (if applicable) of this study; however, no higher dose than the 
proposed highest dose (100 mg BID) based on the exposures from the previous study 
 will be given without 
Sponsor and institutional review board (IRB) approval to revise the study protocol.
In either Cohort 1, 2, or 3, each subject will be confined from Day -1 to the morning of Day 8 and discharged after the 
investigator’s confirmation of no significant abnormality in his health through physical examination and tests on 
Day 8, at 24-hour after the morning dose of Day 7.
A single dose and all morning doses of trial medication in multiple dose periods will be administered orally after fast 
of at least 10 hours that continues for at least 4 hours after dosing with restriction of water intake for at least 1 hour 
prior to and after dosing. The evening dose will be administered 12 hours after the morning dose and at least 2 hours 
after dinner. On Day 7, the trial medication will be administered only in the morning.
The study drugs include TAK-906 maleate and matching placebo capsules. The capsules all have the same 
appearance.
Trial Primary Objective:
To evaluate safety and tolerability of single and multiple oral doses of TAK-906 in Japanese healthy male subjects.
Trial Secondary Objectives:
To evaluate PK and PD of single and multiple oral doses of TAK-906 in Japanese healthy male subjects.
Trial Subject Population: Japanese healthy adult male subjects aged 20 to 60 years, inclusive.
Planned Number of Subjects:
Per cohort: 8 each (Cohorts 1, 2, and 3)
(TAK-906: 6, placebo: 2)
Estimated total: 24 (treated)
Planned Number of Sites:
Estimated total: 1 site
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TAK-906
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6 June 2017
CONFIDENTIAL
Dose Levels:
Single dose period: 10, 50, or 100 mg TAK-906 
maleate single dose or placebo.
Multiple dose period: 10, 50, or 100 mg TAK-906 
maleate BID or placebo.
Route of Administration:
Oral
Duration of Treatment:
Single dosing on Day 1 and BID dosing for 5 days on 
Days 3 to 7 (morning dose only on Day 7), for a total of 
6 dosing days.
Planned Trial Duration:
Screening period: Days -28 to -2
Check-in: Day -1
Treatment period: Days 1 to 8
(single dose period: Days 1 and 2, multiple dose period: 
Days 3 to 8)
Follow-up period: Days 9 to 14
Main Criteria for Inclusion:
•
The subject is a Japanese healthy adult male, aged 20 to 60 years, inclusive, at the time of informed consent.
•
The subject weighs at least 50 kg and has a body mass index (BMI) from 18.5 to 25 kg/m2, inclusive at Screening.
•
A male subject who is nonsterilized and sexually active with a female partner of childbearing potential agrees to 
use adequate contraception from the signing of informed consent to 12 weeks (84 days) after the last dose of study 
drug. The female partner of a male subject should also be advised to use adequate contraception.
Main Criteria for Exclusion:
•
The subject has a history of any psychiatric disease that would interfere with the evaluation of study drug activity 
(prolactin concentration) or safety.
•
The subject has a history of seizure or tardive dyskinesia.
•
The subject has a history of hyperprolactinemia, pituitary adenoma, and/or hypothyroidism.
•
The subject has a family history of prolonged QT.
•
The subject has undergone previous gastric bypass surgery or currently has a gastric band fitted.
•
The subject has dysphagia and/or inability to swallow study medication whole.
•
The subject has a QT interval by the Fridericia correction method (QTcF) of >450 msec on the electrocardiogram 
(ECG) at Screening, at Check-in (Day -1), or prior to the first dose of study drug (Day 1 predose).
•
The subject has abnormal Screening or Day -1 laboratory values that suggest a clinically significant underlying 
disease or any subject with the following lab abnormalities:
•
Transaminase (alanine aminotransferase and/or aspartate aminotransferase) and/or total bilirubin >1.5 × 
upper limit of normal.
•
Creatinine >1.2 mg/dL.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study:

Safety and tolerability will be assessed through treatment-emergent adverse events (TEAEs) including corrected 
QT interval prolongation associated AE, neurologic AE, and hyperprolactinemia associated AE, physical 
examinations, vital signs, clinical laboratory tests, and 12-lead electrocardiogram (ECG).
The secondary endpoints will be assessed through evaluation of the following parameters:

PK: Plasma and urine concentrations of TAK-906 and its metabolite M23.

PD: Serum prolactin level.


TAK-906
Study No. TAK-906-1004
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Protocol 
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CONFIDENTIAL
Statistical Considerations:
Safety:
The following analyses will be based on the Safety Analysis Set.
A treatment-emergent AE (TEAE) is defined as an AE whose date of onset occurs on or after the start of study drug. 
TEAEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) dictionary. Frequency 
distribution will be provided by system organ class and preferred term for each regimen. TEAEs will be summarized 
by pooled placebo and each TAK-906 dose level for single dose period and combined single and multiple dose 
periods.
For continuous variables, the observed values and their changes from baseline will be summarized by dose over each 
scheduled sampling time using descriptive statistics. For categorical variables, shift tables showing the number of 
subjects in each category at baseline and each post-baseline visit will be provided by dose.
PK:
The following analyses will be based on the PK Analysis Set.
Plasma concentrations of TAK-906 and M23 will be summarized by dose over each scheduled sampling time using 
descriptive statistics. Individual plasma concentration data versus time will be presented in a data listing. Plasma PK 
parameters for TAK-906 and M23 will be summarized by dose over each scheduled sampling time using descriptive 
statistics (arithmetic mean, SD, median, minimum and maximum). In addition, geometric mean and coefficient of 
variation will be computed for Cmax and AUC. Dose proportionality for TAK-906 and M23 plasma exposures (Cmax
and AUC) will be assessed statistically using a power function model.
Individual urine concentration data versus time will be presented in a data listing. The urine PK parameters for
TAK-906 and M23will be summarized by dose using descriptive statistics.
PD:
The following analyses will be based on the PD Analysis Set.
For the serum prolactin concentration, the observed values and their changes from baseline will be summarized by 
dose over each scheduled sampling time using descriptive statistics.
Sample Size Justification:
A sample size of 8 subjects per cohort (6 active: 2 placebo) will be used in this study, and is considered sufficient for 
the evaluation of TAK-906 safety, tolerability, PK and PD following oral single and multiple doses. The sample size is 
not based on statistical power considerations.


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CONFIDENTIAL
2.0
STUDY SCHEMATIC
Figure 2.a
Schematic of Trial Design
Cohorts 1, 2, and 3
Screening 
Period
Check-in
Single Dose Period
Multiple Dose Period
Follow-up
Visit
Dose/Sample 
Collection
/Safety 
Assessment
Sample 
Collection
/Safety 
Assessment
Dose/Sample 
Collection
/Safety 
Assessment
Sample 
Collection
/Safety 
Assessment
/Discharge
Days -28 to -2
Day -1
Day 1
Day 2
Days 3 to 7
Day 8
Day 14
outpatient
Confinement 
outpatient
BID=twice daily
Cohort 1
Cohort 2
100 mg
Day 1
100 mg BID, 5 days
Day 3 to 7
No dose
Day 2
50 mg
Day 1
50 mg BID, 5 days
Day 3 to7
No dose
Day 2
Cohort 3 (in parallel with Cohort 1/2)
10 mg
Day 1
10 mg BID, 5 days
Day 3 to 7
No dose
Day 2


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CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES
Screening
Check-in
Single Dose Period
Multiple Dose Period
Follow-up
Study Day:
Days
-28 to -2
Day -1
Predose
Day 1
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Early Termination 
Visit
Day 14
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical history/Demography
X
Concomitant medications
---------------------------------------------------Continuous Review-------------------------------------------------------
Clinical Procedures/Assessments (a)
Physical examination
X
X
X
X
X
X
X
X
Height, BMI
X
Weight 
X
X
X
X
X
Vital signs (b)
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG (c)
X
X
X
X
X
X
X
X
X
Study drug administration (d)
X
X
X
X
X
X
AE Monitoring
---------------------------------------------------Continuous Monitoring----------------------------------------------------------
Laboratory Procedures/Assessments (a)
Hematology
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
HBsAg, anti-HCV, HIV antibody/antigen, and 
syphilis screen
X
Prolactin assessment for safety
X(i)
Urine drug screen, urine cotinine test, and alcohol 
screen (urine alcohol test/alcohol breath test)
X


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Study No. TAK-906-1004
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Protocol 
6 June 2017
CONFIDENTIAL
Screening
Check-in
Single Dose Period
Multiple Dose Period
Follow-up
Study Day:
Days
-28 to -2
Day -1
Predose
Day 1
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Early Termination 
Visit
Day 14
PK Evaluations
Plasma sample for TAK-906 PK (e)
X
X
X
X
X
X
X
X
X
X (j)
Urine sample for TAK-906 PK (f)
X
X
X
X
PD Evaluations
Serum sample for PD (g)
X
X
X
X
X
X
X
X
X
X
X
X
Other
Confinement
X
X
X
X
X
X
X
X
X
X
X (j)
Footnotes are on the following page.
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CONFIDENTIAL
AE=adverse event, BMI=body mass index,
, ECG=electrocardiogram, HBsAg=hepatitis B virus surface antigen, HCV=hepatitis C 
virus, HIV=human immunodeficiency virus, PD=pharmacodynamics,
, PK=pharmacokinetics.
(a) Where applicable, all assessments will be conducted in the morning (predose on dosing days) except for Screening, Check-in, and Follow-up.
(b) Vital sign measurements will occur:
Days 1-2: Predose, 1, 2, 4, 6, and 24 hours post single dose.
Days 3-6: Before morning dose.
Days 7-8: Predose, 1, 2, 4, 6, and 24 hours post morning dose.
Day 14
(c) 12-lead ECG measurements will occur:
Days 1-2: Predose, 1, 2, 4, 6, and 24 hours post single dose.
Day 5: Predose, 1, and 2 hours post morning dose.
Days 7-8: Predose, 1, 2, 4, 6, and 24 hours post morning dose.
(d) TAK-906 or matching placebo will be administered as a witnessed dose at approximately 07:00-08:00 and at approximately 19:00-20:00. Daily study drug 
administration in the multiple dose period should be within ±5 minutes of nominal dosing times on Day 3. On Day 7, study drug administration time should be 
as close to the time of Day 3 dosing as possible. An evening dose of study drug will not be administered on Day 7.
(e) Plasma sample for TAK-906 PK and M23 will be collected:
Days 1-2: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post single dose.
Days 3-6: Just before morning dose.
Days 7-8: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post morning dose.
(f) Urine sample for TAK-906 PK and M23 will be collected:
Days 1-2: Predose (spot), 0-6, 6-12, and 12-24 hours post single dose.
Day 7: 0-6 and 6-12 hours post morning dose.
(g) Serum sample for PD will be collected:
Days 1-2: Predose, 1, 2, 4, 6, and 24 hours post single dose.
Days 3-6: Just before morning dose.
Days 7-8: Predose, 1, 2, 4, 6, and 24 hours post morning dose.
Day 14
.
(i)
Serum prolactin level will be measured at Screening by the local laboratory for safety assessment.
(j)
For any early termination during Follow-up, outpatient assessments should be performed, and PK blood sample will not be collected.
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4.0
INTRODUCTION
4.1
Background
TAK-906 is a peripherally selective dopamine (DA) D2/D3 receptor antagonist and being 
developed as a potential treatment for gastrointestinal (GI) motility disorders, such as diabetic or 
idiopathic gastroparesis.
Gastroparesis is a disorder of the stomach characterized by delayed gastric emptying in the 
absence of mechanical obstruction. After food intake, the normal stomach serves to triturate the 
food and to deliver it into the duodenum by peristalsis; however, this gastric motility is known to 
be reduced in patients with gastroparesis and the delayed gastric emptying causes gastrointestinal 
symptoms, such as abdominal bloating and vomiting. Idiopathic, diabetic, and postsurgical 
etiologies comprise the majority of gastroparesis cases [1].
The prevalence of gastroparesis in the United States (US) is 24.2 per 100,000 person [2]. In 
another report, the prevalence of gastroparesis is approximately 4% to 5% of the general 
population and higher prevalence is associated with diabetes mellitus patients; diabetic 
gastroparesis is present in 5% to 12% of overall diabetes mellitus population, particularly in 30%
to 50% of patients with type 1 diabetes mellitus [3]. In Japan, a diagnostic procedure has not been
established for gastroparesis and the prevalence has not been well described; however, considering 
the prevalence of gastroparesis in patients with diabetes mellitus in the US, gastroparesis seems
not to be a rare disease but an infrequently diagnosed disease in Japan, where a number of potential 
patients are expected to be found.
Dopamine D2 and D3 receptors are demonstrated to be involved in the development of 
gastroparesis [4][5][6]. Activation of dopamine D2 and D3 receptors lying in the upper 
gastrointestinal tract and in the area postrema induces suppression of acetylcholine release, 
decreased muscle tension of the lower esophageal sphincter and stomach, and relaxation of
stomach smooth muscle. Dopamine D2/D3 receptor antagonists are reported to eliminate the 
suppression of acetylcholine release by suppressing activation of dopamine D2 and D3 receptors, to 
increase lower esophageal sphincter and stomach muscle tension, and to promote the gastric 
emptying.
Currently in the US, there exists a large unmet medical need because there are no approved 
therapies for the chronic treatment of diabetic gastroparesis. Metoclopramide, a dopamine D2
receptor antagonist, and domperidone, a peripherally-acting dopamine D2/D3 receptor antagonist, 
are prokinetic agents marketed in Japan. They are known to cause extrapyramidal symptoms 
(EPS) and cardiovascular side effects, respectively. The most notable toxicities of metoclopramide 
are a category of movement disorders known as EPS [7]. EPS are caused by blockade of dopamine
D2 receptors in the dorsal striatum and thus are potential side effects of all centrally-penetrant 
drugs that share this mechanism of action, particularly selective dopamine D2 receptor antagonists.
Of greatest concern is tardive dyskinesia, a severe and often irreversible EPS. The risk of 
developing tardive dyskinesia increases with dose level and duration of treatment and as such, the 
US package insert includes a black box warning regarding the chronic use of metoclopramide for 
longer than 12 weeks. Domperidone is a peripherally-acting dopamine D2/D3 receptor antagonist 


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marketed for use as an antiemetic and prokinetic agent in a number of countries worldwide
including Japan, although not in the US due to its cardiovascular safety profile which includes 
risks for drug-induced long QT syndrome, torsades de pointes, and sudden cardiac death [8].
Nonclinical in vitro and in vivo pharmacology studies have demonstrated that TAK-906 has D2/D3
antagonism with a potency comparable to or greater than domperidone and metoclopramide.
TAK-906 does not readily penetrate the blood brain barrier (BBB) and therefore it can block 
dopamine D2/D3 receptors in the area postrema outside of the BBB to reduce symptoms of 
gastroparesis, such as nausea and vomiting, but not block those inside of the BBB which are likely 
to cause EPS [9][10]. In addition, TAK-906 is a very weak inhibitor of the human ether-a-go-go 
related gene (hERG) channel, thus reducing the potential for fatal arrhythmias [8]. Therefore, 
TAK-906 is expected to exhibit comparable or greater prokinetic effects and less adverse effects
compared with existing products on the market, which makes TAK-906 a promising drug for the 
treatment of gastroparesis.
4.2
Rationale for the Proposed Study
This is a phase 1, randomized, double-blind, placebo-controlled, single and multiple ascending 
dose, parallel-group study in Japanese healthy male subjects, to assess the safety, tolerability, PK, 
and PD of TAK-906.
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TAK-906 is a peripherally-acting dopamine D2/D3 receptor antagonist belonging to a class of 
prokinetic drugs shown to be effective in the treatment of gastroparesis. However, chronic use of 
these agents has been limited due to their toxicity. Nonclinical in vitro and in vivo pharmacology 
studies have demonstrated that TAK-906 has D2/D3 antagonism with a potency comparable to or 
greater than domperidone and metoclopramide. In addition, TAK-906 is not expected to result in 
the adverse effects including EPS and cardiovascular event associated with these two agents due to 
its limited BBB penetration (relative to metoclopramide) and weak hERG channel affinity 
(relative to domperidone). As TAK-906 is expected to exhibit comparable or greater prokinetic 
effects and less adverse effects compared with existing dopamine D2/D3 receptor antagonists on 
the market, TAK-906 is being developed as a potential treatment for gastroparesis.
In Japan, no diagnostic procedure or criteria has not been established for gastroparesis, while a 
number of potential patients are expected to be found. Therefore, it is considered clinically 
important to promptly introduce TAK-906 in clinical settings by advancing its development
simultaneously in Japan and other countries.
As described above, a foreign phase 1 study has been completed and shown that administration of 
single and multiple oral TAK-906 maleate doses has been well tolerated in healthy men and 
women and that TAK-906 is expected to have a better safety profile over existing products on the 
market. Based on theese results, a global phase 2 study in other countries is being contemplated. 
With intent to participate in the global phase 2 study from Japan, this study was planned to 
evaluate the safety and PK of TAK-906 in Japanese subjects and assess safety and 
pharmacokinetic data similarity between Japanese and non-Japanese subjects. In order to enable 
comparisons of non-Japanese subjects’ safety and pharmacokinetic data in the foreign phase 1 
study with those of the Japanese subjects in this study, this trial design, doses, and endpoints were 
set by referencing the foreign phase 1.
4.3
Benefit/Risk Profile
There will be no benefit to subjects in this study other than receiving physical examinations and 
obtaining information about their general health. Instead, patients with gastroparesis may benefit 
in the future from what can be learned in this study.
As for risk to subjects, clinical safety information is limited to data from the one foreign phase 1 
trial.
For further information on TAK-906, please refer to the Investigator’s Brochure.


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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
This study was designated based on the following hypotheses:

TAK-906 will be safe and well tolerated in Japanese healthy male subjects in the doses to be 
tested.

Following the first dose, one or more well-tolerated doses of TAK-906 will result in a 3-fold 
increase in serum prolactin at the maximum level of serum prolactin (Cmax) as compared to 
baseline for each treatment period (single dose period, multiple dose period).
5.2
Trial Objectives
5.2.1
Trial Primary Objective
The primary objective of the study is to evaluate safety and tolerability of single and multiple oral 
doses of TAK-906 in Japanese healthy male subjects.
5.2.2
Trial Secondary Objective
The secondary objective of the study is to evaluate PK and PD of single and multiple oral doses of 
TAK-906 in Japanese healthy male subjects.
5.2.3
Trial Exploratory Objectives
5.3
Endpoints
5.3.1
Primary Endpoint
The study’s primary endpoints of safety and tolerability will be assessed through TEAEs including 
QTc prolongation associated AE, neurologic AE, and hyperprolactinemia associated AE, physical 
examinations, vital signs, clinical laboratory tests, and 12-lead electrocardiogram (ECG).
5.3.2
Secondary Endpoints
Secondary endpoints include:
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1. PK: Plasma and urine concentrations of TAK-906 and its metabolite, M23.
2. PD: Serum prolactin level.


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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design
This is a phase 1, randomized, double-blind, placebo-controlled, single and multiple dose, 
parallel-group study in up to 3 cohorts of Japanese healthy male subjects, to assess the safety, 
tolerability, PK, and PD of TAK-906.
Each cohort will consist of 8 subjects where 6 subjects will be randomized to receive TAK-906 
and 2 subjects will be randomized to receive matching placebo. The study population will be 
24 Japanese healthy male subjects. The randomized subjects will receive a single dose of blinded 
study drug on Day 1 followed by multiple doses of blinded study drug BID for 5 days from Day 3 
to Day 7, except that an evening dose of study drug will not be administered on Day 7. If a subject 
discontinues from the trial, a replacement subject may be enrolled, if deemed appropriate by the 
investigator and Sponsor. The investigational site should contact the Sponsor for the replacement 
subject’s medication identification number.
In Cohorts 1 and 2, subjects will be randomized to receive TAK-906 maleate 50 mg, 100 mg, or 
matching placebo. In Cohort 3, subjects will be randomized to receive TAK-906 maleate 10 mg, or 
matching placebo. For each cohort, follow-up assessments will occur on Day 14 which is 7 days 
after completion of the last treatment dose. Dose escalation to Cohort 2 will be based on a full 
blinded review of safety and tolerability data until follow-up assessments from Cohort 1. Cohort 3 
will be conducted in parallel with Cohort 1 or 2. Dose level in Cohort 2 may be changed within the 
range up to 100 mg, as appropriate, based on safety and pharmacokinetic data in preceding 
cohorts, ie, 50 mg BID in Cohort 1 or 10 mg BID in Cohort 3 (if applicable) of this study; 
however, no higher dose than the proposed highest dose (100 mg BID) 
 
 will be given without Sponsor and institutional review board 
(IRB) approval to revise the study protocol.
The planned dose levels of TAK-906 to be evaluated are outlined in Table 6.a.
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Table 6.a
Summary of Dose Cohorts
Cohort (a)
TAK-906 maleate Dose (a, b, c)
Subjects
Single Dose Period
Multiple Dose Period (d)
1
50 mg single dose
on Day 1
50 mg BID for 5 days
from Days 3 to 7
6 TAK-906
2 Placebo
2
100 mg single dose
on Day 1
100 mg BID for 5 days
from Days 3 to 7
6 TAK-906
2 Placebo
3
10 mg single dose
on Day 1
10 mg BID for 5 days
from Days 3 to 7
6 TAK-906
2 Placebo
BID=twice daily
(a) Dose escalation to Cohort 2 will be based on a full blinded review of safety and tolerability data until follow-up 
assessments from Cohort 1. Cohort 3 will be conducted in parallel with Cohort 1 or 2.
(b) A single dose and all morning doses of trial medication in multiple dose periods will be administered after fast of 
at least 10 hours that continues for at least 4 hours after dosing with restricted water intake for at least 1 hour prior 
to and after dosing. The evening dose will be administered 12 hours after the morning dose and at least 2 hours 
after dinner.
(c) Dose level in Cohort 2 may be changed within the range up to 100 mg, as appropriate, based on safety and 
pharmacokinetic data in preceding cohorts, ie, 50 mg BID in Cohort 1 or 10 mg BID in Cohort 3 (if applicable) of 
this study
(d) An evening dose of study drug will not be administered on Day 7.
6.2
Dose Escalation
The investigator will comprehensively examine the blinded safety results (AEs, physical 
examinations, vital signs, records of laboratory tests, and 12-lead ECG findings) obtained at all 
examinations by 14 days after the start of study drug administration in Cohort 1 and then 
determines the entry of Cohort 2 after discussion(s) with the Sponsor, and if appropriate, with 
medical experts.
Other criteria to consider discontinuation of the entry of Cohort 2 are as follows.
1. On an occasion that a SAE, of which relationship to the study drug cannot be denied, is 
observed.
2. At the onset of an AE for which relationship to the study drug cannot be denied and for which 
it is considered difficult to give medications continuously.
Furthermore, the maximum dose in this study was set at 100 mg BID for Cohort 2, based on the 
data from preceding studies, as described in Section 6.3.2. Dose level in Cohort 2 may be changed
within the range up to 100 mg, as appropriate, based on the safety and pharmacokinetic data of 
preceding cohorts, ie, 50 mg BID in Cohort 1 or 10 mg BID in Cohort 3 (if applicable) of this 
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6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale of Trial Design
In this study, a single dose period will be followed by a multiple dose period in each cohort
 
 
 
 Therefore, combining single and multiple doses 
in one study, with safety evaluations for at least 24 hours after the single dose is considered 
appropriate for the assessment of safety and PK in Japanese subjects receiving single and multiple 
doses of TAK-906 maleate. For  each cohort, follow-up assessments will occur on Day 14 which is 
7 days after completion of the last treatment dose, based on an 11 hour half-life ensuring that 
TAK-906 PK washout will be completed in 4 days.
Double-blind fashion using a matching placebo were selected for this first study in Japanese 
healthy male volunteers in order to adequately evaluate safety in Japanese subjects.
6.3.2
Rationale for Dose
 
The proposed starting dose is 50 mg BID and the proposed 
highest dose is 100 mg BID. Several considerations were given in selecting these doses: safety, 
tolerability, PK and PD (serum prolactin concentration).
Based on the overall nonclinical safety profile, the dog was considered the most sensitive species 
for TAK-906 and was used as the basis for the maximum recommended starting dose (MRSD) in
the foreign phase 1 study. The TAK-906 maleate no-observed-adverse-effect level (NOAEL) in 
the pivotal 28-day repeat-dose study in dogs was 50 mg/kg/day, at which central nervous system 
(CNS)-associated pharmacological effects typical of this pharmacologic class occurred on 
multiple occasions in all animals, including mild sedation, mild intermittent and/or continuous 
tremors and ataxia. The lowest observed effect level (LOEL) for CNS effects in the dog was 
considered to be 10 mg/kg/day. At 1 mg/kg/day of TAK-906 mateate, a single occurrence of mild 
tremors was observed in 1 female dog on Day 1 and thus a 1 mg was considered an appropriately 
conservative dose at which to establish MRSD. The MRSD of 0.06 mg/kg/day (3.6 mg/day per 
60 kg person) was calculated based on human equivalent dose converted using body surfice area 
and safety factor (10). Based on the results, a dose of 5 mg is considered as an safe initial clinical 
dose. In the foreign phase 1 study, single dose ranging from 5 to 300 mg and multiple doses of 50 
and 100 mg BID for 5 days were examined. From the results, favorable safety and tolerability of 
TAK-906 in non-Japanese subjects was demonstrated within the range of doses studied.The 
proposed starting dose for this study is 50 mg BID 
 
At a dose of 50 mg BID at steady state (AUC24 116 h*ng/mL; Cmax 31.2 ng/mL), 
AUC and Cmax exposure margins at the dog LOEL for CNS effects are ≥3-fold and ≥8-fold, 
respectively.
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The proposed highest dose for this study is 100 mg BID
 
There was little if any accumulation in serum prolactin concentrations with repeated dosing. As 
TAK-906 maleate dosing at 100 mg BID is predicted to be associated to nearly maximum 
prolactin production at steady state, 100 mg BID is considered an appropriate maximum dose for 
examination. This regimen was shown to be safe and well tolerated in non-Japanese subjects. In 
addition, this regimen was associated with a geometric means of AUC12 of 200.5 h*ng/mL and 
Cmax of 71.6 ng/mL as TAK-906 exposures in non-Japanese subjects, and provides approximately 
15- and 27-fold margin in daily exposure compared with the exposures in female dogs, which are 
lower than those in male dogs (AUC 10800 and 5880 h*ng/mL, Cmax 4340 and 1900 ng/mL in 
male and female dogs, respectively) observed at the dog NOAEL of 50 mg/kg/day, respectively.
Modification of this dose level may be taken into consideration depending onpreceding Cohort 1
results, in which dose level will corresponding to the 50 mg BID starting dose.
In this study, a 10 mg BID dose regimen will also examined in Cohort 3. The regimen was selected 
to enable safety, PK, and PD evaluations over a wider dose range than that for the multiple dose 
period in the foreign phase 1 study. This cohort will be conducted in parallel with the other cohorts
of 50 mg BID or 100 mg BID.
6.3.3
Rationale for Endpoints
6.3.3.1
Safety Endpoints
The commonly used safety endpoints of AEs, physical examinations, vital signs, clinical 
laboratory tests, and 12-lead ECG assessment will be used in this study as safety endpoints. In 
addition, considering the mechanism of action of TAK-906 and the safety profile of existing 
dopamine D2/D3 receptor antagonists on the market, the following AEs will be monitored more 
carefully: QTc prolongation associated AE, neurologic AE, and hyperprolactinemia associated 
AE.
Consistently elevated serum prolactin levels greater than 30 ng/mL in the absence of pregnancy 
and postpartum lactation are indicative of hyperprolactinemia. Hyperprolactinemia can result in 
galactorrhea, amenorrhea, and infertility in females, and in impotence and hypogonadism in 
males. Serum prolactin levels measured for PD analysis will not be used for safety evaluations by 
the investigator or sub-investigator.
6.3.3.2
PK Endpoints
To assess the PK of TAK-906 (at single and multiple oral doses up to 100 mg and 100 mg BID, 
respectively) in Japanese healthy male subjects, plasma and urine concentration of TAK-906 and 
its metabolite, M23 will be examined, and the following PK parameters for TAK-906 will be 
derived:

Single dose period (Day 1): AUC∞, AUCt, Cmax, tmax, Aet, fe,t, CLR

Multiple dose period (Day 7): AUCτ,ss, Cmax,ss, tmax,ss, Aeτ, fe,τ, CLR
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Other PK parameters maybe calculated if deemed necessary for the interpretation of data.
6.3.3.3
PD Endpoints
The following PD parameters for serum prolactin will be derived:

Single dose period (Day 1): AUCt, Cmax

Multiple dose period (Day 7): AUCτ,ss, Cmax,ss
Other PD parameters maybe calculated if deemed necessary for the interpretation of data.
Serum prolactin levels will be measured as a target engagement marker. Dopamine inhibits 
prolactin production by pituitary lactotroph cells. When the D2 receptor is inhibited, serum 
prolactin levels rise and can serve as a marker for dopamine D2 receptor engagement.
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures
For this trial, the collection of blood samples for TAK-906 PK is the critical procedure.

At any post-dose time point, the blood samples for TAK-906 PK need to be collected as close 
to the exact nominal time point as possible.

All other procedures should be completed as close as possible, either before or after these
prescribed/scheduled times.

When ECG and/or vital signs measurements are scheduled at the same time as PK sampling, 
the blood draw will take priority and ECG and/or vital signs will be obtained within an 
acceptable time window (see Appendix C).

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 a safety concern will take 
precedence over all routine scheduled procedures.
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
Dose level in Cohort 2 may be changed within the range up to 100 mg, as appropriate, based on the 
safety and pharmacokinetic data of preceding cohorts, ie, 50 mg BID in Cohort 1 or 10 mg BID in 
Cohort 3 (if applicable) of this study.
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6.5
Trial Beginning and End/Completion
6.5.1
Definition of Beginning of the Trial
The overall trial begins when the first subject signs the trial’s informed consent form.
6.5.2
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).
6.5.3
Definition of Trial Discontinuation
Trial discontinuation because of nonsafety reasons, such as:

A finding (eg, PK, PD, efficacy, biologic targets) from another nonclinical or clinical trial 
using the trial treatment(s) results in the trial being stopped for a nonsafety-related reason.

Data from comparator(s), drug(s) of the same class, or methodology(ies) used in this trial 
become available and results in the trial being stopped for a nonsafety-related reason.

The trial is stopped because of nonscientific and nonsafety reasons, such as slow enrollment.
Trial discontinuation because of safety reasons:

Early trial termination because of unanticipated concerns of safety to the trial subjects arising 
from clinical or preclinical trials with the trial treatment(s), comparator(s), drug(s) of the same 
class, or methodology(ies) used in this trial.
6.5.4
Criteria for Premature Termination or Suspension of the Trial
6.5.4.1
Criteria for Premature Termination or Suspension of the Trial
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study.
1. New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for TAK-906, such that the risk is no 
longer acceptable for subjects participating in the study.
2. Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
3. Two or more subjects in any single cohort or across more than 1 cohort experience any of the 
Takeda Medically Significant List events (as outlined in Table 10.a).
4. Two or more subjects in any single cohort experience a QTcF of >500 msec or an increased 
QTcF of >60 msec relative to baseline.
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a.
Two or more subjects in any single cohort or across more than 1 cohort experience 
alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations of 
>5 × upper limit of normal (ULN) in the absence of a concomitant bilirubin increase.
b.
One or more subjects in any single cohort experience ALT and/or AST elevations of >3 
×ULN in the presence of a total bilirubin increase of >2 ×ULN or an international 
normalized ratio (INR) of >1.5 without findings of cholestasis or other alternate etiology 
to explain the elevations (ie, “Hy’s Law cases”).
c.
Two or more subjects in any single cohort or across more than 1 cohort experience ALT 
and/or AST elevations of >3 ×ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).
6.5.4.2
Procedures for Premature Termination or Suspension of the Trial
In the event that the Sponsor, an IRB, or a regulatory authority elects to terminate or suspend the 
study or the participation of an investigational site, a study-specific procedure for early 
termination or suspension will be provided by the Sponsor; the procedure will be followed by 
applicable investigational sites during the course of termination or study suspension.
6.5.5
Criteria for Premature Termination or Suspension of an Investigational Site
6.5.5.1
Criteria for Premature Termination or Suspension of an Investigational Site
An investigational site may be terminated prematurely or suspended if the site (including the 
investigator) is found in significant violation of GCP, protocol, or contractual agreement, is unable 
to ensure adequate performance of the study, or as otherwise permitted by the contractual 
agreement.
6.5.5.2
Procedures for Premature Termination or Suspension of an Investigational Site
In the event that the Sponsor, an IRB, or a regulatory authority elects to terminate or suspend the 
study or the participation of an investigational site, a study-specific procedure for early 
termination or suspension will be provided by the Sponsor; the procedure will be followed by 
applicable investigational sites during the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to the first dose of study drug.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study:
1. In the opinion of the investigator or sub-investigator, the subject is capable of understanding 
and complying with protocol requirements.
2. The subject signs and dates a written, informed consent form prior to the initiation of any study 
procedures.
3. The subject is a Japanese healthy adult male, aged 20 to 60 years, inclusive, at the time of 
informed consent.
4. The subject weighs at least 50 kg and has a body mass index (BMI) from 18.5 to 25 kg/m2, 
inclusive at Screening.
5. A male subject who is nonsterilized and sexually active with a female partner of childbearing 
potential agrees to use adequate contraception* from the signing of informed consent to 12 
weeks (84 days) after the last dose of study drug. The female partner of a male subject should 
also be advised to use adequate contraception*.
* Definitions and procedures for adequate contraception and pregnancy avoidance, and 
reporting responsibilities are defined in Appendix B.
[Justification for inclusion criteria]
Criteria 1, 2, 3 and 5 are set as standard criteria for the conduct of clinical pharmacological studies
in healthy adults.
Criterion 4
Since whole blood collections of 400 mL from individuals weighing less than 50 kg is harmful to 
health according to the Act on Securing a Stable Supply of Safe Blood Products (Ministry of 
Health and Welfare [MHW] ordinance No. 22 in 1956) [11], the lower weight limit is set at 50 kg.
For BMI, Japanese subjects are to be within range of the standard weight according to the Criteria 
for Obesity Disease proposed by the Japan Society for the Study of Obesity [12].
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has received any investigational compound within 16 weeks (112 days) prior to the
first dose of study drug.
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3. The subject is an immediate family member of or an investigational site employee, or is in a 
dependent relationship with an investigational site employee who is involved in the conduct of 
this study (eg, spouse, parent, child, sibling) or may consent under duress.
4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality, which 
may impact the ability of the subject to participate in the study or potentially confound its
results.
5. The subject has a history of any psychiatric disease that would interfere with the evaluation of 
study drug activity (prolactin concentration) or safety.
6. The subject has a history of seizure or tardive dyskinesia.
7. The subject has a history of hyperprolactinemia, pituitary adenoma, and/or hypothyroidism.
8. The subject has a family history of prolonged QT.
9. The subject has undergone previous gastric bypass surgery or currently nad a gastric band
fitted.
10. The subject has dysphagia and/or inability to swallow study medication whole.
11. The subject has a known hypersensitivity to any component of the TAK-906 formulation or 
related compounds.
12. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within 2 years prior to the Screening visit, or is unwilling to agree to abstain from 
alcohol and drugs throughout the study, or has a positive urine test result for drugs of abuse or 
a positive alcohol screen (urine alcohol test/breath test) result for alcohol at Screening.
13. The subject has taken any excluded medication, supplements, or dietary products during the 
time periods listed in the Excluded Medications, Supplements, and Dietary Products table in 
Section 7.3.
14. If male, the subject intends to donate sperm during the course of this study or for at least 
12 weeks (84 days) after the last dose of study drug.
15. The subject has current or recent (within 24 weeks [168 days]) gastrointestinal disease that 
would be expected to influence the absorption of drugs (ie, a history of malabsorption, 
esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent [more than once per 
week] occurrence of heartburn, or any surgical intervention).
16. The subject has a history of cancer, except basal cell carcinoma which has been in remission 
for at least 5 years prior to Day 1.
17. The subject has a positive test result for hepatitis B virus surface antigen (HBsAg), hepatitis C 
virus (HCV) antibody, human immunodeficiency virus (HIV) antibody/antigen, or serological 
reactions for syphilis at Screening.


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18. The subject has used nicotine-containing products (including but not limited to cigarettes, 
pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 4 weeks (28 days) prior 
to the first dose of study drug. Cotinine test is positive at Screening.
19. The subject has poor peripheral venous access.
20. The subject has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) 
or at least 400 mL within 12 weeks (84 days) prior to the start of study drug administration.
21. The subject has undergone whole blood collection of at least 800 mL in total within 52 weeks 
(364 days) prior to the start of study drug administration.
22. The subject has undergone blood component collection within 2 weeks (14 days) prior to the 
start of study drug administration.
23. The subject has a Screening or Check-in (Day -1) ECG that was abnormal (clinically 
significant).
24. The subject has a QTcF of >450 msec on the ECG at Screening, at Check-in (Day -1), or prior 
to the first dose of study drug (Day 1 predose).
25. The subject has abnormal Screening or Day -1 laboratory values that suggest a clinically 
significant underlying disease or any subject with the following lab abnormalities:

Transaminase (ALT and/or AST) and/or total bilirubin >1.5 ×ULN.

Creatinine >1.2 mg/dL.
26. The subject who, in the opinion of the investigator or sub-investigator, is unlikely to comply 
with the protocol or is unsuitable for any other reason.
[Justification for exclusion criteria]
Criterion 1 is set to specify a minimum interval not affected by any previous clinical trial in order 
to ensure the safety of subjects, in reference to “General Considerations for Clinical Trials” [13].
Criteria 2, 3, 4, 12, 13, 14, 16,17, 18, 19, and 26 are set as standard criteria for clinical 
pharmacological studies in healthy adults and in consideration of subjects’ safety.
Criterion 5 is set due to the possibility of effects on safety and PD evaluations.
Criterion 6, 7, 8, 9, 11, 23, 24, and 25 are set in consideration of subjects’ safety.
Criterion 10 is set due to the possibility of effects on PK evaluations.
Criterion 13 is set as a standard criterion for clinical pharmacological studies in healthy adults and 
in consideration of subjects’ safety, and also due to the possibility of effects on PK evaluations.
Criterion 15 is set in consideration of subjects’ safety and also due to the possibility of effects on 
PK evaluations.


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Criteria 20 to 22 are set in accordance with the Act on Securing a Stable Supply of Safe Blood 
Products (MHW ordinance No. 22 in 1956) [11].
7.3
Excluded Medications, Supplements, Dietary Products
Use of excluded agents (prescription or nonprescription) or dietary products is outlined in Table 
7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
28 days prior to 
treatment (Day 1)
to Follow-up
7 days prior to 
treatment (Day 1)
to Follow-up
7 days prior to 
treatment (Day 1)
to Discharge (Day 8)
24 hours prior to 
treatment (Day 1)
to Discharge (Day 8)
• Prescription medications
• OTC medications
• Neutraceuticals 
(St. John’s wort, ginseng, 
kava kava, ginkgo biloba, 
and melatonin)
• Chinese herbals
• Immunization/Vaccines
• Nicotine-containing 
products
• Grapefruit/
grapefruit juice
• Brassica vegetables
(eg, kale, broccoli, 
watercress, collard 
greens, kohlrabi, 
Brussels sprouts, 
and mustard)
• Charbroiled meats
• Vitamin supplements
• Alcohol-containing 
products
• Caffeine-containing 
products
• Fruit juice
OTC=over-the-counter.
Note: If required to treat an AE, certain medications may be allowed after discussion and agreement between the 
Sponsor and the investigator.
Subjects must be instructed not to take any medications including over-the-counter (OTC) 
products, without first consulting with the investigator or sub-investigator.
7.4
Diet, Fluid, Activity
7.4.1
Diet and Fluid
Subjects must abstain from all food and drink (except water) at least 8 hours before any clinical 
laboratory evaluations. On a day of study drug administration, subjects must not drink water, with 
the exception of water (240 mL) to take medication, between 1 hour prior to and 1 hour after 
dosing.
On the day of Check-in (Day -1), dinner will be consumed by 21:00. On Days 3 through 7, dinner 
will be taken at least 2 hours before evening doses (no evening dose on Day 7).
Breakfast must not be taken on the all days of study drug administration. The subjects must fast for 
10 hours or more prior to and 4 hours after a single dose and all morning doses of trial medication 
in multiple dose periods. 
An overview of the diet/meal considerations is presented in Table 7.b.


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Table 7.b
Overview of Diet/Meal Considerations
Cohorts 1, 2, and 3
Day 1
Approximate Time
Dose
Meal
08:00-09:00
X
No breakfast
12:00-13:00
Standard Lunch
19:00-20:00
Standard Dinner
Day 2
Approximate Time
Dose
Meal
08:00-09:00
Standard Breakfast
12:00-13:00
Standard Lunch
19:00-20:00
Standard Dinner
Days 3 through 7
Approximate Time
Dose
Meal
08:00-09:00
X
No breakfast
12:00-13:00
Standard Lunch
17:00-18:00
Standard Dinner (at least 2 hours before evening dose)
20:00-21:00
X (No evening dose on Day 7)
During hospitalization, subjects will take given meals and will not be allowed to take any other 
food. The caloric content and meal composition will be the same for each cohort.
After discharge, excessive eating or drinking should be avoided until all follow-ups are completed.
7.4.2
Activity
Supine positions are not allowed for 1 hour after dosing, unless irequired for examinations, etc.
Excessive exercise is not allowed during the study period. Subjects should do 15 minutes of light 
exercise a day during the hospitalization.
Blood donations are not allowed for at least 12 weeks (84 days) after the final examination in this 
study.
If a subject visits another medical institution during the study period, the investigator or 
sub-investigator should be informed of the visit in advance whenever possible, and should be 
reported the circumstances and therapy after visit. The investigator should communicate that
medical institution about the subject’s participation in the study.
No photosafety assessment has been performed to date with TAK-906; therefore, subjects should 
be cautioned to avoid exposure to direct sunlight during hospitalization.


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7.5
Documentation of Subjects Failure
The investigator or sub-investigator must account for all subjects who sign informed consent. If a 
subject is withdrawn from the study before the first study drug administration, the investigator or 
sub-investigator should complete the electronic case report form (eCRF).
Primary reasons for subject failure are to be recorded in the eCRF using the following categories:

Death.

AE.

Screen Failure (failed inclusion criteria or did meet exclusion criteria) <specify reason>.

Protocol deviation.

Lost to follow-up.

Withdrawal by subject <specify reason>.

Study terminated by Sponsor.

Sample size sufficient.

Other <specify reason>.
Subject identification numbers assigned to subjects who fail screening should not be reused. 
However if a reserve subject is to participate in another cohort, the same subject identification 
number may be used.
7.6
Criteria for Discontinuation or Withdrawal of a Subject
Primary reasons for discontinuation or withdrawal of a subject from the study or study drug should 
be recorded in the eCRF using the following categories. For subject failure, refer to Section 7.5.
1. Death. The subject died on study.
Note: If the subject dies on study, the event will be considered as SAE. See Section 10.2.9.3 for 
the reporting procedures.
2. AE. The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.
In multidose studies, study drug should be discontinued immediately with appropriate clinical 
follow-up (including repeat laboratory tests, until the subject’s laboratory profile has returned 
to normal/baseline status, see Section 9.2.8), if the following circumstances occur at any time 
during study drug treatment:

Liver Function Test (LFT) Abnormalities
-
ALT or AST >8×ULN, or
-
ALT or AST >5×ULN and persists for more than 2 weeks, or


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-
ALT or AST >3×ULN in conjunction with elevated total bilirubin >2×ULN or INR 
>1.5, or
-
ALT or AST >3×ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%).

QT prolongation
-
QTcF >500 msec or ∆QTcF (change from baseline in QTcF) >60 msec.
3. Protocol deviation. The discovery post-dose that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
5. Withdrawal by subject. The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category).
6. Study terminated by the Sponsor. The Sponsor terminates the study.
7. Other
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.7
Procedures for Discontinuation or Withdrawal of a Subject
The investigator or sub-investigator may discontinue a subject’s study participation at any time 
during the study if the subject meets the study termination criteria described in Section 7.6. In 
addition, a subject may discontinue his or her participation without giving a reason at any time 
during the study. Should a subject’s participation be discontinued, the primary criterion for 
termination must be recorded by the investigator or sub-investigator. In addition, efforts should be 
made to perform all procedures scheduled for the Early Termination Visit.
7.8
Subject Replacement
If a subject discontinues from the trial, a replacement subject may be enrolled, if deemed 
appropriate by the investigator and Sponsor. The investigational site should contact the Sponsor 
for the replacement subject’s medication identification number.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug
[Compound]
Code name: TAK-906
The study drugs include TAK-906 maleate and matching placebo capsules. The capsules all have 
the same appearance.
Dosage form and strength:
Category of study drug
Dosage Form
Strength
TAK-906 maleate 5 mg 
capsules
Capsule
One capsule containing 5 mg of TAK-906 maleate.
TAK-906 maleate 25 mg 
capsules
Capsule
One capsule containing 25 mg of TAK-906 maleate.
Placebo capsules
Capsule
One capsule containing microcrystalline cellulose NF in place of 
TAK-906 maleate.
[Package]
TAK-906 maleate and matching placebo capsules are packaged in high density polyethylene 
(HDPE) bottles with polypropylene caps and induction seals.
[Manufacturing]
TAK-906 maleate capsules and placebo capsules were manufactured by Takeda Pharmaceutical
Company Limited (and formerly by Altos Therapeutics, LLC).
8.1.1
Clinical Study Drug Labeling
The labels affixed to the HDPE bottles give a description of the study drug (drug name, count, 
strength, storage conditions, manufacturing number, and expiration date), the study number, the 
name and address of the Sponsor, and state that the drug is for study use only.
8.1.2
Clinical Study Drug Inventory and Storage
TAK-906 maleate and matching placebo capsules may be stored at controlled room temperature 
(20°C to 25°C, with excursions allowed between 15°C to 30ºC) conditions per United States 
Pharmacopeia (USP).
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the Sponsor or designee for destruction. Study drugs must be stored under the conditions 
specified on the label, and remain in their original container until dispensed bottle containing one 
dose of study drug. A daily temperature log of the drug storage area must be maintained every 
working day.


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8.1.3
Clinical Study Drug Blinding
Randomization personnel designated by the investigational site and it’s assistant will retain the 
blind according to the randomization schedule and procedure, by affixing a label with a medication 
identification number on each dispensing bottle containing one dose of TAK-906 maleate 5 mg, 
TAK-906 maleate 25 mg or matching placebo; this should be done in the room where the other site 
personnel or the Sponsor employees are kept out.
8.1.4
Randomization Code Creation and Storage
Randomization responsible personnel designated by the Sponsor will prepare the randomization 
schedule and procedure prior to the start of the study. All randomization information will be stored 
in a secured area, accessible only by authorized personnel.
8.1.5
Clinical Trial Blind Maintenance/Unblinding Procedure
The investigator must store the emergency key until the time of an emergency blind break or the 
end of the trial.
Since maintenance of the blind may be compromised because of results from drug concentrations 
and PD assessments, such results should not be disclosed prior to blind breaking. In the event that 
results must be reported to the investigator prior to breaking the blind, all efforts should be made to 
maintain the blind (eg, by changing a medication identification number in order to avoid 
identification of subjects by laboratory site personnel). Detailed procedures for measuring subject 
drug concentration levels and PD assessments are provided in the separately created procedure for 
directions on the handling of biological samples for measuring drug concentrations and PD 
assessments.
To unblind a subject, the study drug blind can be obtained by opening a sealed envelope.
The Sponsor must be notified as soon as possible if the study drug blind is broken. The date, time, 
and reason the blind is broken must be recorded in the document called Record of Early 
Blind-Breaking and the same information (except the time) must be recorded in the (e)CRF.
If any site personnel are unblinded to a subject, study drug must be stopped immediately and that
subject must be withdrawn from the study.
No change should be made to any subject assessment after unblinding.
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
The on-site pharmacist (a site designee) will receive the pharmacy manual created by the Sponsor, 
and follow the procedures for manageing the Sponsor-supplied drug supplies. A copy of these 
procedures will be provided to the investigator as well. The manual will provide instructions on 
ensuring appropriate receipt, handling, storage, management, and dispensation of the 
Sponsor-supplied drug. The manual will also describe procedures for the collection of unused 
medications from the subject and their return to the Sponsor, or the destruction of any unused 
supplies.


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The on-site pharmacist (a site designee) will immediately return any unused study drugs in a sealed 
package to the Sponsor after the study is closed at the investigational site.


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9.0
STUDY PROCEDURES
The investigator or sub-investigator should collect data according to the procedures described in 
the following sections. For each procedure, subjects are to be assessed by the same investigator, 
sub-investigator or site designee whenever possible. The Schedule of Study Procedures is located 
in Section 3.0.
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
Informed consent must be obtained prior to the initiation of any study procedures. The 
requirements of informed consent are described in Section 13.2.
A separate informed consent form pertaining to the collection, storage, and analysis of samples
must be obtained prior to collecting any blood sample for pharmacogenomic research for this 
study.
9.1.1.1
Assignment of Subject Identification Numbers
A unique subject identification number will be assigned to each subject at the time that informed
consent is explained; this subject identification number will be used throughout the study.
9.1.1.2
Study Drug Assignment
Subjects will be assigned, sequential in ascending order of their subject identification number, to 
receive study drug according to the randomization schedule for each cohort.
Subjects will be assigned to receive a 4-digit medication identification number. The number will 
be assigned by the investigational site personnel in sequential order beginning with 1001 and 
ending with 1008 in Cohort 1, beginning with 2001 and ending with 2008 in Cohort 2, and 
beginning with 3001 and ending with 3008 in Cohort 3. The 4-digit number will be used by the 
investigational site to facilitate the prelabeling of PK and PD samples, and will be the only subject 
identifier used on all PK and/or PD sample collections. It should also be contained on the PK and 
PD transport vials shipped to the bioanalytical laboratory, and will be used by the laboratory to 
report the subject data results. The 4-digit number should only be used for the purposes described 
in this section. It does not replace the 3-digit subject number which is assigned at the time the 
informed consent is obtained and which is used for all other procedures to identify the subjects 
throughout the study. Furthermore, if treatment is given to a reserve subject, the study drug with 
the medication identification number for the initial subject who fails screening will be used. And if 
a subject is replaced, the study drug with a different medication identification number from that for 
the withdrawn subject will be used for the replacement subject.
9.1.2
Inclusion and Exclusion
Each subject will be assessed according to the eligibility criteria provided in Section 7.0.


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9.1.3
Medical History/Demography
Demographic information to be obtained will include date of birth, sex, race as described by the 
subject, height, weight, caffeine use, alcohol use, and smoking classification of the subject.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases that resolved within 1 year prior to the signing of informed consent. 
Ongoing conditions will be considered concurrent medical conditions. This includes clinically 
significant laboratory, ECG, or physical examination abnormalities noted at screening/baseline 
examination. Any conditions (ie, diagnoses) should be described.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and safety evaluations stopped at or within 4 weeks (28 days) prior to the signing of 
informed consent.
9.1.4
Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication is not provided 
by the Sponsor. Subjects will be asked whether they have taken any medication other than the 
study drug (used from the signing of informed consent through the end of the study), and all 
medication including vitamin supplements, OTC medications, and oral herbal preparations, must 
be recorded in the eCRF. Documentation will include generic medication names, route of 
administrations, start and end dates, and reasons for use.
9.2
Clinical Procedures and Assessments
9.2.1
Full Physical Exam
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and 
(11) other.
9.2.2
Height and Weight
Each subject should have a height and weight measured. Height will be recorded in centimeters 
without decimal places (rounding off the first decimal place). Weight will be collected in 
kilograms (kg) with the first decimal place (rounding off the second decimal place).
9.2.3
BMI
BMI should be derived as:
Metric: BMI=weight (kg)/height (m)2
The values should be calculated to the first decimal place (rounding off the second decimal place).
When the BMI is used as entry criteria, then this determination must be made after rounding.


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9.2.4
Vital Signs
Vital signs will include body temperature (axilla measurement), respiratory rate, supine blood 
pressure (systolic and diastolic, after resting more than 5 minutes), and pulse (beats per minute).
The same method (eg, the same and appropriately sized cuff, manual or automated) must be used 
for all measurements for each individual subject and should be the same for all subjects. All 
measurements will be recorded on the source documents and in the eCRF.
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within an acceptable time window (see Appendix C).
9.2.5
12-Lead ECG
A standard 12-lead ECG will be recorded. Subjects should be resting in a recumbent position for at 
least 5 minutes before each ECG measurement. The investigator or sub-investigator (or a qualified 
observer at the investigational site) will interpret the ECG using 1 of the following categories: 
normal or abnormal. If an ECG is abnormal, the investigator or sub-investigator (or a qualified 
observer at the investigational site) will judge clinical significance of the abnormality. The time 
that the ECG was performed will be recorded. The following parameters will be recorded on the 
eCRF from the subject’s ECG trace: heart rate, RR interval, PR interval, QT interval, QRS
interval, and QTcF.
When 12-lead ECG measurements are scheduled at the same time as blood draws, the blood draw 
will take priority and 12-lead ECGs will be obtained within an acceptable time window (see 
Appendix C).
9.2.6
Study Drug Administration
The subjects will receive a single dose of blinded study drug on Day 1 followed by multiple doses 
of blinded study drug BID for 5 days from Day 3 to Day 7, except that an evening dose of study 
drug will not be administered on Day 7.
Daily study drug administration in the multiple dose period should be within ±5 minutes of 
nominal dosing times on Day 3. On Day 7, study drug administration time should be as close to the 
time of Day 3 dosing as possible.
The number of capsules per dose is presented in Table 9.a.


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Table 9.a
Number of Capsules per Dose
Cohort
Treatment
TAK-906 maleate 
5 mg Capsule
TAK-906 maleate 
25 mg Capsule
Placebo Capsule
1
TAK-906 maleate 50 mg
0
2
0
Placebo
0
0
2
2
TAK-906 maleate 100 mg
0
4
0
Placebo
0
0
4
3
TAK-906 maleate 10 mg
2
0
0
Placebo
0
0
2
All subjects will take study drug during each period with 240 mL of water.
A single dose and all morning doses of trial medication in multiple dose periods will be 
administered  orally after fast of at least 10 hours that continues for at least 4 hours after dosing 
with restricted of water intake for at least 1 hour prior to and after dosing. The evening dose will be 
administered 12 hours after the morning dose and at least 2 hours after dinner.
9.2.7
AE Monitoring
AE monitoring begins after the signing of informed consent. A complete description of AE 
collections and procedures is provided in Section 10.2.
9.2.8
Laboratory Procedures and Assessments
All samples will be collected in accordance with acceptable laboratory procedures. Laboratory 
samples will be taken following a minimum 8 hour overnight fast on the days stipulated in the 
Schedule of Study Procedures (Section 3.0).
9.2.8.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Erythrocytes (red blood cells [RBCs])
Leukocytes (white blood cells [WBCs]) with absolute differential
Hemoglobin
Mean corpuscular hemoglobin (MCH)
Hematocrit
Mean corpuscular hemoglobin concentration (MCHC)
Platelets
Mean corpuscular volume (MCV)


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Chemistry
Chemistry evaluations will consist of the following standard chemistry panel:
Albumin
Potassium
Alkaline phosphatase
Protein (total)
ALT
Sodium
AST
C-reactive protein
Bilirubin (total)
Total cholesterol
Blood urea nitrogen
Lactate dehydrogenase
Calcium
Magnesium
Chloride
Phosphorus
Creatinine
Triglycerides
Gamma-glutamyl transferase (GGT)
Uric acid
Glucose
Urinalysis
Urinalysis will consist of the following tests:
Protein
Ketones
Urine microscopy 
Glucose
pH
RBC
Blood
Specific gravity
WBC
Nitrite
Urobilinogen
Squamous epithelial cells
Other
Diagnostic Screening:
Serum
Urine
Immunology
Hepatitis panel (HBsAg and anti-HCV)
HIV antibody/antigen
Syphilis screen (serological reactions for syphilis)
Drug screen
(phencyclidines, benzodiazepines, cocaines, amphetamines, 
cannabinoids, morphines, barbiturates, and tricyclic 
antidepressants)
Prolactin
Cotinine screen
Alcohol screen 
(urine alcohol test/alcohol breath test)
Note: The investigator or sub-investigator will report the results of immunology, urine drug screen, cotinine screen, 
and alcohol screen directly to subjects. The Sponsor will confirm the overall test results (as “Positive” or “All 
negative”), rather than detailed results, for subjects (including reserve subjects) to be administered the study drug.
The local laboratory will perform laboratory tests for hematology, chemistry, urinalysis, and 
prolactine assessment for safety (at Screening). The results of laboratory tests will be returned to 
the investigator or sub-investigator, who is responsible for reviewing and filing these results.


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If subjects experience an ALT or AST of >3 ×ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed 
within a maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. 
(Refer to Section 7.6 and Section 10.2.9.5 for the appropriate guidance on reporting abnormal 
LFTs.)
The investigator will maintain a copy of the reference ranges for the laboratory used.
9.3
PK, PD, and 
Samples for PK, PD, and 
 will be collected as specified in the Schedule of Study
Procedures (Section 3.0). Please refer to the separately created procedure for information on the 
collection, processing, and shipment of samples to the central laboratory. The actual time of 
sample collection for PK and PD analyses will be recorded on the source documents and eCRF.
Primary specimen collection parameters are provided in Table 9.b.
Table 9.b
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for TAK-906 PK
Plasma
PK measurement
Mandatory
Urine sample for TAK-906 PK
Urine
PK measurement
Mandatory
Serum sample for PD (prolactin)
Serum
PD measurement
Mandatory
PK=pharmacokinetics, PD=pharmacodynamics.
9.3.1
PK Measurements
The PK parameters of TAK-906 and M23 will be determined from the concentration-time profiles 
for all evaluable subjects. Actual sampling times, rather than scheduled sampling times, will be 
used in all computations involving sampling times.
CCI
CCI
CCI
CCI


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The following PK parameters will be calculated for plasma concentration values of TAK-906 and 
M23, unless otherwise specified:
Symbol/Term
Definition
Plasma
AUCτ,ss
Area under the plasma concentration-time curve during a dosing interval, at steady state.
AUCt
Area under the plasma concentration-time curve from time 0 to time t.
AUC∞
Area under the plasma concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration.
Cmax
Maximum observed plasma concentration.
Cmax,ss
Maximum observed plasma concentration during a dosing interval, at steady state.
tmax
Time of first occurrence of Cmax.
tmax,ss
Time of first occurrence of Cmax, at steady state.
The following urine PK parameters of TAK-906 and M23 will be derived from urine 
concentrations of TAK-906, unless otherwise specified:
Symbol/Term
Definition
Urine
Aet
Amount of drug excreted in urine from time 0 to time t.
Aeτ
Amount of drug excreted in urine during a dosing interval.
fe,t
Fraction of administered dose of drug excreted in urine from time 0 to time t. Molecular weight 
adjustment needed for metabolites.
fe,τ
Fraction of administered dose of drug excreted in urine during a dosing interval. Molecular weight 
adjustment needed for metabolites.
CLR
Renal clearance.
9.3.1.1
Plasma for PK Measurements
Blood samples (one 4-mL sample per scheduled time) for PK analyses of TAK-906 and M23 will 
be collected into Vacutainers 
 
Serial blood samples for PK analyses of TAK-906 and M23 will be collected according to Table 
9.c.
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Table 9.c
Collection of Blood Samples for PK Analysis
Analyte
Matrix
Study Day
Scheduled Time
TAK-906
and M23
Plasma
1-2
Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post single dose
TAK-906
and M23
Plasma
3-6
Just before morning dose
TAK-906
and M23
Plasma
7-8
Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post morning dose
Blood samples for subjects randomized to placebo will not be analyzed.
If a subject is prematurely terminating from the study between the first dose of study drug and the 
completion of procedures on Day 8, a final PK blood sample needs to be drawn from that subject 
in confinement; however, for any early termination during Follow-up, a PK blood sample will not 
be collected.
9.3.1.2
Urine for PK Measurements
Serial urine samples for PK analyses of TAK-906 and M23 will be collected according to Table 
9.d.
Table 9.d
Collection of Urine Samples for PK Analysis
Analyte
Matrix
Study Day
Scheduled Time
TAK-906
and M23
Urine
1-2
Predose (spot), 0-6, 6-12, and 12-24 hours post single dose
TAK-906
and M23
Urine
7
0-6 and 6-12 hours post morning dose
Urine samples for subjects randomized to placebo will not be analyzed.
9.3.1.3
Bioanalytical Methods
Plasma and urine concentrations of TAK-906 and M23 will be measured by high-performance 
liquid chromatography with 
9.3.2
PD Measurements
The following PD parameters will be calculated for serum concentration values of prolactin, 
unless otherwise specified:
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Symbol/Term
Definition
Serum
AUCτ,ss
Area under the serum concentration-time curve from time 0 to time t, at steady state.
AUCt
Area under the serum concentration-time curve from time 0 to time t.
Cmax
Maximum observed serum concentration.
Cmax,ss
Maximum observed serum concentration during a dosing interval, at steady state.
9.3.2.1
Serum for PD Measurements
Serial blood samples (one 5-mL sample per scheduled time) for PD analysis will be collected 
according to Table 9.e. In addition, serum prolactin level will be measured in a laboratory test at 
Screening for safety assessment by local laboratory.
Table 9.e
Collection of Blood Samples for PD Analysis
Analyte
Matrix
Study Day
Scheduled Time
Prolactin
Serum
1-2
Predose, 1, 2, 4, 6, and 24 hours post single dose
Prolactin
Serum
3-6
Just before morning dose
Prolactin
Serum
7-8
Predose, 1, 2, 4, 6, and 24 hours post morning dose
Prolactin
Serum
14
－
9.3.2.2
Bioanalytical Methods
Serum prolactin levels for PD analysis will be measured using an in vitro diagnostic assay 
9.3.3
9.3.3.1
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9.3.3.2
Not applicable.
9.3.4
Confinement
In either Cohort 1, 2, or 3, each subject will be confined from Day -1 to the morning of Day 8 and 
discharged after the investigator’s or sub-investigator’s confirmation of no significant abnormality
in his health through physical examination and tests on Day 8, at 24-hour post morning dose of
Day 7.
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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 or study participation.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the study participation, 
whether or not it is considered related to the drug or study procedure.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator or sub-investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator or 
sub-investigator judges the change to be beyond the range of normal physiologic fluctuation). 
A laboratory re-test and/or continued monitoring of an abnormal value are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical condition and should NOT be recorded as an AE. A baseline evaluation 
(eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless related to a 
study procedure. However, if the subject experiences a worsening or complication of such a 


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


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database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.9.

In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes/ventricular fibrillation/
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome/malignant hyperthermia
Spontaneous abortion/stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual 
activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.2.2 Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
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10.2.3 Assigning Causality of AEs to Study Procedures
The causality of each AE to study procedures will be assessed.
The causality should be assessed as Related if the investigator or sub-investigator considers that 
there is reasonable possibility that an event is due to a study procedure. Otherwise, the causality 
should be assessed as Not Related.
10.2.4 Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.5
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.
10.2.6
Pattern of Adverse Event (Frequency)
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.7
Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE.
10.2.8
Outcome

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
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.”


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
Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.9
Collection and Reporting of AEs, SAEs, and Abnormal LFTs
10.2.9.1 Collection Period
Collection of AEs (ie, AEs, SAEs, and Abnormal LFTs) will commence at the time the subject 
signs the informed consent. Routine collection of AEs will continue until the follow-up visit on 
Day 14.
10.2.9.2 Reporting AEs
At each study visit, the investigator or sub-investigator will assess whether any subjective AEs 
have occurred. A neutral question, such as “How have you been feeling since your last visit?” may 
be asked. Subjects may report AEs occurring at any other time during the study. Subjects 
experiencing an SAE prior to the first exposure to study drug 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. Nonserious AEs that 
begin prior to the first exposure to study drug, whether related or unrelated to study procedure, 
need not be followed-up for the purposes of the protocol.
All subjects experiencing an AE after first exposure to study drug, whether it is considered 
associated with 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 or sub-investigator concludes that the event is related to 
the drug treatment. The following information will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Investigator’s or sub-investigator’s opinion of the causality between the event and 
administration of study drug(s) (related or not related).

Investigator’s or sub-investigator’s opinion of the causality to study procedure(s), including 
the details of the suspected procedure.

Action taken with trial drug.


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
Outcome of event.

Seriousness.

Timing of occurrence (after administration of study drug).

QTc prolongation associated AEs, neurologic AEs or hyperprolactinemia associated AEs, or 
not.
10.2.9.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
An SAE should be reported by the investigator or sub-investigator to the Sponsor (see Protocol 
Annex 1) within 1 business day of the first onset or notification of the SAE, along with any 
relevant information. The investigator should submit a detailed SAE Form to the Sponsor within 
10 calendar days. The information should be completed as fully as possible but contain, at a 
minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s or sub-investigator’s name.

Name of the study medication(s).

Causality assessment.
Any SAE spontaneously reported to the investigator or sub-investigator following the AE 
collection period should be reported to the Sponsor if considered related to study participation.
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator or sub-investigator should complete a follow-up SAE form or provide other written 
documentation and submit it to the Sponsor. Copies of any relevant data from hospital notes (eg, 
ECGs, laboratory tests, discharge summary, postmortem results) should be submit to the Sponsor, 
if requested.
All SAEs should be followed up until resolution or a permanent outcome for the event.
10.2.9.4 Reporting QTc prolongation associated AEs, neurologic AEs, and hyperprolactinemia 
associated AEs
Considering the mechanism of action of TAK-906 and the safety profile of existing dopamine 
D2/D3 receptor antagonists on the market, the following AEs (treatment-emergent only, serious or 
non-serious) are considered to be ones for which ongoing monitoring and rapid communication by 
the investigator to Takeda may be appropriate, and may require further investigation in order to 
characterize and understand in this study.


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QTc prolongation associated AEs:

Torsade de pointes, Sudden death, Ventricular tachycardia, Ventricular fibrillation and flutter, 
Syncope, and Seizure.
Neurologic AEs:

Extrapyramidal disorder, Tardive dyskinesia, Akathisia, and Parkinsonian like disorder.
Hyperprolactinemia associated AEs.

Hyperprolactinemia, Libido decreased, Sexual dysfunction, Gynecomastia, and 
Galactorrhoea.
If these AEs are considered to be clinically significant, it should be reported to the Sponsor 
immediately or within 1 business day of onset or subject’s notification of the event. An AE Form 
specified to these AEs or an SAE Form should be completed, signed, or signed and sealed by the 
investigator and reported to the Sponsor within 10 business days.
The investigator should record these AEs as AEs in the eCRF, and submit the original copy of the 
AE Form or the SAE Form along with all other required documentation to the Sponsor.
10.2.9.5 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.9.3. The investigator or sub-investigator must report to the monitor and 
evaluate relevant subject details and possible alternative etiologies, such as acute viral hepatitis A 
or B or other acute liver disease or medical history/concurrent medical conditions. Follow-up 
laboratory tests as described in Section 9.2.8 must also be performed.
10.2.10
Safety Reporting to Investigators, IRBs, and Regulatory Authorities
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, IRBs, and the 
head of the investigational site. Relative to the first awareness of the event by/or further provision 
to the Sponsor or its designee, SUSARs will be submitted to the regulatory authorities as expedited 
report within 7 days for fatal and life-threatening events and 15 days for other serious events, 
unless otherwise required by national regulations. The Sponsor will also prepare an expedited 
report for other safety issues where these might materially alter the current benefit-risk assessment 
of study drug or that would be sufficient to consider changes in the study drug administration or in 
the overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB.


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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definitions of analysis variables, and analysis 
methodologies to address all study objectives.
11.1.1
Analysis Sets
In this study, three analysis sets are defined: the Safety Analysis Set, the PK Analysis Set, and the 
PD analysis Set. The definition of each analysis set will be described in the SAP.
11.1.1.1 Safety Analysis Set
The Safety Analysis Set will be defined as all subjects who received at least one dose of study 
drug.
11.1.1.2 PK Analysis Set
The PK Analysis Set will consist of subjects who received at least one dose of study drug, 
completed the minimum protocol-specified procedures with no significant protocol deviations, 
and who were evaluable for the PK.
11.1.1.3 PD Analysis Set
The PD Analysis Set will consist of subjects who received at least one dose of study drug, 
completed the minimum protocol-specified procedures with no significant protocol deviations, 
and who were evaluable for the PD.
11.1.2
Analysis of Demography and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized overall and by cohort using 
the PK Analysis Set and Safety Analysis Set.
11.1.3
PK Analysis
Plasma concentrations of TAK-906 and M23 will be summarized by dose over each scheduled 
sampling time using descriptive statistics. Individual plasma concentration data versus time will be 
presented in a data listing.
Plasma PK parameters for TAK-906 and M23 will be summarized by dose over each scheduled 
sampling time using descriptive statistics (arithmetic mean, SD, median, minimum and 
maximum). In addition, geometric mean and coefficient of variation will be computed for Cmax and 
AUC.
Dose proportionality for TAK-906 and M23 plasma exposures (Cmax and AUC) will be assessed 
statistically using a power function model.
Individual urine concentration data versus time will be presented in a data listing.


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The urine PK parameters for TAK-906 and M23 will be summarized by dose using descriptive 
statistics.
A more detailed analysis will be presented in the SAP.
11.1.4
PD Analysis
For the serum prolactin concentration, the observed values and their changes from baseline will be 
summarized by dose over each scheduled sampling time using descriptive statistics.
A more detailed analysis will be presented in the SAP.
11.1.5
Safety Analysis
11.1.5.1 AEs
A TEAE is defined as an AE whose date of onset occurs on or after the start of study drug. TEAEs 
will be coded using Medical Dictionary for Refulatory Activities (MedDRA) dictionary. 
Frequency distribution will be provided by system organ class and preferred term for each 
regimen. TEAEs will be summarized by pooled placebo and each TAK-906 dose level for single 
dose period and combined single and multiple dose periods. All TEAE data will be provided in the 
data listings.
11.1.5.2 Clinical Laboratory Evaluation
For continuous variables, the observed values and their changes from baseline will be summarized 
by dose over each scheduled sampling time using descriptive statistics. For categorical variables, 
shift tables showing the number of subjects in each category at baseline and each post-baseline 
visit will be provided by dose. All clinical laboratory data will be provided in the data listings.
11.1.5.3 Vital Signs
The observed values and their changes from baseline will be summarized by dose over each 
scheduled sampling time using descriptive statistics. All vital sign data will be provided in the data 
listings.
11.1.5.4 Other Safety Parameters
ECG parameters are summarized as follows: for continuous variables, the observed values and 
their changes from baseline will be summarized by dose over each scheduled sampling time using 
descriptive statistics. For categorical variables, shift tables showing the number of subjects in each 
category at baseline and each post-baseline visit will be provided by dose. All ECG data will be 
provided in the data listings.
Physical examination findings will be presented in the data listings.
11.2
Interim Analysis and Criteria for Early Termination
No formal interim analysis is planned.


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11.3
Determination of Sample Size
A sample size of 8 subjects per cohort (6 active: 2 placebo) will be used in this study, and is 
considered sufficient for the evaluation of TAK-906 safety, tolerability, PK and PD following oral 
single and multiple doses. The sample size is not based on statistical power considerations.


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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Investigational Site Monitoring Visits
Monitoring visits to the investigational 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 the head of investigational site guarantee access to source documents 
by the Sponsor or its designee (CRO) and by the IRB.
All aspects of the study and its documentation will be subject to review by the Sponsor or its
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study drug, subject medical records, informed consent documentation, and review of 
eCRFs and associated source documents. It is important that the investigator, sub-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 or sub-investigator can deviate and change from the protocol for any medically 
unavoidable reason, for example, to eliminate an immediate hazard to study subjects, without a 
prior written agreement with the Sponsor or a prior approval from IRB. In the event of a deviation 
or change, the investigator should notify the Sponsor and the head of the investigational site of the 
deviation or change as well as its reason in a written form, and then retain a copy of the written 
form. When necessary, the investigator may consult and agree with the Sponsor on a protocol 
amendment. If the protocol amendment is appropriate, the amendment proposal should be 
submitted to the head of the investigational site as soon as possible and an approval from IRB 
should be obtained.
The investigator or sub-investigator should document all protocol deviations.
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The investigational site also may be subject to quality assurance audits by the Sponsor or 
designees. In this circumstance, the Sponsor-designated auditor will contact the investigational 
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 Food and Drug 
Administration [FDA], the United Kingdom Medicines and Healthcare products Regulatory 
Agency [MHRA], the Pharmaceuticals and Medical Devices Agency of Japan [PMDA]). If the 
investigational site is contacted for an inspection by a regulatory body, the Sponsor should be 
notified immediately. The investigator and the head of investigational site guarantee access for 
quality assurance auditors to all study documents as described in Section 12.1.


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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Conference on 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” that are listed in Appendix A.
13.1
IRB Approval
IRBs must be constituted according to the applicable local requirements of each participating 
region. The Sponsor or designee will require documentation noting all names and titles of 
members who make up the respective IRB. If any member of the IRB has direct participation in 
this study, written notification regarding his or her abstinence from voting must also be obtained.
The Sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements and 
other documents required by all applicable laws and regulations, must be submitted to a central or 
local IRB for approval. The IRB’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the Sponsor or designee before commencement of the study. 
The IRB approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, informed consent form) reviewed; and state the approval date. 
The Sponsor will notify investigational site once the Sponsor has confirmed the adequacy of 
investigational site regulatory documentation. Until the investigational site receives notification,
no protocol activities, including screening, may occur.
Investigational Sites must adhere to all requirements stipulated by their respective IRB. This may 
include notification to the IRB regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and Sponsor.
Regarding pharmacogenomic investigation using collected and stored specimens, analysis will be 
carried out at the time when details for this analysis are determined. The Sponsor will create a 
research protocol for pharmacogenomics investigations.
13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form describes the planned and permitted 


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uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
The informed consent form will detail the requirements of the participant and the fact that he is 
free to withdraw at any time without giving a reason and without prejudice to his further medical 
care.
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form. The informed consent form must be approved by both the IRB and the Sponsor prior 
to use.
The informed consent form must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator or sub-investigator to explain the detailed 
elements of the informed consent form to the subject. Information should be given in both oral and 
written form whenever possible and in the manner deemed appropriate by the IRB.
The subject must be given ample opportunity to: (1) inquire about details of the study, and (2) 
decide whether or not to participate in the study. If the subject determines he will participate in the 
study, then the informed consent form must be signed and dated by the subject at the time of 
consent and prior to the subject entering into the study. The subject should be instructed to sign 
using his legal name, not nicknames, using blue or black ballpoint ink. The investigator or 
sub-investigator must also sign and date the informed consent form at the time of consent and prior 
to subject entering into the study.
Once signed, the original informed consent form will be stored in the investigator’s site file. The 
investigator or sub-investigator must document the date the subject signs the informed consent in 
the subject’s medical record. Copies of the signed informed consent form shall be given to the 
subject.
All revised informed consent forms must be reviewed and signed by relevant subjects in the same 
manner as the original informed consent. The date the revised consent was obtained should be 
recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form.
 
 
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number.
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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, MHRA, PMDA), the Sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
13.4
Publication, Disclosure, and Clinical 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 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. The investigator or 
sub-investigator needs to obtain a prior written approval from the Sponsor to publish any 
information from the study externally such as to a professional association.
13.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with facility name, investigator’s city, country, and recruiting status 
will be registered and available for public viewing.
13.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
investigational site where the subject is participating. If a local underwriter is required, then the 


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Sponsor or its 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. If the investigator or sub-investigator has questions 
regarding this policy, he or she should contact the Sponsor or its designee.


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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information
A separate contact information list (Protocol Annex 1) will be provided to the investigational site.
14.1.2 INVESTIGATOR AGREEMENT
A separate agreement will be provided to the investigational site.
14.1.3 Study-Related Responsibilities
A separate contact information list (Protocol Annex 1) will be provided to the investigational site.
14.1.4 List of Abbreviations
Term
Definition
AE
adverse event
Ae
amount of drug excreted in urine
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BBB
blood brain barrier
BID
twice daily
BMI
body mass index
CLR
renal clearance
Cmax
maximum observed concentration
CNS
central nervous system
DA
dopamine
eCRF
electronic case report form
ECG
electrocardiogram
EPS
extrapyramidal symptoms
FDA
Food and Drug Administration
fe
fraction of administered dose of drug excreted in urine
FIH
first-in-human
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HBsAg
hepatitis B virus surface antigen
HCV
hepatitis C virus
HDPE
high density polyethylene
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Term
Definition
hERG
human ether-á-go-go related gene
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
INR
international normalized ratio
IRB
institutional review board
LFT
liver function test
LOEL
lowest observed effect level
MAD
multiple-ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MHW
Ministry of Health and Welfare
MRSD
maximum recommended starting dose
NOAEL
no-observed-adverse-effect level
OTC
over-the-counter
PD
pharmacodynamics
PK
pharmacokinetics
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
RBC
red blood cell
SAD
single-ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
t1/2
half-life period
ULN
upper limit of normal
US
United States
WBC
white blood cell
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent medical conditions will be coded using the MedDRA. Drugs 
will be coded using the World Health Organization Drug Dictionary.
15.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The Sponsor or its designee will supply investigational sites with access to eCRFs. The Sponsor 
will make arrangements to train appropriate investigational site staff in the use of the eCRF. These 
forms are used to transmit information collected in the performance of this study to the Sponsor 
and regulatory authorities. eCRFs must be completed in English. Data are transcribed directly onto 
eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the investigational 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 madeThe 
investigator must review the eCRFs for completeness and accuracy and must e-sign appropriate 
eCRFs as indicated. Furthermore, the investigator must retain full responsibility for the accuracy,
and authenticity of all data entered on the eCRFs.
The following data will not be recorded into the eCRFs:


Laboratory results

Measurement results of drug concentrations

PD analysis result
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The investigator must review the data change for completeness and accuracy, and must 
e-sign.
eCRFs will be reviewed for completeness and acceptability at the investigational 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.
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15.2
Record Retention
The investigator and the head of the investigational site agree 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 for all participating subjects, medical records, all original signed 
and dated informed consent forms, electronic copy of eCRFs, including their audit trail, and 
detailed records of drug disposition that will enable evaluations or audits by regulatory authorities, 
the Sponsor or its designees. The investigator and the head of the investigational site are required 
to retain relevant essential documents until the day specified as 1 or 2 below, whichever comes 
later. However, if the Sponsor requests a longer time period for retention, the head of the 
investigational site should discuss how long and how to retain those documents with the Sponsor.
1. The day on which marketing approval for the study drug is obtained (or the day 3 years after 
the date of notification in the case that the investigation is discontinued.)
2. The day 3 years after the date of early termination or completion for the study.
In addition, the investigator and the head of the investigational site should retain the relevant 
essential documents until the receipt of a Sponsor-issued notification that states the retention is no 
longer required.


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16.0
REFERENCES 
1. Parkman HP, Hasler WL, Fisher RS, American Gastroenterological A. American 
Gastroenterological Association technical review on the diagnosis and treatment of 
gastroparesis. Gastroenterology 2004;127(5):1592-622.
2. Jung HK, Choung RS, Locke GR 3rd, Schleck CD, Zinsmeister AR, et al. The incidence, 
prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 
1996 to 2006. Gastroenterology 2009;136:1225-1233.
3. Inamori M, Nakajima A, Fukudo S, Miwa H, editors. Diagnostic manual of functional 
gastrointestinal disorder (in Japanese). Tokyo: Shindan To Chiryo Sya. 2015. p.91-97.
4. Darmani NA, Zhao W, Ahmad B. The role of D2 and D3 dopamine receptors in the mediation 
of emesis in Cryptotis parva (the least shrew). J Neural Transm (Vienna) 
1999;106(11-12):1045-61.
5. Kashyap P, Micci MA, Pasricha S, Pasricha PJ. The D2/D3 agonist PD128907 
(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin- 9-ol) 
inhibits stimulated pyloric relaxation and spontaneous gastric emptying. Dig Dis Sci 
2009;54(1):57-62.
6. Lee A and Kuo B. Metoclopramide in the treatment of diabetic gastroparesis. Expert Rev 
Endocrinol Metab 2010;5(5):653-662.
7. Meltzer HY. Update on typical and atypical antipsychotic drugs. Annu Rev Med 
2013;64:393-406.
8. Michaud V, Turgeon J. Domperidone and sudden cardiac death: How much longer should we 
wait? J Cardiovasc Pharmacol 2013;61(3):215-7.
9. Andrews PL, Davis CJ, Bingham S, Davidson HI, Hawthorn J, Maskell L. The abdominal 
visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J 
Physiol Pharmacol 1990;68(2):325-45.
10. Yoshikawa T, Yoshida N, Hosoki K. Involvement of dopamine D3 receptors in the area 
postrema in R(+)-7-OH-DPAT-induced emesis in the ferret. Eur J Pharmacol 
1996;301(1-3):143-9.
11. Regulations for Enforcement of the Act on the Securing a Stable Supply of Safe Blood 
Products (Ordinance of Ministry of Health, No.22, 25/Jun/1956).
12. Society for the Study of Obesity. Criteria for Obesity Disease in 2011. Journal of Japan Society 
for the Study of Obesity. 2011; Oct (extra edition).
13. General Considerations for Clinical Trials (PMSB/ Examination and Licensing Division 
Nortification No.380, 21/Apr/1998).


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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
1. Conduct the appropriate study in accordance with the protocol and GCP considering the rights, 
safety and wellbeing of human subjects.
2. When a part of the important activities related to the study are delegated to a sub-investigator 
or the study collaborator, prepare the lists of activities to be delegated and responsible 
personnel, submit the lists to the head of the investigational site in advance to get them 
accepted.
3. Prepare a written informed consent form and other written information, and update as 
appropriate.
4. Confirm the contents of the clinical study agreement.
5. Provide necessary information on the protocol, medications and responsibilities of individual 
personnel to the sub-investigator and study collaborator, and provide guidance and 
supervision.
6. Screen subjects who meet the requirements of the protocol, provide the explanation of the 
study in writing and obtain the written consent.
7. Assume responsibility for all the medical judgement related to the study.
8. Ensure in collaboration with the head of the investigational site that sufficient medical care for 
all clinically significant AEs related to the study are provided to subjects throughout and 
beyond the period when subjects participate in the study, upon obtaining consent from the 
subject.
9. If a subject consults other medical institution or other department, notify the physician of the 
medical institution or department of the subject’s participation in the study, as well as the end 
and termination of the study in writing, and document such records.
10. In case of urgent report of a SAE, immediately notify the head of the investigational site and 
the Sponsor in writing.
11. Determine the need of emergency key code blinding of a subject in case of emergency.
12. Prepare correct and complete eCRFs, and submit them to the Sponsor with electronic 
signature.
13. Check and confirm the contents of eCRFs prepared by the sub-investigator or transcribed from 
the source data by the study collaborator, and submit them to the Sponsor with electronic 
signature.
14. Discuss any proposal from the Sponsor including update of the protocol.
15. Notify the head of the investigational site of the end of the study in writing.


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Appendix B
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Subjects and Their Female Partners
From the signing of informed consent, throughout the duration of the study, and for 12 weeks (84 
days) after last dose of study drug, any nonsterilized** male subjects who are sexually active with 
a female partner of childbearing potential* must use adequate contraception. In addition, they must 
be advised not to donate sperm during this period. Females of childbearing potential who are 
partners of male subjects are also advised to use additional contraception as shown in the table on 
containing adequate contraception below.
* Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation), or who are postmenopausal (eg, defined 
as at least 2 years since last regular menses with an FSH of >40 IU/L).
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documented absence of sperm in the ejaculate, or have had a bilateral orchidectomy.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate.
Barrier methods (each time 
the subject has intercourse)
Intrauterine devices (IUDs)
Hormonal contraceptives
Male condom with spermicide.
Copper T PLUS condom.
Progesterone T PLUS condom.
Combined pill.
Subjects will be provided with information on acceptable methods of contraception for 12 weeks 
(84 days) after last dose of study drug, as part of their informed consent process, and will be asked 
to sign a consent form stating that they understand the requirements for avoidance of pregnancy in 
partners and of sperm donations for 12 weeks (84 days) after their last dose of study drug.
Pregnancy
If any pregnancies in the partner of a male subject, during the study or for 12 weeks (84 days) after 
the last dose, should be recorded following authorization from the subject’s partner.
If the pregnancy in the partner of a male subject occurs during or after administration of blinded 
drug, the investigator or sub-investigator must inform the subject of his right to receive treatment 
information. If the subject chooses to receive unblinded treatment information, that individual’s
blind should be broken by the investigator or sub-investigator. Any subjects randomized to
placebo need not be followed.
If the female partner of a male subject agrees to have her primary care physician informed, the 
investigator or sub-investigator should notify the primary care physician that her partner was 
participating in a clinical study at the time she became pregnant and provide details on the study 
drug that the subject has received (blinded or unblinded, as applicable).


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All pregnancies in the female partners of male subjects will be followed to final outcome, using the 
pregnancy form, with the consent of the female partners of those male subjects. The outcome, 
including any premature termination, must be reported to the Sponsor. An evaluation after any
birth of a child will also be conducted.


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Appendix C
Acceptable Time Window for Study Procedure
Variables
Timing of procedures (standard)
Acceptable window
Examinations only for 
diagnostic screening (a)
Screening period
Days -28 to -2
Not applicable
Physical examination
Screening period
Days -28 to -2
Not applicable
Check-in
Day -1
Not applicable
Treatment period
Day 1: Predose.
Day 5: Before morning dose.
From awakening to immediately 
prior to (morning) dose
Days 2 and 8: 24 hours
postdose of Days 1 and 7, 
respectively.
Within ±1 hour
Follow-up
Day 14
Within ±2 days
Weight
Screening period
Days -28 to -2
Not applicable
Check-in
Day -1
Not applicable
Treatment period
Day 7: Predose.
From awakening to immediately 
prior to dose
Follow-up
Day 14
Within ±2 days
Vital signs
Screening period
Days -28 to -2
Not applicable
Check-in
Day -1
Not applicable
Treatment period
Days 1 and 7: Predose.
Days 3 to 6: Before morning 
dose.
From awakening to immediately 
prior to (morning) dose
Days 1 and 7: 1, 2, 4, and 
6 hours postdose.
Within ±30 minutes
Days 2 and 8: 24 hours
postdose of Days 1 and 7, 
respectively.
Within ±1 hour
Follow-up
Day 14
Within ±2 days
12-lead ECG
Screening period
Days -28 to -2
Not applicable
Check-in
Day -1
Not applicable
Treatment period
Days 1 and 7: Predose.
Day 5: Predose.
From awakening to immediately 
prior to (morning) dose
Days 1 and 7: 1, 2, 4, and 
6 hours postdose.
Within ±30 minutes
Days 2 and 8:24 hours
postdose of Days 1 and 7, 
respectively.
Within ±1 hour
Day 5: 1 and 2 hours postdose. Within ± 30 minutes


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Variables
Timing of procedures (standard)
Acceptable window
Hematology and chemistry 
for safety assessments (b) 
Screening period
Days -28 to -2
Not applicable
Check-in
Day -1
Not applicable
Treatment period
Days 2 and 8: 24 hours 
postdose of Days 1 and 7, 
respectively.
Within ±1 hour
Day 5: Before morning dose.
From awakening to immediately 
prior to morning dose
Follow-up
Day 14
Within ±2 days
Urinalysis for safety 
assessments
Screening period
Days -28 to -2
Not applicable
Check-in
Day -1
Not applicable
Treatment period
Days 2 and 8: 24 hours 
postdose of Days 1 and 7, 
respectively.
From awakening to 1 hour
post-scheduled time
Day 5: Before morning dose.
From awakening to immediately 
prior to morning dose
Follow-up
Day 14
Within ±2 days
Plasma sample for 
TAK-906 PK 
Treatment period
Day 1: Predose.
From awakening to immediately 
prior to dose
Day 1: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 
12, and 16 hours postdose.
Within ±5 minutes
Day 2: 24 hours postdose of 
Day 1.
Within ±15 minutes
Days 3 to 6: Just before 
morning dose.
From 15 minutes predose to 
immediately prior to morning dose
Day 7: Predose.
Immediately prior to dose
Day 7: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 
12, and 16 hours postdose.
Within ±5 minutes
Day 8: 24 hours postdose of 
Day 7.
Within ±15 minutes
Urine sample for TAK-906
PK 
Treatment period
Day 1: Predose (spot).
From awakening to immediately 
prior to dose
Days 1 to 2: 0-6, 6-12, and 
12-24 hours postdose.
Not applicable
Day 7: 0-6 and 6-12 hours 
postdose.
Not applicable
Footnotes are on the following page.


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Variables
Timing of procedures (standard)
Acceptable window
Serum sample for PD 
(prolactin)
Treatment period
Day 1: Predose.
From awakening to immediately 
prior to dose
Day 1: 1, 2, 4, and 6 hours 
postdose.
Within ±5 minutes
Day 2: 24 hours postdose of 
Day 1.
Within ±15 minutes
Days 3 to 6: Just before 
morning dose.
From 15 minutes predose to 
immediately prior to morning dose
Day 7: Predose.
Immediately prior to dose
Day 7: 1, 2, 4, and 6 hours 
postdose..
Within ±5 minutes
Day 8: 24 hours postdose of 
Day 7.
Within ±15 minutes
Follow-up
Day 14
Within ±2 days
BMI=body mass index, ECG=electrocardiogram, HBsAg=hepatitis B virus surface antigen, HCV=hepatitis C virus, 
HIV=human immunodeficiency virus,
PK=pharmacokinetics, PD=pharmacodynamics.
(a) Including height measurement, BMI calculation, immunological test (HBsAg, anti-HCV, HIV antibody/antigen, 
and syphilis screen), prolactin assessment for safety, urine drug screen, urine cotinine test, and alcohol screen 
(urine alcohol test/alcohol breath test).
(b) Serum prolactin level will be measured at Screening for safety assessment.
Total blood sampling volumes for an individual subject is shown below:
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening
Day -1
Days 1-2
Days 3-8
Follow-up
Hematology
2
1
1
1
2
1
12
Chemistry
5
1 (a)
1
1
2
1
30
Blood for TAK-906 PK
4
0
0
12
16
0
112
Blood for PD
5
0
0
6
10
1
85
PK=pharmacokinetics, PD=pharmacodynamics,
 
HBsAg=hepatitis B virus surface antigen, HCV=hepatitis C virus, HIV=human immunodeficiency virus.
(a) One 5-mL sample collected for blood chemistry test at Screening will be also used for immunological test 
(HBsAg, anti-HCV, HIV antibody/antigen, and syphilis screen), and prolactin assessment for safety.
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680612af7
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose, Phase 1 Study to
Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynanics of TAK-906 in Japanese Health Male
Subjects
Clinical Pharmacology Approval
07-Jun-2017 04:42 UTC
Biostatistics Approval
07-Jun-2017 07:38 UTC
Clinical Approval
07-Jun-2017 11:20 UTC
PPD

SAP_001.pdf: 
 
 
Title: A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending 
Dose, Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of TAK-906 in Japanese Healthy Male Subjects 
 
NCT Number: NCT03237156 
Statistical analysis plan Approve Date: 10-Nov-2017 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
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. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


1.0 
TITLE PAGE 
 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: TAK-906-1004 
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose, 
Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of TAK-906 in Japanese Healthy Male Subjects 
Phase 1 TAK-906 Single and Multiple Ascending Dose Study  
in Japanese Healthy Male Subjects 
PHASE 1 
Version: Initial 
Date: 10 November 2017 
 
Prepared by:  
 
 
 
Based on: 
Protocol Version: Initial version 
Protocol Date: 6 June 2017 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda. 
PPD


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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 
List of In-Text Tables ................................................................................................................4 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................6 
4.0 
OBJECTIVES ......................................................................................................................8 
4.1 
Primary Objectives.........................................................................................................8 
4.2 
Secondary Objectives.....................................................................................................8 
4.3 
Additional Objectives ....................................................................................................8 
4.4 
Study Design ..................................................................................................................8 
4.4.1 
Trial Design .............................................................................................................8 
4.4.2 
Dose Escalation ........................................................................................................9 
5.0 
ANALYSIS ENDPOINTS ................................................................................................11 
5.1 
Primary Endpoint .........................................................................................................11 
5.2 
Secondary Endpoints ...................................................................................................11 
6.0 
DETERMINATION OF SAMPLE SIZE ..........................................................................12 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................13 
7.1 
General Principles ........................................................................................................13 
7.1.1 
Study Definitions ...................................................................................................13 
7.1.2 
Definition of Study Days .......................................................................................13 
7.1.3 
Definition of Study Visit Windows .......................................................................13 
7.1.4 
Method of Data Conversion and Handling of Missing Data .................................13 
7.2 
Analysis Sets ................................................................................................................13 
7.3 
Disposition of Subjects ................................................................................................14 
7.3.1 
Study Information ..................................................................................................14 
7.3.2 
Screen Failures .......................................................................................................14 
7.3.3 
Subject Eligibility ..................................................................................................14 
7.3.4 
Disposition of Subjects ..........................................................................................15 
7.3.5 
Protocol Deviations ................................................................................................15 
7.3.6 
Analysis Sets ..........................................................................................................15 
7.4 
Demographic and Other Baseline Characteristics .......................................................16 
7.5 
Medical History and Concurrent Medical Conditions .................................................16 
7.6 
Medication History and Concomitant Medications .....................................................16 


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7.7 
Study Drug Exposure and Compliance ........................................................................16 
7.8 
Efficacy Analysis .........................................................................................................16 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................17 
7.9.1 
Pharmacokinetic Analysis ......................................................................................17 
7.9.2 
Pharmacodynamic Analysis ...................................................................................18 
7.10 
Other Outcomes ...........................................................................................................19 
7.11 
Safety Analysis ............................................................................................................19 
7.11.1 Adverse Events ......................................................................................................19 
7.11.1.1 
Overview of Treatment-Emergent Adverse Events .........................................19 
7.11.1.2 
Overview of Treatment-Emergent Adverse Events Occurred in Single 
Dose Period ............................................................................................................20 
7.11.1.3 
Overview of Treatment-Emergent Adverse Events Occurred in Multiple 
Dose Period ............................................................................................................21 
7.11.1.4 
Displays of Treatment-Emergent Adverse Events ...........................................22 
7.11.1.5 
Displays of Treatment-Emergent Adverse Events Occurred in Single Dose 
Period .....................................................................................................................23 
7.11.1.6 
Displays of Treatment-Emergent Adverse Events Occurred in Multiple 
Dose Period ............................................................................................................24 
7.11.1.7 
Displays of Pretreatment Events ......................................................................25 
7.11.2 Clinical Laboratory Evaluations ............................................................................26 
Hematology and Serum Chemistry ....................................................................................26 
Urinalysis ...........................................................................................................................27 
7.11.3 Vital Signs ..............................................................................................................28 
7.11.4 12-Lead ECGs ........................................................................................................28 
7.11.5 Other Observations Related to Safety ....................................................................29 
7.12 
Interim Analysis ...........................................................................................................29 
7.13 
Changes in the Statistical Analysis Plan ......................................................................29 
8.0 
REFERENCES ..................................................................................................................30 
APPENDIX 1. CRITERIA FOR MARKEDLY ABNORMAL VALUES ...................................31 
 
 
LIST OF IN-TEXT TABLES 
Table 1 
Summary of Dose Cohorts .......................................................................................9 
 


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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CRO 
contract research organization 
CYP 
cytchrome P-450 
DA 
dopamine 
 
 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EPS 
extrapyramidal symptoms 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GE 
gastric emptying 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GP 
gastroparesis 
HBsAg 
hepatitis B virus surface antigen 
HCV 
hepatitis C virus 
HDPE 
high density poleythylene 
hERG 
human ether-a-go-go related gene 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harminsation 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 
LFT 
liver function test 
LLC 
limited liability company 
LOEL 
lowest observed effect level 
MAD 
multiple-ascending dose 
CCI


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MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHW 
Ministry of Health and Welfare 
NOAEL 
no-observed-adverse-effect level 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
OTC 
over-the-counter 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
P-gp 
P-glycoprotain 
 
 
RBC 
red blood cell 
SAD 
single-ascending dose 
SAE 
Serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SUSARs 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
tmax 
maximum concentration time 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopoeia 
WBC 
white blood cell 
 
CCI


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4.0 
OBJECTIVES 
4.1 
Primary Objectives 
The primary objective of the study is to evaluate safety and tolerability of single and multiple oral 
doses of TAK-906 in Japanese healthy male subjects. 
4.2 
Secondary Objectives 
The secondary objective of the study is to evaluate PK and PD of single and multiple oral doses of 
TAK-906 in Japanese healthy male subjects. 
4.3 
Additional Objectives 
 
4.4 
Study Design 
4.4.1 Trial Design 
This is a phase 1, randomized, double-blind, placebo-controlled, single and multiple dose, 
parallel-group study in up to 3 cohorts of Japanese healthy male subjects, to assess the safety, 
tolerability, PK, and PD of TAK-906. 
Each cohort will consist of 8 subjects where 6 subjects will be randomized to receive TAK-
906 and 2 subjects will be randomized to receive matching placebo. The study population 
will be 24 Japanese healthy male subjects. The randomized subjects will receive a single dose 
of blinded study drug on Day 1 followed by multiple doses of blinded study drug BID for 5 
days from Day 3 to Day 7, except that an evening dose of study drug will not be administered 
on Day 7. If a subject discontinues from the trial, a replacement subject may be enrolled, if 
deemed appropriate by the investigator and Sponsor. The investigational site should contact 
the Sponsor for the replacement subject’s medication identification number. 
In Cohorts 1 and 2, subjects will be randomized to receive TAK-906 maleate 50 mg, 100 mg, or 
matching placebo. In Cohort 3, subjects will be randomized to receive TAK-906 maleate 10 mg, or 
matching placebo. For each cohort, follow-up assessments will occur on Day 14 which is 7 days 
CCI


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after completion of the last treatment dose. Dose escalation to Cohort 2 will be based on a full 
blinded review of safety and tolerability data until follow-up assessments from Cohort 1. Cohort 3 
will be conducted in parallel with Cohort 1 or 2. Dose level in Cohort 2 may be changed within the 
range up to 100 mg, as appropriate, based on safety and pharmacokinetic data in preceding 
cohorts, ie, 50 mg BID in Cohort 1 or 10 mg BID in Cohort 3 (if applicable) of this study; 
however, no higher dose than the proposed highest dose (100 mg BID)
 
 will be given without Sponsor and institutional review board 
(IRB) approval to revise the study protocol. 
The planned dose levels of TAK-906 to be evaluated are outlined in Table 1. 
Table 1 
Summary of Dose Cohorts 
Cohort (a) 
TAK-906 malesate Dose (a, b, c) 
Subjects 
Single Dose Period 
Multiple Dose Period (d) 
1 
50 mg single dose 
on Day 1 
50 mg BID for 5 days 
from Days 3 to 7 
6 TAK-906 
2 Placebo 
2 
100 mg single dose 
on Day 1 
100 mg BID for 5 days 
from Days 3 to 7 
6 TAK-906 
2 Placebo 
3 
10 mg single dose 
on Day 1 
10 mg BID for 5 days 
from Days 3 to 7 
6 TAK-906 
2 Placebo 
BID=twice daily 
(a) Dose escalation to Cohort 2 will be based on a full blinded review of safety and tolerability data until follow-up 
assessments from Cohort 1. Cohort 3 will be conducted in parallel with Cohort 1 or 2. 
(b) A single dose and all morning doses of trial medication in multiple dose periods will be administered after fast 
of at least 10 hours that continues for at least 4 hours after dosing with restricted water intake for at least 1 hour 
prior to and after dosing. The evening dose will be administered 12 hours after the morning dose and at least 2 
hours after dinner. 
(c) Dose level in Cohort 2 may be changed within the range up to 100 mg, as appropriate, based on safety and 
pharmacokinetic data in preceding cohorts, ie, 50 mg BID in Cohort 1 or 10 mg BID in Cohort 3 (if applicable) 
of this study 
(d) An evening dose of study drug will not be administered on Day 7. 
4.4.2 Dose Escalation 
The investigator will comprehensively examine the blinded safety results (AEs, physical 
examinations, vital signs, records of laboratory tests, and 12-lead ECG findings) obtained at all 
examinations by 14 days after the start of study drug administration in Cohort 1 and then 
determines the entry of Cohort 2 after discussion(s) with the Sponsor, and if appropriate, with 
medical experts. 
Other criteria to consider discontinuation of the entry of Cohort 2 are as follows. 
1. On an occasion that a SAE, of which relationship to the study drug cannot be 
denied, is observed. 
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2. At the onset of an AE for which relationship to the study drug cannot be denied and for 
which it is considered difficult to give medications continuously. 
Furthermore, the maximum dose in this study was set at 100 mg BID for Cohort 2, based on the 
data from preceding studies, as described in Section 6.3.2 of protocol. Dose level in Cohort 2 may 
be changed within the range up to 100 mg, as appropriate, based on the safety and 
pharmacokinetic data of preceding cohorts, ie, 50 mg BID in Cohort 1 or 10 mg BID in Cohort 3 
(if applicable) of this study. 


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5.0 
ANALYSIS ENDPOINTS 
5.1 
Primary Endpoint 
The study’s primary endpoints of safety and tolerability will be assessed through TEAEs including 
QTc prolongation associated AE, neurologic AE, and hyperprolactinemia associated AE, physical 
examinations, vital signs, clinical laboratory tests, and 12-lead electrocardiogram (ECG). 
5.2 
Secondary Endpoints 
Secondary endpoints include: 
1. PK: Plasma and urine concentrations of TAK-906 and its metabolite, M23. 
2. PD: Serum prolactin level. 


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6.0 
DETERMINATION OF SAMPLE SIZE 
A sample size of 8 subjects per cohort (6 active: 2 placebo) will be used in this study, and is 
considered sufficient for the evaluation of TAK-906 safety, tolerability, PK and PD following oral 
single and multiple doses. The sample size is not based on statistical power considerations. 


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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
7.1.1 Study Definitions 
The following definitions and calculation formulas will be used. 
- TEAE: An AE whose date of onset occurs on or after the start of study drug. A TEAE whose relationship to 
study drug is missing will be considered drug-related. A TEAE whose intensity is missing will be considered 
severe. 
- PTE: An AE whose date of onset occurs before the start of study drug.. 
- Descriptive statistics: number of subjects with non-missing values, mean, standard deviation, maximum, 
minimum, and quartiles, including geo-mean, geo-CV as needed 
- QTcF interval (msec): QT interval (msec) / (RR interval (msec)/1000)0.33 (rounded to the nearest whole 
number) 
- Baseline values: The last evaluable observation (ie, non-missing) before the first dose of study drug. If no 
evaluable observation is obtained before the first dose, the baseline value will be missing. 
- TEAE occurred in single dose period: A TEAE occurred prior to start of multiple dosing.  
- 
TEAE occurred in multiple dose period: A TEAE occurred from Day 3 postdose through Day 14 (follow-up 
visit). 
7.1.2 Definition of Study Days 
Study Day: The day before the first dose of the study drug will be defined as Study Day -1 and the day of the first 
dose will be defined as Study Day 1. Other study days are defined relative to Study Day 1, eg, the day 2 days prior 
to Study Day 1 is Day -2 and the day after Study Day 1 is Day 2. 
7.1.3 Definition of Study Visit Windows 
The baseline visit is defined as the period before the first dose of study drug, and post-baseline visits are defined in 
line with CRF-recorded visits. The last evaluable observation (ie. non-missing) in the baseline visit will be used as 
the baseline value, and all evaluable observation will be used for each post-baseline visit.  
7.1.4 Method of Data Conversion and Handling of Missing Data 
No imputation of missing data or of excluded data will be applied. Values below the lower limit of quantification 
will be handled as 0. 
7.2 
Analysis Sets 
The Safety Analysis Set will be defined as all subjects who received at least one dose of the study drug. 
The PK Analysis Set will consist of subjects who received at least one dose of the study drug, completed the 
minimum protocol specified procedures with no significant protocol deviations which are listed below, and were 
evaluable for the pharmacokinetics. 
- Subjects who did not meet inclusion criteria #3or #4 
- Subjects who met exclusion criteria #1, #4, #5, #6, #7, #9, #10, #12, #13, #15, #17, #18, #19, #23 or #25 


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The PD Analysis Set will consist of subjects who received at least one dose of the study drug, completed the 
minimum protocol specified procedures with no significant protocol deviations which are listed below, and were 
evaluable for the pharmacodynamics. 
- Subjects who did not meet inclusion criteria #3or #4 
- Subjects who met exclusion criteria #1, #4, #5, #6, #7, #9, #10, #12, #13, #15, #17, #18, #19, #23 or #25 
7.3 
Disposition of Subjects 
7.3.1 Study Information 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variables: 
Date First Subject Signed Informed Consent Form 
 
Date of Last Subject’s Last Visit/Contact 
 
MedDRA Version 
 
SAS Version Used for Creating the Datasets 
Analytical Methods: 
(1) Study Information 
Study information shown in the analysis variables section will be provided. 
 
7.3.2 Screen Failures 
Analysis Set: 
All Subjects Who Did Not Enter the Treatment Period 
Analysis Variables: 
Age (years)  
[Min<= - <30, 30<= - <40, 40<= - <=Max] 
Analytical Methods: 
(1) Screen Failures 
Frequency distributions for categorical variables and descriptive statistics for continuous 
variables will be provided. 
 
7.3.3 Subject Eligibility 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variables: 
Eligibility Status 
[Eligible for Randomization, Not Eligible 
for Randomization] 
 
Primary Reason for Subject Not Being Eligible 
[Adverse Event, Death, Lost to Follow-
Up, Protocol Deviation, Sample Size 
Sufficient, 
Screen 
Failure, 
Study 
Terminated by Sponsor, Withdrawal by 
subject, Other] 
Analytical Methods: 
(1) Eligibility for Entrance into the Treatment Period 
Frequency distributions will be provided. When calculating the percentages for the 
primary reasons for subject not being eligible, the total number of ineligible subjects will 
be used as the denominator. 
 


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7.3.4 Disposition of Subjects 
Analysis Set: 
Randomized Set 
Analysis Variables: 
Study Drug Administration Status 
[Randomized but Not Treated] 
 
Reason for Not Being Treated 
[Adverse Event, Death, Lost to Follow-Up, 
Protocol Deviation, Study Terminated by 
Sponsor, Withdrawal by subject, Other] 
 
Study Drug Completion Status 
[Completed Study Drug,  
Prematurely Discontinued Study Drug] 
 
Reason for Discontinuation of Study Drug [Adverse Event, Death, Lost to Follow-Up, 
Protocol Deviation, Study Terminated by 
Sponsor, Withdrawal by subject, Other] 
Analytical Methods: 
(1) Disposition of Subjects 
Frequency distributions will be provided by dose and overall. When calculating 
percentages for the reasons for not being treated, the total number of subjects not treated 
by the study drug will be used as the denominator. When calculating percentages for the 
reasons for discontinuation of study drug, the total number of subjects who prematurely 
discontinued the study drug will be used as the denominator. 
 
7.3.5 Protocol Deviations 
Analysis Set: 
Randomized Set 
Analysis Variables : 
Protocol Deviation 
[Entry Criteria, Concomitant Medication, Procedure Not 
Performed Per Protocol, Study Medication, Withdrawal Criteria, 
Major GCP Violations] 
Analytical Methods : 
(1) Protocol Deviations 
Frequency distribution will be provided by dose and overall for each deviation category. A 
subject who has several deviations will be counted once in each appropriate category. A 
subject who has several deviations that can be classified into the same category will be 
counted only once. 
 
7.3.6 Analysis Sets 
Analysis Set: 
Randomized Set 
Analysis Variables: 
Handling of Subjects 
and Subject Data 
[Entry Criteria] 
 
Analysis Sets 
Safety Analysis Set 
PK Analysis Set 
 
[Included, Excluded] 
[Included, Excluded]  


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PD Analysis Set 
[Included, excluded] 
Analytical Methods: 
(1) Analysis Sets 
Frequency distributions will be provided by dose. 
 
7.4 
Demographic and Other Baseline Characteristics 
Analysis Set: 
PK Analysis Set 
 
PD Analysis Set 
 
Safety Analysis Set 
Analysis Variables: 
Age (years) 
[Min<= - <30, 30<= - <40, 40<= - <=Max] 
 
Height (cm) 
[Min<= - <150, 150<= - <160,  
160<= - <170, 170<= - <=Max] 
 
Weight (kg) (Baseline) 
[Min<= - <50.0, 50.0<= - <60.0,  
60.0<= - <70.0, 70.0<= - <80.0,  
80.0<= - <=Max] 
 
BMI (kg/m2) (Baseline) 
[Min<= - <18.5, 18.5<= - <=25.0,  
25.0< - <=Max] 
 
Smoking Classification 
[Never, Current, Former] 
 
Consumption of Alcohol 
[Daily, A Few Times Per Week, A Few Times Per 
Month, No] 
 
Consumption of Caffeine 
[Yes, No] 
Analytical Methods: 
(1) Summary of Demographics and Other Baseline Characteristics 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided by dose and overall. 
7.5 
Medical History and Concurrent Medical Conditions 
There will be no analysis of medical history and concurrent medical conditions. 
7.6 
Medication History and Concomitant Medications 
There will be no analysis of medication history and concomitant medications. 
7.7 
Study Drug Exposure and Compliance 
Not applicable 
7.8 
Efficacy Analysis 
Not applicable 


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7.9 
Pharmacokinetic/Pharmacodynamic Analysis 
7.9.1 Pharmacokinetic Analysis 
7.9.1.1 Plasma Concentrations of TAK-906 and M23 
Analysis Set: 
PK Analysis Set except subjects with placebo   
Analysis Variable: 
Plasma Concentrations of TAK-906 and M23 
Time Point: 
Visit: Days 1 and 7 
Pre–morning dose (0 hours) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 hours post–morning dose 
(relative to start time of morning dose at Day 1 or 7) 
Visit: Days 3-6 
Pre–morning dose (0 hours) 
Analytical Methods: 
The following summaries will be provided for each analyte by dose. 
(1)  Summary of Plasma Concentrations by Time Point 
Descriptive statistics for observed values will be provided for each time point. In 
addition, geometric mean, geometric standard deviations, and %CV will be provided 
(2)  Concentration-time Profiles for Individual Subjects 
Observed values will be plotted using individual case plot. 
(3)  Mean Concentration-time Profiles with Standard Deviations 
Mean of plasma concentration will be plotted by time point using linear scale for Days 
1-7, Day 1 and Day 7 respectively. 
(4)  Geometric Mean Concentration-time Profiles with Geometric Standard Deviations 
Geometric Mean of plasma concentration will be plotted by time point using natural log 
scale for Days 1-7, Day 1 and Day 7 respectively. 
 
7.9.1.2 Plasma PK Parameters of TAK-906 and M23 
Analysis Set: 
PK Analysis Set except subject with placebo 
Analysis Visit and 
Variable: 
 
Plasma Concentrations of TAK-906 and M23 
 
Visit: Day 1 
 
Cmax 
tmax 
AUC∞ 
 
AUClast 
AUC24 
AUCτ 
 
t1/2z 
λz 
CL/F (TAK-906 only) 
 
Vz/F (TAK-906 only) 
MRT∞,ev 
 
 
Visit: Day 7 
 
Cmax,ss 
tmax,ss 
AUCτ,ss 
 
t1/2z 
λz 
CL/Fss (TAK-906 only) 
 
Vz/Fss (TAK-906 only) 
MRT∞,ev 
Cav,ss 


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Cmin,ss 
tmin,ss 
PTF% 
 
Rac(AUC) 
Rac(Cmax) 
 
Analytical Methods: 
The following summaries will be provided for each analyte by dose. 
 
(1)  Summary of Plasma PK Parameters 
Descriptive statistics for PK parameters will be provided. In addition, geometric mean 
and %CV will be computed for Cmax and AUCs. 
(2)  Exposure versus dose plots 
Scatter plot will be created with the X axis as dose levels and Y axis as Cmax or AUCs.  
(3)  Dose-normalized exposure versus dose plots 
Plots of dose-normalized Cmax and AUCs versus dose levels will be prepared with 
individual subjects data. 
(4)  Dose proportionality 
Dose proportionality of Cmax and AUCs across dose levels will be assessed using linear 
and power model. 
 
7.9.1.3 Urine PK Parameters of TAK-906 and M23 
Analysis Set: 
PK Analysis Set except subject with placebo 
Analysis Visit and 
Variable: 
Urine PK Parameters of TAK-906 and M23, and the Total of TAK-906 and M23 
 
Visit: Day 1 
 
Ae24 
fe,24 
CLR 
 
Visit: Day 7 
 
Aeτ 
fe, τ 
CLR 
Analytical Methods: 
The following summaries will be provided for each analyte by dose. 
 
(1)  Summary of Urine PK Parameters 
Descriptive statistics for PK parameters will be provided. Here, only fe will be 
summarized for the total of TAK-906 and M23.  
 
7.9.2 Pharmacodynamic Analysis 
7.9.2.1 Serum Concentrations of prolactin level 
Analysis Set: 
PD Analysis Set 
Analysis Variables : Serum concentration of prolactin  
Visit: 
Day 1: Predose, 1, 2, 4, 6, and 24 hours post single dose. 
Days 3-6: Just before morning dose. 
Day 7: Predose, 1, 2, 4, 6, and 24 hours post morning dose. 
Day 14 
Analytical Methods: The following summaries will be provided by dose.  
 
(1)  Summary of Serum Concentrations by Time Point 


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Descriptive statistics for observed values and change from Day 1predose will be provided 
for each time point. In addition, geometric mean, geometric standard deviations, 
and %CV will be provided 
(2)  Concentration-time Profiles for Individual Subjects 
Observed values will be plotted using individual case plot. 
(3)  Mean Concentration-time Profiles with Standard Deviations 
Mean of serum concentration will be plotted by time point using linear scale for Days 1-
7, Day 1 and Day 7 respectively. 
(4)  Geometric Mean Concentration-time Profiles with Geometric Standard Deviations 
Geometric Mean of serum concentration will be plotted by time point using natural log 
scale for Days 1-7, Day 1 and Day 7 respectively. 
7.9.2.2 PD Parameters of Serum prolactin level  
Analysis Set: 
PD Analysis Set 
Analysis Visit and 
Variable: 
 
Serum concentration of prolactin 
 
Visit: Day 1 
 
Cmax 
tmax 
AUC∞ 
 
AUClast 
AUC24 
AUCτ 
 
t1/2z 
λz 
 
 
Visit: Day 7 
 
Cmax,ss 
tmax,ss 
AUCτ,ss 
 
t1/2z 
λz 
 
Analytical Methods: 
The following summaries will be provided by dose. 
 
(1)  Summary of PD Parameters 
Descriptive statistics for PD Parameters will be provided. In addition, geometric mean 
and %CV will be computed for Cmax and AUCs. 
(2)  PD Parameters versus dose plots 
Plots of Cmax and AUCs versus dose levels will be prepared with individual subjects 
data. 
 
7.10 
Other Outcomes 
Not applicable 
7.11 
Safety Analysis 
7.11.1 Adverse Events 
7.11.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: TEAE 


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Categories: 
Relationship to Study Drug 
[Related, Not Related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analytical Methods: The following summaries will be provided by dose. 
 
(1) Overview of Treatment-Emergent Adverse Events 
 
1) All Treatment-Emergent Adverse Events (number of events, number and percentage of 
subjects)  
 
2) Relationship of Treatment-Emergent Adverse Events to Study Drug (number of events, 
number and percentage of subjects)  
 
3) Intensity of Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)  
 
4) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation (number 
of events, number and percentage of subjects)  
 
5) Serious Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)  
 
6) Relationship of Serious Treatment-Emergent Adverse Events to Study Drug (number of 
events, number and percentage of subjects)  
 
7) Serious Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
(number of events, number and percentage of subjects)  
 
8) Treatment-Emergent Adverse Events Resulting in Death (number of events, number 
and percentage of subjects)  
 
TEAEs will be counted according to the rules below. 
Number of subjects 
・ Summaries for 2) and 6)  
A subject with occurrences of TEAE in both categories (ie, Related and Not Related) will 
be counted once in the Related category. 
・ Summary for 3) 
A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum intensity. 
・ Summaries other than 2),  3) and 6)  
A subject with multiple occurrences of TEAE will be counted only once. 
Number of events 
For each summary, the total number of events will be calculated. 
7.11.1.2 Overview of Treatment-Emergent Adverse Events Occurred in Single Dose 
Period 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: TEAE occurred in single dose period 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analytical Methods: The following summaries will be provided by dose. 
 
(1) Overview of Treatment-Emergent Adverse Events 
 
1) All Treatment-Emergent Adverse Events (number of events, number and percentage of 


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subjects)  
 
2) Relationship of Treatment-Emergent Adverse Events to Study Drug (number of events, 
number and percentage of subjects)  
 
3) Intensity of Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)  
 
 
 
4) Serious Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)  
 
5) Relationship of Serious Treatment-Emergent Adverse Events to Study Drug (number of 
events, number and percentage of subjects)  
 
6) Serious Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
(number of events, number and percentage of subjects)  
 
7) Treatment-Emergent Adverse Events Resulting in Death (number of events, number 
and percentage of subjects)  
 
TEAEs will be counted according to the rules below. 
Number of subjects 
・ Summaries for 2) and 5)  
A subject with occurrences of TEAE in both categories (ie, Related and Not Related) will 
be counted once in the Related category. 
・ Summary for 3) 
A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum intensity. 
・ Summaries other than 2),  3) and 5)  
A subject with multiple occurrences of TEAE will be counted only once. 
Number of events 
For each summary, the total number of events will be calculated. 
7.11.1.3 Overview of Treatment-Emergent Adverse Events Occurred in Multiple Dose 
Period 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: TEAE occurred in multiple dose period 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analytical Methods: The following summaries will be provided by dose. 
 
(1) Overview of Treatment-Emergent Adverse Events 
 
1) All Treatment-Emergent Adverse Events (number of events, number and percentage of 
subjects)  
 
2) Relationship of Treatment-Emergent Adverse Events to Study Drug (number of events, 
number and percentage of subjects)  
 
3) Intensity of Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)  
 
4) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation (number 


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of events, number and percentage of subjects)  
 
5) Serious Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)  
 
6) Relationship of Serious Treatment-Emergent Adverse Events to Study Drug (number of 
events, number and percentage of subjects)  
 
7) Serious Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
(number of events, number and percentage of subjects)  
 
8) Treatment-Emergent Adverse Events Resulting in Death (number of events, number 
and percentage of subjects)  
 
TEAEs will be counted according to the rules below. 
Number of subjects 
・ Summaries for 2) and 6) 
A subject with occurrences of TEAE in both categories (ie, Related and Not Related) will 
be counted once in the Related category. 
・ Summary for 3) 
A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum intensity. 
・ Summaries other than 2),  3) and 6) 
A subject with multiple occurrences of TEAE will be counted only once. 
Number of events 
For each summary, the total number of events will be calculated. 
7.11.1.4 Displays of Treatment-Emergent Adverse Events 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Analytical Methods: The following summaries will be provided using frequency distribution by dose.  
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency for tables provided 
by SOC and PT. SOC and PT will be sorted in decreasing frequency for tables provided by 
SOC only or PT only. 
 
 
(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
 
(2) Treatment-Emergent Adverse Events by System Organ Class 
 
(3) Treatment-Emergent Adverse Events by Preferred Term 
 
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
 
(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
 
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ Class, 
and Preferred Term 


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(7) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System 
Organ Class and Preferred Term 
 
(8) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
 
(9) QTc prolongation associated Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
(10) Neurologic Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
 
(11) Hyperprolactinemia associated Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(12) Drug-Related QTc prolongation associated Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
(13) Drug-Related Neurologic Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
(14) Drug-Related Hyperprolactinemia associated Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
・ Summary tables other than (5), and (6) 
A subject with multiple occurrences of TEAE within a SOC will be counted only once in 
that SOC. A subject with multiple occurrences of TEAE within a PT will be counted 
only once in that PT. Percentages will be based on the number of subjects in the safety 
analysis set. 
・ Summary tables for (5) and (6) 
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted only 
once for the TEAE with the maximum intensity. Percentages will be based on the 
number of subjects in the safety analysis set. 
7.11.1.5 Displays of Treatment-Emergent Adverse Events Occurred in Single Dose Period 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: TEAE occurred in single dose period 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Analytical Methods: The following summaries will be provided using frequency distribution by dose.  
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency for tables provided 
by SOC and PT. SOC and PT will be sorted in decreasing frequency for tables provided by 
SOC only or PT only. 
 
 
(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
 
(2) Treatment-Emergent Adverse Events by System Organ Class 
 
(3) Treatment-Emergent Adverse Events by Preferred Term 


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(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
 
(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
 
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ Class, 
and Preferred Term 
 
(7) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
 
(8) QTc prolongation associated Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
(9) Neurologic Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
 
(10) Hyperprolactinemia associated Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(11) Drug-Related QTc prolongation associated Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
(12) Drug-Related Neurologic Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
(13) Drug-Related Hyperprolactinemia associated Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
・ Summary tables other than (5), and (6) 
A subject with multiple occurrences of TEAE within a SOC will be counted only once in 
that SOC. A subject with multiple occurrences of TEAE within a PT will be counted 
only once in that PT. Percentages will be based on the number of subjects in the safety 
analysis set. 
・ Summary tables for (5) and (6) 
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted only 
once for the TEAE with the maximum intensity. Percentages will be based on the 
number of subjects in the safety analysis set. 
7.11.1.6 Displays of Treatment-Emergent Adverse Events Occurred in Multiple Dose 
Period 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: TEAE occurred in multiple dose period 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Analytical Methods: The following summaries will be provided using frequency distribution by dose.  
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency for tables provided 
by SOC and PT. SOC and PT will be sorted in decreasing frequency for tables provided by 
SOC only or PT only. 
 


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(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
 
(2) Treatment-Emergent Adverse Events by System Organ Class 
 
(3) Treatment-Emergent Adverse Events by Preferred Term 
 
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
 
(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
 
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ Class, 
and Preferred Term 
 
(7) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System 
Organ Class and Preferred Term 
 
(8) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
 
(9) QTc prolongation associated Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
(10) Neurologic Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
 
(11) Hyperprolactinemia associated Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(12) Drug-Related QTc prolongation associated Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
(13) Drug-Related Neurologic Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
(14) Drug-Related Hyperprolactinemia associated Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
・ Summary tables other than (5), and (6) 
A subject with multiple occurrences of TEAE within a SOC will be counted only once in 
that SOC. A subject with multiple occurrences of TEAE within a PT will be counted 
only once in that PT. Percentages will be based on the number of subjects in the safety 
analysis set. 
・ Summary tables for (5) and (6) 
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted only 
once for the TEAE with the maximum intensity. Percentages will be based on the 
number of subjects in the safety analysis set. 
7.11.1.7 Displays of Pretreatment Events 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variables: PTE 
Analytical Methods: The following summaries will be provided using frequency distribution. 
PTEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC will 


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be sorted alphabetically and PT will be sorted in decreasing frequency. 
 
(1) Pretreatment Events by System Organ Class and Preferred Term 
(2) Serious Pretreatment Events by System Organ Class and Preferred Term 
 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
A subject with multiple occurrences of PTE within a SOC will be counted only once in that 
SOC. A subject with multiple occurrences of PTE within a PT will be counted only once in 
that PT. 
 
7.11.2 Clinical Laboratory Evaluations 
Hematology and Serum Chemistry 
Analysis Set: 
Safety Analysis Set 
Analysis Variables : Hematology 
 
RBCs (×1010/L) 
WBCs (×108/L) 
Hemoglobin (g/dL) 
 
Hematocrit (%) 
Platelets (×1010/L) 
 
 
White blood cell differential (Neutrophils (×108/L), Eosinophils (×108/L), Basophils 
(×108/L),  
Monocytes (×108/L), Lymphocytes (×108/L)) 
 
MCH (pg) 
MCHC (%) 
MCV (fL) 
 
Serum Chemistry 
 
ALT (U/L) 
Alkaline Phosphatase (U/L) AST (U/L) 
 
GGT (IU/L) 
Bilirubin (Total) (mg/dL) 
 
 
Lactose Dehydrogenase 
(U/L) 
C-reactive Protein (mg/dL) 
 
Albumin (g/dL) 
 
Protein (Total) (g/dL) 
Creatinine (mg/dL) 
Blood Urea Nitrogen(mg/dL)  
 
Uric Acid (mg/dL) 
Total Cholesterol (mg/dL) 
Phosphorus (mg/dL) 
 
Triglycerides (mg/dL) 
Glucose (mg/dL) 
Potassium (mEq/L) 
 
Sodium (mEq/L) 
Magnesium (mg/dL)  
Calcium (mg/dL) 
 
Chloride (mmol/L) 
 
 
Visit: 
Baseline, Days 2, 5, 8 and 14 
Analytical Methods: The following summaries will be provided by dose.  
 
(1) Summary of Laboratory Test Results and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline (each post-baseline 
visit - baseline) will be provided for each visit.  
 
(2) Case Plots  


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Spaghetti plots will be prepared for each ECG parameters by dose levels. 
 
(3) Summary of Shifts of Laboratory Test Results 
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided. For each laboratory test, the laboratory values will be 
classified as "Low", "Normal", or "High" relative to the normal reference range provided 
by the central laboratory. The shift tables will be based on these classifications. 
 
(4) Number and Percentage of Subjects with Markedly Abnormal Values of Laboratory 
Test results 
Overall frequency distributions of MAV after first dose will be provided. If a laboratory 
test result has both lower and upper MAV criteria, analysis will be performed for each. 
Further details are given in Appendix. 
 
Urinalysis 
Analysis Set: 
Safety Analysis Set 
Analysis Variables : pH 
[Min<= - <5.0, 5.0<= - <=8.5, 8.5< - <=Max] 
 
Specific gravity  
[Min<= - <1.005, 1.005<= - <=1.030, 1.030< - <=Max] 
 
Protein 
[-, -+, 1+, 2+, 3+, 4+ ] 
 
Glucose 
[-, 1+, 2+, 3+, 4+] 
 
Nitrites 
[-, 1+, 2+] 
 
Ketones 
[-, 1+, 2+, 3+] 
 
Urobilinogen 
[-, -+, 1+, 2+, 3+, 4+ ]] 
 
Blood 
[-, 1+, 2+, 3+] 
 
Urine microscopy  
RBC/high-power field 
 
WBC/high-power field 
 
Squamous epithelial cells 
 
[1-5/WF, 6-10/WF, 0-1/LF, 1-5/HF, 6-10/HF, 11-
20/HF, 21-50/HF, 51-99/HF, 100≦/HF]  
[1-5/WF, 6-10/WF, 0-1/LF, 1-5/HF, 6-10/HF, 11-
20/HF, 21-50/HF, 51-99/HF, 100≦/HF] 
[1-5/WF, 6-10/WF, 0-1/LF, 1-5/HF, 6-10/HF, 11-
20/HF, 21-50/HF, 51-99/HF, 100≦/HF] 
Visit: 
Baseline, Days 2, 5, 8, and 14. 
Analytical Methods: The following summaries will be provided by dose. For only specific gravity, summarie (2) 
will be provided 
 
(1) Summary of Shifts of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided.  
 
(2) Case Plots 
Plots over time for each subject will be presented. 
 


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7.11.3 Vital Signs 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: Body Temperature (°C) 
 
 
Systolic Blood Pressure (mmHg) 
 
 
Diastolic Blood Pressure (mmHg) 
 
 
Respiratory Rate (bpm) 
 
 
Pulse (bpm) 
 
Visit: 
Day 1: Predose, 1, 2, 4, 6, and 24 hours post single dose. 
Days 3-6: Before morning dose. 
Day 7: Predose, 1, 2, 4, 6, and 24 hours post morning dose 
Day 14 
Analytical Methods: For each variable, following summary will be provided by dose. 
 
(1) Summary of Vital Signs Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline (each post- Day 1: 
Predose) will be provided for each visit 
 
(2) Case Plots  
Plots over time for each subject will be presented. 
 
(3) Number and Percentage of Subjects with Markedly Abnormal Values of Vital Signs 
Parameters 
Overall frequency distributions of MAV after first dose will be provided. If a vital sign 
parameter has both lower and upper MAV criteria, analysis will be performed for each. 
Further details are given in Appendix. 
 
7.11.4 12-Lead ECGs 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: Heart Rate (bpm) 
 
 
RR Interval (msec) 
 
 
PR Interval (msec) 
 
 
QT Interval (msec) 
 
 
QTcF Interval (msec) 
 
 
QRS Interval (msec) 
 
 
12-Lead ECG Interpretation 
["Within Normal Limits", 
"Abnormal, Not Clinically Significant", 
"Abnormal, Clinically Significant"] 
Visit: 
Day 1: Predose, 1, 2, 4, 6, and 24 hours post single dose. 
Day 5: Predose, 1, and 2 hours post morning dose. 
Day 7: Predose, 1, 2, 4, 6, and 24 hours post morning dose 
Analytical Methods: For each variable other than 12-lead ECG interpretations, summary (1), (2), and (3) will be 
provided by dose. 
For 12-lead ECG interpretations, summary (4) will be provided by dose. 
 
(1) Summary of ECG Parameters and Change from Baseline by Visit 


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Descriptive statistics for observed values and changes from baseline (each post- Day 1: 
Predose) will be provided for each visit. 
 
(2) Case Plots  
Plots over time for each subject will be presented. 
 
(3) Number and Percentage of Subjects with Markedly Abnormal Values of ECG 
Parameters 
Overall frequency distributions of MAV after first dose will be provided. If an ECG 
parameter has both lower and upper MAV criteria, analysis will be performed for each. 
Further details are given in Appendix. 
 
(4) Summary of Shifts of ECG Parameters 
Shift tables showing the number of subjects in each category at Day 1 Predose and each 
post-Day 1 Predose visit will be provided. 
 
7.11.5 Other Observations Related to Safety 
Not applicable 
7.12 
Interim Analysis 
Not applicable 
7.13 
Changes in the Statistical Analysis Plan  
From the SAP version 1.0, the following parts were updated. In 7.11.2, the units for white blood 
cell differential modified. In Appendix 1, since there is no abnormal criteria for white blood cell 
differential in the site, the MAV criteria for white blood cell differential was deleted.  


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8.0 
REFERENCES 
Not applicable 
 
 


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Appendix 1. Criteria for Markedly Abnormal Values  
Hematology, Serum Chemistry, Urinalysis, Vital Signs, and 12-lead ECG (except Upper 
MAV Criteria of QTcF Interval) 
For each parameter, all evaluable data obtained up to Day 14(or Day 8 for 12-lead ECG) will be 
classified as a MAV or not. The criteria in the table below will be used. The lower limit of the 
normal range and the upper limit of the normal range are abbreviated as LLN and ULN.  
For each parameter and subject, classifications will be made according to the conditions i) to iii) 
provided below. The lower and the upper criteria will be considered separately. 
i) 
A subject with at least one evaluable data after baseline or "Day 1: Predose" that meets the 
MAV criteria will be classified as a subject with MAV. 
ii) A subject who does not meet condition i) and has at least one evaluable data after baseline or 
"Day 1: Predose" that doesn't meet the MAV criteria will be considered as a subject without 
MAV. 
iii) A subject who does not meet conditions i) or ii) will be excluded from the analysis of MAV 
for that parameter. 
Hematology 
Parameter 
Gender 
Age 
MAV Criteria 
Lower Criteria 
Upper Criteria 
RBCs (×106/μL) 
- 
- 
<0.8×LLN 
>1.2×ULN 
Platelets (×103/μL) 
- 
- 
<75 
>600 
WBCs (×103/μL) 
- 
- 
<0.5×LLN 
>1.5×ULN 
 
Serum Chemistry 
Parameter 
Gender 
Age 
MAV Criteria 
Lower Criteria 
Upper Criteria 
Protein (total) (g/dL) 
- 
- 
<0.8×LLN 
>1.2×ULN 
Albumin (g/dL) 
- 
- 
<2.5 
- 
Blood urea nitrogen (mg/dL) 
- 
- 
- 
>30 
Uric acid (mg/dL) 
- 
- 
- 
>13.0 
Creatinine (mg/dL) 
- 
- 
- 
>2.0 


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Parameter 
Gender 
Age 
MAV Criteria 
Lower Criteria 
Upper Criteria 
Total cholesterol (mg/dL) 
- 
- 
- 
>300 
Triglycerides (mg/dL) 
- 
- 
- 
>2.5×ULN 
Bilirubin (total) (mg/dL) 
- 
- 
- 
>2.0 
Sodium (mEq/L) 
- 
- 
<130 
>150 
Potassium (mEq/L) 
- 
- 
<3.0 
>6.0 
Chloride (mEq/L) 
- 
- 
<75 
>126 
Calcium (mg/dL) 
- 
- 
<7.0 
>11.5 
Phosphorus (mg/dL) 
- 
- 
<1.6 
>6.2 
Alkaline phosphatase (IU/L) 
- 
- 
- 
>3×ULN 
AST (IU/L) 
- 
- 
- 
>3×ULN 
ALT (IU/L) 
- 
- 
- 
>3×ULN 
GGT (IU/L) 
- 
- 
- 
>3×ULN 
Glucose (mg/dL) 
- 
- 
<50 
>350 
Magnesium (mg/dL) 
- 
- 
<1.2 
>3.0 
 
Vital Signs 
Parameter 
Gender 
Age 
MAV Criteria 
Lower Criteria 
Upper Criteria 
Systolic blood pressure (mmHg) 
- 
- 
<85 
>180 
Diastolic blood pressure (mmHg) 
- 
- 
<50 
>110 
Pulse (bpm) 
- 
- 
<50 
>120 
Body temperature (°C) 
- 
- 
<35.6 
>37.7 
 
12-lead ECG 
Parameter 
Gender 
Age 
MAV Criteria 
Lower Criteria 
Upper Criteria 
Heart rate (bpm) 
- 
- 
<50 
>120 
QTinterval (msec) 
- 
- 
<=50 
>=460 
QTcF interval (msec) 
- 
- 
<=50 
- 


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12-lead ECG (Upper MAV Criteria of QTcF Interval) 
All evaluable data (ie, non-missing data) obtained up to Day 8 will be classified as a MAV or not. 
The criteria in the table below will be used.  Note that the observed value and the change from 
Day 1 Predose used for classification should be measurements taken on the same day. 
For each subject, classifications will be made according to the conditions i) to iii) provided 
below. 
i) 
A subject with at least one evaluable data after Day 1 Predose that meets the MAV criteria will 
be classified as a subject with MAV. 
ii) A subject who does not meet condition i) and has at least one evaluable data after Day 1 
Predose that meets any of the following will be considered as a subject without MAV. 
・ Observed value is less than 450 msec and not missing. 
・ Change from Day 1 Predose is less than 30 msec and not missing, and observed value is less 
than 500 msec and not missing. 
iii) A subject who does not meet conditions i) or ii) will be excluded from the analysis of MAV. 
 
Parameter 
Gender 
Age 
MAV Criteria 
Upper Criteria 
QTcF Interval (msec) 
- 
- 
If either of the following 
conditions is met: 
・ observed value >=500 
・ change from Day 1 Predose >= 30 
and observed value >=450